Substituted 5-amino-4-hydroxyvaleryl derivatives

Claim 1

A process for the preparation of a compound of the formula ##STR33## wherein R 3 is hydrogen, lower alkyl, cycloalkyl, aryl-lower alkyl, or aryl; R 5 is lower alkyl, cycloalkyl, aryl-lower alkyl, or aryl; and R 6 is (A) amino; (B) mono or di-substituted amino or substituted hydroxy, which substituents are selected from (i) unsubstituted and substituted, saturated and unsaturated, aliphatic hydrocarbon radicals having up to and including 18 carbon atoms; and (ii) aromatic, heteroaromatic, aromatic-aliphatic and heteroaromatic-aliphatic radicals having up to and including 18 carbon atoms; (C) a natural alpha-amino acid residue that is N-terminally bound to the group --CO--, said natural alpha-amino acid being C-terminally free, esterified, or amidated; (D) a di- or tri-peptide residue consisting of amino acids selected from natural alpha-amino acids and statin, said di- or tri-peptide being N-terminally bound to the group --CO-- and, being C-terminally free, esterfied, or amidated; and salts thereof comprising: (a) converting a compound of the formula ##STR34## wherein R 3 is as defined above and Z 1 is an amino-protecting group, with a methylide selected from dialkylsulphonium methylide, alkyl or phenyl dialkylamino sulphoxonium methylide, and dialkylsulphoxonium methylide, into an expoxide of the formula ##STR35## wherein Z 1 and R 3 are as defined above; (b) reacting said epoxide of formula (X) with a nucleofugal leaving group X introducing agent to result in the compound of the formula ##STR36## wherein R 3 Z 1 and X are as defined above; (c) reacting a compound of formula (XI) with a carbonyl compound of the formula Ra--(C═O)--R.sub.b (XII) wherein each of R a and R b are independently hydrogen, lower alkyl, aryl, or aryl-lower alkyl, or R a and R b together are an alkylidene or bridged alkylidene having 4-12 carbon atoms, or a reactive derivative of said carbonyl compound, in the presence of an acidic reagent to result in a compound of the formula ##STR37## wherein R a , R b , R 3 , Z 1 , and X are as defined above; (d) reacting said compound of formula (XIII) with a carboxylic acid ester salt of the formula ##STR38## wherein R 5 is as defined above, Z 2 is a carboxy protecting group and Y.sup.⊖ is a cation to yield a compound of the formula ##STR39## wherein R a , R b R 3 , R 5 , Z 1 , and Z 2 are as defined above; (e) removing said carboxy-protecting group Z 2 ; (f) opening the ring of formula (XV) with a solvolysis reagent; and then (g) removing said protecting group Z 1 .