WO2006013965A1

WO2006013965A1 - Process for producing tricyclic sulfone

Info

Publication number: WO2006013965A1
Application number: PCT/JP2005/014409
Authority: WO
Inventors: Eiichiro Imai; Yukiteru Mimura; Noriko Koizumi; Sachiko Kato; Masahiko Kinugawa; Toru Sugaya
Original assignee: Kyowa Hakko Kogyo Co., Ltd.
Priority date: 2004-08-06
Filing date: 2005-08-05
Publication date: 2006-02-09
Also published as: JPWO2006013965A1

Abstract

A process for producing a tricyclic sulfone represented by the formula (II) [wherein X represents hydrogen, halogeno, (un)substituted alkyl, mono((un)substituted alkyl)aminocarbonyl, di((un)substituted alkyl)aminocarbonyl, or (un)substituted alkanoylamino], characterized by oxidizing a tricyclic sulfide represented by the formula (I) (wherein X has the same meaning as defined above) with potassium hydrogen monopersulfate composite salt (2KHSO5·KHSO4·K2SO4).

Description

Production method of tricyclic sulfone

Technical field

The present invention relates to a method for producing a tricyclic sulfone useful as a pharmaceutical product or a synthetic intermediate thereof.

Background art

[0002] For example, a method for producing compound (IIa) from compound (la) by an oxidation reaction with peroxy acid such as metabenzoic perbenzoic acid is known / referred (see Patent Documents 1 and 2).

[0003] [Chemical 1]

[0004] (wherein R ¹ represents a hydrogen atom, a substituted or unsubstituted alkyl having 1 to 6 carbon atoms, etc.) However, use of a large amount of metabenzoic perbenzoic acid on an industrial scale is, for example, a safety aspect. However, the above-mentioned method, which is not necessarily preferable, remains a problem as an industrial production method (see, for example, Experimental Chemistry Guidebook, edited by The Chemical Society of Japan, Maruzen, June 15, 1984, page 436). , Potassium hydrogen persulfate double salt [2KHSO -KHSO · Κ SO, oxon (registered)

5 4 2 4

(Trademark)] is known as an example of an acid-sulfuration reaction from a sulfide to a sulfone [Tetrahedron Letters, 1981, No. 22, ρ.1287-1290; 1994, 35th, Ρ.3457-3460].

Patent Document 1: Pamphlet of International Publication No. 98/46587

Patent Document 2: JP 2002-53580 A

Disclosure of the invention Problems to be solved by the invention

[0005] An object of the present invention is to provide a method for producing a tricyclic sulfone that is safer and has a higher yield than conventional methods and is suitable for mass synthesis.

Means for solving the problem

[0006] The present invention relates to the following (1) to (5).

(1) Formula (I)

[0007] [Chemical 2]

[Wherein, X is a hydrogen atom, halogen, substituted or unsubstituted alkyl, mono (substituted or unsubstituted alkyl) aminocarbol, di (substituted or unsubstituted alkyl) aminocarbo]

A tricyclic sulfide represented by the formula (II), which is represented by the formula (II), characterized in that the tricyclic sulfide represented by the formula (II) represents a substituted or unsubstituted alkanoylamino]

[0009] [Chemical 3]

(II)

(Wherein X is as defined above), a method for producing a tricyclic sulfone.

(2) The method for producing a tricyclic sulfone according to the above (1), wherein X is halogen.

(3) The method for producing a tricyclic sulfonate according to the above (1), wherein X is a substituted or unsubstituted alkanoylamino. (4) is the formula (111)

[0011] [Chemical 4]

[0012] The method for producing a tricyclic sulfone according to (1),

(5) X is the formula (IV)

[0013] [Chemical 5]

[0014] The method for producing a tricyclic sulfone according to (1), wherein

The invention's effect

[0015] The present invention provides a method for producing a tricyclic sulfone that is safer and has a higher yield than conventional methods and is suitable for mass synthesis.

BEST MODE FOR CARRYING OUT THE INVENTION

[0016] Hereinafter, the compounds represented by the formula (I) and the formula (にお) are defined in the definitions of the respective groups of the compound (I), the compound (II), the formula (I) and the formula (II), respectively. !

Halogen represents each atom of fluorine, chlorine, bromine and iodine.

Examples of the alkyl moiety of alkyl, mono (alkyl) aminocarbol, di (alkyl) aminocarbole and alkanoylamino include, for example, linear, branched, cyclic, or a combination thereof having 1 to 10 carbon atoms. Alkyl is mentioned. Note that the two alkyl moieties in the di (alkyl) aminocarboxyl may be the same or different! /, May! /. [0017] Examples of linear or branched alkyl include methyl, ethyl, n-propyl, isopropinole, n-butyl, isobutyl, sec-butynole, tert-butyl, n-pentyl, neopentyl, n- Hexyl, n-heptyl, n-octyl, n-nor, n-decyl and the like can be mentioned. Examples of the cyclic alkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, noradamantyl, adamantyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [ 3.3.0] octyl, bicyclo [3.3.1] nor and the like.

[0018] Examples of the alkyl having a combination force of linear or branched and cyclic include cyclopropylmethyl, cyclopentylmethyl, cyclooctylethyl and the like. The substituents in substituted alkyl, mono (substituted alkyl) aminocarbol, di (substituted alkyl) aminocarbol and substituted alkanoylamino are the same or different and can be substituted from the number of substitutions 1, preferably the number of substitutions. 1 to 4, for example, halogen, amino-containing hydroxy, alkoxy, aryl, heterocyclic group and the like can be mentioned.

[0019] In the definition of the substituent in the substituted alkyl, mono (substituted alkyl) aminocarbol, di (substituted alkyl) aminocarbol and substituted alkanoylamino, the halogen is as defined above, and the alkyl part of alkoxy is as defined above. It is synonymous with alkyl, and examples of aryl include fur and naphthyl, and examples of heterocyclic groups include aromatic heterocyclic groups and alicyclic heterocyclic groups. Examples of the aromatic heterocyclic group include pyridyl, furyl, chenyl, quinolyl, imidazolyl, benzoimidazolyl, thiazolyl, oxazolyl and the like, and examples of the alicyclic heterocyclic group include tetrahydrofuryl, tetrahydrophenylenole, and chromyl. , Pyrrolidyl, piperazil, piperidyl, pipecolinyl, monorephoryl, thiomorpholinyl and the like.

[0020] Hereinafter, the production method of the present invention will be described.

Compound (II) can be produced, for example, by the following method.

Compound (I) is added to 1 to 100 equivalents, preferably 1 to 5 equivalents of oxone (registered trademark) with compound (I) in a solvent, preferably a hydrous solvent, more preferably a hydrous Ν, Ν- Dimethylformamide (DMF), hydrous acetonitrile, hydrous methanol, hydrous acetone or hydrous 1,4-dioxane, more preferably hydrous DMF or hydrous acetonitrile, from -78 ° C Compound (II) can be obtained by reacting at a temperature between the boiling points of the solvents, preferably at a temperature between 0 and 60 ° C., for 5 minutes to 24 hours, preferably 2 to 10 hours. The ratio of solvent to water in the hydrous solvent may be any ratio as long as there is no problem in carrying out the reaction, but is preferably solvent: water = 10: 1 to 1:10, more preferably Solvent: water = 3: 1 to 1: 1.

[0021] Compound (I) can be obtained by the method described in W098 / 46587, JP-A-2002-53580 or the like, or a method analogous thereto.

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.

Example 1

[0022] (S)-(+)-5,5-Dioxo-9- (3,3,3-trifluoro-2-hydroxy-2-methylpropanoylamino) -4, 10-dihydroceno [3,2 -c] [l] Benzochepin-10-one (I compound 1)

(S)-(+)-9- (3,3,3-trifluoro-2-hydroxy-2-methylpropanoylamino) -4,10-dihydrocheno synthesized according to the method described in W098 / 46587 [3, 2-c] [l] benzochepin-10-one (compound 2) (10.0 g, 25.8 mmol) was dissolved in DMF (45 mL) and water (15 mL) at 35 ° C and at the same temperature, oxone ( (Registered trademark) (Mitsubishi Gas Chemical) (31.7 g, 51.6 mmol) was added. The reaction mixture was stirred at the same temperature for 5 hours, water (200 mL) was added, and the mixture was crystallized at 50 ° C for 1 hour. The crystals were collected by filtration and washed with hot water (100 mL) at 50 ° C. Compound 1 (10.3 g, yield 95%) was obtained as a pale yellowish white solid by drying under reduced pressure at ° C. Compound 1 is the same compound as Compound 1-25 described in W098 / 46587.

[0023] In addition, W098 / 46587 and JP-A-2002-53580 describe an oxidation reaction from compound 2 to compound 1 using methacrobenzoic perbenzoic acid. In this case, the yield of compound 1 is! All were 65%.

Example 2

[0024] Production of Compound 1

Compound 2 (10.0 g, 25.8 mmol) is dissolved in acetonitrile (150 mL), water (100 mL) is added, followed by oxon (registered trademark) (Mitsubishi Gas Chemical) (63.7 g, 103 mmol) at room temperature. Karo. The reaction mixture was stirred at 45 ° C for 8 hours, then ethyl acetate (50 mL) was added, and water was added twice. Washed (100 mL, 200 mL). Water (200 mL) and toluene (100 mL) were added to the obtained organic layer and washed again. The obtained organic layer was concentrated to 50 mL under reduced pressure. Toluene (150 mL) was added to the residue, crystallized at 70 ° C for 1 hour, then crystallized for 6 hours under ice-cooling, and the crystals were collected by filtration and washed with toluene (30 mL). By drying under reduced pressure at 50 ° C., Compound 1 (10.3 g, yield 95%) was obtained as a pale yellowish white solid.

Example 3

[0025] Production of Compound 1

(S) -3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (7.7 g, 48.9 mmol) synthesized according to the method described in W098 / 46587 was dissolved in ethyl acetate (130 mL) at 25 ° C. At the same temperature, chlorochloride (4.2 mL, 57.6 mmol) and pyridine (1.2 mL, 14.9 mmol) were calorieated. The reaction mixture was stirred at the same temperature for 5 hours to prepare a solution of (S) -3,3,3-trifluoromethyl-2-hydroxy-2-methylpropiochloride.

[0026] Next, 9-amino-4,10-dihydrocheno [3,2-c] [l] benzochepin-10-one (10.0 g, 40.4 mmol) synthesized according to the method described in W098 / 46587 was converted to ethyl acetate ( 150 mL) was dissolved at 30 ° C., and at the same temperature, water (80 mL) and the previously prepared acid chloride solution (about 140 mL) were added. The reaction mixture was stirred at the same temperature for 2 hours, then washed twice with 2 mol / L aqueous sodium hydroxide solution (60 mL, 80 mL) and once with 10% aqueous sodium sulfate solution (80 mL), and the solvent was distilled under reduced pressure. After leaving, the obtained residue was dissolved in DMF (45 mL) and water (15 mL) at 35 ° C, and Oxon (registered trademark) (Mitsubishi Gas Chemical) (31.7 g, 51.6 mmol) was added at the same temperature. It was. The reaction mixture was stirred at the same temperature for 5 hours, and then water (200 mL) was added and crystallized at 50 ° C for 1 hour to obtain Compound 1 (16.1 g, 2-step yield of 95%). Obtained as a pale yellowish white solid.

Example 4

[0027] Preparation of 5,5-dioxo-9-fluoro-4,10-dihydrocheno [3,2-c] [l] benzochepin-10-one

9-Fluoro-4,10-dihydroceno [3,2-c] [l] benzochepin-10-one (10.0 g, 40.0 mmol) synthesized according to the method described in JP-A-2002-53580 was added to acetonitrile (150 mL). Oxone (registered trademark) (Mitsubishi Gas Chemical) (98.2 g, 160 mmol) and water (150 mL) were added at the same temperature. The reaction mixture was stirred at the same temperature for 2 hours, then insoluble materials were filtered off, The filtrate was concentrated under reduced pressure to 150 mL. By adding water (150 mL) to the concentrated residue and crystallization at room temperature for 1 hour, 5,5-dioxo-9-fluoro-4,10-dihydrocheno [3,2-c] [l] benzochepine- 10-one (10.9 g, 96% yield) was obtained as a white solid.

1H-NMR (CDC1, δ, ppm) 7.95 (d, J = 8.1 Hz, 1H), 7.71 (ddd, J = 8.4, 8.1, J = 5

3 H-F

.2 Hz, 1H), 7.71 (d, J = 5.0 Hz, 1H), 7.51 (ddd, J = 8.4, 8.1, J = 5.2 Hz, 1H), 7.0

H-F

1 (d, J = 5.0 Hz, 1H), 4.66 (s, 2H)

MS (EI); (m / z) 282 (M)

IR (KBr, cm " ¹ ) 1639, 1597, 1456, 1410, 1313, 1275, 1252, 1194, 1126, 928, 804, 74 1, 685, 588

[0028] From Examples 1 to 4, it can be seen that by using Oxon (registered trademark), acid conversion from tricyclic sulfide to tricyclic sulfone can be performed in high yield. Oxone (registered trademark) is a safer oxidant than oxidants such as metachloroperbenzoic acid, and is considered to be particularly suitable for use on a large scale!

Reference Example 1: Production of high purity compound 1

Compound 1 (10.0 g, 23.8 mmol) obtained in Example 1 was dissolved in ethanol (225 mL) by heating to obtain water (225 mL). After cooling, crystallization was performed for 3 hours under ice cooling to obtain Compound 1 (9.7 g, yield 97%) with a purity of 99.9% or more (high performance liquid chromatography analysis) as a pale yellowish white solid. .

[0029] The analysis conditions of high performance liquid chromatography are as follows.

Column: YMC- Pack AM- 312 ODS (diameter 6.0 mm, length 150 mm, made in ヮ cine) Column temperature: 35 ° C

Mobile phase: potassium dihydrogen phosphate 4.48 gZ water 1.640 mLZ-acetonitrile 1.460 mL Flow rate: 1.0 mLZ min

Detection wavelength: 242 nm

Measurement time: 40 minutes

Compound 1 retention time: about 9 minutes

Industrial applicability

[0030] According to the present invention, a tricyclic system that is safer and has higher yield than conventional methods and is suitable for mass synthesis. A process for the production of sulfones is provided.

Claims

(I)

[Wherein x is a hydrogen atom, halogen, substituted or unsubstituted alkyl, mono (substituted or unsubstituted alkyl) aminocarbol, di (substituted or unsubstituted alkyl) aminocarbo

-Represents a tricyclic sulfide represented by-or a substituted or unsubstituted alkanoylamino] using potassium hydrogen persulfate double salt (2KHSO -KHSO · Κ SO).

5 4 2 4

Characterized by the formula (II)

[Chemical 7]

(II)

(Wherein X is as defined above), a method for producing a tricyclic sulfone.

[2] The process for producing a tricyclic sulfone according to claim 1, wherein X is halogen.

[3] The process for producing a tricyclic sulfone according to claim 1, wherein X is a substituted or unsubstituted alkanoylamino.

[4] X is the formula (III)

[Chemical 8]

The method for producing a tricyclic sulfone according to claim 1, wherein

X is the formula (IV)

[Chemical 9]

The method for producing a tricyclic sulfone according to claim 1, wherein