WO1995002585A1

WO1995002585A1 - Enanthioselective preparation of thiazole derivatives

Info

Publication number: WO1995002585A1
Application number: PCT/IB1994/000062
Authority: WO
Inventors: George Joseph Quallich
Original assignee: Pfizer Inc
Current assignee: Pfizer Inc
Priority date: 1993-07-16
Filing date: 1994-04-06
Publication date: 1995-01-26
Anticipated expiration: 1996-01-16
Also published as: FI960180A0; FI960180L; CA2167287A1; JPH08507310A; FI960180A7; EP0708764A1

Abstract

An enanthioselective process for preparing the compounds of formulas (I) and (II) from the prochiral ketone precursor of the alcohol of formula (I). The compounds of formulas (I) and (II) are thus obtained in substantially enantiomerically pure form by reducing the ketone with a borane reducing agent in the presence of a chiral oxazaborolidine catalyst.

Description

ENANTHIOSELECTIVE PREPARATION OF THIAZOLE DERIVATIVES Background of the Invention This invention relates to a particularly useful process for preparing the compounds of formulas (I) and (II),

( i ) π ι >

in substantially enantiomerically pure form by enantioselectively reducing the prochiral ketone of formula (III)

( I I I )

with a borane reducing agent in the presence of an oxazaborolidine catalyst. The optically pure compounds of formulas (I) and (II) are useful intermediates in the synthesis of useful antidiabetic compounds of formula (IV),

(IV)

which are disclosed in U.S.4,886,814, and which is incorporated herein by reference.

Summary of the Invention The present invention provides a process for enantioselectively preparing the compound of formula (I)

(I) in substantially enantioselectively pure form. The process of this invention comprises reacting the prochiral ketone of formula (III),

(III) with a borane reducing agent in the presence of a chiral oxazaborolidine catalyst of the formula (V),

R¹

( V ) wherein R¹ is hydrogen, (C,-C₈)alkyl, benzyl, heterocyclyl or phenyl optionally substituted independently with up to three (C,-C₈)alkyl, (C C₈)alkoxy or halo groups; R² and R³ are syt7, are taken separately, and are each independently (O,-C₈)alkyl, benzyl, heterocyclyl or phenyl optionally substituted with up to three (C^CoJalkyl, (C,- C₈)alkoxy or halo groups, provided that when R² is CH₃ and R³ is phenyl, R¹ is H, or with a chiral oxazaborolidine catalyst of the formula (VI),

( V I )

wherein R¹ is as defined above and D is a cis-fused 4-6 membered carbomonocyclic ring optionally substituted independently with up to three (C,-C₈)alkyl, heterocyclyl or phenyl optionally substituted independently with up to three (C_|-C₈)alkyl, (O,-C₈)alkoxy or halo groups; a cis-fused 6-9 membered carbobicyclic system optionally substituted independently with up to three (C.,-C₈)alkyl, heterocyclyl or phenyl optionally substituted independently with up to three (C-,-C₈)alkyl, (C.,-C_B)alkoxy or halo groups; or a cis-fused system having the structure R⁶ and R⁷ are each independently

H, (C-,-C₈)alkyl, (C,-C₈)alkoxy or halo, in a reaction inert solvent under a reaction inert atmosphere.

A preferred process of this invention is the above process wherein said oxazaborolidine catalyst is

H H

( V I I ) ( V I I I )

A particularly preferred process within the preferred process is the process wherein said reaction inert solvent is tetrahydrofuran, dioxane, diethyl ether, toluene or benzene; said reaction inert atmosphere is nitrogen and said borane reducing agent is borane methylsulfide complex.

A more particularly preferred process within the particularly preferred process is the process wherein said chiral oxazaborolidine catalyst is prepared in situ prior to the addition of said prochiral ketone of formula (III). The present invention also provides a process for enantioselectively preparing the compound of the formula (II),

( I I )

which comprises preparing the compound of formula (I) as described hereinabove and reacting said compound of formula (I) with a base to form the compound of formula (II) in substantially enantiomerically pure form.

