JP2007217409A - Processes and intermediates for the preparation of prostaglandins - Google Patents

Abstract

該化合物は、シクロペンテノン誘導体に、ビニルハライド類との共役付加反応により合成できる。
【選択図】なしA cyclopentanone derivative useful for the production of prostaglandins and a method for synthesizing the same are provided.
A cyclopentanone derivative represented by the following formula II:

The compound can be synthesized by a conjugate addition reaction with a vinyl halide to a cyclopentenone derivative.
[Selection figure] None

Description

  The present invention relates to novel processes and intermediates for preparing prostaglandins and derivatives thereof.

  Prostaglandins and their derivatives have various biological effects such as vasodilatory action, prophogistic action, platelet aggregation inhibitory action, uterine muscle contraction action, intestinal contraction action, and intraocular pressure reduction action. It can be used for the treatment or prevention of infarction, angina pectoris, arteriosclerosis, hypertension, and duodenal ulcer, and is useful in various applications for humans and animals.

  Over the past decades, many academic researchers and industrial institutions have been instrumental in exploring a variety of important intermediates for innovative prostaglandin synthesis processes that are efficient and cost-saving (Non-Patent Document 1).

  Specifically, Formula I:

Is a very important intermediate in the latter half of the synthesis of the prostaglandin 2α compound.

For example, a lactone represented by I-1 or I-2 (wherein R ₂ represents methylene and R ₃ represents n-butyl) is a natural prostaglandin F ₂ α, E ₂ and I ₂ . It is an important intermediate for synthesis and is reported in Non-Patent Documents 2 and 3.

Lactone represented by formula I-1 or I-2 (wherein R ₂ represents methylene and R ₃ represents benzyl) is an excellent intermediate for bimatoprost synthesis, and is disclosed in Patent Document 1. Has been.

Lactones represented by formula I-1 or I-2 (wherein R ₂ represents —CH ₂ O— and R ₃ represents substituted phenyl) are (+)-cloprostenol, travoprost and ( It is an intermediate for the synthesis of (+)-fluprostenol and is described in US Pat.

A lactone represented by formula I-3 (wherein R ₂ represents methylene and R ₃ represents benzyl) is an intermediate for synthesizing latanoprost and is disclosed in Patent Document 4.

  Industrially, the lactone of formula I is derived from the famous intermediate III (so-called cholaldehyde) from the following scheme 1:

Wherein P is a protecting group and R ₂ and R ₃ are as defined above.

The synthesis of Coryaldehyde III (Cori's process) consists of more than 12 continuous reaction steps using cyclopentadiene as the starting material. In the Kori process, not only is it difficult to proceed reproducibly but usually the yield of the final target compound obtained is low. Furthermore, the main problem of the Cori process is related to the low selectivity for the reduction of the 15-ketone function of the ω-side chain (Scheme 1), and in many cases a significant amount as a major impurity. 15β-isomer is produced (Non-Patent Documents 4 to 7). In order to remove the 15β-isomer, it is necessary to use column chromatography in the Cori process in order to separate the isomer that has almost the same R _f value as the target product. It is not preferable.

  Kalnins A. Have a double formula represented by formula II-1a by conjugate addition of a racemic cyclopentenone represented by formula IV-a and a cue plate derived from a racemic vinyl halide represented by formula V-1a. The preparation of racemic cyclopentanone was reported (Non-patent Document 8). Further, the cyclopentanone represented by the formula II-1a thus obtained was purified by column chromatography to remove excess 15β-isomer represented by the formula II-1b and then reduced / lactone To give a racemic lactone represented by the formula I-1a.

  The foregoing approach appears to be a shortcut for synthesizing cyclopentanone and lactones, which are excellent intermediates for prostaglandin synthesis. Unfortunately, the reported yields are low (about 27%) and a considerable amount of 15β-isomer (about 24%) was observed. Problems related to the formation of various diastereomers (eg, 8-isomer and 11-isomer) in the conjugate addition reaction are overlooked and unexamined. Most importantly, the 15α isomer represented by Formula II-1a, the 15β-isomer represented by Formula II-1b and the following Formula II-2a:

None of the unprotected compounds represented by is non-crystalline (Non-Patent Documents 9 to 11), and therefore an industrially feasible purification method (for example, crystallization) for removing undesirable isomers. It cannot be used and purification to further reduce the isomer content can only be done by column chromatography, which makes commercial production difficult.

The cyclopentanone of formula II used for the further synthesis of prostaglandin products for pharmaceutical use, in particular for human use, should be of high enantiomeric and high diastereomeric purity. . However, some of the prior art documents show high enantiomeric and high diastereomeric purity due to conjugate addition of optically enriched cyclopentenone represented by formula IV and vinyl halide represented by formula V-1. None have focused on the preparation of cyclopentanones of formula II having
US Patent Application Publication No. 2005/0209337 European Patent Application No. 0362686 US Patent Application Publication No. 2005/0209337 US Pat. No. 5,359,095 Colllines P.M. W. Et al., 1993, Chem. Rev. 93, 1533 E. J. et al. Corey et al., 1970, J. MoI. Am. Chem. Soc. , 92, 397 E. J. et al. Corey et al., 1977, J. MoI. Am. Chem. Soc. , 99, 2006 Corey et al., 1987, J. Am. Am. Chem. Soc. 109, 7925 Cori et al., 1972, J. MoI. Am. Chem. Soc. , 94, 8616 Cori et al., 1971, J. MoI. Am. Chem. Soc. 93, 1491 Noyori et al., 1979, J. MoI. Am. Chem. Soc. , 101, 5843 Zhurnal Organicheskoi Kimii (1988), 24 (4), 742 Latvijas PSR Zinatnu Akademijas Vestis, Kimijas Serija 1990, 1, 78 Zhurnal Analitechkoi Kimii 1985, 40, 872; Journal of Organic Chemistry, 1984, 49, 5279 Latvijas PSR Zinatnu Akademijas Vestis, Kimijas Serija, 1983, 5, 556

The following describes some of the problems that may arise from the asymmetric process described above.
(1) Mechanism of chirality transfer

  There are no studies on the asymmetric synthesis of cyclopentanone represented by formula II that have been described in publications. From the cyclopentenone represented by formula IV to the cyclopentanone represented by formula II There is no known way to move it. Since there is no further optical resolution step performed in the final process (starting from the cyclopentanone represented by Formula II to the final prostaglandin) to further increase the optical purity, the final target prostaglandin The enantiomeric purity of is determined purely by the enantiomeric purity of the cyclopentanone of formula II. Therefore, in order to obtain a prostaglandin product having a high enantiomeric purity from the cyclopentanone represented by the formula II, it is important to obtain the cyclopentanone having a very high optical purity. This not only requires the optical purity of the cyclopentenone represented by formula IV, which is a substrate for the conjugate addition reaction, to be expressed by formula II from the cyclopentenone represented by formula IV. This means that it is necessary to move the chirality to 100% of cyclopentanone. However, the prior art has not paid attention to the study of the chirality transfer mechanism in the asymmetric conjugate addition reaction.

(2) Removal of 15β-isomer formation or minimization of isomer formation in the production of cyclopentanone represented by formula II

  The 15β-isomer has been considered one of the most difficult diastereomers to remove from prostaglandin products or related intermediates. This is because other diastereomers differ in orientation on the cyclopentane ring from the desired product, whereas the 15β-isomer has only a slightly different side chain structure. As a recent pharmacopoeia trend, it is desirable to reduce the content of 15β-isomer to less than 0.10% (Pharmacopoeia Forum 31 (4), [July-Aug. 2005], 1119). The amount of 15β-isomer produced in the production of cyclopentanone represented by Formula II may be directly related to the optical purity of the vinyl halide represented by Formula V-1, but the enantiomeric excess (e E.) When cyclopentanone of formula II is prepared from 100% of the vinyl halide of formula V-1, there is no evidence that the cyclopentanone is definitely free of the 15β-isomer. In the production of cyclopentanone represented by formula II, problems remain with minimizing the residual 15β-isomer content.

(3) Removal of 8-isomer and 11-isomer in the production of cyclopentanone represented by formula II

  In the conjugate addition reaction, formation of 8-isomer and 11-isomer cannot be avoided. There remains a problem with how to efficiently remove these two isomers.

  As described above, Kalnins A.I. Reported the preparation of racemic lactone I-1a by reduction / lactonization of racemic cyclopentanone of formula II-1a:

  A similar reduction / lactonization reaction is also described in Marino J. et al. P. Et al. Org. Chem. 1984, 49, 5279 reported as the following reaction:

  In addition, the next reaction was performed by Beraldi P. et al. G. (Tetrahedron, 1987, 43, 4669):

In the above reaction, the 9β-isomer of formula VII which is a by-product resulting from the reduction reaction cannot be lactonized due to steric hindrance and can therefore be easily removed from the desired lactone. The reaction reported in the prior art is carried out only when R ₁ is lower alkyl. In the present invention, R ₁ is preferably bulky, and the results are expected to be different. When the reduction product (ie hydroxyl ester) has a bulky R ₁ , it does not lactonize easily, and as a result, it is difficult to remove the 9β-isomer from the 9α-isomer of the hydroxyl ester. . However, there are no related studies reporting on the preparation of lactones of formula I which are carried out by reducing / lactonizing cyclopentanones of formula II when R ₁ is bulky alkyl, aralkyl or aryl.

As mentioned above, conventional approaches for the production of lactones of formula I face various problems to be solved.
The present invention provides a simple and cost effective lactone of formula I in order to eliminate the various problems associated with conventional processes in terms of the length of the synthetic route or in the need to remove unwanted isomers. It aims to provide a high synthetic route.

