Tanabe Seiyaku Co, Ltd

Kawaru, M., Kanno, T., Saito, S. and Tamaki, H., assigned to Tanabe Seiyaku Co., Ltd. (Japan)... 

L-aspartic add has been produced on an industrial scale by the Tanabe Seiyaku Co Ltd, Japan, in a batch wise process using whole cells of Escherichia coli with high aspartase activity. In this process, L-aspartic add is produced from fumaric add and ammonia using aspartase, as described in Figure A8.13. 

Hiroshi Yamahara / Tanabe Seiyaku Co., Ltd., Osaka, Japan... 

Diltiazem hydrochloride belongs to the benzothiazepine class of compounds. It was first synthesized in the laboratories of Tanabe Seiyaku Co., LTD in Japan and was granted its first patent in 1969 (3). The first non-patent literature reference to diltiazem appeared in 1970 (4). Since the introduction of diltiazem hydrochloride in pharmaceutical formulations, it has gained wide acceptance as an anti-anginal and antihypertensive agent. A search of Chemical Abstracts (1967-July, 1992) and Pharma-ceutical Abstracts (1974-July, 1992) produced over 200 bibliographic citations dealing with diltiazem or diltiazem hydrochloride. 

Tanabe Seiyaku Co. Ltd., United States of America Patent 4416819 (1983) Chem. Abstr., 100, 85733X (1983). 

ICHIRO CHIBATA is Director of the Research Laboratory of Applied Biochemistry, Tanabe Seiyaku, Co., Ltd. Bom Osaka, Japan, 1926 B.S., 1948, Ph.D, 1959, Kyoto University. With Research Laboratories, Tanabe Seiyaku, Co., Ltd. since 1948, Director since 1971. 

Optical resolution of racemic amino acids (methionine, phenylalanine, tryptophan, valine) by the action of L-specific amino acylase from Aspergillus oryzae (Tanabe Seiyaku Co., Ltd.). The theoretical productivity of 1000 liter immobilized amino acylase columns ranges from 214 kg per day for L-Ala to 715 kg per day for L-Met. 

Production of an optically active diltiazem intermediate (2R, 3S)-methoxyophenylglyci-date methyl ester ((-)-MPGM) from racemic MPGM by the action of lipase from Serratia marcescens in a toluene aqueous biphasic system (Tanabe Seiyaku Co., Ltd.). For the continuous production of (-)-MPGM, a hollow fiber bioreactor was set up in collaboration with Sepracor Inc. The introduction of this enzymatic step allowed the shortening of the diltiazem synthesis from nine down to five steps. 

Production of L-aspartic acid from fumaric acid by stereoselective addition of ammonia under the action of the intracelluar aspartase in E. coli (Tanabe Seiyaku Co., Ltd.). When a 1000-liter column is used, theoretical yield of L-aspartic acid is 3.4 tons per day (and even considerably higher for mutant strains and plasmid pNKl01-harboring strains). A similar industrial process using the immobilized E. coli aspartase (instead of the whole cells) was established earlier by Kyowa Hakko Kogyo, Co., Ltd.. L-Aspartate is mainly used as a building block for the manufacture of the sweetener aspartame [170]. 

Production of L-malic acid from fumaric acid by stereoselective hydration under the action of the intracellular fumarase in Brevibacterium ammoniagenes (Tanabe Seiyaku Co., Ltd). A 1000-liter column bioreactor can typically yield 30 tons of L-malic acid per month. 

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