Oxalyl chloride → N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-2-(tetrahydro-2H-pyran-4-ylamino)benzamide

HRID 1773387Notes

Reaction equation

HRID 1773387 reaction equation
FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([N:25]([CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)C(=O)C(F)(F)F)[CH:17]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[F:53][C:54]1[CH:55]=[C:56]([CH:68]=[C:69]([F:71])[CH:70]=1)[CH2:57][C:58]1[CH:59]=[C:60]2[C:64](=[CH:65][CH:66]=1)[NH:63][N:62]=[C:61]2[NH2:67]>C(Cl)Cl.CN(C=O)C.C1COCC1.CCOC(C)=O.CO>[F:53][C:54]1[CH:55]=[C:56]([CH:68]=[C:69]([F:71])[CH:70]=1)[CH2:57][C:58]1[CH:59]=[C:60]2[C:64](=[CH:65][CH:66]=1)[NH:63][N:62]=[C:61]2[NH:67][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([O:15][CH2:14][C@@H:10]2[CH2:11][CH2:12][CH2:13][N:9]2[CH3:8])=[CH:17][C:18]=1[NH:25][CH:32]1[CH2:33][CH2:34][O:35][CH2:36][CH2:37]1

Participants

9

Reactant 4

HCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 441342655-[(3,5-difluorophenyl)methyl]-1H-indazol-3-amineHCID 866476184-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzoic acid trifluoroacetate

Product 1

HCID 59577333N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-2-(tetrahydro-2H-pyran-4-ylamino)benzamideYield 45%

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×HCID 21584119Ethylacetate methanolSolvent

Procedure

4-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzoic acid trifluoroacetate (1 mmol, 531 mg) was dissolved in DCM and two drops of anhydrous DMF under nitrogen atmosphere. Oxalyl chloride (0.17 ml, 2 mmol) was added and the mixture was stirred at room temperature for 2 hours. Solvents were evaporated to obtain a yellow powder. The solid was redissolved in THF under an argon atmosphere and cooled at −20° C. DIPEA (0.56 ml, 3.2 mmol) was added. 5-(3,5-Difluorobenzyl)-1H-indazol-3-amine, dissolved in 10 mL of dry THF was then added dropwise in 15′. The reaction mixture was kept at −20° C. for 6 hours then the temperature was allowed to raise at room temperature overnight. The reaction was quenched with 15 mL of NaHCO3 5% and extracted twice with AcOEt (15 ml). Solvents were then evaporated and the residue was redissolved in 20 ml of MeOH. TEA (10 mmol, 1.5 ml) was added and the mixture was heated to 65° C. for 3 hr. Then the reaction was cooled to room temperature and the solvents removed to yield the crude product which was purificated by means of silica gel flash chromatography (AcOEt/MeOH/NH3Aq. 85:15:05) to yield the title compound as a white powder (258 mg, 0.45 mmol, 45%).

Workup

  1. customSolvents were evaporated
  2. customto obtain a yellow powder
  3. temperaturecooled at −20° C
  4. additionwas then added dropwise in 15′
  5. waitThe reaction mixture was kept at −20° C. for 6 hours
  6. temperatureto raise at room temperature overnight
  7. customThe reaction was quenched with 15 mL of NaHCO3 5%
  8. extractionextracted twice with AcOEt (15 ml)
  9. customSolvents were then evaporated
  10. dissolutionthe residue was redissolved in 20 ml of MeOH
  11. temperaturethe mixture was heated to 65° C. for 3 hr
  12. temperatureThen the reaction was cooled to room temperature
  13. customthe solvents removed
  14. customto yield the crude product which

Sources & evidence

ORD record
ord-4993be600ea540a8b30ced5552bd0b61
Source dataset
uspto-grants-2016_02
Patent number
US09255087B2

Reaction notes

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