Methylamine → 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide

HRID 2272289Notes

Reaction equation

HRID 2272289 reaction equation
[CH:1]1([C:4]2[C:5]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([OH:21])=O)[C:8]=3[CH:22]=2)[CH2:3][CH2:2]1.[CH3:28][N:29](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.CN>ClCCl.C(=O)(O)[O-].[Na+].CO.C(Cl)(Cl)Cl>[CH:1]1([C:4]2[C:5]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)=[C:9]([C:19]([NH:29][CH3:28])=[O:21])[C:8]=3[CH:22]=2)[CH2:3][CH2:2]1

Participants

8

Reactant 4

HCID 6329MethylamineHCID 8471TriethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 673529905-Cyclopropyl-2-(4-fluorophenyl)-6-((methylsulfonyl)amino)-3-benzofurancarboxylic acid

Product 1

HCID 160735125-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolvent2×HCID 516892Sodium BicarbonateSolventHCID 21584188Chloroform methanolSolvent

Procedure

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxylic acid (2.52 g, 6.47 mmol), HATU (2.95 g, 7.77 mmol) and triethylamine (1.984 mL, 14.24 mmol) in dry dichloromethane (100 mL) was stirred at room temperature for 1 hour, then treated with methylamine (16.18 mL, 32.4 mmol). The solution was stirred at room temperature under nitrogen for 4 hours, during which time a precipitate formed. The reaction was diluted with dichloromethane (300 mL) and sodium bicarbonate solution (200 mL) and stirred for 10 minutes. The layers were separated and the aqueous layer extracted with further dichloromethane (150 mL). The combined organics were washed with brine (200 mL), dried using a hydrophobic frit and evaporated to dryness to give an off-white solid. The crude product was purified by flash chromatography (eluting with 0-100% ethyl acetate/cyclohexane followed by 10% methanol/dichloromethane) to give a white solid. The solid was dissolved in hot methanol-chloroform (10% v/v), preabsorped onto silica gel and purified by flash chromatography (0-10% methanol/dichloromethane) to give the 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-1-benzofuran-3-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.30 (br s, 1H) 8.42 (q, 1H) 7.88-7.98 (m, 2H) 7.60 (s, 1H) 7.37 (t, 2H) 7.16 (s, 1H) 3.06 (s, 3H) 2.83 (d, 3H) 2.23-2.36 (m, 1H) 0.93-1.05 (m, 2H) 0.65-0.74 (m, 2H). LCMS (m/z, ES+)=403 (M+H+).

Workup

  1. customformed
  2. stirringstirred for 10 minutes
  3. customThe layers were separated
  4. extractionthe aqueous layer extracted with further dichloromethane (150 mL)
  5. washThe combined organics were washed with brine (200 mL)
  6. customdried
  7. customevaporated to dryness
  8. customto give an off-white solid
  9. customThe crude product was purified by flash chromatography (eluting with 0-100% ethyl acetate/cyclohexane followed by 10% methanol/dichloromethane)
  10. customto give a white solid
  11. custompurified by flash chromatography (0-10% methanol/dichloromethane)

Sources & evidence

ORD record
ord-dd0ee5c2d28349a9baefb43f576b541d
Source dataset
uspto-grants-2015_09
Patent number
US09119868B2

Reaction notes

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