GB1290787A - - Google Patents

Abstract

1290787 Penicillin esters; amino acid derivatives LOVENS KEMISCKE FABRIK PRODUKTIONS AS 19 April 1971 [12 March 1970 26 Aug 1970] 11995/70 and 41167/70 Headings C2A and C2C Novel penicillin esters of the general Formula I wherein the asterisk indicates the possibility of an asymmetric carbon atom, n is an integer from 0 to 5, R 1 -CO-NH represents the 6- acylamino group of a known penicillin, R 2 is hydrogen or an aliphatic, aromatic or heterocyclic radical which radical may be substituted; R 3 , R 4 and R 5 each are hydrogen or a C 1 to C 6 aliphatic radical or R 2 and R 5 together with the common carbon atom may form a 5-, 6- or 7- membered carbocyclic ring, or R 3 and R 4 together with the N atom may form a heterocycle or R 4 and R 5 together with the N atom and the adjacent C atom may form a heterocycle, and salts of such esters, are prepared by either (a) reacting a penicillin salt of Formula II with a compound of formula Y-CH 2 -Cl, where R 1 is as defined above, X is a cation and Y is a bromine or iodine atom or an alkylsulphonyloxy or arylsulphonyloxy radical, to give a compound of Formula IV and then reacting this compound with a salt of a compound of Formula V wherein R 2 , R 5 and n are as defined above and Z is a substituted or unsubstituted amino group, a protected amino group or a group, e.g. NO 2 , Cl or azide) which can easily be converted to an amino group, to give a compound of Formula VI or (b) reacting a penicillin salt of Formula II above with a compound of Formula VII wherein Z, n, R 2 and R 5 are as above, to give a compound of Formula VI; and when Z is a protected amino group or a group which can be converted to an amino group, subjecting the compound (VI) to hydrolysis, hydrogenation or amination to convert Z to a substituted or unsubstituted amino group. Alternatively the compounds of Formula I may be prepared by acylating a corresponding ester of 6-aminopenicillanic acid or a salt thereof with an acid of formula R 1 COOH or an acylating derivative thereof. The compounds of Formula IV above are novel intermediates. N-protected amino acid chloromethyl esters of Formula VII above are prepared by treating the following N-protected amino acids with chloroiodomethane: N-tritylglycine, N-tert.- butoxycarbonylglycine; N - carbobenzoxyglycine; N - tert. - butoxycarbonylphenylalanine; N - tert. - butoxycarbonylproline; and N - tert.- butoxycarbonyltryptophan. The N-tritylglycinechloromethyl ester is treated with ptoluenesulphonic acid to give glycine chloromethyl ester p-toluenesulphonate. N-tert.butoxycarbonylphenylalanine chloromethyl ester is reacted with HBr/Acetic acid to give phenyl alanine chloromethyl ester hydrobromide. Potassium salts of N-[1-methyl-2-carbomethoxyvinyl]amino acids of Formula V above are prepared by the procedure described in Example I of Specification 986,904; the amino acid moieties are: L-, D- and D,L-valine; L- leucine; L-isoleucine; D,L-tert-leucine; L- aspartic acid α- and #-methyl esters; glycine; D-α-phenylglycine and L-methionine. Pharmaceutical compositions having antibiotic activity comprise a penicillin ester of Formula I or a non-toxic salt thereof together with a pharmaceutically acceptable carrier.