Process for manufacture and resolution of 2-acylamino-3-diphenylpropanoic acid

摘要

The invention relates to a novel process, novel process steps and novel intermediates useful in the synthesis of pharmaceutically active compounds, in particular neutral endopeptidase (NEP) inhibitors.

主权项

1. A process for preparing a compound of formula (I), or salt thereof, wherein R1 is C1-7alkyl or is substituted or unsubstituted C6-10aryl, and “*” means a chiral center with absolute stereochemistry (R) or (S), comprising the steps of i) preparing in a one-step reaction a compound of formula (III) or salt thereof, wherein R1 is as defined for the compound of formula (I); by reacting a compound of formula (IV), or salt thereof, wherein R1 is as defined for the compound of formula (I); under decarboxylation reaction conditions to provide the compound of formula (III); ii) treating the obtained compound of formula (III) or a salt thereof with a chiral amine of formula (V) wherein R2 is C1-7alkyl; or is R3R4NC(═O)— or R5OC(═O)—, wherein R3 and R4 are independently selected from hydrogen or C1-7alkyl; and R5 is C1-7alkyl; R6 is C6-10aryl, and “*” means a chiral center with absolute stereochemistry (R) or (S); and resolving the resulting diastereomeric mixture via crystallization to provide a composition of formula (II) wherein R1 is as defined for the compound of formula (I); R2 is C1-7alkyl; or is R3R4NC(═O)— or R5OC(═O)—, wherein R3 and R4 are independently selected from hydrogen or C1-7alkyl; and R5 is C1-7alkyl; R6 is C6-10aryl, and “*” means a chiral center with absolute stereochemistry (R) or (S); and iii) treating the obtained composition of formula (II), with an acidic reagent to provide the compound of formula (I).