Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Reexamination Certificate
2001-02-28
2003-09-02
Lilling, Herbert J. (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
C435S170000, C435S171000, C435S195000, C435S252100, C435S253500, C435S254300, C435S256100
Reexamination Certificate
active
06613550
ABSTRACT:
BACKGROUND OF THE INVENTION
Several methods have been disclosed for the preparation of optically active 3-hydroxypyrrolidine derivatives. Some of these methods involve the resolution of racemic 3-hydroxypyrrolidine derivatives by the formation of salts with optically active organic acids. Japanese Pat. Appl. Nos. 96-103965, 92-77749, and 84-185583 all describe processes for the resolution of racemic 3-hydroxypyrrolidine derivatives with optically active organic acids. Enzymatic processes have also been disclosed for the resolution of racemic 3-hydroxypyrrolidine derivatives (Hasegawa, et al, Enantiomer, 2(3-4): 311-314 (1997); Jap Pat. Appl. No. 87-301052). These enzymatic methods involve the stereoselective hydrolysis of racemic N-benzyl-3-acyloxypyrrolidines with hydrolytic enzymes. Other methods involve the chemical modification of optically active precursors. Eur. Pat. Appl. No. 95-110685 discloses a method for the preparation of optically active 3-hydroxypyrrolidine derivatives by the reduction of optically active 3-hydroxypyrrolidine-2,5-diones with activated alkali borohydrides. Another process involves the chemical modification of optically active butanoate derivatives (Eur. Pat. Appl. No. 91-303245). A microbiological method has also been reported for the preparation of (−)-(3-hydroxy-pyrrolidin-1-yl)-phenyl-methanone from phenyl-pyrrolidin-1-yl-methanone with the fungus
Cunninghamella verticillata
VKM F-430 (Parshikov, et al, Khimiya
Geterotsiklicheskikh Soedinenii,
2: 195-199 (1992)). Another microbiological method reports the preparation of optically active N-benzyl-3-hydroxypyrrolidine by the hydroxylation of N-benzylpyrrolidine with
Pseudomonas oleovorans
Gpo1 and other bacterial species (Li et al,
Tetrahedron. Asymmetry,
10: 1323-1333 (1999)).
SUMMARY OF THE INVENTION
In one embodiment, the present invention is directed to a process for the production of a compound of the formula:
from a compound of the formula
comprising hydroxylating a compound of the formula I in the presence of at least one hydroxylating enzyme produced by a microorganism.
In a preferred embodiment, the present invention is directed to a process wherein said microorganism is selected from the group consisting of
Aspergillus ochraceus
ATCC 18500,
Streptomyces aureofaciens
ATCC 10762,
Cunninghamella echinulata
v. elegans ATCC 8688b,
Cunninghamella echinulata
v. elegans ATCC 8688a,
Cunninghamella echinulata
v. echinulata ATCC 9244,
Cunninghamella homothallica
ATCC 16161,
Cunninghamella echinulata
v. elegans ATCC 36112,
Cunninghamella echinulata
v. echinulata ATCC 36190,
Cunninghamella echinulata
v. elegans ATCC 10028b,
Cunninghamella echinulata
v. elegans ATCC 9245,
Cunninghamella echinulata
v. elegans ATCC 8983,
Cunninghamella echinulata
v. elegans ATCC 26269,
Pithomyces cynodontis
ATCC 26150,
Absidia glauca
ATCC 22752,
Beauveria bassiana
ATCC 7159,
Nocardia sp. ATCC 53758,
Streptomyces rimosus
ATCC 55043, and
Streptomyces rimosus
ATCC 23955,
In another embodiment, the present invention is directed to a process for the production of a compound of the formula:
from a compound of the formula
comprising hydroxylating a compound of the formula I in the presence of at least one hydroxylating enzyme produced by a microorganism of the Cunninghamella species.
Preferred is the process wherein said Cunninghamella species is
Cunninghamella echinulata
var elegans.
Also preferred is the process wherein said
Cunninghamella echinulata
species is
Cunninghamella echinulata
var. elegans ATCC 8688b.
In another embodiment, the present invention is directed to a process for the production of a compound of the formula:
from a compound of the formula:
comprising hydroxylating a compound of the formula I in the presence of at least one hydroxylating enzyme produced by a culture of a microorganism of the gemus Aspergillus.
