Process and intermediates for synthesis of peptide compounds

A process for preparing a dipyrrolidine peptide compound or a pharmaceutically acceptable salt, stereoisomer, metabolite, or hydrate thereof, comprising the steps:

• a) contacting a compound of Formula IX, or a salt thereof:
• with a carbamate-cleaving reagent to produce a compound of Formula XI, or a salt thereof:
• b) contacting a compound of Formula X, or a salt thereof:
• with an activating reagent and the compound of Formula XI, or a salt thereof, in the presence of at least one solvent to produce a compound of Formula XIIa, or a salt thereof:
• and
• c) contacting the compound of Formula XIIa, or a salt thereof, with a silyl ether cleaving reagent to produce a compound of Formula XII, or a salt thereof:
• and
• d) contacting the compound of Formula XII, or a salt thereof, with a carbamate-cleaving reagent to produce a compound of Formula XIII, or a salt thereof:
• wherein:
• R1 and R2 may be independently selected from the group consisting of hydrogen;
• halogen;
• hydroxyl;
• substituted or unsubstituted C1-6alkyl;
• substituted or unsubstituted C1-6alkoxy;
• and substituted or unsubstituted aryl;
• or R1 and R2, together with the atoms to which they are attached, form a substituted or unsubstituted 4-6 membered heterocyclic or cycloalkyl ring;
• R4, R5, and R12 may be independently —C1-6alkylene-phenyl, wherein C1-6alkylene is optionally substituted by one or more substituents each independently selected from Rf;
• R6 and R7 may be independently selected from the group consisting of hydrogen;
• halogen;
• hydroxyl;
• substituted or unsubstituted C1-6alkyl;
• substituted or unsubstituted C1-6alkoxy;
• and substituted or unsubstituted aryl:
• or R6 and R7, together with the atoms to which they are attached, form a substituted or unsubstituted 4-6 membered heterocyclic or cycloalkyl ring;
• R8 and R9 may be independently selected from the group consisting of hydrogen;
• halogen;
• C1-6alkyl;
• C2-6alkenyl;
• C2-6alkynyl;
• C3-6cycloalkyl;
• phenyl;
• naphthyl;
• heteroaryl;
• heterocyclyl;
• C3-6cycloalkyl-C1-6alkyl-;
• phenyl-C1-6alkylene-;
• naphthyl-C1-6alkylene-;
• heteroaryl-C1-6alkylene-;
• and heterocyclyl-C1-6alkylene-;
• —ORx;
• —NO2;
• —N3;
• —CN;
• —SCN;
• —SRx;
• —C(O)Rx;
• —CO2(Rx);
• —C(O)N(Rx)2;
• —C(NRx)N(Rx)2;
• —OC(O)Rx;
• —OCO2R′;
• —OC(O)N(Rx)2;
• —N(Rx)2;
• —SORx;
• —S(O)2Rx;
• —NRxC(O)Rx;
• —NRxC(O)N(Rx)2;
• —NRxC(O)ORx;
• —NRxC(NRx)N(Rx)2;
• and —C(Rx)3;
• wherein heteroaryl is a 5-6 membered ring having one, two, or three heteroatoms each independently selected from N, O, or S;
• wherein heteroaryl is optionally substituted with one or more substituents each independently selected from Rb;
• wherein heterocyclyl is a 4-7 membered ring optionally substituted by one or more substituents each independently selected from Rc;
• wherein when heterocyclyl contains a —NH— moiety, that —NH— moiety is optionally substituted by Rd;
• wherein C2-6alkenyl and C2-6alkynyl are each independently optionally substituted by one or more substituents each independently selected from Re;
• wherein C1-6alkyl and C1-6alkylene are each independently optionally substituted by one or more substituents each independently selected from Rf;
