Water → Begacestat

Temperature

22.5 °C

To a suspension of (2S)-2-amino-4,4,4-tri-fluoro-3-(trifluoromethyl)butan-1-ol (2 g, 8.1 mmol) in isopropyl acetate (10 mL), 4-methyl morpholine (2.7 mL, 24.6 mmol) was added. The mixture was stirred at 20 to 25° C. for 5 to 10 minutes and then 5-chlorothiophene-2-sulfonyl chloride (2.0 g, 9.2 mmol) was added. The reaction mixture was stirred at 20 to 25° C. for 6 to 18 hours. Water (10 mL) was added to the reaction mixture and the solid dissolved. The two layers were separated, the organic layer was washed with 10% NaHCO3 (10 mL) and 10% NaCl (10 mL), and heptane (10 mL) was added to the isopropyl acetate layer (about 10 mL). The mixture was reduced in volume by about half by distillation under atmospheric conditions. While the solution remained at 80 to 90° C., heptane (10 mL) was added over 5 to 10 minutes. A solid began to form during heptane addition. After addition, the mixture was cooled to 20 to 25° C., the solution was stirred for 1 to 2 hours, and then further cooled to 5 to 10° C. for 1 hour. The solid was collected by filtration, washed with heptane (5 mL), and oven-dried to give 2.15 g (67%) of an off-white solid. 98% area HPLC purity and >99% chiral purity by HPLC.

1. additionwas added
2. stirringThe reaction mixture was stirred at 20 to 25° C. for 6 to 18 hours
3. dissolutionthe solid dissolved
4. customThe two layers were separated
5. washthe organic layer was washed with 10% NaHCO3 (10 mL) and 10% NaCl (10 mL), and heptane (10 mL)
6. additionwas added to the isopropyl acetate layer (about 10 mL)
7. distillationThe mixture was reduced in volume by about half by distillation under atmospheric conditions
8. customremained at 80 to 90° C.
9. additionheptane (10 mL) was added over 5 to 10 minutes
10. customto form during heptane addition
11. additionAfter addition
12. temperaturethe mixture was cooled to 20 to 25° C.
13. stirringthe solution was stirred for 1 to 2 hours
14. temperaturefurther cooled to 5 to 10° C. for 1 hour
15. filtrationThe solid was collected by filtration
16. washwashed with heptane (5 mL)
17. customoven-dried

ORD record

ord-8c6ee9780b554c7993b00284762077f5

Source dataset

uspto-grants-2010_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07838550B2