Thiophosgene → HCID 25235302, compound

HRID 1513253Notes

Reaction equation

HRID 1513253 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[C:9](Cl)(Cl)=S.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[C:21]1[NH:22][C:23]2[CH:29]=[C:28]([C:30]([NH:32][NH2:33])=[O:31])[CH:27]=[CH:26][C:24]=2[N:25]=1.CCN=C=NCCCN(C)C>C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+].CCOC(C)=O.CN(C=O)C>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[C:21]1[NH:22][C:23]2[CH:29]=[C:28]([C:30]3[O:31][C:9]([NH:1][C:2]4[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=4)=[N:33][N:32]=3)[CH:27]=[CH:26][C:24]=2[N:25]=1

Participants

9

Reactant 4

HCID 10040ThiophosgeneHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 27377012-Amino-5-fluoropyridine2×HCID 577865852-(2,6-Dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide

Product 1

HCID 25235302HCID 25235302, compound

Reagents, catalysts & solvents 4

HCID 6212ChloroformSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolventHCID 516892Sodium BicarbonateSolvent

Procedure

Dissolve 2-amino-5-fluoro-pyridine (68 mg, 0.606 mmol) in a biphasic solution of CHCl3 (15 mL) and saturated NaHCO3 (15 mL). Add thiophosgene (46 uL, 0.606 mmol) to the organic phase and stir the reaction vigorously for 1 hr. Add 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (146 mg, 0.455 mmol) and stir for 7 hr. Add additional 2-amino-5-fluoro-pyridine (68 mg, 0.606 mmol) and stir overnight. Filter the reaction and wash the collected solid with DCM. Concentrate the organic phase of the filtrate and combine with the solid. Add DMF (3 mL) and EDCI (174 mg, 0.910 mmol) and heat the reaction to 80° C. for 1 hr. Allow the reaction to cool to room temp. Dilute with EtOAc (75 mL) and extract with water (15 mL). Dry the organic phase over Na2SO4 and concentrate. Purify the concentrate by silica gel chromatography (3-6% MeOH/DCM) followed by reversed phase HPLC (20-60% ACN/H2O+5 mM NH4OH) to afford the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) ppm 7.62-7.68 (m, 1 H) 7.70 (s, 1 H) 7.72 (d, J=1.77 Hz, 1 H) 7.74-7.94 (m, 3 H) 8.01 (dd, J=9.22, 3.66 Hz, 1 H) 8.05 (tautomer, s, 1 H) 8.19 (tautomer, s, 1 H) 8.35 (d, J=3.03 Hz, 1 H) 11.37 (br. s., 1 H) 13.29 (s, 1 H); MS m/z=441.7 (M+1).

Workup

  1. customthe reaction vigorously for 1 hr
  2. filtrationFilter
  3. customthe reaction
  4. washwash the collected solid with DCM
  5. concentrationConcentrate the organic phase of the filtrate
  6. customthe reaction to 80° C. for 1 hr
  7. customthe reaction
  8. extractionextract with water (15 mL)
  9. dry with materialDry the organic phase over Na2SO4
  10. concentrationconcentrate
  11. customPurify the
  12. concentrationconcentrate by silica gel chromatography (3-6% MeOH/DCM)

Sources & evidence

ORD record
ord-404de2032de445bab94cd652226b70e2
Source dataset
uspto-grants-2012_07
Patent number
US08217065B2

Reaction notes

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