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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