tert-Butyl 2-oxopiperidine-1-carboxylate

Off-White Low Melting Solid

N-(tert-butoxycarbonyl)piperidin-2-one is piperidin-2-one N-protected by t-Boc. It is a piperidinecarboxylate ester and a delta-lactam.

To a solution of piperidin-2-one (0.97 g, 9.78 mmol) in DCM (20 mL) were added EtPiperidin-2-one (0.97 g, 9.78 mmol) was dissolved in DCM (20 mL) and then Et3N (1.36 mL, 9.78 mmol), DMAP (0.12 g, 0.978 mmol) and Boc2O (3.20 g, 14.7 mmol) were sequentially added to the solution to obtain a reaction system. The resulting reaction mixture was stirred at room temperature for 3 hours, then concentrated under reduced pressure and the resulting residue was subjected to silica gel column chromatography (EtOAc / PE (v / v) = 1/7) to give the title compound as a pale yellow oil (1.78 g, 91percent).Piperidin-2-one (0.97 g, 9.78 mmol) was dissolved in DCM (20 mL), and triethylamine (1.36 mL, 9.78 mmol), DMAP (0.12 g, 0.978 mmol) and Boc2O (3.20 g, 14.7 mmol) were added thereto and the resulting reaction mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc / PE (v / v) = 1/7) to give a pale yellow oil (1.78 g, 91percent).To a stirred solution of piperidin-2-one (5 g, 50.4 mmol, 1.0 equiv.), triethylamine (14.022 mL, 100.9 mmol, 2.0 equiv.) and N, N-4-dimethylaminopyridine (0.123 g, 1.0 mmol) in methylene chloride (100 mL) at 0° C. was added di-tert-butyl dicarbonate (16.512 g, 75.7 mmol, 1.5 equiv.). The mixture was slowly warmed to room temperature and stirred for 48 hrs. The reaction was quenched with water and the organic layer was washed sequentially with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column (0-100percent ethyl acetate/hexanes) to afford the desired product as a yellow oil (8.5 g, 85percent). To a stirred solution ofpiperidin-2-one (5 g, 50.4 mmol, 1.0 equiv.), triethylamine (14.022 mL, 100.9 mmol, 2.0 equiv.)andN, N-4-dimethylaminopyridine (0.123 g, 1.0 mmol)in dichloromethane (100 mL)at 0 °Cwas addeddi-tert-butyl dicarbonate (16.512 g, 75.7 mmol, 1.5 equiv.).The mixture was slowly warmed to room temperature and stirred for 48 hrs. The reaction was quenched with water and the organic layer was washed sequentially with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonateand saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate, filtered and concentratedin vacuo. The residue was purified by silica gel column (0-100percent ethyl acetate/hexanes) to afford the desired product as a yellow oil (8.5 g, 85percent).In addition, this reaction can also be performed in a different reaction step. In a three necked round bottom flask fitted with: a stirring bar, a thermometer, and a bubler at 22° C., 1000 mg, (10 mmol) ö-Valerolactam was placed. Then a 0.7M solution of DMAP (60 g 0.4 mmol) in ACN (0.8 mE) was added. To the light-yellow solution (BOC)20 (3260 g 15 mmol) was portion wise added accompanied by gas evolution. After flall conversion (stirring at internal temperature 22° C. for 2 h) 10 mE 0.1M HC1 aq. solution were added and extracted with dichloromethane (3x20 mE). The organic phase was evaporated. Upon addition of 40 ml hexane and cooling to —30° C. and crystals where formed. Yield 82percent. Purity 98percent. The advantage of this reaction compared to the reaction mentioned above can be seen in that the reaction is performed at room temperature and that DMAP is easier to handle compared to BuEi. Furthermore, a higher degree of purity is achievable.To a solution of 5.00 g (50.4 mmol, 1.0 eq.) 2-piperidinone in 250 mL acetonitrile, 8.44 mL (6.12 g, 60.5 mmol, 1.2 eq.) triethylamine and 616 mg (5.04 mmol, 0.1 eq.) DMAP are added and the mixture iscooled to 0 °C. After slow addition of 12.7 mL (12.1 g, 55.4 mmol, 1.1 eq.) di-tert-butyl dicarbonate, the reaction mixture is stirred for 18 hours at ambient temperature. The solvent is removed and the crudeproduct is purified via column chromatography (SiO2, 6.5 10 cm, pentane/EtOAc = 5/1 3/1 1/1)to obtain 7.71 g (77 percent) tert-butyl-2-oxopiperidine-1-carboxylate as yellow oil.10300] To a solution of compound 1 (31.00 g, 312.72 mmol) in CH3CN (500 mE) was added TEA (63.29 g, 625.44 mmol), 13oc20 (88.73 g, 406.54 mmol), DMAP (1.91 g, 15.64 mmol) in portions under N2. The mixture was stirred at 18° C. for 16 hours. TLC showed the reaction was completed. The mixture was concentrated in reduced pressure at 35° C. The residue was purified by silica gel chromatography (PE/EA30/1 to 5/1) to afford compound 2 (41.90 g, 210.29 mmol, 67.25percent yield) as yellow oil. LCMS:200 [M+1].In 250mL eggplant-shaped flask were successively added piperidin-2-one (5g, 50mmol), di- tert -butyl dicarbonate (13.1g, 60mmol), acetonitrile, 100mL, ice-cooling to 0 , was slowly added portionwise 4- dimethylaminopyridine (1.22g, 10mmol, plus complete, The reaction temperature 24h, TLC the reaction was complete, solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1), to giveColorless oily liquid (6.07g, 30.5mmol).4-Benzensulfonylmethyl-4-hydroxy-piperidine TFA (B-1)

Intermediate in the preparation of various biological inhibitors.

Molecular Weight:199.25
XLogP3:1.3
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:199.12084340
Monoisotopic Mass:199.12084340
Topological Polar Surface Area:46.6
Heavy Atom Count:14
Complexity:242
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes