Dichloromethane → HCID 67142322, compound

Temperature

6 °C

In a 4 L flask with overhead stirrer, thermometer, dropping funnel and under nitrogen were combined 150 g boc-(D)-serine (0.731 mol) (ee>99%), 2.13 kg dichloromethane and 221.5 g 4-methylmorpholine (2.19 mol). The reactor was cooled in an ice bath to 4-8° C. and 129.4 g benzylamine (1.24 mol) slowly added. After complete addition, a slurry was obtained. 516 g of T3P® in dichloromethane (2,4,6-tri-n-propyl-2,4,6-trioxo-1,3,5,2,4,6-trioxatriphosphorinane as a 50% w/w solution in dichloromethane, 0.811 mol) were slowly added, maintaining the temperature below 8° C. The mixture was cooled and stirred on ice at 4-8° C. for 2 hours. The reaction was quenched by the addition of 400 ml water, brought to room temperature and stirred for a further 30 minutes. The phases were separated and the aqueous phase re-extracted with 750 ml dichloromethane. The combined organic phases were washed 140 ml water, adjusted to pH 6 with 10% HCl and stirred for a further 1 hour at room temperature. The phases were separated and the organic phase re-washed with 200 ml water. The dichloromethane was stripped and exchanged to toluene. The product was crystallised from 1 kg toluene by cooling to room temperature over 3 hours, then standing in the fridge overnight. The product was filtered and washed with 2×150 ml toluene. After drying under vacuum at 40° C., 165 g (yield 76.5%) (R)-boc-2-amino-N-benzyl-3-hydroxy-propionamide (III) were obtained. HPLC purity >99%, ee >99%. The X-ray diffraction pattern of the isolated crystals is shown in FIG. 1. X-ray diffraction pattern of (R)-boc-2-amino-N-benzyl-3-hydroxy-propionarnide (III). Major peaks observed at around Theta values of 5.7, 6.0 9.2, 10.8, 12.4, 17.6, 18.2, 18.7, 19.7, 20.4 and 22.3.

1. customIn a 4 L flask with overhead stirrer, thermometer, dropping
2. customfunnel and under nitrogen were combined
3. additionAfter complete addition
4. customa slurry was obtained
5. temperaturemaintaining the temperature below 8° C
6. temperatureThe mixture was cooled
7. customThe reaction was quenched by the addition of 400 ml water
8. custombrought to room temperature
9. stirringstirred for a further 30 minutes
10. customThe phases were separated
11. extractionthe aqueous phase re-extracted with 750 ml dichloromethane
12. washThe combined organic phases were washed 140 ml water
13. stirringstirred for a further 1 hour at room temperature
14. customThe phases were separated
15. washthe organic phase re-washed with 200 ml water
16. customThe product was crystallised from 1 kg toluene
17. temperatureby cooling to room temperature over 3 hours
18. customstanding in the fridge overnight
19. filtrationThe product was filtered
20. washwashed with 2×150 ml toluene
21. customAfter drying under vacuum at 40° C.

ORD record

ord-61d0d377004445d6ab2dcf851c7b492f

Source dataset

uspto-grants-2013_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08598386B2