Enzymatic resolution of selective estrogen receptor modulators

A process for preparing a compound of the formula:

• wherein:
• A is selected from CH2 and NR;
• B, D and F are independently selected from CH and N;
• Y is
• (a) phenyl, optionally substituted with 1-3 substituents independently selected from R4;
• (b) naphthyl, optionally substituted with 1-3 substituents independently selected from R4;
• (c) C3-C8 cycloalkyl, optionally substituted with 1-2 substituents independently selected from R4;
• (d) C3-C8 cycloalkynyl, optionally substituted with 1-2 substituents independently selected from R4;
• (e) a five membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR2— and —S(O)n—, optionally substituted with 1-3 substituents independently selected from R4;
• (f) a six membered heterocycle containing up to two heteroatoms selected from the group consisting of —O—, —NR2— and —S(O)n— optionally substituted with 1-3 substituents independently selected from R4;
• or
• (g) a bicyclic ring system consisting of a five or six membered heterocyclic ring fused to a phenyl ring, said heterocyclic ring containing up to two heteroatoms selected from the group consisting of —O—, —NR2—, NR2— and —S(O)n—, optionally substituted with 1-3 substituents independently selected from R4;
• Z1 is
• (a) —(CH2)pW(CH2)q—;
• (b) —O(CH2)pCR5R6—;
• (c) —O(CH2)pW(CH2)q;
• (d) —OCHR2CHR3—;
• or
• (e) —SCHR2CHR3—;
• G is
• (a) —NR7R8;
• (b)
• wherein n is 0, 1 or 2;
• m is 1, 2 or 3;
• Z2 is —NH—, —O—, —S—, or —CH2—;
• optionally fused on adjacent carbon atoms with one or two phenyl rings and, optionally independently substituted on carbon with one to three substituents and, optionally, independently on nitrogen with a chemically suitable substituent selected from R4;
• or
• (c) a bicyclic amine containing five to twelve carbon atoms, either bridged or fused and optionally substituted with 1-3 substituents independently selected from R4;
• Z1 and G in combination may be
• W is
• (a) —CH2—;
• (b) —CH═CH—;
• (c) —O—;
• (d) —NR2—;
• (e) —S(O)n—;
• (f)
• (g) —CR2(OH)—;
• (h) —CONR2—;
• (i) —NR2CO—;
• (j)
• or
• (k) —C≡C—;
• R is hydrogen or C1-C6 alkyl;
• R2 and R3 are independently
• (a) hydrogen;
• or
• (b) C1-C4 alkyl;
• R4 is
• (a) hydrogen;
• (b) halogen;
• (c) C1-C6 alkyl;
• (d) C1-C4alkoxy;
• (e) C1-C4 acyloxy;
• (f) C1-C4 alkylthio;
• (g) C1-C4 alkylsulfinyl;
• (h) C1-C4 alkylsulfonyl;
• (i) hydroxy (C1-C4)alkyl;
• (j) aryl (C1-C4)alkyl;
• (k) —CO2H;
• (l) —CN;
• (m) —CONHOR;
• (n) —SO2NHR;
• (o) —NH2;
• (p) C1-C4 alkylamino;
• (q) C1-C4 dialkylamino;
• (r) —NHSO2R;
• (s) —NO2;
• (t) -aryl;
• or
• (u) —OH,
• R5 and R6 are independently C1-C8 alkyl or together form a C3-C10 carbocyclic ring;
• R7 and R8 are independently
• (a) phenyl;
• (b) a C3-C10 carbocyclic ring, saturated or unsaturated;
• (c) a C3-C10 heterocyclic ring containing up to two heteroatoms, selected from —O—, —N— and —S—;
• (d) H;
• (e) C1-C6 alkyl;
• or
• (f) form a 3 to 8 membered nitrogen containing ring with R5 or R6;
• R7 and R8 in either linear or ring form may optionally be substituted with up to three substituents independently selected from C1-C6 alkyl, halogen, alkoxy, hydroxy and carboxy;
• a ring formed by R7 and R8 may be optionally fused to a phenyl ring;
• e is 0, 1 or 2;
• m is 1, 2 or 3;
• n is 0, 1 or 2;
• p is 0, 1, 2 or 3;
• q is 0, 1, 2 or 3;
• and optical and geometric isomers thereof;
• comprising enzymatically resolving of a compound of the formula
• wherein R1 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl wherein the alkyl, alkenyl or alkynyl groups are optionally substituted by one to three halo in the presence of a lipase and an aqueous buffer solution;
• and (b) reacting the compound of formula IV so formed
• wherein R1 is as defined above, with a base in the presence of a polar protic solvent.