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
2002-03-06
2004-10-05
Beisner, William H. (Department: 1744)
Chemistry: molecular biology and microbiology
Process of utilizing an enzyme or micro-organism to destroy...
Resolution of optical isomers or purification of organic...
C435S156000, C435S911000, C435S938000
Reexamination Certificate
active
06800477
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to a novel stereoselective process for the preparation of (S)-1-arylethanol by the reduction of the corresponding keto group containing compounds by microorganisms. The present invention relates to novel processes for the preparation of chiral alcohols by microbial reduction of the corresponding ketones.
BACKGROUND OF THE INVENTION
Bing-nan Zhou et al.
J. Am Chem. Soc.
,Vol. 105, pages 5926-5928, 1983 describe the chemomicrobiological synthesis of L-carnitine, which plays an important role in the human metabolism and transport of long-chain fatty acids. Particularly, this paper teaches the reduction by baker's yeast, i.e.
Saccharomyces cerevisiae
, of ethyl 4-chloroacetoacetate to ethyl (S)-4-chloro-3-hydroxybutanoate.
Kazutoshi Ushio et al
Tetrahedron Letters
, Vol. 27, No. 23, pages 2657-2660, 1986, disclose the reduction of beta-keto esters by methanol grown yeast. This paper teaches that the subject reaction causes dramatic shifts of the enantiomer excess of the resultant product in the direction of the D-isomer. This phenomena was produced when the reaction was carried out utilizing yeast grown in methanol due to enzymes characteristic of yeast grown in such media.
Markus Christen et al.
J. Chem. Soc., Chem. Commun
. pages 264-266, 1988, discloses the synthesis of four stereoisomers of methyl-6-(p-chlorophenylthio)-3,4-dihydrohexanoate in w appropriate yeast reduction. It is stated therein that, although the reduction of beta-keto esters with yeast has been studied extensively, it remains difficult to predict either the absolute configuration of the product(s) or, in particular, the enantiomeric excess likely to be achieved.
Antonio Trincone et al.,
Biotechnology and Bioengineering
, Vol. 35, pages 559-564, 1990 describe asymmetric reduction of ketones with resting cells of
Sulfolobus solfataricus
. It is stated that the reductive ability of the resting cells of this organism strongly depends on the phase of cell growth.
Ramesh Patel et al.,
Enzyme Microb. Technol
., Vol. 13, pages 906-912, 1991 describe the stereospecific microbial reduction of 4,5-dihydro-4-(4-methoxyphenyl)-6-(trifluoromethyl-1H-1)-benzazepin-2-one. In particular, it is disclosed that a key intermediate (3R-cis)-1,3,4,5-tetrahydro-3-hydroxy-4-(4-methoxyphenyl)-6-(trifluoromethyl)-2H-1-benzazepine-2-one was made by the stereoselective microbial reduction of the parent ketone. It is stated that it was possible by the selection of specific conditions to obtain a single isomer from among four known possibilities.
Ramesh Patel et al.,
Enzyme Microb. Technol
., Vol. 15, pages 1014-1021, 1993, describes the stereoselective reduction of a diketo compound, 3,5-dioxo-6-(benzyloxy) hexanoic acid, methyl ester, to a single enantiomer of the resulting dihydroxy compound.
Ramesh Patel et al.,
Enzyme Microb. Technol
., Vol. 14, pages 731-738, 1992, describe a process of heat treating
Geotrichum candidum
to improve the optical purity of the hydroxy product obtained from the reduction of beta-keto esters thereby.
Kometani et al.,
Journal of Fermentation and Bioengineering
, Vol. 80, No. 2, pages 208-210, 1995, teaches yeast-mediated bioreduction utilizing ethanol as the energy source. The relationship between the rate of consumption of ethanol and the prochiral ketone reduction rate in Baker's Yeast is examined and it is concluded that ethanol could be applicable to large-scale production of chiral alcohols from prochiral ketones.
Ramesh Patel et al., U.S. Pat. No. 5,391,495, issued Feb. 21, 1995, discloses the stereoselective reduction of certain keto-containing sulfonamide compounds to form the corresponding hydroxyl group-containing compounds utilizing a microorganism or an enzyme capable of catalyzing the reduction. The enzymes named are oxido-reductase or dehydrogenase and the microorganisms are preferably selected from Hansenula, Rhodococcus and Norcardia species.
SUMMARY OF THE INVENTION
The present invention is directed to a novel stereoselective process for the preparation of (S)-1-arylethanol by the reduction of the corresponding keto group containing compounds by microorganisms. The present invention relates to novel processes for the preparation of chiral alcohols by microbial reduction of the corresponding ketones in order to synthesize, inter alia 4-[2-((1R)-1-{[(4-chlorophenyl)sulfonyl]-2,5-difluoroanilino}ethyl-5-fluorophenyl]butanoic acid which is a novel &ggr;-secretase inhibitor for the treatment of Alzheimer's disease.
Thus according to a first aspect of the present invention is provided a process for the preparation of compounds of Formula (I)
wherein
X and Y are each independently selected from the group consisting of H, Cl, Br, I and R
1
;
R
1
is substituted or unsubstituted alkyl, alkenyl or (CH
2
)
n
COR
2
;
n is an integer from 1 to 10;
R
2
is OH, OR
3
or NH
2
; and
R
3
is substituted or unsubstituted alkyl, alkenyl, C
3-7
cycloalkyl or substituted or unsubstituted aryl;
by stereoselective reduction of a compound of Formula (II)
wherein
X and Y are each independently selected from the group consisting of H, Cl, Br, I and R
1
;
R
1
is substituted or unsubstituted alkyl, alkenyl, or (CH
2
)
n
COR
2
;
n is an integer from 1 to 10;
R
2
is OH, OR
3
or NH
2
; and
R
3
is substituted or unsubstituted alkyl, alkenyl, C
3-7
cycloalkyl or substituted or unsubstituted aryl;
by reaction with an oxidoreductase enzyme capable of catalyzing the enzymatic reduction of ketones represented by Formula (II).
According to a second aspect of the present invention is provided a process for the preparation of compounds of Formula (I)
wherein
X and Y are each independently selected from the group consisting of H, Cl, Br, I and R
1
;
R
1
is substituted or unsubstituted alkyl, alkenyl, or (CH
2
)
n
COR
2
;
n is an integer from 1 to 10;
R
2
is OH, OR
3
or NH
2
; and
R
3
is substituted or unsubstituted alkyl, alkenyl, C
3-7
cycloalkyl or substituted or unsubstituted aryl;
by stereoselective reduction of a compound of Formula (II)
wherein
X and Y are each independently selected from the group consisting of H, Cl, Br, I and R
1
;
R
1
is substituted or unsubstituted alkyl, alkenyl, or (CH
2
)
n
COR
2
;
n is an integer from 1 to 10;
R
2
is OH, OR
3
or NH
2
; and
R
3
is substituted or unsubstituted alkyl, alkenyl, C
3-7
cycloalkyl or substituted or unsubstituted aryl;
by reaction with a microorganism that supplies an oxidoreductase enzyme capable of catalzying the enzymatic reduction of ketones represented by Formula (II).
Other aspects and embodiments of the present invention are provided for hereinbelow.
REFERENCES:
patent: 5391495 (1995-02-01), Patel et al.
patent: 5393663 (1995-02-01), Patel et al.
patent: 5523223 (1996-06-01), Kula et al.
patent: WO 99/23242 (1999-05-01), None
Bing-nan Zhou et al. J. Am. Chem. Soc., vol. 105, pp. 5925-5926, 1983.
Kazutoshi Ushio et al. Tetrahedron Letters, vol. 27, No. 23, pp. 2657-2660, 1986.
Markus Christen et al. J. Chem. Soc., Chem. Commun. pp. 264-266, 1988.
Antonio Trincone et al., Biotechnology and Bioengineering, vol. 35, pp. 559-564, 1990.
Ramesh Patel et al., Enzyme Microb. Technol., vol. 13, pp. 906-912, 1991.
Ramesh Patel et al., Enzyme Microb. Technol., vol. 15, pp. 1014-1021, 1993.
Ramesh Patel et al., Enzyme Microb. Technol., vol. 14, pp. 731-738, 1992.
Kometani et al., Journal of Fermentation and Bioengineering, vol. 80, No. 2, pp. 208-210, 1995.
Chu Linda N.
Donovan Mary Jo
Goldberg Steven L.
Goswami Animesh
Johnston Robert M.
Baxam Deanna L.
Beisner William H.
Bristol-Myers Squibb Co.
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