Processes for the preparation and purification of gabapentin enacarbil
AssigneeTeva Pharmaceutical Industries Ltd.
InventorsElena Ben Moha-Lerman, Tamar Nidam, Meital Cohen, Sharon Avhar-Maydan, Anna Balanov
Life of this patent
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Abstract
Gabapentin enacarbil was prepared and purified from intermediates such as 1-haloalkyl carbamate or carbonate and diacid acetal skeleton. For example, a 1-haloalkyl carbonate or carbamate was prepared by combining a C1 to C10 alcohol or C1 to C10 primary amine, a solvent selected from the group consisting of: acetonitrile, C3 to C7 ketone, C5 to C10 ether, C2 to C7 ester, C5 to C10 hydrocarbon and a combination thereof; a 1-haloalkyl haloformate of the following formula: wherein each X is independently selected from Br, I, or Cl; R1 is alkyl or H; and a C6 to C21 tertiary amine.
Claims34
A process for preparing 1-haloalkyl carbonate or carbamate comprising:
- combining C1 to C10 alcohol or C1 to C10 primary amine, a solvent selected from the group consisting of:
- acetonitrile, C3 to C7 ketone, C5 to C10 ether, C2 to C7 ester, C5 to C10 hydrocarbon and a combination thereof;
- a 1-haloalkyl haloformate of the following formula:
- wherein each X is independently selected from Br, I, or Cl;
- R1 is alkyl or H;
- and a C6 to C21 tertiary amine.
2-11. (canceled)
(canceled)
(canceled)
A process for preparing diacid acetal skeleton having the following structure:
- wherein Y is O or NH, R1 is alkyl or H, R3 is alkyl and R2 is alkyl or a substituted aromatic hydrocarbon comprising:
- combining a carboxylic acid with a 1-haloalkyl carbamates or carbonates in the presence of a coupling agent selected from the group consisting of Cu(OAc)2, Zn(OAc)2, Cu2O, CuO, CeO2, NiO, ZnO and Cu(O2CCHMe2)2.
16-31. (canceled)
A one-pot process for preparing diacid acetal skeleton comprising:
- combining a C1 to C10 alcohol or C1 to C10 primary amine;
- a solvent selected from the group consisting of:
- acetonitrile, C3 to C7 ketone, C5 to C10 ether, C2 to C7 ester, C5 to C10 hydrocarbon and a combination thereof;
- a 1-haloalkyl haloformate of the following formula:
- wherein each X is independently selected from Br, I, or Cl;
- R1 is alkyl or H;
- and a C6 to C21 tertiary amine to obtain a reaction mixture;
- and adding carboxylic acid to the reaction mixture in the presence of a coupling agent selected from the group consisting of Cu(OAc)2, Zn(OAc)2, Cu2O, CuO, CeO2, NiO, ZnO and Cu(O2CCHMe2)2.
33-48. (canceled)
A process for preparing gabapentin enacarbil comprising:
- combining gabapentin with a solvent selected from the group consisting of:
- acetonitrile, C3 to C7 ketone, C5 to C10 ether, C2 to C7 ester, C5 to C10 hydrocarbon and a combination thereof;
- a base selected from a group consisting of:
- C6 to C21 tertiary amine, K2CO3, KHCO3, Na2CO3 and NaHCO3;
- and 1-(isobutyryloxy)ethyl 4-nitrophenyl carbonate.
51-54. (canceled)
A process for purifying GBPE from NP and NP derivatives comprising reducing the NP and NP derivatives in GBPE, followed by acidic extraction.
56-70. (canceled)
A process for purifying gabapentin enacarbil, comprising:
- loading gabapentin enacarbil containing nitrophenol and/or nitrophenol derivatives on a column filled with cross-linked dextran gel in toluene;
- and eluting purified gabapentin enacarbil with toluene or a toluene/hexane solution.
72-74. (canceled)
A one-pot process for preparing gabapentin enacarbil comprising:
- combining C1 to C10 alcohol or C1 to C10 primary amine;
- a solvent selected from the group consisting of:
- acetonitrile, C3 to C7 ketone, C5 to C10 ether, C2 to C7 ester, C5 to C10 hydrocarbon and a combination thereof;
- a 1-haloethyl haloformate of the following formula:
- wherein X is Br, I, or Cl and R1 is methyl;
- and a C6 to C21 tertiary amine;
- adding isobutyric acid in the presence of a coupling agent selected from the group consisting of Cu(OAc)2, Cd(OAc)2, Zn(OAc)2, Cu2O, CuO, CeO2, CdO, NiO, ZnO and Cu(O2CCHMe2)2;
- adding gabapentin and a base selected from a group consisting of:
- C6 to C21 tertiary amine, K2CO3, KHCO3, Na2CO3 and NaHCO3 to obtain gabapentin enacarbil;
- reducing gabapentin enacarbil, followed by acidic extraction, distilling toluene and adding hexane, heptane or a solution of heptane and EtOAc to obtain a precipitate.
A one-pot process for preparing gabapentin enacarbil comprising:
- combining 4-nitrophenol, toluene, 1-chloroethyl chloroformate and a base selected from the group consisting of TEA and TBA;
- adding isobutyric acid in the presence of ZnO;
- adding GBP and a base selected from the group consisting of TEA and K2CO3;
- adding potassium formate in the presence of palladium over carbon;
- and adding hexane, heptane or heptane/EtOAc.
Dependencies are inferred from the claim text.