Patent ID: 6307044
Filing Date: 2001-10-23
Classification: A61P,C07C,C07D

Abstract:
A process for the preparation of a compound of formula (VII): ##STR57##or a salt form thereof;wherein:D is P.sup.1 --NR.sup.11 --CH.sub.2 CH.sub.2 CH.sub.2 --;G is a halogen or --OP;P is a suitable oxygen protecting group;P.sup.1 is a suitable nitrogen protecting group;R.sup.1 is selected from the group consisting of:C.sub.1-5 alkyl substituted with 0-5 R.sup.1a, --(CH.sub.2).sub.r --C.sub.3-10 cycloalkyl substituted with 0-5 R.sup.1a, and --(CH.sub.2).sub.r -aryl substituted with 0-5 R.sup.1a ;R.sup.1a is selected independently at each occurrence from the group consisting of:hydrogen, --CF.sub.3, --CF.sub.2 CF.sub.3, --NR.sup.1b R.sup.1c, --Si(R.sup.1d).sub.3, C.sub.1-5 alkyl, C.sub.3-10 cycloalkyl, and aryl substituted with 0-5 R.sup.1e ;R.sup.1b and R.sup.1c are selected independently at each occurrence from the group consisting of:C.sub.1-5 alkyl, C.sub.3-5 cycloalkyl and phenyl;R.sup.1d is selected independently at each occurrence from the group consisting of:C.sub.1-5 alkyl, C.sub.1-5 haloalkyl, and aryl substituted with 0-5 R.sup.1e ;R.sup.1e is selected independently at each occurrence from the group consisting of:C.sub.1-5 alkyl, --(CH.sub.2).sub.r --OR.sup.1f, --OH, halo, --NH.sub.2, and --(CF.sub.2).sub.r CF.sub.3 ;R.sup.1f is selected independently at each occurrence from the group consisting of:C.sub.1-5 alkyl, C.sub.3-5 cycloalkyl and phenyl;R.sup.2 is selected from the group consisting of:C.sub.1-10 alkyl, C.sub.3-10 cycloalkyl, and --(CH.sub.2).sub.r -phenyl substituted with 0-3 R.sup.2a ;R.sup.2a is selected independently at each occurrence from the group consisting of:C.sub.1-5 alkyl, --(CH.sub.2).sub.r --OR.sup.2b, --OH, halo, --NH.sub.2, and --(CF.sub.2).sub.r CF.sub.3 ;R.sup.2b is selected independently at each occurrence from the group consisting of:C.sub.1-5 alkyl, C.sub.3-5 cycloalkyl and phenyl;R.sup.3 is selected from the group consisting of:--OR.sup.4, --NR.sup.5 R.sup.6, --NR.sup.6 (OR.sup.5), C.sub.1-5 alkyl substituted with 0-3 R.sup.3a, --(CH.sub.2).sub.r -aryl substituted with 0-5 R.sup.3a, and --(CH.sub.2).sub.r -heterocyclic substituted with 0-3 R.sup.3a ;R.sup.3a is selected independently at each occurrence from the group consisting of:hydrogen, C.sub.1-5 alkyl, halo, hydroxy, --O--(CH.sub.2).sub.r --R.sup.3b, --(CH.sub.2).sub.r --C(O)R.sup.3b, --(CH.sub.2).sub.r --SO.sub.2 NHR.sup.3b, --(CH.sub.2).sub.r --C(O)NHR.sup.3b, --(CH.sub.2).sub.r --OC(O)R.sup.3b, --(CH.sub.2).sub.r --NHSO.sub.2 R.sup.3b, aryl, --(CH.sub.2).sub.r --NHC(O)R.sup.3b, and --(CH.sub.2).sub.r --C(O)OR.sup.3b ;R.sup.3b is selected independently at each occurrence from the group consisting of:C.sub.1-5 alkyl, C.sub.3-5 cycloalkyl and phenyl;R.sup.4 is selected from the group consisting of:hydrogen, C.sub.1 -C.sub.10 alkyl, --(CH.sub.2).sub.r --C.sub.3-10 cycloalkyl, --(CH.sub.2).sub.r -heterocyclic, and --(CH.sub.2).sub.r -aryl substituted with 0-5 R.sup.4a ;R.sup.4a is selected independently at each occurrence from the group consisting of:C.sub.1-5 alkyl, --(CH.sub.2).sub.r --OR.sup.4b, --OH, halo, --NH.sub.2, and --(CF.sub.2).sub.r CF.sub.3 ;R.sup.4b is selected independently at each occurrence from the group consisting of:C.sub.1-5 alkyl, C.sub.3-5 cycloalkyl and phenyl;R.sup.5 is selected from the group consisting of:C.sub.1 -C.sub.5 alkyl, --(CH.sub.2).sub.r --C.sub.3 -C.sub.10 cycloalkyl, --(CHR.sup.5a Y).sub.n --R.sup.9, --(CR.sup.7 R.sup.8).sub.n --O--C(R.sup.7 R.sup.8).sub.r --R.sup.9, --(CR.sup.7 R.sup.8).sub.r --R.sup.9, and --(CR.sup.7 R.sup.8).sub.r CONR.sup.7 R.sup.8 ;R.sup.5a is selected independently at each occurrence from the group consisting of:hydrogen, C.sub.1-10 alkyl substituted with 0-3 R.sup.5b, --(CH.sub.2).sub.r -aryl substituted with 0-3 R.sup.5b, and --(CH.sub.2).sub.r --O--(CH.sub.2).sub.r -aryl substituted with 0-3 R.sup.5b ;R.sup.5b is selected independently at each occurrence from the group consisting of:hydrogen, halo, hydroxy, --OR.sup.5c, --NHC(O)CH.sub.3, -aryl-(CH.sub.2).sub.r --NH.sub.2, -aryl-(CH.sub.2).sub.r -aryl, C.sub.1-10 alkyl substituted with 0-3 R.sup.5d, and --(CH.sub.2).sub.r -aryl substituted with 0-3 R.sup.5d ;R.sup.5c is selected independently at each occurrence from the group consisting of:C.sub.1-5 alkyl, C.sub.3-5 cycloalkyl and phenyl;R.sup.5d is selected independently at each occurrence from the group consisting of;hydrogen, C.sub.1-5 alkyl, --O--(CH.sub.2).sub.r --R.sup.5e, --OH, halo, --NHC(O)CH.sub.3, and --C(O)NH.sub.2 ;R.sup.5e is selected independently at each occurrence from the group consisting of:C.sub.1-5 alkyl, C.sub.3-5 cycloalkyl and phenyl;R.sup.6 is selected from the group consisting of:hydrogen, C.sub.1 -C.sub.10 alkyl, --(CH.sub.2).sub.r -aryl, --(CH.sub.2).sub.r --C(O)R.sup.6a, --(CH.sub.2).sub.r -heterocyclic, and phenyl substituted with 0-5 R.sup.6c ;R.sup.6a is selected independently at each occurrence from the group consisting of;hydrogen, C.sub.1-5 alkyl, --O--(CH.sub.2).sub.r --R.sup.6b, --OH, halo, --NHC(O)CH.sub.3, and --C(O)NH.sub.2 ;R.sup.6b is selected independently at each occurrence from the group consisting of:C.sub.1-5 alkyl, C.sub.3-5 cycloalkyl and phenyl;R.sup.6c is selected independently at each occurrence from the group consisting of:halogen, NO.sub.2, --R.sup.6d, and --O--(CH.sub.2).sub.r --R.sup.6d ;R.sup.6d is selected independently at each occurrence from the group consisting of:C.sub.1-5 alkyl, C.sub.3-5 cycloalkyl and phenyl;alternatively, R.sup.5 and R.sup.6 combine to form a 3--to 8-- membered heterocyclic ring containing 1 to 3 additional heteroatoms selected from --O--, --NR.sup.6 --, --S(O)p-, and --C(O)--, optionally fused to a phenyl ring;R.sup.7 and R.sup.8 may be H or R.sup.5a ;alternatively, R.sup.7 and R.sup.8 combine to form 3 to 7 membered heterocyclic ring substituted with 1-3 R.sup.7a, containing 1-3 additional heteroatoms selected from --O--, --S(O)p-, and --NR.sup.6 --, optionally fused to an aryl ring substituted with 0-3 R.sup.7c ;R.sup.7a is selected independently at each occurrence from the group consisiting of:hydrogen, C.sub.1-5 alkyl, C.sub.3-5 cycloalkyl, hydroxy, halo, --OR.sup.7b, --NHC(O)CH.sub.3, --C(O)NH.sub.2, and