反应详情

温度

42.5 °C

Under nitrogen, chlorotrimethyl silane (28.0 g) was added to a slurry of 5-(1,3-dioxolan-2-yl)-(S)-2-amino-pentanoic acid (20.0 g) and dimethyl sulfite (12.0 g) in methanol (240 mL) to afford a homogeneous solution. Following the observation of an exotherm to 29° C., the solution was heated to 40-45° C., stirred at that temperature for 8 h and at ~22° C. for up to 72 hours. In-process HPLC analysis showed that the reaction was complete (~93 M % conversion to product) and the resulting solution was cooled to -5 to -10° C. With stirring, the apparent pH of the mixture was adjusted to 11.7 to 11.9 by the slow careful addition of 32% (or 4.45 M) methanolic potassium methoxide solution (70 mL) maintaining the temperature in the range -5 to 0° C. Analysis of the product slurry (NMR) indicated that the neutralization was complete (chemical shift of the alpha proton of BMS-205787 was<3.36 ppm). The solvent of the product slurry was exchanged with ethyl acetate by first concentrating the thin slurry under vacuum at<30° C. to 300 mL volume followed by the addition of ethyl acetate until the removal of methanol was completed as judged by in-process GC analysis (<1 AP). Upon completion of the solvent exchange, the batch volume was adjusted to ~400 mL with ethyl acetate and the resulting slurry was filtered. Poly(acrylic acid co-acrylamide), potassium salt (3.0 to 3.2 g) and water (30-32 mL) were added to the filtrate. The mixture was stirred for ~35 minutes and filtered. Optionally, the Poly(acrylic acid co-acrylamide), potassium salt treatment can be repeated on the filtrate if the quantity of ethylene glycol exceeds 0.15 equivalents, as judged by in-process GC analysis. Following in-process HPLC analysis, (S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester (17.4 g) was obtained as an ethyl acetate solution in 80.8 M % yield.

1. customto afford a homogeneous solution
2. customto 29° C.
3. temperaturethe resulting solution was cooled to -5 to -10° C
4. stirringWith stirring
5. temperaturemaintaining the temperature in the range -5 to 0° C
6. concentrationby first concentrating the thin slurry under vacuum at<30° C. to 300 mL volume
7. additionfollowed by the addition of ethyl acetate until the removal of methanol
8. filtrationthe resulting slurry was filtered
9. additionPoly(acrylic acid co-acrylamide), potassium salt (3.0 to 3.2 g) and water (30-32 mL) were added to the filtrate
10. stirringThe mixture was stirred for ~35 minutes
11. filtrationfiltered