• wherein C3-6cycloalkyl is independently optionally substituted by one or more substituents each independently selected from Rg;
• R8a and R9a may be independently selected from the group consisting of hydrogen;
• halogen;
• C1-6alkyl;
• C2-6alkenyl;
• C2-6alkynyl;
• C3-6cycloalkyl;
• phenyl:
• naphthyl;
• heteroaryl;
• heterocyclyl;
• C3-6cycloalkyl-C1-6alkyl-;
• phenyl-C1-6alkylene-;
• naphthyl-C1-6alkylene-;
• heteroaryl-C1-6alkylene-;
• and heterocyclyl-C1-6alkylene-;
• —ORx;
• —ORy, —NO2;
• —N3:
• —CN;
• —SCN;
• —SRx;
• —C(O)Rx;
• —CO2(Rx);
• —C(O)N(Rx)2;
• —C(NRx)N(Rx)2;
• —OC(O)Rx;
• —OCO2Rx;
• —OC(O)N(Rx)2;
• —N(Rx)2:
• —SORx;
• —S(O)2Rx;
• —NRxC(O)Rx;
• —NRC(O)N(Ry)2;
• —NRxC(O)ORx;
• —NRxC(NRx)N(Rx)2;
• and —C(Rx)3;
• wherein heteroaryl is a 5-6 membered ring having one, two, or three heteroatoms each independently selected from N, O, or S;
• wherein heteroaryl is optionally substituted with one or more substituents each independently selected from Rb;
• wherein heterocyclyl is a 4-7 membered ring optionally substituted by one or more substituents each independently selected from Rc;
• wherein when heterocyclyl contains a —NH— moiety, that —NH— moiety is optionally substituted by Rd;
• wherein C2-6alkenyl and C2-6alkynyl are each independently optionally substituted by one or more substituents each independently selected from Re;
• wherein C1-6alkyl and C1-6alkylene are each independently optionally substituted by one or more substituents each independently selected from Rf;
• wherein C3-6cycloalkyl is independently optionally substituted by one or more substituents each independently selected from Rg;
• wherein one of R8a or R9a is —ORy;
• R10 and R11 are independently selected from the group consisting of hydrogen;
• C1-6alkyl;
• —C(O)—C1-6alkylene;
• —C(O)—O—C1-6alkylene;
• and —C(O)-phenyl;
• wherein C1-6alkyl, C1-6alkylene, and phenyl are optionally independently substituted by one or more substituents selected from Ra;
• R13 is selected from hydrogen or benzyl;
• Rb may be selected, independently for each occurrence, from the group consisting of halogen;
• hydroxyl;
• —NO2;
• —N3;
• —CN;
• —SCN;
• C1-4alkyl;
• C2-6alkenyl;
• C2-6alkynyl;
• C3-6cycloalkyl;
• C1-6alkoxy;
• C3-6alkenyloxy;
• C3-6alkynyloxy;
• C3-6cycloalkoxy;
• C1-6alkyl-S(O)w—, where w is 0, 1, or 2;
• C1-6alkylC3-6cycloalkyl-;
• C3-6cycloalkyl-C1-6alkyl-;
• C1-6alkoxycarbonyl-N(Ra)—;
• C1-6alkylN(Ra)—;
• C1-6alkyl-N(Ra)carbonyl-;
• RaRa′N—;
• RaRa′N-carbonyl-;
• RaRa′N-carbonyl-N(Ra);
• RaRa′N—SO2—;
• and C1-6alkyl-carbonyl-N(Ra)—;
• Ra and Ra′ may be selected, independently for each occurrence, from the group consisting of hydrogen and C1-6alkyl, or Ra and Ra′ when taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein C1-6alkyl is optionally substituted by one or more substituents each independently selected from the group consisting of halogen, oxo, and hydroxyl, and wherein the heterocyclic ring is optionally substituted by one or more substituents each independently selected from the group consisting of halogen, alkyl, oxo, or hydroxyl;
• Re may be selected, independently for each occurrence, from the group consisting of halogen;
• hydroxyl;
• —NO2;
