JPH08507310A - Enantioselective preparation of thiazole derivatives - Google Patents

Abstract

(57) Summary An enantioselective method for preparing compounds of general formulas (I) and (II) from brochiral ketone precursors of alcohols of general formula (I). Thus, the compounds of general formulas (I) and (II) are obtained in substantially enantiomerically pure form by reducing a ketone with a borane reducing agent in the presence of a chiral oxazaborolidine catalyst.

Description

Detailed Description of the Invention                     Enantioselective preparation of thiazole derivatives                                   Background of the Invention   The present invention provides a compound of general formula (II) with a borane reducing agent in the presence of an oxaazaborolidine catalyst. I) Enantioselectively reducing the prochiral ketone of Formulas (I) and (II) in sexually pure form Particularly useful methods of preparing the compounds of Light of the general formulas (I) and (II) The chemically pure compounds are described in US Pat. No. 4,886,81, which is hereby incorporated by reference. The general formula (IV) disclosed in 4 Is a useful intermediate in the synthesis of useful antidiabetic compounds of                                   Summary of the invention   The present invention provides compounds of general formula (I) in substantially enantioselectively pure form. A method of enantioselectively preparing a compound of The method of the present invention is generally Formula (V) (Where R¹Is hydrogen, (C₁-C₈) Alkyl, benzyl, heterocyclyl Or up to three (C₁-C₈) Alkyl, (C₁-C₈) Alkoxy or R is phenyl optionally substituted with a halo group; R²And R³Is a thin and distinct Each independently, (C₁-C₈) Alkyl, benzyl, heterocyclyl Or up to 3 (C₁-C₈) Alkyl, (C₁-C₈) Alkoxy or halo Phenyl optionally substituted with a group, with the proviso that R is²Is CH₃And R³But fe If nil, R¹Is H) in the presence of a chiral oxazaborolidine catalyst With a borane reducing agent or in an atmosphere inert to the reaction in a solvent inert to the reaction, General formula (VI) (Where R¹, As defined above, and D is independently up to 3 (C₁-C₈ ) Alkyl, heterocyclyl or independently up to 3 (C₁-C₈) Alkyl , (C₁-C₈) Optionally with phenyl optionally substituted with an alkoxy or halo group Substituted cis-fused 4-6 membered carbon monocyclic ring: independently up to 3 (C₁-C₈) Archi , Heterocyclyl or up to three (C₁-C₈) Alkyl, (C₁- C₈) Optionally substituted with phenyl optionally substituted with alkoxy or halo groups Cis-fused 6-9 membered carbon bicyclic system; or R⁶And R⁷, Each independently, H, ( C₁-C₈) Alkyl, (C₁-C₈) A structural formula that is alkoxy or halo Is a cis-condensation system having a) chiral oxazaborolidine catalyst, General formula (III) It is characterized by reacting with a prochiral ketone of.   The preferred method of the present invention is that this oxaazaborolidine catalyst is Is the above method.   A particularly preferable method among the preferable methods is that the solvent inert to this reaction is tetra Hydrofuran, dioxane, diethyl ether, toluene or benzene The atmosphere inert to the reaction is nitrogen and the borane reducing agent is borane methyls. The method is a Ruffido complex.   Among the particularly preferred methods, the even more particularly preferred method is that of the formula (III) This chiral oxazaborolidine catalyst was in-situ prior to the addition of the lochiral ketone. It is a method of preparing.   The present invention also provides a compound of the general formula (I) The compound of I) is reacted with a base to give a compound of general formula (I) in a substantially enantiomerically pure form. A compound of general formula (II) formed by forming a compound of II) Also provided are methods of enantioselectively preparing the compounds of                                Detailed Description of the Invention   The present invention comprises substantially the optically active compounds of the above general formulas (I) and (II). A method for preparing a substantially enantiomerically pure form is provided. A schematic diagram of this method, A schematic diagram I is shown below.   