Diisopropylethylamine → 5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-N-(N,N-dimethylsulfamoyl)-2-fluorobenzamide

HRID 1427841Notes

Reaction equation

HRID 1427841 reaction equation
[Cl:1][C:2]1[C:3]([CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][C:20]([CH3:25])([CH3:24])[O:21]3)=[CH:16][CH:15]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:26][N:27]([CH3:32])[S:28](=[O:31])(=[O:30])[NH2:29].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.Cl>[Cl:1][C:2]1[C:3]([CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][C:20]([CH3:25])([CH3:24])[O:21]3)=[CH:16][CH:15]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:29][S:28](=[O:31])(=[O:30])[N:27]([CH3:32])[CH3:26])=[O:8]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 134472N,N-DimethylsulfamideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 867028665-Chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-2-fluorobenzoic acid

Product 1

HCID 867028685-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-N-(N,N-dimethylsulfamoyl)-2-fluorobenzamideYield 18%

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 6228DimethylformamideSolvent

Procedure

A mixture of 5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-2-fluorobenzoic acid (50 mg, 0.14 mmol), dimethyl(sulfamoyl)amine (26 mg, 0.21 mmol), N,N-Diisopropylethylamine (54 mg, 0.42 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (106 mg, 0.28 mmol) in DMF (2.5 mL) was stirred at room temperature for 16 hrs. The mixture was diluted with HCl (2.0 N, 20 mL) and extracted with EtOAc (50×3 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase combiflash (15%-25% MeCN in 0.5% NH4HCO3) to give target product (11.8 mg, 18%) as a white solid. LCMS (ESI) Method A: RT=5.57 min, m/z: 471.2 [M+H]; 1H-NMR (500 MHz, MeOH-d4,): δ 7.62 (d, J=6.0 Hz, 1H), 7.31 (d, J=10.5 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 6.40 (dd, J=8.0, 2.5 Hz, 1H), 6.24 (d, J=2.5 Hz, 1H), 5.02 (s, 2H), 2.86 (s, 6H), 2.61 (t, J=7.0 Hz, 2H), 1.68 (t, J=7.0 Hz, 2H), 1.20 (s, 6H).

Workup

  1. extractionextracted with EtOAc (50×3 mL)
  2. washThe combined organic layers were washed with brine
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe residue was purified by reverse phase combiflash (15%-25% MeCN in 0.5% NH4HCO3)

Sources & evidence

ORD record
ord-34ca4c1515c74fa8bdb12bb47006ff80
Source dataset
uspto-grants-2015_01
Patent number
US08933236B2

Reaction notes

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