| 88% |
Stage #1: 2-chloro-3,4-bis[(4-methoxyphenyl)methoxy]benzoic acid With triethylamine In N,N-dimethyl acetamide at -10℃; for 0.0833333h;
Stage #2: With methanesulfonyl chloride In N,N-dimethyl acetamide at -10℃; for 0.5h;
Stage #3: (R)-(+)-3-(dimethylamino)pyrrolidine In N,N-dimethyl acetamide at -10℃; for 0.5h; |
20.1 Step (1): Compound 20a + Compound 2d → Compound 20b
To a solution of Compound 2d (2.14 g, 5 mmol) in N,N-dimethylacetamide (20 mL) triethylamine (0.83 ml, 6 mmol) was added, and then stirred at -10°C for 5 minutes. Methanesulfonyl chloride (0.51 ml, 6.5 mmol) was added in one portion, and then stirred at -10°C for 30 minutes. Subsequently, Compound 20a (0.57 g, 5 mmol) was added thereto, and then stirred at the same temperature for 30 minutes. The reaction solution was diluted with ethyl acetate, and then washed with aqueous saturated sodium hydrogen carbonate solution, water, then saturated brine. The organic layer was then dried with magnesium sulfate. After magnesium sulfate was filtered, the filtrate was concentrated in vacuo, and then subjected to silica gel column chromatography, eluting with chloroform - methanol. Fractions containing the desired compound were concentrated under reduced pressure to yield Compound 20b (2.3 g, 88%).MS: 525.83 (M+H)1H-NMR (CDCl3) δ: 1.69-1.86 (2H, m), 2.71-2.78 (1H, m), 2.94 (3H, s), 3.01 (3H, s), 3.16-3.38 (2H, m), 3.51-3.61 (1H, m), 3.79 (3H, s), 3.83 (3H, s), 3.87-4.16 (1H, m), 4.97 (2H, s), 5.06 (2H, s), 6.81 (2H, d, J=6.8), 6.89-6.99 (4H, m), 7.31-7.36 (4H, m). |
| 88% |
Stage #1: 2-chloro-3,4-bis[(4-methoxyphenyl)methoxy]benzoic acid With methanesulfonyl chloride; triethylamine In N,N-dimethyl-formamide at -10℃; for 0.5h; Inert atmosphere;
Stage #2: (R)-(+)-3-(dimethylamino)pyrrolidine In N,N-dimethyl acetamide; N,N-dimethyl-formamide at 0℃; for 1h; Inert atmosphere; |
[Method B]
General procedure: To a solution of 1.0 equivalent of the acid derivative in DMF were added 1.1 equivalent of Et3N. To this solution was added 1.1 equivalent of MsCl at one portion at-10°C and stirred for 30min. To this resulting mixture were added 1.1 equivalent of Et3N and 1.1 equivalent of amine, and stirred for 1hat 0°C. The solvent was evaporated in vacuo, the resulting residue was diluted with a mixture of aq. 2mol/L NaOH and EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc and the combined extracts were washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The resulting residue was subjected to silica gel chromatography, eluting with EtOAc (containing 5% of Et3N)-MeOH. The eluted fractions containing the desired compound were concentrated in vacuo to afford a target amide derivative. |
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