HK1133890A

HK1133890A - Process to prepare eplerenone

Info

Publication number: HK1133890A
Application number: HK09110469.2A
Authority: HK
Inventors: B‧A‧皮尔曼; A‧G‧派迪拉; J‧L‧海文斯; S‧S‧麦奇; 吴海峰
Original assignee: 法玛西雅厄普约翰美国公司
Priority date: 2002-03-22
Filing date: 2009-11-10
Publication date: 2010-04-09

Description

Process for preparing eplerenone

this application is a divisional application of the invention patent application with patent application number 03806590.8.

Background

1. Field of the invention

The invention includes 3-enol ether delta^3，5-steroid to corresponding Δ^4，6-3-ketal steroid (I-P).

The invention includes^4，6-3-ketosteroid or ketal (I) thereof to the corresponding delta⁴-3-ketosteroid-7 alpha-carboxylic acid (VI).

The invention also includes novel processes and novel intermediates for the production of the pharmaceutically useful compound eplerenone.

Further, the invention includes the corresponding delta of 11 alpha-hydroxy-17-lactone (CI) or 11 alpha-hydroxy steroid (CIV)⁹⁽¹¹⁾-17-lactone (CII) or Δ⁹⁽¹¹⁾-a process for steroid (CV) conversion using a N-fluoroalkylamine reagent (CVI).

2. Description of the related Art

3-keto-delta by acid-catalyzed ketalization^4，6Conversion of steroids to the corresponding steroids Δ^4，6-3-ketals are known. The yield is moderate and early dissociation of the double bond can be competitive. E.g. Δ^4，6The cholesta-3-one-3-cyclic ethylene ketal is via delta^4，6-ketalization of cholestan-3-one in 64% yield, see j.org.chem.26, 2549 (1961). Furthermore, 17 beta-hydroxyandrostan-4, 6-dien-3-one-3-ringsEthylene ketal is prepared via ketalization of 6-dehydrotestosterone in 55% crude yield, see j.am.chem.soc., 86, 2183 (1964). Steroid delta may be used in the process for preparing eplerenone^4，6-3-ketal (I-P) as starting material.

Chem., 29, 601(1964) reports Δ in the presence of water^3，5Reaction of the-3-alkoxysteroid with DDQ to give the corresponding Delta^4，6-3-keto steroids. The process of the invention is carried out in the presence of an alcohol^3，5Reaction of a 3-alkoxy steroid (3-alkyl enol ether) with DDQ under essentially anhydrous conditions to give a^4，6-3-ketal steroid (I-P). In addition, production of^4，6Prior art method of the 3-ketal steroids (I-P) employs two steps, 6-dehydrogenation of enol ethers to give Delta^4，6-3-ketosteroid followed by ketalization, but the present invention is a one-step reaction.

Eplerenone, also known as epoxyxexenone, is a useful pharmaceutical ingredient with the chemical name 9 α, 11 α -epoxy-17 β -hydroxypregn-4-en-3-one-7 α, 21-dicarboxylic acid, γ -lactone, methyl ester.

International publication WO98/25948 of PCT application PCT/US97/23090 discloses eplerenone and various methods for preparing eplerenone. See schemes 1 through 10 for specificity.

U.S. patent 4,874,754 discloses 19-norsteroids with 7 α -aryl substitution. The 7 α -aryl substituents include a wide variety of groups including phenyl, thienyl, furyl, thiazolyl, pyrrolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isothiazolyl and isoxazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl. Regardless of which group is used, 19-norsteroids have antiproliferative, antiestrogenic and/or estrogenic properties and are not useful eplerenone intermediates because there is no practical method to install a 19-methyl group into 19-norsteroids. The 7 α -substituted steroids (II) of the present invention are intermediates, not end products, and do not have estrogenic properties, since they are not 19-nor steroids.

U.S. Pat. No. 4,502,989 discloses a large amount of Δ¹¹Steroid-gamma-lactones, many of which are substituted at the 7 alpha-position, have aldosterone antagonist activity. The 7 α -substitution is 6 α,7 α -methylene-, 7 α -trimethylacetylthio-, 7 α -acetylthio-and 7 α -benzoylthio-, see claim 1. These compounds differ from the compounds of the invention in that the C-ring double bond is Δ¹¹And the 7 α -substituent is such that these compounds cannot be used in the same manner as the 7 α -substituted steroid (II).

Het, 25, 399(1987) and Bull. Soc. Chim. Fr.131, 900(1994) disclose the use of boron trifluoride diethyl etherate to catalyze the conjugate addition of non-steroidal 2-methylfuran to α, β -unsaturated ketones in ethanol/nitromethane. The method of the invention involves steroidal furans. Furthermore, the enone substrates in het, 25, 399(1987) and Bull. Soc. Chim. Fr.131, 900(1994) do not contain stereocenters and therefore do not present problems of stereocontrol.

Carbon nucleophiles are known to be saturated with- Δ at 9(11)^4，6The conjugate addition method of the (3) -keto steroid gives a stereoselectively 9(11) -saturated (7 a) -substituted steroid. J.am.chem.Soc., 94, 4654(1972) discloses the conversion of carbon nucleophiles to 9(11) -saturated-. DELTA.^4，6Conjugate addition of-3-keto steroids stereoselectively to give 9(11) -saturated-7 α -substituted steroids. Tet, 49, 9955(1993) and tet.lett, 29, 1533(1988) disclose the stereoselective addition of allyltrimethylsilane to canrenone (titanium tetrachloride, dichloromethane, -78 °), yielding a mixture of two difficult to separate products (7 α -allyl-canrenone and the corresponding 6 α,7 α -fused silylcyclopentane), in poor yields (43-73% and 7-15%, respectively). Note that in these cases the steroid substrate is 9(11) -saturated. All attempts to apply these or similar methods to 9(11) -unsaturated steroids have failed due to the lack of stereocontrol. For example, U.S. Pat. No. 4,559,332, example 7, discloses the use of DMSO in DMSOAt room temperature, to delta using sodium hydride⁹⁽¹¹⁾Addition of canrenone (I) to trimethylsulfoxonium iodide gives exclusively 6 beta, 7 beta-methylene-delta⁹⁽¹¹⁾-canrenone. Furthermore, Δ was converted to Δ over 7.5 hours in tetramethylguanidine at room temperature⁹⁽¹¹⁾Addition of canrenone (I) to nitromethane gives exclusively the 7 beta stereoisomer (7 beta-nitromethyl-. DELTA.⁹⁽¹¹⁾-6, 7-dihydrocanrenone.

Helv. Chim. acta, 80, 566(1997) and U.S. Pat. No. 4,559,332 disclose Δ⁹⁽¹¹⁾Reaction of-canrenone with diethylaluminium cyanide to give 7 α -cyano- Δ⁹⁽¹¹⁾6, 7-dihydrocanrenone, but the crude product is described as a "brown amorphous residue", "filtration through silica gel gives an amorphous" semi-purified product ", and" is used in the next step without further purification ". The ratio of the 7-alpha to 7-beta epimers is not disclosed.

J.am. chem.soc.79, 3120(1957), j.am. chem.soc.82, 6136(1960) and j.org.chem.27, 1192(1962) disclose the degradation of non-steroidal enediones to carboxylic acids via alkoxy hydroperoxide intermediates rather than hydroxy hydroperoxide intermediates. The method of the present invention involves steroidal enediones.

Oxidative ring opening of furans to carboxylic acids or carboxylic acid derivatives by direct ozonolysis is known. However, the yield is generally rather poor. Chem., 61, 9126(1996) reported that 2, 5-disubstituted furans undergo partial cleavage under ozonization to give enol acetates, rather than complete cleavage to carboxylic acids. Het, 34, 895(1992) reported direct ozonization of 2-substituted furans to give methyl esters in 59% yield after esterification. J.am.chem.soc.101, 259(1979) reported direct ozonation of 2-substituted furans to give methyl esters in 55% yield after esterification. J.am. chem.soc., 107, 7762(1985) reported direct ozonation of 2-saccharide-substituted furans to give primary alcohols in 50% yield after borane reduction. Tet.lett., 34, 7323(1993) reported direct ozonization of 2-substituted furans to give methyl esters after esterification in 60% yield. Res, 150, 163(1986) reported direct ozonation of 2-saccharide-substituted furans to give primary alcohols in 11% yield after triphenylphosphine followed by lithium aluminum hydride reduction. Let's, 22, 141(1981) reported direct ozonation of 2-substituted furans to give carboxylic acids in about 30% yield after oxidative treatment. J.am. chem.soc., 109, 2082(1987) reported direct ozonization of 2-substituted furans to give methyl esters in 77% yield after esterification. Tet.lett., 39, 7013(1998) reported direct ozonization of 2-substituted furans to give methyl esters in 78% -87% yields after esterification. Chem, 54, 2085(1989) reported direct ozonation of two 2-substituted furans to give carboxylic acids in 89-95% yield, although in this study the 2-substituted furans were very simple (that is, they did not contain any reactive functional groups other than furan). There is no disclosure of a two-step furan ring-opening, reoxidative cleavage to carboxylic acid, with high yields.

Chem.63, 7505(1998) discloses the use of dibroma tin, sodium bicarbonate and aqueous acetone to open up non-steroidal furans to form enediones. The method of the invention involves steroidal furans.

Chem.lett., 1771(1983) discloses the use of hydrochloric acid to catalyze the isomerization of non-steroidal cis-enedione to trans-enedione in an ether. The method of the present invention involves steroidal enediones.

J.am. chem.soc., 79, 3120(1957), j.am.chem.soc., 82, 6136(1960) and j.org.chem., 27, 1192(1962) disclose the degradation of enediones to carboxylic acids via alkoxy hydroperoxide intermediates, using ozone and an oxidative cleavage agent. The yield is not particularly high. For example, the yield of benzoic acid from trans-dibenzoylethylene was 54%. According to this process, methoxy hydroperoxide (IV-OOH, where R is_7-2＝-CH₃) To give the desired carboxylic acid (VI) and the alpha-ketomethyl ester (where R is_bOMe) 65.2/34.8 mixtures. The α -ketomethyl ester cannot be converted to an eplerenone useful compound, the formation of which makes this process not commercially useful. In contrast, in the process of the invention, the enedione (III) passes through the hydroxy hydroperoxide intermediate (I)V-OOH, wherein R_7-2H) to the carboxylic acid (VI), which surprisingly rearranges to the desired carboxylic acid (VI), the yield is almost quantitative. The process of the present invention uses ozone, a peroxy-hydroxy-deoxidizer and an oxidative cracking agent to avoid the formation of alpha-keto methyl esters and to increase the yield.

Drugs of the Future, 24, 488(1999) disclose the conversion of the 5, 7-lactone (VII) to the corresponding methyl ester (VIII), treated with the aid of a "basic medium containing methyl iodide". The methylation process of the invention is a continuous process.

International publication WO98/25948 discloses (5, 7) -17-dilactone and 3-protected forms.

International publication WO98/25948 discloses the conversion of steroidal 7 alpha-acids to (5, 7) -17-dilactone. This process requires an orthoester. The process of the present invention does not require ortho esters.

International publication WO98/25948 discloses the corresponding reaction of (5, 7) -17-dilactone to 7 alpha-CO-OCH in one step₃The transformation of (3). The present invention employs two steps, but achieves better yields and consumes less reagents.

Eplerenone is 9(11) α -epoxy-17 β -hydroxypregn-4-en-3-one-7 α, 21-dicarboxylic acid, γ -lactone, methyl ester, and thus contains a 7 α -carbomethoxy substituent. From a production point of view, the main difficulty in eplerenone production is the introduction of the 7 α -carbomethoxy substituent. The present invention includes an improved method for introducing a 7 alpha-substituent.

It is known that carboxylic acids can be obtained in one step from (substituted) furans by ozonolysis. However, the yield is rather low. Further, furans are known to be capable of ring opening to provide enediones. It is also known that enediones can be oxidized to carboxylic acids.

Bulletin of the Chemical Society of Japan, 52, 3377-3380(1979) discloses that an olefin is obtained by replacing or eliminating a hydroxyl group with a fluorine atom using N- (1, 1, 2, 2, 3, 3, 3) hexafluoropropyldiethylamine, i.e., the "Ishikawa reagent". With cyclohexanol, a simple monocyclic system, the elimination of product olefins is 78%. However, when the "Ishikawa reagent" was applied to steroids, i.e., cholesterol, the corresponding fluoro compound was obtained as fluorinated cholesterol in 83% yield; no elimination product was reported.

J. org. chem., 2187-2195(1964) discloses the reaction of 11 α -hydroxypregn-4-ene-3, 20-dione with 2-chloro-1, 1, 2-trifluorotriethylamine to give the elimination product pregna-4, 9(11) -diene-3, 20-dione in 86% yield. The process of the invention does not use 2-chloro-1, 1, 2-trifluorotriethylamine, also known as Yarovenko's reagent. Furthermore, the use of 2-chloro-1, 1, 2-trifluorotriethylamine is problematic because its stability is not sufficient to make scale-up practical. In addition, it is derived from a chlorofluorocarbon compound and is not environmentally friendly.

Tetrahedron Letters, 1065-1069(1962) also discloses the reaction of 11 α -hydroxypregn-4-ene-3, 20-dione with 2-chloro-1, 1, 2-trifluorotriethylamine to give the elimination product pregna-4, 9(11) -diene-3, 20-dione.

Steroids, 29, 2187(1964) disclose the reaction of a steroid alcohol with 2-chloro-1, 1, 2-trifluorotriethylamine, the hydroxyl group being replaced with fluorine. The invention does not use 2-chloro-1, 1, 2-trifluoro triethylamine, and does not replace the hydroxyl with fluorine atom.

Fluorine chem., 109, 25-31(2001) describes and compares the use of 1, 1, 2, 2-tetrafluoroethyl-N, N-dimethylamine and yarovinko-Raksha and Ishikawa reagents as fluorination and dehydration agents. Although this document discloses examples of elimination reactions in aliphatic and cyclic systems, the primary use is as fluorinating agents. The only steroid example is the reaction of 1, 1, 2, 2-tetrafluoroethyl-N, N-dimethylamine with cholesterol to form a product in which fluorine is located at the C-3 position of cholesterol.

Summary of The Invention

Disclosed is a compound of the formula (I-P) Delta^4，6Process for the preparation of (E) -ketals

Wherein R is₃₁And R₃₂Is that

(1) Same or different is C₁-C₃An alkyl group, a carboxyl group,

(2) together with the attached-O-C-O-form a 5 or 6 atom cyclic ketal of the formula

-(CH₂)-(CR₃₃R₃₄)_n1-(CH₂)-

Wherein n is₁Is 0 or 1;

wherein R is₃₃And R₃₄Are the same or different and are

-H，

C₁-C₃An alkyl group, a carboxyl group,

the method comprises

(1) Let the following formula Δ^3，5-3-enol ether (alkyl enol ether)

(alkyl enol ethers)

Wherein R is³Is that

C₁-C₃An alkyl group, a carboxyl group,

CH₃-CO-，

phi-CO-or

R_Si-1R_Si-2R_Si-3Si-, wherein R_Si-1、R_Si-2And R_Si-3Are identical or different and are C₁-C₄An alkyl group; with a hydride extractionContacting the agent with an alcohol selected from the group consisting of alcohols of the formula:

(a)R₃₁-OH, wherein R₃₁Is as defined above in that the first and second parts are,

(b)R₃₂-OH, wherein R₃₂Is as defined above in that the first and second parts are,

(c)HO-(CH₂)-(CR₃₃R₃₄)_n1-(CH₂) -OH, wherein n₁、R₃₃And R₃₄Is as defined above in that the first and second parts are,

(d)HO-CH₂-CH₂-OH。

also disclosed are 7 alpha-substituted steroids of formula (II)

Wherein

(I)R₃Is ═ O; r₄Is R_4-1:R_4-2Wherein R is_4-1And R_4-2One of them is-H, R_4-1And R_4-2The other of which is connected with R₅Together form a second bond between the carbon atoms to which they are attached; r₆is-H;

(II)R₃is R_3-3:R_3-4，R₄Is R_4-3:R_4-4Wherein R is_3-3And R_3-4One of them is-O-R₃₁Wherein R is₃₁Is C₁-C₃Alkyl radical, R_3-3And R_3-4The other of which is connected with R_4-3And R_4-4One together forming a second bond between the carbon atoms to which they are attached, R_4-3And R_4-4The other of which is-H; r₆Is R_6-3:R_6-4Wherein R is_6-3And R_6-4One and R₅Together form a second bond between the carbon atoms to which they are attached,R_6-3and R_6-4The other of which is-H;

(III)R₃is alpha-R_3-5:β-R_3-6Wherein R is_3-5is-O-R₃₁，R_3-6is-O-R₃₂Wherein R is₃₁And R₃₂Are the same or different and are selected from the group consisting of:

C₁-C₃alkyl, and

R₃₁and R₃₂Together with the attached-O-C-O-form a 5 or 6 atom cyclic ketal of the formula

-(CH₂)-(CR₃₃R₃₄)_n1-(CH₂)-

Wherein n is₁Is 0 or 1;

wherein R is₃₃And R₃₄Are identical or different and are-H and C₁-C₃An alkyl group; r₄is-H; r₆Is R_6-5:R_6-6Wherein R is_6-5And R_6-6One and R₅Together forming a second bond between the carbon atoms to which they are attached, R_6-5And R_6-6The other of which is-H;

(IV)R₃is alpha-R_3-7:β-R_3-8Wherein R is_3-7is-O-R₃₁，R_3-8is-O-R₃₂Wherein R is₃₁And R₃₂Is as defined above; r₄Is R_4-7:R_4-8Wherein R is_4-7And R_4-8One and R₅Together forming a second bond between the carbon atoms to which they are attached, R_4-7And R_4-8The other of which is-H; r₆is-H;

wherein R is_7-1Is a molecular fragment of the formula (-A1)

Or a molecular fragment of formula (-A2)

Wherein X₁Is that

-S-，

-O-or

-NX_1-1-, wherein X_1-1Is that

-H，

C₁-C₄An alkyl group, a carboxyl group,

-CO-OX_1-2wherein X is_1-2Is C₁-C₄Alkyl or-CH₂-φ，

-CO-X_1-2Wherein X is_1-2Is as defined above in that the first and second parts are,

-CO-phi, wherein-phi is substituted at the O-position by-CO-O- (C)₁-C₄Alkyl) is substituted with (a) a (b),

-SO₂-(C₁-C₃an alkyl group),

-SO₂phi, where phi is optionally 1 or 2

C₁-C₄An alkyl group, a carboxyl group,

C₁-C₄alkoxy substitution;

wherein R is_bSelected from the group consisting of:

-H，

C₁-C₄alkyl, or

Phenyl, optionally substituted by 1 or 2

C₁-C₄An alkyl group, a carboxyl group,

C₁-C₄alkoxy substitution;

wherein R is_cSelected from the group consisting of:

-H，

C₁-C₄an alkyl group, a carboxyl group,

C₁-C₄an alkoxy group,

-O-Si(R)₃wherein R, which are identical or different, are-H, C₁-C₄Alkyl, -phi, C₁-C₄An alkoxy group and-OH,

-F、-Cl、-Br、-I，

-CO-OCH₃and are and

-CO-R_c-1wherein R is_c-1Is C₁-C₄Alkyl or-phi;

wherein R is_dSelected from the group consisting of:

-H，

-C≡N，

C₁-C₁₀an alkyl group, a carboxyl group,

C₁-C₄an alkoxy group,

-CH₂-OR_d-1wherein R is_d-1is-H or C₁-C₄An alkyl group, a carboxyl group,

-CH₂-N(R_d-6)₂wherein two R are_d-6Are the same or different and are:

C₁-C₄an alkyl group, a carboxyl group,

-φ，

-CO-R_d-6awherein R is_d-6aIs C₁-C₄An alkyl group or a group represented by the formula-phi,

-CH₂-O-CO-R_d-1wherein R is_d-1Is as defined above in that the first and second parts are,

-CH(OR_d-1)₂wherein R is_d-1Is as defined above, wherein two R are_d-1Together, are:

-CH₂-CH₂-，

-CH₂-CH₂-CH₂-，

-CH₂-C(CH₃-)₂-CH₂-，

-CH(-O-CO-R_d-1)₂wherein R is_d-1Is as defined above in that the first and second parts are,

-Si(R)₃wherein R is as defined above,

-O-Si(R)₃wherein R is as defined above,

-Sn(R_b-1)₃wherein R is_b-1Is as defined above in that the first and second parts are,

-S-R_d-5wherein R is_d-5Is C₁-C₄An alkyl group or a group represented by the formula-phi,

-N(R_d-6)₂wherein R is_d-6Is as defined above in that the first and second parts are,

wherein R is_cAnd R_dTogether with the atoms to which they are attached

Wherein E₁Are the same or different and are:

-H，

C₁-C₄an alkyl group, a carboxyl group,

-F、-Cl、-Br、-I，

-OE_1-1in which E_1-1The method comprises the following steps:

-H，

C₁-C₄an alkyl group, a carboxyl group,

phi, or

-SiE_1-2E_1-3E_1-4In which E_1-2、E_1-3And E_1-4Are identical or different and are C₁-C₄Alkyl or C₁-C₄An alkoxy group,

-S-E_1-5in which E_1-5Is C₁-C₄An alkyl group or a group represented by the formula-phi,

-S-(O)_1-2-E_1-5in which E_1-5Is as defined above in that the first and second parts are,

-N(R_d-6)₂wherein two R are_d-6Are identical or different, are as defined above,

-P(O)(O-E_1-1)₂in which E_1-1Is as defined above in that the first and second parts are,

-Si(R)₃wherein R is as defined above;

-CE₁＝M (-B)

wherein E₁Is as defined above in that the first and second parts are,

wherein M is:

(1)＝O，

(2)＝N-E₂in which E₂Selected from the group consisting of:

-H，

C₁-C₄an alkyl group, a carboxyl group,

c containing 1 or 2 double bonds₁-C₄An alkenyl group, which is a radical of an alkenyl group,

c containing 1 triple bond₁-C₄An alkynyl group,

-CO-OE_2-1in which E_2-1is-H or C₁-C₄An alkyl group, a carboxyl group,

-C(E_2-1)₂-OE_2-2in which E_2-1Are identical or different, are as defined above,

wherein E_2-2Is that

C₁-C₄An alkyl group, a carboxyl group,

phi, or

Si(R)₃Wherein the three R are the same or different and are as defined above,

-OE_2-2in which E_2-2Is as defined above in that the first and second parts are,

-S-E_2-3in which E_2-3Is C₁-C₄An alkyl group or a group represented by the formula-phi,

-S-(O)_1-2-E_2-3in which E_2-3Is as defined above in that the first and second parts are,

-N(R_d-6)₂wherein two R are_d6Are the same or different and are as defined above;

-Si(R)₃wherein three R are as defined above;

(3)＝C(E₂)₂in which E₂Are identical or different, are as defined above,

wherein E₁And E₂Together with the atoms to which they are attached form a 5 to 7 membered ring, optionally containing 3 to 5

-O-，

-S-，

-N＝，

-NX_1-1-, wherein X_1-1Is as defined above in that the first and second parts are,

-CE₂wherein E₂Is as defined above in that the first and second parts are,

-C(R_b)₂-, wherein R_bIs as defined above, optionally containing 1 or 2 additional double bonds;

-C≡C-E₂(-C)

wherein E₂Is as defined above;

-CH₂-CH＝CH₂ (-D1)

-CH＝C＝CH₂ (-D2)

-CH₂-C≡C-H (-D3)

wherein R is₉The method comprises the following steps:

(1)-H，

(2)-OH，

(3) -O- (hydroxy protecting group), wherein the hydroxy protecting group is selected from the group consisting of:

-Si(-CH₃)₃，

-Si(-CH₂-CH₃)₃，

-CO-CH₃，

-CO-H, and

-SiH(CH₃)₂，

(4)-F；

wherein R is₁₁The method comprises the following steps:

(1)＝O，

(2)-H:-H，

(3)α-R_11-1:β-R_11-2wherein R is_11-1The method comprises the following steps:

(a)-H，

(b)-O-R_11-3wherein R is_11-3The method comprises the following steps:

(i)-H，

(ii) a hydroxyl protecting group, wherein the hydroxyl protecting group is as defined above, wherein R_11-2The method comprises the following steps:

(a)-H，

(b)-O-R_11-4wherein R is_11-4The method comprises the following steps:

(i)-H，

(ii) a hydroxy protecting group, wherein the hydroxy protecting group is as defined above, with the proviso that R is_11-1And R_11-2One of them must be-H and,

(4)R_11-5:R_11-6wherein R is_11-5Or R_11-6One and R₉Together form a second bond between C-9 and C-11, R_11-5Or R_11-6The other of which is-H, and,

(5)α-R_11-7:β-R_11-8wherein R is_11-7And R₉Together with-O-to form an epoxide between C-9 and C-11, R_11-8is-H;

wherein R is₁₇The method comprises the following steps:

(1)＝O；

(2)α-R_17-1:β-R_17-2wherein R is_17-1The method comprises the following steps:

(a)-H，

(b)-C≡C-H，

(c)-C≡N，

(d)-C≡C-CH₂-O-R_17-1-1wherein R is_17-1-1Selected from the group consisting of:

(i)-H，

(ii)-Si(R_17-1-2)₃wherein R is_17-1-2Are identical or different and are C₁-C₄An alkyl group, a carboxyl group,

(iii) 1-ethoxy ethyl group, and a pharmaceutically acceptable salt thereof,

(iv) 2-a-tetrahydropyranyl group, a 2-tetrahydropyranyl group,

(e)-C≡C-CH₂-O- (hydroxy protecting group), wherein the hydroxy protecting group is as defined above,

(f)-CH₂-CH₂-CH₂-OH，

(g)-CH₂-CH₂-CH₂-O- (hydroxy protecting group), wherein the hydroxy protecting group is as defined above,

(h)-CH₂-CH₂-CO-O^-wherein R is_17-2is-OH;

(3)α-R_17-3:β-R_17-4wherein R is_17-3is-OH, wherein R_17-4The method comprises the following steps:

(a)-CO-CH₃，

(b)-CO-CH₂-OH，

(c)-CO-CH₂-O-CO-(CH₂)_0-3-CH₃；

(4)α-R_17-5:β-R_17-6wherein R is_17-5And R_17-6Together with the carbon atom to which they are attached to form a radical containing-O-CH₂The ternary epoxide of (A) wherein the point of attachment of (A) to (B) is at R_17-6In the beta-orientation, CH₂The point of attachment of-is at R_17-5In the alpha-orientation;

(5)α-R_17-7:β-R_17-8wherein R is_17-7And R_17-8Together with the carbon atom to which they are attached form a radical containing-O-CO-CH₂-CH₂Pentalactone of (a), wherein CH₂The point of attachment of-is at R_17-7In the alpha-orientation, the point of attachment of the-O is at R_17-8In the beta-orientation;

(6)-O-CH(OR_17-9)-CH₂-CH₂ ^......wherein the bond (-O) from oxygen is one of the four bonds of C-17, in the beta configuration, and the bond (-CH) from methylene is₂ ^.....) Is another of the four bonds of C-17 in the alpha-configuration, constituting a 5-membered heterocyclic ring containing one oxygen atom, wherein R_17-9is-H or C₁-C₃An alkyl group;

(7)α-R_17-11:β-R_17-12wherein R is_17-10Is- (CH)₂)_1-2-CH＝CH₂，R_17-12is-OH.

Further disclosed are cis-enediones of the formula (III-cis)

And trans-enediones of the formula (III-trans)

C₁-C₃alkyl, and

R₃₁and R₃₂Together with the attached-O-C-O-form a cyclic ketal of the following formula 5 or 6 atom

-(CH₂)-(CR₃₃R₃₄)_n1-(CH₂)-

Wherein n is₁Is 0 or 1;

wherein R is₉、R₁₁、R₁₇Is as defined above;

wherein R is_bSelected from the group consisting of:

-H，

C₁-C₄alkyl, or

Phenyl, optionally substituted by 1 or 2

C₁-C₄An alkyl group, a carboxyl group,

C₁-C₄the substitution of alkoxy groups is carried out,

wherein R is_cIs selected from the group consisting of：

-H，

C₁-C₄An alkyl group, a carboxyl group,

C₁-C₄an alkoxy group,

-F、-Cl、-Br、-I，

-CO-OCH₃and are and

-CO-R_c-1wherein R is_c-1Is C₁-C₄Alkyl or-phi;

wherein R is_dSelected from the group consisting of:

-H，

-C≡N，

C₁-C₁₀an alkyl group, a carboxyl group,

C₁-C₄an alkoxy group,

-CH₂-OR_d-1wherein R is_d-1is-H or C₁-C₄An alkyl group, a carboxyl group,

-CH₂-N(R_d-6)₂wherein two R are_d-6Are the same or different and are:

C₁-C₄an alkyl group, a carboxyl group,

-φ，

-CH₂-CH₂-，

-CH₂-CH₂-CH₂-，

-CH₂-C(CH₃-)₂-CH₂-，

-Si(R)₃wherein R is as defined above,

-O-Si(R)₃wherein R is as defined above,

wherein R is_cAnd R_dTogether with the atom to which they are attached are

Wherein E₁Are the same or different and are:

-H，

C₁-C₄an alkyl group, a carboxyl group,

-F、-Cl、-Br、-I，

-OE_1-1in which E_1-1The method comprises the following steps:

-H，

C₁-C₄an alkyl group, a carboxyl group,

phi, or

-Si(R)₃wherein R is as defined above.

Further disclosed are hydroxy compounds of formula (IV-OH)

And a hydroperoxy compound (IV-O-OH)

Wherein R is₃、R₄、R₅And R₆Are as defined for cis-and trans-enediones (III-cis) and (III-trans), where R is₉、R₁₁、R₁₇And R_bIs as defined aboveWherein R is_7-2is-H and C₁-C₄Alkyl, optionally substituted with one or two-OH.

Disclosed are bis-carbonyl compounds of formula (V)

Wherein R is₃、R₄、R₅And R₆Are as defined for cis-and trans-enediones (III-cis) and (III-trans), where R is₉、R₁₁、R₁₇And R_bIs as defined above.

Also disclosed are cis-oxyalkylene diones of the formula (X-cis)

And trans-enediones of the formula (X-trans)

Wherein R is₃、R₄、R₅And R₆Are as defined for cis-and trans-enediones (III-cis) and (III-trans), where R is₉、R₁₁、R₁₇、R_b、R_cAnd R_dIs as defined above.

Further disclosed are 7 alpha-unsaturated steroids of formula (XIV)

Wherein R is₃、R₄、R₅And R₆Are as defined for cis-and trans-enediones (III-cis) and (III-trans), where R is₉、R₁₁、R₁₇、R_bAnd R_dIs as defined above.

Further disclosed are 7 alpha-proacids of formula (XV)

Disclosed is a process for the preparation of 7 alpha-substituted steroids of formula (II),

wherein

(II)R₃is R_3-3:R_3-4，R₄Is R_4-3:R_4-4Wherein R is_3-3And R_3-4One of them is-O-R₃₁Wherein R is₃₁Is C₁-C₃Alkyl radical, R_3-3And R_3-4The other of which is connected with R_4-3And R_4-4Are formed togetherIn a second bond between the carbon atoms to which they are attached, R_4-3And R_4-4The other of which is-H; r₆Is R_6-3:R_6-4Wherein R is_6-3And R_6-4One and R₅Together forming a second bond between the carbon atoms to which they are attached, R_6-3And R_6-4The other of which is-H;

C₁-C₃alkyl, and

-(CH₂)-(CR₃₃R₃₄)_n1-(CH₂)-

Wherein n is₁Is 0 or 1;

wherein R is_7-1、R₉、R₁₁And R₁₇Is as defined above;

the method comprises the following steps:

(1) let formula (I) Δ^4，6-3-ketosteroids or ketals thereof

Wherein

(I)R₃Is ═ O; r₄Is R_4-1:R_4-2Wherein R is_4-1And R_4-2One of them is-H, R_4-1And R_4-2The other of which is connected with R₅Together form a second bond between the carbon atoms to which they are attached;

(I-Keto) R₃Is R_3-9:R_3-10Wherein R is_3-9is-O-R₃₁，R_3-10is-O-R₃₂Wherein R is₃₁And R₃₂Are the same or different and are selected from the group consisting of:

C₁-C₃alkyl, and

-(CH₂)-(CR₃₃R₃₄)_n1-(CH₂)-

Wherein n is₁Is 0 or 1;

wherein R is₃₃And R₃₄Are identical or different and are-H and C₁-C₃An alkyl group; r₄Is R_4-9:R_4-10Wherein R is_4-9And R_4-10One and R₅Together forming a second bond between the carbon atoms to which they are attached，R_4-9And R_4-10The other of which is-H;

wherein R is₉、R₁₁And R₁₇Is as defined above in that the first and second parts are,

with an adduct selected from the group consisting of:

(a) formula (A)

Or

Wherein X₁、R_b、R_cAnd R_dIs as defined above in that the first and second parts are,

wherein R is_aSelected from the group consisting of-H, -ZnL, -BL, -Sil₃、-SnL₃、-Cu、-CuL、-AlL₂-HgL, -Ag, -MgL, -Li and-COOH, wherein L is-OH, C₁-C₄Alkyl, -F, -Cl, -Br, -I, -CN, -O (C)₁-C₃Alkyl), 2-thienyl, (CH)₃)₂C(O-)-C(O-)C(CH₃)₂And

(b) formula (A')

R_b-CO-CHR_b-CHR_c-CO-R_d (A’)

Wherein R is_b，R_cAnd R_dIs as defined above;

(c) formula (A')

Wherein R is_eThe method comprises the following steps:

C₁-C₄an alkyl group, a carboxyl group,

-CO-(C₁-C₄alkyl or-phi),

-Si(R)₃wherein R is as defined above, wherein X₁、R_b、R_cAnd R_dIs as defined above;

(d) formula (B)

R_a-CE₁＝M (B)

Wherein R is_a、E₁And M is as defined above;

(e) formula (C)

R_a-C≡C-E₂(C)

Wherein R is_aAnd E₂Is as defined above;

(f) formula (D1, D2 and D3)

R_a-CH₂-CH＝CH₂ (D1)

R_a-CH＝C＝CH₂ (D2)

R_a-CH₂-C≡C-H (D3)

Wherein R is_aIs as defined above in that the first and second parts are,

the contacting is in the presence of the following reagents:

(1) a Lewis acid, a basic metal oxide or a metal oxide,

(2)pK_aless than about 5, or

(3) A secondary amine of the formula

Wherein

R_S-2is-H, C₁-C₄Alkyl, -phi and-CH₂-φ；

R_S-3is-H, C₁-C₄An alkyl group;

R_S-4is-H, C₁-C₄Alkyl, - φ;

R_S-5is-H, C₁-C₄Alkyl, - φ;

and a secondary amine of the formula

Wherein

R_S-2is-H, C₁-C₄Alkyl, -phi and-CH₂-φ；

R_S-4is-H, C₁-C₄Alkyl, - φ;

R_S-5is-H, C₁-C₄Alkyl, - φ;

and pK_aSalts of acids of < about 2.

Also disclosed are methods for purifying 7 alpha-substituted steroids of formula (II), wherein R₃、R₄、R₅And R₆Is as defined for the 7 alpha-substituted steroid (II) wherein R is_7-1、R₉、R₁₁And R₁₇Is as defined above; the method comprises the following steps:

(1) crystallizing a 7 α -substituted steroid (II) containing greater than 5% of the 7 β -isomer from a solvent selected from the group consisting of ethyl acetate, propyl acetate and butyl acetate.

Further disclosed is a process for the purification of cis-enedione of formula (III-cis),

wherein R is₃、R₄、R₅And R₆Are as defined for cis-and trans-enediones (III-cis) and (III-trans), where R is_7-1、R_7-2、R₉、R₁₁、R₁₇、R_b、R_c、R_dIs as defined above;

the method comprises the following steps:

(1) reacting a 7 alpha-substituted steroid of formula (II)

Wherein R is₃、R₄、R₅、R₆、R_7-1、R₉、R₁₁And R₁₇Is as defined above; contacting with an agent selected from the group consisting of:

(a) halogenating agents, in the presence of water and a base, the pK of the conjugate acid of which_aIs greater than the total weight of the slurry to be about 8,

(b) an oxygen-supplying agent, which is a mixture of oxygen-supplying agent,

(c) the oxidation is carried out in an electrochemical way,

(d) quinone in the presence of water, or

(e) A non-quinone oxidizing agent.

Further disclosed is a process for the purification of trans-enediones of the formula (III-trans),

wherein R is₃、R₄、R₅And R₆Are as defined for cis-and trans-enediones (III-cis) and (III-trans), where R is₉、R₁₁、R₁₇、R_b、R_cAnd R_dIs as defined above;

the method comprises the following steps:

(1) reacting a cis-enedione of formula (III-cis)

Wherein R is₃、R₄、R₅、R₆、R₉、R₁₁、R₁₇、R_b、R_cAnd R_dIs as defined above, with an isomerization catalyst selected from the group consisting of:

(a)pK_aa strong acid of < about 2;

(b) pK of tertiary amine, its conjugate acid_aIs greater than the total weight of the slurry to be about 8,

(c) a salt of a tertiary amine, the pK of the conjugate acid of said amine_aIs greater than the total weight of the slurry to be about 8,

(d)I₂，

(e)(C₁-C₄)₃P，

(f)φ₃P，

(g) heat to about 80 deg..

Disclosed is a process for preparing hydroxy compounds of formula (IV-OH)

Or a peroxy hydroxy compound of the formula (IV-OOH)

Or a dicarbonyl compound of formula (V)

Or carboxylic acids of the formula (VI)

Or mixtures thereof, wherein R₃、R₄、R₅And R₆Are as defined for cis-and trans-enediones (III-cis) and (III-trans), where R is_7-2、R₉、R₁₁、R₁₇、R_bIs as defined above;

the method comprises the following steps:

(1) reacting a cis-enedione of formula (III-cis)

Or trans-enediones of the formula (III-trans)

Or mixtures thereof, wherein R₃、R₄、R₅、R₆、R₉、R₁₁、R₁₇、R_b、R_cAnd R_dIs as defined above in that the first and second parts are,

with ozone in the formula R_7-2In the presence of an-OH alcohol, wherein R_7-2Is as defined above.

Also disclosed is a process for the preparation of the hydroxy compound of formula (IV-OH),

wherein R is₃、R₄、R₅And R₆Are as defined for cis-and trans-enediones (III-cis) and (III-trans), where R is_7-2、R₉、R₁₁、R₁₇And R_bIs as defined above;

the method comprises the following steps:

(1) reacting a peroxy hydroxy compound of formula (IV-OOH)

Wherein R is₃、R₄、R₅、R₆、R₉、R₁₁、R₁₇、R_bAnd R_7-2Is as defined above in that the first and second parts are,

contact with a peroxy hydroxyl-deoxidizer.

Further disclosed is a process for the preparation of a carboxylic acid of formula (VI) or a pharmaceutically acceptable salt thereof,

wherein R is₃、R₄、R₅And R₆Are as defined for cis-and trans-enediones (III-cis) and (III-trans), where R is₉、R₁₁、R₁₇Is as defined above;

the method comprises the following steps:

(1) reacting a peroxy hydroxy compound of formula (IV-OOH)

Wherein R is₃、R₄、R₅、R₆、R₉、R₁₁、R₁₇、R_bAnd R_7-2Is as defined above; with a carboxylic acid generator selected from the group consisting of:

(a) heating the mixture to be heated, wherein the mixture is heated,

(b) pK of a base, its conjugate acid_aIs a compound having a molecular weight of about 5 or more,

(c) an acid, its pK_aLess than about 3 of the total weight of the composition,

(d) an acylating agent.

Also disclosed is a process for the preparation of carboxylic acids of formula (VI),

wherein R is₃、R₄、R₅And R₆Are as defined for cis-and trans-enediones (III-cis) and (III-trans), where R is₉、R₁₁And R₁₇Is as defined above;

the method comprises the following steps:

(1) reacting a hydroxy compound of formula (IV-OH)

Or a dicarbonyl compound of formula (V)

Or mixtures thereof, wherein R₃、R₄、R₅And R₆Are as defined for cis-and trans-enediones (III-cis) and (III-trans), where R is₉、R₁₁、R₁₇And R_bIs as defined above;

contacting with an oxidative cracking agent.

Disclosed is a process for the preparation of 5, 7-lactones of formula (VII),

wherein

(Va)R₂is-H; r₃Is ═ O; r₄is-H;

(Vb)R₂is-H; r₃Is R_3a:R_3bWherein R is_3aAnd R_3bAre all-OH, R₄is-H;

wherein R is₉、R₁₁And R₁₇Is as defined above;

the method comprises the following steps:

(1) reacting a carboxylic acid of formula (VI)

Wherein

C₁-C₃alkyl, and

-(CH₂)-(CR₃₃R₃₄)_n1-(CH₂)-

Wherein n is₁Is 0 or 1;

wherein R is₉、R₁₁、R₁₇Is as defined above;

is contacted with a reaction medium having a pH of less than about 5.

Also disclosed is a process for the preparation of 5, 7-lactones of formula (VII),

wherein

(Va)R₂is-H, R₃Is ═ O, R₄is-H;

wherein R is₉、R₁₁And R₁₇Is as defined above;

the method comprises the following steps:

(1) reacting a carboxylic acid of formula (VI)

Wherein

(I)R₃Is ═ O; r₄Is R_4-1:R_4-2Wherein R is_4-1And R_4-2One of them is-H, R_4-1And R_4-2The other of which is connected with R₅Together form a second bond between the carbon atoms to which they are attached; r₆is-H; wherein R is₉、R₁₁And R₁₇Is as defined above;

contacting under anhydrous conditions with an anhydrous reaction medium having a pH of less than about 5.

Disclosed is a process for the preparation of 5, 7-lactones of formula (VII),

wherein

(Vc)R₂is-H, R₃is-O-R_3a:-O-R_3bWherein R is_3aAnd R_3bIs the same C₁-C₃Alkyl, or wherein R_3aAnd R_3bTogether with the attached-O-C-O-form a 5 or 6 atom cyclic ketal of the formula

-(CH₂)-(CR₃₃R₃₄)_n1-(CH₂)-

Wherein n is₁Is 0 or 1;

wherein R is₃₃And R₃₄Are identical or different and are-H and C₁-C₃Alkyl radical, R₄is-H;

(VI)R₂is-H; r₃Is R_3c:R_3d，R₄Is R_4c:R_4dWherein R is_3cAnd R_3dOne and R_4cOr R_4dOne together forming a second bond between the carbon atoms to which they are attached, R_3cAnd R_3dThe other of which is CH₃-O-or C₂H₅-O-；R_4cAnd R_4dThe other of which is-H; or

(VII)R₂Is R_2e:R_2f，R₃Is R_3e:R_3fWherein R is_2eAnd R_2fOne and R_3eOr R_3fOne together forming a second bond between the carbon atoms to which they are attached, R_2eAnd R_2fThe other of which is-H; r_3eAnd R_3fThe other of which is CH₃-O-or C₂H₅-O-; or mixtures thereof;

wherein R is₉、R₁₁And R₁₇Is as defined above;

the method comprises the following steps:

(1) reacting a carboxylic acid of formula (VI)

Wherein

C₁-C₃alkyl, and

-(CH₂)-(CR₃₃R₃₄)_n1-(CH₂)-

Wherein n is₁Is 0 or 1;

wherein R is₃₃And R₃₄Are identical or different and are-H and C₁-C₃An alkyl group; r₄is-H; r₆Is R_6-5:R_6-6Wherein R is_6-5And R_6-6One and R₅Together forming a second bond between the carbon atoms to which they are attached, R_6-5And R_6-6The other of which is-H; (IV) R₃Is alpha-R_3-7:β-R_3-8Wherein R is_3-7is-O-R₃₁，R_3-8is-O-R₃₂Wherein R is₃₁And R₃₂Is as defined above; r₄Is R_4-7:R_4-8Wherein R is_4-7And R_4-8One and R₅Together forming a second bond between the carbon atoms to which they are attached, R_4-7And R_4-8The other of which is-H; r₆is-H;

wherein R is₉、R₁₁And R₁₇Is as defined above;

with at least a catalytic amount of an acid.

Disclosed is a process for the preparation of methyl esters of the formula (VIII),

wherein

(I)R₃is-O; r₄Is R_4-1:R_4-2Wherein R is_4-1And R_4-2One of them is-H, R_4-1And R_4-2The other of which is connected with R₅Together form a second bond between the carbon atoms to which they are attached; r₆is-H;

wherein R is₉、R₁₁And R₁₇Is as defined above;

the method comprises the following steps:

(1) reacting a 5, 7-lactone of formula (VII)

Wherein R is₄is-H, wherein R₃、R₉、R₁₁And R₁₇Is as defined above, is contacted with a base,

(2) contacting the reaction mixture of step (1) with a methylating agent.

Also disclosed are processes for the preparation of carboxylic acids of formula (VI) or a pharmaceutically acceptable salt thereof,

wherein

wherein R is₉、R₁₁、R₁₇Is as defined above;

the method comprises the following steps:

(1) reacting a 5, 7-lactone of formula (VII)

Wherein R is₄is-H; wherein R is₃、R₉、R₁₁And R₁₇Is as defined above, with a pH > 7And (4) contacting.

Further discloses a preparation method of cis-oxyalkylene diketone with the formula (X-cis),

the method comprises the following steps:

(1) reacting a 7 alpha-substituted steroid of formula (II)

Wherein R is₃、R₄、R₅And R₆Are as defined for cis-and trans-enediones (III-cis) and (III-trans), where R is_7-1、R₉、R₁₁And R₁₇Is as defined above;

with ozone in C₁-C₄In the presence of an alcohol, and then contacting,

(2) contacting the mixture of step (1) with a peroxy hydroxy-deoxidant.

Also disclosed is process 355, a process for the preparation of trans-oxyalkylene diones of formula (X-trans),

the method comprises the following steps:

(1) reacting a cis-oxyalkylene diketone of the formula (X-cis)

(a)pK_aa strong acid of < about 2;

(d)I₂，

(e)(C₁-C₄)₃P，

(f)φ₃P，

(g) heat to about 80 deg..

Disclosed is a process for preparing hydroxy compounds of formula (IV-OH)

or a peroxy hydroxy compound of the formula (IV-OOH)

Wherein R is₃、R₄、R₅、R₆、R_7-2、R₉、R₁₁、R₁₇And R_bIs as defined above, or a dicarbonyl compound of formula (V)

Wherein R is₃、R₄、R₅、R₆、R₉、R₁₁、R₁₇And R_bIs as defined above in that the first and second parts are,

or carboxylic acids of the formula (VI)

Wherein R is₃、R₄、R₅、R₆、R₉、R₁₁And R₁₇Is as defined above in that the first and second parts are,

or a mixture thereof, the method comprising:

(1) reacting an oxyalkylene diketone of the formula (X-cis)

Wherein R is₃、R₄、R₅、R₆、R₉、R₁₁、R₁₇、R_b、R_cAnd R_dIs as defined above, or an oxyalkylene diketone of the formula (X-trans)

Wherein R is₃、R₄、R₅、R₆、R₉、R₁₁、R₁₇、R_b、R_cAnd R_dIs as defined above in that the first and second parts are,

or mixtures thereof with ozone in the formula R_7-2In the presence of an-OH alcohol, wherein R_7-2Is as defined above.

Also disclosed is a process for preparing a carboxylic acid of formula (VI) or a salt thereof,

the method comprises the following steps:

(1) reacting a 7 alpha-substituted steroid of formula (II)

contacting with an agent selected from the group consisting of:

(b) an oxygen-supplying agent, which is a mixture of oxygen-supplying agent,

(c) the oxidation is carried out in an electrochemical way,

(d) quinone in the presence of water, or

(e) A non-quinone oxidizing agent;

(2) reacting the reaction mixture of step (1) with ozone in the formula R_7-2In the presence of an-OH alcohol, wherein R_7-2Is as defined above;

(3) contacting the reaction mixture of step (2) with a peroxy hydroxy-deoxidant;

(4) contacting the reaction mixture of step (3) with an oxidative cleavage agent.

Disclosed is a process for preparing a carboxylic acid of formula (VI) or a salt thereof,

the method comprises the following steps:

(1) reacting a 7 alpha-substituted steroid of formula (II)

Wherein R is₃、R₄、R₅And R₆Are as defined for cis-and trans-enediones (III-cis) and (III-trans), where R is_7-1、R₉、R₁₁、R₁₇Is as defined above;

(1) with ozone in the formula R_7-2In the presence of an-OH alcohol, wherein R_7-2Is as defined above;

(2) contacting the reaction mixture of step (1) with a peroxy hydroxy-deoxidant;

(3) contacting the reaction mixture of step (2) with an oxidative cleavage agent.

the method comprises the following steps:

(1) reacting a cis-oxyalkylene diketone of the formula (X-cis)

Or trans-oxyalkylene diones of the formula (X-trans)

Or mixtures thereof, wherein R₃、R₄、R₅And R₆Are as defined for cis-and trans-enediones (III-cis) and (III-trans), where R is₉、R₁₁、R₁₇、R_b、R_cAnd R_dIs as defined above in that the first and second parts are,

contacting with an oxidative cracking agent.

Also discloses a⁹⁽¹¹⁾A method for preparing 17-lactone (CII),

the method comprises the following steps:

(1) reacting 11 alpha-hydroxy-17-lactone (CI)

With an N-fluoroalkylamine reagent of formula (CVI),

wherein:

Z₁is C₁-C₄An alkyl group;

Z₂is C₁-C₄Alkyl radical, wherein Z₁And₂together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclic ring selected from the group consisting of pyrrolidinyl, piperazinyl, piperidinyl and morpholinyl;

Z₃is-F or-CF₃。

Further discloses a⁹⁽¹¹⁾A process for the preparation of steroids (CV),

wherein W₅The method comprises the following steps:

(1) is absent at C₄And C₅A double bond exists between the two;

(2)W₆is W_6-1:W_6-2Wherein W is_6-1Or W_6-2One and W₅Together forming a second bond between the carbon atoms to which they are attached, W_6-1And W_6-2The other of which is-H;

(3)W₅is alpha-O-, W₇Is alpha-W_7-1:β-W_7-2Wherein W is_7-1is-CO-to form lactone (-O-CO-), oxygen atom is bonded at C-5 position and is alpha-configuration, carbonyl group is bonded at C-7 position and is alpha-configuration, W_7-2is-H;

wherein W₆The method comprises the following steps:

(1)-H；-H；

(2)W_6-3:W_6-4wherein W is_6-3And W_6-4One and W₅Together form a double bond between C-5 and C-6, W_6-3And W_6-4The other of which is-H;

(3)W_6-3:W_6-4，W₇is W_7-3:W_7-4Wherein W is_6-3And W_6-4One and W_7-3Or W_7-4One together forming a double bond between C-6 and C-7, W_6-3And W_6-4The other of which is-H, W_7-3And W_7-4The other of which is-H;

wherein W₇The method comprises the following steps:

(1)α-W_7-5:β-W_7-6wherein W is_7-5The method comprises the following steps:

(a)-H，

(b)-C≡N，

(c)-C≡C-H，

(d)-CH＝CH-CH₃，

(e)-CO-OH，

(f)-CO-OW_7-5Awherein W is_7-5AThe method comprises the following steps:

(i)C₁-C₄an alkyl group, a carboxyl group,

(ii) phi, optionally one to three C₁-C₃Alkyl, -F, -Cl, -Br, -I, C₁-C₃The substitution of alkoxy groups is carried out,

(g) phi, optionally one to three C₁-C₃Alkyl, -F, -Cl, -Br, -I, C₁-C₃The substitution of alkoxy groups is carried out,

(h)-CO-SW_7-5Awherein W is_7-5AIs as defined above in that the first and second parts are,

(i)-CO-CH＝CH-O-CO-W_7-5Awherein W is_7-5AIs as defined above in that the first and second parts are,

(j)-CO-CO-H，

(k)-CH₂-NO₂，

(l)-S-CO-W_7-5Awherein W is_7-5AIs as defined above in that the first and second parts are,

(m) 5-methylfuran-2-yl,

(n) 5-tert-butylfuran-2-yl,

W_7-6is-H;

(3)α-W_7-7:β-W_7-8wherein W is_7-7is-H, W_7-8The method comprises the following steps:

(a)-H，

(b)-O-CO-(C₁-C₄an alkyl group),

(c)-O-CO-OW_7-8Awherein W is_7-8AThe method comprises the following steps:

(i)C₁-C₄an alkyl group, a carboxyl group,

(ii i)-CH₂phi, wherein phi is optionally one to three C₁-C₃Alkyl, -F, -Cl, -Br, -I, C₁-C₃Alkoxy substitution;

the method comprises the following steps:

(1) reacting 11 alpha-hydroxy steroid (CIV)

Wherein W₅、W₆And W₇Is as defined above in that the first and second parts are,

with an N-fluoroalkylamine reagent of formula (CVI),

wherein:

Z₁is C₁-C₄An alkyl group;

Z₃is-F or-CF₃。

Further disclosed is a compound of formula (II) Δ⁹⁽¹¹⁾A process for the preparation of an-7 alpha-substituted steroid,

wherein R is₁₇The method comprises the following steps:

(1)＝O；

(3)α-R_17-3；β-R_17-4wherein R is_17-3is-OH, wherein R_17-4The method comprises the following steps:

(a)-CO-CH₃，

(b)-CO-CH₂-OH，

(c)-CO-CH₂-O-CO-(CH₂)_0-3-CH₃；

(5)α-R_17-7:β-R_17-8wherein R is_17-7And R_17-8Together with the carbon atom to which they are attached form a radical containing-O-CO-CH₂-CH₂Pentalactone of (a), wherein CH₂Of (A) toThe point of attachment is at R_17-7In the alpha-orientation, the point of attachment of the-O is at R_17-8In the beta-orientation;

(7)α-R_17-11:β-R_17-12wherein R is_17-10Is- (CH)₂)_1-2-CH＝CH₂，R_17-12is-OH;

wherein R is₃、R₄、R₅And R₆Are as defined for cis-and trans-enediones (III-cis) and (III-trans), where R is_7-1Is as defined above;

the process comprises reacting an 11 alpha-hydroxy 7 alpha-substituted steroid of formula (II)

Wherein R is₃、R₄、R₅、R₆、R_7-1And R₁₇Is as defined above in that the first and second parts are,

with an N-fluoroalkylamine reagent of formula (CVI).

Disclosed is a compound of the formula (III-trans) Delta⁹⁽¹¹⁾A process for the preparation of trans-enediones,

wherein R is₁₇The method comprises the following steps:

(1)＝O；

(a)-CO-CH₃，

(b)-CO-CH₂-OH，

(c)-CO-CH₂-O-CO-(CH₂)_0-3-CH₃；

wherein R is₃、R₄、R₅And R₆As defined by cis-and trans-enediones (III-cis) and (III-trans),wherein R is_b、R_cAnd R_dIs as defined above;

the process comprises reacting an 11 alpha-hydroxy cis-enedione of the formula (III-cis)

Or 11 alpha-hydroxy trans-enediones of the formula (III-trans)

Wherein R is₃、R₄、R₅、R₆、R₁₇、R_b、R_cAnd R_dIs as defined above in that the first and second parts are,

with an N-fluoroalkylamine reagent of formula (CVI).

Also disclosed is the preparation of Δ of formula (VI)⁹⁽¹¹⁾-a carboxylic acid or a salt thereof,

wherein R is₁₇The method comprises the following steps:

(1)＝O；

(a)-CO-CH₃，

(b)-CO-CH₂-OH，

(c)-CO-CH₂-O-CO-(CH₂)_0-3-CH₃；

wherein R is₃、R₄、R₅And R₆Are as defined for cis-and trans-enediones (III-cis) and (III-trans);

the method comprises the following steps:

(1) reacting a compound of formula (IV-OH)11 alpha-hydroxy

Or a compound of formula (IV-OOH)11 alpha-hydroxy-hydroperoxy

Or 11 alpha-hydroxydicarbonyl compounds of the formula (V)

Wherein R is₃、R₄、R₅And R₆Are as defined for cis-and trans-enediones (III-cis) and (III-trans), where R is_7-2、R₁₇And R_bIs as defined above;

with an N-fluoroalkylamine reagent of formula (CVI);

(2) contacting the reaction mixture of step (1) with an oxidative cleavage agent.

Detailed description of the invention

Eplerenone is 9 α, 11 α -epoxy-17 β -hydroxypregn-4-en-3-one-7 α, 21-dicarboxylic acid, γ -lactone, methyl ester, and thus contains a 7 α -carbomethoxy substituent. It can be used as a medicinal ingredient for treating hypertension and congestive heart failure. The main difficulty in eplerenone production is the introduction of the 7 α -carbomethoxy substituent. The process and intermediates of the present invention are improved processes for the preparation of eplerenone.

Panel A discloses the general process of the invention when the 7 alpha-position adduct-R_7-1Is (-A1). The method of the invention starts with a delta, either protected or unprotected^4，6-3-keto steroid (I). Since the steroid A-ring may or may not be protected, Panel B discloses^4，6Improved protection of starting materials of (I) 3-keto steroids protected as C-3 protected DELTA^4，6-3-ketal steroid (I-P). Panel C discloses 7 alpha-substituted steroids (II) alternative route to eplerenone (IX) (ozonolysis). Panel D discloses a general procedure when the steroid A-ring is unprotected, R_7-1Is the substituent variable (-A1). Panel E discloses^4，6-a preferred process for the conversion of a 3-keto steroid or a ketal (I) thereof to eplerenone (IX). Panel F discloses the reversibility of the conversion of carboxylic acid (VI) with 5, 7-lactone (VII). FIG. G discloses the general method of the invention, when-R_7-1Is (-A2). FIG. H discloses the general process of the invention, when-R_7-1Is (-B), (-C), (-D1), (-D2) or (-D3).

The first step in the process of scheme A is the preparation of 7 α -substituted steroids of formula (II)

Wherein

(II)R₃is R_3-3:R_3-4，R₄Is R_4-3:R_4-4Wherein R is_3-3And R_3-4One of them is-O-R₃₁Wherein R is₃₁Is C₁-C₃Alkyl radical, R_3-3And R_3-4The other of which is connected with R_4-3And R_4-4One together forming a second bond between the carbon atoms to which they are attached, R_4-3And R_4-4The other of which is-H; r₆Is R_6-3:R_6-4Wherein R is_6-3And R_6-4One and R₅Together forming a second bond between the carbon atoms to which they are attached, R_6-3And R_6-4The other of which is-H;

C₁-C₃alkyl, and

-(CH₂)-(CR₃₃R₃₄)_n1-(CH₂)-

Wherein n is₁Is 0 or 1;

wherein R is_7-1Is a molecular fragment of the formula (-A1)

Or a molecular fragment of formula (-A2)

Wherein X₁Is that

-S-，

-O-or

-NX_1-1-, wherein X_1-1Is that

-H，

C₁-C₄An alkyl group, a carboxyl group,

-CO-OX_1-2wherein X is_1-2Is C₁-C₄Alkyl or-CH₂-φ，

-SO₂-(C₁-C₃an alkyl group),

-SO₂phi, where phi is optionally 1 or 2

C₁-C₄An alkyl group, a carboxyl group,

C₁-C₄alkoxy substitution;

wherein R is_bSelected from the group consisting of:

-H，

C₁-C₄alkyl, or

Phenyl, optionally substituted by 1 or 2

C₁-C₄An alkyl group, a carboxyl group,

C₁-C₄alkoxy substitution;

wherein R is_cSelected from the group consisting of:

-H，

C₁-C₄an alkyl group, a carboxyl group,

C₁-C₄an alkoxy group,

-F、-Cl、-Br、-I，

-CO-OCH₃and are and

-CO-R_c-1wherein R is_c-1Is C₁-C₄Alkyl or-phi;

wherein R is_dSelected from the group consisting of:

-H，

-C≡N，

C₁-C₁₀an alkyl group, a carboxyl group,

C₁-C₄an alkoxy group,

-CH₂-OR_d-1wherein R is_d-1is-H or C₁-C₄An alkyl group, a carboxyl group,

-CH₂-N(R_d-6)₂wherein two R are_d-6Are the same or different and are:

C₁-C₄an alkyl group, a carboxyl group,

-φ，

-CH₂-CH₂-，

-CH₂-CH₂-CH₂-，

-CH₂-C(CH₃-)₂-CH₂-，

-Si(R)₃wherein R is as defined above,

-O-Si(R)₃wherein R is as defined above,

wherein R is_cAnd R_dTogether with the atoms to which they are attached

Wherein E₁Are the same or different and are:

-H，

C₁-C₄an alkyl group, a carboxyl group,

-F、-Cl、-Br、-I，

-OE_1-1in which E_1-1The method comprises the following steps:

-H，

C₁-C₄an alkyl group, a carboxyl group,

phi, or

-Si(R)₃wherein R is as defined above;

-CE₁＝M (-B)

wherein E₁Is as defined above in that the first and second parts are,

wherein M is:

(1)＝O，

(2)＝N-E₂in which E₂Selected from the group consisting of:

-H，

C₁-C₄an alkyl group, a carboxyl group,

c containing 1 triple bond₁-C₄An alkynyl group,

-CO-OE_2-1in which E_2-1is-H or C₁-C₄An alkyl group, a carboxyl group,

wherein E_2-2Is that

C₁-C₄An alkyl group, a carboxyl group,

phi, or

Si(R)₃Wherein the three R are the same or different and are as defined above,

-Si(R)₃wherein three R are as defined above;

(3)＝C(E₂)₂in which E₂Are identical or different, are as defined above,

-O-，

-S-，

-N＝，

-NX_1-1-, wherein X_1-1Is as defined aboveIn the meaning of (1) or (b),

-CE₂wherein E₂Is as defined above in that the first and second parts are,

-C≡C-E₂(-C)

wherein E₂Is as defined above;

-CH₂-CH＝CH₂ (-D1)

-CH＝C＝CH₂ (-D2)

-CH₂-C≡C-H (-D3)

wherein R is₉The method comprises the following steps:

(1)-H，

(2)-OH，

-Si(-CH₃)₃，

-Si(-CH₂-CH₃)₃，

-CO-CH₃，

-CO-H, and

-SiH(CH₃)₂，

(4)-F；

wherein R is₁₁The method comprises the following steps:

(1)＝O，

(2)-H:-H，

(a)-H，

(b)-O-R_11-3wherein R is_11-3The method comprises the following steps:

(i)-H，

(a)-H，

(b)-O-R_11-4wherein R is_11-4The method comprises the following steps:

(i)-H，

wherein R is₁₇The method comprises the following steps:

(1)＝O；

(a)-H，

(b)-C≡C-H，

(c)-C≡N，

(i)-H，

(iii) 1-ethoxy ethyl group, and a pharmaceutically acceptable salt thereof,

(iv) 2-a-tetrahydropyranyl group, a 2-tetrahydropyranyl group,

(f)-CH₂-CH₂-CH₂-OH，

(h)-CH₂-CH₂-CO-O^-wherein R is_17-2is-OH;

(a)-CO-CH₃，

(b)-CO-CH₂-OH，

(c)-CO-CH₂-O-CO-(CH₂)_0-3-CH₃；

(7)α-R_17-11:β-R_17-12wherein R is_17-10Is- (CH)₂)_1-2-CH＝CH₂，R_17-12is-OH; this includes:

(1) let formula (I) Δ^4，6-3-ketosteroids or ketals thereof

Wherein

C₁-C₃alkyl, and

-(CH₂)-(CR₃₃R₃₄)_n1-(CH₂)-

Wherein n is₁Is 0 or 1;

wherein R is₃₃And R₃₄Are identical or different and are-H and C₁-C₃An alkyl group; r₄Is R_4-9:R_4-10Wherein R is_4-9And R_4-10One and R₅Together forming a second bond between the carbon atoms to which they are attached, R_4-9And R_4-10The other of which is-H;

with an adduct selected from the group consisting of:

(a) formula (A)

Or

(b) formula (A')

R_b-CO-CHR_b-CHR_c-CO-R_d (A’)

Wherein R is_b，R_cAnd R_dIs as defined above;

(c) formula (A')

Wherein R is_eThe method comprises the following steps:

C₁-C₄an alkyl group, a carboxyl group,

-CO-(C₁-C₄alkyl or-phi),

(d) formula (B)

R_a-CE₁＝M (B)

Wherein R is_a、E₁And M is as defined above;

(e) formula (C)

R_a-C≡C-E₂(C)

Wherein R is_aAnd E₂Is as defined above;

(f) formula (D1, D2 and D3)

R_a-CH₂-CH＝CH₂ (D1)

R_a-CH＝C＝CH₂(D2)

R_a-CH₂-C≡C-H (D3)

Wherein R is_aIs as defined above in that the first and second parts are,

the contacting is in the presence of the following reagents:

(1) a Lewis acid, a basic metal oxide or a metal oxide,

(2)pK_aless than about 5, or

(3) A secondary amine of the formula

Wherein

R_S-2is-H, C₁-C₄Alkyl, -phi and-CH₂-φ；

R_S-3is-H, C₁-C₄An alkyl group;

R_S-4is-H, C₁-C₄Alkyl, - φ;

R_S-5is-H, C₁-C₄Alkyl, - φ;

and a secondary amine of the formula

Wherein

R_S-2is-H, C₁-C₄Alkyl, -phi and-CH₂-φ；

R_S-4is-H, C₁-C₄Alkyl, - φ;

R_S-5is-H, C₁-C₄Alkyl, - φ;

and pK_aSalts of acids of < about 2.

Is a⁴Starting from the 3-keto group or ketal (I) thereof, preferably R₃、R₄And R₅Is (I) R₃Is ═ O; r₄Is R_4-1:R_4-2Wherein R is_4-1And R_4-2One of them is-H, R_4-1And R_4-2The other of which is connected with R₅Together form a second bond between the carbon atoms to which they are attached; r₆is-H.

For the 7 α -substituted steroid (II), there are four groups of steroid A-/B-rings as identified above. Groups (I), (III) and (IV) are implementable in the process of the invention. Not in group (II), wherein R₃Is R_3-3:R_3-4，R₄Is R_4-3:R_4-4Wherein R is_3-3And R_3-4One of them is-O-R₃₁Wherein R is₃₁Is C₁-C₃Alkyl radical, R_3-3And R_3-4The other of which is connected with R_4-3And R_4-4One together forming a second bond between the carbon atoms to which they are attached, R_4-3And R_4-4The other of which is-H; r₆Is R_6-3:R_6-4Wherein R is_6-3And R_6-4One and R₅Together forming a second bond between the carbon atoms to which they are attached, R_6-3And R_6-4The other of which is-H; is Δ^3，5-3, 3-dialkoxy ring systems and therefore cannot be converted into other intermediates of the invention. It is useful because it can be converted to the corresponding Δ⁴-3-keto steroid a-/B-ring systems, which can be used in the process of the present invention.

With respect to the 7 α -substituted steroid (II) and other steroids of the present invention, in addition to the 5, 7-dilactone (VII), with respect to the steroid A-/B-ring, preferably, R₃、R₄、R₅And R₆Selected from the group consisting of:

(I)R₃is ═ O;R₄is R_4-1:R_4-2Wherein R is_4-1And R_4-2One of them is-H, R_4-1And R_4-2The other of which is connected with R₅Together form a second bond between the carbon atoms to which they are attached; r₆is-H;

(III)R₃is alpha-R_3-5:β-R_3-6Wherein R is_3-5is-O-R₃₁，R_3-6is-O-R₃₂Wherein R is₃₁And R₃₂Together with the attached-O-C-O-form- (CH)₂)-(CR₃₃R₃₄)_n1-(CH₂) A 5-atom cyclic ketal of (A) wherein n₁Is 0; r₄is-H; r₆Is R_6-5:R_6-6Wherein R is_6-5And R_6-6One and R₅Together forming a second bond between the carbon atoms to which they are attached, R_6-5And R_6-6The other of which is-H;

(III)R₃is alpha-R_3-5:β-R_3-6Wherein R is_3-5is-O-R₃₁，R_3-6is-O-R₃₂Wherein R is₃₁And R₃₂Together with the attached-O-C-O-form- (CH)₂)-(CR₃₃R₃₄)_n1-(CH₂) A 6-atom cyclic ketal of (A) wherein n₁Is 1, R₃₃And R₃₄Are all C₁An alkyl group; r₄is-H; r₆Is R_6-5:R_6-6Wherein R is_6-5And R_6-6One and R₅Together forming a second bond between the carbon atoms to which they are attached, R_6-5And R_6-6The other of which is-H.

With respect to the 7 α -substituted steroid (II) and other steroids of the present invention, in addition to the 5, 7-dilactone (VII), more preferably, R is selected with respect to the steroid A-/B-ring₃、R₄、R₅And R₆The method comprises the following steps:

(I)R₃is ═ O; r₄Is R_4-1:R_4-2Wherein R is_4-1And R_4-2One of them is-H, R_4-1And R_4-2The other of which is connected with R₅Together form a second bond between the carbon atoms to which they are attached; r₆is-H.

With respect to the steroidal C-ring, preferably, R₉And R₁₁The method comprises the following steps:

(a)R₁₁is R_11-5:R_11-6Wherein R is_11-5Or R_11-6One and R₉Together form a second bond between C-9 and C-11, R_11-5Or R_11-6The other of which is-H, (b) alpha-R_11-7:β-R_11-8Wherein R is_11-7And R₉Together with-O-to form an epoxide between C-9 and C-11, R_11-8Is a group of formula (I) having the formula-H,

(c)R₉is-H, R₁₁Is alpha-R_11-1:β-R_11-2Wherein R is_11-1is-O-R_11-3Wherein R is_11-3is-H, wherein R_11-2is-H.

More preferably, R₉And R₁₁The method comprises the following steps:

(a)R₁₁is R_11-5:R_11-6Wherein R is_11-5Or R_11-6One and R₉Together form a second bond between C-9 and C-11, R_11-5Or R_11-6The other of which is-H.

With respect to the steroidal D-ring, preferably, R₁₇Selected from the group consisting of:

(a)α-R_17-7:β-R_17-8wherein R is_17-7And R_17-8Together with the carbon atom to which they are attached form a radical containing-O-CO-CH₂-CH₂Pentalactone of (a), wherein CH₂The point of attachment of-is at R_17-7In the alpha-orientation, the point of attachment of the-O is at R_17-8In the beta-orientation;

(b)＝O；

(c)α-R_17-1:β-R_17-2wherein R is_17-1is-C ≡ C-H, wherein R is_17-2Is a group of-OH,

(d)-C≡C-CH₂-O-R_17-1-1。

with respect to the 7 α -substituted steroid (II), preferably, R_7-1Is a substituent of formula (-A1). Also preferably, X₁is-O-. Preferably, R_bAnd R_cis-H, preferably, R_dIs C₁An alkyl group. Preferably, R_ais-H. Then R_aPreferably, wherein L is:

-ZnL：-Cl、-Br、-I；

-BL: a catecholate compound of a compound selected from the group consisting of catechins,

two of the-OH groups are in a group,

HO-CH₂-CH₂-OH，

HO-CH₂-CH₂-CH₂-OH，

HO-CH₂-C(CH₃)₂-CH₂-OH；

-SiL₃：C₁an alkyl group;

-SnL₃：C₁or n-C₄An alkyl group;

-CuL: 2-thienyl or-CN;

-AlL₂：C₁-C₂an alkyl group.

When R is_aWhen Cu, one Cu may have two R_aThe radical, in this case Cu, is anionic.

Substituent variable R₃、R₄、R₅、R₆、R_7-1、R₉、R₁₁、R₁₇、R_a、R_b、R_c、R_dAnd X₁Is preferably not only a^4，6-3-keto steroid or the likeKetal (I) and/or 7 α -substituted steroid (II), but for all compounds (I) to (XV) of the invention, except where explicitly mentioned. Similarly, other substituent variables, such as R discussed below_7-2And/or chemical agents used in this patent, such as oxygen donors, halogenating agents, isomerization catalysts, hydroperoxy-scavengers, acid generators, acylation catalysts, oxidative cracking agents, deoxygenation agents, all of which are defined in this patent as in the first discussion. Since many of these substituent variables and chemical reagents are referred to multiple times, it would be redundant to refer to what is included, preferably and more preferably, each iteration.

Preferably, the acid reactant is a lewis acid. The electrophilicity of the Lewis acid must be sufficient to react with the Delta^4，6-3-keto steroid or ketal (I) complex, but not with nucleophile (A1), (A2), (B), (C), (D1), (D2) or (D3), as known to the person skilled in the art. Further, preferably, the Lewis acid is used in the presence of an alcohol selected from the group consisting of C₁-C₃Alcohols, ethylene glycol, 1, 2-or 1, 3-propanediol, 2-dimethyl-or 2, 2-diethyl-1, 3-propanediol and phenol. More preferably, the alcohol is C₁-C₃An alcohol or a mixture thereof. Useful lewis acids include those selected from the group consisting of:

BX₃、AlX₃、SnX₂、SnX₄、SiX₄、MgX₂、ZnX₂、TiX₄，

Rh(acac)(CH₂CH₂)₂(2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl),

Rh(CH₃-C≡N)₂(cyclooctadiene) (BF)₄)，

Rh(acac)(CH₂CH₂)₂(dppb)，

LiClO₄，

The K10 montmorillonite clay is used as a base,

Yb(OTf)₃，

LiCo(B₉C₂H₁₁)₂，

PdX₂，

CrX₃，

FeX₃，

CoX₃，

NiX₂，

SbX₅，

InX₃，

Sc(OTf)₃，

φ₃C⁺X^-，

(R)₃SiX, wherein R is C₁-C₄Alkyl and phi; wherein X is selected from the group consisting of: f^-、Cl^-、Br^-、I^-、-O-SO₂CF₃ ^-、PF₆ ^-、BF₄ ^-And ClO₄ ^-；

Pd(CH₃-CO-O^-)₂；

BF₃-a diethyl etherate complex;

BF₃-an acetic acid complex;

BF₃-methyl-tert-butyl ether complex;

BF₃-a di-n-butyl etherate complex;

BF₃-dimethyl ether complex;

BF₃-a dimethyl sulphur complex;

BF₃-a phenol complex;

BF₃-a phosphoric acid complex; and

BF₃-tetrahydrofuran complex.

Preferably, the Lewis acid is selected from BF₃、BF₃-diethyl etherate complex, BF₃-acetic acid complex, BF₃-methyl-tert-butyl ether complex, BF₃-di-n-butyl etherate complex, BF₃-dimethyl Ether Complex, BF₃-dimethyl sulfide complex, BF₃-phenol complex, BF₃-phosphoric acid complex and BF₃-tetrahydrofuran complexes. More preferably, the Lewis acid is BF₃-diethyl etherate. Even more preferably, at C₁-C₃Using BF in the presence of an alcohol₃-diethyl etherate, even more preferably, at C₂Using BF in the presence of an alcohol₃-diethyl etherate. Useful pK_aThe acid < about 5 is selected from the group consisting of formic acid, acetic acid, propionic acid, benzoic acid, acids, hydrofluoric acid, fluoroboric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonic acid, perchloric acid, trifluoroacetic acid and trichloroacetic acid. Preferably, pK_aThe acid < about 5 is acetic acid. At a time of proceeding^4，6Conversion of the 3-keto steroid or ketal (I) thereof to the corresponding 7 α -substituted steroid (II), at least one equivalent of the reagent of formula (A), (B) or (C) should be used, preferably one to two equivalents. The use of additional reagents is not an issue, but is wasteful of the compound. The reaction may be carried out in a variety of solvents, for example a solvent/solvent mixture selected from the group consisting of:

C₁-C₆the alcohol is added into the mixture of the alcohol,

C₁-C₆a solvent mixture of an alcohol and a solvent selected from the group consisting of acetonitrile, nitromethane, toluene, dichloromethane and acetic acid. One factor to be considered in the choice of lewis acid and solvent is the acid sensitivity of the 7 α -substituted steroid (II). The reaction must be carried out with a lewis acid and in a solvent, where the product is stable,as known to those skilled in the art. Preferably, the solvent is a protic solvent, pK_aLess than about 19. The reaction may be carried out at a temperature in the range of about-78 ° to about 60 °; preferably in the temperature range of about-40 deg. to about-15 deg.. More preferably at about-20 deg.. The reaction will typically take several hours to one day, depending on the number of equivalents used and the reaction temperature.

Useful 7 α -substituted steroids (II) include those selected from the group consisting of:

17 beta-hydroxy-7 alpha- (5 '-methyl-2' -furyl) -pregna-4, 9-dien-3-one-21-carboxylic acid, gamma-lactone,

11 alpha, 17 beta-dihydroxy-7 alpha- (5 '-methyl-2' -furyl) -pregn-4-en-3-one-21-carboxylic acid, gamma-lactone,

9 α, 11 α -epoxy-17 β -hydroxy-7 α - (5 '-methyl-2' -furyl) -pregn-4-en-3-one-21-carboxylic acid, γ -lactone,

17 beta-hydroxy-7 alpha- (5 '-tert-butyl-2' -furyl) -pregna-4, 9(11) -dien-3-one-21-carboxylic acid, gamma-lactone,

11 α, 17 β -dihydroxy-7 α - (5 '-tert-butyl-2' -furyl) -pregn-4-en-3-one-21-carboxylic acid, γ -lactone,

11 α, 17 β -dihydroxy-7 α - (4 '-bromo-2' -furyl) -pregn-4-en-3-one-21-carboxylic acid, γ -lactone,

11 α, 17 β -dihydroxy-7 α - (4 '-methyl-2' -furyl) -pregn-4-en-3-one-21-carboxylic acid, γ -lactone, and

7 alpha-allyl-17 beta-hydroxypregna-4, 9(11) -dien-3-one, 21-carboxylic acid, gamma-lactone.

Instead of bringing the 7 α -substituted steroid (II) to the next step in situ, the 7 α -substituted steroid (II) is preferably isolated and purified before proceeding to the next step. A preferred purification method for the 7 α -substituted steroid (II) is crystallization. The process for purifying the 7 α -substituted steroid of formula (II) comprises crystallizing the 7 α -substituted steroid (II) containing greater than 5% of the 7 β -isomer from a solvent selected from the group consisting of ethyl acetate, n-propyl acetate and butyl acetate. Preferably the 7 α -substituted steroid (II) is obtained in an isomeric purity of more than 99.8%, preferably the crystallization solvent is n-propyl acetate. A crystallization co-solvent may be used.

The next step in the process of scheme a is the conversion of the 7 α -substituted steroid (II) to the corresponding cis-enedione (III-cis) by an oxidation process comprising (1) contacting the 7 α -substituted steroid of formula (II) with a reagent selected from the group consisting of:

(b) an oxygen-supplying agent, which is a mixture of oxygen-supplying agent,

(c) the oxidation is carried out in an electrochemical way,

(d) quinone in the presence of water, or

(e) A non-quinone oxidizing agent. Preferably, the reagent is a halogenating agent. Useful halogenating agents include those selected from the group consisting of dibromodimethylhydantoin, dichlorodimethylhydantoin, diiododimethylhydantoin, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, trichloroisocyanuric acid, t-butyl hypochlorite, and 3-bromo-1-chloro-5, 5-dimethylhydantoin; preferably, the halogenating agent is dibromodimethylhydantoin. When a halogenating agent is used, it should be used in an amount of at least one equivalent of halogenating agent; preferably, about 1.0 to about 1.05 equivalents of halogenating agent are used. More preferably, the amount of halogenating agent is about 1.01 equivalents. The reason is that one equivalent is required to complete the reaction, but any excess needs to be quenched. Suitable quenchers include bisulphite, isobutyl vinyl ether, 2-methylfuran and hypophosphorous acid. Useful oxygen donors include those selected from the group consisting of:

the acid is a peracid,

singlet oxygen, followed by phosphite or thiourea,

tri-state oxygen is introduced into the reactor,

hydrogen peroxide and a ketone selected from the group consisting of Q₄-CO-Q₅Group of (I), wherein Q₄And Q₅Are the same or different and are:

C₁-C₄alkyl, optionally substituted with 1 to 9-Cl or-F,

Q₄and Q₅Together with the carbon atom to which they are attached form a 5 to 7 membered cyclic ketone and a ketone of the formula:

and

a combination of hydrogen peroxide and methyltrioxorhenium,

the trichloroacetonitrile/hydrogen peroxide is mixed with the solvent,

the trichloroacetamide/hydrogen peroxide is mixed with trichloroacetamide,

the ratio of DDQ to water is,

p-chloranil/water is added to the mixture,

φ-C(CH₃)₂-O-OH or an alkyl hydroperoxide with a metal-containing activator, wherein the alkyl group is C₄-C₁₀Alkyl, metal-containing activator selected from the group consisting of Ti (isopropoxide)₄Peroxytungstophosphoric acid, VO (acetylacetonate)₂And MO hexacarbonyl. Preferably, the oxygen donor is a peracid. Useful peracids include those selected from the group consisting of:

(a) perbenzoic acid, optionally substituted with 1 or 2-Cl or-NO₂The substitution is carried out by the following steps,

(b) formula C_n2(Q₆)2_n2+1-CO₃H percarboxylic acid, wherein n₂Is 1 to 4, Q₆is-H, -Cl or-F,

(c) perphthalic acid, and

(d) magnesium peroxyphthalate. Excess oxygen donor present must also be quenched, as with the halogenating agent. A base is required to neutralize the acid formed during the conversion of the 7 α -substituted steroid (II) to the cis-enedione (III-cis). Useful bases include those selected from the group consisting of acetates, bicarbonates, carbonates, propionates, benzoates, dibasic phosphates and borates; more preferably, the base is an acetate salt. For example, when the halogenating agent is dibromodimethylhydantoin, hydrobromic acid is generated. Thus, one equivalent of base per equivalent of acid produced is required. In practice, a slight excess, about 1.5 equivalents, is used. Suitable solvents for this reaction are those which are water-miscible, dissolving both the 7 α -substituted steroid (II) and the halogenating agent or oxygen donor. Acetone and THF are preferred solvents. The reaction is carried out at room temperature, about 20 to about 25 °. The reaction takes several hours, depending on the reactivity of the oxygen donor or halogenating agent. After formation, the cis-enedione (III-cis) does not have to be isolated and purified, but can be used "as is" or in situ for subsequent transformations. Preferably, the cis-enedione (III-cis) is 17 β -hydroxy-7 α - (cis-1 ', 4' -dioxopent-2 '-en-1' -yl) pregna-4, 9(11) -dien-3-one-21-carboxylic acid, γ -lactone. Other oxidizing agents that may be used for the conversion of the 7 α -substituted steroid (II) to the cis-enedione (III-cis) include quinones (listed elsewhere). The 7 α -substituted steroid (II) is contacted with a stoichiometric amount of quinone and at least a stoichiometric amount of water in a water miscible organic solvent. The contacting is preferably carried out at about room temperature. In addition, oxidation can also be accomplished electrochemically. The electrochemical oxidation is accomplished by contacting the 7 α -substituted steroid (II) with a substoichiometric amount of quinone (preferably DDQ) and at least a stoichiometric amount of water in an electrochemical cell using standard electrochemical techniques, such as described in US4,270,994. Finally, oxidation can be accomplished using non-quinone reagents, including manganese acetate, potassium permanganate, cerium ammonium nitrate, iodosobenzene, iodobenzene diacetate, iodobenzene bistrifluoroacetate, chromic acid ("Jones reagent"), and lead tetraacetate. These reactions are typically carried out in aqueous acetone solvents at about room temperature (20-25 deg.), although many water-miscible organic co-solvents may be used in place of acetone. Other oxidizing agents for carrying out this conversion include hydrogen peroxide or organic hydroperoxides (listed elsewhere) in combination with a metal catalyst, such as methyltrioxorhenium, palladium acetate, ruthenium trichloride, or ruthenium tetroxide. These reactions can be carried out in any solvent in which the 7 α -substituted steroid (II) is soluble, such as dichloromethane, acetone, and the like. The reaction involving the ruthenium catalyst is preferably carried out in aqueous acetonitrile.

