Process for the syntheses of triazoles

A process for preparing a compound (I) having the formula

• comprising the steps of:
• (Step 1) combining a compound (II) having the formula:
• with a compound (III) having the formula:
• X—N3 Compound (III)
• in a solvent, optionally in the presence of a copper catalyst, to form a compound (IV) having the formula:
• (Step 2) combining a compound (IV) with a compound (V) having the formula:
• in a solvent in the presence of a reducing agent to form a compound (VI) having the formula:
• (Step 3) combining compound (VI) with a compound (VII) having the formula:
• in a solvent in the presence of a base and a palladium catalyst to form a compound (VIII) having the formula:
• (Step 4) heating a compound (VIII), in a solvent in the presence of an acid, followed by the addition of a neutralizing agent to form a compound (I);
• wherein:
• A is selected from:
• phenyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl;
• B is selected from:
• phenyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl;
• Het-CH2—R3 is selected from:
• Q is a borane having the formula —BY2, wherein:
• Y, at each occurrence, independently is selected from:
• a) —OH, b) —OC1-6 alkyl, c) —OC2-6 alkenyl, d) —OC2-6 alkynyl, e) —OC1-14 saturated, unsaturated, or aromatic carbocycle, f) C1-6 alkyl, g) C2-6 alkenyl, h) C2-6 alkynyl, and i) C1-14 saturated, unsaturated, or aromatic carbocycle,
• wherein any of b)-i) optionally is substituted with one or more halogens;
• alternatively, two Y groups taken together comprise a chemical moiety selected from:
• a) —OC(R4)(R4)C(R4)(R4)O—, and b) —OC(R4)(R4)CH2C(R4)(R4)O—;
• alternatively, Q is a BF3 alkali metal salt, a BF3 ammonium salt, a BF3 tetralkyl ammonium salt, a BF3 phosphate salt, or 9-borabicyclo[3.3.1]nonane;
• X is selected from:
• a) —CH2-phenyl, b) —SO-phenyl, c) —SO2-phenyl, d) —CH2—O-phenyl, e) —CH2—O—CH2-phenyl, f) —CH2—O—R21, g) —Si—(R21)3, and h) —P(O)—(W)2,
• wherein each W is independently C1-6 alkyl or phenyl;
• each R21 is independently C1-6 alkyl;
• each phenyl in a), b), c), d), e), or h) is optionally substituted with one or more R12, wherein R12 is selected from the group consisting of a) F, b) Cl, c) Br, d) I, e) —CF3, f) —OR22, g) —CN, h) —NO2, i) —NR22R22, j) —C(O)R22, k) —C(O)OR22, l) —OC(O)R22, m) —C(O)NR22R22, n) —NR22C(O)R22, o) —OC(O)NR22R22, p) —NR22C(O)OR22, q) —NR22C(O)NR22R22, r) —C(S)R22 s) —C(S)OR22, t) —OC(S)R22, u) —C(S)NR22R22, v) —NR22C(S)R22, w) —OC(S)NR22R22, x) —NR22C(S)OR22, y) —NR22C(S)NR22R22, z) —C(NR22)R22, aa) —C(NR22)OR22, bb) —OC(NR22)R22, cc) —C(NR22)NR22R22, dd) —NR22C(NR22)R22, ee) —OC(NR22)NR22R22, ff) —NR22C(NR22)OR22, gg) —NR22C(NR22)NR22R22, hh) —S(O)pR22, ii) —SO2NR22R22 and jj) R22, wherein each R22 is independently, H or C1-6 alkyl;
• Z is selected from:
• a) I, b) Br, c) Cl, d) R9OSO3-, and e) N2BF4;
• R1, at each occurrence, independently is selected from:
• a) F, b) Cl, c) Br, d) I, e) —CF3, f) —OR4, g) —CN, h) —NO2, i) —NR4R4, j) —C(O)R4, k) —C(O)OR4, l) —OC(O)R4, m) —C(O)NR4R4, n) —NR4C(O)R4, o) —OC(O)NR4R4, p) —NR4C(O)OR4, q) —NR4C(O)NR4R4, r) —C(S)R4, s) —C(S)OR4, t) —OC(S)R4, u) —C(S)NR4R4, v) —NR4C(S)R4, w) —OC(S)NR4R4, x) —NR4C(S)OR4, y) —NR4C(S)NR4R4, z) —C(NR4)R4, aa) —C(NR4)OR4, bb) —OC(NR4)R4, cc) —C(NR4)NR4R4, dd) —NR4C(NR4)R4, ee) —OC(NR4)NR4R4, ff) —NR4C(NR4)OR4, gg) —NR4C(NR4)NR4R4, hh) —S(O)pR4, ii) —SO2NR4R4, and jj) R4;
