Patent ID: 6022977
Filing Date: 2000-02-08
Classification: A61P,C07D,C12P

Abstract:
A process for preparation of an optically active compound of Formula (R)-(II) or Formula (S)-(II): ##STR30## or a salt form thereof, wherein: R.sup.2 is --H, halo, --CF.sub.3, --CN, --NO.sub.2, --OH, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.10 alkylcarbonyl, --N(R.sup.12)R.sup.13, --CHO, --CO.sub.2 H, --C(.dbd.O)R.sup.5a, --CONR.sup.5 R.sup.5a, --C(.dbd.NH)NR.sup.5 R.sup.5a, --SR.sup.5a, --SO.sub.2 R.sup.5a, --SO.sub.2 NR.sup.5 R.sup.5a,C.sub.1 -C.sub.8 alkyl substituted with 0-3 R.sup.4,C.sub.2 -C.sub.8 alkenyl substituted with 0-3 R.sup.4,C.sub.2 -C.sub.8 alkynyl substituted with 0-2 R.sup.4,C.sub.3 -C.sub.10 cycloalkyl substituted with 0-3 R.sup.4,C.sub.6 -C.sub.10 aryl substituted with 0-3 R.sup.4,a 5-10 membered heterocyclic ring consisting of 1-4 N, 0, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R.sup.4,an amino acid, ora peptide;R.sup.3 is hydrogen, C.sub.1 -C.sub.4 alkyl substituted with 0-3 R.sup.4, or phenyl substituted with 0-3 R.sup.4 ;R.sup.4 is selected from H, C.sub.1 -C.sub.10 alkyl, --OH, C.sub.1 -C.sub.10 alkoxy, --NO.sub.2, C.sub.1 -C.sub.10 alkylcarbonyl, --N(R.sup.12)R.sup.13, --CN, halo, --CF.sub.3, --CHO, --CO.sub.2 H, --C(.dbd.O)R.sup.5a, --CONR.sup.5 R.sup.5a, --C(.dbd.NH)NR.sup.5 R.sup.5a, --OC(.dbd.O)R.sup.5a, --OR.sup.5a, --OC(.dbd.O)NR.sup.5 R.sup.5a, --OCH.sub.2 CO.sub.2 H, --CO.sub.2 CH.sub.2 CO.sub.2 H, --NR.sup.5a C(.dbd.O)R.sup.5a, --NR.sup.5a C(.dbd.O)OH, --NR.sup.5a C(.dbd.O)NR.sup.5 R.sup.5a, --NR.sup.5a SO.sub.2 NR.sup.5 R.sup.5a, --NR.sup.5a SO.sub.2 R.sup.5, --SR.sup.5a, --SO.sub.2 R.sup.5a, --SO.sub.2 NR.sup.5 R.sup.5a, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylmethyl orC.sub.6 -C.sub.10 aryl optionally substituted with 1-3 groups selected from halogen, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, --CF.sub.3, --S(O).sub.2 Me, or --NMe.sub.2 ;R.sup.5 is selected from H, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylmethyl, C.sub.6 -C.sub.10 aryl, C.sub.7 -C.sub.11 arylalkyl, or C.sub.1 -C.sub.10 alkyl substituted with 0-2 R.sup.6 ;R.sup.5a is selected from H, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.3 -C.sub.11 cycloalkyl, C.sub.4 -C.sub.11 cycloalkylmethyl, C.sub.6 -C.sub.10 aryl, C.sub.7 -C.sub.11 arylalkyl, or C.sub.1 -C.sub.10 alkyl substituted with 0-2 R.sup.6 ;alternately, R.sup.5 and R.sup.5a can be taken together to be 3-azabicyclononyl, 1-piperidinyl, 1-morpholinyl or 1-piperazinyl, each being optionally substituted with C.sub.1 -C.sub.6 alkyl, C.sub.6 -C.sub.10 aryl, C.sub.7 -C.sub.11 arylalkyl, C.sub.1 -C.sub.6 alkylcarbonyl, C.sub.3 -C.sub.7 cycloalkylcarbonyl, C.sub.1 -C.sub.6 alkylsulfonyl or C.sub.6 -C.sub.10 arylsulfonyl;R.sup.6 is selected from H, C.sub.1 -C.sub.10 alkyl, hydroxy, C.sub.1 -C.sub.10 alkoxy, nitro, C.sub.1 -C.sub.10 alkylcarbonyl, or --N(R.sup.12)R.sup.13 ;R.sup.12 and R.sup.13 are independently selected from H, methyl, or ethyl;said process comprising:contacting, in a suitable solvent, a stereoisomeric mixture of a compound of Formula (I) ##STR31## wherein: Y is S;R.sup.1 is --C(R.sup.10).sub.2 (R.sup.10a),--C(R.sup.10).sub.2 --C(R.sup.10b).sub.2 (R.sup.10c),--C(R.sup.10).sub.2 --C(R.sup.10b).sub.2 --C(R.sup.10c).sub.3,--C(R.sup.10).sub.2 --C(R.sup.10b).dbd.C(R.sup.10c).sub.2,--C(R.sup.10).sub.2 --C.tbd.C(R.sup.10c),--C(R.sup.10).dbd.C(R.sup.10b) (R.sup.10c),--C(R.sup.10).dbd.C(R.sup.10b)--C(R.sup.10c).sub.3,--C.tbd.C(R.sup.10c),--C.tbd.C--C(R.sup.10c).sub.3,R.sup.10 is H or F;R.sup.10a is selected from H, F, Cl, Br, --CH.sub.3, --CH.sub.2 CH.sub.3, --CH.sub.2 CH.sub.2 CH.sub.3, --CF.sub.3, --CF.sub.2 CF.sub.3, --OCH.sub.3, --OCH.sub.2 CH.sub.3, --OCH.sub.2 CH.sub.2 CH.sub.3, --SCH.sub.3, --SCH.sub.2 CH.sub.3, --SCH.sub.2 CH.sub.2 CH.sub.3, and cyclopropyl;R.sup.10b is H, F, Cl, or Br;R.sup.10c at each occurrence is, independently, selected from H, halo, C.sub.1 -C.sub.3 haloalkyl, --OH, C.sub.1 -C.sub.4 alkoxy, --CF.sub.3, --SCH.sub.3, --SCH.sub.2 CH.sub.3, --SCH.sub.2 CH.sub.2 CH.sub.3, --CN, --NO.sub.2, --S(O).sub.2 Me, --NMe.sub.2,C.sub.1 -C.sub.6 alkyl substituted with 0-3 R.sup.11,C.sub.2 -C.sub.6 alkenyl substituted with 0-3 R.sup.11,C.sub.2 -C.sub.6 alkynyl substituted with 0-2 R.sup.11,C.sub.3 -C.sub.6 cycloalkyl substituted with 0-3 R.sup.11,C.sub.6 -C.sub.10 aryl substituted with 0-3 R.sup.11, orC.sub.4 -C.sub.10 heterocycle substituted with 0-3 R.sup.11 ; andR.sup.11 is selected from the group H, halo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 haloalkyl, C.sub.1 -C.sub.4 alkoxy, phenyl, --OH, --NO.sub.2, --CN, --CF.sub.3, --S(O).sub.2 Me, and --NMe.sub.2 ;with a suitable lipase in the presence of a racemization agent, while maintaining a suitable basic pH by addition of a base or an acid, to form a compound of formula (R)-(II) or formula (S)-(II) in greater than 51% yield and greater than 80% optical purity.