In the process of scheme a, cis-enedione (III-cis) may be converted into the corresponding trans-enedione (III-trans), or may be converted into a peroxy compound (IV-OOH), a hydroxy compound (IV-OH), a dicarbonyl compound (V) or a carboxylic acid (VI), or a mixture thereof. When the term carboxylic acid (VI) is used, it means and includes pharmaceutically acceptable salts thereof. These salts will include sodium, potassium, lithium, magnesium, tetrabutylammonium and salts of carboxylic acids with DBU, tetramethylguanidine, triethylamine and the like. The identity of the particular cation is not important since it is eventually lost in the formation of the acid which is ultimately converted to the methyl ester (VIII) and eplerenone (IX), which requires the methyl ester at the 7 α -position. It is preferred to convert cis-enedione (III-cis) to the corresponding trans-enedione (III-trans) rather than to convert cis-enedione (III-cis) to a mixture of peroxy (IV-OOH), hydroxy (IV-OH) and bis-poor carbonyl (V) compounds.

Contacting cis-enedione (III-cis) with an isomerization catalyst, which may be a chemical reagent, during the conversion of cis-enedione (III-cis) to the corresponding trans-enedione (III-trans), comprising:

(a)pK_aa strong acid of < about 2;

(d)I₂，

(e)(C₁-C₄)₃P，

(f)φ₃P，

or a physical agent, e.g.

(g) Heat to about 80 deg..

Preferably, the isomerization catalyst is pK_aA strong acid of < about 2. When the isomerization catalyst is pK_aUseful pK for strong acids of < about 2_aStrong acids < about 2 include those selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, trichloroacetic acid and trifluoroacetic acid, preferably, pK_aThe strong acid < about 2 is hydrochloric acid. When the isomerization catalyst is pK_a< about 2 of the strong acids, preferably, its anhydrous form is used, or if an aqueous mixture is used, the reaction is carried out in a two-phase system and the aqueous phase is separated. When the isomerization catalyst is a tertiary amine and the pK of its conjugate acid_a> about 8, pK of a useful tertiary amine and its conjugate acid_a> about 8 includes these, selected from the group consisting of₃)₃N (wherein Q)₃Is C₁-C₃Alkyl), DBU, DBN, DABCO, pyridine, p-dimethylaminopyridine and pyrrolidinyl-pyridine. When the isomerization catalyst is a salt of a tertiary amine and the pK of the conjugate acid of the amine_a> about 8, preferably the pK of the salt of the tertiary amine and the conjugate acid of the amine_a> about 8 is pyridine hydrochloride. Regardless of which chemical agent is used, only catalytic amounts are required. For example, after the formation of cis-enedione (III-cis), the addition of commercial chloroform with only common hydrochloric acid impurities is sufficient to effect conversion to the corresponding trans-enedione (III-trans), see example 4, section 2. Isomerization of cis-enedione (III-cis) to the corresponding trans-enedione (III-trans) can be carried out at 20-25 ° (room temperature).The reaction usually takes several hours at room temperature. It is necessary to monitor the progress of the reaction by standard methods, such as LC or TLC, to ensure that it does not proceed too long. If the reaction is carried out too long, the reaction is regenerated with a⁶-a double-bonded 7 α -substituted steroid (II). Once the reaction has proceeded to completion, it is desirable to terminate the reaction, which can be done as follows. When the isomerization catalyst is a salt of an acid or a tertiary amine and the pK of the conjugate acid of the amine_aWhen > about 8, the reaction can be stopped by washing with water. If an aqueous acid is used as the isomerization catalyst, it is advantageous to separate the phases and then wash the non-aqueous phase with water. If the isomerization catalyst is a tertiary amine and the pK of its conjugate acid_a(> about 8), the reaction mixture is washed with aqueous acid followed by water. The trans-enedione (III-trans) can be isolated and purified, but preferably it is not isolated and purified, but the reaction is continued in situ.

In the process of scheme A, the next step is the conversion of cis-enedione (III-cis) or trans-enedione (III-trans) or mixtures thereof to the corresponding hydroperoxy hydroxy (IV-OOH) compound, hydroxy (IV-OH) compound, dicarbonyl (V) compound and/or carboxylic acid (VI) or mixtures thereof. Cis-enedione (III-cis) or trans-enedione (III-trans) or mixtures thereof are converted into the corresponding hydroxy compounds, peroxy compounds (IV-OOH), dicarbonyl compounds (V) or carboxylic acids (VI) by reacting cis-enedione (III-cis) or trans-enedione (III-trans) or mixtures thereof with ozone in the formula R_7-2In the presence of-OH, wherein R_7-2is-H or C₁-C₄Alkyl, optionally substituted with one or two-OH. This includes water, methanol, ethanol, propanol, isopropanol, ethylene glycol, glycerol, and the like. Preferably, R_7-2is-H, C₁Or is iso-C₃(ii) a More preferably, R_7-2is-H, C₁And iso-C₃A mixture of (a). This means that a mixture of water, methanol and isopropanol is the preferred R_7-2-OH. The steroid starting materials must be in solution and the solvent used will dissolve them at low temperatures, which is preferred for carrying out the reaction. Methylene chloride is the preferred solvent. The reaction temperature can be as low as about-100 deg., up to about 40 deg.. Preferably, the temperature is from about-78 ° to about-20 °; more preferably, the temperature is about-50 deg.. The lower the temperature, the greater the selectivity; the higher the temperature, the lower the selectivity. Thus, the actual temperature used will depend on the particular reactants used and the degree of selectivity desired. The reaction was allowed to proceed until the starting material was reduced to a small amount. The action of ozone must be terminated when the feedstock is consumed, otherwise the ozone will react with delta⁴-and/or Δ⁹⁽¹¹⁾Double bonds (if present) react to destroy the product. Alcohol R_7-2The amount of-OH is in large excess to effectively trap the carbonyl oxide intermediates formed. Further, the reaction temperature, the time allowed for the reaction and the specific alcohol R_7-2The nature of the-OH groups determines the nature of the product or, if more than one product is formed, the proportion of the product. If the alcohol R is_7-2-OH has a hindered R_7-2Group, then the product is most likely the bis-carbonyl compound (V), all other things being equal. Similarly, if the alcohol R is_7-2-OH has no hindered R_7-2A group such as methyl, the product is most likely a hydroxy compound (IV-OH), all other things being equal. The preferred product produced by the oxidation process is carboxylic acid (VI).

The hydroperoxy compound (IV-OOH) may be converted into the corresponding hydroxyl compound (IV-OH) by contacting the hydroperoxy compound (IV-OOH) with a hydroperoxy-deoxidating agent. Preferably, mild peroxy-hydroxy-deoxidizers are used, which firstly deoxidize and secondly do not add to the steroid molecule. Useful peroxy hydroxy-deoxidizers include those selected from the group consisting of: q₁Q₂S, wherein Q₁And Q₂Are identical or different and are C₁-C₄An alkyl group or a phenyl group, or a substituted or unsubstituted alkyl group,

a bisulfite (bisufite),

the amount of the sulfite is set to be,

a thiosulfate salt, which is a salt of a thiosulfate,

the tetrahydrothiophene is used as a solvent for the reaction,

bisulfite (hydrosulfite),

the thiourea is used for the reaction of thiourea,

a butyl vinyl ether (a) and a butyl vinyl ether (b),

(C₁-C₄alkyl radical)₃A phosphine, which is a compound of a phosphine,

triphenylphosphine, and

tetramethyl ethylene. Preferably, the peroxy hydroxyl-deoxidizer is dimethyl sulfide. Sodium and potassium are preferred cations when the peroxy-hydroxy-deoxidizer is a bisulfite or sulfite. One equivalent of the peroxy hydroxy-deoxidizer is required, but more than one equivalent, for example about two equivalents, is generally used to ensure that all of the peroxy hydroxy compound (IV-OOH) is reduced. The reaction is carried out at 20-25 deg.C and is generally complete in about 1 hour. The hydroxy compound (IV-OH) may be isolated and purified if desired, but the reaction is preferably continued in situ without isolation or purification. Preferably, the hydroxy compound (IV) is 17 β -hydroxy-7 α - (1 ' -oxo-2 ' -isopropoxy-2 ' -hydroxy-ethyl) pregna-4, 9(11) -dien-3-one-21-carboxylic acid, γ -lactone.

The hydroperoxy compound (IV-OOH) may be converted to the corresponding carboxylic acid (VI) by contacting the hydroperoxy compound (IV-OOH) with a carboxylic acid generator selected from the group consisting of:

(a) heating the mixture to be heated, wherein the mixture is heated,

(c) an acid, its pK_aLess than about 3 of the total weight of the composition,

(d) an acylating agent. When the carboxylic acid generator is (a) heated, the reaction mixture should be heated to a range of about 30 ° to about 120 °; preferably from about 80 ° to about 90 °. When the carboxylic acid generator is (b) a base and the pK of its conjugate acid_aWhen about 5 or more, useful bases include inorganic bases selected from the group consisting of hydroxides, bicarbonates, and carbonates, and organic bases selected from the group consisting of (Q)₃)₃N (wherein Q)₃Is C₁-C₃Alkyl), DBU, and,DBN, DABCO, pyridine and p-dimethylaminopyridine. Preferably, the base is bicarbonate. Sufficient base is necessary to neutralize the steroid acid and any additional acid by-products formed. When the carboxylic acid generator is (c) an acid and its pK_aLess than about 3, useful acids include those selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and acids of formula R_acid-1-COOH organic acids, wherein R_acid-1is-H and C₁-C₃Alkyl, optionally substituted with 1 to 3-Cl and-F; formic acid and trifluoroacetic acid are preferred. Although catalytic amounts of acid are sufficient, several equivalents are preferred. When the carboxylic acid generator is (d) an acylating agent, useful acylating agents are selected from the group consisting of_acid-2-CO-O-CO-R_acid-2Group of (I) wherein R_acid-2Is a group of formula (I) having the formula-H,

C₁-C₃alkyl, optionally substituted with 1 to 3-Cl and-F, and

-phi. Preferably, the acylating agent is acetic anhydride or trifluoroacetic anhydride. One equivalent of acylating agent is required. When an acylating agent is used, it and an acylation catalyst are preferably used. Preferred acylation catalysts are pyridine and p-Dimethylaminopyridine (DMAP). With respect to the solvent, it is important to carry out the process under homogeneous reaction conditions to avoid decomposition of the peroxy hydroxyl compound (IV-OOH). This means that one phase conditions are used. Therefore, the choice of solvent will depend on the carboxylic acid generator used. If the carboxylic acid generator requires water to dissolve the reactants, for example when the carboxylic acid generator is a bicarbonate, a water miscible organic solvent, such as acetone, methanol, DMF or isopropanol, is required. If the carboxylic acid generator is pyridine, the organic solvent may be a water-immiscible organic solvent, such as acetonitrile, dichloromethane or ethyl acetate. Thus, the choice of solvent depends on the nature of the carboxylic acid generator used, as is known to those skilled in the art. In addition to heating of the carboxylic acid generator (a), other acid generators (b), (c) and (d) may be reacted at 20 to 25 ℃. The reaction is quite rapid, typically less than an hour.

Both the hydroxy compound (IV-OH) and the dicarbonyl compound (V) are converted into the corresponding carboxylic acid (VI) in the same manner. The process involves contacting the hydroxy compound (IV-OH) or the dicarbonyl compound (V) or mixtures thereof with an oxidative cleavage agent. Useful oxidative breakers are selected from the group consisting of:

(1) hydrogen peroxide with a carboxylic acid generator selected from the group consisting of:

(a) heating the mixture to be heated, wherein the mixture is heated,

(c) an acid, its pK_aLess than about 3 of the total weight of the composition,

(d) an acylating agent and an acylating catalyst;

(2)KHSO₅；

(3) hydrogen peroxide and a ketone selected from the group consisting of Q₄-CO-Q₅Group of (I), wherein Q₄And Q₅Are the same or different and are:

C₁-C₄alkyl, optionally substituted with 1 to 9-Cl or-F,

wherein Q₄And Q₅Together with the carbon atom to which they are attached form a 5 to 7 membered cyclic ketone and a ketone of the formula:

and

(4) a combination of hydrogen peroxide and methyltrioxorhenium,

(5)φ-C(CH₃)₂O-OH or alkyl hydroperoxides with goldCombinations of metal activators, wherein alkyl is C₄-C₁₀Alkyl, metal-containing activator selected from the group consisting of Ti (isopropoxide)₄Too-much tungstophosphoric acid, VO (acetylacetonate)₂And Mo hexacarbonyl;

(6) a peracid selected from the group consisting of:

(c) perphthalic acid, and

(d) magnesium peroxyphthalate. Preferably, the oxidative cleavage agent is hydrogen peroxide and a carboxylic acid generator. When the carboxylic acid generator is (a) heated, (b) a base and the pK of its conjugate acid_aAbout 5 or more, (c) an acid and its pK_aLess than about 3 or (d) acylating agent and acylating catalyst should be used in the same manner as discussed above with respect to the conversion of the peroxyhydroxy compound (IV-OOH) to the corresponding carboxylic acid (VI). As mentioned above, one equivalent of oxidative cleavage agent is required. Two equivalents are typically used and the reaction is monitored so that it is stopped or quenched when it approaches completion, a.DELTA.in oxidative cleavage agent attack⁴-and/or Δ⁹⁽¹¹⁾-steroid double bonds are treated before. Hydrogen peroxide and bicarbonate are preferred oxidative breakers. With respect to the solvent, it is important to carry out the process under homogeneous reaction conditions, i.e., one-phase conditions. Thus, the choice of solvent will depend on the oxidative cleavage agent used. If the carboxylic acid generator requires water to dissolve the reactants, for example when the carboxylic acid generator is a bicarbonate, a water miscible organic solvent, such as acetone, DMF, methanol or isopropanol, is required. If the carboxylic acid generator is pyridine, the organic solvent may be a water-immiscible organic solvent, such as acetonitrile, dichloromethane or ethyl acetate. The choice of solvent is therefore dependent on the nature of the carboxylic acid generator used, asKnown to those skilled in the art. In addition to heating of the carboxylic acid generator (a), other acid generators (b), (c) and (d) may be reacted at 20 to 25 ℃. The reaction is quite rapid, typically less than an hour. If the reaction mixture contains some hydroperoxy compound (IV-OOH), it is useful to first treat the reaction mixture with a hydroperoxy-deoxidising agent. Preferably, the peroxy hydroxyl-deoxidizer is dimethyl sulfide.

There are a number of ways in which the carboxylic acid (VI) can be converted to the corresponding 5, 7-lactone (VII), where the C-and D-rings of the starting carboxylic acid (VI) and the product 5, 7-lactone are identical. The respective process varies depending on the nature of the steroid A-/B-ring of the starting carboxylic acid (VI). They use different reactants to form 5, 7-lactones (VII) with different steroid A-/B-rings. One of these processes produces 5, 7-lactones of formula (VII)

Wherein

(Va)R₂is-H; r₃Is ═ O; r₄is-H;

(Vb)R₂is-H; r₃Is R_3a:R_3bWherein R is_3aAnd R_3bAre all-OH, R₄is-H; wherein R is₉、R₁₁And R₁₁As defined above, the method comprising:

(1) reacting a carboxylic acid of formula (VI)

Wherein

C₁-C₃an alkyl group, a carboxyl group,

-(CH₂)-(CR₃₃R₃₄)_n1-(CH₂)-

Wherein n is₁Is 0 or 1;

wherein R is₉、R₁₁And R₁₇Is as defined above;

is contacted with a reaction medium having a pH of less than about 5. Carboxylic acidsThe conversion of (VI) to the corresponding 5, 7-lactone (VII) is an equilibrium reaction. The lower the pH used in the reaction medium, the more the equilibrium shifts towards the 5, 7-lactone (VII), so it is necessary to keep the pH below 5, preferably in the range of 1 to 5. The reaction is preferably carried out under anhydrous conditions; preferably, the acid is pK under anhydrous conditions_aA strong acid of less than about 2. Useful strong acids include those selected from the group consisting of fluorosulfonic acid, chlorosulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid; preferably, the acid is benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid. Alternatively, the process is carried out using an aqueous acid as the catalyst. The process is preferably carried out in a two-phase system under these conditions. The amount of acid used is not critical and can range from catalytic amounts to an excess. The base may also catalyze the reaction of carboxylic acid (VI) to the corresponding 5, 7-lactone (VII), provided that a catalytic amount is used. Useful bases include those selected from the group consisting of hydroxide, bicarbonate, carbonate, DBU, DBN, DABCO, pyridine, p-dimethylaminopyridine, Q₇-COO^-(wherein Q)₇is-H, C₁-C₃Alkyl or-phi), (Q)₃)₃N (wherein Q)₃Is C₁-C₃Alkyl) groups; preference is given to hydroxides, hydrogen carbonates, triethylamine or pyridine. The solvent used for the conversion of the carboxylic acid (VI) to the corresponding 5, 7-lactone (VII) helps to achieve equilibrium for the reaction. It is preferred to use a solvent in which the starting carboxylic acid (VI) is soluble and in which the 5, 7-lactone (VII) is not soluble. The 5, 7-lactone (VII) then precipitates as it is formed, driving the equilibrium towards the desired 5, 7-lactone (VII). The preferred solvent is acetone. The reaction is carried out at about 0 ° to about 25 ° and is complete within a few hours. Depending on the pH of the reaction medium and the solvent used, carboxylic acid (VI)/5, 7-lactone (VII) of < 95/5 is obtained. Since this process step is an equilibrium reaction, the pH of the reaction medium helps control the final position of the equilibrium, as is known to those skilled in the art.

Second method for producing 5, 7-lactones of formula (VII)

Wherein

(Va)R₂is-H, R₃Is ═ O, R₄is-H;

comprises the following steps:

(1) reacting a carboxylic acid of formula (VI)

Wherein

wherein R is₉、R₁₁And R₁₇Is as defined above;

contacting under anhydrous conditions with an anhydrous reaction medium having a pH of less than about 5. Preferably, the reaction medium contains pK_a< about 4 acids. Useful pK_aAcids < about 4 include those selected from the group consisting of fluorosulfonic acid, chlorosulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid. Preferably, the acid is benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid. Also preferably, the carboxylic acid (VI) is reacted with the acid in a two-phase system. The process further comprises reacting the carboxylic acid (VI) with a catalytic amount of a base. Useful basesIncluding those selected from the group consisting of hydroxide, bicarbonate, carbonate, DBU, DBN, DABCO, pyridine, p-dimethylaminopyridine, Q₇-COO^-(wherein Q)₇is-H, C₁-C₃Alkyl or-phi), (Q)₃)₃N (wherein Q)₃Is C₁-C₃Alkyl) groups.

A third process for the production of 5, 7-lactones of formula (VII)

Wherein

(Vc)R₂is-H, R₃is-O-R_3a:-O-R_3bWherein R is_3aAnd R_3bIs the same as C₁-C₃Alkyl, or wherein R_3aAnd R_3bTogether with the attached-O-C-O-form a 5 or 6 atom cyclic ketal of the formula

-(CH₂)-(CR₃₃R₃₄)_n1-(CH₂)-

Wherein n is₁Is 0 or 1;

(VI)R₂is-H; r₃Is R_3c:R_3d，R₄Is R_4c:R_4dWherein R is_3cAnd R_3dOne and R_4cOr R_4dOne together forming a second bond between the carbon atoms to which they are attached, R_3cAnd R_3dThe other of which is CH₃-O-or C₂H₅-O-；R_4cAnd R_4dThe other of which is-H;

(VII)R₂is R_2e:R_2f，R₃Is R_3e:R_3fWherein R is_2eAnd R_2fOne and R_3eOr R_3fOne together forming a second bond between the carbon atoms to which they are attached, R_2eAnd R_2fThe other of which is-H, R_3eAnd R_3fThe other of which is CH₃-O-or C₂H₅-O-; or mixtures thereof;

comprises the following steps:

(1) reacting a carboxylic acid of formula (VI)

Wherein

C₁-C₃alkyl, and

-(CH₂)-(CR₃₃R₃₄)_n1-(CH₂)-

Wherein n is₁Is 0 or 1;

wherein R is₃₃And R₃₄Are identical or different and are-H and C₁-C₃An alkyl group; r₄is-H; r₆Is R_6-5:R_6-6Wherein R is_6-5And R_6-6One and R₅Together forming the carbon atom to which they are attachedA second bond between R_6-5And R_6-6The other of which is-H; (IV) R₃Is alpha-R_3-7:β-R_3-8Wherein R is_3-7is-O-R₃₁，R_3-8is-O-R₃₂Wherein R is₃₁And R₃₂Is as defined above; r₄Is R_4-7:R_4-8Wherein R is_4-7And R_4-8One and R₅Together forming a second bond between the carbon atoms to which they are attached, R_4-7And R_4-8The other of which is-H; r₆is-H;

wherein R is₉、R₁₁And R₁₇Is as defined above;

with at least a catalytic amount of an acid. Preferably, the pK of the acid_a< about 4, as discussed above.

The invention comprises a process for the preparation of the methyl ester of the formula (VIII),

wherein

the method comprises the following steps:

(1) reacting a 5, 7-lactone of formula (VII)

Wherein R is₄is-H, wherein R₃、R₉、R₁₁And R₁₇Is as defined above, is contacted with a base, and

(2) contacting the reaction mixture of step (1) with a methylating agent.

The strength of the base needs to be sufficient to open the 5, 7-lactone (VII), but will not react with the methylating agent, which is a weak nucleophile. Useful bases include those selected from the group consisting of bicarbonate, carbonate, hydroxide and R_baseO^-Group of (I) wherein R_baseIs C₁-C₄An alkyl group. Preferably, the base is bicarbonate. The amount of base required is from about 1 to about 1.5 equivalents. Useful methylating agents include those selected from the group consisting of dimethyl sulfate, methyl iodide, methyl bromide, trimethyl phosphate, dimethyl carbonate and methyl chloroformate; dimethyl sulfate is preferred. The amount of methylating agent used should be the same as or in slight excess of the number of equivalents of base used. The preferred method is to react it first with the base and then with the methylating agent in a two-step reaction in a sequential manner. If the reactions are all carried out in one step, the base reacts with the methylating agent, necessitating more base and more methylating agent. A more efficient way is to first react the 5, 7-lactone (VII) with at least one equivalent of base, preferably from about 1 to about 1.5 equivalents, and then react the resulting salt of the carboxylic acid (VI) with a methylating agent. The solvent used depends on the nature of the base used. If it is water-soluble, for example bicarbonate or hydroxide, then a mixture of water and a water-miscible organic solvent is preferred. These water-miscible organic solvents include methanol, ethanol, isopropanol, acetone, THF and DMF. If the base is water-soluble and the solvent is a mixture of water and a water-immiscible solvent, then a phase transfer catalyst is used, for example tetrabutylammonium hydrogen sulfate or tributylmethylammonium chloride. If the base is soluble in the water-immiscible organic solvent, it will also dissolve the 5, 7-lactone (VII), and the water-immiscible organic solvent is suitable. Reaction ofThe temperature depends on the reactivity of the methylating agent. If reagents such as dimethyl carbonate are used, the reaction will proceed slowly and heating to about 150 deg.C may be necessary. On the other hand, if a more reactive reagent, such as dimethyl sulfate, is used, the reaction is carried out at 40 ℃ for about 1 hour. Although in theory one equivalent of base and one equivalent of methylating agent should be sufficient, in practice more than one equivalent is required to optimize the reaction conditions.

The 5, 7-lactones (VII) can be converted into the corresponding carboxylic acids (VI) (salts) by contacting the 5, 7-lactones of the formula (VII) with a reaction medium having a pH > 7. The reaction is analogous to the conversion of 5, 7-lactone (VII) to methyl ester (VIII) except that no methylating agent is used. Since only a base is used, the product formed is a salt of the carboxylic acid (VI). Furthermore, the amount of base used is not critical since no methylating agent is present. If the acid form of carboxylic acid (VI) is desired, the salt form may be acidified to produce the corresponding acid form of carboxylic acid (VI), as known to those skilled in the art.

As illustrated in fig. a, there are numerous alternative approaches to the use of the present invention, as will be explained below, and as will also be known to those skilled in the art. For example, during the conversion of (I) to (II), the steroid a-ring may be protected as compound (I-P), see fig. B and explanation below, or used in unprotected form (I). Furthermore, the C-and D-rings may have a variety of functionalities during the various steps of the process. C-ring functionalities include, for example, 9 α -hydroxy, 9 α -O- (hydroxy protecting group), 9 α -F, 11-keto, 11-saturated, 11 α -hydroxy, 11 α -O- (hydroxy protecting group), 11 β -hydroxy, 11 β -O- (hydroxy protecting group), Δ⁹⁽¹¹⁾And 9 α, 11 α -epoxy. D-ring functionalities include, for example, 17-keto, 17 β -hydroxy, 17 α -ethynyl-17 β -hydroxy, 17 α -cyano-17 β -hydroxy, 17 α -C.ident.C-CH₂-O- (-H or substituted silyl) -17 β -OH, 17 α -C ≡ C-CH₂-O- (hydroxy protecting group) -17 beta-OH, 17 alpha-CH₂-CH₂-CH₂-OH-17β-OH、17α-CH₂-CH₂-CH₂-O- (hydroxy protecting group) -17 beta-OH, 17 alpha-hydroxy-17 beta-CO-CH₃、17β-CO-CH₂-OH、17β-CO-CH₂-O-CO-(CH₂)_0-3-CH₃、17β-O-CH₂-17 α (forming a three-membered ring oxide), γ -lactone and-O-CH (OR)_17-9)-CH₂-CH₂ ^......Wherein the bond (-O) from oxygen is one of the four bonds of C-17, in the beta configuration, and the bond (-CH) from methylene is₂ ^.....) Is another of the four bonds of C-17 in the alpha-configuration, constituting a 5-membered heterocyclic ring containing one oxygen atom, wherein R_17-9is-H or C₁-C₃An alkyl group. However, the D-ring functionality of the compound of claims 539, 548 and 556 and the method does not include R_17-2Is the case with hydroxyl groups. Hydroxy protecting groups are well known to those skilled in the art. The same hydroxyl protecting groups are available at C-9, C-11 and C-17 and are selected from the group consisting of-Si (-CH)₃)₃、-Si(-CH₂-CH₃)₃、-CO-CH₃-CO-H and-SiH (CH)₃)₂Group (d) of (a).

