| 97% |
With sodium hydrogencarbonate; In ethanol; water; at 20℃; for 4.5h; |
<strong>[6859-99-0]3-Hydroxypiperidine</strong> (20.20 g, 0.2 mol) was dissolved in 1 L of H2O/EtOH (1:1, v/v). Then, NaHCO3 was added (100.80 g, 1.6 mol), stirring at rt, followed by the addition of Boc2O (52.30 g, 0.24 mol). The reaction was completed in 4.5 h (TLC in 10% EtOH/CHCl3, ninhydrin detection). The mixture was filtered and the filtrate was evaporated. The crude product was then purified by flash chromatography on a silica gel by a linear gradient of ethanol in CHCl3 (0?10%). The product was obtained in a 97% (39.30 g, 0.195 mol) yield as a colorless oil, which crystallized in the fridge (mp=71.2-73.4 C).numax (KBr) 3468 (vs), 2981 (s), 2943 (s), 2864 (s), 1695 (vs), 1670 (vs), 1481 (s), 1472 (s), 1459 (s), 1450 (s), 1432 (vs), 1393 (vs), 1367 (vs), 1259 (vs), 1241 (vs), 1169 (vs), 1154 (vs), 1104 (m), 1073 (vs), 1024 (m), 1003 (w), 460 (w); deltaH (CDCl3, 400.1 MHz) 3.78-3.82 (2H, m, Jgem 12.9 Hz, H-2a), 3.68-3.73 (1H, m, H-3), 3.56-3.61 (1H, m, H-6a), 2.98 (2H, dd, Jgem 12.9 Hz, J2b-3 7.9 Hz, H-2b), 2.99-3.06 (1H, m, H-6b), 1.89-1.93 (1H, m, H-4a), 1.72-1.77 (1H, m, H-5a), 1.38-1.54 (11H, m, (CH3)3, H-4b, H-5b); deltaC (CDCl3, 100.6 MHz) 155.1 (CO), 79.7 (C(CH3)), 66.0 (C-3), 50.5 (C-2), 44.0 (C-6), 32.5 (C-4), 28.4 (CH3), 22.5 (C-5); HRMS (FAB) C10H20NO3 (M+H)+ calcd 202.1447, found 202.1443. |
| 96.47% |
With sodium hydrogencarbonate; at 20℃; for 4h; |
(4) The (S) -3-hydroxypiperidine (101 g, 1 mol) obtained in step (3) and saturated sodium bicarbonate solution (1 L) and BOC anhydride (258 g, 1.2 mol) were stirred at room temperature for 4 h. The reaction solution was extracted with dichloromethane (500 ml × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness, 250 grams of ethyl acetate was added and heated to 60 C to completely dissolve. Cool to room temperature, add 150 grams of petroleum ether, cool to 0-5 C and stir overnight. A large amount of white crystals precipitated. Filtration at low temperature and drying under vacuum at room temperature gave 202.6 g of product (S) -N-BOC-3-hydroxypiperidine with a purity of 99.29% and a yield of 96.47%. |
| 84% |
With triethylamine; In ethanol; at 0 - 20℃; for 1h; |
[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 10% 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, 84%). 1H NMR (CDCl3) delta 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, 75%). 1H NMR (CDCl3) delta 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, 28%). 1H NMR (CDCl3) delta 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×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, 20%). [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×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, 41%). [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×5), then dried under reduced pressure giving COMPOUND 8 as a yellow solid (26 mg, 0.038 mmol, 70%). 1H NMR (D2O) delta 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) delta 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 ... |
| 83.6% |
With triethylamine; In dichloromethane; at 20℃; for 1h; |
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)20 (2.60 g, 11.9 mmol). The reaction mixture was stirred at rt for 1 h and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v) = 50/1) to give the title compound as light yellow liquid (1.88 g, yield 83.6%). LC-MS (ESI, pos.ion) m/z: 146.3 [(M+H)-56]+. |
| 78% |
With sodium hydroxide; In tetrahydrofuran; water; |
1-(1,1-Dimethylethoxycarbonyl)-3-hydroxypiperidine <strong>[6859-99-0]3-Hydroxypiperidine</strong> (10.1 g, 0.1 mol) was dissolved in tetrahydrofuran (50 ml) and 1N aqueous sodium hydroxide solution (95 ml) was introduced. The solution was cooled to 0 C. and a solution of di-tert-butyl dicarbonate (24.0 g, 0.11 mol) in tetrahydrofuran was added over 1 h. The reaction mixture was stirred at ambient temperature for 18 h and evaporated to an aqueous suspension. Water (100 ml) was added and the mixture was extracted with dichloromethane (3*100 ml). The combined extracts were dried (MgSO4), evaporated and the residue was recrystallized from n-heptane to provide the title product as a solid (15.71 g, 78%), mp 67-69 C. |
| 70% |
In water (50 ml)-acetonitrile; water; |
115a) tert-Butyl 3-hydroxypiperidine-1-carboxylate Di-tert-butyl dicarboxylate (26.19 g) was added dropwise to a solution of 3-hydroxypiperidine (10.1 g) in water (50 ml)-acetonitrile (100 ml) at room temperature. The reaction mixture was stirred for 1 hour and then concentrated under reduced pressure, followed by addition of water and extraction with ethyl acetate. The extract was washed with eater and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was crystallized from hexane to obtain the title compound as colorless crystals (14.13 g, 70%). NMR (CDCl3) delta: 1.40-1.60 (2H, m), 1.46 (9H, s), 1.70-1.80 (1H, m), 1.84-1.94 (1H, m), 3.00-3.18 (2H, m), 3.48-3.60 (1H, m), 3.66-3.78 (2H, m). |
|
With triethylamine; In ethanol; at 10 - 20℃; |
3-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (B): A 3-L flask was charged with A (Scheme 1) (100 g, 0.726 mol), 1.5 L EtOH, and triethylamine (145 g). The solution was cooled to 10 C. and (BOC)2O was added dropwise as an EtOH solution (500 mL) via addition funnel over 20 min. The ice bath was remover and the reaction was stirred at room temperature overnight. The solvent was then removed in vacuo. The residue was taken up in 2 L CH2Cl2 and washed with water (*2). The organic phase was dried (Na2SO4) and concentrated to an oil. The oil was passed through a short plug of silica gel (4:1 EtOAc:hexane), which after concentration and drying gave B (150 g) as a white waxy solid. |
|
With triethylamine; In dichloromethane; at 0 - 20℃; for 12h; |
Synthesis of tert-Butyl 3-hvdroxypiperidine-l-carboxylateTo a mixture of 3-hydroxy piperidine (4.0gm, 39.6 mmole) and triethyl amine (11.0ml, 79.0mmole) in dichloromethane (70 ml) at 00C was added tert-butoxy carbonyl anhydride (10.4 gm, 47.4 mmole) and stirred the reaction mixture at room temperature for 12 hrs. The reaction mixture was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the title compound. Mass (m/z): 128 (MH+- tert. butanol). |
|
In sodium carbonate; |
Step A N-(tert-Butoxycarbonyl)-3-piperidinol To a solution of 3-piperidinol (2.51 g; 18.2 mmol) in 10% Na2 CO3 (66 ml) and dioxane (27 ml), cooled to 0 C., is added di-tert -butyl dicarbonate (3.57 g; 17.1 mmol) portionwise. After the addition, the reaction mixture was stirred for an additional two hours at room temperature. The aqueous phase was extracted with EtOAc (5*100 ml). The combined organic extracts were then washed with 10% aqueous citric acid, water, saturated aqueous NaCl, dried (MgSO4), filtered, and evaporated. The compound was dried in vacuo to afford 2.93 g of the title compound which was used in the next step without further purification. 1 H-NMR (300 MHz, CD3 OD, ppm): delta1.03-1.53 (m, 11H), 1.54-1.79 (m, 1H), 1.80-1.95 (m, 1H), 2.53-3.09 (m, 2H), 3.4-3.53 (m, 1H), 3.55-3.72 (m, 1H), 3.73-3.90 (dd, 1H). |
|
With sodium hydrogencarbonate; In water; at 20℃; |
A. N-BOC-3-(R,S)-Hydroxy-piperidine 202.4 g of 3-(R,S)-hydroxypiperidine are dissolved in 4,5 I of deionised water in a 10 I reactor. 336 g of sodium hydrogencarbonate, dissolved in 1.1 I water are added. To the vigorously stirred solution 534 g of di-tert.-butyl-dicarbonate are added at room temperature. After stirring overnight the mixture is extracted with CH2Cl2 (3x). The combined extracts are washed with deionised water and the solvent is distilled off. The residue is dissolved in CH2Cl2 again and the solution is evaporated to dryness. 423 g of N-BOC-3(R,S)-hydroxypiperidine are obtained which can be used in the next step without further purification. |
|
With triethylamine; In tetrahydrofuran; at 0℃; |
10 g of 3-hydroxypiperidine and 15 ml of triethylamine were dissolved in 100 ml of tetrahydrofuran. While stirring in an ice bath, a solution of 22.9 g of di-tert-butyl dicarbonate in 50 ml of tetrahydrofuran was added dropwise thereto. After completion of the dropwise addition, the reaction mixture was stirred for 1 hour and then evaporated. 25 ml of triethylamine was added to the residue and a solution of 25 g of pyridine trioxide-sulfur complex in 100 ml of dimethyl sulfoxide was added dropwise thereto, followed by stirring for 2 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with an aqueous hypochlorous acid solution, water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography with 30% ethyl acetate/hexane, to give 13.1 g of the title compound.1H-NMR(CDCl3) deltappm=1.47(9H, s), 1.94-2.02(2H, m), 2.47(2H, t, J=7Hz), 3.59(2H, t, J=6Hz), 4.00(2H, s) |
|
With potassium carbonate; In water; ethyl acetate; at 20℃; for 16h; |
A mixture of 3-hydroxypiperidine (10.0 g, 98.9 mmol), di-tert-butyldicarbonate (22.7 g, 103.8 mmol) and potassium carbonate (68.3 g, 495 mmol) in ethyl acetate-water (200 mL - 300 mL) was stirred at room temperature for 16 hr. The ethyl acetate layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 80: 20 - 50: 50) to give a colorless oil (18.9 g). This was dissolved in pyridine (100 mL), p-toluenesulfonyl chloride (19.7 g, 103.3 mmol) was added, and the mixture was stirred at room temperature for 2 days. The reaction solution was concentrated under reduced pressure, and the obtained residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed with 1N hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 90:10 - 80:20 - 50:50) to give the title compound (32.2 g, 96%) as a colorless oil. 1H NMR (300 MHz, CDCl3) delta 7.81 (d, J=8.5Hz, 2H), 7.34 (d, J=7.9Hz, 2H), 4.45 (br s, 1H), 3.63-3.48 (m, 1H), 3.48-3.15 (m, 3H), 2.45 (s, 3H), 1.95-1.66 (m, 3H), 1.52-1.36 (m, 10 H). |
|
With triethylamine; In dichloromethane; for 3h; |
To 3-hydroxypiperidine (3.03 g, 30 mmol) in dichloromethane (30 mL) was added triethylamine (6 mL) and Boc20 (7 g, 32 mmol). After stirring for 3h, the reaction mixture quenched with saturated NaHC(¾, and extracted with dichloromethane. The combined organic layer was washed with H20, dried and concentrated to give crude product, which was washed with hexane to give tert-butyl 3-hydroxypiperidine-l-carboxylate as white power (5.4 g). |
| 675 g |
With sodium carbonate; In methanol; water; at 9 - 20℃; |
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. |
|
With sodium hydroxide; In tetrahydrofuran; water; at 0 - 20℃; for 2h;pH 11.0; |
(R)-pyrrolidinol (Tokyo Chemical Industry Co., Ltd., 12.4 g, 100 mmol) was dissolved in 100 ml of a 3 N aqueous solution of sodium hydroxide. A solution (50 ml) of di-tert-butyl dicarbonate (Tokyo Chemical Industry Co., Ltd., 25.0 g, 120 mmol) in tetrahydrofuran was added dropwise thereto at 0C. The pH value of the mixture was confirmed to be 11 with a pH test paper. The mixture was stirred at room temperature for 2 hr and was then concentrated to remove a major part of tetrahydrofuran. The aqueous layer was extracted three times with ethylacetate. The combined organic layer was dried over sodium sulfate and was concentrated to give a crude product. The crude product and triethylamine (20 ml) were dissolved in anhydrous dimethylsulfoxide (100 ml). Finely triturated sulfur trioxide/trimethylamine complex (Aldrich, 28.0 g, 200 mmol) was added thereto little by little at room temperature. The mixture was stirred at room temperature for 18 hr. Thereafter, 200 ml of water was added to stop the reaction. The aqueous layer was extracted three times with ethylacetate. The combined organic layer was dried over sodium sulfate and was concentrated to give a crude product. The crude product was purified by a silica gel column eluted with chloroform. The development was carried out with chloroform to give an intermediate (15.6 g). The intermediate (3.70 g, 20 mmol) and 5-aminoisoquinoline (Aldrich, 2.48 g, 17 mmol) were dissolved in 100 ml of acetic acid. Sodium sulfate (14.2 g, 100 mmol) was added thereto, and the mixture was stirred at room temperature for 30 min. The reaction mixture was cooled to 0C. Sodium hydride triacetate (Aldrich, 4.44 g, 20 mmol) was added thereto little by little, and the mixture was stirred at room temperature for 18 hr. The reaction solution was concentrated under the reduced pressure to remove a major part of acetic acid. The reaction mixture was then adjusted to pH 8 by the addition of a saturated sodium hydrogencarbonate solution and was filtered through Celite, and the filtrate was separated into an organic layer and an aqueous layer. The aqueous layer was extracted three times with ethylacetate. The combined organic layer was dried over sodium sulfate and was concentrated to give a crude product. The crude product dissolved in methylene chloride was purified by a silica gel column and developed with hexane. The development was first carried out with hexane only, then with hexane/chloroform (1 : 1), and finally with chloroform only to collect a fraction having UV absorption with Rf = 0.6 to give the title compound (3.720 g, 12 mmol). 1H-NMR (CDCl3, 400 MHz): 1.44 (s, 9H), 1.48 - 1.68 (m, 1 H), 1.73 - 1.83 (m, 2H), 1.90 - 2.10 (m, 1 H), 3.10 - 3.32 (m, 2H), 3.52 - 3.65 (m, 2H), 3.92 - 3.98 (m, 1H), 6.86 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1 H), 7.45 (t, J = 7.9 Hz, 1 H), 7.54 (d, J = 5.8 Hz, 1 H), 8.42 (d, J = 5.8 Hz, 1 H), 9.13 (s, 1 H). Mass spectrometric value (ESI-MS, m/z): 328 (M++1) |
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
HazMat Fee +
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
