Patent EA-001970-B1 (EA)
Title: Lipase catalyzed dynamic resolution of isoxazoline thioesters t isoxazoline carboxylic acids
Inventor: ZHANG LIN-HUA
IPC: C12P17/14
Filed: 1998-03-26
Abstract: 1. A process for preparation of an optically active compound of Formula (R)-(II) or Formula (S)-(II):   or the salts thereof, wherein: R<2> is -H, halo, -CF3, -CN, -NO2, -OH, C1-C8-alkoxy, C1-C10-alkylcarbonyl, -N(R<12>)R<13>, -CHO, -CO2H, -C(=O)R<5a>, -CONR<5>R<5a>, -C(=NH)NR<5>R<5a>, -SR<5a>, -SO2R<5a>, -SO2NR<5>R<5a>, C1-C8-alkyl substituted with 0-3 R<4>, C2-C8-alkenyl substituted with 0-3 R<4>, C2-C8-alkynyl substituted with 0-2 R<4>, C3-C10-cycloalkyl substituted with 0-3 R<4>, C6-C10-aryl substituted with 0-3 R<4>, a 5-10 membered heterocyclic ring containing 1-4 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R<4>, an amino acid, or a peptide; R<3> is hydrogen, C1-C4-alkyl substituted with 0-3 R<4>, or phenyl substituted with 0-3 R<4>; R<4> is selected from H, C1-C10-alkyl, -OH, C1-C10-alkoxy, -NO2, C1-C10-alkylcarbonyl, -N(R<12>)R<13>, -CN, halo, -CF3, -CHO, -CO2H, -C(=O)R<5a>, -CONR<5>R<5a>, -C(=NH)NR<5>R<5a>, -OC(=O)R<5a>, -OR<5a>, -OC(=O)NR<5>R<5a>, -OCH2CO2H, -CO2CH2CO2H, -NR<5a>C(=O)R<5a>, -NR<5a>C(=O)OH, -NR<5a>C(=O)NR<5>R<5a>, -NR<5a>SO2NR<5>R<5a>, -NR<5a>SO2R<5>, -SR<5a>, -SO2R<5a>, -SO2NR<5>R<5a>, C2-C6-alkenyl, C3-C11-cycloalkyl, C4-C11-cycloalkylmethyl or C6-C10-aryl optionally substituted with 1-3 groups selected from halogen, C1-C4-alkoxy, C1-C4-alkyl, -CF3, -S(O)2Me, or -NMe2; R<5> is selected from H, C1-C8-alkyl, C2-C6-alkenyl, C3-C11-cycloalkyl, C4-C11-cycloalkylmethyl, C6-C10-aryl, C7-C11-arylalkyl, or C1-C10-alkyl substituted with 0-2 R<6>; R<5a> is selected from H, C1-C8-alkyl, C2-C6-alkenyl, C3-C11-cycloalkyl, C4-C11-cycloalkylmethyl, C6-C10-aryl, C7-C11-arylalkyl, or C1-C10-alkyl substituted with 0-2 R<6>; alternately, R<5> and R<5a> can be taken together to be 3-azabicyclononyl, 1-piperidinyl, 1-morpholinyl or 1-piperazinyl, each being optionally substituted with C1-C6-alkyl, C6-C10-aryl, C7-C11-arylalkyl, C1-C6-alkylcarbonyl, C3-C7-cycloalkylcarbonyl, C1-C6-alkylsulfonyl or C6-C10-arylsulfonyl; R<6> is selected from H, C1-C10-alkyl, hydroxy, C1-C10-alkoxy, nitro, C1-C10-alkylcarbonyl, or -N(R<12>)R<13>; R<12> and R<13> are independently selected from H, methyl, or ethyl; comprising contacting, in a suitable solvent, a stereoisomeric mixture of a compound of Formula (I)   wherein: Y is S; R<1> is -C(R<10>)2(R<10a>), -C(R<10>)2-C(R<10b>)2(R<10c>), -C(R<10>)2-C(R<10b>)2-C(R<10c>)3, -C(R<10>)2-C(R<10b>)=C(R<10c>)2, -C(R<10>)2-C=C(R<10c>), -C(R<10>) [triple bond] C(R<10b>)(R<10c>), -C(R<10>)=C(R<10b>)-C(R<10c>)3, -C [triple bond] C(R<10c>), -C [triple bond] C-C(R<10c>)3, R<10> is H or F; R<10a> is selected from H, F, Cl, Br, -CH3, -CH2CH3, -CH2-CH2CH3, -CF3, -CF2CF3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, and cyclopropyl; R<10b> is H, F, Cl, or Br; R<10c> at each occurrence is, independently, selected from H, halo, C1-C3-haloalkyl, -OH, C1-C4-alkoxy, -CF3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -CN, -NO2, -S(O)2Me, -NMe2, C1-C6-alkyl substituted with 0-3 R<11>, C2-C6-alkenyl substituted with 0-3 R<11>, C2-C6-alkynyl substituted with 0-2 R<11>, C3-C6-cycloalkyl substituted with 0-3 R<11>, C6-C10-aryl substituted with 0-3 R<11>, or C4-C10-heterocycle substituted with 0-3 R<11>; and R<11> is selected from the group H, halo, C1-C4-alkyl, C1-C3-haloalkyl, C1-C4-alkoxy, phenyl, -OH, -NO2, -CN, -CF3, -S(O)2Me, and -NMe2; 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. 2. A process of Claim 1 for preparation of an optically active compound of Formula (R)-(II):   or a salt form thereof, wherein: R<2> is phenyl substituted with 0-3 R<4>, R<3> is hydrogen; R<4> is selected from H, C1-C10-alkyl, -OH, C1-C10-alkoxy, -NO2, C1-C10-alkylcarbonyl, -N(R<12>)R<13>, -CN, halo, -CF3, -CHO, -CO2H, -C(=O)R<5a>, -CONR<5>R<5a>, -C(=NH)NR<5>R<5a>, -OC(=O)R<5a>, -OR<5a>, -OC(=O)NR<5>R<5a>, -OCH2CO2H, -CO2CH2CO2H, -NR<5a>C(=O)R<5a>, -NR<5a>C(=O)OH, -NR<5a>C(=O)NR<5>R<5a>, -NR<5a>SO2NR<5>R<5a>, -NR<5a>SO2R<5>, -SO2R<5a>, -SO2NR<5>R<5a>, C2-C6-alkenyl, C3-C11-cycloalkyl, C4-C11-cycloalkylmethyl or C6-C10-aryl optionally substituted with 1-3 groups selected from halogen, C1-C4-alkoxy, C1-C4-alkyl, -CF3, -S(O)2Me, or -NMe2; R<5> is selected from H, C1-C8-alkyl, C2-C6-alkenyl, C3-C11-cycloalkyl, C4-C11-cycloalkylmethyl, C6-C10-aryl, C7-C11-arylalkyl, or C1-C10-alkyl substituted with 0-2 R<6>; R<5a> is selected from H, C1-C8-alkyl, C2-C6-alkenyl, C3-C11-cycloalkyl, C4-C11-cycloalkylmethyl, C6-C10-aryl, C7-C11-arylalkyl, or C1-C10-alkyl substituted with 0-2 R<6>; alternately, R<5> and R<5a> can be taken together to be 3-azabicyclononyl, 1-piperidinyl, 1-morpholinyl or 1-piperazinyl, each being optionally substituted with C1-C6-alkyl, C6-C10-aryl, C7-C11-arylalkyl, C1-C6-alkylcarbonyl, C3-C7-cycloalkylcarbonyl, C1-C6-alkylsulfonyl or C6-C10-arylsulfonyl; R<6> is selected from H, C1-C10-alkyl, hydroxy, C1-C10-alkoxy, nitro, C1-C10-alkylcarbonyl, or -N(R<12>)R<13>; R<12> and R<13> are independently selected from H, methyl, or ethyl; comprising contacting, in a suitable solvent, a stereoisomeric mixture of a compound of Formula (I):   wherein: Y is S; R<1> is -C(R<10>)2(R<10a>), -C(R<10>)2-C(R<10b>)2(R<10c>), -C(R<10>)2-C(R<10b>)2-C(R<10c>)3, -C(R<10>)2-C(R<10b>)=C(R<10c>)2, -C(R<10>)2-C [triple bond] C(R<10c>), -C(R<10>)=C(R<10b>)(R<10c>), -C(R<10>)=C(R<10b>)-C(R<10c>)3, -C [triple bond] C(R<10c>), -C [triple bond] C-C(R<10c>)3, R<10> is H or F; R<10a> is selected from H, F, Cl, Br, -CH3, -CH2CH3, -CH2-CH2CH3, -CF3, -CF2CF3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, and cyclopropyl; R<10b> is H, F, C1, or Br; R<10c> at each occurrence is, independently, selected from H, halo, C1-C3-haloalkyl, -OH, C1-C4-alkoxy, -CF3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -NMe2, C1-C6-alkyl substituted with 0-3 R<11>, C2-C6-alkenyl substituted with 0-3 R<11>, C2-C6-alkynyl substituted with 0-2 R<11>, C3-C6-cycloalkyl substituted with 0-3 R<11>, C6-C10-aryl substituted with 0-3 R<11>, or C4-C10-heterocycle substituted with 0-3 R<11>; and R<11> is selected from the group H, halo, C1-C4-alkyl, C1-C3-haloalkyl, C1-C4-alkoxy, phenyl, -OH, -NO2, -CN, -CF3, -S(O)2Me, and -NMe2; 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) in greater than 51% yield and greater than 80% optical purity. 