Water → HCID 122643080, compound

HRID 2272391Notes

Reaction equation

HRID 2272391 reaction equation
[Br:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([N:10]([C:15]2[C:34]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][C:18]3[C:19]([C:29]([NH:31][CH3:32])=[O:30])=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[O:21][C:17]=3[CH:16]=2)[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][C:3]=1[Cl:38].CCN(C(C)C)C(C)C.[CH2:48](Cl)[O:49][CH3:50].O>C1COCC1.CCOC(C)=O.CCCCCC>[Br:1][C:2]1[C:7]([CH2:8][O:9][CH2:48][O:49][CH3:50])=[CH:6][C:5]([N:10]([C:15]2[C:34]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][C:18]3[C:19]([C:29]([NH:31][CH3:32])=[O:30])=[C:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[O:21][C:17]=3[CH:16]=2)[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][C:3]=1[Cl:38]

Participants

8

Reactant 4

HCID 962WaterHCID 7864Chloromethyl Methyl EtherHCID 81531DiisopropylethylamineHCID 131732335HCID 131732335, compound

Product 1

HCID 122643080HCID 122643080, compoundYield 68.3%

Reagents, catalysts & solvents 3

HCID 8028TetrahydrofuranSolventHCID 8058HexaneSolventHCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
50 °C

Procedure

A solution of 50.0 g (80.0 mmol) of crude 6-(N-(4-bromo-3-chloro-5-(hydroxymethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide in 500 mL of THF was treated with 42.1 mL (241 mmol) of DIEA followed by 15.3 mL (201 mmol) of MOM-Cl and the resulting solution was heated to 50° C. with stirring. After 18 hours LCMS indicated complete reaction. The solution was cooled to RT and diluted with 600 mL of EtOAc followed by 600 mL of water. After stirring vigorously for 10 minutes the mixture was transferred to a separatory funnel and the phases separated. The aqueous phase was extracted with one additional 200 mL portion of EtOAc. The combined EtOAc solutions were washed with an aqueous solution of 5% citric acid and 5% NaCl (3×300 mL), saturated aqueous sodium bicarbonate (2×300 mL), saturated brine (1×300 mL), and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate concentrated to dryness at reduced pressure to give an orange-brown foam. This material was dissolved in 250 mL of EtOAc and the solution heated to reflux with stirring. To the solution was added 375 mL of hexane over a 5 minute period maintaining reflux temperature. The solution was then allowed to cool to RT with stirring during which time a light tan solid crystallized. After 2 hours the solution was cooled in an ice water bath and stirred for an additional 2 hours. The solid was collected by filtration in a medium fritted funnel. The filter cake was washed with 250 mL of cold 3:2 hexane/EtOAc, dried by suction filtration for 30 minutes, and then dried in vacuo to give 36.4 g of 6-(N-(4-bromo-3-chloro-5-((methoxymethoxy)methyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide as a light tan solid. 1H NMR (400 MHz, DMSO-d6) ppm 8.49 (q, J=4.30 Hz, 1H) 8.14 (s, 1H) 7.93-8.00 (m, 2H) 7.62 (d, J=2.74 Hz, 1H) 7.52 (d, J=2.74 Hz, 1H) 7.40 (t, J=8.94 Hz, 2H) 7.21 (s, 1H) 4.68 (s, 2H) 4.57 (s, 2H) 3.44 (s, 3H) 3.24 (s, 3H) 2.83 (d, J=4.59 Hz, 3H) 2.06-2.19 (m, 1H) 0.74-1.05 (m, 3H) 0.44 (br. s., 1H).

Workup

  1. customAfter 18 hours LCMS indicated complete reaction
  2. temperatureThe solution was cooled to RT
  3. stirringAfter stirring vigorously for 10 minutes the mixture
  4. customwas transferred to a separatory funnel
  5. customthe phases separated
  6. extractionThe aqueous phase was extracted with one additional 200 mL portion of EtOAc
  7. washThe combined EtOAc solutions were washed with an aqueous solution of 5% citric acid and 5% NaCl (3×300 mL), saturated aqueous sodium bicarbonate (2×300 mL), saturated brine (1×300 mL)
  8. dry with materialdried over sodium sulfate
  9. customThe drying agent was removed by filtration
  10. concentrationthe filtrate concentrated to dryness at reduced pressure
  11. customto give an orange-brown foam
  12. temperaturethe solution heated
  13. temperatureto reflux
  14. stirringwith stirring
  15. temperaturemaintaining
  16. temperaturereflux temperature
  17. temperatureto cool to RT
  18. stirringwith stirring during which time a light tan solid
  19. customcrystallized
  20. temperatureAfter 2 hours the solution was cooled in an ice water bath
  21. stirringstirred for an additional 2 hours
  22. filtrationThe solid was collected by filtration in a medium fritted funnel
  23. washThe filter cake was washed with 250 mL of cold 3:2 hexane/EtOAc
  24. customdried by suction filtration for 30 minutes
  25. customdried in vacuo

Sources & evidence

ORD record
ord-c03716fd224c40139c18c0c42828a8b6
Source dataset
uspto-grants-2015_09
Patent number
US09119868B2

Reaction notes

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