Substituted alkylketo compounds and process

Details Substituted alkylketo compounds and process Substituted alkylketo compounds and process

2001-05-03

2002-11-26

Owens, Amelia (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S357000, C562S579000, C560S179000

Reexamination Certificate

active

06486331

ABSTRACT:

FIELD OF INVENTION
The present invention concerns a stereoselective enzymatic reductive amination process.
BACKGROUND OF THE INVENTION
Robl in U.S. Pat. No. 5,508,272 disclose compounds of the formula
wherein A is
as possessing neutral endopeptidase and angiotensin converting enzyme inhibition activity. Among these compounds is [4S-[4&agr;(R*), 7&agr;, 10a&bgr;]]-octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-5-oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid which is currently undergoing clinical evaluation.
Robl discloses that the amino lactam portion of this compound; i.e., the intermediate
can be prepared by coupling an alkyl ester compound such as (S)-2-amino-6,6-dimethoxyhexanoic acid methyl ester with the N-protected amino acid
wherein P
1
is an amino protecting group and P
2
is a sulfur protecting group to give the dipeptide of the formula
Removal of the P
2
protecting group, followed by acid catalyzed cyclization, and removal of the P
1
protecting group gives [4S-(4&agr;, 7&agr;, 10a&bgr;)]-octahydro-4-amino-5-oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid, methyl ester.
Robl discloses preparing (S)-2-amino-6,6-dialkoxyhexanoic acid, alkyl ester, such as (S)-2-amino-6,6-dimethoxyhexanoic acid, methyl ester, by converting N-protected L-&egr;-hydroxynorleucine to its methyl ester, oxidizing to a corresponding aldehyde, such as of the formula
then reacting with trimethyl orthoformate in the presence of a strong acid catalyst, and removing the P
3
protecting group.
SUMMARY OF THE INVENTION
The present invention provides a process for the stereoselective enzymatic conversion of certain keto carboxylic acid derivatives to form the corresponding alkylamino acid compounds. The amino compounds prepared by the enzymatic process of the invention can be conveniently converted to the corresponding (S)-2-amino-6,6-dialkoxyhexanoic acid, alkyl ester or stable salts of such compounds such as phosphate, oxalate or bis salt with a compound such as N-(trifluoroacetyl)-L-homocysteine, (1→1′)-disulfide.
More specifically, the present invention is directed to a process for preparing an alkylamino acid compound of the formula (formula I)
wherein R
1
is hydrogen or a monovalent cation or a C
1
-C
18
alkyl (preferably C
1
-C
10
alkyl, more preferably lower alkyl), R
2
is a moiety of the formula
a moiety of the formula
wherein each R
3
is a C
1
-C
18
alkyl (preferably C
1
-C
10
alkyl, more preferably lower alkyl); or a moiety of the formula
wherein each R
4
is H or R
3
comprising contacting an alkylketo compound of the formula (formula II)
wherein R
2
is as defined above, and R
1
is as defined above, with an amino acid dehydrogenase in the presence of ammonia and a co-factor under conditions suitable for formation of the compound of formula I.
The present invention also concerns an engineered yeast host cell containing recombinant nucleic acid capable of expressing a phenylalanine dehydrogenase enzyme and endogenous or recombinant nucleic acid capable of expressing a formate dehydrogenase enzyme.


REFERENCES:
patent: 5508272 (1996-04-01), Robl
patent: 6174707 (2001-01-01), Taoka et al.
patent: 919630 (1999-06-01), None
patent: WO98/48040 (1998-10-01), None
Winn, Martin e al Tasker, Andrew S.; Von Geldern, Thomas W.; Kester Jeffrey Preparation of benzo-1,3-dioxolyl- and benzofuranyl-substituted pyrrolidine derivatives as endothelin antagonists. CA 127:248099 (1997).

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