2-(6-{2-[(2R)-2-Methyl-1-pyrrolidin-1-yl]-ethyl}-2-naphthalen-2-yl)-2H-pyridazin-3-one salts and their preparation
View Patent ↗The present invention relates to salts of 2-(6-{2-[(2R)-2-methyl-1-pyrrolidin-1-yl]-ethyl}-2-naphthalen-2-yl)-2H-pyridazin-3-one, processes for their preparation, pharmaceutical compositions comprising such compounds, method of using them, and a process for preparing the active agent.
1. A method of preparing crystalline 2-(6-{2-[(2R)-2-methyl-1-pyrrolidin-1-yl]-ethyl}-2-naphthalen-2-yl)-2H-pyridazin-3-one citrate, comprising the steps of:
(a) dissolving 2-(6-{2-[(2R)-2-methyl-1-pyrrolidin-1-yl]-ethyl}-2-naphthalen-2-yl)-2H-pyridazin-3-one in a solution of citric acid and ethanol;
(b) heating the reaction mixture to a temperature of about 40° C. to about 65° C.;
(c) adding a seed slurry of 2-(6-{2-[(2R)-2-methyl-1-pyrrolidin-1-yl]-ethyl}-2-naphthalen-2-yl)-2H-pyridazin-3-one crystals;
(d) cooling the resulting solution to less than 5° C. for at least one hour to provide a suspension; and
(e) filtering the resulting suspension.
2. A method of preparing a 2-{6-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one, comprising the steps of:
(a) converting the trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester to 2-bromo-6-vinyl-naphthalene;
(b) reacting 2-bromo-6-vinyl-naphthalene with 2-methylpyrrolidine in the presence of n-butyllithium to provide 1-[2-(6-bromo-naphthalen-2-yl)-ethyl]-2-methyl-pyrrolidine; and
(c) reacting 1-[2-(6-bromo-naphthalen-2-yl)-ethyl]-2-methyl-pyrrolidine with 2H-pyridazin-3-one.
3. The method of claim 2 , wherein the trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester is obtained by:
(a) providing 6-bromo-naphthalen-2-ol; and
(b) reacting 6-bromo-naphthalen-2-ol with a suitable trifluoromethanesulfonic reagent.
4. The method of claim 1 , wherein the 2-(6-{2-[(2R)-2-methyl-1-pyrrolidin-1-yl]-ethyl}-2-naphthalen-2-yl)-2H-pyridazin-3-one is obtained by:
(a) converting the trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester to 2-bromo-6-vinyl-naphthalene;
(b) reacting 2-bromo-6-vinyl-naphthalene with (2R)-methylpyrrolidine in the presence of n-butyllithium to provide 1-[2-(6-bromo-naphthalen-2-yl)-ethyl]-2-methyl-pyrrolidine; and
(c) reacting 1-[2-(6-bromo-naphthalen-2-yl)-ethyl]-(2R)-methyl-pyrrolidine with 2H-pyridazin-3-one.