Chemistry: molecular biology and microbiology – Micro-organism – per se ; compositions thereof; proces of... – Fungi
Reexamination Certificate
1998-03-30
2001-06-05
Marx, Irene (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, per se ; compositions thereof; proces of...
Fungi
C435S911000, C435S136000, C435S280000
Reexamination Certificate
active
06242243
ABSTRACT:
FIELD OF INVENTION
This invention relates to the filed of biotechnology. It describes an efficient bio-resolution process for the preparation of an anti-inflammatory drug S(+)-6-methoxy-&agr;-methyl-2-naphthalene acetic acid (naproxen) of formula (2). Through the bio-resolution process, two enantiomers of (±)-6-methoxy-a-methyl-2-naphthalene acetic acid alkyl esters are resolved. The bio-resolution is effected by the mediation of an organism belonging to the genus Trichosporon sp. The organism may be used in the form of whole wet cell pellet or dry cell powder or cell free extract or pure enzyme isolated from the cell culture. The use of Trichosporon sp. (RRLY-15) DSM 11829 is novel for kinetic resolution of the said compound through its maximum enantioselectivity and near theoritical yields.
PRIOR ART AND BACKGROUND OF THE INVENTION
S(+)-6-methoxy-&agr;-methyl-2-naphthalene acetic acid of formula (2) belongs to the class of &agr;-methyl aryl acetic acids also known as 2-aryl propanoic acids which in turn belong to an important class of non-steroidal anti-inflammatory drugs (NSAID). Most commonly used drugs in this class besides naproxen include ibuprofen, ketoprofen and fluriprofen. These drugs have wide applications in checking pain and inflammation caused by arthritis and related connective tissue diseases (Shen, T. Y.; Angew, Chem, Int.Ed., 1972, 11, 460). These drug molecules being chiral in nature appear as racemates, when synthesised through a normal chemical synthetic process. In recent years, the use of enantiomerically pure drugs in chemotherapy is becoming almost mandatory and FDA's of many countries are bringing in new drug legislations for this purpose. The use of enantiomerically pure drugs, not only improves the specificity of action, but also minimises the toxicity and undesirable load on the host. The validity of this statement is very true for &agr;-aryl propanoic acid also. In case of (±)-6-methoxy-&agr;-methyl-2-naphthalene acetic acid, the S(+) enantiomer is 28 times more active than its R(−) enantiomer (Roszokwski, A. P., Rooks, W. H., Tomolonis, A. J. and Miller, L. M. J. Pharmcol Exp. Ther, 1971, 179, 114). Another drug belonging to the same class of non-steroidal anti-inflammatory drug (NSAID) which till recently was being prescribed as a racemic mixture is ibuprofen. It has been observed that although the inactive R(−)-antipode of this drug is converted to S(+)-enantiomer in vivo via a CoA thioester intermediate, the epimerisation process leads to metabolic complications as R(−)-ibuprofen-CoA complex competitively inhibits many CoA dependent reactions, which results in perturbation of hepatocyte intermediary metabolism and mitochondrial function. Pure S(+)-ibuprofen may therefore be a preferred drug of future (Ann. Rep. Med. Chem. Vol 30(1995) p.298, Ed. James a Bristol, Academic Press inc. California).
As the chemical synthesis of compound (2) leads to the formation of racemic mixture, one or the other resolution techniques are employed for the separation of S(+) enantiomer (Harrison, I. T., Lewis, B., Nelson, P., Rooks, W., Roszwkoski, A., Tomolonis, A. J. and Fried, J. H. J. Med. Chem., 1970 13 203). These methods generally employ the selective crystallisation of d1-stereoisomeric salts by the use of expensive optically active amines such as cinconidine, dehydroabietyl amine acetate, phenyl ethyl amine etc. (Newman, P. in Optical Resolution Process for Organic Compound Vol.2(II) p.653 (1981), Manhattan College, New York). Resolution of (2) has also been carried out using camphor-10-sulfonic acid (Tsuchihashi, G., Tetrahedron Lett, 1982, 23, 5427).
Asymmetric synthesis of &agr;-aryl propanoic acids offers another important methodology for obtaining enantiomerically pure compounds. Various strategies employed in these methods include Lewis acid catalyzed 1,2-aryl-migration, use of chiral catalysts in stereoselective C—C bond formation, hydroformylation, asymmetric hydrogenation etc. Asymmetric synthesis of &agr;-aryl propanoic acids has recently been reviewed [Sonawane, H. R., Bellur, N. S., Ahuja, J. K. and Kulkarni, D. G., Tetrahedron Asym. 1992, 3(2), 162; Vill. C., Giordans, M., Pannosion, S. Sheldrak, G. N. in Naproxen: Industrial Asymmetric syn. (1992). p.303 Ed. Collins, A. N. and Crosby, J. N., Chechester, U.K.: Jia, C., Le, J., Zhonogguo Yiyao Zazhi 1990, 21(3) 137].