In some positions, the A-ring is not already the desired Δ⁴The-3-keto functionality has to be converted into Δ⁴-3-keto functionality. Similarly, the C-ring must be converted to a 9 α, 11 α -epoxide if it is not already the desired 9 α, 11 α -epoxide functionality. Similarly, if the D-ring is not already the desired γ -lactone, it must be converted to γ -lactone. However, these transformations can occur before, during, or after the various other processes and/or steps of fig. a. Preferably starting with a⁴An a-ring of an-3-keto group, having a⁹⁽¹¹⁾-C-ring and D-ring γ -lactones of functionality. With respect to the C-ring, it is preferred to maintain Δ throughout the inventive process⁹⁽¹¹⁾Functionality until complete synthesis of-CO-O-CH at the 7 alpha-position₃Group, then a⁹⁽¹¹⁾Conversion of the-functionality into the corresponding 9 α, 11 α -epoxide. With respect to the C-ring, one can start with the 11-keto functionality, at some positions, reduce to the 11 α -hydroxy functionality in the process, and then dehydrate the 11 α -hydroxy functionality at some later positions to give the corresponding Δ⁹⁽¹¹⁾Olefin functionality, by means of the methods of examples 18 to 20, using PCl₅Alternatively, by the method of example 31, N- (1, 1, 2, 2, 3, 3, 3) hexafluoropropyl diethylamine, also known as Ishikawa reagent, is used. As will be discussed more fully below, the use of Ishikawa reagent for dehydration of 11 α -hydroxysteroids to give the corresponding Δ⁹⁽¹¹⁾-an olefin. If the 11 alpha-hydroxy group is dehydrated to give the corresponding delta⁹⁽¹¹⁾5 '-methyl-2' -furyl substituent in which the alkene occurs at C-7. alpha. As exemplified by the compound of formula (II), it appears that PCl₅Is preferred, but if dehydration occurs on the methyl ester (VII), the Ishikawa reagent is preferred. Delta⁹⁽¹¹⁾The olefin is then converted to the desired 9 α, 11 α -epoxide functionality by means well known to those skilled in the art. Also, with respect to the D-ring, it is not necessary to begin with a^4，6-3-ketosteroids or their ketals (I) starting gamma-lactones. The starting D-ring 17-functionality can be converted to the desired γ -lactone at the desired position, starting with a 17-keto group or 17 β -hydroxy group, etc. Preferred procedures include what functionality needs to be started and what transformations are to be made, as depicted in panel E. In short, for the A-ring and D-ring, it is desirable to start with the same functionality as that desired in the final product. Preferably starting with a⁹⁽¹¹⁾-C-ring of olefin functionality, identified as-CO-O-CH at the 7 alpha-substituent₃And then converted to the desired 9 α, 11 α -epoxide functionality. However, as explained above and as known to those skilled in the art, starting from different functionalities in the A-, C-and D-rings, there are a number of alternative ways to prepare eplerenone by means of the scheme A process.

Panel B discloses the corresponding Δ^3，5-3-alkyl enol ether production protected delta^4，6-ketal steroid (I-P), the former being easily derivable from the corresponding Delta by methods known to the person skilled in the art⁴-3-keto steroids. Unprotected Δ is preferably used in the graph A method^4，6-3-keto steroid (I) as starting material. However, steroid Δ may also be used^4，6-3-ketal (I-P) as starting material for the process of FIG. A. In the method of graph B, Δ^4，6-3-ketonesKetal steroids (I-P)

Wherein R is₃₁And R₃₂

(1) Are identical or different and are C₁-C₃An alkyl group, a carboxyl group,

-(CH₂)-(CR₃₃R₃₄)_n1-(CH₂)-

Wherein n is₁Is 0 or 1;

wherein R is₃₃And R₃₄Are the same or different and are

-H，

C₁-C₃An alkyl group, a carboxyl group,

is from the corresponding Δ^3，5-3-alkyl enol ether,

(alkyl enol ethers)

Wherein R is³Is that

C₁-C₃An alkyl group, a carboxyl group,

CH₃-CO-，

phi-CO-, or

R_Si-1R_Si-2R_Si-3Si-, wherein R_Si-1、R_Si-2And R_Si-3Are identical or different and are C₁-C₄An alkyl group; the method makes^3，5-contacting a 3-alkyl enol ether (alkyl enol ether) with a hydride extractant and an alcohol selected from the group consisting of alcohols of the formula:

(d)HO-CH₂-CH₂-OH by (1) contact Δ^3，5-3-enol ethers (3-alkyl enol ethers).

Useful hydride extractants include those selected from the group consisting of:

DDQ，

the p-chloranil compound is a compound of p-chloranil,

the o-chloranil compound is an ortho-chloranil compound,

Mn⁺³、Mn⁺⁷、Pb⁺⁴、Pd⁺²、Ru⁺⁸、Cr⁺⁶，

the o-iodoxybenzoic acid is a compound of,

a complex of o-iodoxybenzoic acid and DMSO,

o-iodoxybenzoic acid with

4-methoxypyridine-N-oxide,

N-methylmorpholine-N-oxide,

a complex of trimethylamine-N-oxide,

iodic acid (HIO)₃)，

Iodine pentoxide (I)₂O₅)，

The cerium-containing cerium nitrate is added with ammonium cerium nitrate,

the preparation method of the iodosobenzene comprises the following steps of,

the preparation method of the bis (trifluoroacetic acid) iodobenzene,

the iodine-benzene diacetate is added into the reaction kettle,

trityl fluoroborate, and electrochemical oxidation using a catalytic amount of hydride extractant. Preferably, the hydride extractant is p-chloranil or DDQ, more preferably DDQ. One equivalent of hydride extractor is required; and the method is more harmless and only wasteful. Preferably, the alcohol is neopentyl glycol, also known as dimethylpropanediol or 2, 2-dimethyl-1, 3-propanediol. The solvent needs to dissolve the 3-alkyl enol ether (3-alkyl enol ether) raw material. Suitable solvents include dichloromethane, acetonitrile, THF, and the like. The reaction is feasible at a temperature in the range of about-78 deg. to about 40 deg., preferably about-15 deg.. The reaction was very rapid and completed within a few minutes at-15 ℃. The entire process is preferably carried out under essentially anhydrous conditions. The term "hydride extractor" is used herein to refer to an agent that effects a net removal of one of the 3-dienol ether C-7 hydrogen atoms, which removal occurs without implying any mechanism. Preferably, Δ^4，6-the ketal (I-P) is selected from the group consisting of:

17 beta-hydroxypregna-4, 6, 9(11) -trien-3-one-21-carboxylic acid, gamma-lactone, cyclic 3- (2 ', 2' -dimethyl-1 ', 3' -propanedione acetal),

17 beta-hydroxypregna-4, 6, 9(11) -trien-3-one-21-carboxylic acid, gamma-lactone, cyclic 3-ethanediylketal.

Panel C discloses that the 7 α -substituted steroid (II) can also be converted to the corresponding cis-oxyalkylene diketone (X-cis) by (1) reacting the 7 α -substituted steroid (II) with ozone at C₁-C₄Contacting in the presence of an alcohol, and (2) contacting the mixture of step (1) with a peroxy hydroxy-deoxidizer. R_7-1、X₁R_b、R_c、R_dAnd other substituent variables are preferably as described above. Dissolving the 7 alpha-substituted steroid (II) in a suitable C₁-C₄Alcohols or mixtures thereofA compound (I) is provided. Preferably, C₁-C₄The alcohol being C₁And C₃An alcohol; more preferably the alcohol is C₁An alcohol. If necessary, a co-solvent such as methylene chloride may also be used. The nature of the solvent/co-solvent is not critical as long as it will dissolve the reactants at the low temperatures at which the process is carried out. The nature of the alcohol is not critical as it is eventually lost from the steroid molecule. The reaction temperature may be as low as about-100 deg., up to about 40 deg.. Preferably, the temperature is from about-78 ° to about-20 °; more preferably, the temperature is about-50 deg.. Passing ozone through the reaction mixture, as known to those skilled in the art, until the process of step (1) is complete. The progress of the reaction is monitored, as known to those skilled in the art. When the reaction of step (1) is complete, the reaction mixture of step (1) is contacted with a peroxy hydroxy-deoxidizer. Preferably, the peroxy hydroxy-deoxidizer is trimethyl phosphite. For the other processes of the invention, the preferred peroxy hydroxy-deoxidizer is dimethylsulfide, but the preferred reagent herein is trimethyl phosphite. The reaction mixture was then allowed to warm slowly to 20-25 °. The reaction will proceed rapidly to reach the correct temperature for the particular 7 α -substituted steroid (II). If desired, the cis-oxyalkylene diketone (X-cis) product may be used without isolation and purification.

Panel C further discloses that cis-oxyalkylene diketones (X-cis) can be converted to the corresponding trans-oxyalkylene diketones (X-trans). This process was carried out in the same manner as for the conversion of cis-enedione (III-cis) to the corresponding trans-enedione (III-trans) in FIG. A.

Cis-oxyalkylene-diones (X-cis) or trans-oxyalkylene-diones (X-trans) or mixtures thereof can be converted into the corresponding peroxy hydroxy compounds (IV-OOH) and/or hydroxy compounds (IV-OH) and/or dicarbonyl compounds (V) and/or carboxylic acids (X) or mixtures thereof in the same manner as cis-enediones (III-cis) or trans-enediones (III-trans) or mixtures thereof are converted into the corresponding peroxy hydroxy compounds (IV-OOH) and/or hydroxy compounds (IV-OH) and/or dicarbonyl compounds (V) and/or carboxylic acids (VI) or mixtures thereof. The hydroperoxy compound (IV-OOH) and/or the hydroxy compound (IV-OH) and/or the dicarbonyl compound (V) and/or the carboxylic acid (X) or a mixture thereof are then converted into eplerenone (IX) in the same manner as in the previous FIG. A process.

Cis-oxyalkylene-diones (X-cis) or trans-oxyalkylene-diones (X-trans) or mixtures thereof can be converted into the corresponding carboxylic acids (VI) by reaction with oxidative cleavage agents in the same manner as the hydroxy compounds (IV-OH) and/or dicarbonyl compounds (V) are converted into the corresponding carboxylic acids (VI).

Panel D illustrates a preferred inventive process for the A-/B-ring of steroids (when R is_7-1Is-a 1), the steroid a-ring is not protected. However, as it will be apparent to those skilled in the art that the steroid a-ring may be preferably protected in some cases, since the substituent variables and combinations of substituent variables for the C-and D-rings of the steroid may vary. In general, however, it is preferred that the steroid a-ring is not protected and the preferred method is scheme D.

Graph E illustrates for Δ^4，6Preferred inventive process for the conversion of 3-keto steroid (I) to eplerenone (IX) with respect to the preferred substituent variables for each intermediate.

Panel F discloses the reversibility of the conversion of carboxylic acid (VI) with 5, 7-lactone (VII).

Panel G discloses when the adduct-R_7-1Is a cyclic adduct (-A2). The 7 α -substituted steroid (II) was formed in the same manner as discussed above with respect to fig. a when the adduct was (-a 1). Then reacting R therein_7-1The 7 α -substituted steroid (II) which is (-a2) is reacted in the same manner with the same reagents used in figure a in relation to (-a1) to give the same type of intermediate as described in figure a in relation to the adduct (-a 1). The process of panels a and G is similar, the reactants are the same and used in the same order. The intermediates produced are isomers or homologs of each other.

Panel H discloses that when the adduct R is_7-1Is (-B), (-C), (-D1), (-D2)D3) The general process of the present invention. The graph H method is a two-step process. The first step of the process is to convert Δ^4，6-conversion of the starting 3-keto steroid or ketal (I) thereof into the corresponding 7 alpha-substituted steroid (II) wherein R is_7-1Is a substituent selected from the group consisting of:

-CR_b2＝M (-B)

-C≡C-R_c2 (-C)

-CH₂-CH＝CH₂ (-D1)

-CH＝C＝CH₂ (-D2)

-CH₂-C≡C-H (-D3)

the second step is oxidative cleavage of the 7 α -substituent to give the carboxylic acid functionality, i.e., -CO-OH of carboxylic acid (VI). In the olefinic substituent (-B), "M" is a group which forms a double bond with carbon and is limited to carbon, nitrogen and oxygen. Substituent R_b2Is a group which can be converted to a hydroxyl group by oxidation or hydrolysis. With respect to the acetylenic substituent (-C), the group R_c2In fact, any group is possible, since it is eventually lost upon cleavage of the triple bond to the carboxylic acid (VI). Also with respect to the three-carbon unsaturated substituents (-D1), (-D2) and (-D3), two of the three carbon atoms are oxidatively cleaved to form carboxylates. At conversion of delta^4，6When the starting material of the 3-keto steroid or the ketal (I) thereof is the corresponding 7 alpha-substituted steroid (II), the reaction is carried out in the presence of a catalyst^4，6-reacting a starting 3-keto steroid or a ketal (I) thereof with a nucleophile selected from the group consisting of:

(d) formula (B)

R_a-CE₁＝M (B)

(e) Formula (C)

R_a-C≡C-E₂(C)

(f) Formula (D1, D2 and D3)

R_a-CH₂-CH＝CH₂ (D1)

R_a-CH＝C＝CH₂ (D2)

R_a-CH₂-C≡C-H (D3)

Wherein R is_a、E₁、E₂M is as defined above, and M is a compound of formula,

the reaction is in the presence of the following reagents:

(1) a Lewis acid, a basic metal oxide or a metal oxide,

(2)pK_aless than about 5, or

(3) Salts of secondary amines of the formula

And

and pK_aAcids of < about 2. Lewis acids promote both conjugate addition and formation of 7 alpha-stereochemistry.

The adducts (-B) and (-C) are converted to-CO-OH of the carboxylic acid (VI) by treatment with one or more oxidizing agents. The oxidizing agent must be capable of cleaving the C ═ M double bond to a carbon-oxygen double bond, and C — R_b2Single bonds are cleaved to carbon-oxygen single bonds and carbon-carbon triple bonds are cleaved to carboxylic acids. The choice of oxidizing agent depends on the substituent-CR_b2M or-C ≡ C-R_c2The inherent difficulty of oxidation. The more difficult the oxidation, the stronger the oxidant will be required. Suitable oxidizing agents include ozone, singlet oxygen, triplet oxygen, hydrogen peroxide, hydroperoxides, percarboxylic acids, hypohalites, and the like. In 2-methylfuranIn the case of compound (II), the conversion to carboxylic acid (VI) is preferably accomplished by treatment with potassium hypobromite, followed by ozone, followed by dimethyl sulfide, followed by hydrogen peroxide.

The allyl adduct (-D1) is converted to the-CO-OH of carboxylic acid (VI) in such a way that the double bond is isomerized to-CH ═ CH-CH₃Followed by ozonation using an oxidative treatment (e.g., sodium chlorite). Isomerization of the double bond can be accomplished with the aid of the following reagents: refluxing rhodium trichloride and ethanol; HRuCl [ P (-phi)₃]₃About 90 °; LiNH (CH)₂)₃NH₂(1, 3-diaminopropyllithium), 20-25 °; PdCl₂(φ-CN)₂Toluene, about 80 °; HRh (CO) [ P (-phi)₃]₃，20-25°；ClRh[P(-φ)₃]₃Toluene, refluxing; cl₂Ru[P(-φ)₃]₃100 °; cobalt chloride/sodium borohydride/P (-phi)₃About-18.

The propargyl adduct (-D2) is thus converted to the-CO-OH functionality of the carboxylic acid (VI) when R is_c2Is C₁In the case of alkyl radicals, the isomerization is carried out by means of bases or transition metals to give adducts (-C) which are then cleaved by the abovementioned methods. Suitable bases for (-D2) isomerization to (-C) include sodium amide, ammonia or THF; potassium 3-aminopropyl amide ("KAPA"), THF; potassium hydroxide, ethylene glycol, about 150 °; potassium tert-butoxide, DMSO or tert-butanol; sodium or potassium hydride, DMF or THF. Suitable transition metal catalysts include Yb [ phi ]₂C＝N-φ](HMPA)₄And HCo (N)₂)[P(-φ)₃]₃。

The alkenyl adduct (-D3) is thus converted to the-CO-OH functionality of carboxylic acid (VI) and ozonized using oxidative treatment (e.g. sodium chlorite).

The present invention comprises a four-step process for the conversion of a 7 α -substituted steroid (II) to the corresponding carboxylic acid (VI) product. The four steps are (1) ring opening, (2) ozonolysis, (3) reaction with a peroxy hydroxyl-deoxidizer, and (4) reaction with an oxidative cracking agent. The yield of carboxylic acid (VI) obtained by the four-step process of the present invention is better than expected based on the prior art process steps. The carboxylic acid (VI) is obtained by:

(1) contacting a 7 α -substituted steroid of formula (II):

(b) an oxygen-supplying agent, which is a mixture of oxygen-supplying agent,

(c) the oxidation is carried out in an electrochemical way,

(d) quinone in the presence of water, or

(e) A non-quinone oxidizing agent;

(2) reacting the reaction mixture of step (1) with ozone in the formula R_7-2-an OH alcohol;

(3) contacting the reaction mixture of step (2) with a peroxy hydroxy-deoxidant; and

(4) contacting the reaction mixture of step (3) with an oxidative cleavage agent. Each of these steps has been discussed above in full. The method combines these same steps and is performed in the same manner and in the same way as discussed above.

The present invention comprises a three step process comprising the conversion of the 7 α -substituted steroid (II) to the corresponding carboxylic acid (VI) product, see example 34 step (1). These three steps are (1) ozonolysis, (2) reaction with a peroxy hydroxyl-deoxidizer, and (3) reaction with an oxidative cracking agent. The three-step process of the present invention is a process for preparing a carboxylic acid (VI), comprising:

(1) reacting a 7 alpha-substituted steroid (II) with ozone in the formula R_7-2-an OH alcohol;

(2) contacting the reaction mixture of step (1) with a peroxy hydroxy-deoxidant; and

(3) contacting the reaction mixture of step (2) with an oxidative cleavage agent. Each of these steps has been discussed above in full. The method combines these same steps and is performed in the same manner as discussed above. The carboxylic acid (VI) can be easily converted into its tautomer-like dilactone (VII) by contacting with an acid, see step (2) of example 34. In the process of the invention, it is the carboxylic acid (VI) which is converted into the methyl ester (VIII) and ultimately into eplerenone (IX). It is possible to isolate and purify this carboxylic acid (VI) by means of crystallization. However, this would risk isomerization to the dilactone (VII), which is thermodynamically more stable. It is therefore actually preferred not to stop at the end of step (1) of example 34, but to continue working up the reaction mixture and then isolating and crystallizing the dilactone (VII). It is therefore easier and more preferred to carry out the process of example 34 up to step (2), purify the resulting dilactone (VII) and then convert the dilactone (VII) back to the carboxylic acid (VI) for further conversion to the methyl ester (VIII).

Eplerenone (IX) is a pharmaceutical agent useful in the treatment of hyperaldosteronism, edema, hypertension and congestive heart failure, see U.S. patent No. 4,559,332.

The invention also includes the conversion of 11 alpha-hydroxy steroids to the corresponding delta⁹⁽¹¹⁾Novel processes for steroids. Delta⁹⁽¹¹⁾The functionality is very useful in the production of eplerenone (IX) because it is readily converted to the corresponding 9 α, 11 α -epoxide functionality of eplerenone (IX).

The starting 11 α -hydroxy steroid (CIV) materials are known to those skilled in the art. More specifically, 11 α -hydroxy-17-lactone (CI), 11 α, 17 β -dihydroxypregn-4-en-3-one-7 α, 21-dicarboxylic acid, γ -lactone, methyl ester are known, see Drugs of the Future, 24(5), 488-501(1999), compound (VI).

For 11 α -hydroxy steroids (CIV), preferably, the steroid a-ring is:

(1)W₁is-H, W₂is-H, or W₁Is W_1-1:W_1-2，W₂Is W_2-1:W_2-2Wherein W is_1-1Or W_1-2One and W_2-1Or W_2-2One together forming a second bond between the carbon atoms to which they are attached, W_1-1Or W_1-2The other of which and W_2-1Or W_2-2The other of which is-H; w₃Is ═ O, W₄Is W_4-1:W_4-2Wherein W is_4-1And W_4-2One and W₅Together forming a second bond between the carbon atoms to which they are attached, W_4-1And W_4-2The other of which is-H;

(2)W₃is ═ O, W₄is-H, W₅Is alpha-oriented^......O-CO- (bonded at C)₇To give 5, 7-lactones), in which W₁And W₂Is as defined above;

(3)W₃is-O-W_3-3:-O-W_3-4；W₄Is W_4-3:W_4-4Wherein W is_4-3And W_4-4One and W₅Together forming a second bond between the atoms to which they are attached, W_4-3And W_4-4The other of which is-H; w_3-3And W_3-4The method comprises the following steps:

(a) same or different is C₁-C₅An alkyl group, a carboxyl group,

(b) together form a cyclic moiety selected from the group consisting of:

(i)-CH₂-CH₂-，

(ii)-CH₂-CH₂-CH₂-，

(iii)-CH₂-C(CH₃)₂-CH₂-; wherein W₁And W₂Is as defined above;

(4)W₃is-O-W_3-3:-O-W_3-4；W₄is-H; w₅Is formed at C₅And C₆A second bond in between; w_3-3And W_3-4Is as defined above;

(5)W₃is W_3-5:W_3-6Wherein

(a)W_3-5And W_3-6One of them is-H, W_3-5And W_3-6The other one is:

(i)-O-W_3-5Awherein W is_3-5AIs C₁-C₃An alkyl group, a carboxyl group,

(ii)-O-CO-W_3-5Awherein W is_3-5AIs as defined above in that the first and second parts are,

(iii)-N(W_3-5A)₂wherein W is_3-5AIs as defined above in that the first and second parts are,

(iv) a piperazine group,

(v) a morpholino group in a group of amino acids,

(vi) a piperidinyl group which is a substituent of the cyclic structure,

(b)W_3-5and W_3-6Together with the carbon atoms to which they are attached form a cyclic moiety comprising:

(i)-O-CH₂-CH₂-O-，

(ii)-O-CH₂-CH₂-CH₂-O-，

(iii)-O-CH₂-C(CH₃)₂-CH₂-O-wherein W₄is-H; w₅Is formed at C₅And C₆A second bond in between;

(6)W₃is W_3-7:W_3-8(ii) a Wherein W₄Is W_4-7:W_4-8Wherein

(a)W_3-7And W_3-8One of them is:

(i)-O-W_3-7Awherein W is_3-7AIs C₁-C₃An alkyl group, a carboxyl group,

(ii)-O-CO-W_3-7Awherein W is_3-7AIs as defined above in that the first and second parts are,

(iii)-N(W_3-7A)₂wherein W is_3-7AIs as defined above in that the first and second parts are,

(iv) a piperazine group,

(v) a morpholino group in a group of amino acids,

(vi) piperidinyl group in which W_3-7And W_3-8The other of which is connected with W_4-7And W_4-8One together forming a second bond between the carbon atoms to which they are attached, W_4-7And W_4-8Is the other of-H; w₅Is formed at C₅And C₆A second bond in between;

(7)W₃is alpha-W_3-9:β-W_3-10Wherein W is_3-9is-H, W_3-10The method comprises the following steps:

(a)-O-CO-W_3-10Awherein W is_3-10AIs C₁-C₃An alkyl group, a carboxyl group,

(b)-O-CO-O-W_3-10Bwherein W is_3-10BIs that

(i)C₁-C₄An alkyl group, a carboxyl group,

(iii)-CH₂phi, where phi is optionally substituted by one to three C₁-C₃Alkyl, -F, -Cl, -Br, -I, C₁-C₃Alkoxy substitution; wherein WR₄is-H; w₅Is formed at C₅And C₆A second bond between carbon atoms; wherein W₁And W₂Is as defined above;

(8)W₃is alpha-W_3-9:β-W_3-10(ii) a Wherein W₄Is W_4-9:W_4-10Wherein W is_3-9And W_3-10Is as defined above; wherein W_4-9And W_4-10One and W₅Together forming a second bond between the atoms to which they are attached, W_4-9And W_4-10The other of which is-H; wherein W₁And W₂Is as defined above.

More preferably, the steroid a-ring functionality is:

(b)-CO-W_3-10Awherein W is_3-10AIs C₁-C₃An alkyl group, a carboxyl group,

(c)-CO-O-W_3-10Bwherein W is_3-10BIs that

(i)C₁-C₄An alkyl group, a carboxyl group,

even more preferably, the steroid a-ring functionality is:

(1)W₁is-H, W₂-H, or W₁Is W_1-1:W_1-2，W₂Is W_2-1:W_2-2Wherein W is_1-1Or W_1-2One and W_2-1Or W_2-2One together forming a second bond between the carbon atoms to which they are attached, W_1-1Or W_1-2The other of which and W_2-1Or W_2-2The other of which is-H; w₃Is ═ O, W₄Is W_4-1:W_4-2Wherein W is_4-1And W_4-2One and W₅Together forming a second bond between the carbon atoms to which they are attached, W_4-1And W_4-2The other of which is-H.

For 11 α -hydroxy steroids (CIV), preferably, the steroid D-ring is:

wherein W₁₇The method comprises the following steps:

(1)＝O，

(2)α-W_17-1:β-W_17-2wherein:

(a)W_17-1and W_17-2Together with the carbon atom to which they are attached form^....CH₂-an O-epoxide compound, in particular,

(b)W_17-1and W_17-2Together with the carbon atom to which they are attached form^....CH₂-CH₂-CO-O-lactone;

(3)αW_17-3:β-W_17-4wherein

(a)W_17-3The method comprises the following steps:

(i)-H，

(ii)-O-CO-W_17-3Awherein W is_17-3Ais-H or-CO-W_17-3BWherein W is_17-3BIs C₁-C₄An alkyl group or a group represented by the formula-phi,

(b)W_17-4is-CO-CH₃；

(4)α-W_17-5:β-W_17-6Wherein

(a)W_17-5The method comprises the following steps:

(i)-O-CO-W_17-5Awherein W is_17-5AIs C₁-C₄An alkyl group or a group represented by the formula-phi,

(b)W_17-6the method comprises the following steps:

(i)-CO-CH₂-O-W_17-6Awherein W is_17-6AIs C₁-C₄Alkyl or-phi.

