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
2001-08-08
2004-06-08
Tate, Christopher R. (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,...
C435S243000, C435S254100, C435S254300, C435S254500
Reexamination Certificate
active
06746856
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel processes for preparing the carboxylic acids of bicyclic heteroaromatic compounds and, more specifically, relates to the microbial oxidation of 2-methylquinoline to 2-quinolinecarboxylic acid, 3-methylquinoline to 3-quinolinecarboxylic acid, 8-methylquinoline to 8-quinolinecarboxylic acid, 3-methylisoquinoline to 3-isoquinolinecarboxylic acid, 2-methylindole to 2-indolecarboxylic acid, and 5-chloro-2-methylindole to 5-chloro-2-indolecarboxylic acid.
BACKGROUND OF THE INVENTION
Methods are known in the art for microbial oxidation of certain aromatic heterocycles and, in particular, for microbial oxidation of methyl groups on certain aromatic heterocycles, such as, for example, those described in the following two articles and patent: (a) “Gene Order of the TOL Catabolic Plasmid Upper Pathway Operon and Oxidation of Both Toluene and Benzyl Alcohol by the xy/A Product,” by S. Harayama et al.,
J. Bacteriol.,
167(2): 455-461 (1986), (b) “Enzymatic Oxidation of Methyl Groups on Aromatic Heterocycles: A Versatile Method for the Preparation of Heteroaromatic Carboxylic Acids,” by A. Keiner,
Angew. Chem. Int. Ed. Engl.,
31(6): 774-775 (1992), and (c) U.S. Pat. No. 4,859,592 (a microbial process for the production of picolinic acid).
“The Initiation and Longevity of Patulin Biosynthesis,” by Gaucher et al. as published in
Dev. Ind. Microbiol.,
22: 219-232 (1981), describes that the fungus
Penicillium griseofulvum
contains three enzymes for the conversion of m-cresol to m-hydroxybenzoic acid: m-cresol methyl hydroxylase, m-hydroxybenzyl alcohol dehydrogenase and m-hydroxybenzaldehyde hydroxylase.
As described earlier with reference to the aforementioned article by Harayama et al., the TOL plasmid pWWO of
P. putida
mt-2 is a transmissible extrachromosomal element which encodes all of the enzymes required for the oxidative catabolism of several aromatic hydrocarbons, including toluene, m-xylene and p-xylene. Bacteria carrying TOL plasmids, e.g.,
P. putida
ATCC No. 33015, can convert certain aromatic hydrocarbons to their corresponding aromatic carboxylic acids: both the xyl operon which codes for enzymes of xylene degradation and the genes which are responsible for the regulation of the xyl gene lie on the TOL plasmid pWWO. The genes on the TOL plasmid pWWO which code for the enzymes required for the above oxidations must be induced to produce such enzymes.
U.S. Pat. Nos. 5,104,798; 5,213,973; and 5,236,832 disclose a microbial process for the oxidation of methyl groups in certain aromatic 5- or 6-member ring heterocycles to the corresponding carboxylic acids which is performed by a bacterium of the species Pseudomonas, the strain
P. putida
ATCC No. 33015, utilizing toluene, xylene or cymene as the inducer.
U.S. patent application Ser. No. 09/492,548 (“the '548 application”) filed Jan. 27, 2000, and claiming priority from U.S. Provisional Patent Application No. 60/119,942 filed on Feb. 12, 1999, discloses microbial processes for substantially oxidizing 2-methylquinoxaline to 2-quinoxalinecarboxylic acid. In addition, the processes of the '548 application allow for suitable recovery of the 2-quinoxalinecarboxylic acid. As mentioned therein, U.S. Provisional Patent Application No. 60/073,801 (“the '801 application”) filed Feb. 5, 1998, now International PCT Application No. PCT/IB99/00067 filed Jan. 18, 1999, and published on Aug. 12, 1999 as WO99/40061, discloses the use of 2-quinoxalinecarboxylic acid as an intermediate in the synthesis of novel dihydroxyhexanoic acids which are useful to treat, e.g., inflammation and other immune disorders. The 2-quinoxalinecarboxylic acid provided by the novel processes of the '548 application can be used to synthesize such dihydroxyhexanoic acids.
To reiterate, as is known in the art, certain fungi and bacteria contain enzymes for the oxidation of methyl groups on certain aromatic rings to their corresponding carboxylic acids. While it is known then that methyl groups on such heteroaromatic rings can be oxidized to their corresponding carboxylic acids using microorganisms, as would be appreciated by those skilled in the art, the chemical and optical yields of such microbial oxidations generally vary substantially depending on, for example, the particular microorganism chosen, the concentration of the substrate, the structure of the substrate, and the like.
It has now been found that a range of microorganisms, including fungi and bacteria, and suitable mutants thereof, oxidize certain bicyclic heteroaromatic compounds to an amount of their corresponding carboxylic acids, and that these carboxylic acids so generated can be suitably recovered.
The 5-chloro-2-indolecarboxylic acid provided by the novel processes of the present invention can be used to synthesize indole-2-carboxamides disclosed in International PCT Application No. PCT/IB95/00443 (“the '443 application) filed Jun. 6, 1995, and published on Dec. 12, 1996 as WO96/39385, which can be used, e.g., as inhibitors of glycogen phosphorylase, and to treat, e.g., glycogen phosphorylase-dependent diseases or conditions.
All of the documents cited herein, including the foregoing, are incorporated by reference herein in their entireties.
SUMMARY OF THE INVENTION
The present invention relates to microbiological processes for preparing the carboxylic acids of bicyclic heteroaromatic compounds.
The present invention relates to microbiological processes for preparing the compound of Formula I
by contacting the compound of Formula II
with a microorganism capable of accomplishing the oxidation of the methyl group of the compound of Formula II to the carboxyl group of the compound of Formula I, and incubating the resultant mixture under suitable conditions to yield an amount of the compound of Formula I.
The present invention also relates to microbiological processes for preparing the compound of Formula III
by contacting the compound of Formula IV
with a microorganism capable of accomplishing the oxidation of the methyl group of the compound of Formula IV to the carboxyl group of the compound of Formula III, and incubating the resultant mixture under suitable conditions to yield an amount of the compound of Formula III.
The present invention also relates to microbiological processes for preparing the compound of Formula V
by contacting the compound of Formula VI
with a microorganism capable of accomplishing the oxidation of the methyl group of the compound of Formula VI to the carboxyl group of the compound of Formula V, and incubating the resultant mixture under suitable conditions to yield an amount of the compound of Formula V.
The present invention also relates to microbiological processes for preparing the compound of Formula VII
by contacting the compound of Formula VIII
with a microorganism capable of accomplishing the oxidation of the methyl group of the compound of Formula VII to the carboxyl group of the compound of Formula V, and incubating the resultant mixture under suitable conditions to yield an amount of the compound of Formula VII.
The present invention further relates to microbiological processes for preparing the compound of Formula IX
by contacting the compound of Formula X
with a microorganism capable of accomplishing the oxidation of the methyl group of the compound of Formula X to the carboxyl group of the compound of Formula IX, and incubating the resultant mixture under suitable conditions to yield an amount of the compound of Formula IX.
The present invention further yet relates to microbiological processes for preparing the compound of Formula XI
by contacting the compound of Formula XII
with a microorganism capable of accomplishing the oxidation of the methyl group of the compound of Formula XII to the carboxyl group of the compound of Formula XI, and incubating the resultant mixture under suitable conditions to yield an amount of the compound of Formula XI.
Accordingly, the present invention provides processes for carrying out the microbial oxidation of the compound of For
Cawley James J.
Wong John W.
Benson Gregg C.
Lee Christine S.
Pfizer Inc.
Richardson Peter C.
Srivastava Kailash C.
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