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US 12,583,821 B2Granted
Salt of omecamtiv mecarbil and process for preparing salt
AssigneeCytokinetics, Inc.
InventorsSheng Cui, Henry Morrison, Karthik Nagapudi, Shawn D. Walker, Charles Bernard, Karl Bennett Hansen, Neil Fred Langille, Alan Martin Allgeier, Steven M. Mennen, Jacqueline C. S. Woo, Bradley Paul Morgan, Alex Muci
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Abstract
Provided are omecamtiv mecarbil dihydrochloride salt forms, compositions and pharmaceutical formulations thereof, and methods for their preparation and use.
Claims8
A method of preparing omecamtiv mecarbil free base
- comprising:
- admixing methyl 4-(3-amino-2-fluorobenzyl) piperazine-1-carboxylate (Piperazine Aniline)
- and phenyl (6-methylpyridin-3-yl)carbamate hydrochloride (Phenyl Carbamate·HCl)
- in the presence of diisopropylethylamine and tetrahydrofuran.
1 more element
A method of preparing omecamtiv mecarbil free base
- comprising:
- step (i) admixing 2-fluoro-3-nitrotoluene (FN-Toluene)
- with N-bromosuccinimide, benzoyl peroxide, and acetic acid to form a mixture;
- step (ii) contacting the mixture from step (i) with diethylphosphite and diisopropylethylamine in methanol to form a solution of FN-bromide
- step (iii) admixing the solution of FN-bromide from step (ii) with diisopropylethylamine and piperazine carboxylate
- in toluene to form a solution of Piperazine Nitro free base
- and
- step (iv) admixing the solution of Piperazine Nitro free base with IPA, water, and HCl to form methyl 4-(2-fluoro-3-nitrobenzyl) piperazine-1-carboxylate hydrochloride (Piperazine Nitro·HCl)
- wherein the method further comprises:
- step (v) neutralizing the Piperazine Nitro·HCl with sodium bicarbonate in water and isopropyl acetate to yield methyl 4-(2-fluoro-3-nitrobenzyl) piperazine-1-carboxylate
- step (vi) hydrogenating methyl 4-(2-fluoro-3-nitrobenzyl) piperazine-1-carboxylate in the presence of palladium on carbon in isopropyl acetate to form methyl 4-(3-amino-2-fluorobenzyl) piperazine-1-carboxylate;
- and
- step (vii) isolating 4-(3-amino-2-fluorobenzyl) piperazine-1-carboxylate from isopropyl acetate and heptane, to form methyl 4-(3-amino-2-fluorobenzyl) piperazine-1-carboxylate (Piperazine Aniline)
- wherein the method further comprises:
- step (viii) admixing Amino Pyridine
- with phenyl chloroformate in acetonitrile and N-methyl-2-pyrrolidinone to form phenyl (6-methylpyridin-3-yl)carbamate hydrochloride (Phenyl Carbamate·HCl)
- and
- step (ix) admixing the Piperazine Aniline and the Phenyl Carbamate·HCl in the presence of diisopropylethylamine and tetrahydrofuran to form the omecamtiv mecarbil free base.
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Dependencies are inferred from the claim text.