Hydrochloric Acid → HCID 178436353, compound

HRID 2367123Notes

Reaction equation

HRID 2367123 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])O2)=[CH:4][C:3]=1[N+:18]([O-])=O.Cl.[C:22]([C:24]1[C:25]([F:31])=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27])#[CH:23].O.O.[Sn](Cl)[Cl:35].S([O-])([O-])(=O)=O.[Na+].[Na+].COC(N[C:49](=[N:52][C:53]([O:55]C)=[O:54])SC)=O.Cl.[CH3:58]N1C(=O)CCC1>[Cl-].[Na+].O.O1CCOCC1.C(OCC)(=O)C.O>[ClH:35].[CH3:49][N:52]([C:58]1[NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[C:12]4[C:11](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:10](=[O:17])[N:27]3[C:26]3[CH:28]=[CH:29][CH:30]=[C:24]([C:22]#[CH:23])[C:25]=3[F:31])=[CH:4][C:3]=2[N:18]=1)[C:53](=[O:54])[OH:55]

Participants

12

Reactant 7

HCID 313Hydrochloric AcidHCID 13387N-methyl-2-pyrrolidoneHCID 24436Sodium SulfateHCID 61436Stannous chloride dihydrateHCID 98708Methyl [[(methoxycarbonyl)amino](methylthio)methylene]carbamateHCID 67044913HCID 67044913, compoundHCID 86083501HCID 86083501, compound

Product 1

HCID 178436353HCID 178436353, compound

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
150 °C

Procedure

To a solution of 3-(4-amino-3-nitrophenyl)-2-benzofuran-1(3H)-one (1.0 g, 3.7 mmol) in NMP (6 mL) was added 3-ethynyl-2-fluoroaniline hydrochloride (1.9 g, 11.1 mmol). The mixture was heated to 150° C. for 2.25 h, and then the temperature was raised to 170° C. for a further 45 min. After cooling to rt, water and brine were added, and the resulting aqueous mixture was extracted twice with ethyl acetate. The organic extracts were dried over magnesium sulfate, filtered, and pre-absorbed on silica gel. The residue was run through a column, eluting with 60% hexanes and 40% ethyl acetate. The product-containing fractions were combined and concentrated. The resulting brown sticky film was not pure. This material was dissolved in acetic acid, and to this solution was added tin(II) chloride dihydrate (4.2 g, 18.5 mmol). The mixture was then heated to 80° C. for 1.5 h. After cooling to rt, the acetic acid was removed in vacuo. The residue was transferred to a 500-mL erlenmeyer flask in a minimal amount of ethyl acetate. The resulting suspension was then diluted with approximately 200 mL of ether, and then the flask was placed into an ice bath. To the vigorously stirring mixture was added 50% aqueous sodium hydroxide (20 mL), and a pale yellow solid formed. Celite and sodium sulfate were added to adsorb the precipitate and dry the mixture. The solids were removed by filtration and rinsed twice with hot ethyl acetate. The organic filtrates were combined and concentrated. The crude residue was dissolved in acetic acid (10 mL) and treated with 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (565 mg, 2.7 mmol) at 80° C. for 25 min. After cooling to rt, the acetic acid was removed in vacuo. The residue was purified by HPLC. The product containing fractions were combined, and sufficient saturated sodium bicarbonate was added to make the pH >7. The organic solvents were removed in vacuo, and the resulting aqueous mixture was extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was taken up in a minimal amount of ethyl acetate and 1 equiv of hydrochloric acid was added (4 N in dioxane). A white precipitate formed, and it was collected by filtration. The material was dried in vacuo yielding methyl{5-[2-(3-ethynyl-2-fluorophenyl)-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate hydrochloride (202 mg, 0.46 mmol) as a white solid. 1H NMR (400 MHz, DMSO-d6): 7.90 (d, 1H), 7.66-7.57 (m, 3H), 7.67-7.54 (m, 3H), 7.41 (m, 1H), 7.31-7.26 (m, 3H), 7.21 (t, 1H), 6.88 (d, 1H), 6.50 (s, 1H), 4.56 (s, 1H), 3.73 (s, 3H); MS (EI) for C25H17FN4O3: 441 (MH+).

Workup

  1. temperaturethe temperature was raised to 170° C. for a further 45 min
  2. temperatureAfter cooling to rt
  3. extractionthe resulting aqueous mixture was extracted twice with ethyl acetate
  4. dry with materialThe organic extracts were dried over magnesium sulfate
  5. filtrationfiltered
  6. custompre-absorbed on silica gel
  7. washeluting with 60% hexanes and 40% ethyl acetate
  8. concentrationconcentrated
  9. dissolutionThis material was dissolved in acetic acid
  10. temperatureThe mixture was then heated to 80° C. for 1.5 h
  11. temperatureAfter cooling to rt
  12. customthe acetic acid was removed in vacuo
  13. customThe residue was transferred to a 500-mL erlenmeyer flask in a minimal amount of ethyl acetate
  14. additionThe resulting suspension was then diluted with approximately 200 mL of ether
  15. customthe flask was placed into an ice bath
  16. additionwas added 50% aqueous sodium hydroxide (20 mL)
  17. customa pale yellow solid formed
  18. customdry the mixture
  19. customThe solids were removed by filtration
  20. washrinsed twice with hot ethyl acetate
  21. concentrationconcentrated
  22. dissolutionThe crude residue was dissolved in acetic acid (10 mL)
  23. temperatureAfter cooling to rt
  24. customthe acetic acid was removed in vacuo
  25. customThe residue was purified by HPLC
  26. additionThe product containing fractions
  27. additionsufficient saturated sodium bicarbonate was added
  28. customThe organic solvents were removed in vacuo
  29. extractionthe resulting aqueous mixture was extracted with ethyl acetate
  30. dry with materialThe organic extracts were dried over magnesium sulfate
  31. filtrationfiltered
  32. concentrationconcentrated
  33. customA white precipitate formed
  34. filtrationit was collected by filtration
  35. customThe material was dried in vacuo

Sources & evidence

ORD record
ord-93f40d45128b4a0092cce09e2758affc
Source dataset
uspto-grants-2014_04
Patent number
US08697737B2

Reaction notes

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