In the case of eplerenone-type compounds, preferably, W₁₇The method comprises the following steps:

(1)＝O，

(2)α-W_17-1:β-W_17-2wherein:

(b)W_17-1and W_17-2Together with the carbon atom to which they are attached form^....CH₂-CH₂-CO-O-lactone.

More preferably, in the case of an eplerenone-type compound, W₁₇The method comprises the following steps:

(1)＝O，

(2)α-W_17-1:β-W_17-2wherein:

For progesterone and hydroxyprogesterone, preferably, W₁₇The method comprises the following steps:

(3)αW_17-3:β-W_17-4wherein

(a)W_17-3The method comprises the following steps:

(i)-H，

(ii)-O-CO-W_17-3Awherein W is_17-3Ais-H or-CO-W_17-3BWherein W is_17-3BIs C₁-C₄Alkyl or-phi;

(b)W_17-4is-CO-CH₃。

In the case of corticosteroids, preferably, W₁₇The method comprises the following steps:

(4)α-W_17-5:β-W_17-6wherein

(a)W_17-5The method comprises the following steps:

(b)W_17-6the method comprises the following steps:

(i)-CO-CH₂-O-W_17-6Awherein W is_17-6AIs C₁-C₄Alkyl or-phi.

Preferred combinations of steroid a-, B-and D-rings, especially in the case of eplerenone-type compounds, include the ring systems depicted in figure C. The 11 α -hydroxy steroid (CIV) of figure C is known to those skilled in the art or can be readily prepared from known compounds by known methods.

In the process of the invention, a starting 11 α -hydroxy-17-lactone (CI) or 11 α -hydroxy steroid (CIV) is contacted with an N-fluoroalkylamine reagent of formula (CVI)

Wherein:

Z₁is C₁-C₄An alkyl group;

Z₂is C₁-C₄Alkyl radical, wherein Z₁And Z₂Together with the nitrogen atom to which they are attached form a 5 or 6 membered heterocyclic ring selected from the group consisting of pyrrolidinyl, piperazinyl, piperidinyl and morpholinyl;

Z₃is-F or-CF₃. Preferably, Z₁And Z₂Is C₁-C₃An alkyl group. More preferably, Z₁And Z₂Is C₁Alkyl or C₂An alkyl group. Preferably, the N-fluoroalkylamine (CVI) is N- (1, 1, 2, 3, 3, 3-hexafluoropropyl) diethylamine, which is a known Ishikawa reagent, or 1, 1, 2, 2-tetrafluoroethyl-N, N-dimethylamine.

The process of the invention is preferably carried out using 1 equivalent of 11 α -hydroxy-17-lactone (CI) or 11 α -hydroxy steroid (CIV) and from about 1 to about 1.5 equivalents of Ishikawa reagent; more preferably about 1.2 equivalents of Ishikawa reagent. The process of the present invention is preferably carried out at a temperature in the range of from about 20 to about 82 °; more preferably from about 40 to about 70. The reaction usually takes from about 1 to about 24 hours to complete, depending on the reaction conditions, especially temperature and concentration. For example at about 60 ° and 0.8 moles, the reaction takes about 3 hours.

Either 11 α -hydroxy-17-lactone (CI) or 11 α -hydroxy steroid (CIV) can be added to the N-fluoroalkylamine reagent (CVI), or the N-fluoroalkylamine reagent (CVI) can be added to either 11 α -hydroxy-17-lactone (CI) or 11 α -hydroxy steroid (CIV); it is more realistic to add the N-fluoroalkylamine reagent (CVI) to 11 α -hydroxy-17-lactone (CI) or 11 α -hydroxy steroid (CIV).

The process of the invention is preferably carried out in a solvent which is anhydrous (KF < 0.5%), for example acetonitrile.

Of the formula (CII) Δ⁹⁽¹¹⁾-17-lactones, namely 17 β -hydroxypregna-4, 9(11) -diene-3-one-7 α, 21-dicarboxylic acid, γ -lactone, methyl ester are known, see U.S. Pat. No. 4,559,332, example 1(d) and international publication WO98/25948, page 284. It can be used for preparing medicinal components 9 alpha, 11 alpha-epoxy-17 beta-hydroxypregn-4-ene-3-one-7 alpha, 21-dicarboxylic acid, gamma-lactone and methyl ester, also known as eplerenone (CIII).

Steroid C-ring functionality Delta of Compounds (CII) and (CV)⁹⁽¹¹⁾Functionalities which are very useful to the chemical man in the steroid field. It can be readily converted to the corresponding 9 α, 11 α -epoxy functionality and 9 α -fluoro-11 β -hydroxy functionality as well as 11-keto and others, as is well known to those skilled in the art. These compounds are useful pharmaceutical ingredients. Thus, the process of the present invention involves the conversion of 11 α -hydroxy steroid (CIV) to the corresponding Δ⁹⁽¹¹⁾-conversion of steroids (CV), a very useful process, applicable to a wide variety of 11 α -hydroxy steroids (CIV), as will be apparent to those skilled in the art. This includes progesterone, 17 α -hydroxyprogesterone, corticosteroids and their common derivatives and analogs such as esters and the like. Thus, the process produces Δ⁹⁽¹¹⁾Steroids (CV), which are useful intermediates in the preparation of pharmaceutically useful steroids. According to a given Δ by a person skilled in the art⁹⁽¹¹⁾Steroids (CV) will know how to convert into pharmaceutically useful products.

The invention also includes the extensive hydroxylation of 11 alpha-hydroxyConversion of the compound to the corresponding Delta⁹⁽¹¹⁾A method of preparing a compound by one or more of the above methods. For example, the following transformation methods are described: (1)11 α -hydroxy-7 α -substituted steroid (II) to the corresponding Δ⁹⁽¹¹⁾-conversion of 7 α -substituted steroid (II), (2)11 α -hydroxy cis-enedione (III-cis) or 11 α -hydroxy trans-enedione (III-trans) to the corresponding Δ⁹⁽¹¹⁾-conversion of trans-enedione (III-trans), and (3) conversion of 11 α -hydroxy compound (IV-OH) or 11 α -hydroxy-peroxy-hydroxy compound (IV-OOH) or 11 α -hydroxy-dicarbonyl compound (V) or mixtures thereof to the corresponding Δ⁹⁽¹¹⁾-conversion of carboxylic acid (VI).

Definition and contract

The following definitions and explanations apply to the terms used throughout this specification, including the specification and claims.

I. Conventions regarding formula and variable definitions

The chemical formulae representing the various compounds or molecular fragments in the description and claims may contain substituent variables in addition to the explicitly defined structural features. The substituent variables being distinguished by letter or letter followed by a numerical suffix, e.g. "Z₁"or" R_i", wherein" i "is an integer. These substituent variables are monovalent or divalent, that is, they represent a group attached to a formula by one or two chemical bonds. For example, the group Z₁Will represent a divalent variable if attached to the formula CH₃-C(＝Z₁) And H. Radical R_iAnd R_jWill represent a monovalent substituent variable if attached to the formula CH₃-CH₂--C(R_i)(R_j)H₂. When the formula is depicted in a linear fashion, such as those described above, the substituent variables contained in parentheses are bonded to the atom immediately to the left of the substituent variables in parentheses. When two or more consecutive substituent variables are included in parentheses, each consecutive substituent variable is bonded to the immediately preceding atom to the left which is not included in the parentheses. Thus in the above formulaTwo R_iAnd R_jAre bonded to the previous atom. Furthermore, for any molecule having a given numbering system of carbon atoms, such as steroids, these carbon atoms are designated C_iWherein "i" is an integer corresponding to the number of carbon atoms. E.g. C₆Represents the 6-or 6-carbon atom of the steroid core, as is conventionally named by those skilled in the steroid chemistry art. "R₆"represents C₆The variables of the site substituents (monovalent or divalent).

The chemical formula depicted in a linear fashion, or a portion thereof, represents an atom in a linear chain. The symbol "-" generally represents a bond between two atoms in a chain. Thus, CH₃-O-CH₂-CH(R_i)-CH₃Represents a 2-substituted-1-methoxypropane compound. In a similar manner, the symbol "═" represents a double bond, for example CH₂＝C(R_i)-O-CH₃The symbol "≡" represents a triple bond, e.g. HC ≡ C-CH (R)_i)-CH₂-CH₃. The carbonyl group is represented in one of two ways: -CO-or-C (═ O) -, the former being preferred for simplicity.

The chemical formula of the cyclic (cyclo) compound or the molecular fragment may be expressed in a linear manner. Thus, the compound 4-chloro-2-methylpyridine can be represented in a linear manner as N^*＝C(CH₃)-CH＝CCl-CH＝C^*H, and atoms approximately marked with an asterisk (#) are bonded to each other to form a ring. Likewise, the cyclic molecular fragment 4- (ethyl) -1-piperazinyl can be represented by-N^*-(CH₂)₂-N(C₂H₅)-CH₂-C^*H₂。

The rigid cyclic (ring) structure of any of the compounds herein defines the orientation of the substituents attached to each carbon atom of the rigid cyclic compound with respect to the plane of the ring. In the case of saturated compounds, they have two substituents attached to a carbon atom which is part of a ring system, i.e., -C (X)₁)(X₂) The two substituents may be in axial or equatorial positions with respect to the ring and may be in axial/equatorial positionsVarying between volts. However, the positions of these two substituents relative to the ring and each other remain fixed. While one substituent may sometimes lie in the plane of the ring (equatorial) rather than above or below the plane (axial), one substituent is always above the other. In the chemical structural formulae depicting such compounds, at another substituent (X)₂) A substituent (X) of the following₁) Will be identified as the alpha configuration, indicated by a broken or dotted line attached to a carbon atom, i.e., the symbol "- -" or "- -". Is connected to another (X)₁) The corresponding substituent (X) as above₂) Is determined as the beta configuration, represented by the unbroken line attached to the carbon atom.

When a substituent variable is divalent, the valences may be together or separate or both in the definition of the variable. For example, with-C (═ R)_i) The variable R attached to the carbon atom_iMay be divalent, may be defined as an oxo or keto group, constituting a carbonyl group (-CO-), or as two singly linked monovalent substituent variables α -R_i-jAnd beta-R_i-k. When the divalent variable R_IWhen defined as consisting of two monovalent substituent variables, the convention is that the divalent variable is "α -R_1-j:β-R_i-k"form or some variant thereof. In this case, α -R_i-jAnd beta-R_i-kAre all attached to the carbon atom to give-C (alpha-R)_i-j)(β-R_i-k) -. For example, when the divalent variable R₆I.e., -C (═ R)₆) -is defined as consisting of two monovalent substituent variables, the two monovalent substituent variables being α -R_6-1:β-R_6-2、......α-R_6-9:β-R_6-10Etc. to give-C (. alpha. -R)_6-1)(β-R_6-2)-、......-C(α-R_6-9)(β-R_6-10) -and the like. Also, for divalent variable R₁₁I.e., -C (═ R)₁₁) -for two monovalent substituent variables, α -R_11-1:β-R_11-2. The above convention applies in the absence of separate alpha and beta oriented ring substituents (e.g., due to the presence of a carbon-carbon double bond in the ring) and substituents bonded to a carbon atom that is not part of the ring, butThe alpha and beta designations are omitted.

Just as a divalent variable may be defined as two separate monovalent substituent variables, two separate monovalent substituent variables may be defined to together constitute a divalent variable. For example in the formula-C₁(R_i)H-C₂(R_j) H-middle (C)₁And C₂Random definition of the first and second carbon atoms, respectively), R_iAnd R_jCan be defined as constituting together (1) C₁And C₂A second bond therebetween, or (2) a divalent group, such as oxa (-O-), which formula thereby describes an epoxide. If R is_iAnd R_jTogether forming a more complex entity, e.g. the group-X-Y-, the orientation of the entity is such that C in the above formula₁Bound to X, C₂Bonded to Y. Thus, according to the convention, ".... R_iAnd R_jTogether form-CH₂-CH₂"denotes a compound in which the carbonyl group is bonded to C₂The lactone of (1). However, "... R_jAnd R_iTogether form-CO-O-CH₂-CH₂A. "contract means where the carbonyl is bonded to C₁The lactone of (1).

The number of carbon atoms in a substituent variable is represented in one of two ways. The first method employs a prefix of the complete variable name, e.g. "C₁-C₄", wherein" 1 "and" 4 "are integers representing the minimum and maximum number of carbon atoms in the variable. Prefixes are separated from variables by spaces. For example, "C₁-C₄Alkyl "represents an alkyl group of 1 to 4 carbon atoms (including isomeric forms thereof, unless the contrary expression is given). Whenever such a single prefix is given, the prefix indicates the total number of carbon atoms for the defined variable. Thus, C₂-C₄Alkoxycarbonyl describing the radical CH₃-(CH₂)_n-O-CO-, wherein n is 0, 1 or 2. The second method is, with "C" in parentheses_i-C_j"alone" means only a fraction of the number of carbon atoms in the definition that immediately precedes the defined moiety (no intervening space). With this optional convention, (C)₁-C₃) The alkoxycarbonyl group hasAnd C₂-C₄Alkoxycarbonyl has the same meaning because of "C₁-C₃"represents only the number of carbon atoms of an alkoxy group. Similarly, C₂-C₆Alkoxyalkyl and (C)₁-C₃) Alkoxy (C)₁-C₃) Alkyl defines alkoxyalkyl groups containing 2 to 6 carbon atoms, and the two definitions are distinguished in that the former definition allows individual alkoxy or alkyl moieties to contain 4 or 5 carbon atoms, while the latter definition defines these groups as 3 carbon atoms.

When the claims contain a fairly complex (cyclic) substituent, there will be a parenthetical annotation at the end of the phrase naming/designating that particular substituent, corresponding to the same name/designation in one of the figures that also describes the chemical formula for that particular substituent.

Definition of

All temperatures are in degrees Celsius.

TLC indicated thin layer chromatography.

LC liquid chromatography.

ESTDLC stands for external standard liquid chromatography.

THF represents tetrahydrofuran.

DMAP stands for p-dimethylaminopyridine.

DDQ represents 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone.

DBU represents 1, 8-diazabicyclo [5.4.0] undec-7-ene.

DBN represents 1, 5-diazabicyclo [4.3.0] non-5-ene.

DABCO represents 1, 4-diazabicyclo [2.2.2] octane.

Chromatography (column chromatography and flash chromatography) indicates the purification/separation of the compounds, expressed as (carrier, eluent). It will be appreciated that the appropriate fractions are pooled and concentrated to give the desired compound.

Carboxylic acid (VI) represents and includes pharmaceutically acceptable salts thereof.

CMR represents the C-13 magnetic resonance spectrum, with chemical drift reported in ppm (δ) located downstream of TMS.

NMR represents nuclear (proton) magnetic resonance spectroscopy, and the chemical shift is reported in ppm (d) downstream of TMS.

In the present invention, the terms conversion or verb conversion are used interchangeably to mean the same thing, i.e. one compound is produced by the process described to another compound.

TMS means trimethylsilyl.

Potassium hydrogen persulfate represents KHSO₅。

Phi represents phenyl (C)₆H₅)。

MS means mass spectrum expressed in m/e, m/z or mass/charge units. [ M + H ]]⁺A cation representing the parent hydrogen atom. EI denotes electron impact. CI denotes chemical ionization. FAB stands for fast atom bombardment.

Pharmaceutically acceptable means that the properties and/or substances, with respect to composition, formulation, stability, patient acceptance and bioavailability, are acceptable to the patient from a pharmacological/toxicological point of view and to the pharmacist from a physical/chemical point of view.

When a solvent pair is used, the ratio of solvents used is volume/volume (v/v).

Where the solubility of a solid in a solvent is used, the ratio of solid to solvent is weight/volume (wt/v).

Δ⁹-canrenone denotes 17 β -hydroxypregna-4, 6, 9-trien-3-one-21-carboxylic acid, γ -lactone.

Eplerenone refers to 9 α, 11 α -epoxy-17 β -hydroxypregn-4-en-3-one-7 α, 21-dicarboxylic acid, γ -lactone, methyl ester.

Neopentyl glycol represents HO-CH₂-C(CH₃)₂-CH₂-OH。

Iodosobenzene represents phi I ═ O.

Iodobenzene bistrifluoroacetate represents phi I (O-CO-CF)₃)₂。

Iodobenzene diacetate represents phi I (O-CO-CH)₃)₂。

Triphenylmethyl fluoroborate is also known as triphenylcarbonium fluoroborate and represents φ₃C⁺BF₄ ^-。

acac represents acetylacetonate.

dppb represents diphenylphosphinobutane.

Tf represents trifluoromethanesulfonate.

Dimethylsulfide represents CH₃SCH₃。

Ishikawa reagent represents N- (1, 1, 2, 2, 3, 3, 3) hexafluoropropyl diethylamine.

An "oxidative cleavage agent" is a reagent that oxidizes a dicarbonyl compound (V) or a hydroxyl compound (IV-OH) to a carboxylic acid (VI).

The "hydroperoxy-deoxidating agent" is a reagent for removing oxygen atoms from the hydroperoxide compound (IV-OOH) to obtain the corresponding hydroxyl compound (IV-OH).

A "deoxidizer" is an agent that removes one oxygen atom from a molecule. "hydroperoxy-deoxidizing agents" are thus a particular type of deoxidizing agent.

"Carboxylic acid generator" is an agent that induces the rearrangement of the hydroperoxide compound (IV-OOH) to carboxylic acid (VI).

An "oxygen donor" is an agent that donates an oxygen atom to a 7 α -substituted steroid (II), converting it to a cis-enedione (III-cis).

Examples

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare and/or perform various compounds of the present invention and/or methods of the present invention and are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Those skilled in the art will quickly recognize the appropriate changes to these processes with respect to reactants and reaction conditions and techniques.

Example 117 beta-hydroxypregna-4, 6, 9(11) -trien-3-one-21-carboxylic acid, gamma-lactone, cyclic 3- (2 ', 2' -dimethyl-1 ', 3' -propanedione) (I-P)

17 β -hydroxypregna-4, 6, 9(11) -trien-3-one-21-carboxylic acid, γ -lactone 3-methylenol ether (I, 3.00g, 8.4629mmol) and lithium perchlorate (199.6mg, 1.8761mmol, 0.22 equiv.) were suspended in acetonitrile (20ml) and dichloromethane (10ml), cooled to-15 °, treated with 2, 2-dimethyl-1, 3-propanediol (2.19g, 21.027mmol, 2.48 equiv.), then treated dropwise with a solution of DDQ (2.29g, 10.088mmol, 1.19 equiv.) in ethyl acetate for 73 minutes. After stirring for 40 min, the reaction mixture was quenched with ammonium hydroxide (28%, 5ml), diluted with ethyl acetate, concentrated, diluted with dichloromethane and filtered. The filtrate was diluted with ethyl acetate, washed with aqueous sodium bicarbonate/sodium chloride followed by water, then filtered through magnesium acidic silicate eluting with dichloromethane. The eluate was concentrated to give a solid, triturated with toluene and dried under a stream of nitrogen to give the title compound, CMR (CDCl)₃)14.44，22.53，22.78，23.02，24.89，28.85，29.22，30.07，30.18，31.31，32.92，35.37，38.56，39.03，44.35，44.43，70.54，70.65，95.17，95.43，116.80，120.23，127.82，130.27，141.83，145.08and 176.61δ；NMR(CDCl₃)0.95，0.97，1.03，1.18，1.3-2.8，3.5-3.7，5.44，5.71，5.80and 6.02δ。

Example 217 beta-hydroxypregna-4, 6, 9(11) -trien-3-one-21-carboxylic acid, gamma-lactone, cyclic 3-ethanediyl ketal (I-P)

A solution of 17 β -hydroxypregna-4, 6, 9(11) -trien-3-one-21-carboxylic acid, γ -lactone 3-methylenol ether (I, 300mg, 0.8463mmol) in dichloromethane (5ml) was cooled to-15 ° and then treated with ethylene glycol (220mg, 3.544mmol, 4.19 equivalents). To the mixture was added dropwise a solution of DDQ (230mg, 1.0132mmol, 1.20 equiv) over 30 minutes. After the addition was complete, the reaction was stirred at-15 ℃ for 5 minutes at which time TLC analysis (ethyl acetate/cyclohexane, 66/34) showed the starting methylenol ether (R)_f0.69) to the corresponding ethylene ketal (R)_f0.54) was almost complete. The reaction was then quenched with concentrated ammonium hydroxide (0.5ml) and filtered. The filtrate is then filtered through 1.0g cartridge grade magnesium silicate acid and concentrated to give the title compound, CMR (CDCl), as compared to a real sample₃)14.37，22.95，24.54，29.15，30.28，31.23，32.87，35.30，38.17，38.45，44.27，44.37，64.15，64.70，95.07，105.94，116.85，122.39，127.41，130.24，141.71，145.76and 176.51δ；NMR(CDCl₃)0.97，1.18，1.3-2.9，3.8-4.1，5.29，5.45，5.70and 5.99δ.

Example 317 beta-hydroxy-7 alpha- (5 '-methyl-2' -furyl) -pregna-4, 9(11) -dien-3-one-21-carboxylic acid, gamma-lactone (II)

Will be delta⁹-canrenone (I, 90.0g, 0.2659mol) was mixed with nitromethane (730-. 2-Methylfuran (49.5ml, 45.04g, 0.5487 mo) was then addedl, 2.06 equivalents). The resulting mixture was cooled to-20 °, then treated with absolute ethanol (15.8ml, 12.55g, 0.2723mol, 1.02 eq), followed by boron trifluoride etherate (d ═ 1.120; 37.2ml, 41.66g, 0.2936mol, 1.10 eq). The mixture was cooled again to-18.4 deg.C and stirred for 17 hours, at which time LC indicated that the reaction was complete. The reaction mixture was quenched with ammonia (15% aqueous, 225 ml). The mixture was warmed to above 0 °, water (200ml) was added, the organic phase was separated and the aqueous phase was extracted with dichloromethane (2 × 200 ml). The organic extracts were dried over magnesium sulphate (100g) and then filtered through magnesium acid silicate (100g cartridge grade) and the filter cake washed with dichloromethane (5X 200 ml). The eluate was then concentrated to a foam under reduced pressure, suspended in ethyl acetate (200ml), reconcentrated and then dissolved in ethyl acetate (950ml) at 50 ° to 60 °. The mixture was concentrated to a volume of about 500ml and then diluted with cyclohexane (250 ml). The product began to crystallize slowly. The crystal slurry was re-concentrated to a volume of about 500ml, cooled to 20-25 °, further concentrated to a volume of about 400ml, and then cooled to 0 °. After overnight at 0 °, the crystal slurry was filtered, the filter cake was washed with cyclohexane followed by heptane and dried in a 50 ° vacuum oven to give the title compound, TLC 0.37 (ethyl acetate/cyclohexane, 66/34), CMR (CDCl)₃)13.38，14.12，23.18，26.83，29.14，31.26，32.93，33.93，34.18，35.39，37.57，38.52，40.78，41.90，42.39，44.08，95.19，105.89，107.12，119.73，126.24，149.99，152.74，167.45，76.53and 198.56；NMR(CDCl₃)0.95，1.43，1.4-2.6，2.16，2.93，3.30，5.68and 5.74δ.

The filtrate was concentrated to a foam, dissolved in ethyl acetate (40ml), concentrated to about 20ml, seeded, diluted with cyclohexane (20ml), concentrated to about 30ml, cooled to 0 ° over the weekend, then filtered, washed with ethyl acetate/cyclohexane (1/2), dried to give additional title compound.

Example 417 β -hydroxy-7 α - (trans-1 ', 4' -dioxopent-2 '-en-1' -yl) pregna-4, 9(11) -diene-3-one-21-carboxylic acid, γ -lactone (III-trans)

Step A: 17 beta-hydroxy-7 alpha- (cis-1 ', 4' dioxopent-2 '-en-1' -yl) pregna-4, 9(11) -diene-3-one-21-carboxylic acid, gamma-lactone (III-cis)

A mixture of 17 β -hydroxy-7 α - (5 '-methyl-2' -furyl) -pregna-4, 9(11) -dien-3-one-21-carboxylic acid, γ -lactone (II, example 3, 5.04g, 11.9843mmol) and potassium acetate (1.7g, 17.32mmol, 1.45 equivalents) in THF (40ml) and water (12.5ml) was treated with dibromantin (2.0g, 6.995mmol, 0.58 equivalents), followed by isobutyl vinyl ether (500 μ l, 384mg, 3.834mmol, 0.32 equivalents) at 23.8 °. The reaction mixture was stirred at 20-25 ℃ for 1 hour, at which time TLC indicated starting material (II, R)_f0.50) to cis-and trans-enediones (R)_f0.11) was complete (ethyl acetate/cyclohexane, 66/34). The reaction mixture was diluted with water (200ml) and extracted with dichloromethane (2X 100 ml). The extracts were combined, washed with water (50ml), dried over magnesium sulfate, filtered and concentrated to give cis-enedione (III-cis).

And B: 17 beta-hydroxy-7 alpha- (trans-1 ', 4' dioxopent-2 '-en-1' -yl) pregna-4, 9(11) -diene-3-one-21-carboxylic acid, gamma-lactone (III-trans)

The concentrate (step a) was dissolved in chloroform (100ml) and the mixture was stirred at 20-25 ° for 20 h, at which time the conversion of cis-enedione to trans-enedione was judged complete according to TLC and LC measurements (cis/trans ═ 1.1/98.9). The mixture was then concentrated, and the concentrate was dissolved in ethyl acetate (20ml) at 20-25 ℃ and diluted with cyclohexane (80ml) to induce crystallization. The crystal slurry was cooled, filtered, and the filter cake was washed with cyclohexane and dried under reduced pressure of 50 ℃ to give the title compound, CMR (CDCl)₃)13.98，23.28，27.08，28.66，29.01，31.26，32.77，33.61，34.01，35.22，35.28，40.48，40.51，42.41，44.43，48.13，94.77，118.81，126.03，135.89，137.04，142.16，165.21，176.32，197.81，198.26and 200.18；NMR(CDCl₃)1.04，1.30，1.51, 1.5-3.6, 2.45, 5.71, 5.78and 6.89 δ; MS (Electron spray) m/e 435 (p)⁺-1) negative ion mode.

Example 517 beta-hydroxypregna-4, 9(11) -diene-3-one-7 alpha, 21-dicarboxylic acid, gamma-lactone (VI)

Step A: 17 β -hydroxy-7 α - (1 ' -oxo-2 ' -isopropoxy-2 ' -hydroxy-ethyl) pregna-4, 9(11) -dien-3-one-21-hydroxyacid, γ -lactone (IV-OH); 17 beta-hydroxy-7 alpha- (1 '-oxo-2' -isopropoxy-2 '-hydroperoxyethyl) pregna-4, 9(11) -dien-3-one-21-carboxylic acid, gamma-lactone (IV-OOH) and 17 beta-hydroxy-7 alpha- (2' -oxo-acetyl) -pregna-4, 9(11) -dien-3-one-21-carboxylic acid, gamma-lactone (V)

A mixture of 17 β -hydroxy-7 α - (trans-1 ', 4' -dioxo-pent-2 '-en-1' -yl) pregna-4, 9(11) -dien-3-one-21-carboxylic acid, γ -lactone (III-trans, example 4, 551.8mg, 1.2640mmol) in isopropanol (11ml) and dichloromethane (5ml) was cooled to-55 °. Ozone-containing oxygen was bubbled through the mixture until 0.4 area% of trans-enedione (III) remained (according to LC). The mixture was sparged with nitrogen for 7 minutes and purged of ozone to give a mixture of the title compounds.

