| 86.4% |
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A solution of 0.9M n-butyl magnesium chloride in tetrahydrofuran (0.9M, 7.3mL) was added to toluene (18.0mL) at -16 C and a solution of n-butyl lithium in n-hexane was added dropwise at -12~-16 C (2.66 M, 4.9 mL) and stirred at -12 to -15 C for 16 minutes.2- (5-bromo-2-fluorobenzyl) -1-benzothiophene (Compound I, 2.000 g) at -12 to -15 C,Of a toluene solution (10.0 mL)The reaction solution was dropped,At -12 to -16 CStir for one hour.A solution of 2,3,4,6-di-O- (trimethylsilyl) -D-glucono-1,5-lactone (Compound II, 3.197g) in toluene (10.0 ML) was added dropwise to the reaction solution, and the mixture was stirred at -12 to -15 C for 3 hours.The reaction mixture was poured into a methanol solution (10.0 mL) of methanesulfonic acid (3.0 mL) at 0 C or less, and the mixture was stirred at room temperature for 16 hours and 36 minutes. The reaction mixture was quenched by the addition of an aqueous sodium carbonate solution at a pH of about 8.The organic layer was washed with saturated brine (10 mL, once) and dried over anhydrous sodium sulfate, and extracted with ethyl acetate (50 mL, twice). After filtration, the filtrate was distilled off under reduced pressure, and the title compound (2.336 g, yield 86.4%) was isolated from the obtained residue by silica gel column chromatography. |
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Forth step: Synthesis of (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]glucitol; To a toluene (32.5 ml)-diisopropyl ether (25 ml) solution of <strong>[1034305-17-3]2-(5-bromo-2-fluorobenzyl)-1-benzothiophene</strong> (5.0 g) was dropwise added a n-hexane solution (10 ml) of n-butyl lithium (1.6 M) at -43.5 to -33.3C, followed by stirring for 10 minutes. To the reaction mixture was added, at -72.6 to -65.0C, a toluene (17.5 ml) solution of 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucono-1,5-lactone (8.0 g), followed by stirring for 6 hours. The reaction mixture was added to a methanol (25 ml) solution of an ethyl acetate solution (7.8 ml) of hydrogen chloride (4 M) at a temperature of 0C or lower, followed by stirring at 0C for 17 hours. The reaction mixture was added to a water (35 ml) solution of potassium carbonate (1.29 g). Thereto was added ethyl acetate, followed by extraction. The aqueous layer was extracted with toluene (20 ml)-ethyl acetate (10 ml). The organic layers obtained by extraction were combined and subjected to vacuum distillation to distil off the solvent until the reside became 40 ml. Toluene (25 ml) was added to the residue and the mixture was subjected to vacuum distillation to distil off the solvent until the residue became 40 ml. This operation of adding toluene to the residue and subjecting the mixture to vacuum distillation to distil off the solvent, was repeated twice to obtain methyl 1-C-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-alpha-glucopyranoside as a toluene solution. 1H-NMR (CD3OD): delta 3.08 (3H, s), 3.10 (1H, m), 3.42 (1H, dd), 3.58 (1H, m), 3.75 (1H, dd), 3.82 (1H, m), 3.92 (1H, dd), 4.23 (1H, d), 4.32 (1H, d), 7.05 (1H, s), 7.09 (1H, dd), 7.22 (1H, m), 7.27 (1H, m), 7.54 (1H, m), 7.64-7.65 (2H, m), 7.72 (1H, d) |
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