Oxalyl chloride → N-[5-(3,5-difluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzamide

HRID 1640989Notes

Reaction equation

HRID 1640989 reaction equation
FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[C:17]([N:24]([CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:16]=2)[CH2:11][CH2:10]1.C(Cl)(=O)C(Cl)=O.C(N(CC)C(C)C)(C)C.[F:52][C:53]1[CH:54]=[C:55]([S:60]([C:63]2[CH:64]=[C:65]3[C:69](=[CH:70][CH:71]=2)[N:68]([C:72]([C:85]2[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=2)([C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)[C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[N:67]=[C:66]3[NH2:91])(=[O:62])=[O:61])[CH:56]=[C:57]([F:59])[CH:58]=1>ClCCl.CN(C)C=O>[F:52][C:53]1[CH:54]=[C:55]([S:60]([C:63]2[CH:64]=[C:65]3[C:69](=[CH:70][CH:71]=2)[N:68]([C:72]([C:79]2[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=2)([C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[C:85]2[CH:86]=[CH:87][CH:88]=[CH:89][CH:90]=2)[N:67]=[C:66]3[NH:91][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([N:12]3[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]3)=[CH:16][C:17]=2[N:24]([CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[C:25](=[O:30])[C:26]([F:28])([F:27])[F:29])(=[O:62])=[O:61])[CH:56]=[C:57]([F:59])[CH:58]=1

Participants

7

Reactant 4

HCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 667370025-(3,5-difluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-ylamineHCID 866438384-(4-Methylpiperazin-1-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)benzoic acid 2,2,2-trifluoroacetate

Product 1

HCID 86643843N-[5-(3,5-difluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzamideYield 93%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent

Procedure

To a suspension of 4-(4-methyl-piperazin-1-yl)-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzoic acid trifluoroacetate (2.16 g, 4.1 mmol) in dry dichloromethane (20 mL) were added oxalyl chloride (0.69 mL, 8.2 mmol) and N,N-dimethylformamide (1-2 drops). The mixture was stirred at room temperature for 1.5 hours then evaporated to dryness. The resulting crude acyl chloride was taken-up with toluene and evaporated again then dissolved in dry tetrahydrofuran (30 mL) and N,N-diisopropylethylamine (2.8 mL, 16.4 mmol) and treated with 5-(3,5-difluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-ylamine (1.5 g, 2.72 mmol). The mixture was stirred at room temperature overnight then evaporated to dryness. The residue was dissolved in dichloromethane, washed with saturated solution of sodium hydrogenocarbonate and with brine, dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel using dichloromethane/acetone 1:1 as the eluant, affording the title compound as a pale yellow solid (2.4 g, 93% yield).

Workup

  1. customthen evaporated to dryness
  2. customevaporated again
  3. dissolutionthen dissolved in dry tetrahydrofuran (30 mL)
  4. stirringThe mixture was stirred at room temperature overnight
  5. customthen evaporated to dryness
  6. dissolutionThe residue was dissolved in dichloromethane
  7. washwashed with saturated solution of sodium hydrogenocarbonate and with brine
  8. dry with materialdried over sodium sulfate
  9. customevaporated to dryness
  10. customThe crude was purified by flash chromatography on silica gel

Sources & evidence

ORD record
ord-221f9f7a388145a3968ed44a550eca7e
Source dataset
uspto-grants-2012_02
Patent number
US08114865B2

Reaction notes

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