Salt of omecamtiv mecarbil and process for preparing salt

1. 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.

2. The method of claim 1 , wherein the methyl 4-(3-amino-2-fluorobenzyl) piperazine-1-carboxylate (Piperazine Anilline)

is prepared by a process comprising:

step (i) neutralizing methyl 4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate hydrochloride (Piperazine Nitro·HCl)

with sodium bicarbonate in water and isopropyl acetate to yield methyl 4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate

step (ii) 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 (iii) isolating methyl 4-(3-amino-2-fluorobenzyl)piperazine-1-carboxylate from isopropyl acetate and heptane.

3. The method of claim 2 , wherein methyl 4-(2-fluoro-3-nitrobenzyl) piperazine-1-carboxylate hydrochloride

is prepared by a process 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 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.

4. The method of claim 1 , wherein the phenyl (6-methylpyridin-3-yl)carbamate (Phenyl Carbamate·HCl)

is prepared by admixing Amino Pyridine

with phenyl chloroformate in acetonitrile and N-methyl-2-pyrolidinone.

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.