Chloride → HCID 178423982, compound

HRID 241941Notes

Reaction equation

HRID 241941 reaction equation
S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:7]=1[C:8]([OH:10])=O.[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].Cl[CH2:25][C:26](Cl)=O.[Cl-].O.[SH:31][C:32]1[N:40]=[CH:39][N:38]=[C:37]2[C:33]=1[NH:34][CH:35]=[N:36]2.C([O-])([O-])=O.[K+].[K+]>C1C=CC=CC=1.CN(C=O)C.O.CCOC(C)=O.CCCCCC>[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[N:19]1[C:8](=[O:10])[C:7]2[C:6](=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:15])[N:5]=[C:25]1[CH2:26][S:31][C:32]1[N:40]=[CH:39][N:38]=[C:37]2[C:33]=1[N:34]=[CH:35][NH:36]2

Participants

12

Reactant 7

HCID 312ChlorideHCID 6577Chloroacetyl chlorideHCID 95842-FluoroanilineHCID 11430Potassium CarbonateHCID 24386Thionyl ChlorideHCID 1512106-Methylanthranilic acidHCID 178527204HCID 178527204, compound

Product 1

HCID 178423982HCID 178423982, compound

Reagents, catalysts & solvents 4

HCID 241BenzeneSolventHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 21226206Ethyl acetate hexaneSolvent

Procedure

Thionyl chloride (2.2 mL, 30 mmol) was added to a stirred solution of 2-amino-6-methylbenzoic acid (1.51 g, 10 mmol) in benzene (50 mL) and the mixture was heated at reflux for 18 h. Once cooled, the solvent was removed in vacuo and stripped down twice with benzene (25 mL). The residue was dissolved in CHCl3 (50 mL) and treated with 2-fluoroaniline (1.93 mL, 20 mmol). The slurry was then heated at reflux for 3 h. At that time TLC (50% EtOAc/hexane) indicated that the reaction was complete. After cooling to room temperature, the reaction mixture was poured atop a 4 cm plug of silica gel and flushed through with 20% EtOAc/hexane. The product containing fractions were combined and concentrated in vacuo. The residue was dissolved in HOAc (50 mL) and treated with chloro-actyl chloride (1.6 mL, 20 mmol) and the mixture was heated at reflux for 18 h. The reaction was cooled and concentrated in vacuo. The remaining HOAc was removed by azeotroping with toluene (25 mL) three times. The residue was dissolved in toluene (10 mL) and poured through a 4 cm plug of silica gel, flushing through with 20% EtOAc/hexane. The product containing fractions were identified by LCMS [MS (ES): m/z 303 (M+)), and concentrated in vacuo to afford 1.12 g (37%) as a white foam. The white foam chloride (455 mg, 1.50 mmol) was dissolved in DMF (10 mL) and treated with 6-mercaptopurine monohydrate (510 mg, 3.0 mmol) and K2CO3 (414 mg, 3.0 mmol) and the mixture was stirred overnight at room temperature. The suspension was then poured into 200 mL of water, stirred at room temperature for 30 min then chilled in the refrigerator for 30 min. The resultant solid was collected by vacuum filtration and recrystallized from EtOH to afford 487 mg (77%) of an off white solid. mp 151.9-152.2° C. 1H NMR (DMSO-d6) δ: 8.48 (s, 1H0, 8.44 (s, 1H), 7.70 (m, 2H), 7.48 (m, 2H), 7.33 (m, 3H), 4.55 (d, J=15.1 Hz, 1H), 4.48 (d, J=15.1 Hz, 1H), 2.73 (s, 3H). 13C NMR (DMSO-d6) ppm: 161.3, 157.8 (d, J=249.1 Hz), 156.9, 152.8, 151.5, 149.6, 148.6, 143.6, 140.9, 134.7, 131.9 (d, J=8.0 Hz), 131.4, 130.2, 125.6 (d, J=3.6 Hz), 125.5, 124.4 (d, J=13.5 Hz), 118.8, 116.6 (d, J=19.6 Hz), 56.4, 22.9. MS (ES): m/z 419.5 (M+). Anal. calcd. for C21H15FN6OS∘0.15 C2H6O: C, 60.14; H, 3.77; F, 4.47; N, 19.76; S, 7.54. Found: C, 59.89; H, 3.88; F, 4.42; N, 19.42; S, 7.23.

Workup

  1. temperaturethe mixture was heated
  2. temperatureat reflux for 18 h
  3. temperatureOnce cooled
  4. customthe solvent was removed in vacuo
  5. dissolutionThe residue was dissolved in CHCl3 (50 mL)
  6. temperatureThe slurry was then heated
  7. temperatureat reflux for 3 h
  8. additionthe reaction mixture was poured atop a 4 cm plug of silica gel
  9. customflushed through with 20% EtOAc/hexane
  10. additionThe product containing fractions
  11. concentrationconcentrated in vacuo
  12. dissolutionThe residue was dissolved in HOAc (50 mL)
  13. temperaturethe mixture was heated
  14. temperatureat reflux for 18 h
  15. temperatureThe reaction was cooled
  16. concentrationconcentrated in vacuo
  17. customThe remaining HOAc was removed
  18. customby azeotroping with toluene (25 mL) three times
  19. dissolutionThe residue was dissolved in toluene (10 mL)
  20. additionpoured through a 4 cm plug of silica gel
  21. customflushing through with 20% EtOAc/hexane
  22. additionThe product containing fractions
  23. concentrationm/z 303 (M+)), and concentrated in vacuo
  24. customto afford 1.12 g (37%) as a white foam
  25. stirringstirred at room temperature for 30 min
  26. temperaturethen chilled in the refrigerator for 30 min
  27. filtrationThe resultant solid was collected by vacuum filtration
  28. customrecrystallized from EtOH
  29. customto afford 487 mg (77%) of an off white solid

Sources & evidence

ORD record
ord-554be7251c284cd08f930f6a5cc01acd
Source dataset
uspto-grants-2014_02
Patent number
US08653077B2

Reaction notes

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