Detailed Description of the Invention The present invention provides a process for preparing the optically active compounds of formulas (I) and (II) hereinabove in substantially enantiomerically pure form. The scheme for this process is shown in Scheme I, below.

chiral 1 ,2-d i substi tuted borane reduc ing (III) aminoe thanol ^{+ a}9^{en t}

Borane reducing agent chiral catalyst

( I I I ) ( I )

( I I )

SCHEME I

The process of this invention is readily carried out. The compound of formula (I) is prepared in substantially enantiomerically pure form via the reduction of the prochiral ketone, 4-bromoacetyl-2-trifluoromethylthiazole (III).

In the reduction process of this invention, the precursor to the chiral oxazaborolidine catalyst, in the form of a chiral 1 ,2-disubstituted aminoethanol derivative, is dissolved in a reaction inert solvent under a reaction inert atmosphere at ambient temperature. The chiral 1 ,2-disubstituted amino-ethanol derivative can be chosen from among any of the 1 ,2-disubstituted aminoethanol derivatives which give rise to the chiral oxazaborolidine catalysts which are used in the process of this invention. However, preferred 1 ,2-disubstituted amino-ethanol derivatives are (1S, 2R)- (+)-2-amino-1 ,2-diphenylethanol and (1S, 2R)-(+)-norephedrine. The reaction inert solvents which are particularly preferred include but are not limited to dioxane, tetrahydrofuran, diethyl ether, toluene and benzene. More particularly preferred solvents are tetrahydrofuran and toluene. A suitable borane reducing agent is added to the reaction mixture and the reaction mixture is left at ambient temperature for 2 to 24 hours. The borane reducing agent may be selected from borane methylsulfide complex and borane tetrahydrofuran complex, but most preferred is borane methylsulfide complex. Generally the chiral oxazaborolidine catalyst will have formed within 10-16 hours.

After the chiral oxazaborolidine catalyst has formed, the prochiral ketone of formula (III) is added to the reaction mixture at ambient temperature. The reaction reducing the ketone to the alcohol is generally complete within 10-15 minutes after addition is complete. However, occasionally a longer amount of time may be required to ensure complete reaction depending upon a variety of factors including the particular solvents chosen or amounts of materials used and so on. The reaction mixture is then cooled, generally to about 0°C, and quenched by the careful addition of a proton source, generally methanol. The compound of formula (I) is isolated according to the standard methods of organic chemistry.

Alternatively, the reduction process of this invention can be carried out by reacting a prochiral ketone of the formula R⁴R⁵CO, wherein R⁴ and R⁵ are defined hereinbelow with a borane reducing agent in the presence of a chiral oxazaborolidine catalyst according to formula (V) or formula (VI). Said process results in the enantioselective reduction of said prochiral ketone, such that only one of two possible alcohol enantiomers is formed in preference to the corresponding enantiomer. The degree of enantio-selectivity which is obtained will vary depending upon the size of the R⁴ and R⁵ groups attached to the carbonyl group forming the prochiral ketone. When the R⁴ and R^s groups are similar in size, the degree of enantioselection will be lower. As the R⁴ and R^s groups become increasingly disparate in size, the degree of enantio¬ selection will be greater. However, it should be understood that the size of the R⁴ and R⁵ groups is not the sole determining factor affecting the degree of enantioselectivity achieved. Ordinarily, with prochiral ketones wherein R⁴ and R⁵ are at least moderately different in size, at least 90% of the desired enantiomer will be obtained. However, typically greater than 90% of the desired enantiomer is obtained

