Novel method for synthesizing esters of N-[(S)-1-carboxybutyl]-(S)-alanine and use thereof for synthesizing perindopril

Process for the synthesis of N-((S)-1-carboxy butyl)-(S)-alanine esters (I), by reaction of a morpholinone (III) either with allyl triflate or bromide to give (3S,5S) (IV) which is then hydrogenated, or with iodopropane, to give (V), and this is treated with lithium hydroxide and esterified to give (VI) which, following oxidation and removal of the protecting group gives (I). Process for the synthesis of N-((S)-1-carboxy butyl)-(S)-alanine esters of formula (I), by reaction of a morpholinone of formula (III), either with allyl triflate or bromide in the presence of a base such as lithium diisopropyl amide, sodium bis(trimethyl silyl) amide, or potassium tert. butanoate, to give (3S,5S) fo formula (IV), which is then hydrogenated in the presence of palladium on charcoal to give a compound of formula (V); or (III) is reacted with iodopropane to give a compound of formula (V), and (V) is treated with LiOH and esterified to give (VI) which, following oxidation (preferably NaIO4 and RuCl3) and removal of the protecting group gives (I). R = 1-6C alkyl, especially ethyl; and P = a group protecting the amino group, especially tert. butoxy carbonyl. Independent claims are included: (a) for compounds of formula (V) and (VI) where P = tert. butoxy carbonyl, and R = ethyl; and (b) for a process for the preparation of perindopril and its salts starting from (I) obtained by the above process.