4-Fluoroaniline → N-(4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

HRID 2241200Notes

Reaction equation

HRID 2241200 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C1(C(O)=O)(C(O)=O)CC1.FC1C=CC([NH2:31])=CC=1.C(Cl)(=O)C(Cl)=O.[CH3:40][O:41][C:42]1[CH:66]=[CH:65][C:45]([CH2:46][N:47]2[C:51]3=[N:52][CH:53]=[CH:54][C:55]([O:56][C:57]4[CH:62]=[CH:61][C:60](N)=[CH:59][CH:58]=4)=[C:50]3[C:49]([CH3:64])=[N:48]2)=[CH:44][CH:43]=1>C1COCC1.O.C([O-])(O)=O.[Na+].CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:60]2[CH:59]=[CH:58][C:57]([O:56][C:55]3[CH:54]=[CH:53][N:52]=[C:51]4[N:47]([CH2:46][C:45]5[CH:44]=[CH:43][C:42]([O:41][CH3:40])=[CH:66][CH:65]=5)[N:48]=[C:49]([CH3:64])[C:50]=34)=[CH:62][CH:61]=2)[C:9]([C:11]2([C:14]([NH2:31])=[O:16])[CH2:12][CH2:13]2)=[O:10])=[CH:6][CH:7]=1

Participants

10

Reactant 5

HCID 97314-FluoroanilineHCID 65578Oxalyl chlorideHCID 690171,1-Cyclopropanedicarboxylic acidHCID 210815301-[(4-Fluorophenyl)carbamoyl]cyclopropanecarboxylic AcidHCID 685150574-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline

Product 1

HCID 68513243N-(4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideYield 28%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent2×HCID 516892Sodium BicarbonateSolvent

Procedure

A 100 mL round-bottomed flask was charged with 1-((4-fluorophenyl)carbamoyl)cyclopropane carboxylic acid (0.3516 g, 0.9767 mmol; prepared from cyclopropane-1,1-dicarboxylic acid and 4-fluoroaniline in THF (25 mL) using the methods of WO 2005/030140 and Shih and Rankin, Synth. Comm., 1996, 26(4), 833-836). Next, catalytic DMF (10 microliters) was added. While stirring oxalyl dichloride (0.08387 mL, 0.9767 mmol) was added. The reaction mixture was stirred for 30 minutes and 4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)benzenamine (0.160 g, 0.3907 mmol) in THF (2 mL) was added. The reaction mixture was stirred for 1 hour, the diluted with water (50 mL) and saturated NaHCO3 (50 mL). The reaction mixture was extracted with EtOAc, washed with brine, dried organic over sodium sulfate, filtered and concentrated. The reaction mixture was purified by preparative TLC (0.5 mm) eluting with EtOAc. The product (90 mg, 28%) was obtained as a white solid. LRMS (esi pos) m/e 566 (M+1).

Workup

  1. additionwas added
  2. stirringThe reaction mixture was stirred for 1 hour
  3. extractionThe reaction mixture was extracted with EtOAc
  4. washwashed with brine, dried organic over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe reaction mixture was purified by preparative TLC (0.5 mm)
  8. washeluting with EtOAc

Sources & evidence

ORD record
ord-32e250da6a0f4e76a2ec48c4ba7df900
Source dataset
uspto-grants-2010_05
Patent number
US07723330B2

Reaction notes

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