And B: 17 beta-hydroxy-7 alpha- (1 '-oxo-2' -isopropoxy-2 '-hydroxy-ethyl) pregna-4, 9(11) -dien-3-one-21-carboxylic acid, gamma-lactone (IV-OH), 17 beta-hydroxy-7 alpha- (1', 2 '-dioxo-ethyl) pregna-4, 9(11) -dien-3-one-21-carboxylic acid, gamma-lactone (V) and 17 beta-hydroxy-7 alpha- (2' -oxo-acetyl) -pregna-4, 9(11) -dien-3-one-21-carboxylic acid, gamma-lactone (V)

The mixture of step A was then quenched with dimethylsulfide (340. mu.l, 288mg, 4.630mmol, 3.66 equiv.), warmed to 20-25 ℃ and stirred at 20-25 ℃ for 50 minutes to give a mixture of the title compounds.

And C: 17 beta-hydroxypregna-4, 9(11) -diene-3-one-7 alpha, 21-dicarboxylic acid, gamma-lactone (VI)

The mixture from step B was then treated with a solution of hydrogen peroxide (70% water, 430. mu.l, 560mg, containing 392mg (11.52mmol, 9.12 equivalents) of hydrogen peroxide) and potassium bicarbonate (637.7mg, 6.369mmol, 5.04 equivalents) in water (8 ml). The resulting biphasic mixture was diluted with sufficient methanol to form a single phase mixture (5ml) which was then stirred at 20-25 ℃ for 16 hours and then diluted with methanol to a volume of 500ml for LC analysis. LC analysis indicated that the title compound was obtained, compared to known compounds.

20.0ml of the 500ml solution was taken and further diluted with methanol to a volume of 50 ml. The solution (containing 17.3mg (0.0450mmol) carboxylic acid according to LC) was concentrated to a small volume, diluted with water, acidified with hydrochloric acid (1N) and extracted with dichloromethane (2 ×). The two extracts were washed sequentially with water, combined and concentrated. The concentrate was dissolved in methanol/toluene (1/1; 2ml) and washed with trimethylsilyldiazomethane (CH)₃)₃SiCHN₂A mixture in hexane (2.0M, 0.25ml, 0.50mmol, 11.1 equiv.) was treated. TLC analysis (ethyl acetate/cyclohexane, 66/34) indicated that the title compound was obtained, R_f0.23; LC analysis (210nm detection) indicated that the retention time was the same as for the known standard, giving the title compound.

Example 617 beta-hydroxypregna-4, 9(11) -diene-3-one-7 alpha, 21-dicarboxylic acid, gamma-lactone, methyl ester (VIII)

The remaining part (479ml, containing 414.4mg [1.0777 mmol) of 500ml of the mixture from step C, example 5]17 β -hydroxypregna-4, 9(11) -dien-3-one 7 α, 21-dicarboxylic acid, γ -lactone (VI, example 5C) was partially concentrated, diluted with water (20ml), concentrated to a volume of about 20ml, treated with hydrochloric acid (18ml), and extracted with dichloromethaneTake (25ml, then 2X 15 ml). The extracts were washed with water (30ml), combined and concentrated to a volume of 50.0 ml. Half of the mixture was concentrated to small volume, diluted with ethyl acetate and extracted with potassium bicarbonate (25% aqueous, 20ml, 10ml more). The combined extracts were acidified to pH 3 with hydrochloric acid (1N) and extracted with dichloromethane (40ml, then 2X 15 ml). The extracts were then combined, washed with water, concentrated to a volume < 1ml, and treated with a solution of sodium carbonate (349.6mg, 3.298mmol, 6.12 equivalents based on carboxylic acid) in water (1.0ml), followed by tetra-n-butylammonium hydrogen sulfate (n-butyl)₄NHSO₄(20.4mg, 0.0601mmol, 0.11 equiv.), followed by dimethyl sulfate (108. mu.l, 144.0mg, 1.14mmol, 2.11 equiv.). The mixture was diluted with dichloromethane (0.1ml), stirred at 20-25 ℃ for 11.5 h, treated with hydrochloric acid (1N, 10ml) and extracted with dichloromethane (10ml, again 2X 5 ml). The combined extracts were washed with water and concentrated to give the title compound, in accordance with known standards.

Example 717 beta-hydroxy-7 alpha- (cis-3' -acetoxyacryloyl) -pregna-4, 9(11) -diene-3-one-21-carboxylic acid, gamma-lactone (X-cis)

Make O be₃/O₂(ozone/oxygen) gas stream cooled (-78 ℃) mixture of 17 β -hydroxy-7 α - (5 '-methyl-2' -furyl) -pregna-4, 9(11) -dien-3-one-21-carboxylic acid, γ -lactone (II, example 3, 3.0138g, 7.1663mmol) in dichloromethane (40ml) and methanol (10ml) until the starting material had been consumed (LC, 25min) and the mixture was then treated with O₂Followed by nitrogen purge, quenching with trimethyl phosphite (3.0ml, 3.16g, 25.435mmol, 3.55 eq.) and warming to 20-25 °. After stirring for 1 hour, LC analysis indicated that the title compound, CMR (100MHz, CDCl), was obtained₃)198.49，198.23，176.43，166.63，166.10，142.74，142.44，125.87，118.12，110.39，94.99，49.30，44.47，42.30，40.59，～40，35.46，35.33，34.11，33.63，32.83，31.37，29.11，27.26，23.31，20.67and 14.06δ；NMR(400MHz，CDCl₃)0.94，1.40，1.5-2.9，2.29，5.38，5.63and 7.48δ.

Example 817 β -hydroxy-7 α - (trans-3' -acetoxyacryloyl) -pregna-4, 9(11) -diene-3-one-21-carboxylic acid, γ -lactone (X-trans)

After stirring the reaction mixture 17 β -hydroxy-7 α - (cis-3' -acetoxyacryloyl) -pregna-4, 9(11) -dien-3-one-21-carboxylic acid, γ -lactone of example 7 for 1 hour, the reaction mixture was quenched with hydrochloric acid (5% water, 25ml) and stirred at 20-25 ° for 20 minutes, at which time the isomerization to the trans isomer was complete. The organic phase was then separated, concentrated and subjected to flash chromatography (silica gel 150 g; gradient elution 40% → 70% ethyl acetate/cyclohexane) to give the title compound. The product was then crystallized from ethyl acetate/heptane (70/30) to give the title compound, CMR (100MHz, CDCl) in pure form₃)199.25，198.39，176.41，166.79，166.39，149.00，142.57，125.67，118.20，113.11，94.90，47.75，44.40，42.40，40.45，～40，35.63，35.25，34.01，33.56，32.73，31.29，29.04，27.14，23.32，20.47and 13.98δ；NMR(400MHz，CDCl₃)1.14，1.4-4.1，1.61，2.44，5.75，6.14and 8.41δ.

Example 917 beta-hydroxy-7 alpha- (2 '-hydroperoxy-2' -methoxyacetyl) pregna-4, 9(11) -dien-3-one-21-carboxylic acid, gamma-lactone (IV-OOH)

A mixture of cold (-78 °)17 β -hydroxy-7 α - (trans-3' -acetoxyacryloyl) -pregna-4, 9(11) -dien-3-one-21-carboxylic acid, γ -lactone (X-trans, example 8, 311.0mg, 0.6872mmol) in dichloromethane/methanol (2/1, 6ml) was passed through ozone/oxygen stream until the blue color persisted (3 min.). Excess ozone was purged with oxygen followed by nitrogen, and then the reaction mixture was warmed to 20-25 ° and diluted to 10ml with dichloromethane. A portion of this mixture (3.5ml from 0.2405mmol of trans-enol acetate) was concentrated to dryness to give the title compound.

Example 105 α, 17 β -dihydroxypregn-9 (11) -en-3-one 7 α, 21-dicarboxylic acid, bis- γ -lactone (VII)

17 β -hydroxy-7 α - (2 '-hydroperoxy-2' -methoxyacetyl) pregna-4, 9(11) -dien-3-one-21 carboxylic acid, γ -lactone (IV-OOH, example 9, 3.5ml, from 0.2405mmol trans-enol acetate) was concentrated to dryness, the residue was dissolved in trifluoroacetic acid (1.0ml), stirred at 20-25 ℃ for 20 minutes, then diluted with ethyl acetate (1.0ml), washed with aqueous sodium bicarbonate, diluted with dichloromethane (2.0ml), washed with dilute aqueous hydrochloric acid, concentrated. The concentrate was dissolved in dichloromethane (1.0ml), stirred with aqueous hydrochloric acid (6N) for 30 minutes and then concentrated to give the title compound, CMR (100MHz, CDCl)₃)206.39，176.80，175.59，139.66，124.11，95.12，91.11，47.14，43.99，42.45，41.66，41.63，41.15，39.01，37.04，35.23，33.08，32.50，31.42，29.21，23.16，23.06and 14.30δ；NMR(400MHz，CDCl₃)0.94，1.40，1.5-2.6，2.80，5.70δ；MS(CI，NH₃)m/e＝402(100％，P+NH₄).

Example 1117 β -hydroxy-7 α - (2' -oxo-acetyl) -pregna-4, 9(11) -dien-3-one-21-carboxylic acid, γ -lactone (V)

Flowing ozone/oxygenBy means of a mixture of cold (-79 ℃)17 β -hydroxy-7 α - (trans-1 ', 4' -dioxopent-2 '-en-1' -yl) pregna-4, 9-dien-3-one-21-carboxylic acid, γ -lactone (III-trans, example 4B, 503.4mg, 1.1531mmol) in dichloromethane/methanol (1/1, 4.0ml) until TLC analysis (acetone/dichloromethane, 3/7) shows that the starting material (R) (R-H-E-R) is not soluble in water_fTo more polar products (R) 0.70_f0.45) conversion was complete (10 min.). The reaction mixture was then quenched with dimethylsulfide (0.20ml, 169mg, 2.72mmol, 2.34 equivalents), stirred at 20-25 ℃ for 1 hour, and then concentrated. The concentrate was subjected to flash chromatography (silica gel 60 g; gradient elution acetone/dichloromethane 5% → 25%) to give the title compound, CMR (100MHz, CD₃CN)198.68，197.54，187.93，176.09，166.40，142.33，125.02，118.56，94.44，～44，42.49，40.34，～40，39.87，34.60，33.83，33.56，33.32，32.39，30.53，28.39，26.16，22.43and 13.22δ；NMR(400MHz，CD₃CN)0.87，1.37，1.2-2.9，5.49，5.63and 8.93δ；MS(CI，NH₃)m/e＝397(P+H，100％).

Example 1211 α, 17 β -dihydroxy-7 α - (5 '-methyl-2' -furyl) -pregn-4-en-3-one-21-carboxylic acid, γ -lactone (II)

A mixture of 11 α -hydroxycarvenone (I, 30.00g, 84.1586mmol) in nitromethane (240ml) and dichloromethane (60ml) was cooled to-20 °, then 2-methylfuran (15.6ml, 14.20g, 0.1729mol, 2.05 equiv), followed by ethanol (5.1ml, 4.03g, 87.454mmol, 1.04 equiv), followed by boron trifluoride diethyl etherate (BF)₃ OEt₂12.0ml, 13.44g, 94.695mmol, 1.13 equiv). The reaction mixture was stirred at-17 ℃ for 20 h, then quenched with ammonia (15% aqueous, 60ml), extracted with dichloromethane (120ml), dried over sodium sulfate (40g) and concentrated. The concentrate was dissolved in methylene chloride/ethyl acetate (1/1, 300ml) and concentrated to a solidVolume 75ml, diluted with 150ml cyclohexane, concentrated to a volume of 200ml and filtered to give the title compound, CMR (75MHz, CDCl)₃)199.59，176.67，170.11，152.92，150.28，126.20，108.67，105.90，95.18，68.55，52.05，45.84，45.58，43.08，39.73，38.62，38.42，37.47，36.54，35.26，34.17，30.91，29.05，22.62，18.40，15.58and 13.44δ；NMR(300MHz，CDCl₃)1.01，1.1-3.2，1.41，2.20，4.12，5.73，5.83and 5.93δ.

The filtrate was concentrated. The concentrate was dissolved in ethyl acetate (30ml warm), cooled to 10 ° and filtered to give a second crop of crystals of the title compound.

Example 1317 β -hydroxy-7 α - (5 '-methyl-2' -furyl) -pregna-4, 9(11) -dien-3-one-21-carboxylic acid, γ -lactone (II)

A mixture of 11 α, 17 β -dihydroxy-7 α - (5 '-methyl-2' -furyl) -pregn-4-en-3-one-21-carboxylic acid, γ -lactone (II, example 12, 438.3mg, 0.9994mmol) in THF (7.3ml) was cooled to-50 °, then all over with solid phosphorus pentachloride (PCl)₅287.5mg, 1.381mmol, 1.38 equivalents). After 42 minutes of stirring, LC analysis indicated complete conversion to the title compound. After an additional 21 minutes, the mixture was quenched with water (22ml) and warmed to 20-25 °. After 20 minutes, the mixture was extracted with dichloromethane (2 × 15ml), dried over magnesium sulfate and concentrated to give the title compound, which was measured for retention time by LC and compared to the sample of example 3.

Example 149 α, 11 α -epoxy-17 β -hydroxy-7 α - (5 '-methyl-2' -furyl) -pregn-4-en-3-one-21-carboxylic acid, γ -lactone (II)

A mixture of 9 α, 11 α -epoxycanrenone (I, J.Med. chem., 6, 732(1963) and Helv.Chim.acta 80, 566(1997), 10.0135g, 28.2508mmol) in nitromethane (80ml) and dichloromethane (20ml) was cooled to-20 °, followed by 2-methylfuran (5.10ml, 4.64g, 56.529mmol, 2.00 equivalents), followed by ethanol (1.7ml, 1.343g, 29.151mmol, 1.03 equivalents), followed by boron trifluoride diethyl etherate (BF)₃ OEt₂3.6ml, 4.03g, 28.408mmol, 1.01 equiv). The reaction mixture was stirred at-20 ℃ for 24 h, at which time the conversion to product was complete as determined by LC, whereupon the reaction was quenched with aqueous ammonia (15%, 10ml), extracted with dichloromethane (2X 100ml), concentrated to a residue and subjected to flash chromatography (560g silica gel; gradient elution 50% → 90% ethyl acetate/cyclohexane). The chromatographed product was triturated with cyclohexane (100ml) at reflux for 2 h, then cooled to 0 ℃ and filtered to give the title compound, CMR (75MHz, CDCl)₃)198.10，176.26，165.67，153.19，149.96，127.56，107.92，106.14，94.66，65.45，49.92，43.82，40.00，39.18，37.43，37.37，35.54，35.00，33.24，31.00，30.81，28.91，26.98，22.26，22.00，16.61and 13.47δ；NMR(300MHz，CDCl₃)1.02, 1.3-3.0, 1.52, 2.20, 3.28, 5.85, 5.92and 6.01 delta.

Example 1517 direct ozonization of β -hydroxypregna-4, 9(11) -diene-3-one-7 α, 21-dicarboxylic acid, γ -lactone (VI) via 17 β -hydroxy-7 α - (cis-4 '-oxo-pent-2' -enoyl) -3-oxo-pregna-4, 9(11) -diene-21-carboxylic acid, γ -lactone (III-cis)

A mixture of cold (-55 °)17 β -hydroxy-7 α - (cis-4 '-oxo-pent-2' -enoyl) -pregna-4, 9(11) -dien-3-one-21-carboxylic acid, γ -lactone (III-cis, example 4 step a, 52.4mg, 0.1200mmol) in dichloromethane/isopropanol (1/1, 3.0ml) containing water (50mg, 2.77mmol, 23.1 equivalents) was passed through ozone/oxygen stream until the LC assay material completely disappeared (126 secs.). The reaction mixture was then quenched with dimethyl sulfide (0.033ml, 27.9mg, 0.449mmol, 3.74 equivalents), stirred at 20-25 ℃ for 45 minutes, then diluted with methanol (5ml), treated with aqueous hydrogen peroxide (70%, 50 μ l, containing 45.6mg [1.34mmol, 11.2 equivalents ] hydrogen peroxide), treated with a mixture of potassium bicarbonate (62.4mg, 0.623mmol, 5.19 equivalents) in water (2ml), and the resulting mixture stirred at 20-25 ℃. After 15 hours, LC analysis indicated the title compound was formed.

Example 1617 β -hydroxypregna-4, 9(11) -diene-3-one-7 α, 21-dicarboxylic acid, γ -lactone (VI) direct ozonization via 17 β -hydroxy-7 α - (trans-4 '-oxo-pent-2' -enoyl) -pregna-4, 9(11) -diene-3-one-21-carboxylic acid, γ -lactone (III-trans)

A mixture of cold (-55 °)17 β -hydroxy-7 α - (trans-4 '-oxo-pent-2' -enoyl) -pregna-4, 9(11) -dien-3-one-21-carboxylic acid, γ -lactone (III-trans, example 4 step B, 103.5mg, 0.2371mmol) in dichloromethane/isopropanol (1/1, 3ml) containing water (50mg, 2.77mmol, 11.7 equivalents) was passed through ozone/oxygen stream until the LC assay material completely disappeared (100 secs.). The reaction mixture was then treated with dimethylsulfide (CH)₃SCH₃65 μ l, 55.0mg, 0.885mmol, 3.73 equivalents), stirred at 20-25 ℃ for 45 minutes, then diluted with methanol to a volume of 10.0 ml. 5.0ml of this mixture was treated with aqueous hydrogen peroxide (70%, 50. mu.l, containing 45.6mg [1.34mmol, 11.3 equivalents)]Hydrogen peroxide), treated with a mixture of potassium bicarbonate (59mg, 0.589mmol, 4.97 equivalents) in water (2.1ml) and the resulting mixture stirred at 20-25 °. After 15 hours, LC (ESTD) analysis showed the formation of the title compound, CMR (100MHz, CDCl)₃)199.96，177.42，174.28，169.06，142.10，124.86，118.60，95.60，44.23，43.48，42.61，40.38，39.79，35.59，35.08，33.73，33.30，32.57，31.05，28.98，26.80，22.92and 13.68δ；NMR(400MHz，CDCl₃)0.96，1.42，1.5-3.0，4.28，5.64and 5.74δ；MS(CI，NH₃；m/e)＝402(P+NH₄ ⁺).

Example 175 α, 17 β -dihydroxypregn-9 (11) -en-3-one 7 α, 21-dicarboxylic acid, bis- γ -lactone, 3-dimethylketal (VII-ketal)

The title compound is obtained by treating 5 α, 17 β -dihydroxypregn-9 (11) -en-3-one 7 α, 21-dicarboxylic acid, bis- γ -lactone (VII, example 10) with at least one equivalent of trimethyl orthoformate in the presence of catalytic amounts of p-toluenesulfonic acid according to the procedure of International publication WO 98/25948.

Example 1817 beta-hydroxypregna-4, 9(11) -diene-3-one-7 alpha, 21-dicarboxylic acid, gamma-lactone, methyl ester (VIII)

11 α, 17 β -dihydroxypregn-4-en-3-one-7 α, 21-dicarboxylic acid, γ -lactone, methyl ester (VIII, Drugs of the Future, 24(5), 488-501(1999), Compound (VI)), 5.00g, 12.0mmol) was mixed with acetonitrile (15 ml). To the steroid mixture was added N- (1, 1, 2, 3, 3, 3-hexafluoropropyl) diethylamine (V, 2.55ml, 14.4mmol) and heated to 60 ℃ for 2.5 h. The resulting mixture was cooled to 20-25 ℃ and the reaction was quenched with methanol (100. mu.L). Saturated aqueous potassium bicarbonate (15ml) was added. The acetonitrile was then removed under reduced pressure. The resulting mixture was extracted with dichloromethane (3X 10 ml). The organic phases were combined and washed with aqueous sodium chloride (10%, 20 ml). The solvent was dried over magnesium sulfate. The solvent was replaced from dichloromethane to methyl tert-butyl ether (MTBE). The mixture was concentrated to a final volume of 25 ml. The resulting crystal slurry was stirred overnight and the final product, the title compound, was collected by filtration.

Example 1917 beta-hydroxypregna-4, 9(11) -diene-3-one-7 alpha, 21-dicarboxylic acid, gamma-lactone, methyl ester (VIII)

11 α, 17 β -dihydroxypregn-4-en-3-one-7 α, 21-dicarboxylic acid, γ -lactone, methyl ester (VIII, 5.00g, 12.0mmol) was placed in a flask containing acetonitrile (15 ml). To the mixture was added N- (1, 1, 2, 3, 3, 3-hexafluoropropyl) diethylamine (2.55ml, 14.4mmol) and heated to 60 ℃ for 2 hours. The mixture was cooled to 20-25 ℃ and the reaction was quenched with aqueous potassium bicarbonate (20% solution, 18 ml). Acetonitrile was removed under reduced pressure and the aqueous layer was extracted with dichloromethane (3X 15 ml). The organic phases were combined and washed with sodium chloride solution (10%, 10 ml). The solvent was replaced with methyl isobutyl ketone/heptane from dichloromethane and the title compound was crystallized with mp 198.6-199.5 °; c₂₄H₃₀O₅MS (M/z) calculated 398.5(M +), found 398.9(M +); NMR (CDCl)₃)5.69，5.64，3.62，2.97，2.84-1.47，1.38and 0.93δ；CMR(CDCl₃)98.5，176.4，172.5，166.5，142.3，125.6，118.9，95.0，51.3，43.0，40.3，35.6，35.2，34.1，33.7，32.8，31.2，29.0，27.1，23.2and 14.0δ.

Example 2017 beta-hydroxypregna-4, 9(11) -diene-3-one-7 alpha, 21-dicarboxylic acid, gamma-lactone, methyl ester (VIII)

11 α, 17 β -dihydroxypregn-4-en-3-one-7 α, 21-dicarboxylic acid, γ -lactone, methyl ester (VIII, 80.00g, 192.1mmol) was placed in a flask containing acetonitrile (80 ml). To the mixture was added N- (1, 1, 2, 3, 3, 3-hexafluoropropyl) diethylamine (40.8ml, 224.8mmol), and slowly heated to 45 to 50 ℃ and then held for 1 to 2 hours. The mixture was cooled to 20-25 ℃ and the reaction was quenched with aqueous potassium bicarbonate (72g, 288 ml). Dichloromethane (240ml) was added, and the layers were separated after mixing. The aqueous phase was extracted with dichloromethane (100 ml). The organic phases were combined and washed with water (240 ml). The solvent was replaced with methyl tert-butyl ether from methylene chloride and branched octane was added dropwise to crystallize the product, which was the title compound.

Example 2117 beta-hydroxy-7 alpha- (5 '-methyl-2' -furyl) -pregna-4, 9-dien-3-one-21-carboxylic acid, gamma-lactone (II)

Following the general procedure of example 3, using the same reactants and making non-critical changes, the title compound, CMR (100MHz, CDCl), was obtained₃)198.56，176.53，167.45，152.74，149.99，142.84，126.24，119.73，107.12，105.89，95.19，44.08，42.39，41.90，40.78，38.52，37.57，35.39，34.18，33.93，32.93，31.26，29.14，26.83，23.18，14.12and 13.38δ；NMR(400MHz，CDCl₃)0.95，1.43，1.4-2.6，2.16，2.93and 5.7δ.

Example 2217 beta-hydroxy-7 alpha- (cis-1 ', 4' -dioxopent-2 '-en-1' -yl) pregna-4, 9-dien-3-one-21-carboxylic acid, gamma-lactone (III-cis)

Following the general procedure of example 4, step A, using the same reactants and making non-critical changes, the title compound, CMR (100MHz, CDCl) was obtained₃)202.28，～200，199.05，177.19，166.56，142.34，138.49，134.39，126.37，119.90，95.57，49.63，44.90，42.39，41.08，41.04，35.82，35.75，34.49，34.07，33.25，31.71，30.12，29.64，27.49，23.76and 14.34δ；NMR(400MHz，CDCl₃)0.93，1.40，1.4-2.9，2.24，5.66，5.72，6.15and 6.28δ.

Example 2317 β -hydroxy-7 α - (2 '-hydroperoxy-2' -methoxyacetyl) pregna-4, 9(11) -dien-3-one-21-carboxylic acid, γ -lactone (IV-OOH)

Following the general procedure of example 9, using the same reactants and making non-critical changes, the title compound, CMR (100MHz, CDCl), was obtained₃)203.54，199.91，177.51，168.98，142.42，125.05，117.89，105.90，95.58，55.82，44.21，44.21，42.17，41.21，40.37，35.33，34.84，33.62，33.16，32.38，30.79，28.84，26.72，23.02and 13.55δ；NMR(400MHz，CDCl₃)0.94，1.42，1.4-2.8，3.57，4.34，4.75and 5.63δ.

Example 2417 beta-hydroxy-7 alpha- (5 '-methyl-2' -furyl) -pregna-4, 9(11) -dien-3-one-21-carboxylic acid, gamma-lactone (II)

Will be delta⁹A mixture of-canrenone (I, 105g, 0.31024mol) in acetonitrile (450ml) was treated with ethanol (21.0g, 0.4558mol, 1.47 equiv.), isopropanol (1.5ml, 1.177g, 19.592mmol, 0.063 equiv.) and 2-methylfuran (48.5g, 0.5907mol, 1.90 equiv.), then cooled to-18 ℃ and treated with boron trifluoride diethyl etherate (63.0g, 0.4439mol, 1.43 equiv.) for 4 hours. After stirring for 24 hours at-1 g °, the mixture was quenched with triethylamine (38.0g, 0.3755mol, 1.21 eq), concentrated to a viscous crystal slurry, diluted with water (350ml), extracted with dichloromethane (400ml), washed with water (350ml) then concentrated, n-propyl acetate was added and further concentrated to give a crystal slurry, cooled to 0 °, filtered, and the filter cake was washed with n-propyl acetate/methyl t-butyl ether (1/1), followed by methyl t-butyl ether to give the title compound, the retention time was determined by LC, in comparison to the sample of example 3.

