Pyridine → (-)-4,5-difluoro-2-(S)-methyl-1-[(S)-N-p-toluenesulfonylprolyl]-2,3-dihydroindole

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Reaction Steps

(±)-4,5-difluoro-2-methyl-2,3-dihydroindole, 47.4 g, was dissolved in 470 ml of methylene chloride, to which was added 45 ml of pyridine under ice-cooling. To the resultant mixture was added dropwise under ice-cooling 300 ml of a methylene chloride a solution of the acid chloride prepared from 98.8 g of (S)-N-p-toluenesulfonyl proline and 80 ml of thionyl chloride. After the dropwise addition, the reaction was conducted for 1.5 hours at room temperature. The reaction mixture was washed with 750 ml of 10% hydrochloric acid, with a saturated aqueous solution of sodium hydrogencarbonate, and with a saturated aqueous solution of sodium chloride, in this order, and dried over anhydrous magnesium sulfate. Methylene chloride was evaporated off, the residue was washed with ether, with benzene and with ethanol, in this order. All of the washings were combined and concentrated, and the residue was subjected to column chromatography on 3 kg of silica gel with elution with benzene-ethyl acetate (30:1-15:1), to give a main product and a by-product. The main product was recrystallized from isopropanol-benzene, to give 51.8 g of (-)-4,5-difluoro-2-(S)-methyl-1-[(S)-N-p-tol uenesulfonylprolyl]-2,3-dihydroindole (Compound (a)) having the following physical characteristics.

Provenance & Evidence