4-Methylnicotinic acid Hydrochloride → 4-Methylpiperidine-3-carboxylic acid hydrochloride

4-Methylnicotinic acid hydrochloride (5.00 g, 36.5 mmol, ASDI) and platinum (IV) oxide (0.35 g, 1.54 mmol) were shaken in AcOH (100 mL) under about 60 psi hydrogen for about 72 h at room temperature. The reaction mixture was filtered through Celite® and concentrated under reduced pressure to give 4-methylpiperidine-3-carboxylic acid hydrochloride (7.4 g, contained residual AcOH) that was carried forward without additional purification. To a portion of the acid (1.0 g, 4.92 mmol) in 1,4-dioxane (10 mL) was added HCl (4 N in 1,4-dioxane, 4.0 mL, 16 mmol). The mixture was stirred for about 10 min before adding Et2O (10 mL). The precipitate was collected by vacuum filtration was washed with Et2O (5 mL) to give a solid (0.27 g). To the filtrate was added HCl (4 N in 1,4-dioxane, 4.0 mL, 16 mmol) and the mixture was concentrated under reduced pressure to constant weight, while adding DCM (20 mL) to the resulting residue to give a thick yellow oil (0.56 g). The two portions were combined to give 4-methylpiperidine-3-carboxylic acid hydrochloride (0.83 g, 93%). To the acid (0.83 g, 4.6 mmol) was added N-(benzyloxycarbonyloxy)succinimide (1.27 g, 5.08 mmol), Na2CO3 (1.71 g, 16.2 mmol), and water: 1,4-dioxane (1: 1, 20 mL). The mixture was stirred at room temperature for about 16 h and the organic solvent was removed under reduced pressure. The aqueous phase was neutralized by the addition of 1N HCl. The solution was extracted with EtOAc (2×25 mL) and the combined organic extracts were washed with brine and dried over anhydrous MgSO4. The solution was filtered and concentrated under reduced pressure to give 1-(benzyloxycarbonyl)-4-methylpiperidine-3-carboxylic acid (1.28 g, 100%): LC/MS (Table 2, Method a) Rt=1.97 min; MS m/z: 278 (M+H)+.

1. filtrationThe reaction mixture was filtered through Celite®
2. concentrationconcentrated under reduced pressure

ORD record

ord-6a4f1b7462c84d70b57093f70dc9badf

Source dataset

uspto-grants-2015_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08962629B2