1-Boc-3-hydroxypiperidine

White solid

1) 1) 3-Hydroxypiperidine-1-carboxylic acid tert-butyl ester A solution of triethylamine (15.2 mL) and di-tert-butoxydicarbonate (11.9 g) in methanol (50 mL) was added to a solution of 3-hydroxypiperidine (5.00 g) in methanol (50 mL) at room temperature, and the resultant mixture was stirred for 15 hours. A residue obtained by evaporating the solvent of the reaction solution under reduced pressure was purified by silica gel column chromatography (ethyl acetate-chloroform), to obtain 3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (9.86 g, 99percent) as a solid. To 1.38 gm (10 mmol) of 3-hydroxypyrrolidine were added 50 mL of a solution containing 25 mL of H2O and 25 mL of dioxane, 2.62 gm (12 mmol) of di-t-butyl dicarbonate, and 2.1 mL (12 mmol) of DIEA at ice-bath temperature. The reaction mixture was slowly warmed to room temperature and allowed to stir at room temperature for 5 h. After 5 h, solvents were removed in vacuo. To the residue were added 100 mL of H2O and 100 mL of ethyl acetate. After removing the aqueous layer, the organic layer was washed with H2O (2 x 50 mL) and concentrated under reduced pressure. The crude product was purified by flash chromatography (1 : 1, hexane : ethyl acetate) to obtain 1.97 gm (98.0 percent) of a white solid: 1H NMR (300 MHz, CD3OD) δ 3.86 - 3.50 (3H, m), 2.98 - 2.81 (2H, m), 1.92 -1.73 (2H, m), 1.45 (9H, s), 1.50 -1.36 (2H, m).3-Hydroxypiperidine (20.20 g, 0.2 mol) was dissolved in 1 L of H[0174] To a 0° C. solution of 3-hydroxypiperidine (2.12 g, 21.0 mmol) in EtOH (20 mL) was added NEt3 (5.6 mL, 40.2 mmol), followed by a solution of (Boc)2O (5.03 g, 23.0 mmol) in EtOH (20 mL). The reaction stirred at room temperature for one hour, and then the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with 10percent citric acid (50 mL), water (50 mL) and brine (50 mL). The organic solution was dried (MgSO4), filtered and evaporated under reduced pressure to afford the crude product as a white solid (3.55 g, 17.6 mmol, 84percent). 1H NMR (CDCl3) δ 1.45 (s, 9H), 1.48-1.52 (m, 2H), 1.72-1.78 (m, 1H), 1.84-1.94 (m, 1H), 2.12 (br. s, 1H), 3.01-3.12 (m, 2H), 3.46-3.59 (m, 1H), 3.65-3.78 (m, 2H). [0175] Preparation of Tert-Butyl 3-oxo-1-piperidinecarboxylate: [0176] To a 0° C. solution of the alcohol (2.01 g, 10.0 mmol) in CH2Cl2 (50 mL) was added crushed 3A molecular sieves (5.26 g), 4-methylmorpholine-N-oxide (1.76 g, 15.0 mmol) and tetrapropylammonium perruthenate (357 mg, 1.02 mmol). The resulting black solution was stirred at 0° C. for 20 minutes, then at room temperature for a further one hour. The mixture was filtered through a plug of silica, rinsed with EtOAc and the concentrated filtrate was purified by flash chromatography on silica gel (EtOAc/hexane, 1:1) to afford the ketone as a yellow liquid (1.49 g, 7.48 mmol, 75percent). 1H NMR (CDCl3) δ 1.46 (s, 9H), 1.98 (ddd, 2H, J=12.3, 6.5, 6.0 Hz), 2.47 (t, 2H, J=6.5 Hz), 3.58 (t, 2H, J=6.0 Hz), 4.00 (s, 2H). [0177] Preparation of Tert-Butyl 3-(5, 6, 7, 8-tetrahydroquinolin-8-ylamino)-piperidine-1-carboxylate: [0178] To a solution of 8-amino-5, 6, 7, 8-tetrahydroquinoline (1.00 g, 6.75 mmol) in MeOH (30 mL) was added a solution of the ketone (1.40 g, 7.03 mmol) in MeOH (20 mL). The reaction stirred at room temperature for 16 hours. NaBH4 (848 mg, 22.4 mmol) was added and the mixture stirred for a further 45 minutes. The solvent was evaporated under reduced pressure, and the residue was taken up into CH2Cl2 (50 mL) and washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic solution was dried (MgSO4), filtered and evaporated under reduced pressure. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 9:1:0.5) gave a brown oil which, following a second purification (CH2Cl2/MeOH, 97:3) afforded the amine as a yellow oil (638 mg, 1.92 mmol, 28percent). 1H NMR (CDCl3) δ 1.22-1.40 (m, 2H), 1.47 (s, 9H), 1.65-1.81 (m, 3H), 1.91-2.04 (m, 2H), 2.11-2.25 (m, 2H), 2.44-2.65 (m, 1H), 2.65-2.90 (m, 4H), 3.88-4.05 (m, 2H), 4.05-4.31 (m, 1H), 7.06 (dd, 1H, J=7.7, 4.7 Hz), 7.36 (d, 1H, J=7.8 Hz), 8.37 (d, 1H, J=4.3 Hz). [0179] Preparation of COMPOUND 8: [0180] A mixture of this amine (247 mg, 0.75 mmol), tert-butyl 2-chloromethyl-benzimidazole-1-carboxylate (238 mg, 0.89 mmol), DIPEA (0.20 mL, 1.2 mmol) and KI (14 mg, 0.08 mmol) in CH3CN (4 mL) was heated at 60° C. for 20 hours. After cooling, the reaction was diluted with saturated aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (25 mL.x.3). The organic solution was dried (MgSO4), filtered and evaporated under reduced pressure. The resulting dark red oil was purified by flash column chromatography on silica gel (CH2Cl2/MeOH, 9:1) giving an orange foam. A second purification (CH2Cl2/MeOH, 19:1) gave the tertiary amine as an orange solid (83 mg, 20percent). [0181] This material was stirred in TFA (1.5 mL) at room temperature for 2 hours, and then the excess solvent was evaporated under reduced pressure. The residue was taken up into CH2Cl2 (20 mL) and washed with saturated aqueous NaHCO3 (10 mL). The aqueous solution was extracted with CH2Cl2 (20 mL.x.2) and the combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 89:10:1) gave an approximately 2:1 mixture of diastereomers of the free amine as a yellow foam (21 mg, 0.06 mmol, 41percent). [0182] To a solution of this material (20 mg, 0.055 mmol) in glacial HOAc (1 mL) was added a saturated HBr in HOAc solution (0.5 mL). The reaction stirred at room temperature for 40 minutes. Et2O (2 mL) was added, the suspension was stirred and the solvent was decanted. The precipitate was washed with Et2O (1 mL.x.5), then dried under reduced pressure giving COMPOUND 8 as a yellow solid (26 mg, 0.038 mmol, 70percent). 1H NMR (D2O) δ 1.61-1.94 (m, 3H), 1.98-2.11 (m, 1H), 2.11-2.17 (m, 2H), 2.17-2.49 (m, 1H), 2.80-2.92 (m, 1H), 2.93-3.01 (m, 2H), 3.09-3.25 (m, 2H), 3.31-3.40 (m, 1H), 3.82-3.90 (m, 1H), 4.43 (d, 1H, J=16.5 Hz), 4.55 (d, 1H, J=16.5 Hz), 4.55-4.65 (m, 1H), 7.53-7.60 (m, 2H), 7.67-7.77 (m, 3H), 8.20 (d, 0.67H, J=7.8 Hz), 8.23 (d, 0.33H, J=7.8 Hz), 8.51 (d, 0.67H, J=5.7 Hz), 8.55 (d, 0.33H, J=5.7 Hz). 13C NMR (D2O) δ 20.5 and 20.6, 21.9 and 22.1, 24.2 and 24.5, 26.8 and 27.5, 28.0, 43.2, 44.0, 46.2 and 47.0, 58.5 and 59.2, 114.4, 125.8, 126.8, 131.7, 139.5, 140.5 and 141.6, 147.7 and 147.8, 150.6 and 151.2. ES-MS m/z 362 (M+H). Anal. Calcd. for C22H27N5.3.1HBr.1.8H2O.0.3C4H10O: C, 41.78; H, 5.55; N, 10.50; Br, 37.14. Found: C, 41.48; H, 5.44; N, 10.44; Br, 37.50.Step 1) fert-butyl 3-hydroxypiperidine-l-carboxylate [0400] To a solution of piperidin-3-ol (1.13 g, 11.2 mmol) and triethylamine (3.05 g, 30.2 mmol) in DCM (20 mL) was added (Boc)1-(1, 1-Dimethylethoxycarbonyl)-3-hydroxypiperidine In the reaction flask was added 820ml of water, 206.4 g of sodium carbonate, Stirring to dissolve, After adding methanol, the solution turns white and turbid, Then 328 g of 3-hydroxypiperidine were added, Stir well, cool with ice bath, Slowly add 250g of BoC2O at 9 , the temperature rises, To be cooled to 20 to the reaction flask was added 200g of BoC2O, The temperature rise, and then to be cooled to 20 when the remaining 550g BoC2O slowly added, A total of 2h plus, The reaction overnight; After standing at room temperature for 0.5h, add 1500ml of water, stir, add 1500ml of dichloromethane extraction, the aqueous phase was extracted twice with 1000ml of methylene chloride, the combined organic phase, 1000ml of water washing After drying with 100g of anhydrous Na2SO4, filtering, concentrating and recovering the solvent, 675g of light yellow liquid was obtained, and the product was obtained as a white solid after being refrigerated in the refrigerator to obtain N-BOC-3-hydroxypiperidine.Preparation : Synthesis of 2, 4-bis-trifluoromethyl-5, 6., 7.8- tetrahydropyrido [3 , 4-d]pyrimidine hydrochloride(O Synthesis of S-hydroxy-piperidine-l-carboxylic acid t-butyl ester1.0 equivalent of dibutyl dicarbonate (159 g) in 200 mL of methylene chloride were slowly added to a mixture of 3 -hydroxy piperidine hydrochloride (100 g, 0.73 mol) and 1.1 equivalents of triethylamine (111 mL) in methylene chloride(800 mL) at room temperature. Then, the resulting mixture was stirred additionally for 2 hours. After the reaction was complete, the reaction solution was washed with a 1.0 N hydrochloric acid aqueous solution (1.0 L) and the organic layer was concentrated to give 138 g (yield: 94percent) of the title compound as a white solid. Preparation 117: 1, 1-dimethylethyl 3-hydroxypiperidine-l-carboxylate To a solution of piperidin-3-ol hydrochloride salt (10.1 g, 0.1 MMOL) in dichloromethane (30 ML) and