Synthesis of omecamtiv mecarbil
Provided herein is a synthesis for omecamtiv mecarbil dihydrochloride hydrate and various intermediates. (I)
1. Piperazine methyl carboxylate
phosphate hydrate.
2. A process for synthesizing piperazine methyl carboxylate
phosphate hydrate comprising
(a) admixing piperazine and methyl chloroformate to form PMEC;
(b) admixing the PMEC and 0.5 molar equivalents of phosphoric acid to form PMEC phosphate hydrate; and
(c) optionally filtering the PMEC phosphate hydrate from the admixture of step (b).
3. The process of claim 2 , further comprising isolating the PMEC formed from step (a) as a solution in methylene chloride, dichloroethane, 2-methyltetrahydrofuran, or mixture thereof.
4. The process of claim 3 , wherein the isolating is performed by
(i) washing the resulting PMEC from step (a) with an organic solvent;
(ii) modifying the pH to 8 to 14 by adding a base to form a basic aqueous solution; and
(iii) extracting the PMEC from the basic aqueous solution of step (ii) with methylene chloride, dichloroethane, 2-methyl tetrahydrofuran, or mixture thereof.
5. The process of claim 2 , wherein step (a) is performed in an aqueous solution.
6. The process of claim 2 , wherein step (a) is performed at a temperature of 20 to 55° C. for 1 to 12 hours.
7. A process for synthesizing methyl 4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate
comprising
(a) admixing 2-fluoro-3-nitrotoluene, sodium bromate, and sodium bisulfite in isopropylacetate and water to form 1-(bromomethyl)-2-fluoro-3-nitrobenzene
(b) optionally washing the FNB with aqueous sodium thiosulfate, with aqueous sodium chloride, or both; and
(c) admixing FNB, a trialkylamine base, and piperazine methyl carboxylate
phosphate hydrate to form PIPN.
8. The process of claim 7 , wherein the FNB is washed with aqueous sodium thiosulfate and aqueous sodium chloride.
9. A process for synthesizing methyl 4-(2-fluoro-3-nitrobenzyl)piperazine-1-carboxylate
comprising
(a) admixing 2-fluoro-3-nitrotoluene, benzoyl peroxide, N-bromosuccinimide and acetic acid at a temperature of 70 to 95° C. to form 1-(bromomethyl)-2-fluoro-3-nitrobenzene
(b) optionally extracting FNB with toluene, washing FNB with an aqueous basic solution, or both;
(c) admixing FNB, a trialkylamine base, and piperazine methyl carboxylate
phosphate hydrate to form PIPN.
10. The process of claim 9 , wherein FNB is extracted with toluene and washed with aqueous sodium hydroxide.
11. The process of claim 7 , wherein the PIPN is formed as a hydrochloride salt.
12. The process of claim 7 , wherein the PMEC phosphate hydrate is prepared by a process comprising:
(a) admixing piperazine and methyl chloroformate to form PMEC;
(b) admixing the PMEC and 0.5 molar equivalents of phosphoric acid to form PMEC phosphate hydrate; and
(c) optionally filtering the PMEC phosphate hydrate from the admixture of step (b).
13. The process of claim 7 , wherein the trialkylamine base comprises diisopropylethylamine or triethylamine.
14. The process of claim 7 , wherein prior to admixing the FNB, the trialkylamine base, and the PMEC phosphate hydrate, the process further comprises adding diethylphosphite and a trialkylamine, and admixing the resulting mixture at a temperature of 30 to 65° C.