Synthesis
The general procedure for the synthesis of tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate from (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylate is as follows:
Example 58: Synthesis of N-(2-methylpropyl)-N-(3,5-dichlorophenylmethyl)-(3R)-piperidin-3-ylmethylamine 1.5L-tartrate:
(i) Borane-tetrahydrofuran complex (1M solution of THF, 65.4 ml, 65.4 mmol, 3 eq.) was slowly added dropwise to a solution of (R)-N-Boc-piperidine-3-carboxylic acid (5 g, 21.8 mmol, 1 eq.) in THF (50 ml) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. Subsequently, the solution was cooled to 0°C and hydrolyzed by careful addition of 2N aqueous sodium hydroxide solution (250 ml). The hydrolyzed mixture was heated and refluxed for 48 hours. After completion of the reaction, the mixture was again cooled to 0°C and extracted with ether (3 x 100 ml). The organic layers were combined, washed with brine (100 ml), dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was purified by fast chromatography using isohexane solution of 50-70% ethyl acetate as eluent to give the title compound tert-butyl (3R)-3-(hydroxymethyl)piperidine-1-carboxylate (4.56 g, 98% yield).
1H NMR (300 MHz, CDCl3) δ: 4.0-2.7 (6H, br m), 2.17-1.19 (5H, br m), 1.46 (9H, s).
References
[1] Patent: WO2005/118531, 2005, A1. Location in patent: Page/Page column 74
[2] Patent: WO2006/12308, 2006, A1. Location in patent: Page/Page column 68
[3] Patent: WO2017/103611, 2017, A1. Location in patent: Paragraph 00298