triethylamine (13.3 ml, 95.4 MMOL) was added a solution of di-tert-butyl dicarbonate (19.8 g, 90.9 MMOL) dropwise in dichloromethane. Upon completion the reaction mixture was added to diethyl ether (120 ml) washed with hydrochloric acid (1 M) and then with brine. The combined organic extracts were dried (MGS04) and concentrated in vacuo to give the title compound as a light yellow oil (17.7 g, 88percent).A solution of di-tert-butyl dicarbonate (5.83 g, 26.7 mmol) in dichloromethane (10 ml) was added to a solution of 3-hydroxypiperidine (3.0 g, 29.7 mmol) in dichloromethane (30 ml) at room temperature and stirred for 15 hours. The reaction solution was concentrated, diluted with ethyl acetate, and then washed with a saturated aqueous sodium hydrogencarbonate solution, a 0.5M-aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and then a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was crystallized by the addition of hexane, filtered, and then dried to obtain tert-butyl 3-hydroxy-1-piperidinecarboxylate (5.17 g, 87percent).1H-NMR (DMSO-d6) δ; 1.46 (9H, s, 1.99 (2H, m), 3.34-3.49 (4H, m), 4.45 (1H, m).To a solution of piperidin-3-ol (1.13 g, 11.2 mmol) and triethylamine (3.05 g, 30.2 mmol) in DCM (20 mL) Di-tert-butyl dicarbonate (2.60 g, 11.9 mmol) was added. The resulting reaction system was stirred at room temperature for 1 hour and then concentrated under reduced pressure. By The residue was purified by silica gel column chromatography (DCM / MeOH (v / v) = 50/1) to give the title compound as a pale yellow liquid (1.88 g, Yield 83.6percent).N-(t-Butoxycarbonyl)-3-piperidinol A solution of 89.0 g of 5-chloro-2-hydroxypentylamine hydrochloride ((1-2)) in 250 mL of water was added dropwise with a solution of 20.4 g of sodium hydroxide in 70 mL of water at 10-15 ° C for about 1 hour .After dropping, the reaction was carried out at about 15 ° C for 2 hours.Then heated to 40-50 ° C for 4 hours.After the reaction was stopped, the mixture was cooled to room temperature, a solution of 300 mL of toluene and 70 mL of water containing 20.5 g of sodium hydroxide was added, and then 104.0 g of Boc2O was added dropwise. The mixture was then allowed to warm to room temperature and then left to react overnight.TLC plate, the reaction was complete, liquid separation, the aqueous phase was extracted once with 100mL of toluene. The organic phases were combined and the organic phase was washed with water, then with saturated brine, dried over anhydrous sodium sulphate, filtered off with suction and concentrated to give 92.0 g of colorless oil. The crude product was recrystallized from petroleum ether, crystallized by cooling to 0 ° C, suction filtered and the filter cake was dried under vacuum to give 78.0 g of N-tert-butoxycarbonyl-3-hydroxypiperidine (1-4) as a white solid in a yield of 76percent .40 ml of 5-bromo-2-hydroxypentylamine hydrobromide (2-1) was dissolved in 80 ml of water and a solution of 30 ml of water containing 8.0 g of potassium carbonate was added dropwise at 10 to 15 ° C for about 1 hour .After dropping, the reaction was carried out at about 15 ° C for 2 hours.Then warmed to 30-40 ° C for 2 hours.After the reaction was stopped, the mixture was cooled to room temperature, 100 mL of toluene and 40 mL of water containing 10.0 g of potassium carbonate were added, and then 52.0 g of Boc2O was added dropwise. The mixture was then allowed to warm to room temperature and then reacted overnight.TLC plate, the reaction was complete, liquid separation, the aqueous phase was extracted once with 50mL of toluene. The organic phases were combined and the organic phase was washed with water, then with saturated brine, dried over anhydrous sodium sulfate, filtered off with suction and concentrated to give 28.0 g of colorless oil. The crude product was recrystallized from petroleum ether and crystallized by cooling to 0 ° C. The mixture was suction filtered and the filter cake was dried under vacuum to give 23.0 g of N-tert-butoxycarbonyl-3-hydroxypiperidine (1-4) as a white solid in a yield of 75percent .

Molecular Weight:201.26
XLogP3:1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:201.13649347
Monoisotopic Mass:201.13649347
Topological Polar Surface Area:49.8
Heavy Atom Count:14
Complexity:210
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes