Water → Begacestat

HRID 2247162Notes

Reaction equation

HRID 2247162 reaction equation
CN1CCOCC1.[NH2:8][C@@H:9]([CH:12]([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])[CH2:10][OH:11].[Cl:21][C:22]1[S:26][C:25]([S:27](Cl)(=[O:29])=[O:28])=[CH:24][CH:23]=1.O>C(OC(C)C)(=O)C.CCCCCCC>[Cl:21][C:22]1[S:26][C:25]([S:27]([NH:8][C@H:9]([CH2:10][OH:11])[CH:12]([C:13]([F:14])([F:15])[F:16])[C:17]([F:18])([F:19])[F:20])(=[O:29])=[O:28])=[CH:24][CH:23]=1

Participants

7

Reactant 4

HCID 962WaterHCID 79724-MethylmorpholineHCID 27339255-Chlorothiophene-2-sulfonyl chlorideHCID 25022953HCID 25022953, compound

Product 1

HCID 11269353BegacestatYield 67.8%

Reagents, catalysts & solvents 2

HCID 7915Isopropyl AcetateSolventHCID 8900HeptaneSolvent

Conditions

Temperature
22.5 °C

Procedure

4-methyl morpholine (2.7 mL, 24.6 mmol) was added 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). The mixture was stirred at about 20-25° C. for about 5-10 minutes and then 5-chlorothiophene-2-sulfonyl chloride (2.0 g, 9.2 mmol) was added. The reaction mixture was stirred at 20-25° C. for 6-18 hours. Water (10 mL) was then added to the reaction mixture, whereby the solids dissolved. The two layers were then separated and the organic layer was washed with a solution of 10% NaHCO3 (10 mL) and 10% NaCl (10 mL). Heptane (10 mL) was added to the isopropyl acetate layer (about 10 mL). The mixture was then distilled down to about half of its original volume under atmospheric distillation. While the solution remained at about 80-90° C., heptane (10 mL) was added over 5-10 minutes, during which time solids formed. After the addition of heptane, the mixture was cooled to 20-25° C., stirred for about 1-2 hours, and then further cooled to about 5-10° C. for 1 hour. The solid was then collected by filtration, washed with heptane (5 mL), and oven-dried to give 2.15 g (67%) of the product as an off-white solid. 98 area% HPLC purity and >99% chiral purity by HPLC.

Workup

  1. stirringThe reaction mixture was stirred at 20-25° C. for 6-18 hours
  2. dissolutiondissolved
  3. customThe two layers were then separated
  4. washthe organic layer was washed with a solution of 10% NaHCO3 (10 mL) and 10% NaCl (10 mL)
  5. additionHeptane (10 mL) was added to the isopropyl acetate layer (about 10 mL)
  6. distillationThe mixture was then distilled down to about half of its original volume under atmospheric distillation
  7. customremained at about 80-90° C.
  8. additionheptane (10 mL) was added over 5-10 minutes, during which time solids
  9. customformed
  10. temperaturethe mixture was cooled to 20-25° C.
  11. stirringstirred for about 1-2 hours
  12. temperaturefurther cooled to about 5-10° C. for 1 hour
  13. filtrationThe solid was then collected by filtration
  14. washwashed with heptane (5 mL)
  15. customoven-dried

Sources & evidence

ORD record
ord-5e094a3d6bcc4d51b4e355eafcef4a54
Source dataset
uspto-grants-2010_03
Patent number
US07687666B2

Reaction notes

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