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Production Example 94 N-methoxy-N-methyl-1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxamide After dissolving 2.19 g of <strong>[614731-04-3]1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxylic acid</strong> in 30 ml of dichloromethane, 2.16 g of 1, 1'-carbonyldimidazole was added and the mixture was stirred at room temperature for 1.5 hours. Next, 1.30 g of N-methyl-O-methylhydroxylamine hydrochloride was added and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed Withl aqueous sodium carbonate solution, water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (2.33 g, 90% yield). 1H-NMR (400 MHz, CDCl3); delta (ppm) 1.46 (9H, s), 1.93-2.14 (4H, mn), 3.04-3.18 (2H, m), 3.23 (3H, s), 3.72 (3H, s), 3.86-4.0$ (2H, m).
N-(1-((5-chloro-2-phenyl-benzofuran-7-yl)methyl)-5-methyl-1H-pyrazol-3-yl)-4-fluoro-4-piperidinecarboxamide hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;
Example 53 (E53) <n="93"/>lambda/-f1-f(5-Chloro-2-phenyl-1-benzofuran-7-yl)methvn-5-methyl-1H-pyrazol-3-yl)-4- fluoro-4-piperidinecarboxamide hydrochlorideSolution of 1-[(5-chloro-2-phenyl-1-benzofuran-7-yl)methyl]-5-methyl-1 H-pyrazol-3-amine (0.050 g, 0.15 mmol) in dry DCM (1.0 ml) was stirred at room temperature under argon. 1- [(1 ,1-dimethylethyl)oxy]carbonyl}-4-fluoro-4-piperidinecarboxylic acid (0.037 g, 0.15 mmol), EDAC (0.028 g, 0.15 mmol) and HOBt (0.020 g, 0.15 mmol) were added and the solution stirred at room temperature overnight. After this time, the solution was diluted with DCM and the organics were washed with water. Organics were dried over MgSO4, filtered and concentrated under reduced pressure to give a pale yellow oil. The residue was purified [SiO2, EtOAc:Hex 50-100%] to give the title compound. The compound was further purifed using MDAP and the sample treated with MsOH to remove the Boc group. (12 mg) LC/MS Rt = 2.56 min, [M+H]+ 467, 469.
Description 1 (DD 1-fr(1.1-Dimethylethyl)oxy1carbonyl)-4-fluoro-4-piperidinecarboxylic acid <n="34"/>Solution of 4-fluoro-1-(1 ,1-dimethylethyl)-1 ,4-piperidine dicarboxylic acid -4-methyl ester (1.00 g, 4.02 mmol) in EtOH (16 ml) was stirred at room temperature. 2M NaOH (5.0 ml, 10.05 mmol) was added and the solution heated to 60 0C for 5 % hours. After this time, the solution was left to cool to room temperature overnight. The solution was then acidified using 2M HCI and the organics were extracted into EtOAc (x 2). The combined organics were dried over MgSO4, filtered and concentrated under reduced pressure to give a white coloured solid (0.767 g)
Step 5 To a stirred solution of 16d (0.29 g, 1.173 mmol) in 10 mL of CH2Cl2 was added oxalyl chloride (0.12 mL, 1.38 mmol) followed by a catalytic amount of DMF. The mixture was stirred at room temperature for 1.5 h. Triethylamine (0.4 mL, 2.87 mmol) was added. A solution of 30g (0.34 g, 1.347 mmol) in 2 mL of CH2Cl2 was added. The reaction mixture was allowed to stir for 2.5 days, then was diluted with CH2Cl2 (50 mL), washed with a 1.0 M HCl aqueous solution and brine, dried over Na2SO4, and concentrated in vacuo to provide an oily solid residue. The residue was dissolved in 10 mL of CH2Cl2 and 2 mL of trifluoroacetic acid and allowed to stir for 5 hours, then concentrated in vacuo. The residue obtained was dissolved in 50 mL of CH2Cl2, washed with a saturated NaHCO3 aqueous solution and brine.The organic solution was dried, and concentrated to provide a crude oil, which was purified using preparative TLC (CH2Cl2-7N NH3 in MeOH=25:1, v/v) to provide compound 30h (260 mg, 58%, MH+=382.2).
