Nitrogen → N-(5-(5-(3-amino-1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2',4'-difluoro-[1,1'-biphenyl]-3-yl)cyclopropanesulfonamide

HRID 64190Notes

Reaction equation

HRID 64190 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22](B4OC(C)(C)C(C)(C)O4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:33][S:34]([CH:37]2[CH2:39][CH2:38]2)(=[O:36])=[O:35])[CH:10]=1.N#N.Br[C:43]1[C:44]([NH2:49])=[N:45][N:46]([CH3:48])[CH:47]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.CCO.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:49][C:44]1[C:43]([C:22]2[CH:21]=[CH:20][C:19]3[N:15]([C:13]4[CH:12]=[C:11]([NH:33][S:34]([CH:37]5[CH2:39][CH2:38]5)(=[O:35])=[O:36])[CH:10]=[C:9]([C:3]5[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=5[F:1])[CH:14]=4)[CH:16]=[N:17][C:18]=3[CH:23]=2)=[CH:47][N:46]([CH3:48])[N:45]=1

Participants

7

Reactant 4

HCID 947NitrogenHCID 10796Cesium carbonateHCID 27352834-bromo-1-methyl-1H-pyrazol-3-amineHCID 89501185N-(2',4'-difluoro-5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)-[1,1'-biphenyl]-3-yl)cyclopropanesulfonamide

Product 1

HCID 117777783N-(5-(5-(3-amino-1-methyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-1-yl)-2',4'-difluoro-[1,1'-biphenyl]-3-yl)cyclopropanesulfonamideYield 27%

Reagents, catalysts & solvents 2

HCID 178418851HCID 178418851, compoundCatalystHCID 18504229Ethanol tetrahydrofuran waterSolvent

Conditions

Temperature
90 °C

Procedure

A solution of N-(2′,4′-difluoro-5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide (100 mg, 0.181 mmol) in THF/EtOH/Water (5:5:2) was degassed by N2 bubbling for 5 min. 4-Bromo-1-methyl-1H-pyrazol-3-amine (35 mg, 0.19 mmol, 1.1 eq.) was added and the mixture was degassed for another 5 min. Bis(tri-tert-butylphosphine)palladium(0) (5 mg, 0.009 mmol, 0.05 eq.) and cesium carbonate (170 mg, 0.54 mmol, 3.0 eq.) were added sequentially and the mixture was further degassed for 5 min and heated at 90° C. for 16 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to give the crude residue which was purified by preparative HPLC to give the product in 27% yield (25 mg). 1H NMR (300 MHz, DMSO): δ 10.3 (s, 1H) 8.79 (s, 1H), 7.95-7.92 (m, 2H), 7.77-7.07 (m, 2H), 7.59 (s, 2H), 7.53-7.47 (m, 3H), 7.29 (m, 1H), 3.75 (s, 3H), 2.91 (m, 1H), 1.5-1.49 (d, 2H), 1.30-1.26 (t, 2H), 1.03-1.01 (t, 2H); LC-MS (ESI): Calculated mass: 520.5; Observed mass: 521.0 [M+H]+ (rt: 0.676 min).

Workup

  1. customthe mixture was degassed for another 5 min
  2. customthe mixture was further degassed for 5 min
  3. customThe mixture was quenched
  4. extractionextracted as in Example 1(d)
  5. distillationThe solvent was distilled off

Sources & evidence

ORD record
ord-7ba68167e82d4bb580f0822aee4d4938
Source dataset
uspto-grants-2016_09
Patent number
US09447091B2

Reaction notes

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