Hydrazine hydrate (1:1) → HCID 178428025, compound

HRID 539210Notes

Reaction equation

HRID 539210 reaction equation
[CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][N:13]1[C:17]2[CH:18]=[C:19]([N:25]3[CH2:30][CH2:29]O[CH2:27][CH2:26]3)[CH:20]=[C:21]([C:22]([NH2:24])=O)[C:16]=2[N:15]=[C:14]1[C:31]([F:34])([F:33])[F:32].[CH3:35]OC(OC)N(C)C.[OH2:43].[NH2:44][NH2:45]>>[CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][N:13]1[C:17]2[CH:18]=[C:19]([N:25]3[CH2:30][CH2:29][O:43][CH2:27][CH2:26]3)[CH:20]=[C:21]([C:22]3[N:24]=[CH:35][NH:45][N:44]=3)[C:16]=2[N:15]=[C:14]1[C:31]([F:34])([F:33])[F:32]

Participants

4

Reactant 3

HCID 24654Hydrazine hydrate (1:1)HCID 78373Dimethylformamide dimethyl acetalHCID 56960266HCID 56960266, compound

Product 1

HCID 178428025HCID 178428025, compoundYield 58.7%

Conditions

Temperature
105 °C

Procedure

A mixture of 1-{[2-Methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxamide, prepared as described in Example 54 (250 mg, 0.514 mmol) and N,N-dimethylformamide dimethyl acetal (7 mL, 52.3 mmol) was stirred at 105° C. for 1.5 hour. The reaction mixture was concentrated under reduced pressure and the residue was suspended in Acetic Acid (5 mL). After the addition of hydrazine monohydrate (0.113 mL, 3.60 mmol) the reaction mixture was heated at 100° C. for 1 hour. The solvent was concentrated under vacuum, the residue was azeotroped with toluene (2×), and the residue was dissolved in DMSO and purified by reverse phase-HPLC (20-95% AcCN in water plus 0.1% TFA). The fractions containing product were combined, neutralized by the addition of aq NaHCO3 sat sol and the organic evaporated. The precipitate in the aqueous residue was collected by filtration, washed with water and dried in a vacuum oven (45° C.) overnight to give the desired product (157.1 mg, 0.302 mmol, 58.7% yield) as a white powder. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 13.05 (br. s., 1H), 8.12 (s, 1H), 8.00 (d, J=2.27 Hz, 1H), 7.63 (d, J=7.83 Hz, 1H), 7.18 (t, J=7.83 Hz, 1H), 6.56 (d, J=7.83 Hz, 1H), 6.51 (d, J=2.27 Hz, 1H), 5.54 (s, 2H), 3.71-3.95 (m, 4H), 3.09-3.30 (m, 4H), 2.57 (s, 3H). MS (ES+) m/e 511[M+H]+.

Workup

  1. customprepared
  2. concentrationThe reaction mixture was concentrated under reduced pressure
  3. temperaturewas heated at 100° C. for 1 hour
  4. concentrationThe solvent was concentrated under vacuum
  5. customthe residue was azeotroped with toluene (2×)
  6. dissolutionthe residue was dissolved in DMSO
  7. custompurified by reverse phase-HPLC (20-95% AcCN in water plus 0.1% TFA)
  8. additionThe fractions containing product
  9. additionneutralized by the addition of aq NaHCO3
  10. filtrationThe precipitate in the aqueous residue was collected by filtration
  11. washwashed with water
  12. customdried in a vacuum oven (45° C.) overnight

Sources & evidence

ORD record
ord-9ff59de6749a440dacc49bd5a72de08a
Source dataset
uspto-grants-2014_10
Patent number
US08865912B2

Reaction notes

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