Example 255 α, 17 β -dihydroxypregn-9 (11) -en-3-one, 7 α, 21-dicarboxylic acid, bis- γ -lactone (VII)

A mixture of 17 β -hydroxy-7 α - (5 '-methyl-2' -furyl) -pregna-4, 9(11) -dien-3-one-21-carboxylic acid, γ -lactone (II, example 24, 100g, 0.23778mol) and potassium acetate (50.0g, 0.5094mol, 2.14 equiv) in acetone (500ml) and water (150ml) was cooled to-10 °, treated with a crystalline slurry of dibromantin (34.0g, 0.1189mol, 0.50 molar equiv) in water (100ml) until an increase in redox potential occurred. At this point, LC analysis indicated complete conversion to enedione (C:)III-cis). The reaction mixture containing the enedione (III-cis) was then quenched with isobutyl vinyl ether (1.0ml, 0.768g, 7.668mmol, 0.032 eq.), concentrated to a viscous syrup, diluted with dichloromethane (200ml) and treated with 20 ℃ concentrated hydrochloric acid (50.0ml, 0.50mol, 2.10 eq.). The mixture was stirred at 20-25 ℃ for 2 hours, at which time LC analysis indicated complete conversion to the enedione (III-trans). The organic phase containing the enedione (III-trans) was separated, diluted with dichloromethane (80ml) and methanol (300ml) and cooled to-48 ℃. Make O be₃/O₂The gas stream was passed through the mixture until LC analysis indicated complete disappearance of the enedione (III-trans), then the mixture was quenched with dimethylsulfide (30.0ml, 25.38g, 0.4085mol, 1.72 equivalents), stirred at-20 ° for 16 hours, concentrated to a volume of about 300ml, diluted with methanol (350ml), concentrated to a volume of about 300ml, diluted with isopropanol (40ml) and methanol (80ml), then treated with a warm (55-60 °) solution of potassium bicarbonate (120g, 1.1986mol, 5.04 equivalents) in water (240 ml). The crystal slurry was cooled to 5-10 deg.C and then hydrogen peroxide (50%, 66.0g, containing 33.0g (0.9703mol, 4.08 eq.) of hydrogen peroxide) was added over a period of 3 hours. The mixture was stirred for 4 hours and quenched with dimethylsulfide (40ml, 33.84g, 0.5447mol, 2.29 eq). After stirring at 20-25 ° for 23 h, the mixture was diluted with dichloromethane (100ml) and water (80ml) and acidified to pH 3.0 with concentrated hydrochloric acid. The biphasic mixture was heated to 36 ℃ and the phases were separated and the aqueous phase extracted with dichloromethane (100 ml). The organic phases were combined, washed with water (75ml) and the aqueous phase back-extracted with dichloromethane (25 ml). The organic phases were combined, concentrated to a volume of 150ml and then treated with benzenesulfonic acid (1.0g of 90% pure material containing 0.90g (5.690mmol, 0.0239 equivalents) of benzenesulfonic acid) and acetone (50 ml). The mixture was then concentrated to a volume of 160ml under atmospheric air, then diluted with acetone (250ml), concentrated to a volume of 200ml, cooled to 12 °, and filtered. The filter cake was washed with cold acetone (2X 25ml) and dried under a stream of nitrogen to give the title compound, CMR (100MHz, CDCl)₃)206.08，176.47，175.41，139.63，124.00，94.89，90.97，47.08，43.90，42.36，41.58，41.07，38.93，36.97，35.16，33.01，32.42，32.42，31.35，29.10，23.08，22.98and 14.23δ；NMR(400MHz，CDCl₃)0.94，1.40，1.4-2.8and 5.70；MS(CI，NH₃)m/e＝385(P+H，100％).

Example 2617 beta-hydroxy-7 alpha-carbomethoxypregn-4, 9(11) -dien-3-one-21-carboxylic acid, gamma-lactone (VIII)

A mixture of 5 α, 17 β -dihydroxypregn-9 (11) -en-3-one 7 α, 21-dicarboxylic acid, bis- γ -lactone (VII, example 25, 50.0g, 0.13005mol) and potassium bicarbonate (16.92g, 0.1690mol, 1.30 equivalents) in acetone (200ml) and water (100ml) was stirred at 45 ℃ for 2 hours, at which time the conversion of 5, 7-lactone (VII) to carboxylic acid (VI) was complete, as determined by LC. The resulting mixture was then treated with dimethyl sulfate (22.92g, 0.1817mol, 1.40 equivalents), stirred at 45 ℃ for 3 hours, and then treated with a solution of potassium bicarbonate (1.3g, 0.0130mol, 0.100 equivalents) in water (10ml), followed by neat triethylamine (1.81ml, 1.314g, 0.0130mol, 0.100 equivalents). The mixture was stirred at 45 ℃ for 1 hour, quenched with concentrated hydrochloric acid (1.92ml, 2.304g, containing 0.852g (0.0234mol, 0.180 eq) hydrochloric acid), cooled to 0 ℃, concentrated under reduced pressure to a volume of 150ml (pot temperature 13 ℃) and then filtered, the filter cake was washed with water (2X 25ml) and dried to give the title compound which was compared with the real sample by means of LC.

Example 2717 β -hydroxy-7 α - (5 '-tert-butyl-2' -furyl) -pregna-4, 9(11) -dien-3-one-21-carboxylic acid, γ -lactone (II)Will be delta⁹A mixture of-canrenone (I, 3.0002g, 8.8645mmol) and 2-tert-butylfuran (2.53ml, 2.204g, 17.745mmol, 2.00 equiv.) in nitromethane (12.0ml) was treated with ethanol (0.52ml, 413mg, 8.96mmol, 1.01 equiv.), cooled to-20 deg.C, treated with boron trifluoride diethyl etherate (1.24ml, 1.389g, 9.785mmol, 1.10 equiv.). Mixing the obtained mixtureThe material was stirred at-20 ℃ for 24 hours, then-5 ℃ for 12 hours, then 0 ℃ for 4 hours, at which point about 90% of the reaction was complete according to TLC. The reaction was quenched with ammonium hydroxide (7%, 30ml), extracted with dichloromethane (3 × 50ml), dried over magnesium sulfate and concentrated. The concentrate was subjected to flash chromatography (silica gel 150 g; gradient elution 10% → 50% ethyl acetate/cyclohexane). The fractions containing pure product were combined and concentrated to give the title compound, CMR (100MHz, CDCl)₃)198.56，176.53，167.87，162.48，153.02，142.91，125.84，119.42，106.70，101.88，95.21，44.05，42.87，41.90，40.84，38.17，37.80，35.52，34.20，34.02，32.97，32.40，31.33，29.18，28.71，26.79，23.17and 14.14δ；NMR(400MHz，CDCl₃)0.95，1.16，1.45，1.5-2.6，2.94，3.30，5.64，5.72and 5.76δ.

Example 2811 α, 17 β -dihydroxy-7 α - (5 '-tert-butyl-2' -furyl) -pregn-4-en-3-one-21-carboxylic acid, γ -lactone (II)

A mixture of 11 α -hydroxycarvenone (I, 2.03g, 5.6947mmol) and 2-tert-butylfuran (1.70ml, 1.481g, 11.924mmol, 2.09 equivalents) in nitromethane (16ml) was cooled to-20 °, treated with ethanol (0.35ml, 0.276g, 5.99mmol, 1.05 equivalents) and boron trifluoride diethyl etherate (0.83ml, 0.930g, 6.550mmol, 1.15 equivalents), and stirred at-20 ℃ for 21 hours, at which time LC analysis indicated that the reaction was complete. The reaction mixture was then quenched with ammonium hydroxide (15%, 5.5ml), diluted with water, extracted with dichloromethane (2X 25ml), dried over magnesium sulfate, filtered through 5.0g of magnesium acid silicate, concentrated to a foam and subjected to flash chromatography (silica gel 200 g; gradient elution 20% → 70% ethyl acetate/cyclohexane). The fractions containing the product were combined and concentrated to give the title compound, UV. lamda_max＝238mμ。

Example 2911 α, 17 β -dihydroxy-7 α - (4 '-bromo-2' -furyl) -pregn-4-en-3-one-21-carboxylic acid, γ -lactone (II)

A mixture of 11 α -hydroxycarvenone (I, 2.0g, 5.6425mmol), ethylene glycol (0.84ml, 0.935g, 15.06mmol, 2.67 equiv.) and 3-bromofuran (3.0ml, 4.905g, 33.372mmol, 5.91 equiv.) in nitromethane (32ml) was treated with boron trifluoride diethyl etherate (1.4ml, 1.568g, 11.048mmol, 1.96 equiv.) at 20-25 ℃ and stirred for 20 h at 20-25 ℃ at which point > 80% was complete according to the LC reaction. The reaction was then quenched with water, extracted with ethyl acetate, and concentrated to give a foam which was dissolved in dichloromethane (10ml) and subjected to flash chromatography (silica gel 150 g; gradient elution 0 → 6% isopropanol/dichloromethane). The fractions containing the product were then combined and chromatographed again (silica gel 100 g; gradient elution 0 → 5% isopropanol/dichloromethane). The product-containing fractions were combined and crystallized from ethyl acetate/cyclohexane (1/2) to give the title compound, CMR (100MHz, CDCl)₃)199.77，176.54，168.67，152.83，142.43，126.05，113.41，98.03，95.02，69.19，53.51，46.26，46.19，43.40，39.57，38.72，38.05，37.48，35.39，34.77，34.24，31.09，29.11，22.68，18.46and15.84δ；NMR(400MHz，CDCl₃)0.9-2.9，1.03，1.42，3.35，4.11，6.36and 7.26δ；MS(CI，NH₃)m/e＝503，505(100％，P+H).

Example 3011 α, 17 β -dihydroxy-7 α - (4 '-methyl-2' -furyl) -pregn-4-en-3-one-21-carboxylic acid, γ -lactone (II)

A mixture of 11 α -hydroxycarvenone (I, 816mg, 2.2891mmol) and 3-methylfuran (4.0ml of a 1.218M solution in nitromethane, 4.87mmol, 2.13 eq.) in nitromethane (4.0ml) was cooled to-20 ° and quenched with ethylene glycol (0.168ml, 187Mg, 3.01mmol, 1.32 equiv), followed by boron trifluoride diethyl etherate (0.284ml, 318mg, 2.241mmol, 0.98 equiv). The resulting mixture was stirred at-20 ℃ for 20 hours, at which point 86% was complete according to the LC reaction. The reaction mixture was quenched with aqueous ammonium hydroxide (15%, 4ml), diluted with water (10ml), extracted with dichloromethane (2 × 20ml), dried over magnesium sulfate and concentrated. The concentrate was subjected to flash chromatography (silica gel 60 g; gradient elution 50% → 100% ethyl acetate/cyclohexane). The fractions containing the product were combined and concentrated. The concentrate was crystallized from cyclohexane/ethyl acetate (4/1) to give the title compound, CMR (100MHz, CDCl)₃)199.91，176.62，170.02，150.94，140.81，125.57，115.27，112.29，95.07，69.16，53.50，46.13，45.99，43.24，39.52，39.46，38.14，37.35，35.32，34.18，31.05，29.07，22.28，18.46，15.79and 10.21δ；NMR(400MHz，CDCl₃)1.04，1.0-2.9，1.42，1.96，3.14，4.12，5.34，6.12and 7.15δ；MS(CI，NH₃)m/e＝439(100％，P+H).

Example 3117 beta-hydroxy-7 alpha- (5 '-methyl-2' -furyl) -pregna-4, 9(11) -dien-3-one-21-carboxylic acid, gamma-lactone (II)

Ishikawa reagent (2.4mK, 13.7mmol) was added to a solution of 11 α, 17 β -dihydroxy-7 α - (5 '-methyl-2' -furyl) -pregn-4-en-3-one-21-carboxylic acid, γ -lactone (II, example 12, 5g, 11.4mmol) in acetonitrile (25 ml). The mixture was heated to 60 ° and completed within 1 hour according to HPLC determination. The resulting mixture was cooled to 22 ℃ and quenched with saturated aqueous sodium bicarbonate (15 ml). The organic solvent was removed under reduced pressure and replaced with methylene chloride (50 ml). The organic phase was separated, washed with water (30ml) and concentrated to a volume of 20 ml. Water (30ml) was added and the mixture was concentrated to a volume of 20 ml. This water distillation was repeated twice to remove the N, N-diethyl-2, 3, 3, 3-tetrafluoropropionamide by-product. Then, methylene chloride (30ml) was added to the resulting crystal slurry to dissolve all solids. The organic layer was separated and the solvent was replaced with n-propyl acetate to a final volume of 17-18 ml. The resulting crystal slurry was cooled to-20 ℃ for 12 hours. The product was collected by filtration and dried under ambient nitrogenDrying to give the title compound, mp 198-; NMR (400MHz, CDCl)₃)5.737，5.690，3.300，2.904，2.164，1.431，0.952and 2.569-1.358δ；CMR(100MHz，CDCl₃)198.5，176.5，167.4，152.7，150.0，142.8，126.2，119.7，107.1，105.9，95.2，44.1，42.4，41.9，38.5，37.6，35.4，33.9，32.9，31.3，29.1，26.8，23.2，14.1and 13.4δ；MScalculated for C₂₇H₃₃O₄＝421.238(M+H⁺)，found＝421.2m/z.

Example 329 a, 11 a-epoxy-17 ss-hydroxypregn-4-en-3-one-7 a, 21-dicarboxylic acid, y-lactone (VI)

A mixture of 17 β -hydroxy-7 α - (2' -oxoacetyl) -pregna-4, 9(11) -dien-3-one-21-carboxylic acid, γ -lactone (V, example 11, 6.7mg, 0.0169mmol) in dichloromethane (0.5ml) was treated with peracetic acid (35%, 4 μ l, containing 1.58mg, 0.0208mmol, 1.23 equivalents of peracetic acid), stirred at 20-25 ℃ for 25 hours, then treated with more peracetic acid (35%, 2 μ l, containing 79mg, 0.0104mmol, 0.62 equivalents of peracetic acid), and then stirred at 20-25 ℃ for 49 hours, at which time LC analysis indicated conversion to the title compound, LC-UV (. lamda.) (Lambda.) (LC-UV)_max＝244nm)；LC-MS(m/e 400)。

Example 337 alpha-allyl-17 beta-hydroxypregna-4, 9(11) -dien-3-one, 21-carboxylic acid, gamma-lactone (II)

A mixture of 17 β -hydroxypregna-4, 6, 9(11) -trien-3-one-21-carboxylic acid, γ -lactone (I, 1.0171g, 3.0052mmol) in dichloromethane (62ml) was cooled to-30 °, treated with a solution of titanium tetrachloride in dichloromethane (1.0M, 15.0ml, 15.0mmol, 4.99 equivalents). Using allyl to the mixtureTrimethylsilyl (3.0ml, 2.16g, 18.876mmol, 6.28 equiv.) was treated and stirred at-30 ℃ for 4 h, at which time the starting material was determined by TLC to the product (R)_f0.27) was almost complete (ethyl acetate/cyclohexane 35/65). The reaction mixture was quenched with water (25ml), extracted with dichloromethane (3X 25ml) and concentrated. The concentrate (1.6262 g) was subjected to flash chromatography (silica gel 150 g; gradient elution with ethyl acetate/cyclohexane 15% → 55%). Combining fractions containing more polar products (R)_f0.27) to yield the title compound, UV λ_max＝241nm；CMR(100MHz，CDCl₃)198.65，176.46，167.31，143.22，136.36，126.51，119.84，116.80，95.22，44.15，42.50，41.13，40.73，37.33，35.56，35.43，34.13，33.78，33.05，31.65，31.37，29.14，26.86，23.04，and 13.78δ；NMR(400MHz，CDCl₃)0.94，1.37，1.4-2.6，4.95，5.01，5.65and 5.74δ；MS(CI，NH₃)，m/e＝381(P+H，100％)。

The product was chromatographed again (silica gel 60 g; eluting with a gradient of ethyl acetate/cyclohexane 15% → 45%) to remove the more polar impurities (R)_f0.06). The fractions containing the product were combined and concentrated. A portion of the residue (96.8mg) was dissolved in dichloromethane (1ml), diluted with ethyl acetate (2ml), concentrated to a volume of less than 1ml and cooled to 0 °. The supernatant was decanted and the crystals were recrystallized from ethyl acetate at 0 °. X-ray crystallography studies confirmed that 7 α -allyl-17 β -hydroxypregna-4, 9(11) -dien-3-one, 21-carboxylic acid, γ -lactone.

Example 345 alpha, 17 beta-dihydroxypregn-9 (11) -en-3-one, 7 alpha, 21-dicarboxylic acid, bis-gamma-lactone (VII)

Step (1) -17 β -hydroxypregna-4, 9(11) -diene-3-one-7 α, 21-dicarboxylic acid, γ -lactone (VI)

A mixture of 17 β -hydroxy-7 α - (5 '-methyl-2' -furyl) -pregna-4, 9(11) -dien-3-one-21-carboxylic acid, γ -lactone (II, example 3, 20g, 47.5568mmol) in methanol (60ml) and dichloromethane (60ml) was cooled to-55 °. Oxygen containing ozone was bubbled through the mixture until 0.8 area% (LC) of starting material (II) remained. The mixture was sparged with nitrogen to scavenge ozone, then quenched with dimethyl sulfide (16ml, 13.5g, 217.9mmol, 4.58 equiv), warmed to 20-25 °, and stirred at 20-25 ° for 50 minutes. The resulting mixture was concentrated to 80ml, methanol (25ml) was added, and concentrated again to 80 ml. The mixture was then treated with a solution of potassium bicarbonate (21.6g, 215.7mmol, 4.54 equivalents) in water (44ml) at 5 ℃ followed by hydrogen peroxide (50% aqueous, 23.5g, containing 11.75g (345.5mmol, 7.27 equivalents) of hydrogen peroxide). After warming to 20-30 ℃ for 1 h, the mixture was quenched with dimethylsulfide (8ml, 6.75g, 108.95mmol, 2.29 eq). Dichloromethane (20ml) was added and the pH adjusted to 3 with hydrogen chloride (31.5% aqueous, 26.0g, containing 8.19g (224.4 mmol; 4.72 equivalents) of hydrogen chloride). The mixture was warmed to dissolve and the phases separated. The upper aqueous phase was extracted with dichloromethane (10ml) and the organic phases were combined and extracted with water (10 ml). The LC was performed on a dichloromethane mixture (after aqueous workup) under the following conditions:

column: supelco Discovery RP Amide C16; 5 mu, and then mixing the solution with the mixture; 250mm x 4mm

Flow rate: 1ml/min

And (3) detection: UV; 240nm

Mobile phase: a: 950g of water; 39g of acetonitrile; 1.0g trifluoroacetic acid

B: 754g of acetonitrile; 39g of water; 1.0g trifluoroacetic acid

Gradient: t is₀：80％A/20％B

T₁₅：20％A/80％B

T_15.1：80％A/20％B

T₂₀：80％A/20％B

Operating time: 20 minutes

Flow rate: 1ml/min

Injection volume: 5 lambda

Sample preparation: add 5. lamda. or reaction mixture to 1ml 1/1 acetonitrile: phosphate buffer (1ml 1L aqueous solution of phosphoric acid; pH adjusted to 2.4 with sodium hydroxide)

The main reaction LC peak (72 area%) was at 10.52 min; the retention time of the carboxylic acid (VI) standard is known to be 10.52 minutes.

Step (2) -5 α, 17 β -dihydroxypregn-9 (11) -en-3-one, 7 α, 21-dicarboxylic acid, bis- γ -lactone (VII)

The resulting organic phase containing 17 β -hydroxypregna-4, 9(11) -dien-3-one-7 α, 21-dicarboxylic acid, γ -lactone (VI) was concentrated to 40ml and a solution of p-toluenesulfonic acid monohydrate (10 mg; 0.042 mmol; 0.001 equiv) in acetone (15ml) was added. Crystallization was observed after 30 minutes at reflux. The resulting crystal slurry was concentrated to 50ml, and concentration was continued while adding fresh acetone to maintain the volume constant. After 80ml of acetone had been added, the crystal slurry was cooled to 0 ℃ and the solid collected by filtration to give the title compound, CMR (100MHz, CDCl)₃)206.07，176.44，175.41，139.66，123.98，94.88，90.99，47.09，43.91，42.36，41.57，41.08，38.93，36.98，35.17，33.01，32.44，31.36，29.10，23.08，22.99and 14.24δ；NMR(400MHz，CDCl₃)0.94，1.41，1.5-2.6，2.80and 5.70δ.

Example 3517 beta-hydroxypregna-4, 9(11) -diene-3-one-7 alpha, 21-dicarboxylic acid, gamma-lactone, methyl ester (CII)

11 α, 17 β -dihydroxypregn-4-en-3-one-7 α, 21-dicarboxylic acid, γ -lactone, methyl ester (CI, Drugs of the Future, 24(5), 488-501(1999), compound (VI) and International publication WO98/25948, pages 76 and 280; 5.00g, 12.0mmol) were mixed with acetonitrile (15 ml). To the steroid mixture was added N- (1, 1, 2, 3, 3, 3-hexafluoropropyl) diethylamine (CVI, 2.55ml, 14.4mmol) and heated to 60 ℃ for 2.5 hours. The resulting mixture was cooled to 20-25 ℃ and the reaction was quenched with methanol (100. mu.L). Saturated aqueous potassium bicarbonate (15ml) was added. The acetonitrile was then removed under reduced pressure. The resulting mixture was extracted with dichloromethane (3X 10 ml). The organic phases were combined and washed with aqueous sodium chloride (10%, 20 ml). The solvent was dried over magnesium sulfate. The solvent was replaced from dichloromethane to methyl tert-butyl ether (MTBE). The mixture was concentrated to a final volume of 25 ml. The resulting crystal slurry was stirred overnight and the final product, the title compound, was collected by filtration.

Example 3617 beta-hydroxypregna-4, 9(11) -diene-3-one-7 alpha, 21-dicarboxylic acid, gamma-lactone, methyl ester (CII)

11 α, 17 β -dihydroxypregn-4-en-3-one-7 α, 21-dicarboxylic acid, γ -lactone, methyl ester (CI, 5.00g, 12.0mmol) was placed in a flask containing acetonitrile (15 ml). Ishikawa reagent (2.55ml, 14.4mmol) was added to the mixture and heated to 60 ℃ for 2 hours. The mixture was cooled to 20-25 ℃ and the reaction was quenched with aqueous potassium bicarbonate (20% solution, 18 ml). Acetonitrile was removed under reduced pressure and the aqueous layer was extracted with dichloromethane (3X 5 ml). The organic phases were combined and washed with sodium chloride solution (10%, 10 ml). The solvent was replaced with methyl isobutyl ketone/heptane from dichloromethane and the title compound was crystallized with mp 198.6-199.5 °; MS (m/z) calculated for C₂₄H₃₀O₅＝398.5(M+)，found398.9(M+)；NMR(CDCl₃)5.69，5.64，3.62，2.97，2.84-1.47，1.38and 0.93δ；CMR(CDCl₃)98.5，176.4，172.5，166.5，142.3，125.6，118.9，95.0，51.3，43.0，40.3，35.6，35.2，34.1，33.7，32.8，31.2，29.0，27.1，23.2and 14.0δ.

Example 3717 beta-hydroxypregna-4, 9(11) -diene-3-one-7 alpha, 21-dicarboxylic acid, gamma-lactone, methyl ester (CII)

11 α, 17 β -dihydroxypregn-4-en-3-one-7 α, 21-dicarboxylic acid, γ -lactone, methyl ester (CI, 80.00g, 192.1mmol) was placed in a flask containing acetonitrile (80 ml). Ishikawa reagent (40.8ml, 224.8mmol) was added to the mixture, heated slowly to 45 to 50 ℃ and then held for 1-2 hours. The mixture was cooled to 20-25 ℃ and the reaction was quenched with aqueous potassium bicarbonate (72g of 288ml solution). Dichloromethane (240ml) was added, and the layers were separated after mixing. The aqueous phase was extracted with dichloromethane (100 ml). The organic phases were combined and washed with water (240 ml). The solvent was replaced with methyl tert-butyl ether from methylene chloride and branched octane was added dropwise to crystallize the product, which was the title compound.

Example 3817 beta-hydroxypregna-4, 9(11) -diene-3-one-7 alpha, 21-dicarboxylic acid, gamma-lactone, methyl ester (CII)

11 α, 17 β -dihydroxypregn-4-en-3-one-7 α, 21-dicarboxylic acid, γ -lactone, methyl ester (CI, 80.00g, 192.1mmol) was placed in a flask containing acetonitrile (80 ml). Ishikawa reagent (40.8ml, 224.8mmol) was added to the mixture, heated slowly to 55 to 50 ℃ and then held for 1-2 hours. The mixture was cooled to 20-25 ℃ and the reaction was quenched with aqueous potassium bicarbonate (37.3g of 288ml solution). Dichloromethane (240ml) was added, and the layers were separated after mixing. The aqueous phase was extracted with dichloromethane (100 ml). The organic phases were combined and washed with water (80 ml). The solvent was replaced with methyl isobutyl ketone from methylene chloride and branched octane was added dropwise to crystallize the product, which was the title compound.

FIG. A

When R is_7-1Is (-A1)

Graph A-continuation

FIG. B

FIG. C

Drawing D

When R is_7-1Is (-A1)

Drawing D continues

Drawing D-continuation

FIG. E

FIG. E-continuation

FIG. F

Drawing G

When R is_7-1Is (-A2)

Drawing G-continuation

FIG. H

When R is_7-1Is (-B), (-C) or (-D1, -D2, -D3)

FIG. I

FIG. J

FIG. K

FIG. K-continuation

FIG. L

Drawing M

Or

FIG. N

Or

Drawing N-continuation

Diagram O

FIG. 0 shows a continuation of

FIG. 0-continuation

Claims

1. A compound having the structure:

wherein:

X₁selected from the group consisting of-S-and-O-;

R_bis selected from the group consisting of-H and C₁-C₄Alkyl groups;

R_cis selected from the group consisting of-H, C₁-C₄Alkyl, -F, -Cl, -Br, and-I;

R_dis selected from the group consisting of-H and C₁-C₁₀Alkyl groups;

R₉and R_11aTogether with-O-to form an epoxide; and

R_17aand R_17bTogether form ═ O; or R_17aIs alpha-CH₂-CH₂-CO-O^-And R is_17bIs beta-OH; or R_17aIs alpha-C.ident.C-H and R_17bIs beta-OH; or R_17ais-C ≡ C-CH₂-OH and R_17bIs H; or R_17aAnd R_17bTogether with the attached carbon atom form:

2. the compound of claim 1, wherein X₁is-O-and R_bis-H.

3. The compound of claim 1, wherein:

X₁is-O-;

R_bis-H;

R_cis-H;

R_dis C₁-C₁₀An alkyl group; and

R_17aand R_17bTogether form ═ O; or

R_17aIs alpha-CH₂-CH₂-CO-O^-And R is_17bIs beta-OH; or

R_17aAnd R_17bTogether with the attached carbon atom form:

4. the compound of claim 3, wherein R_17aAnd R_17bTogether with the attached carbon atom form:

5. the compound of claim 3, wherein R_17aAnd R_17bTogether form ═ O.

6. The compound of claim 3, wherein R_17aIs alpha-CH₂-CH₂-CO-O^-And R is_17bIs beta-OH.

7. The compound of claim 4, wherein R_dIs methyl.

8. The compound of claim 4, wherein R_dIs a tert-butyl group.

9. The compound of claim 1, having the structure:

10. a compound having the structure:

wherein:

X₁selected from the group consisting of-S-and-O-;

R_bis selected from the group consisting of-H and C₁-C₄Alkyl groups;

R_dis selected from the group consisting of-H and C₁-C₁₀Alkyl groups;

R₉is-H and R_11ais-OH; and

11. the compound of claim 10, wherein:

X₁is-O-;

R_bis-H;

R_cis-H;

R_dis C₁-C₁₀An alkyl group; and

R_17aand R_17bTogether form ═ O; or

R_17aIs alpha-CH₂-CH₂-CO-O^-And R is_17bIs beta-OH; or

R_17aAnd R_17bTogether with the attached carbon atom form:

12. the compound of claim 11, wherein R_17aAnd R_17bTogether with the attached carbon atom form:

13. the compound of claim 11, wherein R_17aAnd R_17bTogether form ═ O.

14. The compound of claim 11, wherein R_17aIs alpha-CH₂-CH₂-CO-O^-And R is_17bIs beta-OH.

15. The compound of claim 10, having the structure:

16. the compound of claim 10, having the structure:

17. the compound of claim 10, having the structure:

18. the compound of claim 10, having the structure: