Diisopropylethylamine → N-(4-(2-acetamidopyrimidin-4-yloxy)-2,5-difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

HRID 476371Notes

Reaction equation

HRID 476371 reaction equation
[NH2:1][C:2]1[C:18]([F:19])=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[N:8]=2)=[C:4]([F:20])[CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([C:31]2([C:34](O)=[O:35])[CH2:33][CH2:32]2)=[O:30])=[CH:24][CH:23]=1.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>CN(C=O)C.O>[C:14]([NH:13][C:9]1[N:8]=[C:7]([O:6][C:5]2[C:4]([F:20])=[CH:3][C:2]([NH:1][C:34]([C:31]3([C:29]([NH:28][C:25]4[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=4)=[O:30])[CH2:33][CH2:32]3)=[O:35])=[C:18]([F:19])[CH:17]=2)[CH:12]=[CH:11][N:10]=1)(=[O:16])[CH3:15]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 210815301-[(4-Fluorophenyl)carbamoyl]cyclopropanecarboxylic AcidHCID 66604966N-[4-(4-amino-2,5-difluorophenoxy)pyrimidin-2-yl]acetamide

Product 1

HCID 54576298N-(4-(2-acetamidopyrimidin-4-yloxy)-2,5-difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideYield 8.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of Example A3 (300 mg, 1.07 mmol) and 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (240 mg, 1.07 mmol) (as prepared in Example B1) in DMF (20 mL) was added HATU (440 mg, 3.2 mmol) and DIEA (280 mg, 2.1 mmol) in portions. The reaction mixture was stirred at 60° C. under nitrogen overnight. After cooling to room temperature water (30 mL) was added and the solution was extracted with ethyl acetate (3×50 mL). The combined organics were washed with brine (3×50 mL), dried over sodium sulfate, and concentrated. The crude product was purified by preparative HPLC to give N-(4-(2-acetamidopyrimidin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (42 mg, 8% yield) as a white solid. 1HNMR (300 MHz, DMSO-d6): δ 10.95 (s, 1H), 10.40 (s, 1H), 9.75 (s, 1H), 8.49-8.51 (d, J=5.7 Hz, 1H), 7.94-8.01 (dd, J=12.3 Hz, J=8.1 Hz, 1H), 7.48-7.60 (m, 3H), 7.05-7.16 (m, 2H), 6.83-6.84 (d, J=5.4 Hz, 1H), 1.92 (s, 3H), 1.53-1.59 (d, J=19.2 Hz, 4H).

Workup

  1. additionwas added
  2. extractionthe solution was extracted with ethyl acetate (3×50 mL)
  3. washThe combined organics were washed with brine (3×50 mL)
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated
  6. customThe crude product was purified by preparative HPLC

Sources & evidence

ORD record
ord-ffa7765a87d14417873bd36f045236a6
Source dataset
uspto-grants-2014_01
Patent number
US08637672B2

Reaction notes

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