The method of the present invention is easily implemented. A compound of general formula (I) Of 4-bromoacetyl-2-trifluoromethylthiasol (III) Prepared in a substantially enantiomerically pure form through reduction.   In the reduction method of the present invention, a chiral 1,2-disubstituted aminoethanol derivative The precursor of chiral oxazaborolidine, which is in the form of, is reacted in an inert atmosphere. At room temperature, it dissolves in a solvent inert to the reaction. Chiral 1,2-disubstituted aminoethane The nol derivative produces the chiral oxazaborolidine catalyst used in the method of the present invention. One of the 1,2-disubstituted aminoethanol derivatives can be selected. Wear. However, good A good 1,2-disubstituted aminoethanol derivative is (1S, 2R)-(+)-2-a Mino-1,2-diphenylethanol and (1S, 2R)-(+)-norephed It's Rin. Particularly preferred reaction-inert solvents are limited to them Dioxane, tetrahydrofuran, diethyl ether, toluene And benzene. Further particularly preferred solvent is tetrahydrofuran And toluene. Add an appropriate borane reducing agent to the reaction mixture and add the reaction mixture. Place at room temperature for 2 to 24 hours. The borane reducing agent is a borane methyl sulfide complex or And borane tetrahydrofuran complex can be selected, but the most preferred The first is the borane methyl sulfide complex. Usually, chiral oxazaboro The lysine catalyst forms within 10-16 hours.   After forming the chiral oxazaborolidine catalyst, the prochiral compound of general formula (III) Luketone is added to the reaction mixture at ambient temperature. The reaction to reduce a ketone to an alcohol is Usually, it is completed within 10-15 minutes after the addition is completed. However, sometimes, the choice Complete reaction depending on various factors including the specific solvent used or the amount of materials used May require a longer time to guarantee Then the reaction mixture Is cooled to about 0 ° C. and reacted by careful addition of a proton source, usually methanol. Stop. The compounds of general formula (I) are isolated by standard methods of organic chemistry.   Alternatively, the reduction method of the present invention is a method according to general formula (V) or general formula (VI). In the presence of a luoxaazaborolidine catalyst, the general formula R^FourR^FiveCO (where R^Fourand R^FiveIs defined below) and reacts with a borane reducing agent. It can be done with. This method uses two possible alcohol mirror images. This pro-former prefers to form only one of its isomers over the corresponding enantiomer. It is attributed to the enantioselective reduction of chiral ketones. Degree of enantioselectivity obtained Is R bound to a carbonyl group forming a prochiral ketone^FourAnd R^FiveBase size It depends on the size. R^FourAnd R^FiveIf the groups are of similar size, enantioselect The degree of choice is lower. R^FourAnd R^FiveHenin as the size of the base becomes more and more different The degree of thio selection is greater. However, R^FourAnd R^FiveOnly the size of the base Is not the only determinant that affects the degree of enantioselectivity achieved Is natural. Usually R^FourAnd R^FiveDifferent sizes of at least medium With ralketone, less of the desired enantiomer Both yield 90%. However, typically greater than 90% of the desired enantiomer Is obtained.   Prochiral ketone, toluene, diethyl ether, dioxane, tetrahydride Dissolve in a suitable solvent inert to the reaction, such as lofuran. Preferred is Tet It is lahydrofuran. Catalytic amount of chiral compound of general formula (V) or general formula (VI) The xazaborolidine compound is added to the reaction mixture at about -78 ° C to about room temperature, preferably room temperature. However, the preferred temperature depends on the particular borane reducing agent used. And then change. The preferred amount of this catalyst is about 5-10 mol% with respect to this ketone. Is. The reaction mixture is then treated with borane dimethyl