Process and intermediates for growth hormone secretagogues

A process for preparing a compound of Formula Ill,

• 30
• wherein
• Pt is an amine protecting group;
• R2 is hydrogen, (C1-C8)alkyl, —(C0-C3)alkyl-(C3-C8)cycloalkyl, —(C1-C4)alkyl-A1 or A1;
• A1 for each occurrence is independently selected from the group consisting of (C5-C7)cycloalkenyl, phenyl, a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen and a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
• A1 for each occurrence is independently optionally substituted, on one or optionally both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3, OCH3, —OX6, —C(O)N(X6)(X6), —C(O)OX6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, —S(O)m(C1-C6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, —N(X6)(X6), —N(X6)C(O)(X6), —S(O)2N(X6)(X6), —N(X6)S(O)2-phenyl, —N(X6)S(O)2X6, —CONX11X12, —S(O)2NX11X12, —NX6S(O)2X12, —NX6CONX11X12, —NX6S(O)2NX11X12, —NX6C(O)X12, imidazolyl, thiazolyl and tetrazolyl, provided that if A1 is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy;
• where X11 is hydrogen or optionally substituted (C1-C6)alkyl;
• the optionally substituted (C1-C6)alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, (C1-C6)alkoxycarbonyl, —S(O)m(C1-C6)alkyl, 1 to 5 halo groups, 1 to 3 hydroxy groups, 1 to 3 (C1-C10)alkanoyloxy groups or 1 to 3 (C1-C6)alkoxy groups;
• X12 is hydrogen, (C1-C6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X12 is not hydrogen, the X12 group is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH3, OCH3, OCF3 and CF3;
• or X11 and X12 are taken together to form —(CH2)r-L1-(CH2)r—;
• L1 is C(X2)(X2), O, S(O)m or N(X2);
• X6 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl, (C2-C6)halogenated alkyl, optionally substituted (C3-C7)cycloalkyl, (C3-C7)-halogenated cycloalkyl, where optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X6 is optionally independently mono- or di-substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, CONH2, —S(O)m(C1-C6)alkyl, carboxylate (C1-C4)alkyl ester or 1H-tetrazol-5-yl;
• or
• when there are two X6 groups on one atom and both X6 are independently (C1-C6)alkyl, the two (C1-C6)alkyl groups may be optionally joined and, together with the atom to which the two X6 groups are attached, form a 4- to 9- membered ring optionally having oxygen, sulfur or NX7 as a ring member;
• r for each occurrence is independently 1, 2 or 3;
• comprising reacting a compound of Formula IV,
• 31
• wherein R3 is (C1-C4)alkyl and Pt is as defined above,
• with a preformed isocyanate or a carbonyl equivalent and R2NH2, wherein R2 is as defined hereinabove, in a reaction inert solvent for about one hour to about 72 hours at a temperature of about 0° C. to about 80° C.

