Salt of omecamtiv mecarbil and process for preparing salt

Patent metadata

Field	Value
Publication number	US-11958809-B2
Application number	US-202117448833-A
Country	US
Kind code	B2
Filing date	Sep 24, 2021
Priority date	Mar 14, 2013
Publication date	Apr 16, 2024
Grant date	Apr 16, 2024

Abstract

Provided are omecamtiv mecarbil dihydrochloride salt forms, compositions and pharmaceutical formulations thereof, and methods for their preparation and use.

First claim

What is claimed:

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.

Assignees

• Cytokinetics Inc

Inventors

• Cui Sheng
• Morrison Henry
• Nagapudi Karthik
• Walker Shawn D
• Bernard Charles
• Hansen Karl Bennett
• Langille Neil Fred
• Allgeier Alan Martin
• Mennen Steven M
• Woo Jacqueline C S
• Morgan Bradley Paul
• Muci Alex

Classifications

• C07D213/75 Primary

  Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates · CPC title

• A61K9/2013

  Organic compounds, e.g. phospholipids, fats · CPC title

• A61K9/2018

  Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates · CPC title

• A61K9/2054

  Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title