Patent ID: 6258948
Filing Date: 2001-07-10
Classification: A61K,A61P,C07D,C07K

Abstract:
A process for preparing an N-acylamino compound represented by formula (VIII): ##STR809##wherein:R.sub.1 is selected from the group consisting of the following formulae: ##STR810##C is a ring chosen from the set consisting of benzo, pyrido, thieno, pyrrolo, furano, thiazolo, isothiazolo, oxazolo, isoxazolo, pyrimido, imidazolo, cyclopentyl, and cyclohexyl, the ring optionally being singly or multiply substituted by O.sub.1 ; ##STR811##m is 1 or 2;each R.sub.5 is independently selected from the group consisting of:-C(O)-R.sub.10,-C(O)O-R.sub.9,-S(O)-N (R.sub.10)(R.sub.10),-S(O).sub.2 -R.sub.9,-S(O)2-NH-R.sub.10,-C(O)-CH.sub.2 -O-R.sub.9,-C(O)C(O)-R.sub.10,-R.sub.9,-H,-C(O)C(O)-OR.sub.10, and-C(O)C(O)-N(R.sub.9)(R.sub.10);X.sub.5 is CH or N;Y.sub.2 is H.sub.2 or O;X.sub.7 is -N(R.sub.8)- or -O-;R.sub.6 is selected from the group consisting of -H and -CH.sub.3 ;R.sub.8 is selected from the group consisting of:-C(O)-R.sub.10,-C(O)O-R.sub.9,-C(O)-N(H)-R.sub.10,-C(O).sub.2 -R.sub.9,-S(O).sub.2 -NH-R.sub.10,-C(O)-CH.sub.2 -OR.sub.10,-C(O)C(O)-R.sub.10,-C(O)-CH.sub.2 N(R.sub.10)(R.sub.10),-C(O)-CH.sub.2 C(O)-O-R.sub.9,-C(O)-CH.sub.2 C(O)-R.sub.9,-H, and-C(O)-C(O)-OR.sub.10 ;each R.sub.9 is independently selected from the group consisting of -Ar.sub.3 and a -C.sub.1-6 straight or branched alkyl group optionally substituted with -Ar.sub.3, wherein the -C.sub.1-6 alkyl group is optionally unsaturated;each R.sub.10 is independently selected from the group consisting of -H, -Ar.sub.3, a -C.sub.3-6 cycloalkyl group, and a -C.sub.1-6 straight or branched alkyl group optionally substituted with -Ar.sub.3, wherein the -C.sub.1-6 alkyl group is optionally unsaturated;R.sub.13 is selected from the group consisting of H, Ar.sub.3, and a -C.sub.1-6 straight or branched alkyl group optionally substituted with -Ar.sub.3, -CONH.sub.2, -OR.sub.5, -OH, -OR.sub.9, or -CO.sub.2 H;each R.sub.51 is independently selected from the group consisting of R.sub.9, -C(O)-R.sub.9, -C(O)-N(H)-R.sub.9, or each R.sub.51 taken together forms a saturated 4-8 member carbocyclic ring or heterocyclic ring containing -O-, -S-, or -NH-;each R.sub.21 is independently selected from the group consisting of -H or a -C.sub.1-6 straight or branched alkyl group;each Ar.sub.3 is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings and an aromatic heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocyclic group containing at least one heteroatom group selected from -O-, -S-, -SO-, SO.sub.2, =N-, and -NH-, said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by -O.sub.1 ;each O.sub.1 is independently selected from the group consisting of -NH.sub.2, -CO.sub.2 H, -Cl, -F, -Br, -I, -NO.sub.2, -CN, =O, -OH, -perfluoro C.sub.1-3 alkyl, R.sub.5, -OR.sub.5, -NHR.sub.5, -OR.sub.9, -N(R.sub.9)(R10), -R.sub.9, -C(O)-R.sub.10, and ##STR812##provided that when -Ar.sub.3 is substituted with a O.sub.1 group which comprises one or more additional -Ar.sub.3 groups, said additional -Ar.sub.3 groups are not substituted with another -Ar.sub.3 ;comprising the steps of:a) providing a mixture comprising a carboxylic acid with an N-alloc-protected amine in the presence of an inert solvent, triphenylphoshine, a nucleophilic scavenger, and tetrakis-triphenyl phosphine palladium(O) at ambient temperature under an inert atmosphere; andb) adding to the step a) mixture, HOBT and EDC;and optionally comprising the further step of:c) hydrolyzing the step b) mixture in the presence of a solution comprising an acid and H.sub.2 O, wherein the step b) mixture is optionally concentrated.