  The present invention provides an asymmetric process for the synthesis of lactones of formula I. The present invention is based on two unexpected findings. The first finding is that the enantiomeric purity of the cyclopentanone of formula II, which is a conjugated addition product, is greatly improved, and is higher than the enantiomeric purity of each substrate represented by formula IV and formula V in the conjugate addition reaction. is there. This phenomenon showing improved chirality in the reaction does not require that each substrate represented by Formula IV and Formula V be of high optical purity, with an optical purity of about 90% e.e. e. This indicates that it is sufficient for the preparation of high enantiomeric purity cyclopentanone of formula II. This optical purity is 95% e.e. e. It is preferably greater than 99.8% e.e. e. More preferably, it is super. This greatly reduces the production cost of the target product.

  The second finding is that in the prior art Formula II-1a:

(Wherein, R1 is methyl, R2 is methylene, R3 is a is n- butyl) but non-protected form of the racemic cyclopentanone represented by was reported as an oil, methyl and R ₁ It is to be observed that the resulting cyclopentanone shows good crystallinity (mp: 62 ° C.) simply by changing from 1 to ethyl. Furthermore, it has been found that the crystallinity can be further improved when R1 is a more bulky structure such as aralkyl, aryl or a substituted product thereof. Similar findings are obtained when R ₂ and R ₃ are different from methylene and n-butyl, respectively. This good crystallinity allows more efficient removal of the undesired diastereomers, especially the 15β-isomer, produced by the conjugate addition reaction.

  Based on these discoveries, the present invention provides a novel asymmetric process advantageous for the commercial production of lactones of formula I with high enantiomeric and high diastereomeric purity. In particular, the lactone of formula I produced by the process contains less than 1%, preferably less than 0.5%, more preferably less than 0.1% of its enantiomer and 15β-isomer.

  In another aspect, the present invention provides a compound of formula II:

（式中、Ｚは、カップリング及び脱保護反応に関与しないが、還元／ラクトン化反応において脱離基として作用する任意の基であり；Ｒ₂、Ｒ₃、Ｘ₁、Ｘ₂及び

(Wherein Z is any group that does not participate in the coupling and deprotection reactions, but acts as a leaving group in the reduction / lactonization reaction; R ₂ , R ₃ , X ₁ , X ₂ and

Preferably 95% e.e. e. , More preferably 99% e.e. e. Novel enantiomer-enriched cyclopentanone and a process for the preparation of said cyclopentanone.

DEFINITIONS As used herein, the term “alkyl” means a straight or branched hydrocarbon group having 1 to 30 carbon atoms such as methyl, ethyl, isopropyl, tert-butyl, or cyclopropyl, cyclopentyl, cyclohexyl, menthyl. Means a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms, such as

  The term “lower alkyl” as used herein means alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl and the like.

  As used herein, the term “alkenyl” refers to a straight or branched hydrocarbon group having 3 to 20 carbon atoms having one or more carbon-carbon double bonds such as pentenyl, propenyl, or cyclopentenyl, cyclopentyl, and the like. A C5-C20 cyclic unsaturated hydrocarbon group having one or more carbon-carbon double bonds such as hexenyl.

  As used herein, the term “alkynyl” refers to a linear or branched hydrocarbon group having 3 to 20 carbon atoms having one or more carbon-carbon triple bonds such as pentynyl and propynyl, or one or more carbon atoms. A C6-C20 cyclic unsaturated hydrocarbon group having a carbon triple bond is meant.

  The term “aryl” as used herein means a monocyclic or polycyclic aromatic hydrocarbon group such as phenyl, naphthyl, anthryl, phenanthryl and the like. The aryl may be optionally substituted with one or more substituents such as halogen, alkoxyl, thioalkoxyl, alkyl, aryl, etc., and the substituents are not limited thereto.

  As used herein, the term “aralkyl” means a linear or branched hydrocarbon having 1 to 20 carbon atoms and one or more of the above aryl groups, such as benzyl, benzhydryl, fluorenylmethyl and the like. Is mentioned.

  Any of the aforementioned alkyl, alkenyl, alkynyl, aryl and aralkyl is halogen, alkyl, aryl, alkoxyl, aryloxy, thioalkoxyl, thioaryloxy, alkylamino, arylamino, cyano, alkoxycarbonyl, arylcarbonyl, arylaminocarbonyl One or more substituents selected from the group consisting of alkylaminocarbonyl and carbonyl, or selected from the group consisting of pyridinyl, thiophenyl, furanyl, imidazolyl, morpholinyl, oxazolinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl and the like. Optionally substituted by a heterocyclic group.

The term “protecting group” has the meaning conventionally defined in synthetic organic chemistry (ie, a group that can protect a functional group or a compound moiety that is attacked by a chemical reaction). Protecting groups include methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyl, bis (2-chloroethoxy) methyl, tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl , Tetrahydrofuranyl, tetrahydrofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, triphenylmethyl, allyl, benzyl, substituted benzyl and SiR _a R _b R _c (R _a , R _b , R _c are Each independently is C _1-4 alkyl, phenyl, benzyl, substituted phenyl or substituted benzyl), but is not limited thereto.

Aspects of the invention

  A novel approach for the synthesis of lactones of formula I in the present invention is shown in Scheme 2. All reactants have an optical purity of 90% e.e. e. Used as enantiomeric enrichment, usually with a super.

A. Preparation of novel cyclopentanone represented by formula II-1

  Cyclopentanone represented by Formula II-1 as shown in step (a) of Scheme 2

(Wherein Z is any group that does not participate in the coupling and deprotection reactions but acts as a leaving group in the reduction / lactonization reaction; R ₂ is a single bond, or C _1-4- Alkylene or a group represented by the formula —CH ₂ O—; R ₃ is a C _1-7 -alkyl, aryl or aralkyl group, each of which is unsubstituted or C _1-4 -alkyl, halogen Or is substituted by trihalomethyl; preferably R ₂ and R ₃ are the following (i) to (iii):
(I) R ₂ is methylene, R ₃ is n-butyl;
(Ii) R ₂ is ethylene, R ₃ is phenyl; and (iii) R ₂ is —CH ₂ O—, R ₃ is phenyl substituted by a substituent selected from halogen and trihalomethyl,
Selected from the group consisting of
P ₁ and P ₂ are the same or different hydroxy protecting groups)

Is the formula V-1, the formula V-2, the formula V-3:

Wherein Y is halogen; R ₆ is lower alkyl; R ₂ , R ₃ and P ₂ are as defined above, Chen et al., 1978, J. Org. 43, 3450, U.S. Pat. Nos. 4,233,231, 4,415,501 and 6,294,679, respectively, and the formula V derived from vinyl halides, vinyl stannanes or alkynes, wherein R ₂ , R ₃ and P ₂ are as defined above; R ₄ is a non-hindered group; X is —CN, —SCN, —OSO ₂ CF ₃ or —S-phenyl-)

Prepared by a coupling reaction between an enantiomer-enriched ω-side chain unit of the cueplate represented by formula IV and an optically active cyclopentenone represented by formula IV, which reaction is preferably between −100 ° C. and 40 ° C. Perform at a range of temperatures. The preparation of the cyclopentenone is disclosed in the co-pending patent application “Process for the preparation of optically active cyclopentenone and the cyclopentenone prepared by the process” filed on the same day.

  Subsequently, the reaction is quenched with a base (eg, ammonium hydroxide) and subjected to a post-treatment performed by conventional methods. The resulting crude product can be purified by conventional methods (eg, column chromatography), or the crude product can be used directly in the next reaction.

According to an embodiment of the present invention, the substituent Z in the formula is —OR ₁ , —N (R ₁ ) ₂ or —SR _1.
Wherein R ₁ is independently in each case an alkyl, alkenyl, alkynyl, aryl or aralkyl group, each of which is unsubstituted or halogen, alkyl, aryl, alkoxyl, aryloxy, thioalkoxyl, thio One or more substituents selected from the group consisting of aryloxy, alkylamino, arylamino, cyano, alkoxycarbonylphenyl, alkoxycarbonyl, arylcarbonyl, arylaminocarbonyl, alkylaminocarbonyl and carbonyl, or pyridinyl, thiophenyl, furanyl, Substituted by a heterocyclic group selected from the group consisting of imidazolyl, morpholinyl, oxazolinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl and pyrrolidinonyl, , If Z is -OR _1, R ₁ is .Z is a protective group for a carboxyl group is preferably a -OR _1.).

B. Preparation of lactones of formula I

As shown in step (d) of Scheme 2, in a suitable solvent, the formula Y:
M ₁ M ₂ (R ₅ ) _n H (Y)
Wherein M ₁ represents Li, K or Na or is absent; M ₂ represents Al or B; n is 2 or 3; R ₅ represents hydrogen, alkyl or alkoxyl. The cyclopentanone represented by Formula II-1 or II-2 is reduced / lactonized using the reducing agent represented to produce a lactone represented by Formula I-1 or I-2.
According to the invention, the reducing agent is sodium bis (2-methoxyethoxy) aluminum hydride, diisobutylaluminum hydride, lithium tri-tert-butoxyalumino hydride, lithium tri-alkyl borohydride, potassium trialkyl borohydride, sodium tri- Selected from alkyl borohydrides and mixtures thereof. Preferably, the reducing agent is lithium tri-sec-butyl borohydride, lithium triamyl borohydride, sodium tri-sec-butyl borohydride, potassium tri-sec-butyl borohydride, potassium triamyl borohydride or mixtures thereof. . Most preferably, the reducing agent is lithium tri-sec-butylborohydride.
Suitable solvents for use in the reaction can be selected from, but not limited to, tetrahydrofuran, ether, toluene, hexane and mixtures thereof.
The reaction is carried out at a temperature in the range of −120 ° C. to room temperature, preferably −100 ° C. to −40 ° C.
The amount of the reducing agent used is such that the reaction of the substrate or reactant monitored by thin layer chromatography (TLC) is completely performed. Upon completion of the reaction, the lactone represented by formula I-1 or I-2 can be isolated from the reaction solution by post-treatment such as removal of excess reducing agent, extraction, dehydration, concentration, and the like. Furthermore, the product can be purified by column chromatography or crystallization.

