Technical Scale Synthesis of a New and Highly Potent Thrombin Inhibitor

Abstract

In this account, we describe the development of an efficient and convergent process for the peptidomimetic thrombin inhibitor 1 on production plant scale. Starting from nicotinonitrile (13), (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid (5) and (2R)-2-amino-3-cyclohexylpropanoic acid (29) compound 1 was obtained in 16 chemical steps. New methods had been developed for the preparation of the key intermediate dehydroproline 22 and the transformation of nitriles into amidines. The thrombin inhibitor 1 was isolated by special techniques (nanofiltration and spray drying). Almost all salts of 1 are amorphous, however, a crystalline complex was obtained with 1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Saccharin^®).

Key words

amino acids - drugs - enantiomeric resolution - heterocycles - stereoselective synthesis

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  Lange, U. E. W.; Baucke, D.; Hornberger, W.; Mack, H.; Seitz, W.; Höffken, W., manuscript in preparation.

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5

Lit. Ref. [4a] , Example 32 and 93.

32

For ion exchange chromatography an acetate ion exchanger from BIO RAD was used: AG 1-X8 Resin, 100-200 mesh, acetate form (catalog-Nr.: 140-1443) Address: BIO RAD (BIO RAD laboratories, 2000 Alfred Nobel Dr., Hercules, CA 94547. Due to the water content (48%) before chromatography the ion exchanger was treated with an excess of anhyd MeOH. Based on the content of acetate more than two equivalents were used. The column should be thin and long. For ion exchange chromatography MeOH was used as the solvent.

36

ICH Guideline Q7A: http://www.fda.gov/cder/guidance/1289dft.pdf.