Merck s HIV protease inhibitor Crixivan

This procedure can be used to synthesize the key intermediate 34 of Merck s HIV protease inhibitor Crixivan 35 (Fig. 5) [25]. This reaction is done using dichloroacetaldehyde 26 instead of chloroacetaldehyde, forming the classical Ugi product 30. This intermediate is then treated with triethylamine to obtain the corresponding vinylchloride 31. Cyclization with KO Bu followed by stereoselective hydrogenation using the chiral catalyst Rh-BINAP afforded the Crixivan intermediate 34. (Scheme 5) The classical way to make this intermediate requires five steps, and thus makes the MCR route more attractive [25]. 

Avecia identified approximately 60 microorganisms with amidase activity capable of resolving racemic amines [17, 18]. Arthrobacter species predominated in the list of microorganisms identified. The kinetic resolution of N acetyl 1 aminoindanol 35 by a freeze dried microbial sample (BH2 NI amidase) allowed access to (1S,2R) N acetyl 1 aminoindanol 35 in high enantiomeric excess (96%). This compound is a key intermediate in the synthesis of Merck s HIV protease inhibitor Crixivan 37 (indin avir) (Figure 14.12). 

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