Process and chiral intermediates for thiazole antidiabetics

Details Process and chiral intermediates for thiazole antidiabetics Process and chiral intermediates for thiazole antidiabetics

1993-12-02

1996-11-19

Gerstl, Robert

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D27724

Patent

active

055764428

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

The compound depicted in formula I and related compounds have been reported in U.S. 4,886,814 to have utility as antidiabetics. ##STR1##
The present invention relates to novel key intermediates in the synthesis of compound I, said intermediates being (R)-4-(2-bromo-1-hydroxyethyl)-2-trifluoromethylthiazole (II) and (S)-4-oxiranyl-2-trifluoromethylthiazole (III), and to an enantioselective reduction process for the preparation of these compounds which results in their being obtained essentially free of their enantiomeric forms.
The racemic form of the bromohydrin (II), depicted below, has been reported. Within the same reference, the racemic form of the epoxide has also been reported. However, the S-bromohydrin (II) and the (S)-epoxide (III) are both previously unknown in their purified chiral forms.
It is advantageous to prepare the bromohydrin and epoxide in optically pure form since the final product of formula I has the S configuration at the hydroxyl-substituted chiral center. Therefore, a process whereby the desired stereochemistry is directly obtained is highly desirable.
The stereoselective reduction process of this invention involves the use of a borane reducing agent and a chiral oxazaborolidine catalyst. Corey, et al. (Journal of the American Chemical Society, 1987, 109, 5551-3 and 7925-6) have described generally the reduction of a limited number of ketones with boranes utilizing chiral oxazaborolidines to elicit enantioselectivity. However, recent studies by Jones, et al. (Journal of Organic Chemistry, 1991, 56, 763-9) have demonstrated that the method loses its effectiveness when molecules possessing borane coordination sites are present in the reaction mixture. Examples of compounds containing borane coordination sites include but are not limited to such compounds as boronic acids, boroxines, prolinols, amines, thiazoles and oxazoles. This loss of effectiveness is manifested in diminished enantioselectivity. The present invention is directed to a process in which the deleterious effect of said borane coordination sites has been overcome.


SUMMARY OF THE INVENTION

This invention is directed to (R)-4-(2-bromo-1-hydroxyethyl)-2-trifluoromethylthiazole (II) and (S)-4-oxiranyl-2-trifluoromethylthiazole (III), both compounds being substantially free of their corresponding R enantiomer. ##STR2##
Also embraced by the invention is a process for the enantioselective preparation of the above-mentioned compounds from the achiral ketone precursor IV. ##STR3## Thus, said ketone IV is enantioselectively reduced using a borane reducing agent such as borane methyl sulfide complex, catecholborane or borane-tetrahydrofuran in the presence Of a chiral oxazaborole catalyst in a cyclic ether solvent such as dioxane or tetrahydrofuran to afford, in essentially optically pure form, (R)-4-(2-bromo-1-hydroxyethyl)-2-trifluoromethylthiazole (II). A preferred reducing agent is borane-methyl sulfide complex; a preferred catalyst is (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborol e and a preferred solvent is tetrahydro solvent is tetrahydrofuran. The process of this invention results in achievement of a high percent enantiomeric excess.
The bromohydrin (II) is further elaborated to the optically pure (S)-4-oxiranyl-2trifluoromethylthiazole (III) by treatment with sodium hydroxide. This dehydrobromination affords the cyclized product without racemization of the chiral center.


DETAILED DESCRIPTION OF THE INVENTION

The present invention provides two novel, optically pure, key intermediates of structures II and III, depicted above. The depicted compounds, (R)-4-(2-bromo-1-hydroxyethyl)-2-trifluoromethylthiazole (II) and (S)-4-oxiranyl-2-trifluoromethylthiazole(III) are provided in optically pure form, substantially free of their corresponding enantiomers.
Also embraced by the invention is the enantioselective reduction process whereby compound II is prepared. ##STR4##
The process, see Scheme I, comprises treating the ketone, 4-bromoacetyl-2trifluoromethylthiazole, w

REFERENCES:
patent: 4886814 (1989-12-01), Reiffen et al.
patent: 4943635 (1990-07-01), Corey
patent: 5036079 (1991-09-01), Clark
patent: 5512689 (1996-04-01), Quallich
Corey et al., Journal of the American Chemical Society, 1987, 109, 5551-3.
Corey et al., Journal of the American Society, 1987, 109, 7925-6.
Jones et al., Journal of Organic Chemistry, 1991, 56, 763-9.
Quallich et al, Tet. Letters 34(5) 785 (1993).
Lancaster Catalogue 1991/2 p. 888.

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