反应详情

温度

41 °C

To a 250 mL, 3 neck flask equipped with a mechanical agitator, thermocouple, heating mantle, condenser, nitrogen inlet and vent, 5-(1,3-dioxolan-2-yl)-(S)-2-amino-pentanoic acid (100 g), methanol (1200 mL) and dimethyl sulfite (44.8 mL) were charged. Chlorotrimethyl silane (168 mL) was added to the resulting slurry and the reaction mixture was heated at 40 to 42° C. for about 8 hours, followed by stirring at ambient temperature for eight hours to afford a solution of (S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester hydrochloride salt (in-process quantitation 100.9 g, 93 M %). Potassium bicarbonate (208.6 g) was slurried in methanol (400 mL) contained in a 5-L three neck flask and the reaction mixture containing the hydrochloride salt of (S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester, was neutralized by adding it to the potassium bicarbonate slurry slowly (over 1.5 hours) maintaining the pH of mixture above 6.9. The solvent of the resulting slurry was replaced with n-butyl acetate by vacuum distillation (50 to 60 mmHg and 30 to 40° C.) maintaining a pot volume of about 2 L. After 2.25 L of n-butyl acetate was distilled, methanol (1.25 L) was added to the distillation vessel and the distillation was continued, maintaining a pot volume of NLT 2 L, until the water content of the slurry supernatant was<0.05 wt % and the methanol level was<5 relative area %. Hexane (1.5 L) was charged to the resulting slurry and it was then cooled to -5° C. After stirring the mixture for 1 hour, it was filtered and the filter-cake was washed with hexane (2×100 mL). The resulting hazy filtrate was polish filtered to afford a clear filtrate. The clear filtrate was warmed to 20 to 25° C. and a methanolic (1333 mL) solution of oxalic acid dihydrate (33.3 g) was added slowly over about 2 hours. The resulting slurry of (S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester oxalic acid salt (2:1) was agitated for 18 hours at ambient temperature and the product was collected on a filter. The product wet-cake was washed with acetonitrile (4×100 mL) and died under vacuum at 45° C. to afford 103.2 g (78 M %) of (S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester oxalic acid salt (2:1) having a free base potency of 84 wt % (vs. lab standard, theo.=82 wt %) and an HPLC AP of 100.

1. customTo a 250 mL, 3 neck flask equipped with a mechanical agitator
2. additionwere charged