• —N3;
• —CN;
• —SCN;
• oxo;
• C1-6alkyl;
• C2-6alkenyl;
• C2-6alkynyl;
• C3-6cycloalkyl;
• C1-6alkoxy;
• C3-6alkenyloxy;
• C3-6alkynyloxy;
• C3-6cycloalkoxy;
• C1-6alkyl-S(O)w—, where w is 0, 1, or 2;
• C1-6alkylC3-6cycloalkyl-;
• C3-6cycloalkyl-C1-6alkyl-;
• C1-6alkoxycarbonyl-N(Ra)—;
• C1-6alkylN(Ra)—;
• C1-6alkyl-N(Ra)carbonyl-;
• RaRa′N—;
• RaRa′N-carbonyl-;
• RaRa′N-carbonyl-N(Ra)—;
• RaRa′N—SO2—;
• and C1-6alkyl-carbonyl-N(Ra)—;
• Rd may be selected, independently for each occurrence, from the group consisting of C1-6alkyl, C1-6alkylcarbonyl, and C1-6alkylsulfonyl, wherein C1-6alkyl is optionally substituted by one or more substituents each independently selected from halogen, hydroxyl, and RaRa′N—;
• Re may be selected, independently for each occurrence, from the group consisting of halogen;
• hydroxyl;
• —NO2;
• —N3;
• —CN;
• —SCN;
• C1-4alkoxy;
• C1-4alkoxycarbonyl;
• RaRa′N—;
• RaRa′N-carbonyl;
• RaRa′N—SO2—;
• and C1-4alkylS(O)w—, where w is 0, 1, or 2;
• Rf may be selected, independently for each occurrence, from the group consisting of halogen;
• hydroxyl;
• —NO2;
• —N3;
• —CN;
• —SCN;
• C1-4alkoxy;
• C1-4alkoxycarbonyl;
• RaRa′N—;
• RaRa′N-carbonyl;
• RaRa′N—SO2—;
• and C1-4alkylS(O)w—, where w is 0, 1, or 2;
• Rg may be selected, independently for each occurrence, from the group consisting of halogen, hydroxyl, —NO2;
• —N3;
• —CN;
• —SCN;
• C1-6alkyl;
• C1-4alkoxy;
• C1-4alkoxycarbonyl;
• RaRa′N—;
• RaRa′N-carbonyl;
• RaRa′N—SO2—;
• and C1-4alkylS(O)w—, where w is 0, 1, or 2;
• Rx is selected, independently, from the group consisting of hydrogen;
• halogen;
• C1-6alkyl;
• C2-6alkenyl;
• C2-6alkynyl;
• C3-6cycloalkyl;
• phenyl;
• naphthyl;
• heteroaryl;
• heterocyclyl;
• C3-6 cycloalkyl-C1-6alkyl-;
• phenyl-C1-6alkyl-;
• naphthyl-C1-6alkyl-;
• heteroaryl-C1-6alkyl-;
• and heterocyclyl-C1-6alkyl-;
• wherein heteroaryl is a 5-6 membered ring having one, two, or three heteroatoms each independently selected from N, O, or S;
• wherein heteroaryl is optionally substituted with one or more substituents each independently selected from Rb;
• wherein heterocyclyl is a 4-7 membered ring optionally substituted by one or more substituents each independently selected from Rc;
• wherein when heterocyclyl contains a —NH— moiety, that —NH— moiety is optionally substituted by Rd;
• wherein C2-6alkenyl and C2-6alkynyl, are each independently optionally substituted by one or more substituents each independently selected from Re;
• wherein C1-6alkyl is optionally substituted by one or more substituents each independently selected from Rf;
• wherein C3-6cycloalkyl is independently optionally substituted by one or more substituents each independently selected from Rg;
• and
• Ry is selected, independently, from the group consisting of alkylsilyl, arylsilyl and heteroarylsilyl, wherein the heteroaryl of heteroarylsilyl is a 5-6 membered ring having one, two, or three heteroatoms each independently selected from N, O, or S and optionally substituted with one or more substituents each independently selected from Rb;
• wherein the alkyl or aryl of the alkylsilyl or arylsilyl, respectively, is optionally substituted by one or more substituents each independently selected from R.

