Patent ID: 11958809
Assignee: CYTOKINETICS, INC.
Field: Pharmaceuticals (Chemistry)
Classification: CPC C  A | IPC A  C

Claim 4:
5. 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.