Granted Patent B2

US 12,583,821 · App. 18/421,849 · Granted Mar 24, 2026

Inventors: Sheng Cui (Thousand Oaks, CA); Henry Morrison (Thousand Oaks, CA); Karthik Nagapudi (South San Francisco, CA); Shawn D. Walker (Woodland Hills, CA); Charles Bernard (Moorpark, CA); Karl Bennett Hansen (Cohasset, MA); Neil Fred Langille (Thousand Oaks, CA); Alan Martin Allgeier (Wilmington, DE); Steven M. Mennen (Thousand Oaks, CA); Jacqueline C. S. Woo (Sherwood Park, CA); Bradley Paul Morgan (Moraga, CA); Alex Muci (San Francisco, CA)

Assignee: CYTOKINETICS, INC.

C07D213/75A61K9/2013A61K9/2018A61K9/2054A61K31/496A61K47/38

Abstract

Claims (44)

1 . 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.

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

is prepared by admixing Amino Pyridine

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

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

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; and

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

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

is prepared by a process 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.

5 . 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.

6 . The method of claim 3 , wherein the hydrogenating of step (ii) is in the presence of 5.0 wt % palladium on carbon.

7 . The method of claim 3 , wherein the hydrogenating of step (ii) is in a hydrogenator pressurized to 60±5 psig with hydrogen.

8 . The method of claim 3 , wherein the hydrogenating of step (ii) is at a temperature of 30±5° C.

Assignments (3)

Continuity (8)

References Cited (190)