A compound represented by the Formula X, or a salt thereof:

• wherein:
• R8a and R9a may be independently selected from the group consisting of hydrogen;
• halogen;
• C1-6alkyl;
• C2-6alkenyl;
• C2-6alkynyl;
• C3-6cycloalkyl;
• phenyl;
• naphthyl;
• heteroaryl;
• heterocyclyl;
• C3-6cycloalkyl-C1-6alkyl-;
• phenyl-C1-6alkylene-;
• naphthyl-C1-6alkylene-;
• heteroaryl-C1-6alkylene-;
• and heterocyclyl-C1-6alkylene-;
• —ORx;
• —ORy, —NO2;
• —N3;
• —CN;
• —SCN;
• —SRx;
• —C(O)Rx;
• —CO2(Rx);
• —C(O)N(Rx)2;
• —C(NRx)N(Rx)2;
• —OC(O)Rx;
• —OCO2Rx;
• —OC(O)N(Rx)2;
• —N(Rx)2;
• —SORx;
• —S(O)2Rx;
• —NRxC(O)Rx;
• —NRxC(O)N(Rx)2;
• —NRxC(O)ORx;
• —NRxC(NRx)N(Rx)2;
• and —C(Rx)3;
• wherein heteroaryl is a 5-6 membered ring having one, two, or three heteroatoms each independently selected from N, O, or S;
• wherein heteroaryl is optionally substituted with one or more substituents each independently selected from Rb;
• wherein heterocyclyl is a 4-7 membered ring optionally substituted by one or more substituents each independently selected from Rc;
• wherein when heterocyclyl contains a —NH— moiety, that —NH— moiety is optionally substituted by Rd;
• wherein C2-6alkenyl and C2-6alkynyl are each independently optionally substituted by one or more substituents each independently selected from Re;
• wherein C1-6alkyl and C1-6alkylene are each independently optionally substituted by one or more substituents each independently selected from Rf;
• wherein C3-6cycloalkyl is independently optionally substituted by one or more substituents each independently selected from Rg;
• wherein one of R8a or R9a is —ORy;
• R11 is selected from the group consisting of hydrogen;
• C1-6alkyl;
• —C(O)—C1-6alkylene;
• —C(O)—O—C1-6alkylene;
• and —C(O)-phenyl;
• wherein C1-6alkyl, C1-6alkylene, and phenyl are optionally independently substituted by one or more substituents selected from R*;
• Rb is selected, independently for each occurrence, from the group consisting of halogen;
• hydroxyl;
• —NO2;
• —N3;
• —CN;
• —SCN;
• C1-6alkyl;
• C2-6alkenyl;
• C2-6alkynyl;
• C3-6cycloalkyl;
• C1-6alkoxy;
• C3-6alkenyloxy;
• C3-6alkynyloxy;
• C3-6cycloalkoxy;
• C1-6alkyl-S(O)w—, where w is 0, 1, or 2;
• C1-6alkylC3-6cycloalkyl-;
• C3-6cycloalkyl-C1-6alkyl-;
• C1-6alkoxycarbonyl-N(Ra)—;
• C1-6alkylN(Ra)—;
• C1-6alkyl-N(Ra)carbonyl-;
• RaRa′N—;
• RaRa′N-carbonyl-;
• RaRa′N-carbonyl-N(Ra)—;
• RaRa′N—SO2—;
• and C1-6alkyl-carbonyl-N(Ra)—;
• Ra and Ra′ is selected, independently for each occurrence, from the group consisting of hydrogen and C1-6alkyl, or Ra and Ra′ when taken together with the nitrogen to which they are attached form a 4-6 membered heterocyclic ring, wherein C1-6alkyl is optionally substituted by one or more substituents each independently selected from the group consisting of halogen, oxo, and hydroxyl, and wherein the heterocyclic ring is optionally substituted by one or more substituents each independently selected from the group consisting of halogen, alkyl, oxo, or hydroxyl;
• Rc is selected, independently for each occurrence, from the group consisting of halogen;
• hydroxyl;
• —NO2;
• —N3;
• —CN;
• —SCN;
• oxo;
• C1-6alkyl;