sulfide complex, borane tet Borane reducing agent such as lahydrofuran complex, catechol borane, etc. about 4.2 hydrogen Gradually treat with compound equivalent. Prochiral ketone is an R with a borane-coordinating functionality^Four Or R^FiveIf it contains groups, an additional hydride equivalent of reducing agent is required. Normal Preferred for its easy use is borane dimethyl sulfide complex. Communication Usually, the reducing agent is added at a rate that regulates the rate of catalytic reduction. In the standard practice of organic chemistry It can be measured by monitoring the course of the reaction via thinner layer chromatography. However, sometimes the reaction is complete as soon as all the reducing agent has been added. Shi However, to ensure the completion of the reaction, sometimes a long reaction, such as overnight, Stir the mixture or heat the reaction mixture to a temperature between 40 ° C and 65 ° C. Is desirable. Furthermore, when a specific substrate and reducing agent are used, it is 16 hours at -78 ° C It may be necessary to stir the reaction mixture for an extended period of time, such as between. Usually anti The reaction mixture is stirred at about room temperature for about 15 minutes. The temperature of the reaction mixture is then 0 ° C. And stop the reaction using a proton source. This proton source, usually methanol A lower alkanol, such as ruthenium, is added slowly to control the exothermic reaction. vacuum The product was isolated by removing the solvent with, followed by partition between organic solvent and aqueous acid. The layers are then separated and purified by standard techniques of organic chemistry.   The compounds of general formula (II) of this method are also easily prepared. Compound of general formula (I) Dissolve the material in aqueous base and stir vigorously. The preferred base is sodium hydroxide. But with other bases such as potassium hydroxide and potassium t-butoxide Can be Deodorization of compounds of general formula (I) to epoxides of general formula (II) Elementary and cyclization is achieved rapidly without racemization of the chiral center. Normal, Reaction is 5 minutes to 10 Complete within minutes, but include various factors such as base strength, base properties, amount of materials used, etc. It may take longer depending on the factors. After forming the epoxide, The epoxide is isolated from the reaction mixture using well known methods.   The prochiral ketone starting material used in the method of this reaction is described in US Pat. Prepared by the method disclosed in 814. Preparation of antidiabetic compound of general formula (IV) The use of these compounds as intermediates in the manufacturing process is also mentioned there.   Chiral 1,2-disubstituted aminoethanol derivatives are usually obtained from Ardrich or Sigm. It is readily available from commercial sources such as Company a. Chiral 1,2-disubstituted aminoethane This erythroaminoethanol derivative is available if the nor derivative is not readily available. Reetz et al., Angew. Chemie Int. Ed. Eng.,26,1987, 1141-43 and Matsunaga, et al. T etrahedron Letters,32,1991Well known to those skilled in the art, such as those provided by Prepare by the method.   The following terms and phrases are used herein and in the appended claims. Defined as follows:   1. "Alkyl" means a specified number of carbon atoms, eg C₁-C₈Contains A branched or unbranched saturated hydrocarbon group. Examples are methyl, ethyl , Isopropyl, n-butyl, t-butyl, etc., but are not limited to these. Not only.   2. "Alkoxy" means branched or unbranched containing a specified number of carbon atoms. A branched saturated hydrocarbon group and this hydrocarbon is thereby bound to the central skeleton Means the only oxygen atom present. Examples include methoxy, ethoxy, etc. However, it is not limited to these.   3. "Heterocyclyl" contains up to 3 heteroatoms and (B) each represents a 5- or 6-membered aromatic group selected from N, O and S , Which may optionally be benzo-fused, wherein the heterocyclyl group is independently 3 Up to (C₁-C₈) Alkyl, (C₁-C₈) Optionally with an alkoxy or halo group It may be replaced.   