Solabegron zwitterion and uses thereof
This application relates to solabegron zwitterion useful for the treatment of lower urinary tract symptoms such as, for example, overactive bladder and prostate disorders. Additionally, this application relates to pharmaceutical compositions and methods of treatment utilizing the solabegron zwitterion for treating lower urinary tract symptoms. This application also relates to methods of preparing solabegron hydrochloride from the solabegron zwitterion.
1. A processes for preparing a compound of Formula I-HCl
comprising contacting a zwitterion of Formula II
with hydrochloric acid in a reaction vessel.
2. The process according to claim 1 , wherein the reaction vessel additionally contains isopropyl alcohol.
3. The process according to claim 1 , further comprising contacting a sodium salt according to Formula I-Na
with hydrochloric acid to form the zwitterion of Formula II.
4. The process according to claim 3 further comprising contacting an imidazo[2,1,b]oxazole intermediate according to Formula III
with aqueous sodium hydroxide (NaOH) to form the sodium salt of Formula I-Na.
5. The process according to claim 4 further comprising contacting methyl 3′-(2′methyl-4,5-dihydro-1H-imidazol-1-yl)-[1,1′]biphenyl-3-carboxylate according to Formula IV
with (R)-2-(3-chlorophenyl)oxirane to form the imidazo[2,1,b]oxazole intermediate according to Formula III.
6. The process according to claim 5 further comprising contacting the biphenyl amine according to Formula V
with the acetimidoyl chloride according to Formula VI
to form the methyl 3′-(2′methyl-4,5-dihydro-1H-imidazol-1-yl)-[1,1′]biphenyl-3-carboxylate according to Formula IV.
7. The process according to claim 6 further comprising coupling 3-nitrophenyl)boronic acid and methyl 3-bromobenzoate to form the biphenyl amine according to Formula V.
8. A process for preparing the zwitterion according to Formula II
comprising contacting a sodium salt according to Formula I-Na
with hydrochloric acid.
9. A process for the preparation of solabegron hydrochloride comprising:
a. coupling (3-nitrophenyl)boronic acid and methyl 3-bromobenzoate with a coupling agent to form 3′-amino-[1,1′-biphenyl]-3-carboxylate;
b. contacting the 3′-amino-[1,1′-biphenyl]-3-carboxylate from step a. with (Z)—N-(2-chloroethyl)acetimidoyl chloride dichlorophosphate to form methyl (E)-3′-N-(2-chloroethyl)acetimiamido-[1,1′-biphenyl]-3-carboxylate hydrochloride;
c. contacting the methyl (E)-3′-N-(2-chloroethyl)acetimiamido-[1,1′-biphenyl]-3-carboxylate hydrochloride of step b. with an saturated aqueous base to form 3′-(2′methl-4,5-dihydro-1H-imidazol-1-yl)-[1,1′]biphenyl-3-carboxylate;
d. coupling the 3′-(2′methl-4,5-dihydro-1H-imidazol-1-yl)-[1,1′]biphenyl-3-carboxylate of step c. with (R)-3-chlorostyrene oxide to form methyl 3′-((2R)-2-(3-chlorophenyl)-7a-methyltetrahydroimidazo[2,1-b]oxazol-7(7aH)-yl)-[1,1′-biphenyl]-3-carboxylate;
e. contacting the methyl 3′-((2R)-2-(3-chlorophenyl)-7a-methyltetrahydroimidazo[2,1-b]oxazol-7(7aH)-yl)-[1,1′-biphenyl]-3-carboxylate from step d with aqueous sodium hydroxide to form a sodium salt of solabegron;
f. contacting the sodium salt of solabegron from step e. with hydrochloric acid to make a solabegron zwitterion as a solid;
g. isolating the solabegron zwitterion solid from step f; and
contacting the solabegron zwitterion from step g. with hydrochloric acid to make the solabegron hydrochloride salt.