反应详情

温度

90 °C

A 500 ml three-necked round-bottom flask, under nitrogen atmosphere, is added with (S)-3-(isopropoxycarbonyl-amino-methyl)-5-methyl-hexanoic acid salt of (S)-(−)-phenyl-ethyl-amine (70.0 g, 0.190 moles), 35% hydrochloric acid (29.7 g, 0.285 moles), water (200 ml) and toluene (100 ml) and the mixture is vigorously stirred for 10-15 minutes. The phases are separated and the aqueous phase is extracted with toluene (2×100 ml). The collected organic phases are concentrated to small volume to obtain an oil which is added with 30% hydrochloric acid (57.8 g, 0.475 moles). The mixture is heated at 90° C. for 24-48 h. At end-reaction 41% aqueous monomethylamine (26.7 ml) is added till pH of about 6 and left to cool to room temperature. The mixture is cooled to 0-5° C. for at least 1 h and then the solid is filtered off and washed with a 1:1 water/isopropanol mixture cooled to 0-5° C. (3×15 ml). The solid is dried in oven at 50-60° C. for 16-18 h. 26.6 g of a white solid are obtained having an enantiomer ratio 99.94:0.06, with a yield of 88%. The XRPD spectrum of the so obtained product has the most intense peaks at 9.4; 12.2; 14.4; 16.6; 18.2; 19.0; 19.7; 20.1; 22.1; 22.6; 23.1; 23.4; 24.6; 26.8; 27.5; 27.9; 29.8±2θ, as illustrated in FIG. 1. The product has a mean particle size D50 of about 50 micrometers.

1. customThe phases are separated
2. extractionthe aqueous phase is extracted with toluene (2×100 ml)
3. concentrationThe collected organic phases are concentrated to small volume
4. customto obtain an oil which
5. additionis added till pH of about 6
6. waitleft
7. temperatureto cool to room temperature
8. temperatureThe mixture is cooled to 0-5° C. for at least 1 h
9. filtrationthe solid is filtered off
10. washwashed with a 1:1 water/isopropanol mixture
11. temperaturecooled to 0-5° C. (3×15 ml)
12. customThe solid is dried in oven at 50-60° C. for 16-18 h