Optical Resolution of Water-insoluble Intermediate of Diltiazem Hydrochloride by Lipase

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  • SHIBATANI Takeji
    Pharmaceutical Development Research Laboratory Tanabe Seiyaku Co., Ltd.

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  • ジルチアゼム塩酸塩合成における脂溶性合成中間体のリパーゼによる光学分割
  • ジルチアゼム エンサンエン ゴウセイ ニ オケル シヨウセイ ゴウセイ チュウ

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Abstract

Newly developed drugs have asymmetric atoms in their chemical structure, and biological effects reside ordinarily in only one of its enantiomers. Another enantiomer has different biological effects or toxicity. Their action on beings is competitive and differs in adsorption, metabolism, degradation and excretion. Therefore, it is important to establish the optical resolution process in the production of pharmaceuticals. The authors have developed the optical resolution system for the production of diltiazem intermediate and industrialized the hollow fiber type bioreactor with liquid-liquid contact mode. Diltiazem is useful as a coronary vasodilator and has been widely used in more than 100 countries in the world for 20 years. An asymmetric hydrolytic en zyme for trans-3- (4-mehoxyphenyl) glycidic acid methyl ester [(±) -MPGM], a keyintermediate in the synthesis of diltiazem, was found in Serratia marcescens. This lipase was immobilized on a spongy layer of the shell side of hollow fiber ultrafiltration membrane by means of physical adsorption. Asymmetric hydrolysis was carried out semicontinuously in membrane reactor circulating both toluene solution containing (±) -MPGM in the shell loop and aqueous solutioninthe lumen loop. Since reaction and product separation were achieved simultaneously, crystalline (-) -MPGM with a high yield and optical purity of 100 % ee was obtained through 7 repeated runs by concentration of the toluene phase after reaction. Tanabe Seiyaku has industrialized this system with a series of 50 m2 membrane bioreactor. The number of total steps for the synthesis of diltiazem reduced to 5 from 9, and the cost of production reduced 2/3.

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