| 99% |
With triethylamine In dichloromethane at 20℃; for 18h; |
39.1 Step 1. Benzyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (39b)
To a mixture of benzyl 4-hydroxypiperidine-1-carboxylate (10.0 g, 42.50 mmol) and TEA (8.6 g, 85.15 mmol) in DCM (120 mL) was added MsCl (5.4 g, 47.16 mmol) at RT. After stirring at RT for 18 hrs, the reaction mixture was diluted with H 2O (50 mL) and extracted with DCM (40 mL*3). The combined organic layers were concentrated to afford the crude product (13.2 g, 99%) as brown oil. 1H NMR (400 MHz, CDCl 3) δ 7.38 -7.30 (m, 5H), 5.13 (s, 2H), 4.93 -4.87 (m, 1H), 3.78 -3.72 (m, 2H), 3.45 -3.39 (m, 2H), 3.30 (s, 3H), 1.97 -1.96 (m, 2H), 1.88 -1.82 (m, 2H). |
| 90% |
With triethylamine In dichloromethane at 0℃; |
|
| 87.6% |
With triethylamine In dichloromethane at 0℃; |
27
Preparation of compound 27b: ^Methanesulfonyloxy-piperidine-i-carboxylic acid benzyl esterTo a stirred solution of 27a (90 g, 0.38 mol) in CH2CI2 (1.2 L) was added Et3N (46.4 g, 0.459 mol), then methanesulfonyl chloride (43.6 g, 0.459 mol) was added dropwise at 0 0C. The mixture was stirred at 0 0C for 2.5 h, and then the mixture was washed with water (200 ml_), saturated aqueous NH4CI (200 ml_) and brine (200 ml_), dried over Na2SO4 and concentrated which gave the title compound 27b as a yellow oil (105 g, 87.6%). |
| 61% |
With triethylamine In dichloromethane at 20℃; |
1 Step 1 : benzyl 4-(methylsulfonyloxy)piperidine-l-carboxylate
Step 1 : benzyl 4-(methylsulfonyloxy)piperidine-l-carboxylate (0417) To a solution of benzyl 4-hydroxypiperidine-l-carboxylate (2 g, 8.5 mmol, 1.0 eq) and triethylamine (3.4 g, 34 mmol, 4.0 eq) in dichloromethane (20 mL) was added a solution of methanesulfonyl chloride (2.9 g, 25.5 mmol, 3 eq) in dichloromethane (10 mL). The resulting mixture was stirred at room temperature overnight and diluted with dichloromethane (200 mL). The organic phase was washed with water (100 mL x 3), brine (10 mL x 3) and dried over anhydrous Na2SC>4. The organic layer was concentrated in vacuo to afford the crude product. The curde product was purified by column chromatography (silica gel: 300-400 mesh, PE/EtOAc = 3/1 to 1/1) to give the title compound (1.62 g, 61%) as a colorless oil. LRMS m/z (M+H): Calc'd 314.1, found 314.0. |
|
With pyridine In dichloromethane at 20℃; |
|
|
With triethylamine In dichloromethane at 0 - 30℃; for 2.25h; |
155.A; 158.A
To a stirring solution of benzyl 4-hydroxy-1-piperidinecarboxylate (3.55 mL, 23.4 mmol, Aldrich) and Et3N (7.18 mL, 51.5 mmol, Aldrich) in CH2Cl2 (25 mL) at room temperature was added a solution of methanesulfonyl chloride (1.99 mL, 25.8 mmol, Acros) in CH2Cl2 (25 mL) dropwise. The reaction mixture was stirred at room temperature for 1 h and washed with 1N HCl aqueous solution, H2O and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to yield 7.43 g of the desired product as a yellow oil. MS (ESI) 314 (M+H).; To benzyl 4-hydroxypiperidine-1-carboxylate (48.8 g, 207 mmol) in CH2Cl2 (400 mL) was added triethylamine (57.8 mL, 415 mmol), the mixture was cooled to 0° C. under nitrogen and then methanesulfonyl chloride (17.78 mL, 228 mmol) was added over 15 minutes keeping internal temperature below 30° C. After 2 hours at 0° C., the reaction was quenched with 300 mL of 0.1 N aqueous HCl, the organic layer was washed with 300 mL of water, 300 mL of brine, dried with MgSO4, filtered and concentrated to give the product (69.5 g) as an amber liquid which was used without further purification. MS (ESI) 314.4 (M+1). |
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