• R2, at each occurrence, independently is selected from:
• a) F, b) Cl, c) Br, d) I, e) —CF3, f) —OR4, g) —CN, h) —NO2, i) —NR4R4, j) —C(O)R4, k) —C(O)OR4, l) —OC(O)R4, m) —C(O)NR4R4, n) —NR4C(O)R4, o) —OC(O)NR4R4, p) —NR4C(O)OR4, q) —NR4C(O)NR4R4, r) —C(S)R4, s) —C(S)OR4, t) —OC(S)R4, u) —C(S)NR4R4, v) —NR4C(S)R4, w) —OC(S)NR4R4, x) —NR4C(S)OR4, y) —NR4C(S)NR4R4, z) —C(NR4)R4, aa) —C(NR4)OR4, bb) —OC(NR4)R4, cc) —C(NR4)NR4R4, dd) —NR4C(NR4)R4, ee) —OC(NR4)NR4R4, ff) —NR4C(NR4)OR4, gg) —NR4C(NR4)NR4R4, hh) —S(O)pR4, ii) —SO2NR4R4, and jj) R4;
• R3 is selected from:
• a) —OR4, b) —NR4R4, c) —C(O)R4, d) —C(O)OR4, e) —OC(O)R4, f) —C(O)NR4R4, g) —NR4C(O)R4, h) —OC(O)NR4R4, i) —NR4C(O)OR4, j) —NR4C(O)NR4R4, k) —C(S)R4, l) —C(S)OR4, m) —OC(S)R4, n) —C(S)NR4R4, o) —NR4C(S)R4, p) —OC(S)NR4R4, q) —NR4C(S)OR4, r) —NR4C(S)NR4R4, s) —C(NR4)R4, t) —C(NR4)OR4, u) —OC(NR4)R4, v) —C(NR4)NR4R4, w) —NR4C(NR4)R4, x) —OC(NR4)NR4R4, y) —NR4C(NR4)OR4, z) —NR4C(NR4)NR4R4, aa) —S(O)pR4, bb) —SO2NR4R4, and cc) R4;
• R4, at each occurrence, independently is selected from:
• a) H, b) —OR6, c) C1-6 alkyl, d) C2-6 alkenyl, e) C2-6 alkynyl, f) C3-14 saturated, unsaturated, or aromatic carbocycle, g) 3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur, h) —C(O)—C1-6 alkyl, i) —C(O)—C2-6 alkenyl, j) —C(O)—C2-6 alkynyl, k) —C(O)—[C3-14 saturated, unsaturated, or aromatic carbocycle], l) —C(O)-[3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur], m) —C(O)O —C1-6 alkyl, n) —C(O)O—C2-6 alkenyl, o) —C(O)O—C2-6 alkynyl, p) —C(O)O—C3-14 saturated, unsaturated, or aromatic carbocycle, and q) —C(O)O-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur,
• wherein any of c)-q) optionally is substituted with one or more R5 groups;
• R5, at each occurrence, is independently selected from:
• a) F, b) Cl, c) Br, d) I, e) ═O, f) ═S, g) ═NR6, h) ═NOR6, i)═N—NR6R6, j) —CF3, k) —OR6, l) —CN, m) —NO2, n) —NR6R6, o) —C(O)R6, p) —C(O)OR6, q) —OC(O)R6, r) —C(O)NR6R6, s) —NR6C(O)R6, t) —OC(O)NR6R6, u) —NR6C(O)OR6, v) —NR6C(O)NR6R6, w) —C(S)R6, x) —C(S)OR6, y) —OC(S)R6, z) —C(S)NR6R6, aa) —NR6C(S)R6, bb) —OC(S)NR6R6, cc) —NR6C(S)OR6, dd) —NR6C(S)NR6R6, ee) —C(NR6)R6, ff) —C(NR6)OR6, gg) —OC(NR6)R6, hh) —C(NR6)NR6R6, ii) —NR6C(NR6)R6, jj) —OC(NR6)NR6R6, kk) —NR6C(NR6)OR6, ll) —NR6C(NR6)NR6R6, m) —S(O)pR6, m) —SO2NR6R6, oo) —N3, pp) —Si(CH3)3, qq) —O—Si(CH3)3, m) —Si(C2H5)2CH3, ss) —O—Si(C2Hs)2CH3, and tt) R6;
• R6, at each occurrence, independently is selected from:
• a) H, b) —OR8, c) C1-6 alkyl, d) C2-6 alkenyl, e) C2-6 alkynyl, f) C3-14 saturated, unsaturated, or aromatic carbocycle, g) 3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur, h) —C(O)—C1-6 alkyl, i) —C(O)—C2-6 alkenyl, j) —C(O)—C2-6 alkynyl, k) —C(O)—C3-14 saturated, unsaturated, or aromatic carbocycle, l) —C(±)-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur, m) —C(O)O—C1-6 alkyl, n) —C(O)O—C2-6 alkenyl, o) —C(O)O—C2-6 alkynyl, p) —C(O)O—C3-14 saturated, unsaturated, or aromatic carbocycle, and q) —C(O)O-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur,
