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With lithium hydroxide monohydrate; In tetrahydrofuran; water; at 70℃; for 6h;
Step 2. 1-tert-Butyl 3-methyl 3-methylpiperidine-1,3-dicarboxylate. To a solution of 1-tert-butyl 3-methyl 3-methylpiperidine-1,3-dicarboxylate (15.86 g, 0.062 mol) in THF (100 ml) and H2O (10 ml) was added LiOH.H2O (7.76 g, 0.186 mol) at room temperature. The mixture was refluxed at 70 C. for 6 h. After TLC (Petroleum ether/EtOAc, 4:1, stained by iodine) showed the starting material to be consumed, the mixture was concentrated to dryness. The residue was diluted with H2O (300 mL) and then extracted with MTBE (100 mL×2). The organic layers were discarded. The resulting aqueous layer was acidified to pH 1 with 1M HCl (aq.) and then extracted with MTBE twice. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to give 1-tert-butyl 3-methyl 3-methylpiperidine-1,3-dicarboxylate (13.97 g, 93%) as a white solid.
With sodium hydroxide; ethanol; at 25 - 70℃; for 3h;
A solution of ester from Preparative Example X-910-C (1.08 g, 4.20 mmol) in EtOH (16.8 mL) at 25 C. was treated with NaOH (0.050 g, 3 equiv.). The solution was heated at 70 C. for 3 h. The solution was cooled to 25 C. and concentrated under reduced pressure. The residue was dissolved in H2O (50 mL). The aqueous layer was washed with Et2O (2×30 mL). The aqueous layer was acidified to pH=1 with 1 M HCl. The aqueous layer was extracted with Et2O (2×30 mL) and the organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was used directly in the next reaction.
With diphenyl phosphoryl azide; triethylamine; In toluene; at 20 - 90℃; for 2.5h;
Step 3. tert-Butyl 3-isocyanato-3-methylpiperidine-1-carboxylate. To a solution of 1-tert-butyl 3-methyl 3-methylpiperidine-1,3-dicarboxylate (5.97 g, 24.5 mmol) in anhydrous toluene (65 mL) was TEA (3.5 mL, 24.5 mmol) and DPPA (6 mL, 27 mmol) dropwise at room temperature. The reaction mixture was stirred at rt for 30 min and then refluxed at 90 C. for 2 h. The reaction was poured into ice water (100 mL) and extracted with MTBE (100 mL×3). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to dryness to give tert-butyl 3-isocyanato-3-methylpiperidine-1-carboxylate (5.9 g, 100%) as a yellow oil, which was used without purification in the next step
With diphenylphosphoranyl azide; triethylamine; In toluene; at 20 - 90℃; for 1.5h;
To a suspension of 727 mg (3.0 mmol) <strong>[534602-47-6]rac-3-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester</strong> (CAS: 534602-47-6) in 8 ml toluene was added at ambient temperature 0.42 ml (3.0 mmol) triethylamine. To the resulting solution was added under stirring 0.72 ml (3.3 mmol) diphenylphosphoryl azide and the mixture heated to 90 C. (gas evolution) for 90 min. The reaction mixture was poured onto iced water and extracted 3 times with tert-butyl methyl ether. The combined extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. The title compound was obtained as slightly yellow oil which was used without purification in the next step. MS (m/e): 240 (M).
t-butyl 3-((4-chlorophenyl)carbamoyl)-3-methylpiperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; for 48h;Inert atmosphere;
[00179] To the solution of carboxylic acid (0.5g, 2.06 mmole), DMAP (25 mg, 0.20) and 4-chloroaniline (0.26 g) in DCM (20 mL) was added EDC (0.43 g). The reaction mixture was stirred under N2 for 48 h. The reaction mixture was extracted with saturated NaHCO3 (10 mL), 10% KHSO4 (10 mL) and water (2 x 10 mL). The solution was dried (NaSO4) and the solvent was removed under reduced pressure to give the product (0.61g, 84%) in good purity for further transformation.
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