The prochiral ketone is dissolved in a suitable reaction inert solvent such as toluene, diethyl ether, dioxane, tetrahydrofuran or the like. Preferred is tetrahydrofuran. A catalytically effective amount of a chiral oxazaborolidine compound of formula (V) or formula (VI) is added to the reaction mixture at from about -78°C to about room temperature, preferably at room temperature; however, the preferred temperature will vary depending upon the particular borane reducing agent being used. The preferred amount of said catalyst is about 5-10 mole % with, respect to said ketone. The reaction mixture is then treated slowly with about 4.2 hydride equivalents of a borane reducing agent such as borane dimethylsulfide complex, borane tetrahydrofuran complex, catecholborane or the like. When the prochiral ketone contains an R⁴ or R⁵ group which bears a borane-coordinating functionality, additional hydride equivalents of reducing agent are necessary. Generally preferred for its ease of use is borane dimethylsulfide complex. Generally the reducing agent is added at a rate which modulates the rate of the catalytic reduction. The reaction is sometimes complete as soon as all of the reducing agent has been added, as can be determined by monitoring the course of the reaction via thin layer chromatography according to the standard practice of organic chemistry. However, occasionally it will be desirable to allow the reaction mixture to stir for longer periods of time such as overnight, or to heat the reaction mixture to temperatures of up to 40°C to 65°C in order to ensure completion of the reaction. Additionally, with some substrates and reducing agents, it may be necessary to stir the reaction mixture at -78°C for a lengthy period of time such as 16 hours. Ordinarily the reaction mixture is stirred at about room temperature for about fifteen minutes. The temperature of reaction mixture is then adjusted to 0°C and quenched with a proton source. Said proton source, usually a lower alkanol such as methanol, is added slowly to control the exothermic reaction. The product is isolated by removing the solvent in vacuo followed by partitioning between an organic solvent and an aqueous acid followed by separation of layers and purification according to the standard techniques of organic chemistry.

The compound of formula (II) of this process is also readily prepared. The compound of formula (I) is dissolved in aqueous base and vigorously stirred. The preferred base is sodium hydroxide, however other bases such as potassium hydroxide and potassium t-butoxide may also be utilized. The debromination and cyclization of the compound of formula (I) to the epoxide of formula (II) is effected rapidly and without racemization of the chiral center. Generally the reaction is complete within 5 to 10 minutes, however the reaction may require longer periods depending upon a variety of factors including strength of base, nature of base, amount of materials used and so on. After the epoxide is formed, the epoxide is isolated from the reaction mixture utilizing well-known methods of organic chemistry.

The prochiral ketone starting material for the process of this reaction is prepared by the method disclosed in U.S. Patent 4,886,814. The utility of these compounds as intermediates in the process for the preparation of the antidiabetic compound of formula (IV) is also described therein.

The chiral 1 ,2-disubstituted aminoethanol derivatives are generally readily available from commercial sources such as Aldrich or Sigma. Where the chiral 1 ,2- disubstituted aminoethanol derivative is not readily available, said erythro aminoethanol derivatives are prepared by methods well known to those of ordinary skill in the art, such as provided by Reetz et al., Angew. Chemie Int. Ed. Eng., 26, 1987, 1141-43 and Matsunaga et al., Tetrahedron Letters, 32, 1991. 7715-18.

The following terms and phrases, when used herein and in the appendant claims, are defined as follows:

1. "Alkyl" means a branched or unbranched saturated hydrocarbon group containing the specified number of carbon atoms, e.g., C-,-C₈. Examples include, but are not limited to methyl, ethyl, isopropyl, n-butyl, t-butyl and the like.

2. "Alkoxy" means a branched or unbranched saturated hydrocarbon containing the specified number of carbon atoms and a single oxygen atom by which said hydrocarbon is attached to a central backbone. Examples include, but are not limited to methoxy, ethoxy and the like.

3. "Heterocyclyl" means a 5- or 6-membered aromatic group containing up to three heteroatoms, each of said heteroatoms selected from N, O and S and which may be optionally benzo-fused, said heterocyclyl group being optionally substituted independently with up to three (C-,-C₈)alkyl, (C-,-C₈)alkoxy or halo groups.

