Dimethylformamide → HCID 46244298, compound

HRID 1803845Notes

Reaction equation

HRID 1803845 reaction equation
Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([N:18]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)C(=O)C(F)(F)F)[CH:10]=2)[CH2:5][CH2:4]1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[F:42][C:43]1[CH:60]=[CH:59][C:58]([F:61])=[CH:57][C:44]=1[CH2:45][O:46][C:47]1[CH:48]=[C:49]2[C:53](=[CH:54][CH:55]=1)[NH:52][N:51]=[C:50]2[NH2:56]>C(Cl)Cl.N1C=CC=CC=1>[F:42][C:43]1[CH:60]=[CH:59][C:58]([F:61])=[CH:57][C:44]=1[CH2:45][O:46][C:47]1[CH:48]=[C:49]2[C:53](=[CH:54][CH:55]=1)[NH:52][N:51]=[C:50]2[NH:56][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([N:6]2[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]2)=[CH:10][C:11]=1[NH:18][CH:25]1[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 65578Oxalyl chlorideHCID 46928118HCID 46928118, compoundHCID 46928119HCID 46928119, compound

Product 1

HCID 46244298HCID 46244298, compoundYield 75%

Reagents, catalysts & solvents 2

HCID 1049PyridineSolventHCID 6344DichloromethaneSolvent

Procedure

4-(4-Methylpiperazin-1-yl)-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzoic acid hydrochloride (590 mg, 1.31 mmol) in dry DCM (10 mL), under nitrogen, was cooled with an ice bath and treated first with a drop of DMF and then with oxalyl chloride (2.62 mmol, 0.228 mmol). After stirring for 4 hours at room temperature, the solution was evaporated and the solid was dried under vacuum. The crude acid chloride was dissolved in 20 mL of dry pyridine, cooled with an ice bath and treated drop-wise with 5-[(2,5-difluorobenzyl)oxy]-1H-indazol-3-amine (300 mg, 1.09 mmol) in 15 mL of pyridine. The reaction was left overnight at 4° C. Volatiles were evaporated and the residue was diluted with water (300 mL) and extracted with EtOAc (3×300 mL). Organic phases were collected, dried over sodium sulfate and evaporated. Crude product was diluted with MeOH (10 mL) and heated at 80° C. in the presence of triethylamine (2.5 mL). After 3 hours, volatiles were evaporated and the residue was dissolved in DCM (100 mL), washed with NaHCO3 satured solution, water and brine. The organic layer was dried over sodium sulfate, filtered and evaporated under vacuum. Crude product was purified by flash chromatography over silica gel (DCM/MeOH 92:8) affording 470 mg (yield 75%) of title compound

Workup

  1. customthe solution was evaporated
  2. customthe solid was dried under vacuum
  3. dissolutionThe crude acid chloride was dissolved in 20 mL of dry pyridine
  4. temperaturecooled with an ice bath
  5. waitThe reaction was left overnight at 4° C
  6. customVolatiles were evaporated
  7. additionthe residue was diluted with water (300 mL)
  8. extractionextracted with EtOAc (3×300 mL)
  9. customOrganic phases were collected
  10. dry with materialdried over sodium sulfate
  11. customevaporated
  12. additionCrude product was diluted with MeOH (10 mL)
  13. temperatureheated at 80° C. in the presence of triethylamine (2.5 mL)
  14. waitAfter 3 hours
  15. customvolatiles were evaporated
  16. dissolutionthe residue was dissolved in DCM (100 mL)
  17. washwashed with NaHCO3 satured solution, water and brine
  18. dry with materialThe organic layer was dried over sodium sulfate
  19. filtrationfiltered
  20. customevaporated under vacuum
  21. customCrude product was purified by flash chromatography over silica gel (DCM/MeOH 92:8)

Sources & evidence

ORD record
ord-040ceb816ee44b2abb7403062f403ef2
Source dataset
uspto-grants-2013_01
Patent number
US08354399B2

Reaction notes

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