A process for preparing a compound of Formula I,

• 32
• wherein
• R1 is —(CH2)qN(X5)C(O)X6, —(CH2)qN(X6)C(O)(CH2)t-A1, —(CH2)qN(X6)S(O)2(CH2)t-A1, —(CH2)qN(X6)S(O)2X6, —(CH2)qN(X6)C(O)N(X6)C(O)N(X6)(CH2)t-A1;
• —(CH2)qN(X6)C(O)N(X6)(X6), —(CH2)qC(O)N(X6)(X6), —(CH2)qC(O)N(X6)(CH2)t-A1, —(CH2)qC(O)OX6, —(CH2)qC(O)O(CH2)t-A1, —(CH2)qOX6, —(CH2)qOC(O)X6, —(CH2)qOC(O)(CH2)t-A1, —(CH2)qOC(O)N(X6)(CH2)t-A1, —(CH2)qOC(O)N(X6)(X6), —(CH2)qC(O)X6, —(CH2)qC(O)(CH2)t-A1, —(CH2)qN(X6)C(O)OX6, —(CH2)qN(X6)S(O)2N(X6)(X6), —(CH2)qS(O)mX6, —(CH2)qS(O)m(CH2)t-A1, —(C1-C10)alkyl, —(CH2)q-A1, —(CH2)q-(C3-C7)cycloalkyl, —(CH2)q—Y1—(C1-C6)alkyl, —(CH2)q—Y1—(CH2)t-A1, or —(CH2)q—Y1—(CH2)t—(C3-C7)cycloalkyl;
• where the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, —CONH2, —S(O)m(C1 -C6)alkyl, —CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups;
• Y1 is O, S(O)m, —C(O)NX6—, —CH═CH—, —C═C—, —N(X6)C(O)—, —C(O)NX6—;
• —C(O)O—, —OC(O)N(X6)— or —OC(O)—;
• q is 1, 2, 3 or 4;
• t is 0, 1, 2 or 3;
• said (CH2)q group and (CH2)t group in the definition of R1 are optionally independently substituted with hydroxy, (C1-C4)alkoxy, carboxyl, —CONH2, —S(O)m(C1-C6)alkyl, —CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro groups or 1 or 2 (C1-C4)alkyl groups;
• and
• R2 is hydrogen, (C1-C8)alkyl, —(C0-C3)alkyl-(C3-C8)cycloalkyl, —(C1-C4)alkyl-A1 or A1;
• where the alkyl groups and the cycloalkyl groups in the definition of R1 are optionally substituted with hydroxy, —C(O)OX6, —C(O)N(X6)(X6), —N(X6)(X6), —S(O)m(C1-C6)alkyl, —C(O)A1, —C(O)(X6), CF3, CN or 1, 2 or 3 independently selected halo groups;
• A1 for each occurrence is independently selected from the group consisting of (C5-C7)cycloalkenyl, phenyl, a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen and a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
• A1 for each occurrence is independently optionally substituted, on one or optionally both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3, OCH3, —OX6, —C(O)N(X6)(X6), —C(O)OX6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, —S(O)m(C1-C6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, —N(X6)(X6), —N(X6)C(O)(X6), —S(O)2N(X6)(X6), —N(X6)S(O)2-phenyl, —N(X6)S(O)2X6, —CONX11X12, —S(O)2NX11X12, —NX6S(O)2X12, —NX6CONX11X12, —NX6S(O)2NX11X12, —NX6C(O)X12, imidazolyl thiazolyl and tetrazolyl, provided that if A1 is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy;
• where X11 is hydrogen or optionally substituted (C1-C6)alkyl;
• the optionally substituted (C1-C6)alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, (C1-C6)alkoxycarbonyl, —S(O)m(C1-C6)alkyl, 1 to 5 halo groups, 1 to 3 hydroxy groups, 1 to 3 (C1-C10)alkanoyloxy groups or 1 to 3 (C1-C6)alkoxy groups;
• X12 is hydrogen, (C1-C6)alkyl, phenyl, thiazolyl, imidazolyl, furl or thienyl, provided that when X12 is not hydrogen, the X12 group is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH3, OCH3, OCF3 and CF3;
• or X11 and X12 are taken together to form —(CH2)r-L1-(CH2)r—;
• L1 is C(X2)(X2), O, S(O)m or N(X2);
• X6 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl, (C2-C6)halogenated alkyl, optionally substituted (C3-C7)cycloalkyl, (C3-C7)-halogenated cycloalkyl, where optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X6 is optionally independently mono- or di-substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, CONH2, —S(O)m(C1-C6)alkyl, carboxylate (C1-C4)alkyl ester or 1H-tetrazol-5-yl;
• or when there are two X6 groups on one atom and both X6 are independently (C1-C6)alkyl, the two (C1-C6)alkyl groups may be optionally joined and, together with the atom to which the two X6 groups are attached, form a 4- to 9- membered ring optionally having oxygen, sulfur or NX7 as a ring member;
• r for each occurrence is independently 1, 2 or 3;
• X2 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl or optionally substituted (C3-C7)cycloalkyl, where the optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X2 are optionally independently substituted with —S(O)m(C1-C6)alkyl, —C(O)OX3, 1 to 5 halo groups or 1-3 OX3 groups;
• X3 for each occurrence is independently hydrogen or (C1-C6)alkyl;
• X7 is hydrogen or (C1-C6)alkyl optionally substituted with hydroxy;
• m for each occurrence is independently 0, 1 or 2;
• provided that X6 and X12 cannot be hydrogen when attached to C(O) or S(O)2 in the form C(O)X6, C(O)X12, S(O)2X6 or S(O)2X12;
• and
• Pt is an amine protecting group;
• comprising reacting a compound of Formula III,
• 33
• wherein Pt and R2 are as defined hereinabove,
• with an alkylating agent of formula R1-Z, wherein R1 is as defined hereinabove and Z is a leaving group, in the presence of a suitable base and a reaction inert solvent.