4. R^FourR^FiveThe "prochiral ketone" represented by CO is R^FourAnd R^FiveBut Since they are not the same ketone, the secondary alcohol reduction product R^FourR^FiveCHOH Has a chiral center at the alcohol carbon position. R of cyclic prochiral ketones^Four And R^FiveTogether form a ring containing a ketone, and the ring thus formed is A plane containing a bonyl group and two carbon atoms directly attached to it, this plane being Carbo as the inside dot It contains both carbon and oxygen atoms of the nyl group but is drawn perpendicular to it. It goes without saying that they do not have planes that are symmetric across the plane.   7. Solvents inert to the reaction are those that adversely affect the yield of the desired product. By way is meant a solvent that does not interact with the reactants, intermediates or products.   8. "Syn" means a substituent that is substituted on an adjacent ring carbon atom The same plane containing the bonds between the child and each of these carbon atoms bound to a ring Means to be located on the side.   9. "Enantiomeric excess" or e. e. Is usually expressed as a percentage Passed in excess of one of the two enantiomers over the other, ie 90% e. e. Is 95% of one of the substances in question and one of the other is 5%. It reflects the presence of enantiomers.   10. "Normal temperature" means the temperature of the direct external environment surrounding the reaction flask To do. This temperature is usually room temperature (20-25 ° C).   11. <In-situ> means the key of the general formula (V) or the general formula (VI) of the present invention. Raloxaazaborolidine formed from precursor amino alcohols and borane Reaction conditions. After formation of oxazaborolysine, addition of prochiral ketone It The chiral oxaazaborolysines of this invention do not isolate under these conditions.   12. "A reaction-inert atmosphere" adversely affects the yield of the desired product Means a gas that does not interact with reactants, intermediates or products in a To do.   The present invention will be specifically described by the following examples. However, the present invention Of course, it is not limited to the particular details of these embodiments. All of Reactions are run under an inert atmosphere such as nitrogen or argon unless otherwise noted. To do. All solvents are anhydrous, i.e. their water is detrimental to the yield of the desired product. Do not interact with reagents, intermediates or products in a way that affects It contains a small amount of water. As used herein, "THF" means tetrahydro Means franc.                                    Example 1 (S) -oxiranyl-2-trifluoromethylthiazole   A. (S) -4- (2-Bromo-1-hydroxyethyl) -2-trifluoromethyl Thiazole. (1S, 2R)-(+)-2-Amino-1,2-diphenylethanol (586 mg, 2.75 mmol, 0.05 equivalent based on bromoketone) tetrahydrofuran (55 ml) solution in a nitrogen atmosphere under neat borane methyl sulfide complex ( Aldrich, -10M, 7.70 ml, -77 mmol, 1. based on bromoketone. 4 equivalents) were added all at once and allowed to stand for 16 hours. (EIMS) M + 223.11 59 (theoretical 223.1168). Bromo in tetrahydrofuran (28 ml) Ketone III (15.0 g, 54.7 mmol, 1.0 eq) at 25 ° C. for 1 hour It was dripped in between. 15 minutes after the addition was complete, the starting material ketone was consumed, The reaction was cooled to 0 ° C., quenched with methanol (55 ml) and stirred overnight. The solvent was removed under vacuum, toluene (140 ml) was added to the residue and the organic phase was adjusted to pH 4 Of phosphate buffer (140 ml) and water (140 ml), and wash with magnesium sulfate. Treated with sium. Chiral alcohol by filtration and removal of solvent under vacuum Was obtained as a pale yellow oily substance (13.58 g, 90% mass balance, 94% ee).   B. (S) -oxiranyl-2-trifluoromethylthiazole. Aqueous hydroxylation Sodium (4N12.52 ml), with vigorous stirring. Got at Add to neat oil (13.42 g). After 9 minutes, methylene chloride (100 m l) and water (100 ml) were added, the phases were separated and the aqueous phase was washed with water (3 x 100 ml). It was washed with and dried over magnesium sulfate. By filtration and removal of solvent under vacuum The crude chiral epoxide was obtained as an off-white liquid material, 9.35 g. 8.8 Distillation of 3 g of crude product at 4 mm Hg / boiling point 42-44 ° C. gave 6.99 g (broth). 70% of the total of chiral epoxide calculated from romoketone was made as a colorless oily substance. I got it.                                    Example 2 (S) -4- (2-Bromo-1-hydroxyethyl) -2-trifluoromethylthiazo The   (1S, 2R)-(+)-Norephedrine (76 mg, 0.5 mmol) To a solution of trahydrofuran (10 ml) under a nitrogen atmosphere, neat borane methyls Ruffide complex (10 M, 1.4 ml, 14 mmol) at room temperature (20-25 ° C) The reaction was allowed to stand for 16 hours. Bromo in tetrahydrofuran (5 ml) Ketone III (2.74 g, 10 mmol) was added dropwise over 1 hour and added. The reaction was stirred for 15 minutes after the reaction was completed, then cooled to 0 ° C. and methanol (1 The reaction was stopped with 0 ml). Stir the quenched reaction for 18 hours and remove the solvent under vacuum. To remove methylene chloride (25 ml) was added. The organic phase was washed with pH 4 phosphate buffer (25 ml) and water (25 ml). It was washed successively and dried over magnesium sulfate. After filtration, remove the solvent under vacuum To give 2.24 g of (S) alcohol as a yellow oil (83%, 84% ee). It was                                    Example 3 (S) -oxiranyl-2-trifluoromethylthiazole   A. (S) -4- (2-Bromo-1-hydroxyethyl) -2-trifluoromethyl Thiazole. Reduction in toluene and cyclization to a chiral epoxide. (1S, 2 R) -2-Amino-1,2-diphenylethanol (438 mg, 2 mmol, bromine To a toluene (41 ml) solution of 0.05 equivalent based on moketone, under a nitrogen atmosphere. , Neat borane methyl sulfide complex (Aldrich, -10M5.80 ml , 58 mmol, 1.4 equivalents based on bromoketone) all at once, at 16:00 I left it stationary. Bromoketone ((III), 11.31 in toluene (21 ml) g, 41 mmol, 1.0 equiv. was added dropwise at 25 ° C. (1 h. After 15 minutes, the starting material ketone was consumed and the reaction was cooled to 0 ° C. The reaction was quenched with Nol (41 ml) and stirred overnight. Remove solvent under vacuum and leave residue Toluene (100 ml) was added to and the organic phase was added to aqueous sulfuric acid (1M, 50 ml), water ( It was washed successively with 100 ml) and treated with magnesium sulphate. Solvent under vacuum Removal of chiral alcohol to give a pale yellow oil (10.84 g, 95% substance Balance, 90% ee).   B.(S) -oxiranyl-2-trifluoromethylthiazole.Aqueous hydroxylation Sodium (4N(10.53 ml) with vigorous stirring, neat oil (10.84 g). After 10 minutes, toluene (84 ml) and water (84 m) l) was added, the phases were separated, the aqueous phase was washed with water (3 x 84 ml) and magnesium sulfate was added. Dried. Remove the crude chiral epoxide off-orange by removing the solvent under vacuum Was obtained as 6.50 g of the liquid substance. 4 mmHg / boiling point 4 of 6.07 g of crude product By distillation at 2-44 ° C, 4.65 g (total 61 calculated as bromoketone) %) Chiral epoxide as a colorless oil.

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Claims (1)

[Claims]   1. The compound of the general formula (I) in substantially enantiomerically pure form A compound of general formula (V) (Where R₁Is hydrogen, (C₁-C₈) Alkyl, benzyl, heterocyclyl Or up to three (C₁-C₈) Alkyl, (C₁-C₈) Alkoxy or R is phenyl optionally substituted with a halo group; R₂And R₃Is a thin and distinct Each independently, (C₁-C₈) Alkyl, benzyl, heterocyclyl Or up to 3 (C₁-C₈) Alkyl, (C₁-C₈) Alkoxy or halo Phenyl optionally substituted with a group, with the proviso that R is²Is CH₃And R³But fe If nil, R¹Is H) in the presence of a chiral oxazaborolidine catalyst With a borane reducing agent or in an atmosphere inert to the reaction in a solvent inert to the reaction, General formula (VI) (Where R¹As defined above, D is independently up to 3 (C₁-C₈) Alkyl, heterocyclyl or independently up to 3 (C₁-C₈) Alkyl, (C₁-C₈) Optionally substituted with phenyl optionally substituted with an alkoxy or halo group Cis-fused 4-6 membered carbon monocyclic ring, substituted; up to three (C₁-C₈) Alkyl , Heterocyclyl or up to three (C₁-C₈) Alkyl, (C₁-C₈ ) System optionally substituted with phenyl optionally substituted with alkoxy or halo groups. S-fused 6-9 membered carbon bicyclic system; or R⁶And R⁷, Independently of each other, H, (C₁- C₈) Alkyl, (C₁-C₈) A structural formula that is alkoxy or halo Is a cis-condensation system having a) chiral oxazaborolidine catalyst, General formula (III) And a prochiral ketone as described above.   