C. Deprotection of cyclopentanone represented by formula II-1 and lactone represented by formula I-1

As shown in Step (b) of Scheme 2, the cyclopentanone represented by Formula II-1 and the lactone represented by Formula I-1 are each deprotected to give a cyclopenta represented by Formula II-2. Non and lactones of formula I-2 are prepared. Conditions for performing this deprotection reaction will be apparent to those skilled in the art. For example, cyclopentanone represented by Formula II-1 (wherein P ₁ and P ₂ are each a triethylsilyl protecting group) is a suitable solvent (for example, a 5: 1 volume ratio of acetone and water). And then treated with a deprotecting agent (for example, hydrochloric acid, p-toluenesulfonic acid, pyridium p-toluenesulfonate), stirred at room temperature for 10 minutes to 10 hours, and deprotected by the formula II-2. Product is obtained.

  The crude cyclopentanone product represented by II-2 contains a small amount of stereoisomers produced by the conjugate addition reaction (coupling reaction). The isomer can be removed by eluting with a single solvent or a mixture of two or more of hexane, heptane, ethyl acetate, toluene, ether and isopropyl alcohol in column chromatography.

  Alternatively, stereoisomers present in the crude product II-2 can be removed by crystallization of the crude product. Crystallization is selected from ethyl ether, petroleum ether, isopropyl ethyl ether, butyl methyl ether, ethyl acetate, toluene, isopropyl ethyl ketone, methyl isobutyl ketone, hexane, heptane, isopropyl alcohol, methanol, ethanol, acetic acid and mixtures thereof. It is preferably carried out in a suitable organic solvent.

D. Protection of cyclopentanone represented by formula II-2 or lactone represented by formula I-2

  The lactone protected I-1 or the lactone unprotected I-2 shown in Scheme 2 is further subjected to a reduction reaction using diisobutylaluminum hydride (DIBAL) and a Witchig reaction to produce a prostagland which is the final target product. Gin can be obtained. However, in order to avoid excessive consumption of DIBAL and the Wittig reagent for reacting the hydroxyl group, it is preferable to use the protected lactone I-1.

As shown in Scheme 2, in step (c), the cyclopentanone represented by Formula II-2 or the lactone represented by Formula I-2 is protected. Suitable protecting groups used are trialkylsilyl, tetrahydropyranyl (THP) and the like. Suitable reaction conditions will be apparent to those skilled in the art. For example, the lactone of formula I-2 is dissolved in a suitable organic solvent selected from tetrahydrofuran, ethyl acetate, toluene, dimethylformamide and mixtures thereof and more than 2 molar equivalents of a base (eg, trialkylamine). Or imidazole) and about 2 molar equivalents of tert-butyldimethylsilyl chloride at a temperature in the range of about 0-80 ° C. Subsequently, post-treatments such as filtration, extraction, dehydration and concentration are performed to obtain a protected lactone represented by the formula I-1.
According to the present invention, unexpectedly and surprisingly, a high purity lactone represented by crystalline formula I-1a was obtained.

E. Synthesis of 13,14-dihydrolactone represented by formula I-3

As shown in the following scheme 3, the lactone represented by formula I-3 useful for the synthesis of 13,14-dihydro-prostaglandin F ₂ α, particularly for the synthesis of latanoprost, is one of the routes described below. This can be prepared by route and is shown in Scheme 3.
(I) Coupling reaction of a ω-side chain unit of a cue plate of formula VI (which can be prepared according to the method disclosed in US Pat. No. 6,852,880) with a cyclopentenone of formula IV To obtain a protected cyclopentanone represented by the formula II-3, which is further subjected to deprotection and reduction / lactonization reaction to obtain a deprotected lactone represented by the formula I-3. ;
(Ii) reacting the cyclopentenone represented by formula IV with the cue plate represented by formula V to obtain the cyclopentanone represented by formula II, which is further deprotected, hydrogenated and staged (e ) And (d) to give the deprotected lactone of formula I-3; or (iii) the formula II obtained according to the route described in section (ii) Is converted to a lactone protected form of formula I, which is further deprotected and hydrogenated, or hydrogenated without deprotection to give a lactone unprotected or lactone protected form represented by formula I-3 Get.

(Wherein Z, R ₄ , R ₅ , M ₁ , M ₂ , n, P ₁ , P ₂ , X ₁ and X ₂ are as defined above)

  The hydrogenation reaction of step (e) of Scheme 3 is carried out in a suitable solvent under hydrogen in the presence of a hydrogenation catalyst and a suitable base / electrophile. Suitable hydrogenation catalysts contain a metal selected from the group consisting of palladium, platinum, rhodium, nickel and mixtures thereof. Examples of this catalyst include Pd—C, Pt—C and Ni. Suitable solvents can be selected from tetrahydrofuran, ethyl acetate, ethanol, toluene and mixtures thereof.

The lactone of formula I is then subjected to a semi-reduction reaction with diisobutylaluminum hydride (DIBAL) as shown in step (e), followed by a Witchig reaction to produce prostaglandins, particularly PGE ₂ and A PGF ₂ α series is generated. For details regarding the DIBAL and Witchig reactions, see the prior art literature (eg, Lee et al. , 1978, J. Chem. Soc. Perkin trans I 1179; EP-A-0639563; Corey et al., 1969, J. Am. Chem. Soc 91, 5675; and J. Am. Chem. Soc 1972, 94, 8616).

The present invention not only provides a simple and easy method for the synthesis of prostaglandins, but also generates excess 15β-isomers that are confronted by the Cori process, making final purification difficult. To solve the problem. More importantly, the cyclopentanone of formula II prepared according to Scheme 3 can be further purified by crystallization or simple column chromatography to completely eliminate the 15β-isomer. .
In summary, the present invention provides a shortcut for the synthesis of 15β-isomer free prostaglandins.

F. Novel compounds of formula II

  The present invention further provides a compound of formula II:

(Wherein Z is OR ₁ and R ₁ , X ₁ , X ₂ , R ₂ and R ₃ are as defined above), and the enantiomeric rich having an enantiomeric excess of 95% optical purity. A compound is provided.

According to one embodiment of the present invention, X ₁ and X ₂ in Formula II are both hydrogen atoms; R ₁ is alkyl, alkenyl or alkynyl, each of which is unsubstituted or halogen, thioalkoxyl Substituted by one or more substituents selected from the group consisting of thioaryloxy, alkylamino and cyano, or a heterocyclic group selected from the group consisting of morpholinyl, oxazolinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl and pyrrolidinonyl Or R ₁ is unsubstituted or halogen, alkyl, aryl, alkoxyl, aryloxy, thioalkoxyl, thioaryloxy, alkylamino, arylamino, cyano, alkoxycarbonyl, arylcarbonyl, alkylamino Cal Alkenyl, is aryl substituted by one or more substituents selected from the group consisting of aryl aminocarbonyl and carbonyl; or, if R ₁ is unsubstituted or substituted by halogen, alkyl, aryl, alkoxyl, aryloxy Aralkyl substituted with one or more substituents selected from the group consisting of thioalkoxyl, thioaryloxy, alkylamino, cyano, alkoxycarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl and carbonyl.
According to a more preferred embodiment of the invention, R ₁ is C ₁ -C ₁₀ alkyl, benzyl, naphthyl or phenyl, each of which is unsubstituted or halogen, alkyl, aryl, alkoxyl, aryloxy, thio Substituted by one or more substituents selected from the group consisting of alkoxyl, thioaryloxy, alkylamino, cyano, alkoxycarbonyl, alkylaminocarbonyl and morpholinyl.

According to the most preferred embodiment of the present invention, the compound of formula II is
Ethyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentaneacetate;
Benzyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentane acetate;
2-naphthyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentane acetate;
(1'R, 2'S, 5'R) -Mentyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentane acetate ;
2-cyanoethyl (1R, 2R, 3R) 3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentane acetate;
3-ethoxycarbonylphenyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentane acetate;
4-morpholine ethyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentane acetate;
Benzyl (1R, 2R, 3R) -3-hydroxy-2- [5-phenyl- (3S) -hydroxy- (1E) -pentenyl] -5-oxo-cyclopentane acetate;
2-naphthyl (1R, 2R, 3R) -3-hydroxy-2- [5-phenyl- (3S) -hydroxy- (1E) -pentenyl] -5-oxo-cyclopentane acetate;
(1′R, 2 ′S, 5′R) -Mentyl (1R, 2R, 3R) -3-hydroxy-2- [5-phenyl- (3S) -hydroxy- (1E) -pentenyl] -5-oxo -Cyclopentane acetate;
Ethyl (1R, 2R, 3R) -3-hydroxy-2- [5-phenyl- (3S) -hydroxy- (1E) -pentenyl] -5-oxo-cyclopentane acetate;
Ethyl (1R, 2R, 3R) -3-hydroxy-2-[(3R) -hydroxy-4- (3-trifluoromethyl) phenoxy- (1E) -butenyl] -5-oxo-cyclopenane acetate; and ethyl (1R, 2R, 3R) 3-hydroxy-2- [5-phenyl- (3R) -hydroxy-pentanyl] -5-oxo-cyclopentane acetate is selected from the group.

Example 1
4- [3- (Trifluoromethyl) phenoxy]-(3R) -triethylsilyloxy-1-butyne

  (3R) -4- [3- (Trifluoromethyl) phenoxy] -3-hydroxy-1-butyne (6.7 g, 29 mmol) and imidazole (2.96 g, 44 mmol) were dissolved in 100 mL of ethyl acetate, and the solution was dissolved. Cooled to about 5 ° C. To this solution, chlorotriethylsilane (6.3 mL, 38 mmol) was added slowly over 30 minutes keeping the temperature during addition at about 5-10 ° C. The mixture was slowly returned to room temperature. The precipitate was removed by filtration. Next, the reaction solution was washed twice with 50 mL of a saturated aqueous sodium bicarbonate solution, further washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a crude product (13.2 g). The crude product was purified by distillation to give (R) -silyl ether as a colorless oil (9.1 g, 91%).

