Process for the preparation of piperidine derivatives

C - Chemistry – Metallurgy – 07 – D

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C07D 491/056 (2006.01) A61K 31/4355 (2006.01) A61K 31/4741 (2006.01) A61P 31/12 (2006.01) C07D 211/40 (2006.01) C07D 491/02 (2006.01)

Patent

CA 2455018

A process is disclosed for preparation of piperidine derivatives, preferably 1,3-dioxolo [4,5-c] piperidin-7-ols such as (3aS, 4R, 7S, 7aR)-2,2,4-trimethyl- 1,3-dioxolo [4,5-c] piperidin-7-of and its polyhydroxylated derivatives. In a preferred process, 2,3-O-isopropylidene-1,4-lactone (A) is reacted with methanesulfonyl chloride to form (3aR, 4S, 6aR) methanesulfonic acid 2,2-dimethyl-6-oxo-tetrahydro- furo[3,4- d][1,3]dioxol-4-ylmethyl (B). Compound (B) is then reacted with methylmagnesium halide to form (3aR, 4S, 6aR)-methanesulfonic acid 6-hydroxy-2,2,6-trimethyl- tetrahydro-furo[3,4-d][1,3]dioxol-4-ylmethyl ester (C), which is reacted with phthalimide to form (3aR, 4S, 6aR)-2-(6-hydroxy-2,2,6-trimethyl-tetrahydro- furo[3,4- d][1,3]dioxol-4-ylmethyl)-isoindole-1,3-dione (D). Compound (D) is reacted with hydrazine to form (3S, 7S, 7aR)-2,2,4-trimethyl-3a,6,7,7a-tetrahydro- [1,3]dioxolo[4,5-c]pyridin-7-ol (E), which is hydrogenated to give the corresponding 1,3-dioxolo [4,5-c] piperidin-7-ol (F). The synthesis has an overall yield which is typically greater than 50% and avoids the use of reagents such as triflic anhydride and sodium azide.

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