1-Phenethylamine, (-)- → (s)-(+)-3-{1-(1,3-Benzodioxol-5-yl)-2-[(2-methoxy4-methylphenyl)-sulfonylamino]-2-oxoethyl}-1-methyl-1h-indole-6-carboxylic acid

Participants

Reaction Conditions

Reaction Steps

(S)-(−)-α-Methylbenzylamine (0.53 kg) was added over a period of 15 minutes to a stirred suspension of 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy4-methylphenyl)sulfonylamino]-2-oxoethyl}-1-methyl-1H-indole-6-carboxylic acid (from step (c), 1.17 kg, 2.18 moles) in tetrahydrofuran (6.5 liters, 5.5 ml/g) and 1,2-dimethoxyethane (6.5 liters, 5.5 ml/g) at 60° C. under a nitrogen atmosphere. The resulting solution was allowed to cool to 55° C., seeded with 13.6 g of the (S)-(−)-α-methylbenzylamine salt of the title compound of Example 1 (prepared by conventional methods) and stirred for 24 h. The resulting suspension was allowed to cool to 45° C. over a period of 48 h and stirred at this temperature for an additional 48 h. The suspension was allowed to cool to room temperature and the precipitated (S)-(−)-α-methylbenzylamine salt (of the title compound) collected by filtration (1.316 kg, 84%, ratio of (S)-(−)-α-methylbenzylamine to (S)-(+)-acid in the salt 1.5:1). The salt was partitioned between ethyl acetate (6.8 liters), tetrahydrofuran (1.4 liters) and 1M hydrochloric acid (6.8 liters) and the organic phase was separated and then washed with 1M hydrochloric acid (3×0.9 liters) and water (2×0.7 liters). The organic phase was dried by azeotropic distillation with ethyl acetate at constant volume, concentrated to a volume of 3.5 liters and then n-hexane (3.5 liters) added. The precipitated product was granulated at 0° C. for 1 h and filtered to give the title compound as a white crystalline solid (0.936 kg, 91.6%). The enantiomeric excess of the compound was found to be >94% using chiral stationary phase HPLC.

Provenance & Evidence