A number of reports related to the bio-resolution of (±)-naproxen have appeared in last ten years using hydrolases, lipases, esterases or proteases from bacterial, fungal or animal sources. A brief review is presented in the following lines.
Candida cylinderacea
lipase was successfully used for the separation of S(±)-6-methoxy-&agr;-methyl-2-naphthalene acetic acid through its chloromethyl ester (Gu, Qui-Ming; Chen, C. and Sih, C. J., Tetrahedron Lett. 1986, 27 (16), (1763). This work has also been patented (Sih, C. J., Eur. Pat. Appl. E.P. 227, 078, 01 Jul., 1987, U.S. Appl. 811, 260, 20
th
Dec., 1985). Some other important publications in resolution methods for (±)-naproxen and related &agr;-methyl aryl acetic acids derivatives include (Quax, W. J, Broekhuizen, C. P., Applied Microbial. Biotechnol. 1994, 41 (4), 425; Smeets, J. W. H., Kieboom, A. P. G., Recl. Trav. Chim. Pays-Bass 1992, 111(11), 490, CA, 118: 212077; Mutasaers, J. H., G. M., Kooreman, H. J., Recl. Trav. Chim. Pays-Bas 1991, 110(05) 185, CA, 115-207622t; Gu, Q.; Zhongguo Yiyao Gongyu Zazhi, 1991, 22(21) 49, CA, 115: 88688; Alkumark, S., Anderson, S., Chirality 1992, 4(1) 24, Wu, S. H., Guo, Z. W., Sih, C. J., J. Am. Chem. Soc. 1990, 112(5), 1990) Enantioselective esterification of racemic naproxen has also been carried out using Candida lipase in organic solvents] Shan-Wei, T., Hwa-Jou, W., Biocat., 1994, 11(1), 33 and J. Chem. Technol. Biotechnol., 1996, 65(3), 156].
A few other processes have been patented in the past for the kinetic resolution of (±)naproxen using different enzymes. For example the alkyl esters of (±)-naproxen were claimed to be resolved by the use of enzymes from Pseudomonas, Brevibacterium or Mycoplana species (Watanabe, I., Hosoi, A, Kobayashe, E., J.P., 6363396, 19 Mar., 1988, CA, 109:72056). Gist Brocades, employed
Bacillus thai
and other micro-organisms to hydrolyse alkyl esters of (±)naproxen (Gist Brocades, N.V., JP 63, 45,234 26 Feb., 1988, FR. Appl. 88.245 7 Jan, 1986, CA, 109: 168975). Resolution of esters of naproxen stereoisomers was achieved in a multiphase extractive membrane bioreactors in presence of
Candida cyclinderacea;
optically active naproxen was collected in aqueous phase (Matson, S. L. PCT Int. Appl. WO, 88,07,582 06 Oct., 1988 US Appl. 33, 962, 01 Apr., 1987: CA, 111; 113732). A process for the continuous manufacture of S(+)-naproxen was disclosed by Bianchi et al using corresponding alkyl, phenyl, tetrahydropyranyl or tetrahydrofuranyl esters catalyzed by immobilised
Candida cylinderacea
lipase. They obtained 1757 g of S(+) naproxen from 9387 g of (±)ester after 1200h of continuous operation of the reaction (Bianchi, D., Cesti, P., Pina, C., Battislet, E, Eur. Pat. Appl. E.P. 330, 217, 30 Aug., 1989, IT, 88/19, 532, 25 Feb., 1988, CA 112: 215, 202). Water soluble esters of (±) naproxen were hydrolyzed to produce chiral aryl propinoic acids in a two stage extractive membrane reactor (Matson, S. L., Wald, S. A., Zepp, C. M., and Dodds, D. R. PCT Int. Appl. WO 89,09,765, 19 Oct., 1989, US Appl. 178 735, 07 Apr., 1988, CA, 113: 171683). Hydrolytic resolution of (±)-&agr;-methyl naphthylacetonitrile derivatives was achieved by
Cornynebacterium nitrophilus
in 98% ee (Yamamoto, K., Otsubo, K., Oishi, K., Eur. Pat. Appl. E.P. 348, 901, 03 Jan., 1990, JP Appl. 88/156, 911, 27 Jun., 1988, CA 113: 76605). In another approach for the production of S(+)-naproxen a filamentous fungi
Cordyceps milioris
was employed for isomerisation of R(−)-naproxen to S(+) naproxen (Reid, A. J., Phillips, G. T
Dhar Kanaya Lal
Handa Sukhdev Swami
Kotru Ravi Ji
Koul Surrinder
Parshad Rajinder
Council of Scientific & Industrial Research
Marx Irene
Nath & Associates
Novick Harold L.
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