¹ H-NMR (CDCl ₃ / TMS): δ 7.18 (m, 1H), 6.93 (m, 2H), 6.80 (m, 1H), 4.71 (m, 1H), 4.04 (m, 2H), 2.45 (d , 1H), 0.98 (t, 9H), 0.67 (q, 6H).

Example 2
5-Phenyl- (3S) -triethylsilyloxy-1-pentyne

  The same procedure as in Example 1 was performed to give the title compound as an oil in a yield of 88% from 5-phenyl- (3S) -hydroxy-1-pentyne.

¹ H-NMR (CDCl ₃ / TMS): δ 7.39 (m, 2H), 7.29 (m, 3H), 4.47 (m, 1H), 2.89 (m, 2H), 2.53 (d, 1H), 2.12 (m , 2H), 1.08 (t, 9H), 0.77 (q, 6H).

Example 3
(3S) -Triethylsilyloxy-1-octyne

  The same procedure as in Example 1 was performed to obtain the title compound as an oil in a yield of 95% from (3S) -hydroxy-1-octyne.

Example 4
(1E) -Tributylstannyl- (3S) -triethylsilyloxy-1-octene

  (3S) -Triethylsilyloxy-1-octyne (20 g, 78.6 mmol) and azo-bis (isobutyronitrile) (150 mg) were mixed with 30 mL of tri-n-butyltin hydride using a syringe in a nitrogen atmosphere under a nitrogen atmosphere. 113 mmol) was added. The mixture was heated to about 130 ° C., stirred for 2 hours, and then cooled to room temperature. Excess tri-n-butyltin hydride was removed by vacuum distillation at about 70 ° C. (0.05 mmHg). By vacuum distillation at about 165 ° C. (0.05 mmHg), 36.5 g of product was obtained as a colorless liquid in a yield of 87%.

¹ H NMR δ 4.05 (br m, 1H, C-3 H), 6.0 (m, 2H, olefin); ¹³ C NMR δ 152.2, 126.6, 77.0, 38.2, 32, 29.3, 27.4, 25.1, 22.8, 14.1, 13.7, 9.6, 6.9, 5.1.

Example 5
5-Phenyl- (1E) -tributylstannyl- (3S) -triethylsilyloxy-1-pentene

  The same procedure as in Example 4 was followed to give the title compound as an oil in 82% yield from 5-phenyl- (3S) -triethylsilyloxy-1-pentyne.

¹ H-NMR (CDCl ₃ / TMS): δ 7.33 (m, 2H), 7.23 (m, 3H), 5.90-6.21 (m, 2H), 4.15 (q, 1H), 2.74 (m, 2H), 1.88 (m, 2H), 1.57 (m, 2H), 1.30 to 1.80 (m, 12H), 0.90 to 1.08 (m, 24H), 0.67 (q, 6H).

Example 6
(1E) -Tributylstannyl-4- [3- (trifluoromethyl) phenoxy]-(3R) -triethylsilyloxy-1-butene

  The same procedure as in Example 4 was followed to give the title compound as an oil in 74% yield from 4- [3- (trifluoromethyl) phenoxy]-(3R) -triethylsilyloxy-1-butyne. .

¹ H-NMR (CDCl ₃ / TMS): δ 7.22 (m, 1H), 6.96 (m, 2H), 6.81 (m, 1H), 5.90-6.21 (m, 2H), 4.49 (m, 1H), 3.90 (d, 2H).

Example 7
(1E) -Iodo- (3S) -triethylsilyloxy-1-octene

  2.5 g of iodine was added to a solution of 5.3 g of (1E) -tributylstannyl- (3S) -triethylsilyloxy-1-octene in 75 mL of ether. The solution was stirred at room temperature for about 2 hours, concentrated by vacuum distillation and dried. The obtained crude product was further purified by column chromatography using silica gel using a mixed solution of hexane and ether as a gradient eluent. The yield of the title compound was 2.2 g (63%).

¹ H-NMR (CDCl ₃ / TMS): δ 6.49 (dd, 1H), 6.19 (d, 1H), 4.04 (q, 1H), 1.20 to 1.70 (m, 8H), 0.93 (t, 9H), 0.83 (t, 3H), 0.57 (q, 6H).

Example 8
Ethyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentane acetate

  A 250 mL three-necked flask was fired dry and allowed to cool. Copper cyanide (2.7 g, 30 mmol) and 40 mL of anhydrous tetrahydrofuran (THF) were added to the reaction flask, and 40 mL of methyl lithium (1.5 M in ethyl ether) was added dropwise at about −10 ° C. After stirring the reaction for 30 minutes, a solution of (1E) -tributylstannyl- (3S) -triethylsilyloxy-1-octene (15.9 g, 30 mmol) in anhydrous tetrahydrofuran (20 mL) was added. The reaction was stirred at room temperature for 3 hours and then cooled to -70 ° C. To the reaction solution was added ethyl (3R) -triethylsiloxy-5-oxo-1-cyclopentene-1-acetate (6.3 g, 21 mmol) in anhydrous tetrahydrofuran (20 mL). The reaction solution was stirred at −70 ° C. for 30 minutes and quenched with 500 mL of saturated aqueous ammonium chloride solution containing 50 mL of ammonium hydroxide. The reaction solution was phase-separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated under vacuum. The residue was further dissolved in 100 mL of acetone and 20 mL of water, and 0.5 g of p-toluenesulfonic acid monohydrate was added. The reaction solution was stirred at room temperature for 1 hour and further subjected to vacuum distillation until separated into two layers. 150 mL of ethyl acetate was added to the reaction solution, and the reaction solution was phase-separated. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. The title compound contained a trace of 15-epimer and the yield was 5.83 g (89%). The 15-epimer can be removed by crystallization of the title compound from ether / hexane. 4.2 g of the title compound was obtained as crystals (white to off-white powder) (MP: 62 ° C.).

¹ H-NMR (CDCl ₃ / TMS): δ 5.69 (m, 1H), 5.57 (m, 1H), 4.15 (m, 4H), 3.38 (br, 1H), 2.80 (dd, 1H), 2.15-2.65 (m, 6H), 1.20 to 1.84 (m, 10H), 0.90 (t, 3H); ¹³ C-NMR (CDCl ₃ / TMS): δ 213.22, 172.31, 138.26, 131.06, 73.42, 72.86, 61.55, 54.85, 51.64, 45.96, 37.95, 32.36, 32.35, 25.79, 23.24, 14.81, 14.68.

Example 9
Benzyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentane acetate

A solution of (1E) -iodo- (3S) -triethylsilyloxy-1-octene (35.4 g) in ether (200 mL) was cooled to −70 ° C., and 60 mL of 1.6 M n-butyllithium solution was added. The solution thus obtained was designated as Solution A and stirred at -70 ° C for 2 hours. CuCN (8.3 g) and ether (50 mL) were placed in a dry flask. The solution was cooled to −20 ° C. and a 1.5M ether (61 mL) solution of methyllithium was added. This solution mixture was made into solution B and further stirred for 30 minutes. Subsequently, the solution B was cooled to -70 degreeC, and the vinyl lithium solution (solution A) prepared previously was added to this. The mixture was stirred for 1 hour while maintaining the temperature at about -70 ° C. To the reaction solution was added a solution of benzyl (3R) -triethylsilyloxy-5-oxo-1-cyclopentene-1-acetate (26.2 g) in ether (50 mL). After further stirring for 20 minutes, the reaction solution was poured into a mixed solution of 9/1 (v / v) saturated NH ₄ Cl aqueous solution / NH ₄ OH and phase-separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off and the solvent was evaporated under vacuum. The residue was dissolved in 300 mL of acetone and 50 mL of water, and 2 g of p-toluenesulfonic acid monohydrate was added. The reaction solution was stirred at room temperature for 1 hour and concentrated until separation into two layers was observed. Extraction was performed by adding 150 mL of ethyl acetate. The organic layer was further washed with saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The liquid residue was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. The title compound was obtained as crystals (yield: 74%, MP: 74 ° C.).

¹ H-NMR (CDCl ₃ / TMS): δ 7.39 (m, 5H), 5.52 to 5.71 (m, 2H), 5.12 (dd, 2H), 4.05 to 4.20 (m, 2H), 3.36 (s, 1H) , 2.79 (dd, 1H), 2.64 (m, 2H), 2.38 to 2.55 (m, 3H), 2.34 (dd, 1H), 1.10 to 1.80 (m, 7H), 0.89 (t, 3H).
¹³ C-NMR (CDCl _{3 /} TMS): δ213.05, 172.11, 138.37, 136.24, 130.24, 129.29, 129.08, 128.70, 73.37, 72.62, 67.35, 54.81, 51.63, 45.93, 37.93, 32.35, 25.80, 23.29, 14.60 .

Example 10
2-Naphtyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentane acetate

  Instead of benzyl (3R) -triethylsiloxy-5-oxo-1-cyclopentene-1-acetate, equimolar 2-naphthyl (3R) -tetrahydropyranyloxy-5-oxo-1-cyclopentene-1-acetate The same procedure as in Example 9 was performed except that was used as a reaction substrate. The title compound was prepared and obtained as crystals. Yield: 63%

¹ H-NMR (CDCl ₃ / TMS): δ 7.87 (m, 3H), 7.58 (s, 1H), 7.50 (m, 2H), 7.25 (m, 1H), 5.76 (m, 2H), 4.21 (m , 2H), 2.87 (m, 3H), 2.61 (m, 2H), 2.42 (m, 1H), 1.20 to 1.80 (m, 8H), 0.87 (t, 3H).

Example 11
Benzyl (1R, 2R, 3R) -3-hydroxy-2- [5-phenyl- (3S) -hydroxy- (1E) -pentenyl] -5-oxo-cyclopentane acetate

Zirconocene chloride hydride (1.29 g, 5 mmol) was placed in a 100 mL flask equipped with a stir bar and sealed with a septum. The flask was evacuated with a vacuum pump and replaced with argon. This operation was repeated three times. Subsequently, THF (15 mL) was added to the flask and the mixture was stirred until a white slurry formed, to which 5-phenyl- (3S) -triethylsilyloxy-1-pentyne (1.37 g, 5 mmol, 94% ee) was added. The mixture was stirred for 30 minutes and cooled to -70 ° C. Addition of ethereal MeLi (3.5 mL, 5 mmol) produced a bright yellow solution. At the same time, lithium 2-thienyl cyanocubate (20 mL in 0.25 M THF) was added to the zirconium solution. The mixture was stirred for 15 minutes at −70 ° C. and ether of benzyl (3R) -triethylsilyloxy-5-oxo-1-cyclopentene-1-acetate (0.90 g, 2.5 mmol, 95% ee) ( 5 mL) solution was added. After 10 minutes, the mixture was quenched with 10% NH ₄ OH / saturated NH ₄ Cl aqueous solution (40 mL). The product was extracted 3 times with 50 mL of ether and dried over magnesium sulfate. The solution was then filtered and the solvent removed by vacuum evaporation. The liquid residue was dissolved in 20 mL of acetone and 4 mL of water, and 2 g of p-toluenesulfonic acid monohydrate was added. The reaction solution was stirred at room temperature for 1 hour and concentrated until separation into two layers was observed. 30 mL of ethyl acetate was added for extraction and phase separation. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and subjected to vacuum evaporation to remove the solvent and dry. The liquid residue was purified by chromatography using silica gel with a gradient eluent mixture of hexane and ethyl acetate. The title compound was obtained as crystals (yield: 82% (> 99.9% ee measured as a lactone derivative using a chiral column), MP: 81 ° C.).
¹ H-NMR (CDCl _{3 /} TMS): δ 7.17-7.42 (m, 10H), 5.56-5.78 (m, 2H), 5.1 (dd, 2H), 4.13 (m, 2H), 2.16-2.87 (m , 6H), 1.80-2.10 (m, 2H);
¹³ C-NMR (CDCl _{3 /} TMS): δ 212.87,172.07,142.13,138.15,135.63,129.28,129.17,129.09,129.06,128.83,126.70,72.70,72.39,67.39,54.71,51.62,46.04,39.52,32.43,32.42 .

Example 12
(1'R, 2'S, 5'R) -Mentyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentane acetate

  Instead of ethyl (3R) -triethylsiloxy-5-oxo-1-cyclopentene-1-acetate, equimolar (1′R, 2 ′S, 5′R) -menthyl (3R) -triethylsiloxy- The same procedure as in Example 8 was performed, except that 5-oxo-1-cyclopentene-1-acetate was used as a reaction substrate. The title compound is prepared and obtained as crystals (Yield: 62%, MP: 96 ° C.).

¹ H-NMR (CDCl ₃ / TMS): δ 5.59 (m, 2H), 4.59 (m, 1H), 4.05 (m, 2H), 2.71 (m, 1H), 2.49 (m, 3H), 2.28 (m , 2H)

Example 13
3-Ethoxycarbonylphenyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentane acetate

  Instead of ethyl (3R) -triethylsiloxy-5-oxo-1-cyclopentene-1-acetate, equimolar 3-ethoxycarbonylphenyl (3R) -triethylsilyloxy-5-oxo-1-cyclopentene-1- The same procedure as in Example 8 was performed except that acetate was used as a reaction substrate. The title compound can be prepared and obtained in 68% yield.

¹ H-NMR (CDCl ₃ / TMS): δ 7.94 (d, 1H), 7.76 (s, 1H), 7.47 (t, 1H), 7.31 (m, 1H), 5.75 (dd, 1H), 5.63 (dd , 1H), 4.41 (q, 2H), 4.17 (m, 2H), 2.86 (m, 3H), 2.57 (m, 2H), 2.37 (dd, 1H), 1.57 (m, 1H), 1.51 (m, 1H), 1.43 (t, 3H), 1.29 (m, 6H), 0.90 (t, 3H).

Example 14
2-Cyanoethyl (1R, 2R, 3R) 3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentane acetate

  Instead of ethyl (3R) -triethylsiloxy-5-oxo-1-cyclopentene-1-acetate, equimolar 2-cyanoethyl (3R) -triethylsilyloxy-5-oxo-1-cyclopentene-1-acetate The same procedure as in Example 8 was performed except that the reaction substrate was used. The title compound can be prepared and obtained as crystals (yield: 72%, MP: 54 ° C.).

¹ H-NMR (CDCl ₃ / TMS): δ 5.66 (m, 1H), 5.55 (m, 1H), 4.29 (m, 2H), 4.10 (m, 2H), 2.79 (dd, 1H), 2.74 (t , 2H), 2.59 (m, 2H), 2.44 (m, 2H), 2.33 (dd, 1H), 1.58 (m, 1H), 1.49 (m, 1H), 1.31 (m, 6H), 0.91 (t, 3H).

Example 15
Ethyl (1R, 2R, 3R) 3-hydroxy-2- [5-phenyl- (3S) -hydroxy- (1E) -pentenyl] -5-oxo-cyclopentane acetate

  Instead of (1E) -tributylstannyl- (3S) -triethylsilyloxy-1-octene, equimolar (1E) -tributylstannyl-5-phenyl- (3R) -triethylsilyloxy-1-pentene The same procedure as in Example 8 was performed except that the reaction substrate was used. The title compound can be prepared and obtained in 68% yield.

¹ H-NMR (CDCl ₃ / TMS): δ 7.30 (m, 2H), 7.22 (m, 3H), 5.71 (dd, 1H), 5.58 (dd, 1H), 4.11 (m, 4H), 3.34 (brs , 2H), 2.30 to 2.90 (m, 6H), 1.70 to 1.95 (m, 2H), 1.25 (t, 3H).

Example 16
4-morpholine ethyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentane acetate

  Instead of ethyl (3R) -triethylsiloxy-5-oxo-1-cyclopentene-1-acetate, equimolar 4-morpholine ethyl (3R) -triethylsilyloxy-5-oxo-1-cyclopentene-1-acetate The title compound can be prepared in the same manner as described in Example 8 except that is used as the reaction substrate, with a yield of 70%.

¹ H-NMR (CDCl ₃ / TMS): δ 5.64 (dd, 1H), 5.54 (dd, 1H), 4.21 (m, 4H), 4.08 (m, 2H), 3.72 (t, 4H), 2.77 (dd , 1H), 2.63 (t, 2H), 2.57 (t, 1H), 2.52 (brs, 4H), 2.37 (m, 2H), 1.56 (m, 1H), 1.47 (m, 1H), 1.30 (m, 6H), 0.90 (t, 3H).

Example 17
2-Naphthyl (1R, 2R, 3R) 3-hydroxy-2- [5-phenyl- (3S) -hydroxy- (1E) -pentenyl] -5-oxo-cyclopentane acetate

  Instead of ethyl (3R) -triethylsiloxy-5-oxo-1-cyclopentene-1-acetate, equimolar 2-naphthyl (3R) -triethylsilyloxy-5-oxo-1-cyclopentene-1-acetate The same procedure as in Example 15 was performed except that the reaction substrate was used. The title compound can be prepared and obtained as crystals (yield: 72%, MP: 123 ° C.).

Example 18
(1′R, 2 ′S, 5′R) -Mentyl (1R, 2R, 3R) -3-hydroxy-2- [5-phenyl- (3S) -hydroxy- (1E) -pentenyl] -5-oxo -Cyclopentane acetate

  Instead of ethyl (3R) -triethylsiloxy-5-oxo-1-cyclopentene-1-acetate, equimolar (1′R, 2 ′S, 5′R) -menthyl (3R) -triethylsiloxy- The same procedure as in Example 15 was performed, except that 5-oxo-1-cyclopentene-1-acetate was used as a reaction substrate. The title compound can be prepared and obtained as crystals (yield: 67%, MP: 115 ° C.).

Examples 19-20
Ethyl (1R, 2R, 3R) 3-hydroxy-2- [5-phenyl- (3R) -hydroxy-pentanyl] -5-oxo-cyclopentane acetate

Example 19: 1.25 g of (3S) -3- (tert-butyldimethylsilyloxy) -5-bromo-1-phenylpentane was dissolved in ether (20 mL) and cooled to -70 ° C. T-BuLi (1.7 M in pentane, 4.3 mL) was added dropwise and the mixture was stirred for 30 minutes. To this was added (2-thienyl) Cu (CN) Li (0.25M, 30 mL) dropwise. The reaction solution was stirred for 1 hour and ethyl (3R) -triethylsilyloxy-5-oxo-1-cyclopentene-1-acetate (0.74 g, 2.5 mmol) / ether (5 mL) was added. After 10 minutes, the mixture was quenched with 10% NH ₄ OH / saturated NH ₄ Cl aqueous solution (40 mL). The product was extracted 3 times with 50 mL of ether and dried over MgSO ₄ . The solution was then filtered and the solvent removed by vacuum evaporation. The liquid residue was dissolved in dichloromethane (20 mL), a solution of hydrogen fluoride in pyridine (2.5 mL) was added at 0 ° C., and the mixture was stirred for 3 hours. After completion of the reaction, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution, and the aqueous phase was further extracted twice with ethyl acetate. The organic layers were combined, dried over MgSO _4, filtered, and concentrated. The residue was purified by column chromatography to give the title compound in 48% yield.

Example 20: Ethyl (1R, 2R, 3R) 3-hydroxy-2- [5-phenyl- (3S) -hydroxy- (1E) -pentenyl] -5-oxo-cyclopentaneacetate (1 g) in ethyl acetate ( 10 mL) To the stirred solution was added 5% Pd—C catalyst (0.2 g). This solution was stirred under hydrogen for 30 hours. The solution was filtered and the resulting filtrate was further concentrated to dryness. The crude product was further purified by flash column chromatography (silica gel, elution solvent was ethyl acetate: hexane = 1: 1) to give the title compound as a colorless oil (0.68 g).

¹ H-NMR (CDCl ₃ / TMS): δ 7.31 (m, 2H), 7.22 (m, 3H), 4.15 (q, 2H), 3.65 to 4.3 (m, 2H).

Example 21
Ethyl (1R, 2R, 3R) 3-triethylsilyloxy-2-[(3S) -triethylsilyloxy- (1E) -octenyl] -5-oxo-cyclopentane acetate

  Ethyl 3-hydroxy-2- (3-hydroxy-1-octenyl) -5-oxo-cyclopentane acetate (12.5 g, 40 mmol) was dissolved in 100 mL of ethyl acetate, 6.8 g of imidazole was added, and the reaction system was Stir until uniform. To the reaction solution, 14.7 mL of triethylsilyl chloride was slowly added. The stirred reaction liquid was returned to room temperature and stirred overnight. The reaction solution was filtered to obtain a filtrate. Next, the reaction solution was washed twice with 30 mL of a saturated aqueous sodium bicarbonate solution, further washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a crude product (20.2 g).

Examples 22-31
(3aR, 4R, 5R, 6aS) -Hexahydro-5-hydroxy-4-[(1E, 3S) -3-hydroxy- (1E) -octenyl] -2H-cyclopenta [β] furan-2-one

¹ H-NMR (CDCl ₃ / TMS): δ 5.62 (m, 1H), 5.48 (m, 1H), 4.31 (m, 1H), 3.96 to 4.17 (m, 2H), 0.89 (t, 3H).

Example 22: benzyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentaneacetate (20 g, 49 mmol) / THF 200 mL was dried ice Cooled to about −70 ° C. with a methanol bath. To this solution was then added dropwise 1.0 M lithium tri- (sec-butyl) -borohydride (49 mL). The reaction was stirred for 2 hours and quenched with 100 mL of saturated aqueous ammonium chloride. After phase separation, the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The obtained concentrate was purified by column chromatography using silica gel. The title compound was obtained in 82% yield.

Example 23: Instead of benzyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentaneacetate, equimolar ethyl (1R , 2R, 3R) 3-Hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentane acetate was used as in Example 22 except that the reaction substrate was used. It was. The title compound can be prepared and obtained in 75% yield.

Example 24: Instead of benzyl (1R, 2R, 3R) 3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentaneacetate, equimolar 2-naphthyl ( 1R, 2R, 3R) -3-Hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentane acetate was used as the reaction substrate, except that the procedure was similar to Example 22. Went. The title compound can be prepared and obtained in 63% yield.

Example 25: Instead of benzyl (1R, 2R, 3R) 3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentaneacetate, equimolar menthyl (1R, 2R, 3R) -3-Hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentane acetate was used in the same procedure as in Example 22 except that it was used as a reaction substrate. It was. The title compound can be prepared and obtained in 69% yield.

Example 26: Instead of benzyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentane acetate equimolar 4-morpholine Same as Example 22 except that ethyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentaneacetate was used as the reaction substrate. The procedure was performed. The title compound can be prepared and obtained in 67% yield.

Example 27: Instead of benzyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentane acetate equimolar 3-ethoxy Example 22 except that carbonylphenyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentaneacetate was used as the reaction substrate. Similar to the procedure described, the title compound can be prepared and obtained in 69% yield.

Example 28: Instead of benzyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentaneacetate, equimolar 2-cyanoethyl Similar to Example 22 except that (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentaneacetate was used as the reaction substrate. We proceeded. The title compound can be prepared and obtained in 76% yield.

Example 29: The same procedure as in Example 22 was performed, except that equimolar sodium tri-sec-butylborohydride was used as a reducing agent in the reaction instead of lithium tri-sec-butylborohydride. The title compound can be prepared and obtained in 69% yield.

Example 30: The same procedure as in Example 22 was performed, except that equimolar diisobutylaluminum hydride was used as a reducing agent in the reaction instead of lithium tri-sec-butylborohydride. The title compound can be prepared and obtained in 42% yield.

Example 31 The same procedure as in Example 22 was performed, except that equimolar lithium tri-tert-butoxyaluminum hydride was used as the reducing agent in the reaction instead of lithium tri-sec-butylborohydride. The title compound can be prepared and obtained in 57% yield.

Example 32
(3aR, 4R, 5R, 6aS) -Hexahydro-5-triethylsilyloxy-4-[(1E, 3S) -3-triethylsilyloxy- (1E) -octenyl] -2H-cyclopenta [β] furan-2- on

  Instead of ethyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentaneacetate, equimolar ethyl (1R, 2R, 3R ) -3-Triethylsiloxy-2-[(3S) -triethylsilyloxy- (1E) -octenyl] -5-oxo-cyclopentaneacetate was used in the same procedure as in Example 22, except that went. The title compound can be prepared and obtained in 95% yield.

Examples 33-36
(3aR, 4R, 5R, 6aS) -Hexahydro-5-hydroxy-4-[(1E, 3S) -5-phenyl-3-hydroxy- (1E) -pentenyl] -2H-cyclopenta [β] furan-2- on

Example 33: Instead of benzyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentaneacetate, equimolar ethyl (1R , 2R, 3R) -3-hydroxy-2- [5-phenyl- (3S) -hydroxy- (1E) -pentenyl] -5-oxo-cyclopentaneacetate, except that Example 22 was used. A similar procedure was followed. The title compound can be prepared and obtained in 75% yield.

Example 34: Instead of benzyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentaneacetate, equimolar 2-naphthyl Example except that (1R, 2R, 3R) -3-hydroxy-2- [5-phenyl- (3S) -hydroxy- (1E) -pentenyl] -5-oxo-cyclopentaneacetate was used as a reaction substrate. The same procedure as 22 was performed. The title compound can be prepared and obtained in 68% yield.

Example 35: Instead of benzyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentaneacetate, equimolar (1 ′ R, 2'S, 5'R) -Mentyl (1R, 2R, 3R) -3-hydroxy-2- [5-phenyl- (3S) -hydroxy- (1E) -pentenyl] -5-oxo-cyclopentane The same procedure as in Example 22 was performed except that acetate was used as a reaction substrate. The title compound can be prepared and obtained in 77% yield.

Example 36: Instead of benzyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentaneacetate, equimolar benzyl (1R , 2R, 3R) -3-hydroxy-2- [5-phenyl- (3S) -hydroxy- (1E) -pentenyl] -5-oxo-cyclopentaneacetate, except that Example 22 was used. A similar procedure was followed. The title compound can be prepared and obtained in 78% yield.

¹ H-NMR (CDCl _{3 /} TMS): δ7.04-7.28 (m, 5H), 5.57 (m, 1H), 5.39 (m, 1H), 4.81 (m, 1H), 4.03 (m, 1H), 3.87 (m, 1H), 1.58-2.85 (m, 10H);
¹³ C-NMR (CDCl ₃ / TMS):
δ177.47,142.21,137.13,130.85,129.16,129.10,125.88,83.10,77.95,72.60,55.88,43.17,40.52,35.38,34.83,32.41.

Examples 37-40
(3aR, 4R, 5R, 6aS) -Hexahydro-5-hydroxy-4- [5-phenyl- (3R) -hydroxy-pentanyl] -2H-cyclopenta [β] furan-2-one

¹ H-NMR (CDCl ₃ / TMS): δ 0.85 to 1.95 (m, 9H), 2.30 (m, 2H), 2.50 (m, 1H), 2.68 (m, 1H), 2.80 (m, 2H), 3.63 (m, 1H), 4.03 (m, 1H), 4.94 (m, 1H), 7.15-7.42 (m, 5H)

Example 37: Instead of benzyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentaneacetate, equimolar ethyl (1R , 2R, 3R) -3-Hydroxy-2- [5-phenyl- (3R) -hydroxy-pentanyl] -5-oxo-cyclopentaneacetate, the same procedure as in Example 22 was used. went. The title compound can be prepared and obtained as crystals (yield: 75%).

Example 38: (3aR, 4R, 5R, 6aS) -Hexahydro-5-hydroxy-4-[(1E, 3S) -5-phenyl-3-hydroxy-1-pentenyl] -2H-cyclopenta [β] furan- To a solution of 2-one (10 g) in ethyl acetate (100 mL) was added 10% Pt-C catalyst (1 g) and sodium hydroxide (0.2 g). This solution was stirred under a hydrogen atmosphere for 18 hours. After filtration, the filtrate was concentrated in vacuo to remove the solvent. The crude product was subjected to purification by flash column chromatography (silica gel, developing solvent was ethyl acetate: hexane = 1: 1). The title compound was obtained as crystals (yield: 72%).

Example 39: (3aR, 4R, 5R, 6aS) -Hexahydro-5-hydroxy-4-[(1E, 3S) -5-phenyl-3-hydroxy- (1E) -pentenyl] -2H-cyclopenta [β] To a solution of furan-2-one (1 g) in ethyl acetate (10 mL) was added 5% Pd-C catalyst (0.2 g) and sodium hydroxide (0.05 g). The solution was stirred overnight under a hydrogen atmosphere. After filtration, the filtrate was concentrated by vacuum evaporation. The crude product was subjected to flash column chromatography (silica gel, eluted with ethyl acetate: hexane = 1: 1). The title compound was obtained as crystals (yield 78%).

Example 40: (3aR, 4R, 5R, 6aS) -Hexahydro-5-hydroxy-4-[(1E, 3S) -5-phenyl-3-hydroxy- (1E) -pentenyl] -2H-cyclopenta [β] Raney nickel catalyst (0.5 g) and sodium hydroxide (0.1 g) were added to a solution of furan-2-one (1 g) in ethyl alcohol (10 mL). This solution was stirred under a hydrogen atmosphere for 10 hours. After filtration, the filtrate was concentrated by vacuum evaporation. The crude product was subjected to flash column chromatography (silica gel, eluted with ethyl acetate: hexane = 1: 1). The title compound was obtained as crystals (68% yield) containing <0.1% enantiomer (analyzed by chiral column) and 15β-epimer <0.1% (analyzed by reverse phase HPLC).

MP: 68-72 ° C; ¹ H-NMR (CDCL ₃ / TMS): δ 7.15-7.42 (M, 5H), 4.94 (M, 1H), 4.03 (M, 1H), 3.63 (M, 1H), 2.80 (M, 2H), 2.68 (M, 1H), 2.50 (M, 1H), 2.30 (M, 2H), 0.85-1.95 (M, 9H); ¹³ C-NMR (CDCL _{3 /} TMS): δ178.04, 142.41 , 129.19,129.07,126.68,84.45,78.32,72.03,54.72,43.95,41.35,39.79,36.65,35.89,32.73,29.67.

Example 41
(3aR, 4R, 5R, 6aS) -Hexahydro-5-hydroxy-4-[(3R) -hydroxy-4- (3-trifluoromethyl) phenoxy- (1E) -butenyl] -2H-cyclopenta [β] furan -2-one

  Instead of benzyl (3R) -triethylsiloxy-5-oxo-1-cyclopentene-1-acetate and 5-phenyl- (3S) -triethylsilyloxy-1-pentyne, equimolar ethyl (3R) -triethylsilyl Example 11 except that oxy-5-oxo-1-cyclopentene-1-acetate and 4- [3- (trifluoromethyl) phenoxy]-(3R) -triethylsilyloxy-1-butyne were used as reaction substrates. Ethyl (1R, 2R, 3R) -3-hydroxy-2-[(3R) -hydroxy-4- (3-trifluoromethyl) phenoxy- (1E) -butenyl] -5-oxo analogously to the described procedure -Cyclopenane acetate was prepared. The crude product thus obtained was subjected to reduction / lactonization according to exactly the same procedure as in Example 22. The title compound can be prepared and obtained in 25% yield.

¹ H-NMR (CDCl ₃ / TMS): δ 7.41 (m, 1H), 7.25 (m, 1H), 7.14 (s, 1H), 7.09 (m, 1H), 5.75 (m, 2H), 4.93 (q , 1H), 4.57 (s, 1H), 4.04 (m, 2H), 3.92 (m, 1H), 2.28 to 2.82 (m, 4H), 1.92 to 2.18 (m, 2H).

Example 42
(3aR, 4R, 5R, 6aS) -Hexahydro-5-tert-butyldimethylsilyloxy-4-[(1E, 3S) -3-tert-butyldimethylsilyloxy- (1E) -octenyl] -2H-cyclopenta [ β] furan-2-one

  (3aR, 4R, 5R, 6aS) -Hexahydro-5-hydroxy-4-[(1E, 3S) -3-hydroxy- (1E) -octenyl] -2H-cyclopenta [β] furan-2-one (10. 7 g, 40 mmol) was dissolved in 100 mL of ethyl acetate, 8.2 g of imidazole was added, and the mixture was stirred until the reaction system became homogeneous. A solution of 15.7 g of tert-butyldimethylsilyl chloride in 50 mL of ethyl acetate was gradually added to the reaction solution. The reaction was stirred overnight at room temperature. The reaction solution was filtered to obtain a filtrate. Next, the reaction solution was washed twice with 50 mL of a saturated aqueous sodium bicarbonate solution, further washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a crude product. The crude product was crystallized from hexane at −70 ° C. (dry ice cold bath temperature), filtered and washed with cold hexane. The solid was dried to give the title compound as a white solid.

MP: 74 ° C (14.3g). ¹ H-NMR (CDCl ₃ /TMS):δ5.47(dd, 1H), 5.35 (dd, 1H), 4.93 (td, 1H), 4.02 (q, 1H), 3.96 (q, 1H), 2.73 (m, 1H), 2.62 (m, 1H), 2.45 (m, 2H), 2.22 (m, 1H), 1.95 (m, 1H), 1.44 (m, 1H), 1.38 (m, 1H), 1.27 (m, 6H), 0.82 to 0.88 (m, 3H), 0.86 (s, 9H), 0.85 (s, 9H), 0.02 (m, 12H).

Example 43
(3aR, 4R, 5R, 6aS) -Hexahydro-5-triethylsiloxy-4- [5-phenyl- (3R) -triethylsilyloxy-pentanyl] -2H-cyclopenta [β] furan-2-one

  (3aR, 4R, 5R, 6aS) -Hexahydro-5-hydroxy-4- [5-phenyl- (3R) -triethylsilyloxy-pentanyl] -2H-cyclopenta [β] furan-2-one (12.2 g, 40 mmol) was dissolved in 120 mL of ethyl acetate, 8.2 g of imidazole was added, and the mixture was stirred until the reaction system became homogeneous. 15.7 g of triethylsilyl chloride was added to the reaction solution, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was filtered to obtain a filtrate, which was then washed twice with 50 mL of saturated aqueous sodium bicarbonate solution, washed with 50 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give a crude product ( 21g).

Example 44 Preparation of Latanoprost (3aR, 4R, 5R, 6aS) -Hexahydro-5-triethylsiloxy-4- [5-phenyl- (3R) -triethylsilyloxy-pentanyl] -2H-cyclopenta [β] furan- To a stirred solution of 2-one (21 g, 39.4 mol) in dry toluene (250 mL) was added dropwise diisobutylaluminum hydride solution (60 mL, 20% in hexane) at -78 ° C. After stirring for 2 hours, the reaction solution was poured into 2M sodium hydrogensulfate solution and stirred for 30 minutes. The aqueous phase was extracted twice with toluene (2 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The corresponding crude lactol was obtained as a colorless oil. Potassium tert-butoxide (27 g, 240 mmol) was added to a 500 mL THF suspension of 4-carboxybutyl-triphenylphosphonium bromide (53 g, 120 mmol). The mixture was cooled to below −10 ° C. and the crude lactol obtained above was added. The mixture was stirred for 18 hours and 200 mL of saturated aqueous ammonium chloride was added. After phase separation, the organic layer and the inorganic layer were collected separately. The pH of the aqueous phase was adjusted to 6 with 2M sodium hydrogen sulfate solution, and then the aqueous layer was extracted twice with 500 mL of ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated under vacuum. The liquid residue was further dissolved in 120 mL DMF and 15 g 2-iodopropane was added followed by 10 g K ₂ CO ₃ . The reaction solution was stirred at room temperature for 12 hours, then diluted with 500 mL of ethyl acetate and washed with water (2 × 100 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated and purified by column chromatography to obtain the protected latanoprost. The protected latanoprost was dissolved in 100 mL of THF and 10 mL of water, concentrated HCl (1 mL) was added, and the mixture was stirred at room temperature for 30 minutes. Next, 50 mL of a saturated aqueous sodium bicarbonate solution was added. The aqueous layer was extracted twice with ethyl acetate (100 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The crude product was subjected to flash column chromatography (elution with silica gel, ethyl acetate: hexane = 1: 1). The title compound was obtained as a colorless oil (5.4 g). The product was further analyzed by HPLC and found that 5-trans latanoprost, which does not contain the 15-β isomer, was approximately 2-3% in the final product.

Example 45
Preparation of dinoprost

  (3aR, 4R, 5R, 6aS) -Hexahydro-5-triethylsilyloxy-4-[(1E, 3S) -3-triethylsilyloxy- (1E) -octenyl] -2H-cyclopenta [β] furan-2- To a stirred solution of ON (19.9 g, 40 mol) in dry toluene (250 mL) was added dropwise a diisobutylaluminum hydride solution (60 mL, 20% in hexane) at −78 ° C. After stirring for 2 hours, the reaction solution was poured into 2M aqueous sodium hydrogensulfate solution and stirred for 30 minutes. The aqueous layer was separated from the organic layer and extracted twice with toluene (100 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and evaporated to dryness. Crude lactol was obtained as a colorless oil. Potassium tert-butoxide (27 g, 240 mmol) was added to a 500 mL THF suspension of 4-carboxybutyl-triphenylphosphonium bromide (53 g, 120 mmol). The mixture was cooled to less than −10 ° C. and crude lactol was added. The resulting mixture was further stirred at less than −10 ° C. for 18 hours, and then 200 mL of saturated ammonium chloride solution was added. After phase separation, an aqueous layer and an organic layer were separated. The pH of the aqueous phase was adjusted to 4 with 2M sodium hydrogen sulfate solution and extracted twice with 500 mL of ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated under vacuum to give a slightly yellow oil. To the stirred solution of yellow oil obtained above was added 100 mL THF, 10 mL water, 1 mL concentrated HCl. After stirring at room temperature for 30 minutes, 50 mL of a saturated sodium bicarbonate solution was added to the reaction solution. The aqueous layer was separated and extracted twice with ethyl acetate (100 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The resulting crude prostaglandin F2α (dinoprost) was analyzed by HPLC and was found to be about 2-3% of the final product with 5-transPGF2α containing no 15-β isomer.