2. The oxazaborolidine catalyst The method of claim 1, wherein   3. Solvents inert to the reaction include tetrahydrofuran, dioxane, diethyl The method according to claim 2, which is ether, toluene or benzene.   4. The atmosphere inert to the reaction is nitrogen, and the borane reducing agent is borane methyl. The sulfide complex, wherein the temperature of the reaction mixture is maintained at room temperature. How to list.   5. The solvent according to claim 4, wherein the solvent inert to the reaction is tetrahydrofuran. Method.   6. Prior to the addition of the prochiral ketone, the borane methyl sulfide complex is added. Body and (1S, 2R) -2-amino-1,2-amino-1,2-diphenylethanol In situ preparation of the chiral oxaazaborolidine catalyst by reacting The method of claim 5, wherein   7. Prior to the addition of the prochiral ketone, the borane methyl sulfide complex is added. By reacting the body with (1S, 2R)-(+)-norefuedrin, The method of claim 5, wherein the chiral oxazaborolidine catalyst is prepared in situ.   8. The method according to claim 4, wherein the solvent inert to the reaction is toluene.   9. Prior to the addition of the prochiral ketone, the borane methyl sulfide complex is added. Body reacts with (1S, 2R) -2-amino-1,2-cyphenylethanol 9. The chiral oxazaborolidine catalyst is prepared in situ by: The method described in.   10. Prior to the addition of the prochiral ketone, the borane methyl sulfide compound By reacting the combined product with (1S, 2R)-(+)-norephedrine, 9. The method of claim 8, wherein the chiral oxazaborolidine catalyst is prepared in situ.   11. General formula (II) A method of preparing a compound of formula (I) according to the method of claim 1. Is enantioselectively prepared, and the compound of the general formula (I) is reacted with a base. The above method, which comprises forming the compound of the general formula (II).   12. The method according to claim 11, wherein the base is sodium hydroxide.   13. The borane reducing agent is a borane methyl sulfide complex, The inert solvent is toluene, the atmosphere inert to the reaction is nitrogen, The temperature of the mixture is room temperature, and the borane methyl sulfide complex and (1S, 2R )-(+)-Norephedrine by reacting with chiral oxazaborol 13. The method of claim 12, wherein the gin catalyst is prepared in situ.   14. The borane reducing agent is a borane methyl sulfide complex, The inert solvent is tetrahydrofuran and the atmosphere inert to the reaction is nitrogen. Yes, the temperature of the reaction mixture is room temperature, and the borane methyl sulfide complex (( Chiral oxa by reacting with 1S, 2R)-(+)-norephedrine 13. The method of claim 12, wherein the azaborolidine catalyst is prepared in situ.   15. The borane reducing agent is a borane methyl sulfide complex, The inert solvent is toluene, the atmosphere inert to the reaction is nitrogen, The temperature of the mixture is room temperature, and the borane methyl sulfide complex and (1S, 2R )-(+)-2-Amino-1,2-diphenylethanol 13. The method of claim 12, wherein the chiral oxazaborolidine catalyst is prepared in situ. .   16. The borane reducing agent is a borane methyl sulfide complex, The inert solvent is tetrahydrofuran and the atmosphere inert to the reaction is nitrogen. Yes, the temperature of the reaction mixture is room temperature, and the borane methyl sulfide complex (( React with 1S, 2R)-(+)-2-amino-1,2-diphenylethanol A chiral oxazaborolidine catalyst is thereby prepared in situ, according to claim 12. The method described.