A process for preparing a compound of Formula V,

• 34
• wherein
• R1 is —(CH2)qN(X6)C(O)X6, —(CH2)qN(X6)C(O)(CH2)t-A1, —(CH2)qN(X6)S(O)2(CH2)t-A1, —(CH2)qN(X6)S(O)2X6, —(CH2)qN(X6)(CH2)t-A1, —(CH2)qN(X6)C(O)N(X6)(X6), —(CH2)qC(O)N(X6)(X6), —(CH2)qC(O)N(X6)(CH2)t-A1, —(CH2)qC(O)OX6, —(CH2)qC(O)O(CH2)t-A1, —(CH2)qOX6, —(CH2)qOC(O)X6, —(CH2)qOC(O)(CH2)t-A1, —(CH2)qOC(O)N(X6)(CH2)t-A1, —(CH2)qOC(O)N(X6)(X6), —(CH2)qC(O)X6, —(CH2)qC(O)(CH2)t-A1, —(CH2)qN(X6)C(O)OX6, —(CH2)qN(X6)S(O)2N(X6)(X6), —(CH2)qS(O)mX6, —(CH2)qS(O)m(CH2)t-A1, —(C1-C10)alkyl, —(CH2)q-A1, —(CH2)q—(C3-C7)cycloalkyl, —(CH2)q—Y1—(C1-C6)alkyl, —(CH2)q—Y1—(CH2)t-A1 or —(CH2)q—Y—(CH2)t—(C1-C7)cycloalkyl;
• where the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, —CONH2, —S(O)m(C1-C6)alkyl, —CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups;
• Y1 is O, S(O)m, —C(O)NX6—, —CH═CH—, —C≡C—, —N(X6)C(O)—, —C(O)NX6—, —C(O)O—, —OC(O)N(X6)— or —OC(O)—;
• q is 1, 2, 3 or 4;
• t is 0, 1, 2 or 3;
• said (CH2)q group and (CH2)t group in the definition of R1 are optionally independently substituted with hydroxy, (C1-C4)alkoxy, carboxyl, —CONH2, —S(O)m(C1-C6)alkyl, —CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro groups or 1 or 2 (C1-C4)alkyl groups;
• and
• R2 is hydrogen, (C1-C8)alkyl, —(C0-C3)alkyl-(C3-C8)cycloalkyl, —(C1-C4)alkyl-A1 or A1;
• where the alkyl groups and the cycloalkyl groups in the definition of R1 are optionally substituted with hydroxy, —C(O)OX6, —C(O)N(X6)(X6), —N(X6)(X6), —S(O)m(C1-C6)alkyl, —C(O)A1, —C(O)(X6), CF3, CN or 1, 2 or 3 independently selected halo groups;
• A1 for each occurrence is independently selected from the group consisting of (C5-C7)cycloalkenyl, phenyl, a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen and a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
• A1 for each occurrence is independently optionally substituted, on one or optionally both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3, OCH3, —OX6, —C(O)N(X6)(X6), —C(O)OX6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, —S(O)m(C1-C6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, —N(X6)(X6), —N(X6)C(O)(X6), —S(O)2N(X6)(X6), —N(X6)S(O)2-phenyl, —N(X6)S(O)2X6, —CONX11X12, —S(O)2NX11X12, —NX6S(O)2X12, —NX6CONX11X12, —NX6S(O)2NX11X12, —NX6C(O)X12, imidazolyl, thiazolyl and tetrazolyl, provided that if A1 is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy;
• where X11 is hydrogen or optionally substituted (C1-C6)alkyl;
• the optionally substituted (C1-C6)alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, (C1-C6)alkoxycarbonyl, —S(O)m(C1-C6)alkyl, 1 to 5 halo groups, 1 to 3 hydroxy groups, 1 to 3 (C1-C10)alkanoyloxy groups or 1 to 3 (C1-C6)alkoxy groups;
• X12 is hydrogen, (C1-C6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X12 is not hydrogen, the X12 group is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH3, OCH3, OCF3 and CF3;
• or X11 and X12 are taken together to form —(CH2)r-L1-(CH2)r—;
• L1 is C(X2)(X2), O, S(O)m or N(X2);
• X6for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl, (C2-C6)halogenated alkyl, optionally substituted (C3-C7)cycloalkyl, (C3-C7)-halogenated cycloalkyl, where optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X6 is optionally independently mono- or di-substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, CONH2, —S(O)m(C1-C6)alkyl, carboxylate (C1-C4)alkyl ester or 1H-tetrazol-5-yl;
• or when there are two X6 groups on one atom and both X6 are independently (C1-C6)alkyl, the two (C1-C6)alkyl groups may be optionally joined and, together with the atom to which the two X6 groups are attached, form a 4- to 9- membered ring optionally having oxygen, sulfur or NX7 as a ring member;
• r for each occurrence is independently 1, 2 or 3;
• X2 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl or optionally substituted (C3-C7)cycloalkyl, where the optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X2 are optionally independently substituted with —S(O)m(C1-C6)alkyl, —C(O)OX3, 1 to 5 halo groups or 1-3 OX3 groups;
• X3 for each occurrence is independently hydrogen or (C1-C6)alkyl;
• X7 is hydrogen or (C1-C6)alkyl optionally substituted with hydroxy;
• m for each occurrence is independently 0, 1 or 2;
• provided that X6 and X12 cannot be hydrogen when attached to C(O) or S(O)2 in the form C(O)X6, C(O)X12, S(O)2X6 or S(O)2X12;
• comprising reacting a compound of Formula I,
• 35
• wherein
• Pt is an amine protecting group and R1 and R2 are as defined hereinabove;
• with an acid in the presence of a reaction inert solvent.

