Chemistry: molecular biology and microbiology – Process of utilizing an enzyme or micro-organism to destroy... – Resolution of optical isomers or purification of organic...
Patent
1998-10-09
2000-08-29
Saucier, Sandra E.
Chemistry: molecular biology and microbiology
Process of utilizing an enzyme or micro-organism to destroy...
Resolution of optical isomers or purification of organic...
C07C 104, C07F 104
Patent
active
061107298
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to methods of synthesizing pharmaceutical compounds and intermediates used in the synthesis of such chemical compounds. In particular the present invention relates to novel enzymatic processes for stereoselective preparation of N-aryl or -pyridyl propanamides having a tertiary alcohol stereogenic center, and enantiomeric intermediates useful for the synthesis of such compounds.
BACKGROUND OF THE INVENTION
N-(4-benzoylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide and other N-aryl or -pyridyl propanamides are disclosed in U.S. Pat. No. 5,272,163 which issued Dec. 21, 1993 to Russell et al. Such compounds are cellular potassium channel openers and are thus usefull in the treatment of urinary incontinence and other diseases and conditions including hypertension, asthma, peripheral vascular disease and angina, as disclosed in the aforementioned patent. U.S. Pat. No. 5,272,163 also discloses a method of preparing the (S)-(-) enantiomer of N-(4-benzoylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide which method employs diastereomeric ester formation followed by chromatographic separation, and subsequent removal of the ester group by treatment with a base.
SUMMARY OF THE INVENTION
The present invention provides novel enzymatic process for stereoselective preparation of N-aryl or -pyridyl propanamides having a tertiary alcohol stereogenic center, as exemplified by the preparation of (S)-(-)-N-(4-benzoylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide. Such compounds are cellular potassium channel openers and are thus useful in the treatment of urinary incontinence and other diseases and conditions including hypertension, asthma, peripheral vascular disease and angina.
The novel methods of the invention employ an enzymatic step to selectively cleave an ester group from one enantiomer of a racemic mixture of esters formed from the N-aryl or pyridylpropanamide. The enzymatic step can be followed by separation of the remaining ester from the alcohol so produced. The recovered ester that was not cleaved in the enzymatic step can be hydrolyzed if desired to produce the corresponding alcohol.
The present invention also provides methods for synthesizing intermediates useful in the synthesis of the aforementioned N-aryl or -pyridylpropanamides, as exemplified by the preparation of (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid useful in the preparation of (S)-(-)-N-(4-benzoylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.
Methods for stereoselective synthesis of N-aryl or -pyridyl propanamides having a tertiary alcohol stereogenic center, exemplified by (S)-(-)-N-(4-benzoylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide, and intermediates useful in the synthesis of such compounds are provided herein.
These and other aspects of the present invention as set forth in the appended claims are described in their preferred embodiments in the following detailed description of the invention.
DETAILED DESCRIPTION OF THE INVENTION
A first aspect of the invention provides a method of preparing an optically active compound of Formula I ##STR2## wherein E is selected from nitrogen and CZ wherein C is a ring carbon and Z is a substituent defined below, wherein: and sulfonyl and Ar is selected from the group consisting of: cyano, C.sub.1 -C.sub.4 alkyl, and C.sub.1 -C.sub.4 alkoxy;
six-membered heteroaryl rings containing 1-2 nitrogen atoms as the only heteroatoms; from nitrogen, oxygen, and sulfur; and and C.sub.1 -C.sub.4 alkoxy; and phenylsulfinyl. and phenylsulfonyl the phenyl rings of which are substituted with 0-2 substituents selected from halo, hydroxy, cyano, nitro, C.sub.1 -C.sub.4 alkyl, and C.sub.1 -C.sub.4 alkoxy; and X given above in (A); hydrolase enzyme. The compounds of Formula II are defined as follows: ##STR3## wherein E and X have the meanings previously defined herein; and
R.sup.1 is alkyl optionally substituted by one or more substituents independently selected from hydroxy, halogen, C.sub.1 -C.sub.4 alkoxy, cyano, C.s
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Crosby John
Holt Robert Antony
Pittam John David
Mitchell Kenneth F.
Saucier Sandra E.
Zeneca Limited
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