In recent evaluations of chemical processes trying to comply to the rule of GMF and green chemistry, amide bond formation was identified as one of the most utilized and problematic synthetic step in the pharmaceutical industry. From a detailed study it was found that N-acylation reactions for amide formation were used in more than 50% of current synthesis of drug candidates. We have recently developed an efficient methodology for the amidation of N-protected amino acid thioesters under Dynamic Kinetic Resolution (DKR) conditions, where the relatively high acidity of the α-hydrogen was exploited in a base-catalysed substrate racemization occurring in the same pot with a selective, protease-mediated, amidation. The amides are obtained with high optical purity and high chemical yield by ammoniolysis or aminolysis catalyzed by CLEA-AlcalaseTM starting from the relative thioester, in presence of a racemizing strong organic base (DBU) and a nitrogen nucleophile in tert-butanol with controlled water activity. The reaction is carried out under kinetic control, and different parameters such as amine concentration, base ratio, water content, enzyme amount have been checked for the success of the DKR process.

L-Amino acid amides via dynamic kinetic resolution

CERIOLI, LORENZO;D'ARRIGO, PAOLA;FIORATI, ANDREA;SERVI, STEFANO;TESSARO, DAVIDE;
2012

Abstract

In recent evaluations of chemical processes trying to comply to the rule of GMF and green chemistry, amide bond formation was identified as one of the most utilized and problematic synthetic step in the pharmaceutical industry. From a detailed study it was found that N-acylation reactions for amide formation were used in more than 50% of current synthesis of drug candidates. We have recently developed an efficient methodology for the amidation of N-protected amino acid thioesters under Dynamic Kinetic Resolution (DKR) conditions, where the relatively high acidity of the α-hydrogen was exploited in a base-catalysed substrate racemization occurring in the same pot with a selective, protease-mediated, amidation. The amides are obtained with high optical purity and high chemical yield by ammoniolysis or aminolysis catalyzed by CLEA-AlcalaseTM starting from the relative thioester, in presence of a racemizing strong organic base (DBU) and a nitrogen nucleophile in tert-butanol with controlled water activity. The reaction is carried out under kinetic control, and different parameters such as amine concentration, base ratio, water content, enzyme amount have been checked for the success of the DKR process.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11311/762863
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