Process for the preparation of cis-2-methylspiro (1,3-oxathiolane 5-3′) quinuclidine
AssigneeApicore, LLC
InventorsRavishanker Kovi, Jayaraman Kannapan, Talluri Buhshaiah Chowdari, Chirag Vasantlal Shah
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Abstract
Methods are provided for making pharmaceutical-grade cis-2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine and pharmaceutically acceptable salts thereof by isomerizing racemic 2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine to cis-2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine and subsequent purification of the C-MSOQ by salt formation with inexpensive and commercially available material such as sulfuric acid. Purification methods are disclosed which employ an organic solvent/water system and recrystallization with an organic solvent such as acetone.
Claims15
A process for the preparation of pharmaceutical grade cis-2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine hydrochloride having a purity >99.5% comprising:
- a) treating an epoxide of 3-methylenequinuclidine with hydrogen sulfide gas in a solvent selected from the group consisting of methanol, isopropanol, butanol, and mixtures thereof to obtain 3-hydroxy-3-mercaptomethyl quinuclidine;
- b) treating 3-hydroxy-3-mercaptomethyl quinuclidine with acetaldehyde in the presence of a boron trifluoride etherate to generate 2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine base;
- c) treating the 2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine base with hydrochloric acid to form a racemic hydrochloride salt;
- d) isomerizing the racemic hydrochloride salt with a Lewis acid and an organic solvent to obtain the isomer cis-2-methylspiro(1,3-oxathiolane-5,3′)quinuclidine having a purity of >90%;
- e) Purifying the cis isomer having >90% purity by treatment with an inorganic acid and an organic solvent to obtain the cis isomer having a purity of >99.5%.
Dependencies are inferred from the claim text.