Large scale preparation of chiral building blocks for the P3 site of renin inhibitors.
Racemic ethyl 2-benzyl-3-(tert-butylsulfonyl)propionate (1) and racemic ethyl 2-benzyl-3-[[1-methyl-1-((morpholin-4-yl)carbonyl)ethyl]sulfonyl] propionate (3) were enantioselectively hydrolyzed by subtilisin Carlsberg generating the respective (S)-acids used as building blocks for renin inhibitors. The esters were readily converted as emulsions at elevated temperature, in a suspended form or a two-phase-liquid system. The enzyme maintained its excellent selectivity and a good activity also at high initial substrate concentrations (up to 50% w/w). The enzymatic reaction and work-up were optimized and scaled up. Emulsion problems during work-up encountered with these highly concentrated mixtures were solved by application of a disk separator for phase separation.
Doswald
S
S
F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Estermann
H
H
Kupfer
E
E
Stadler
H
H
Walther
W
W
Weisbrod
T
T
Wirz
B
B
Wostl
W
W
D000804:Angiotensin II / Q000737:chemistry; D004655:Emulsions; D004952:Esters; D006868:Hydrolysis; D007202:Indicators and Reagents; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D009025:Morpholines / Q000737:chemistry*; D009904:Optical Rotation; D010666:Phenylpropionates / Q000737:chemistry*; D013237:Stereoisomerism; D013381:Subtilisins; D013816:Thermodynamics; D000092502:Renin Inhibitors
D000804:Angiotensin II; D004655:Emulsions; D004952:Esters; D007202:Indicators and Reagents; D009025:Morpholines; D010666:Phenylpropionates; D013381:Subtilisins; D000092502:Renin Inhibitors; C091061:ethyl 2-benzyl-3-((1-methyl-1-((morpholin-4-yl)carbonyl)ethyl)sulfonyl)propionate; C091060:ethyl 2-benzyl-3-(tert-butylsulfonyl)propionate