Chemistry: molecular biology and microbiology – Process of utilizing an enzyme or micro-organism to destroy... – Resolution of optical isomers or purification of organic...
Reexamination Certificate
2000-05-31
2001-07-17
Saucier, Sandra E. (Department: 1651)
Chemistry: molecular biology and microbiology
Process of utilizing an enzyme or micro-organism to destroy...
Resolution of optical isomers or purification of organic...
Reexamination Certificate
active
06261830
ABSTRACT:
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 useful 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 processes 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.
One aspect of the invention is a method for preparing an optically active compound of Formula I:
where * indicates the presence of a chiral center, and the method comprises treating a racemic compound of Formula II with a stereoselective hydrolase enzyme
wherein, in Formula I and II:
R
1
is (C
1
-C
7
)alkyl substituted with 0, 1 or more substituents independently selected from hydroxy, halogen, (C
1
-C
4
)alkoxy, cyano, (C
1
-C
4
)alkylamino and (C
1
-C
4
)dialkylamino;
E is selected from nitrogen and C—Z, where C is a ring carbon atom, where:
when E is nitrogen,
X is ArY where Y is a linking group selected from carbonyl, sulfinyl, and sulfonyl, and Ar is selected from phenyl substituted with 0, 1 or 2 substituents selected from halo, hydroxy, cyano, (C
1
-C
4
)alkyl, and (C
1
-C
4
)alkoxy, six-membered heteroaryl rings containing 1 or 2 nitrogen atoms as the only heteroatoms, and five-membered heteroaryl rings containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or
when E is carbon:
either X is as defined above, and Z is selected from hydrogen, cyano, halo, hydroxy, (C
1
-C
4
)alkyl, and (C
1
-C
4
)alkoxy;
or X is cyano, and Z is selected from phenylthio, phenylsulfinyl, and phenylsulfonyl, phenyl rings of which are substituted with 0, 1 or 2 substituents selected from halo, hydroxy, cyano, nitro, (C
1
-C
4
)alkyl, and (C
1
-C
4
)alkoxy.
In a particular aspect of the invention R
1
is (C
1
-C
7
)alkyl substituted with 1 or more moieties selected from hydroxy, halogen, (C
1
-C
4
)alkoxy, cyano, (C
1
-C
4
)alkylamino and (C
1
-C
4
)dialkylamino.
In a further aspect of the invention, the optically active compound of Formula I is (S)-(−)-(4-benzoylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methyl propanamide and the step of treating a racemic mixture of a compound of Formula II with said stereoselective hydrolase enzyme is performed with a compound of Formula II wherein:
E is C—Z, Z is hydrogen, and X is ArY where Ar is phenyl and Y is carbonyl.
Another aspect of the invention is a method for preparing (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid, comprises treating a racemic compound of Formula V
wherein R
2
is selected from (C
1
-C
6
)alkyl, (C
1
-C
4
)alkoxy and phenyl with a hydrolase enzyme.
In a further aspect of the invention the stereoselective hydrolase enzyme is a lipase.
In a particular embodiment of the invention the lipase is selected from porcine pancreatic lipase or
Candida antarctica
lipase.
In a further aspect of the invention compounds of Formula VI, VIII and IX are produced by the method of the invention
wherein:
* indicates the presence of a chiral center; and:
in compounds of Formula VI, R
2
is not ethyl but is otherwise selected from (C
1
-C
6
)alkyl, (C
1
-C
4
)alkoxy, and phenyl;
in compounds of Formula VIII, A is selected from CN, COH, CH(OR
3
)
2
, COR
3
, COOR
3
, CONH
2
, CONHR
3
and CON(R
3
)
2
, wherein R
3
, at each occurrence, is independently selected from (C
1
-C
10
)alkyl, aryl, and aryl(C
1
-C
3
)alkyl and each R
3
may be optionally substituted with substituents selected from hydroxy, halogen, (C
1
-C
4
)alkoxy, cyano, (C
1
-C
4
)alkylamino and (C
1
-C
4
)dialkylamino;
in compounds of Formula IX, A is as defined for formula VIII, and R
9
is selected from (C
1
-C
10
)alkyl, aryl and aryl(C
1
-C
3
)alkyl, and each R
9
is substituted with 0, 1 or more substituents independently selected from hydroxy, halogen, (C
1
-C
4
)alkoxy, cyano, (C
1
-C
4
)alkylamino and (C
1
-C
4
)dialkylamino and with the proviso that when A is CN, R
9
is not methyl.
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 and in the parent of this application, application Ser. No. 09/171,039, allowed, the disclosure of which is incorporated herein in its entirety.
DETAILED DESCRIPTION OF THE INVENTION
In a first aspect the invention provides a method of preparing an optically active compound of Formula I
where * indicates the presence of a chiral center, and the method comprises treating a racemic compound of Formula II with a stereoselective hydrolase enzyme
wherein, in Formula I and II:
R
1
is (C
1
-C
7
)alkyl substituted with 0, 1 or more substituents independently selected from hydroxy, halogen, (C
1
-C
4
)alkoxy, cyano, (C
1
-C
4
)alkylamino and (C
1
-C
4
)dialkylamino;
E is selected from nitrogen and C—Z, where C is a ring carbon atom, where:
when E is nitrogen,
X is ArY where Y is a linking group selected from carbonyl, sulfinyl, and sulfonyl, and Ar is selected from phenyl substituted with 0, 1 or 2 substituents selected from halo, hydroxy, cyano, (C
1
-C
4
)alkyl, and (C
1
-C
4
)alkoxy, six-membered heteroaryl rings containing 1 or 2 nitrogen atoms as the only heteroatoms, and five-membered heteroaryl rings containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or
when E is carbon:
either X is as defined above, and Z is selected from hydrogen, cyano, halo, hydroxy, (C
1
-C
4
)alkyl, and (C
1
-C
4
)alkoxy;
or X is cyano, and Z is selected from phenylthio, phenylsulfinyl, and phenylsulfonyl, phenyl rings of which are substituted with 0, 1 or 2 substituents
Crosby John
Holt Robert Antony
Pittam John David
Mitchell Kenneth F.
Saucier Sandra E.
Zeneca LTD
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