With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 5h;
1-(tert-Butoxycarbonyl)-4-fluoropiperidine-4-carboxylic acid 13a (5.0 g, 20 mmol) was dissolved in 50 mL of THF.A borane tetrahydrofuran solution (50 mL, 1 M/THF) was added dropwise at 0 C, and the mixture was reacted at room temperature for 5 hours. Slow down in the reaction solution at 0 CThe reaction was quenched by slowly adding 20 mL of methanol. Concentrate under reduced pressure to remove the solvent. Add 50 mL of water and extract with ethyl acetate (50 mL×3).The combined organic layers were washed with EtOAc EtOAc (EtOAc)Fluor-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester 13b (4.7 g, colorless oil), yield: 100%.
98%
With borane-THF; In tetrahydrofuran; for 32h;Reflux;
To a solution of 1- (tert-butoxycarbonyl) -4-fluoropiperidine-4-carboxylic acid (5.00 g, 20.20 mmol) in tetrahydrofuran (100 mL) was added a solution of borane tetrahydrofuran complex (30.3 mL, 30.30 mmol, 1.0 M solution in tetrahydrofuran) . The reaction mixture was refluxed for 16 hours, and then another 24 mL of borane tetrahydrofuran complex was added and continued to reflux for another 16 hours. After cooling to ambient temperature the reaction mixture poured onto ice-cold water (50 mL) and saturated ammonium chloride (100 mL) , and extracted with ethyl acetate (3 x 100 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to afford the title compound (4.60 g, 98) . Which was used in the next step without further purification: MS (ES+) m/z 234.1 (M +1) .
With borane-THF; In tetrahydrofuran; for 32h;Reflux; Inert atmosphere;
Step 1. Preparation of tert-Butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (0341) <strong>[614731-04-3]1-(tert-butoxycarbonyl)-4-fluoropiperidine-4-carboxylic acid</strong> (5.00 g, 20.20 mmol) in tetrahydrofuran (100 mL) was added a solution of borane tetrahydrofuran complex (30.3 mL, 30.30 mmol, 1.0 M solution in tetrahydrofuran). The reaction mixture was refluxed for 16 hours, and then another 24 mL of borane tetrahydrofuran complex was added and continued to reflux for another 16 hours. After cooling to ambient temperature the reaction mixture poured onto ice-cold water (50 mL) and saturated ammonium chloride (100 mL), and extracted with ethyl acetate (3×100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to afford the title compound (4.60 g, 98%). Which was used in the next step without further purification: MS (ES+) m/z 234.1 [M+H]+.
A solution of <strong>[614731-04-3]1-boc-4-fluoro-4-piperidinecarboxylic acid</strong> (300 mg, 1.15 mmol) in ethylene glycol dimethyl ether (15 mL) was treated with 4-methylmorpholine (0.13 mL, 1.15 mmol) and isopropyl chloroformate (1 M solution in toluene, 1.38 mL, 1.38 mmol) at -15C. After stirring for 10 mm, ammonia solution (0.5 M in dioxane, 3.50 mL, 1.75 mmol) was added.The reaction mixture was stirred at RT for 18h. The solvents were evaporated under reduced pressure, the crude product was dissolved in EtOAc, washed with 1 N NaOH solution, water and brine and the organic layers were dried over sodium sulfate, filtered and evaporated to dryness to get 185 mg (65 %) of a white powder. The product was used for the next step without further purification. LCIMS (Method A): Rt = 1.79 mm,(M+H) 173.
90%
With ammonium chloride; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 25℃;
tert-Butyl 4-carbamoyl-4-fluoropiperidine-1-carboxylate (0414) In a 250-mL round-bottom flask were combined <strong>[614731-04-3]1-[(tert-butoxy)carbonyl]-4-fluoropiperidine-4-carboxylic acid</strong> (3 g, 12.13 mmol, 1.00 equiv), DMF (50 mL), NH4Cl (1.75 g, 32.72 mmol, 1.50 equiv), HATU (9.23 g, 24.27 mmol, 2.00 equiv), and iPr2NEt (3.13 g, 24.22 mmol, 2.00 equiv). The resulting solution was stirred overnight at 25 C. The resulting solution was extracted with 200 mL of EtOAc and the organic layers were combined, washed with 5×50 mL of H2O, then applied onto a silica gel column with ethyl acetate/petroleum ether, affording 2.7 g (90%) of the product as a white solid.
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