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With triphenylphosphine; diethylazodicarboxylate; In dichloromethane; toluene; at 20 - 40℃;
The4-chloro-7-methoxy-6-[1- (tert-butoxycarbonyl) piperidin-3-yloxy) ] quinazoline starting material was prepared as follows: Diethyl azodicarboxylate (9. 41ml, 40% solution in toluene) was added to a mixture of <strong>[574745-97-4]4-chloro-6-hydroxy-7-methoxyquinazoline</strong> (2.90g ; prepared as described in Example 16- preparation of starting materials), triphenylphosphine (5.43g) and tert-butoxycarbonyl-3- hydroxypiperidine (4.15g) in dichloromethane (75ml). The resulting solution was heated to 40C for 6 hours, and then allowed to stand overnight at room temperature. This was purified by flash column chromatography eluting with isohexane (79%), acetone (20%), and triethylamine (1%) to give 4-chloro-7-methoxy-6- [l- tert-butoxycarbonyl) piperidin-3- yloxy] quinazoline as a white solid (2.47g, 53%) ; 1H NMR Spectrum : (CDC13) 1. 5 (m, 9H) ; 1.6 (m, 1H); 1.9 (m, 2H) ; 2.1 (m, 1H); 3.5 (m, 1H); 3.6 (m, 1H); 4.0 (s, 3H); 4.2-3. 9 (m, 2H) ; 4.5 (m, 1H); 7.3 (s, 1H) ; 7.4 (s, 1H); 8.9 (s, lH) ; Mass Spectrum : (M+H) : 394.
2-fluoro-5-(2-piperazin-1-yl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
The title compound was prepared using Mitsunobu followed by Buchwald condition from <strong>[2040-90-6]2-chloro-6-fluoro phenol</strong> and racemic N-boc-3-hydroxypiperidine. MS found 380.3 M+1
With triethylamine; In dichloromethane; at 0 - 5℃; for 1h;
Triethylamine (15.1 g) and methane sulfonyl chloride (6.26 g) was slowly added to a solution of N-Boc-3-hydroxy piperidine (10 g) in dichloromethane (200 mL) at 0-5 °C. The mixture was stined for 60 mm at 0-5 °C and water (200 mL) was added. The layers were separated and the organic layer was washed with water (200 mL) and concentrated to give tert-butyl-(S)-3- ((methylsulfonyl)oxy)piperidine- 1 -carboxylate.
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 50℃; for 60h;
Sodium hydride (1 g, 25 mmol) was added to 1-Boc-3-hydroxypiperidine (CAS:85275-45-2; 5 g, 25 mmol) in DMF (100 mL) at 0 °C. The mixture was allowed to warm to rt and then it was cooled again to 0 °C. A solution of 2,6-dimethyl-4- chloropyridine (CAS: 35 12-75-2; 3.52 g, 25 mmol) in DMF (10 mL) was addeddropwise. The mixture was stirred at 50 °C for 60 h. Then the mixture was cooled to rt. Water was added and the mixture was extracted with EtOAc. The organic layer was dried over Mg504, filtered and evaporated under vacuum. The resulting residue was purified by flash chromatography (silica gel, DCM, 1percent MeOH in DCM, 2percent, 4percent) The pure fractions were evaporated under vacuum affording intermediate 1 (2.52 g, 33percent).
To a stirred solution of tert- butyl 3-hydroxy- l-piperidinecarboxylate (2500 mg, 12.42 mmol) in DMF (10 mL) at -40 C, was added 2-chloro-4-iodo-6-trifluoromethyl- pyridine (CAS 205444-22-0, 3.62 g, 12.42 mmol) in DMF (4 mL) dropwise. The mixture was gradually warmed to rt and stirred for 16 h. The mixture was diluted with EtOAc and washed with H20 and brine. The organic layer was separated, dried (Na2S04), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica; EtOAc in heptane 0/100 to 50/50). The desired fractions were collected and concentrated in vacuo to yield intermediate 26 (2.8 g, 59%) as a light- yellow oil.
59%
Sodium hydride (CAS: 7646-69-7; 60% dispersion in mineral oil, 0.50 g, 12.42 mmol) was added to a stirred solution of l-Boc-3-hydroxypiperidine (CAS: 85275-45-2; 2.5 g, 12.42 mmol) in DMF (14 mL) at -40 C. The mixture was stirred at -40 C for 30 min and then a solution of <strong>[205444-22-0]2-chloro-4-iodo-6-trifluoromethylpyridine</strong> (CAS: 205444-22-0; 3.82 g, 12.42 mmol) in DMF (4 mL) was added dropwise. The mixture was allowed to warm to rt and then was stirred for 16 h. Then the mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried (Na2S04), filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica; EtOAc in heptane, gradient from 0/100 to 50/50). The desired fractions were collected and concentrated in vacuo to yield intermediate 4d as a light-yellow oil (2.8 g, 59%).
With sodium hydride; In tetrahydrofuran; mineral oil; at 60℃;
General procedure: l-Boc-3-hydroxypiperidine (CAS 85175-45-2, 0.41 g, 2.05 mmol) was stirred in DMF (1.65 mL), at rt, and then a 60% NaH dispersion in mineral oil (0.082 g, 2.05 mmol) was added. Then 4-chloro-2,6-dimethylpyridine (CAS 3512-75-2, 0.26 mL, 2.05 mmol) in DMF (0.64 mL) was added dropwise at rt. The mixture was stirred overnight at 60 C. The mixture was evaporated diluted with FLO and was extracted with EtOAc. The organic layer was separated, dried (Na2S04), filtered and evaporated, in vacuo. The residue was purified by flash column chromatography (silica; EtOAc in heptane 0/100 to 30/70). The desired fractions were collected and concentrated in vacuo to yield intermediate 22 (0.32 g, 51%) as a colorless oil(0656) Intermediate 129 was prepared following an analogous procedure to the one described for the synthesis of intermediate 22 using <strong>[38557-72-1]2-chloro-3,5-dimethylpyrazine</strong> (CAS 38557- 72-1) as starting material and THF as solvent.
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