297172-16-8, (4-Methylpiperidin-4-yl)methanol is a piperidines compound, ?involved in a variety of chemical synthesis. Rlated chemical reaction is continuously updated
Diisopropylamine (3.14 inL; 22.23 mmol; 1.1 eq.) was dissolved in THF (60 mL) and cooled to -78 C. Butyl lithium (2.5 M in hexane; 8.89 mL; 22.23 mmol; 1.1 eq.) was then added and the solution was stirred for 30 minutes at -78 C. Ethyl l-benzylpiperidine-4-carboxylate (5 g; 20.21 mmol; 1 eq.) was dissolved in THF (40 mL) and added to the LDA solution at -78 C. The solution was stirred at -78 C for 30 minutes and iodomethane (1.32 mL; 21.22 mmol; 1.05 eq.) was added. The solution was slowly warmed to room temperature and stirred at room temperature for 1 hour. Water (100 mL) was then added to the reaction followed by EtOAc (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated under reduced pressure to afford the product (5.0 g, 94% yield) as an oil. The product was analytically pure and used without further purification. LC/MS m/z (M+l) 262.0, Retention time 1.78 minutes; (10-99% CH3CN-H20 gradient with 0.03% TFA, 5 min). .H NMR (400 MHz, CDC13) 8 7.24-7.14 (m, 5H), 4.08 (q, J = 7.1 Hz, 2H), 3.40 (s, 2H), 2.60-2.57 (m, 2H), 2.08-2.02 (m, 4H), 1.47-1.40 (m, 2H), 1.17 (t, J = 7.1 Hz, 3H), 1.10 (s, 3H). [0210] l-Benzyl-4-methylpiperidine-4-carboxylate (5.0 g; 19.15 mmol) was dissolved in Et20 (50 mL) and cooled to 0 C. L1AIH4 (1.0 g; 26.3 mmol) was slowly added portion-wise to the solution. After the addition was complete, the solution was slowly warmed to room temperature and stirred for 1 h. The solution was then cooled to 0 C and slowly quenched with IN NaOH (6 mL). The resultant white precipitates were filtered and washed with EtOAc (100 mL). The combined organic layers were concentrated under reduced pressure to provide the product (3.9 g, 90% yield) as an oil which was used without further purification. LC/MS m/z M+l 220.0, retention time 0.64 minutes; (10-99% CH3CN-H20 gradient with 0.03% TFA, 5 min). .H NMR (400 MHz, CDCI3) 8 7.25-7.16 (m, 5H), 3.46 (s, 2H), 3.30 (d, J= 3.9 Hz, 2H), 2.51-2.46 (m, 2H), 2.26-2.20 (m, 2H), 1.52-1.45 (m, 3H), 1.30-1.25 (m, 2H), 0.87 (s, 3H). (l-benzyl-4-methylpiperidin-4-yl)methanol (3.9 g; 17.8 mmol) was dissolved in MeOH (50 mL) and NH4CO2H (12.5 g; 178.0 mmol) was added. Pd/C (10% by weight, wet; 5.5 g) was then added and the system was flushed with nitrogen and then with hydrogen. The reaction was stirred at room temperature overnight (18 h) and then filtered through a pad of Celite. The solvent was removed under high vacuum to provide a solid that was a mixture of the amino alcohol and NH4CO2H. The crude product (2.4 g as a mixture with NH4COOH) was used in the next step without further purification. LC/MS m/z (M+l) 130.0, retention time 0.35 min; (10-99% CH3CN-H2O gradient with 0.03% TFA, 5 min). .H NMR (400 MHz, CDCI3) 5 3.17 (s, 2H), 3.03-2.98 (m, 2H), 2.95-2.88 (m, 2H), 1.64-1.57 (m, 2H), 1.36-1.31 (m, 2H), 0.89 (s, 3H). [0212] (4-methylpiperidin-4-yl)methanol (2.4 g, a mixture of the amino alcohol andNELtCC^H) was suspended in DCM (70 mL). Et3N (5 mL; 37.2 mmol) was then added followed by the drop-wise addition of ethyl chloroformate (1.05 mL, 13 mmol, 1.4 eq.). After 1 hour at room temperature, IN HC1 (70 mL) was added and the layers were separated. The aqueous layer was extracted with DCM (70 mL) and the combined organic layers were dried over Na2S04, filtered, and concentrated under high vacuum. The product (1.7 g, 47% yield over 2 steps) is obtained analytically pure as an oil and used without further purification. LC/MS m/z (M+l) 202.2, retention time 1.89 minutes; (10-99% CH3CN-H2O gradient with 0.03% TFA, 5 min). .H NMR (400 MHz, DMSC-d6) 8 4.05 (q, J= 7.1 Hz, 2H), 3.66 (dt, J = 13.6,4.7 Hz, 2H), 3.32 (s, 2H), 3.11 (t, .7=5.2 Hz, 1H),3.11 (dd, .7=23.9, 3.5 Hz, 1H), 1.44-1.37 (m, 3H), 1.26-1.22 (m, 2H), 1.19 (t, J= 7.1 Hz, 3H), 0.93 (s, 3H).[0213] To a 100 mL round bottom flask was added DCM (30 mL) and oxalyl chloride (0.88 mL; 10.13 mmol). The solution was cooled to -78 C and treated with DMSO (1.19 mL; 16.88 mmol). The solution was stirred at -78 C for 20 minutes and then treated with ethyl 4-(hydroxymethyl)-4-methylpiperidine-l-carboxylate (1.7 g; 8.44 mmol, dissolved in 10 mL of DCM). The solution was stirred for 30 minutes at -78 C and then treated with Et3N (3.53 mL; 25.32 mmol). The solution was stirred at -78 C for 20 min and then slowly warmed to room temperature and stirred at room temperature for an additional 2 h. The solution was then treated with saturated aqueous NaHCC>3 (50 mL), diluted with DCM (50 mL), and the layers were separated. The organic layer was washed with brine (50 mL), dried over Na2SC>4, filtered, and concentrated under reduced pressure to afford 1.6 g (95% yield) of the product as an oil which was used without further purification. LC/MS m/z (M+l) 200.0, retention time 2.23 minutes; (10-99% CH3CN-H2O gradient with 0.03% TFA, 5 min). .H NMR (400 MHz, CDC13) 5 9.40 (s, 1H), 4.06 (q, J= 7.1 Hz, 2H), 3.66 (dt, J…
297172-16-8, The synthetic route of 297172-16-8 has been constantly updated, and we look forward to future research findings.
Reference：
Patent; VERTEX PHARMACEUTICALS, INCORPORATED; WO2006/23852; (2006); A2;,
Piperidine – Wikipedia
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