Example 46
Benzyl (1R, 2R, 3R) -3-hydroxy-2-[(3R) -hydroxy-4- (3-trifluoromethyl) phenoxy- (1E) -butenyl] -5-oxo-cyclopentane acetate

(1E) -tributylstannyl-4- [3- (trifluoromethyl) phenoxy]-(3R) -triethylsilyloxy-1-butene (2.8 g) in THF (10 mL) was cooled to -70 ° C., and 1.6 M 4.2 mL of n-butyllithium solution was added. The solution thus obtained was designated as Solution A and stirred at -70 ° C for 1 hour. To the dried flask was added CuI (0.76 g) and ether (5 mL). Tributylphosphine (2.5 mL) was added and the mixture was stirred at room temperature to make a uniform solution. This homogeneous solution was added to the previously prepared alkenyl lithium solution. The mixture was stirred at about -70 ° C for 1 hour. A 5 mL ether solution of benzyl (3R) -triethylsilyloxy-5-oxo-1-cyclopentene-1-acetate (1.25 g) was added to the reaction. After stirring for another 20 minutes, the reaction solution was poured into a 9/1 (v / v) saturated NH ₄ Cl aqueous solution / NH ₄ OH mixed solution and phase-separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off and the solvent was evaporated under vacuum. The residue was dissolved in 20 mL of acetone and 5 mL of water, and 0.1 g of p-toluenesulfonic acid monohydrate was added. The reaction solution was stirred at room temperature for 1 hour and concentrated until two separated layers were observed. 20 mL of ethyl acetate was added and extracted. The organic layer was further washed with saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The liquid residue was purified by chromatography using silica gel as a gradient eluent with a mixture of hexane and ethyl acetate. The title compound was obtained in 42% yield.

¹ H-NMR (CDCl ₃ / TMS): δ 6.97-7.39 (m, 9H), 5.64-5.78 (m, 2H), 5.03 (d, 2H), 4.45 (m, 1H), 4.02-4.14 (m, 2H), 3.92 (dd, 1H), 3.83 (m, 1H), 3.61 (m, 1H), 2.22 to 2.90 (m, 6H).

Claims (17)

Formula II having an enantiomeric excess of> 95% enantiomeric excess:

(Wherein Z is any group that does not participate in the coupling and deprotection reactions but acts as a leaving group in the reduction / lactonization reaction; R ₂ is a single bond or C _1-4 -Alkylene or -CH ₂ O-; R ₃ is C _1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or substituted by C _1-4 -alkyl, halogen or trihalomethyl X ₁ and X ₂ are independently hydrogen or P ₁ and P ₂ respectively (where P ₁ and P ₂ are the same or different hydroxyl protecting groups);

A process for the preparation of a compound of formula IV having an optical purity with an enantio-excess greater than 90%:

(Wherein P ₁ is as defined above) are each represented by Formula V-1, Formula V-2 or Formula V-3 having an enantiomeric excess optical purity of greater than 90%:

Wherein Y represents halogen; R ₆ represents lower alkyl;

And reacting with a cue plate derived from the compound represented by the formula, and optionally deprotecting the resulting compound to convert P ₁ or P ₂ , or both P ₁ and P ₂ to H Including the preparation process. Z is —OR ₁ , —N (R ₁ ) ₂ or —SR ₁ , wherein R ₁ is independently in each case an alkyl, alkenyl, alkynyl, aryl or aralkyl group, each of which is unsubstituted Or selected from the group consisting of halogen, alkyl, aryl, alkoxyl, aryloxy, thioalkoxyl, thioaryloxy, alkylamino, arylamino, cyano, alkoxycarbonyl, arylcarbonyl, arylaminocarbonyl, alkylaminocarbonyl and carbonyl Substituted by one or more substituents or a heterocyclic group selected from the group consisting of pyridinyl, thiophenyl, furanyl, imidazolyl, morpholinyl, oxazolinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl and pyrrolidinonyl The process of claim 1, which represents The process of claim ₁ , wherein Z is —OR ₁ and R ₁ is as defined in claim 2. R ₂ and R ₃ are
(I) R ₂ is methylene, R ₃ is n-butyl;
(Ii) R ₂ is ethylene, R ₃ is phenyl; and (iii) R ₂ is —CH ₂ O—, R ₃ is phenyl substituted by halogen or trihalomethyl,
The process of claim 1 selected from the group consisting of: Formula I having an enantiomeric excess of> 95% enantiomeric excess:

Wherein R ₂ represents a single bond or C _1-4 -alkylene or —CH ₂ O—; R ₃ represents C _1-7 -alkyl or aryl or aralkyl, each of which is unsubstituted or C _1-4 -substituted by alkyl, halogen and trihalomethyl;

Wherein X ₁ and X ₂ are as defined in claim 1),
(A) Formula IV with an enantio-excess optical purity greater than 90%:

(Wherein Z is as defined in claim 1; P ₁ represents a protecting group for a hydroxyl group) is converted to a compound of formula V-1 having an optical purity with an enantiomeric excess of more than 90%. Formula V-2 or Formula V-3:

Wherein Y represents halogen; R ₆ represents lower alkyl; P ₂ represents a hydroxyl protecting group;

Reaction with a cue plate derived from

Producing a compound represented by:
(B) optionally removing the protecting group P ₁ or P ₂ or both P ₁ and P ₂ to give a compound of formula II:

Producing a compound represented by:
(C) optionally hydrogenating the compound of formula II under hydrogen using a catalyst containing a metal selected from palladium, platinum, rhodium, nickel and mixtures thereof;
(D) a compound of formula II, wherein M ₁ represents M ₂ (R ₅ ) _n H, wherein M ₁ represents lithium, potassium or sodium or is absent; M ₂ represents aluminum or boron Wherein R ₅ represents hydrogen, alkyl or alkoxyl; n is 2 or 3, and is reduced / lactonized using an effective amount of a reducing agent represented by formula (I) to form a compound represented by the formula I And a preparation process comprising. The process according to claim 5, wherein X ₁ and X ₂ are hydrogen, both P ₁ and P ₂ are removed in step (b) and step (c) is absent.   The process of claim 6, further comprising crystallizing and isolating the compound of Formula II or Formula I. The process according to claim 5, wherein Z represents —OR ₁ and R ₁ is as defined in claim 2.   The reducing agent is selected from lithium tri-sec-butyl borohydride, lithium trisamyl borohydride, sodium tri-sec-butyl borohydride, potassium tri-sec-butyl borohydride, potassium trisamyl borohydride and mixtures thereof. The process of claim 5.   6. The process of claim 5, wherein the reducing agent is lithium tri-sec-butylborohydride. Formula II having an enantiomeric excess of> 95% enantiomeric excess:

Wherein Z is OR ₁ , wherein R ₁ independently represents in each case alkyl, alkenyl, alkynyl, aryl or aralkyl, each of which is unsubstituted or halogen, alkyl, aryl, alkoxyl, aryl One or more substituents selected from the group consisting of oxy, thioalkoxyl, thioaryloxy, alkylamino, arylamino, cyano and alkoxylcarbonylphenyl, or pyridinyl, thiophenyl, furanyl, imidazolyl, morpholinyl, oxazolinyl, piperidinyl, piperazinyl, Substituted with a heterocyclic group selected from the group consisting of tetrahydropyranyl, pyrrolidinyl and pyrrolidinonyl), X ₁ , X ₂ ,

An enantiomer-enriched compound represented by: The compound according to claim 11, wherein X ₁ and X ₂ are both hydrogen atoms. R ₁ represents alkyl, alkenyl or alkynyl, each of which is unsubstituted or one or more substituents selected from the group consisting of halogen, alkoxyl, aryloxy, thioalkoxyl, thioaryloxy, alkylamino and cyano, Or a compound according to claim 11 substituted by a heterocyclic group selected from the group consisting of morpholinyl, oxazolinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl and pyrrolidinonyl. R ₁ is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, alkyl, aryl, alkoxyl, aryloxy, thioalkoxyl, thioaryloxy, alkylamino, arylamino, alkoxycarbonyl and cyano. 12. A compound according to claim 11 which is substituted aryl. R ₁ is aralkyl which is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, alkyl, aryl, alkoxyl, aryloxy, thioalkoxyl, thioaryloxy, alkylamino and cyano. 12. A compound according to claim 11. R ₂ and R ₃ are as defined in claim 4, compound of claim 11. Ethyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentaneacetate;
Benzyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentane acetate;
2-naphthyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentane acetate;
(1'R, 2'S, 5'R) -Mentyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentane acetate ;
2-cyanoethyl (1R, 2R, 3R) 3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentane acetate;
3-ethoxycarbonylphenyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentane acetate;
4-morpholine ethyl (1R, 2R, 3R) -3-hydroxy-2-[(3S) -hydroxy- (1E) -octenyl] -5-oxo-cyclopentane acetate;
Benzyl (1R, 2R, 3R) -3-hydroxy-2- [5-phenyl- (3S) -hydroxy- (1E) -pentenyl] -5-oxo-cyclopentane acetate;
2-naphthyl (1R, 2R, 3R) -3-hydroxy-2- [5-phenyl- (3S) -hydroxy- (1E) -pentenyl] -5-oxo-cyclopentane acetate;
(1′R, 2 ′S, 5′R) -Mentyl (1R, 2R, 3R) -3-hydroxy-2- [5-phenyl- (3S) -hydroxy- (1E) -pentenyl] -5-oxo -Cyclopentane acetate;
Ethyl (1R, 2R, 3R) 3-hydroxy-2- [5-phenyl- (3S) -hydroxy- (1E) -pentenyl] -5-oxo-cyclopentaneacetate;
Benzyl (1R, 2R, 3R) -3-hydroxy-2-[(3R) -hydroxy-4- (3-trifluoromethyl) phenoxy- (1E) -butenyl] -5-oxo-cyclopentane acetate;
Ethyl (1R, 2R, 3R) -3-hydroxy-2-[(3R) -hydroxy-4- (3-trifluoromethyl) phenoxy- (1E) -butenyl] -5-oxo-cyclopentane acetate; and ethyl 12. A compound according to claim 11 selected from the group consisting of (1R, 2R, 3R) 3-hydroxy-2- [5-phenyl- (3R) -hydroxy-pentanyl] -5-oxo-cyclopentane acetate.