Methanesulfonic Acid → HCID 87389983, compound

HRID 2060737Notes

Reaction equation

HRID 2060737 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[O:29])[CH2:27][CH2:26]1)=[O:24].[CH3:38][S:39]([OH:42])(=[O:41])=[O:40]>C(#N)C>[S:39]([OH:42])(=[O:41])(=[O:40])[CH3:38].[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)[C:5]([F:21])=[CH:4][C:3]=1[NH:22][C:23]([C:25]1([C:28]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)=[O:29])[CH2:27][CH2:26]1)=[O:24]

Participants

4

Reactant 2

HCID 6395Methanesulfonic AcidHCID 67408835HCID 67408835, compound

Product 1

HCID 87389983HCID 87389983, compoundYield 74%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

Example B1 (0.092 g, 0.412 mmol) was dissolved in thionyl chloride (6 ml, 82 mmol) and heated at 80° C. for 1 h. The mixture was cooled and azeotroped with toluene (3×10 ml). The crude acid chloride was dissolved in THF (5 ml) and added dropwise to a 0° C. solution of Example A19 (0.113 g, 0.375 mmol) and N,N-diethylisopropylamine (0.131 ml, 0.749 mmol) in THF (5 ml). The mixture was stirred overnight at RT. The reaction was not complete. Additional acid chloride was generated from Example B1 (65 mg, 0.29 mmol) using the above method. The crude acid chloride was dissolved in THF (5 ml) and added to the reaction mixture. The solution was stirred at RT for 4 h, diluted with EtOAc and washed with sat. NaHCO3 (aq). The organic extract was dried, evaporated and purified by silica gel chromatography (hexanes/EtOAc) and reverse phase chromatography (water (0.1% TFA)/acetonitrile (0.1% TFA)), treated with sat. NaHCO3 (aq) until basic and the resulting solid removed by filtration. The solid was dried under vacuum at 80° C. to yield N-(2,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (57 mg, 30% yield). The mesylate salt was formed by taking N-(2,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (0.057 g, 0.112 mmol) and dissolving it in refluxing acetonitrile (5 ml). Methanesulfonic acid (7.29 μl, 0.112 mmol) was added and the mixture was cooled to RT, concentrated (˜2 ml) and ether (5 ml) was added dropwise. A solid precipitated. The resulting mixture was sonicated for 30 min. The solid was filtered off and dried overnight in the drying pistol to yield N-(2,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide mesylate (50 mg, 74% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.27 (s, 1H), 9.74 (s, 1H), 9.11 (s, 1H), 8.49 (d, 1H), 8.43 (s, 1H), 8.22-8.19 (m, 1H), 8.16 (d, 1H), 7.74-7.70 (m, 1H), 7.60-7.57 (m, 2H), 7.21-7.15 (m, 3H), 3.92 (s, 3H), 2.34 (s, 3H), 1.71-1.68 (m, 2H), 1.61-1.59 (m, 2H); MS (ESI) m/z: 508.2 (M+H+).

Workup

  1. dissolutiondissolving it
  2. concentrationconcentrated (˜2 ml) and ether (5 ml)
  3. additionwas added dropwise
  4. customA solid precipitated
  5. customThe resulting mixture was sonicated for 30 min
  6. filtrationThe solid was filtered off
  7. customdried overnight in the drying pistol

Sources & evidence

ORD record
ord-04a7278434944394861cdf467c14ecd9
Source dataset
uspto-grants-2012_10
Patent number
US08278331B2

Reaction notes

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