Ethyl Acetate → (2R)-2-[[(4-Chlorophenyl)sulfonyl][(4-cyano-2-fluorophenyl)methyl]amino]-5,5,5-trifluoropentanamide

HRID 660271Notes

Reaction equation

HRID 660271 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=1[F:38].C(OCC)(=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:29][C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=2[F:38])[C@H:12]([CH2:16][CH2:17][C:18]([F:21])([F:19])[F:20])[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 8857Ethyl AcetateHCID 11430Potassium CarbonateHCID 27831494-(Bromomethyl)-3-fluorobenzonitrileHCID 56953106HCID 56953106, compound

Product 1

HCID 56953105(2R)-2-[[(4-Chlorophenyl)sulfonyl][(4-cyano-2-fluorophenyl)methyl]amino]-5,5,5-trifluoropentanamideYield 78.1%

Reagents, catalysts & solvents 2

HCID 74236Tetrabutylammonium BromideCatalystHCID 962WaterSolvent2×

Conditions

Temperature
50 °C

Procedure

(R)-2-(4-Chlorophenylsulfonamido)-5,5,5-trifluoropentanamide (3.444 kg), potassium carbonate (2.774 kg), tetrabutylammonium bromide (0.484 kg), and 4-(bromomethyl)-3-fluorobenzonitrile (2.092 kg) were charged to a reactor. Ethyl acetate (17.2 L) and water (3.44 L) were then charged and the batch was heated to 50° C. until complete by HPLC (<1 relative AP starting material). The reaction is usually complete in about 15 hours. The batch was cooled to 15-20° C. and water (6.88 L) was charged and the bottom aqueous phase was separated. A solution of sodium phosphate monobasic (0.2 M in water, 20.66 L) was charged and the bottom aqueous phase was separated and the pH was tested to ensure that it was <6.5. (Note: If the pH is >6.5, an additional 20.66 L of 0.2 M sodium phosphate monobasic solution may be charged and the extraction and pH measurement repeated.) The solvent was then exchanged by a constant volume vacuum distillation. The reactor was placed under vacuum (270 mmHg) and the jacket was heated to 75-80° C. Once distillation of ethyl acetate started, isopropanol (41.34 L) was added at the same rate of distillate collection, and the overall batch volume was maintained at a constant level. Once all of the isopropanol was added, the vacuum was released and water (13.76 L) was charged. The batch temperature was maintained at approximately 50° C. during the water addition. The batch was then cooled to 15-20° C. and filtered. The wet cake was washed with 50% (v/v) aqueous isopropanol (4×21.6 kg) and then dried under vacuum at 50° C. to give the title compound as an off-white solid (3.648 kg, 78% yield.) 1H NMR (300 MHz, DMSO-d6) δ ppm 1.42-1.55 (m, 1 H) 1.80-1.93 (m, 1 H) 2.00-2.15 (m, 2 H) 4.44 (dd, J=7.91, 1.13 Hz, 1 H) 4.68 (d, J=17.71 Hz, 1 H) 4.99 (d, J=17.71 Hz, 1 H) 7.26 (s, 1 H) 7.50 (s, 1 H) 7.63-7.73 (m, 4 H) 7.78-7.87 (m, 3 H). 13C NMR (75 MHz, DMSO-d6) ppm 22.58-22.97 (m, 1 C) 29.96 (d, J=29.09 Hz, 1 C) 41.46 (d, J=5.49 Hz, 1 C), 57.86, 110.97, 111.45 (d, J=10.43 Hz, 1 C), 117.58, 119.11 (d, J=25.80 Hz, 1 C), 124.89, 128.53, 128.56, 129.21, 131.17, 131.98, 137.44, 138.32, 158.99 (d, J=247.54 Hz, 2 C), 170.25. 19F NMR, (CDCl3, 282 MHz) δ: −116.5, −65.9. IR (KBr): 3443, 3342, 3210, 2955, 2245, 1699, 1577, 1476, 1163 cm−1.

Workup

  1. temperatureThe batch was cooled to 15-20° C.
  2. customthe bottom aqueous phase was separated
  3. additionA solution of sodium phosphate monobasic (0.2 M in water, 20.66 L) was charged
  4. customthe bottom aqueous phase was separated
  5. addition(Note: If the pH is >6.5, an additional 20.66 L of 0.2 M sodium phosphate monobasic solution may be charged
  6. extractionthe extraction
  7. distillation) The solvent was then exchanged by a constant volume vacuum distillation
  8. temperaturethe jacket was heated to 75-80° C
  9. distillationOnce distillation of ethyl acetate
  10. additionisopropanol (41.34 L) was added at the same rate of distillate collection
  11. temperaturethe overall batch volume was maintained at a constant level
  12. additionOnce all of the isopropanol was added
  13. additionwater (13.76 L) was charged
  14. temperatureThe batch temperature was maintained at approximately 50° C. during the water addition
  15. temperatureThe batch was then cooled to 15-20° C.
  16. filtrationfiltered
  17. washThe wet cake was washed with 50% (v/v) aqueous isopropanol (4×21.6 kg)
  18. customdried under vacuum at 50° C.

Sources & evidence

ORD record
ord-0d165a3d4c2f4e65b6be976e7043060d
Source dataset
uspto-grants-2011_12
Patent number
US08084477B2

Reaction notes

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