• C2-6alkenyl;
• C2-6alkynyl;
• C3-6cycloalkyl;
• C1-6alkoxy;
• C3-6alkenyloxy;
• C3-6alkynyloxy;
• C3-6cycloalkoxy;
• C1-6alkyl-S(O)w—, where w is 0, 1, or 2;
• C1-6alkylC3-6cycloalkyl-;
• C3-6cycloalkyl-C-alkyl-;
• C1-6alkoxycarbonyl-N(Ra)—;
• C1-6alkylN(Ra)—;
• C1-6alkyl-N(Ra)carbonyl-;
• RaRa′N—;
• RaRa′N-carbonyl-;
• RaRa′N-carbonyl-N(Ra)—;
• RaRa′N—SO2—;
• and C1-6alkyl-carbonyl-N(Ra)—;
• Rd is selected, independently for each occurrence, from the group consisting of C1-6alkyl, C1-6alkylcarbonyl, and C1-6alkylsulfonyl, wherein C1-6alkyl is optionally substituted by one or more substituents each independently selected from halogen, hydroxyl, and RaRa′N—;
• Re is selected, independently for each occurrence, from the group consisting of halogen;
• hydroxyl;
• —NO2;
• —N3;
• —CN;
• —SCN;
• C1-4alkoxy;
• C1-4alkoxycarbonyl;
• RaRa′N—;
• RaRa′N-carbonyl;
• RaRa′—N—SO2—;
• and C1-4alkylS(O)w—, where w is 0, 1, or 2;
• Rf is selected, independently for each occurrence, from the group consisting of halogen;
• hydroxyl;
• —NO2;
• —N3;
• —CN;
• —SCN;
• C1-4alkoxy;
• C1-4alkoxycarbonyl;
• RaRa′N—;
• RaRa′N-carbonyl;
• RaRa′N—SO2—;
• and C1-4alkylS(O)w—, where w is 0, 1, or 2;
• Rg is selected, independently for each occurrence, from the group consisting of halogen, hydroxyl, —NO2;
• —N3;
• —CN;
• —SCN;
• C1-6alkyl;
• C1-4alkoxy;
• C1-4alkoxycarbonyl;
• RaRa′N—;
• RaRa′N-carbonyl;
• RaRa′N—SO2—;
• and C1-4alkylS(O)w—, where w is 0, 1, or 2;
• Rx is selected, independently, from the group consisting of hydrogen;
• halogen;
• C1-6alkyl;
• C2-6alkenyl;
• C2-6alkynyl;
• C3-6cycloalkyl;
• phenyl;
• naphthyl;
• heteroaryl;
• heterocyclyl;
• C3-6cycloalkyl-C1-6alkyl-;
• phenyl-C1-6alkyl-;
• naphthyl-C1-6alkyl-;
• heteroaryl-C1-6alkyl-;
• and heterocyclyl-C1-6alkyl-;
• wherein heteroaryl is a 5-6 membered ring having one, two, or three heteroatoms each independently selected from N, O, or S;
• wherein heteroaryl is optionally substituted with one or more substituents each independently selected from Rb;
• wherein heterocyclyl is a 4-7 membered ring optionally substituted by one or more substituents each independently selected from Rc;
• wherein when heterocyclyl contains a —NH— moiety, that —NH— moiety is optionally substituted by Rd;
• wherein C2-6alkenyl and C2-6alkynyl, are each independently optionally substituted by one or more substituents each independently selected from Re;
• wherein C1-6alkyl is optionally substituted by one or more substituents each independently selected from Rf;
• wherein C3-6cycloalkyl is independently optionally substituted by one or more substituents each independently selected from Rg;
• and
• Ry is selected, independently, from the group consisting of alkylsilyl, arylsilyl and heteroarylsilyl, wherein the heteroaryl of heteroarylsilyl is a 5-6 membered ring having one, two, or three heteroatoms each independently selected from N, O, or S and optionally substituted with one or more substituents each independently selected from Rb;
• wherein the alkyl or aryl of the alkylsilyl or arylsilyl, respectively, is optionally substituted by one or more substituents each independently selected from Rf.