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With potassium carbonate; In dimethyl sulfoxide; at 110℃; for 12h; |
General procedure: To a mixture of 5a (5.0g, 32.44 mmol, 1 equiv) and (2S,6R)-2,6-dimethylpiperazine (3.7g, 32.44 mmol, 1 equiv) in 60 mL DMSO was added K2CO3 (8.97g, 64.88 mmol, 2 equiv). The mixture was heated at 110 C for 12 h. The reaction mixture was diluted with 120 mL ice water. Ethyl acetate was added and the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, then dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was further purified via silica gel chromatography to give ethyl 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate as a white solid (7.25g, 90%). 1H NMR (300 MHz, CDCl3) delta 7.85 (d, J=9.0Hz, 2H), 6.79 (d, J=9.0Hz, 2H), 4.26 (q, J=7.1Hz, 2H), 3.60 (d, J=12.0Hz, 2H), 2.96-2.88 (m, 2H), 2.32 (t, J=11.3Hz, 2H), 1.30 (t, J=7.1Hz, 3H), 1.08 (d, J=6.3Hz, 6H). The obtained methyl 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate was dissolved in dichloromethane (DCM) and stirred for 15 min after adding 1 N NaOH (aq) (32.12 mL, 32.12 mmol, 1.1 equiv). Then a solution of di-tert-butyl dicarbonate ester in DCM was added dropwise. The reaction mixture was stirred at room temperature until the starting material was consumed completely. The reaction mixture was then extracted with DCM and the organic phase was washed with saturated NaHCO3 (aq) and brine, then dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was further purified via silica gel chromatography to give 6a as colorless oil. (10.00 g, 98%). 1H NMR (300 MHz, CDCl3) delta 7.77 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 8.7 Hz, 2H), 4.20-4.08 (m, 4H), 3.44 (d, J = 12.5 Hz, 2H), 2.87 (dd, J = 12.4, 3.8 Hz, 2H), 1.35 (s, 9H), 1.20 (t, J = 7.1 Hz, 3H), 1.14 (d, J = 6.8 Hz, 6H). To a solution of 6a (10.00 g, 28.70 mmol, 1 equiv) dissolved in MeOH was added 1 N NaOH (aq) (57.40 mL, 57.40 mmol, 2 equiv). The mixture was heated at 60 C for 4 h and allowed to cool down to room temperature. The reaction mixture was acidified with 2 N HCl (aq) to adjust PH to 5-6. The resulting precipitate was collected by filtration, washed with water and dried to a constant weight to afford 4-((3R,5S)-4-(tert-butoxycarbonyl)-3,5-dimethylpiperazin-1-yl)benzoic acid (9.79 g, 98%). 1H NMR (300 MHz, DMSO) delta 7.76 (d, J = 8.7 Hz, 2H), 6.97 (d, J = 8.9 Hz, 2H), 4.18-4.05 (m, 2H), 3.75 (d, J = 12.8 Hz, 2H), 2.98 (dd, J = 12.9, 4.3 Hz, 2H), 1.42 (s, 9H), 1.19 (d, J = 6.7 Hz, 6H). The obtained acid (9.79 g, 29.28 mmol, 1 equiv) was dissolved in dry DCM and allowed to cool down to 0 C. DMF (22.57 mL, 292.8 mmol, 10 equiv) and thionyl chloride (4.25 mL, 58.56 mmol, 2 equiv) dissolved in dry DCM were added dropwise to the mixture above. Then the reaction mixture was allowed to warm up to room temperature slowly and left to stir for 2 h. The solvent was removed under reduced pressure at room temperature. Then the residue was redissolved in dry DCM, and was added to the DCM solution of NH4OH (11.28 mL, 292.8 mmol, 10 equiv), which was cooled down to 0 C already. The ice-bath was removed and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was then extracted with DCM and the organic phase was washed with saturated NaHCO3 (aq) and brine, then dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was further purified via silicagel chromatography to give 7a as a white solid (4.88 g, 50%). 1H NMR (300 MHz, CDCl3) delta 7.67 (d, J = 8.5 Hz,2H), 6.81 (d, J = 8.7 Hz, 2H), 5.87 (s, 2H), 4.29-4.10 (m, 2H), 3.50 (d, J = 12.3 Hz, 2H), 2.97 (dd, J = 12.3, 3.8 Hz, 2H), 1.43 (s, 9H), 1.25 (d, J = 6.8 Hz, 6H). 14 (8.0 g, 26.69 mmol, 1 equiv), methylamine hydrochloride (2.7 g, 40.04 mmol, 1.5 equiv), EDCl (7.68 g, 40.04 mmol, 1.5 equiv), HOBt (3.61 g, 26.69 mmol, 1.0 equiv) and DIPEA (11.02 mL, 66.72 mmol, 2.5 equiv) were dissolved in dry DCM and the reaction mixture was left to stir at room temperature overnight. The reaction mixture was then extracted with DCM and the organic phase was washed with saturated NaHCO3 (aq) and brine, then dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was further purified via silica gel chromatography to give 15 as white solid (8.0 g, 95.8%). 1H NMR (300 MHz, CDCl3) delta 8.40 (d, J = 9.2 Hz, 1H), 8.18 (d, J = 5.5 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 6.8 Hz, 1H), 7.51-7.42 (m, 2H), 7.24 (dd, J = 9.3, 2.3 Hz, 1H), 6.78 (d, J = 7.6 Hz, 2H), 6.05 (d, J = 4.0 Hz, 1H), 3.05 (d, J = 4.9 Hz, 3H). 7a (100 mg, 0.30 mmol, 1 equiv) and 15 (112.56 mg, 0.36 mmol, 1.2 equiv) were dissolved in 10 mL dry dioxane. Then Pd2(dba)3 (27.47 mg, 0.03 mmol, 0.1 equiv), Xantphos (34.72 mg, 0.06 mmol, 0.2 equiv) and Cs2CO3 (195.49 mg, 0.60 mmol, 2 equiv) were added to the mixture above. The reaction mixture was left to stir at 110 C for 5 h under nitrogen atmosphere. The reaction mixture was then extracted with DCM and the organic phase was washed with saturated NaHCO3 (aq) and brine, ... |
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