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
2000-01-27
2002-03-26
Saucier, Sandra E. (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,...
C435S118000, C435S120000, C435S121000, C435S122000, C435S877000, C435S911000, C435S913000, C435S933000
Reexamination Certificate
active
06361979
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel processes for preparing 2-quinoxalinecarboxylic acid and, more specifically, relates to the microbial oxidation of 2-methylquinoxaline to 2-quinoxalinecarboxylic 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: “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) and “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).
U.S. Pat. No. 4,859,592 discloses a microbial process for the production of picolinic acid which can then be converted to pyridine products by chemical means.
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 utilizing toluene, xylene or cymene as the inducer. As described therein, it is known in the art that the oxidation of the methyl group of toluene to benzoic acid by the strain
Pseudomonas putida
ATCC No. 33015 comprises three steps catalyzed by toluene monooxygenase, alcohol dehydrogenase and aldehyde dehydrogenase, respectively.
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. Hence, the description of such induction in the aforementioned U.S. Pat. Nos. 5,104,798; 5,213,973; and 5,236,832.
As described in an article by Gaucher et al. in
Dev. Ind. Microbiol.,
22: 219-232 (1981), 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.
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, substantially oxidize 2-methylquinoxaline to 2-quinoxalinecarboxylic acid. In addition, the subject process allows for suitable recovery of the 2-quinoxalinecarboxylic acid.
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, 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 present invention can be used to synthesize such dihydroxyhexanoic acids.
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 a microbiological process for preparing 2-quinoxalinecarboxylic acid from 2-methylquinoxaline.
More particularly, 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.
Accordingly, the present invention provides processes for carrying out the microbial oxidation of the compound of Formula II, 2-methylquinoxaline, which comprises:
contacting the compound of Formula II with a microorganism, or a mutant thereof which is known or otherwise obtainable by those skilled in the relevant art and able, despite such mutation, to accomplish the subject oxidation (“a suitable mutant thereof”), and
incubating the resulting mixture under conditions sufficient to yield an amount of the compound of Formula I, 2-quinoxalinecarboxylic acid,
wherein said microorganism is selected from the group consisting of
Absidia glauca
ATCC No. 22752,
Absidia glauca
ATCC No. 74480,
Absidia pseudocylindrospora
ATCC No. 24169,
Absidia repens
ATCC No. 14849,
Absidia repens
ATCC No. 74481,
Actinomucor elegans
ATCC No. 6476,
Alternaria solani
ATCC No. 11078,
Aspergillus tamarii
ATCC No. 16865,
Coniophora puteana
ATCC No. 12675,
Cunninghamella echinulata
ATCC No. 8688a,
Cunninghamella echinulata
ATCC No. 8688b,
Cunninghamella echinulata
ATCC No. 8983,
Cunninghamella echinulata
ATCC No. 9244,
Cunninghamella echinulata
ATCC No. 9245,
Cunninghamella echinulata
ATCC No. 10028b,
Cunninghamella echinulata
ATCC No. 26269,
Cunninghamella echinulata
ATCC No. 36190,
Cunninghamella echinulata
ATCC No. 36112,
Cunninghamella homothallica
ATCC No. 16161,
Cylindrocarpon destructans
ATCC No. 66963,
Diplodia gossypina
ATCC No. 20575,
Epicoccum neglectum
ATCC No. 12723,
Glomerella lagenaria
ATCC No. 14724,
Penicillium claviforme
ATCC No. 10426,
Penicillium duclauxii
ATCC No. 10440,
Penicillium glabrum
ATCC No. 11080,
Pseudocochliobolus lunatus
ATCC No. 24155,
Pseudomonas putida
ATCC No. 33015,
Pseudomonas putida
ATCC No. 202190,
Rhodococcus rhodochrous
ATCC No. 19067
and Thamnostylum piriforme
ATCC No. 8686; and suitable mutants thereof; provided that where said microorganism is said
Pseudomonas putida
ATCC No. 33015 or said
Pseudomonas putida
ATCC No. 202190, said
Pseudomonas putida
ATCC No. 33015 or said
Pseudomonas putida
ATCC No. 202190 is induced by interaction with an inducer prior to said contacting of said
Pseudomonas putida
ATCC No. 33015 or said
Pseudomonas putida
ATCC No. 202190 with said 2-methylquinoxaline.
The subject processes optionally further comprise the isolation of the desired product, 2-quinoxalinecarboxylic acid, by any suitable method. For example, the reaction mixture can be extracted with an organic solvent, preferably, ethyl acetate, and then the extracted material can be chromatographed. Alternatively, 2-quinoxalinecarboxylic acid can be adsorbed from the reaction mixture onto a resin, preferably a polymeric adsorbent resin, eluted therefrom using an organic solvent, preferably ethyl acetate, and crystallized from the eluted material using an organic solvent, or a combination of organic solvents, preferably ethyl acetate and methanol. Further yet, the 2-quinoxalinecarboxylic acid produced by the present processes may be treated with a suitable base, e.g., sodium hydroxide, resulting in the formation of a salt
Burns Michael P.
Cawley James J.
Wong John W.
Afremova Vera
Benson Gregg C.
Kispert Jennifer A.
Pfizer Inc.
Richardson Peter C.
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