Preferred is the process wherein said Aspergillus culture is
Aspergillus flavipes.
Also preferred is the process wherein said
Aspergillus flavipes
culture is
Aspergillus flavipes
ATCC 16795.
In another embodiment the present invention is directed to a process for the production of a compound of the formula
from a compound of the formula
comprising selectively reducing a compound of the formula IV in the presence of at least one reducing enzyme produced by a culture of a microorganism of the gemus Cunninghamella.
In a preferred embodiment, the present invention is directed to a process wherein said Cunninghamella is
Cunninghamella echinulata
var. elegans.
In another preferred embodiment, the present invention is directed to, a process wherein said Cunninghamella species is
Cunninghamella echinulata
var. elegans ATCC 8688b.
In another preferred embodiment, the compounds of formula II is produced from mixtures of compound II and III by a process comprising converting the compound of formula III to the compound of formula II with enzymes from
Cunninghamella echimulata.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a microbiological process for the production of optically active 3-hydroxypyrrolidine derivatives. More particularly, this invention relates to a process that comprises contacting pyrrolidine-1-carboxylic acid phenylester, the compound of formula (I), with a suitable microorganism capable of hydroxylating the compound of formula (I), and recovering the optically active 3-hydroxypyrrolidine derivatives, compounds of formula (II) and (III), that are selectively formed and accumulated. Another aspect of the invention relates to a microbiological process for the production of an optically active 3-hydroxypyrrolidine derivative by the asymmetric reduction of a ketone precursor. This process comprises contacting 3-oxo-pyrrolidine-1-carboxylic acid phenyl ester (IV)
with a suitable microorganism capable of selectively reducing the ketone group to form and accumulate the compound of formula (II). Also disclosed is a process for the production of (II) from racemic mixtures of (II) and (III). This process comprises contacting a racemic mixture of (II) and (III) with a suitable microorganism capable of selectively converting the (R)-isomer of formula (III) to the (S)-isomer of formula (II). Optically active 3-hydroxypyrrolidine derivatives are useful intermediates for the synthesis of pharmaceutical and agrochemical compounds.
The microbiological hydroxylation of pyrrolidine-1-carboxylic acid phenylester, the compound of formula (I), to optically active 3-hydroxypyrrolidine-1-carboxylic acid phenylesters, compounds of formula (II) and (III), can be carried out by contacting the compound of formula (I) with cultures of suitable microorganisms.
In the alternative, the enzyme or enzymes can be purified or partially purified from the microorganism or cell fragments of the microorganism can be used. Immobilized cells of the microorganisms can also be used.
Contacting pyrrolidine-1-carboxylic acid phenylester, the compound of formula (I), with a culture of the microorganism
Cunninghamella echinulata
ATCC 8688b, results in the formation and accumulation of (S)-3-hydroxypyrrolidine-1-carboxylic acid phenylester, the compound of formula (II).
(R)-3-Hydroxypyrrolidine-1-carboxylic acid phenylester, the compound of formula (III), is formed and accumulated by contacting pyrrolidine-1-carboxylic acid phenylester, the compound of formula (I), with a culture of the microorganism
Aspergillus flavipes
ATCC 16795.
(S)-3-Hydroxypyrrolidine-1-carboxylic acid phenylester (II) is also formed and accumulated by contacting 3-oxo-pyrrolidine-1-carboxylic acid phenyl ester (IV) with cultures of the microorganism
C. echinulata
ATCC 8688b.
(S)-3-Hydroxypyrrolidine-1-carboxylic acid phenylester (II) is also formed and accumulated by contacting racemic mixtures of (I) and (III) with cultures of the microorganism
C. echinulata
ATCC 8688b.
REFERENCES:
patent: 452143 (1991-10-01), None
patent: 692471 (1996-01-01), None
patent: 1002871 (2000-05-01), None
patent: 61063652 (1986-04-01), None
patent: 1141600 (1989-06-01), None
patent: 5279326 (
Benson Gregg C.
Kleiman Gabriel L.
Lilling Herbert J.
Pfizer Inc.
Richardson Peter C.
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