Hydrazine hydrate (1:1) → HCID 178427903, compound

HRID 2174800Notes

Reaction equation

HRID 2174800 reaction equation
C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:9]([CH3:37])=[C:10]([CH2:14][N:15]2[C:19]3[CH:20]=[C:21]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:22]=[C:23]([C:24](O)=O)[C:18]=3[N:17]=[C:16]2[C:33]([F:36])([F:35])[F:34])[CH:11]=[CH:12][CH:13]=1.COC(OC)[N:41]([CH3:43])C.O.[NH2:47][NH2:48]>ClCCl>[Cl:7][C:8]1[C:9]([CH3:37])=[C:10]([CH2:14][N:15]2[C:19]3[CH:20]=[C:21]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:22]=[C:23]([C:24]4[N:41]=[CH:43][NH:48][N:47]=4)[C:18]=3[N:17]=[C:16]2[C:33]([F:35])([F:34])[F:36])[CH:11]=[CH:12][CH:13]=1

Participants

6

Reactant 4

HCID 24654Hydrazine hydrate (1:1)HCID 65578Oxalyl chlorideHCID 78373Dimethylformamide dimethyl acetalHCID 569604001-[(3-chloro-2-methylphenyl)methyl]-6-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylic acid

Product 1

HCID 178427903HCID 178427903, compoundYield 19.9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Oxalyl chloride (0.347 mL, 3.97 mmol) was added to a suspension of 1-[(3-chloro-2-methylphenyl)methyl]-6-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylic acid, prepared as described in Example 53 (450 mg, 0.992 mmol) in Dichloromethane (DCM) (8 mL). The reaction mixture was stirred at rt for 10 minutes and then the solvent was evaporated. The residue (crude acid chloride), was suspended in Tetrahydrofuran (THF) (8 mL). NH3 gas was bubbled in (the mixture changed color yellow to white) and the mixture was stirred at rt for 15 minutes and then partitioned between brine (15 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (2×20 mL) and CH2Cl2 (10 mL). The organic phases were combined, dried over Na2SO4 and concentrated. The crude product was suspended in N,N-dimethylformamide dimethyl acetal (10 mL, 74.7 mmol) and stirred at 105° C. for 2 h. The excess solvent was evaporated and the residue was suspended in Acetic Acid (10 mL). After the addition of hydrazine monohydrate (0.194 mL, 3.97 mmol), the mixture was stirred at 100° C. for 1.5 h. The solvent was evaporated and the residue was dissolved in warm DMSO (8 mL) and purified by reverse phase-HPLC (20-90% AcCN in water plus 0.1% TFA) to give the desired product (96 mg, 0.197 mmol, 19.90% yield) as a white powder. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 13.08 (br. s., 1H), 8.11 (s, 1H), 7.98 (d, J=2.27 Hz, 1H), 7.36 (d, J=8.08 Hz, 1H), 7.01 (t, J=7.96 Hz, 1H), 6.51 (d, J=2.02 Hz, 1H), 6.32 (d, J=7.83 Hz, 1H), 5.51 (s, 2H), 3.73-3.97 (m, 4H), 3.12-3.30 (m, 4H), 2.50 (s, 3H). MS (ES+) m/e 476.9 [M+H]+.

Workup

  1. customprepared
  2. customthe solvent was evaporated
  3. customNH3 gas was bubbled in (the mixture
  4. stirringwas stirred at rt for 15 minutes
  5. custompartitioned between brine (15 mL) and EtOAc (20 mL)
  6. extractionThe aqueous phase was extracted with EtOAc (2×20 mL) and CH2Cl2 (10 mL)
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated
  9. stirringstirred at 105° C. for 2 h
  10. customThe excess solvent was evaporated
  11. stirringthe mixture was stirred at 100° C. for 1.5 h
  12. customThe solvent was evaporated
  13. dissolutionthe residue was dissolved in warm DMSO (8 mL)
  14. custompurified by reverse phase-HPLC (20-90% AcCN in water plus 0.1% TFA)

Sources & evidence

ORD record
ord-bd2e3bd234294d80b26a00fc0a0d8afd
Source dataset
uspto-grants-2015_06
Patent number
US09062003B2

Reaction notes

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