• wherein any of c)-q) optionally is substituted with one or more R7 groups;
• R7, at each occurrence, independently is selected from:
• a) F, b) Cl, c) Br, d) I, e) ═O, f) ═S, g) ═NR8, h) ═NOR8, i) ═N—NR8R8, j) —CF3, k) —OR8, l) —CN, m) —NO2, n) —NR8R8, o) —C(O)R8, p) —C(O)OR8, q) —OC(O)R8, r) —C(O)NR8R8, s) —NR8C(O)R8, t) —OC(O)NR8R8, u) —NR C(O)OR8, v) —NR8C(O)NR8R8, w) —C(S)R8, x) —C(S)OR8, y) —OC(S)R8, z) —C(S)NR8R8, aa) —NR C(S)R8, bb) —OC(S)NR8R8, cc) —NR8C(S)OR8, dd) —NR8C(S)NR8R8, ee) —C(NR8)R8, ff) —C(NR8)OR8, gg) —OC(NR8)R8, hh) —C(NR8)NR8R8, ii) —NR C(NR8)R8, jj) —OC(NR8)NR8R8, kk) —NR C(NR8)OR8, ll) —NR C(NR8)NR8R8, m) —S(O)pR8, m) —SO2NR8R8, oo) C1-6 alkyl, pp) C2-6 alkenyl, qq) C2-6 alkynyl, m) C3-14 saturated, unsaturated, or aromatic carbocycle, and ss) 3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur,
• wherein any of oo)-ss) optionally is substituted with one or more moieties selected from R8, F, Cl, Br, I, —CF3, —OR8, —SR8, —CN, —NO2, —NR8R8, —C(O)R8, —C(O)OR8, —OC(O)R8, —C(O)NR8R8, —NR8C(O)R8, —OC(O)NR8R8, —NR8C(O)OR8, —NR C(O)NR8R8, —C(S)R8, —C(S)OR8, —OC(S)R8, —C(S)NR8R8, —NR8C(S)R8, —OC(S)NR8R8, —NR8C(S)OR, —NR8C(S)NR8R8, —C(NR8)R8, —C(NR8)OR8, —OC(NR8)R8, —C(NR8)NR8R8, —NR8C(NR8)R8, —OC(NR8)NR8R8, —NR8C(NR8)OR8, —NR8C(NR)NR8R8, —SO2NR8R8, and —S(O)pRS;
• R8, at each occurrence, independently is selected from:
• a) H, b) an amine protecting group, c) C1-6 alkyl, d) C2-6 alkenyl, e) C2-6 alkynyl, f) C3-14 saturated, unsaturated, or aromatic carbocycle, g) 3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur, h) —C(O)—C1-6 alkyl, i) —C(O)—C2-6 alkenyl, j) —C(O)—C2-6 alkynyl, k) —C(O)—C3-14 saturated, unsaturated, or aromatic carbocycle, l) —C(O)-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur, m) —C(O)O—C1-6 alkyl, n) —C(O)O—C2-6 alkenyl, o) —C(O)O—C2-6 alkynyl, p) —C(O)O—C3-14 saturated, unsaturated, or aromatic carbocycle, and q) —C(O)O-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from nitrogen, oxygen, and sulfur,
• wherein any of c)-q) optionally is substituted with one or more moieties selected from F, Cl, Br, I, —CF3, —OH, —OC1-6 alkyl, —SH, —SC1-6 alkyl, —CN, —NO2, —NH2, —NHC1-6 alkyl, —N(C1-6 alkyl)2, —C(O)C1-6 alkyl, —C(O)OC1-6 alkyl, —C(O)NH2, —C(O)NHC1-6 alkyl, —C(O)N(C1-6 alkyl)2, —NHC(O)C1-6 alkyl, —SO2NH2—, —SO2NHC1-6 alkyl, —SO2N(C1-6 alkyl)2, and —S(O)pC1-6 alkyl;
• R9 is selected from:
• a) C1-6 alkyl, b) phenyl, and c) toluoyl, wherein any of a)-c) optionally is substituted with one or more moieties selected from F, Cl, Br, and I;
• R10 is selected from H and C1-8 alkyl;
• R11 is selected from H and C1-8 alkyl;
• m is 0, 1, 2, 3, or 4;
• n is 0, 1, 2, 3, or 4;
• p, at each occurrence, independently is 0, 1, or 2;
• s is 1, 2, 3, 4, 5, or 6;
• and
• t is 0, 1, 2, 3, 4, 5, or 6,
• wherein —(CH2)s— and —(CH2)t, other than when t is 0, are optionally substituted on any carbon atom thereof by one or more moieties selected from a) C1-6 alkyl, b) C1-6 alkenyl, c) phenyl, d) hydroxyl, e) C1-6 alkoxy, f) F, g) Cl, h) Br, i) I, j) ═O, and k) benzyl.