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US 11,958,809 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.
Claims5
A method of preparing omecamtiv mecarbil dihydrochloride hydrate
- comprising:
- step (a) admixing methyl 4-(3-amino-2-fluorobenzyl)piperazine-1-carboxylate (Piperazine Aniline)
- and phenyl (6-methylpyridin-3-yl)carbamate (Phenyl Carbamate·HCl)
- in the presence of diisopropylethylamine and THF to form a solution of omecamtiv mecarbil free base;
- step (b) swapping solvent of the solution of omecamtiv mecarbil free base to 2-propanol;
- step (c) admixing the solution of omecamtiv mecarbil free base with hydrochloric acid in the presence of water to form omecamtiv mecarbil dihydrochloride hydrate.
3 more elements
A method of preparing omecamtiv mecarbil dihydrochloride hydrate
- comprising:
- step (i) admixing 2-fluoro-3-nitrotolune (FN-Toluene)
- with N-bromosuccinimide, benzoyl peroxide, and acetic acid to form a mixture of 1-(bromomethyl)-2-fluoro-3-nitrobenzene (FN-Bromide)
- and 1-(dibromomethyl)-2-fluoro-3-nitrobenzene (Dibromide)
- step (ii) contacting the mixture of FN-bromide and Dibromide with diethylphosphite and diisopropylethylamine in methanol to form a solution of FN-bromide;
- step (iii) admixing the solution of FN-bromide with diisopropyethylamine, and piperazine carboxylate
- in toluene to form a solution of Piperazine Nitro free base
- 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 methyl 4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate hydrochloride (Piperazine Nitro·HCl) prepared from steps (i)-(iv) 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;
- step (vii) isolating methyl 4-(3-amino-2-fluorobenzyl)piperazine-1-carboxylate from isopropyl acetate and heptane;
- wherein the method further comprises:
- step (viii) admixing Amino Pyridine
- with phenyl chloroformate in acetonitrile and N-methyl-2-pyrolidinone to yield phenyl (6-methylpyridin-3-yl)carbamate (Phenyl Carbamate·HCl)
- and wherein the method further comprises:
- step (ix) admixing the methyl 4-(3-amino-2-fluorobenzyl)piperazine-1-carboxylate prepared from steps (v)-(vii) and the phenyl (6-methylpyridin-3-yl)carbamate from step (viii) in the presence of diisopropylethylamine and THF to form a solution of omecamtiv mecarbil free base;
- step (x) swapping solvent of the solution of omecamtiv mecarbil free base to 2-propanol;
- and
- step (xi) admixing the solution of omecamtiv mecarbil free base with hydrochloric acid in the presence of water to form omecamtiv mecarbil dihydrochloride hydrate.
17 more elements
Dependencies are inferred from the claim text.