4. A "prochiral ketone", denoted by R⁴R CO, is a ketone in which R⁴ and R⁵ are non-identical, so that the secondary alcohol reduction product R⁴R^sCHOH has a chiral center at the alcohol carbon. For cyclic prochiral ketones, it is understood that R⁴ and R⁵ are taken together, forming a ring including the ketone, and that the ring so formed has no plane of symmetry across a plane drawn perpendicular to the plane containing the carbonyl group and the two carbon atoms attached directly thereto, said plane containing both the carbon and oxygen atoms of the carbonyl group as points therein.

7. Reaction inert solvent means a solvent which does not interact with the reactants, intermediates or products in such a way that adversely affects the yield of the desired products. 8. "Syn" means that the substituents substituted on adjacent ring carbon atoms are located on the same side of a plane which encompasses the bond between said carbon atoms and the bonds by which each of said carbon atoms are attached to the ring.

9. "Enantiomeric excess", or e.e., is the excess of one of two enantiomers over the other, usually expressed as a percentage, i.e., a 90% e.e. reflects the presence of 95% of one enantiomer and 5% of the other in the material in question.

10. "Ambient temperature" means the temperature of the immediate external environment surrounding the reaction flask. This temperature is usually room temperature (20°-25°C).

11. In situ is the reaction condition wherein the chiral oxazaborolidines of formula (V) or formula (VI) of the invention are formed from the precursor aminoalcohol and borane. The prochiral ketone is added after the oxazaborolidine is generated. The chiral oxazaborolidines of the invention are not isolated under these conditions.

12. "Reaction inert atmosphere" means a gas which does not interact with the reactants, intermediates or products in such a way that adversely affects the yield of the desired products.

The present invention is illustrated by the following examples. However, it should be understood that the invention is not limited to the specific details of these examples. All reactions are conducted under an inert atmosphere, such as nitrogen or argon, unless otherwise specified. All solvents are anhydrous, i.e., contain such a small amount of water that said water does not interact with the reagents, intermediates or products in such a way that adversely affects the yield of the desired products. Where used herein, HF" means tetrahydrofuran. Example One (S)-Oxiranyl-2-trifluoromethylthiazole.

A. (S)-4-(2-Bromo-1 -hydroxyethyl)-2-trifluoromethylthiazole. To atetrahydrofuran

(55mL) solution of (1 S, 2R)-(+)-2-amino-1 ,2-diphenylethanol (586mg, 2.75mmol, 0.05 5 equivalents based on bromoketone) under a nitrogen atmosphere was added neat borane methylsulfide complex (Aldrich, ~10M, 7.70ml_, 77mmol, 1.4 equivalents based on bromoketone) all at once and allowed to stand 16hrs. (EIMS) M+ 223.1159 (Calcd

223.1168). Bromoketone III, (15.0g, 54.7mmol, 1.0 equivalent) in tetrahydrofuran

(28mL) was added dropwise over 1 hr at 25°C. Fifteen minutes after the addition was complete the starting ketone was consumed, the reaction was cooled to 0°C, quenched with methanol (55ml_), and stirred overnight. The solvents were removed under vacuum, toluene (140mL) was added to the residue, and the organic phase was washed successively with pH4 phosphate buffer (140ml_), water (140mL) and treated ₅ with magnesium sulfate. Filtration and removal of the solvent under vacuum afforded the chiral alcohol as a pale yellow oil (13.58g, 90% mass balance, 94%ee).

B. (S)-Oxiranyl-2-trifluoromethylthiazole. Aqueous sodium hydroxide (4N, 12.52ml_) was added to the neat oil (13.42g) obtained in A. above with vigorous stirring. After 9 min. methylene chloride (100ml_) and water (100ml_) were added, the phases _Q were separated, and the aqueous phase washed with water (3 x 100m L) and dried with magnesium sulfate. Filtration and removal of the solvent under vacuum afforded the crude chiral epoxide as an off white liquid, 9.35g. Distillation of 8.83g of the crude product at 4mmHg/boiling point 42-44°C yielded 6.99g (70% overall from the bromoketone) of the chiral epoxide as a colorless oil. ₅ Example Two

(S)-4-(2-Bromo-1-hydroxyethyl)-2-trifluoromethylthiazole.

