Diisopropylethylamine → N-(2,5-difluoro-4-((2-(2-fluoro-2-methylpropanamido)pyridin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

HRID 476390Notes

Reaction equation

HRID 476390 reaction equation
[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:33][C:34]([CH3:39])([CH3:38])[C:35](O)=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:32][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:35](=[O:36])[C:34]([F:33])([CH3:39])[CH3:38])[CH:7]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH:16][C:17]([C:19]1([C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[O:23])[CH2:21][CH2:20]1)=[O:18]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 27828282-Fluoro-2-methylpropanoic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 59596940N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Product 1

HCID 54576514N-(2,5-difluoro-4-((2-(2-fluoro-2-methylpropanamido)pyridin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideYield 43%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (250 mg, 0.565 mmol) and 2-fluoro-2-methylpropanoic acid (108 mg, 1.02 mmol) in anhydrous CH2Cl2 (30 mL) was added HATU (323 mg, 0.85 mmol) and DIPEA (2.5 mL) under N2. This reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was poured into water (100 mL), extracted with ethyl acetate (3×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. This crude product was purified by silica gel chromatography to give N-(2,5-difluoro-4-((2-(2-fluoro-2-methylpropanamido)pyridin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (128 mg, 43% yield). 1H-NMR (400 MHz, Methanol-d4): δ 8.21-8.17 (m, 2H), 7.73 (d, J=2.4 Hz, 1H), 7.54-7.51 (m, 2H), 7.23 (dd, J=10.8, 7.2 Hz, 1H), 7.08-7.04 (m, 2H), 6.75 (dd, J=5.6, 2.4 Hz, 1H), 1.76-1.69 (m, 4H), 1.62 (s, 3H), 1.56 (s, 3H); MS (ESI): m/z 531.1 [M+H]+.

Workup

  1. customThe solvent was removed in vacuo
  2. additionThe residue was poured into water (100 mL)
  3. extractionextracted with ethyl acetate (3×50 mL)
  4. washwashed with brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. concentrationconcentrated in vacuo
  7. customThis crude product was purified by silica gel chromatography

Sources & evidence

ORD record
ord-b94d8eeecccd4407bbad760821e19c91
Source dataset
uspto-grants-2014_01
Patent number
US08637672B2

Reaction notes

Loading…