aryl;R.sup.7b is selected independently at each occurrence from the group consisting of:C.sub.1-5 alkyl, C.sub.1-5 cycloalkyl and phenyl;R.sup.7c is selected independently at each occurrence from the group consisting of;hydrogen, C.sub.1-5 alkyl, C.sub.3-5 cycloalkyl, hydroxy, halo, --O(CH.sub.2).sub.r --R.sup.7d, --NHC(O)CH.sub.3, --C(O)NH.sub.2, and aryl;R.sup.7d is selected independently at each occurrence from the group consisting of:C.sub.1-5 alkyl, C.sub.1-5 cycloalkyl and phenyl;R.sup.9 is selected from the group consisting of:hydrogen, C.sub.1-5 alkyl, --C(O)OC.sub.1-5 alkyl, --(CH.sub.2).sub.r -aryl substituted with 0-3 R.sup.9a, and a 5 or 6 membered heterocyclic ring containing from 0 to 2 N, O or S(O)p, and substituted with 0-3 R.sup.9a ;R.sup.9a is selected from the group consisting of:--OH, --O--(CH.sub.2).sub.r --R.sup.9b, --C(O)OR.sup.9b, --NHR.sup.10 and aryl;R.sup.9b is selected from the group consisting of:C.sub.1-5 alkyl, C.sub.1-5 cycloalkyl and phenyl;R.sup.10 is independently at each occurrence H or C.sub.1-10 alkylsubstituted with 0-3 R.sup.10a ;R.sup.10a is selected independently at each occurrence from the group consisting of:hydrogen, C.sub.1 -C.sub.10 alkyl substituted with 0-3 R.sup.10b, and --(CH.sub.2).sub.r -aryl substituted with 0-3 R.sup.10b ;R.sup.10b is selected independently at each occurrence from the group consisting of:hydrogen, halo, hydroxy, --OR.sup.10c, --NHC(O)CH.sub.3, --(CH.sub.2).sub.r --C(O)NH.sub.2, -aryl-NH.sub.2, and --SO.sub.2 NH.sub.2 ;R.sup.10c is selected independently at each occurrence from the group consisting of:C.sub.1-5 alkyl, C.sub.1-5 cycloalkyl and phenyl;R.sup.11 is selected independently at each occurrence from the group consisting of:hydrogen, C.sub.1 -C.sub.10 alkyl substituted with 0-3 R.sup.11a, and --(CH.sub.2).sub.r -aryl substituted with 0-3 R.sup.11a ;R.sup.11a is selected independently at each occurrence from the group consisting of:hydrogen, halo, hydroxy, --OR.sup.11b, --NHC(O)CH.sub.3, --(CH.sub.2).sub.r --C(O)NH.sub.2, -aryl-NH.sub.2, and --SO.sub.2 NH.sub.2 ;R.sup.11b is selected independently at each occurrence from the group consisting of:C.sub.1-5 alkyl, C.sub.1-5 cycloalkyl and phenyl;n is selected from 1, 2 and 3;p is selected independently at each occurrence from 0, 1 and 2;r is selected independently at each occurrence from 0, 1, 2, and 3;Y is selected from the group consisting of:--CONR.sup.10 --, --NR.sup.10 CO--, --SO.sub.2 NR.sup.10 --, --NR.sup.10 SO.sub.2 --, and a 5 membered heterocyclic ring; andz is selected from 1, 2, 3, 4 and 5;the process comprising:contacting a compound of formula (IV): ##STR58##wherein the double bond is in the E configuration; with a silylating agent in the presence of a strong base to give a compound of formula (IV-a): ##STR59##wherein R.sup.12 is selected independently at each occurrence from C.sub.1-6 alkyl and phenyl;contacting the compound of formula (IV-a) with hydroxide to form a compound of formula (V): ##STR60##coupling the compound of formula (V) with a compound of the formula (VI): ##STR61##to form a compound of formula (VII), or a salt form thereof.