3. A process of Claim 2 for preparation of an optically active compound of Formula (R)-(IIa):   or a salt form thereof, comprising contacting, in a suitable solvent, a stereoisomeric mixture of a compound of Formula (Ia):   wherein: R<1> is -CH2(R<10a>), -CH2-CH2(R<10c>), -CH2-CH2-C(R<10c>)3, -CH2-CH=C(R<10C>)2, -CH2-C [triple bond] C(R<10c>), R<10a> is selected from H, -CH3, -CH2CH3, and -CH2CH2CH3; R<10c> at each occurrence is, independently, selected from H, -OH, C1-C4-alkoxy, -NMe2, C1-C6-alkyl substituted with 0-3 R<11>, C2-C6-alkenyl substituted with 0-3 R<11> C2-C6-alkynyl substituted with 0-2 R<11>, or C3-C6-cycloalkyl substituted with 0-3 R<11>; and R<11> is selected from the group H, halo, C1-C4-alkyl, C1-C3-haloalkyl, C1-C4-alkoxy, phenyl, -OH, -NO2, -CN, -CF3, -S(O)2Me, and -NMe2; 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)-(IIa) in greater than 51% yield and greater than 80% optical purity. 4. A process of Claim 3 wherein the suitable lipase is Amano PS30 or Amano AK. 5. A process of Claim 3 wherein the racemization agent is selected from the group trimethylamine, triethylamine, tripropylamine and tributylamine. 6. A process of Claim 3 wherein the suitable solvent is either water or a mixture of water and organic solvent wherein the organic solvent is selected from the group methanol, ethanol, propanol, isopropanol, acetonitrile, toluene, xylene and ether. 7. A process of Claim 3 wherein the suitable pH is in the range of about 8,0 to about 10,0. 8. A process of Claim 3 further comprising a suitable buffer added to the suitable solvent to assist in maintaining the suitable pH by addition of a base. 9. A process of Claim 8 wherein the suitable lipase is Amano PS30 or Amano AK. 10. A process of Claim 8 wherein the racemization agent is selected from the group trimethylamine, triethylamine, tripropylamine and tributylamine. 11. A process of Claim 8 wherein the suitable solvent is either water or a mixture of water and organic solvent wherein the organic solvent is selected from the group of methanol, ethanol, propanol, isopropanol, acetonitrile, toluene, xylene and ether. 12. A process of Claim 8 wherein the suitable pH is in the range of about 8,0 to about 11,0. 13. A process of Claim 8 for the preparation of an optically active compound of Formula (R)-(IIa):   or a salt form thereof, said process comprising: contacting in water, in which is dissolved a suitable buffer, a stereoisomeric mixture of a compound of Formula (Ia):   wherein R<1> is n-propyl; with the lipase Amano PS30 in the presence of racemization agent, trimethylamine, while maintaining a suitable pH in the range of about 8,0 to about 10,0 by addition of a base or an acid or an acid, to form a compound of formula (R)-(IIa) in greater than 51% yield and greater than 80% optical purity. 14. A process of Claim 3 further comprising a suitable nonionic, cationic or anionic surfactant added to the suitable solvent. 15. A process of Claim 13 wherein the suitable lipase is Amano PS30 or Amano AK. 16. A process of Claim 13 wherein the racemization agent is selected from the group trimethylamine, triethylamine, tripropylamine, and tributylamine. 17. A process of Claim 13 wherein the suitable solvent is eit