To a tetrahydrofuran (10ml_) solution of (1S, 2R)-(+)-norephedrine (76mg, O.δmmol) under a nitrogen atmosphere was added neat borane methylsulfide complex (10M , 1.4mL, 14mmole) at ambient temperature (20-25°C) and the reaction was allowed 0 to stand for 16 hrs. Bromoketone III, (2.74g, 10mmol) in tetrahydrofuran (5ml_) was added dropwise over 1 hr, the reaction stirred for 15 min after the addition was complete, then cooled to 0°C and quenched with methanol (10ml_). The quenched reaction was stirred for 18hr, the solvents were removed under vacuum and methylene chloride (25ml_) was added. The organic phase was washed successively with pH4 phosphate buffer (25ml_), water (25mL), and dried with magnesium sulfate. After filtering, the solvent was removed under vacuum to afford the (S) alcohol 2.24g as a yellow oil (83%, 84%ee).

Example Three

(S)-Oxiranyl-2-trifluoromethylthiazole

5

A. (S)-4-(2-Bromo-1 -hydroxyethyl)-2-trifluoromethylthiazole. Reduction intoluene and cyclization to the chiral epoxide. To a toluene (41 ml_) solution of (1 S, 2R)-2-amino 1 ,2-diphenylethanol (438mg, 2mmol, 0.05 equivalents based on bromoketone) under a nitrogen atmosphere was added neat borane methylsulfide complex (Aldrich, ~10M, 5.80ml_, 58mmol, 1.4 equivalents based on bromoketone) all at once and allowed to

10 stand 16 hrs. Bromoketone ((III), 11.31g, 41mmol, 1.0 equivalent) in toluene (21mL) was added dropwise over 1 hr at 25°C. Fifteen minutes after the addition was complete the starting ketone was consumed, the reaction was cooled to 0°C, quenched with methanol (41 mL), and stirred overnight. The solvents were removed under vacuum, toluene (100ml_) added to the residue, the organic phase washed successively with

15 aqueous sulfuric acid (1 M, 50m L), water (100mL), and treated with magnesium sulfate. Removal of the solvent under vacuum afforded the chiral alcohol as a pale yellow oil (10.84g, 95% mass balance, 90%ee).

B. (S)-Oxiranyl-2-trifluoromethyl thiazole. Aqueous sodium hydroxide (4N, _₀ 10.53ml_) was added to the neat oil (10.84g) with vigorous stirring. After 10 min., toluene (84m L) and water (84m L) were added, the phases separated, the aqueous phase washed with water (3 X 84mL) and dried with magnesium sulfate. Removal of the solvent under vacuum afforded the crude chiral epoxide as a off orange liquid, 6.50g. Distillation of 6.07g of the crude product at 4mmHg/boiling point 42-44°C ₂₅ yielded 4.65g (61% overall from the bromoketone) of the chiral epoxide as a colorless oil.

30

Claims

Claims What is claimed is:

1. A process for enantioselectively preparing the compound of the formula

( I ) in substantially enantiomerically pure form, comprising: reacting the prochiral ketone of formula (III),

( I I I )

with a borane reducing agent in the presence of a chiral oxazaborolidine catalyst of the formula (V)

( V ) wherein R¹ is hydrogen, (C,-C₈)alkyl, benzyl, heterocyclyl or phenyl optionally substituted independently with up to three (C-,-C₈)alkyl, (C.,-C₈)alkoxy or halo groups; R² and R³ are syn, are taken separately, and are each independently (C,-C₈)alkyl, benzyl, heterocyclyl or phenyl optionally substituted with up to three (C-^C^alkyl, (C-,- C₈)alkoxy or halo groups, provided that when R² is CH₃ and R³ is phenyl, R¹ is H, or with a chiral oxazaborolidine catalyst of the formula (VI),

