反应详情

温度

15 °C

Into a 10 L reactor equipped with anchor stirrer was charged CH2Cl2 (1.64 L). The solvent was cooled to 15° C., then 95% H2SO4 (492 mL) and 2-[1-(S)-cyano-2-(4-methoxyphenyl)-1-methylethylamino]-2-(R)-phenylacetamide 2 (410 g, 1.27 mol) were added alternately in 9 portions over approximately 45 min (specifically: 164 mL of H2SO4 then 82 g of 2; subsequently, at approximately 5 min intervals, 8×[41 mL of H2SO4 then immediately 41 g of 2]). On addition of each portion, the suspension of 2 in the dense oily phase slowly dissolved (1-2 min) to provide a biphasic mixture. The resulting biphasic mixture (a red-brown dense oil with a pale yellow supernatant CH2Cl2 layer) was stirred for 0.5 h at 25° C. Ice-cold water (4.1 L) was added over 30 min, very slowly initially (200 mL dropwise over 15 min) due to a violent exotherm, and the biphasic mixture was stirred for 0.5 h. The phases were separated and the organic phase discarded. The combined aqueous phases were washed with CH2Cl2 (450 mL), and residual CH2Cl2 was stripped from the aqueous phase by distillation under vacuum at 55° C. (20-30 mBar). The aqueous solution was then cooled to 20° C. and was basified with 32% aq NH3 (1150 mL) to pH 8-9 at such a rate that the temperature was kept below 28° C. (approximately 120 min). The suspension was stirred for 30 min to ascertain a stable pH. The white solid which formed was separated by filtration, washed with H2O (2×2050 mL), and was thoroughly drained of water (but was not dried) to provide 2-[(R)-(carbamoylphenylmethy)-amino]-3-(4-methoxyphenyl)-2-(S)-methylpropionamide 3 (1087 g (391 g theoretical, the sample contains 64% w/w of H2O), yield 90%, 97% HPLC purity, 96% de) as a wet white solid. HPLC (Luna C18, H2O/MeCN 95:5 to 0:100 30 min, 254 nm, sample 2 mg/mL in MeOH). tR(3)=15.3 min, 96% de. (2 degrades under these conditions: 3 peaks are detected at 17.7, 18.9 and 19.9 min). HPLC (R,R/S,S)-diastereoisomer of 3, tR=15.0 min. de determination: HPLC comparing integration of peaks at tR=15.3 min (97.3 area % 3) and tR=15.0 min (1.6 area % (R,R)-diastereoisomer of 3 (reference (R,R/S,S) prepared from nearly rac-phenylglycinamide).

1. customInto a 10 L reactor equipped with anchor stirrer
2. additionOn addition of each portion
3. additionthe suspension of 2 in the dense oily phase
4. dissolutionslowly dissolved (1-2 min)
5. customto provide a biphasic mixture
6. customThe phases were separated
7. washThe combined aqueous phases were washed with CH2Cl2 (450 mL), and residual CH2Cl2
8. distillationwas stripped from the aqueous phase by distillation under vacuum at 55° C. (20-30 mBar)
9. temperatureThe aqueous solution was then cooled to 20° C.
10. customwas kept below 28° C.
11. custom(approximately 120 min)
12. stirringThe suspension was stirred for 30 min
13. customThe white solid which formed
14. customwas separated by filtration
15. washwashed with H2O (2×2050 mL)
16. customwas not dried)