O-tert-butyldimethylsilyl or O-TBDMS

Protection

To a solution of (3R,4R)-benzyl 3-(tert-butoxycarbonylamino)-4- hydroxypiperidine-1 -carboxylate (1.0 equiv.) in dichloromethane (0.1 M solution) was added imidazole (1.1 equiv.), DMAP (0.1 equiv.), and TBDMSCl (1.1 equiv.) sequentially. The reaction mixture was stirred at room temperature for 20 h. After worked up with dichloromethane, the crude material was purified by silica column chromatography (10% to 20% EtOAc in hexanes) yielding (3R,4R)-benzyl 3-(tert- butoxycarbonylamino)-4-(tert-butyldimethylsilyloxy)piperidine-1-carboxylate (76%). 

 

Patent reference: WO2010026122 (Novartis)

Deprotection

A mixture of (Z)-5-(2-(3-(2-(fert-butyldimethylsilyloxy)ethylamino)pyrrolidin-1-yl)-4,5-dimethoxybenzylidene)thiazolidine-2,4-dione (120 mg, 0.24 mmol) in 5 mL of 1.25 M HCl in methanol was stirred at room temperature for 30 min. The mixture was then conc., in vacuo to afford the product which was purified via reverse phase HPLC (acetonitrile:water: 0.1 % NH4OAc = 5 % to 55 %) to yield the title compound as a yellow solid (45.0 mg, 48.4 %).

 

Patent reference: WO2010001169 (Astrazeneca)

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