( V I )

wherein R¹ is as defined above and D is a cis-fused 4-6 membered carbomonocyclic ring optionally substituted independently with up to three (C,-C₈)alkyl, heterocyclyl or phenyl optionally substituted independently with up to three (C^C^alkyl, (C-,-C₈)alkoxy or halo groups; a cis-fused 6-9 membered carbobicyclic system optionally substituted independently with up to three (O,-C₈)alkyl, heterocyclyl or phenyl optionally substituted independently with up to three (C₁-C₈)alkyl, (C-,-C₈)alkoxy or halo groups; or a cis-fused

system having the structure wherein R⁶ and R⁷ are each independently

2. A process according to claim 1 wherein said oxazaborolidine catalyst is

( V I I ) ( V I I I )

3. A process according to claim 2 wherein said reaction inert solvent is tetrahydrofuran, dioxane, diethyl ether, toluene or benzene.

4. A process according to claim 3 wherein said reaction inert atmosphere is nitrogen, said borane reducing agent is borane methylsulfide complex and the temperature of the reaction mixture is maintained at ambient temperature.

5. A process according to claim 4 wherein said reaction inert solvent is tetrahydrofuran.

6. A process according to claim 5 wherein said chiral oxazaborolidine catalyst is prepared in situ by reacting said borane methylsulfide complex with (1 S, 2R)- 2-amino-1 ,2-amino-1 ,2-diphenylethanol prior to the addition of said prochiral ketone.

7. A process according to claim 5 wherein said chiral oxazaborolidine catalyst is prepared in situ by reacting said borane methylsulfide complex with (1 S, 2R)- (+)-norephedriηe prior to the addition of said prochiral ketone.

8. A process according to claim 4 wherein said reaction inert solvent is toluene.

9. A process according to claim 8 wherein said chiral oxazaborolidine catalyst is prepared in situ by reacting said borane methylsulfide complex with (1 S, 2R)- 2-amino-1 ,2-diphenylethanol prior to the addition of said prochiral ketone.

10. A process according to claim 8 wherein said chiral oxazaborolidine catalyst is prepared in situ by reacting said borane methylsulfide complex with (1 S, 2R)- (+)-norephedrine prior to the addition of said prochiral ketone.

11. A process for preparing the compound of formula (II),

( I I )

comprising enantioselectively preparing the compound of formula (I) according to the process of claim 1 and reacting said compound of formula (I) with a base to form said compound of formula (II).

12. A process according to claim 11 wherein said base is sodium hydroxide.

13. A process according to claim 12 wherein said borane reducing agent is borane methylsulfide complex, said reaction inert solvent is toluene, said reaction inert atmosphere is nitrogen, the temperature of the reaction mixture is ambient temperature and the chiral oxazaborolidine catalyst is prepared in situ by reacting said borane methylsulfide complex with (1 S, 2R)-(+)-norephedrine.

14. A process according to claim 12 wherein said borane reducing agent is borane methylsulfide complex, said reaction inert solvent is tetrahydrofuran, said reaction inert atmosphere is nitrogen, the temperature of the reaction mixture is ambient temperature and the chiral oxazaborolidine catalyst is prepared in situ by reacting said borane methylsulfide complex with (1 S, 2R)-(+)-norephedrine.

15. A process according to claim 12 wherein said borane reducing agent is borane methylsulfide complex, said reaction inert solvent is toluene, said reaction inert atmosphere is nitrogen, the temperature of the reaction mixture is ambient temperature and the chiral oxazaborolidine catalyst is prepared in situ by reacting said borane methylsulfide complex with (1 S, 2R)-(+)-2-amino-1 ,2-diphenyl ethanol.

16. A process according to claim 12 wherein said borane reducing agent is borane methylsulfide complex, said reaction inert solvent is tetrahydrofuran, said reaction inert atmosphere is nitrogen, the temperature of the reaction mixture is ambient temperature and the chiral oxazaborolidine catalyst is prepared in situ by reacting said borane methylsulfide complex with (1S, 2R)-(+)-2-amino-1 ,2-diphenyl ethanol.