A process for preparing a compound of Formula XIII,

• 36
• comprising:
• (a) reacting piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-(C1-C4)alkyl ester with a carbonyl equivalent and 2,2,2-trifluoroethylamine in the presence of a reaction inert solvent to form the compound of Formula XIV,
• 37
• (b) reacting said compound of Formula XIV with 2-picolyl-Z1, wherein Z1 is halo, methanesulfonyloxy or p-toluenesulfonyloxy, in the presence of a base and a reaction inert solvent to form the compound of Formula XV
• 38
• (c) reacting said compound of Formula XV with an acid in the presence a reaction inert solvent.

A process for preparing a compound of Formula VI,

• 39
• comprising
• (a) reacting a compound of Formula IV,
• 40
• wherein Pt is an amine protecting group and R3 is (C1-C4)alkyl,
• with a carbonyl equivalent and CF3CH2NH2 in a reaction inert solvent to form a compound of Formula VII,
• 41
• wherein Pt is as defined hereinabove;
• (b) reacting said compound of Formula VII with 2-picolyl-Z1, wherein Z1 is halo, methanesulfonyloxy or p-toluenesulfonyloxy, in the presence of a base and a reaction inert solvent at a temperature from about −78° C. to about 25° C. for from about one hour to about 24 hours to form a compound of Formula VIII,
• 42
• (c) reacting said compound of Formula VII with a suitable acid in a reaction inert solvent at a temperature from about −30° C. to about 25° C. for from about one hour to about 10 hours to form a compound of Formula IX,
• 43
• (d) resolving said compound of Formula IX with D-tartaric acid in a reaction inert solvent to form the D-tartrate salt of a compound of Formula X,
• 44
• (e) reacting said D-tartrate salt of a compound of Formula X with a compound of Formula XI,
• 45
• wherein Boc is tert-butyloxycarbonyl, a peptide coupling reagent and a base in a reaction inert solvent to form a compound of Formula XII,
• 46
• (f) reacting said compound of Formula XII under standard t-butyloxycarbonyl group removing conditions to form a compound of Formula VI,
• 47