Process for the preparation of mirabegron free from genotoxic impurities
AssigneeZydus Lifesciences Limited
InventorsKumar Kamlesh SINGH, Kuldeep Natwarlal Jain, Naitik Bharatbhai Patel, Hemantkumar Jagatpal Singh, Pratik Jayantibhai Nariya
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Abstract
The present invention relates to mirabegron substantially free from genotoxic impurities particularly nitrosamine impurities of Formula (I), (II), (III), (IV), (V) and processes for its preparation. In particular, the invention relates to processes for the preparation of high purity mirabegron free from nitrosamine impurities of Formula (I), (II), (III), (IV), (V) and other genotoxic and carcinogenic impurities below threshold concentration.
Claims13
Mirabegron of Formula (IA) substantially free of Nitrosamine impurities, viz.,
- N-Nitroso dimethylamine (NDMA) impurity of Formula (I), N-nitrosodiethylamine (NDEA) impurity of Formula (II), (R)—N-(2-hydroxy-2-phenylethyl)-N-(4-nitrophenethyl)nitrous amide impurity of Formula (III), (R)—N-(4-aminophenethyl)-N-(2-hydroxy-2-phenylethyl)nitrous amide impurity of Formula (IV), and (R)-2-(2-aminothiazol-4-yl)-N-(4-(2-((2-hydroxy-2-phenylethyl) (nitroso) amino)ethyl)phenyl)acetamide impurity of Formula (V).
Use of compounds of Formula (C), Formula (D), and Formula (E)
- substantially free of Nitrosamine impurities, viz., N-Nitrosodimethylamine (NDMA) impurity of Formula (I), N-nitrosodiethylamine (NDEA) impurity of Formula (II), (R)—N-(2-hydroxy-2-phenylethyl)-N-(4-nitrophenethyl)nitrous amide impurity of Formula (III), (R)—N-(4-amino phenethyl)-N-(2-hydroxy-2-phenylethyl) nitrous amide impurity of Formula (IV)
- for the preparation of mirabegron.
A process for the preparation of mirabegron of Formula (IA)
- substantially free of Nitrosamine impurities, viz., N-Nitrosodimethylamine (NDMA) impurity of Formula (I), N-nitrosodiethylamine (NDEA) impurity of Formula (II), (R)—N-(2-hydroxy-2-phenylethyl)-N-(4-nitrophenethyl)nitrous amide impurity of Formula (III), (R)—N-(4-aminophenethyl)-N-(2-hydroxy-2-phenylethyl)nitrous amide impurity of Formula (IV), and (R)-2-(2-aminothiazol-4-yl)-N-(4-(2-((2-hydroxy-2-phenylethyl)(nitroso)amino)ethyl)phenyl)acetamide impurity of Formula (V),
- the process comprising:
- (a) reacting (R)-Mandelic acid of Formula (A) with 2-(4-nitrophenyl)ethanamine hydrochloride salt of Formula (B) with a suitable solvent in the presence of a suitable base and coupling agent to obtain (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide of Formula (C);
- (b) reacting (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide of Formula (C) with a suitable solvent in the presence of a reducing agent to obtain (R)-2-((4-nitrophenethyl)amino)-1-phenylethan-1-ol hydrochloride salt of Formula (D);
- (c) reacting (R)-2-((4-nitrophenethyl)amino)-1-phenylethan-1-olhydrochloride salt of Formula (D) with a suitable solvent in the presence of a suitable reducing agent to obtain (R)-2-((4-aminophenethyl)amino)-1-phenylethan-1-ol hydrochloride salt of Formula (E);
- (d) reacting (R)-2-((4-aminophenethyl)amino)-1-phenylethan-1-ol hydrochloride salt of Formula (E) with 2-(2-aminothiazol-4-yl)acetic acid of Formula (F) in a suitable solvent in the presence of a coupling agent and a suitable base to obtain mirabegron of Formula (IA);
- and
- (e) treating mirabegron of Formula (IA) with a suitable solvent to obtain mirabegron containing less than 0.53 ppm of nitrosamine impurities of Formula (I), (II), (III), (IV) and (V).
A pharmaceutical composition comprising mirabegron of Formula (IA),
- and one or more pharmaceutically acceptable carriers, excipients, or diluents, wherein the pharmaceutical composition comprises less than 0.53 ppm of nitrosamine impurities, viz., N-Nitroso dimethylamine (NDMA) impurity of Formula (I), N-nitrosodiethylamine (NDEA) impurity of Formula (II), (R)—N-(2-hydroxy-2-phenylethyl)-N-(4-nitrophenethyl)nitrous amide impurity of Formula (III), (R)—N-(4-aminophenethyl)-N-(2-hydroxy-2-phenylethyl)nitrous amide impurity of Formula (IV), and (R)-2-(2-aminothiazol-4-yl)-N-(4-(2-((2-hydroxy-2-phenylethyl) (nitroso) amino)ethyl)phenyl)acetamide impurity of Formula (V) by area percentage of LCMS.
Dependencies are inferred from the claim text.