Cyanoacetic acid → N-(4-(2-(2-cyanoacetamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

HRID 476380Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 476380
[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.[C:33]([CH2:35][C:36](O)=[O:37])#[N:34].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.C(OCC)(=O)C.O>[C:33]([CH2:35][C:36]([NH: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:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1)=[O:37])#[N:34]

Komponenten

8

Edukt 4

HCID 9740Cyanoacetic acidHCID 81531DiisopropylethylamineHCID 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

Produkt 1

HCID 54576510N-(4-(2-(2-cyanoacetamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideAusbeute 64,5 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 962WaterLösungsmittelHCID 6228DimethylformamideLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
60 °C

Versuchsvorschrift

To a solution of N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (150 mg, 0.34 mmol) (as prepared in Example 9) and 2-cyanoacetic acid (44 mg, 0.51 mmol) in DMF (2 mL) was added HATU (258 mg, 0.68 mmol) and DIEA (130 mg, 1 mmol) and the mixture was stirred at 60° C. under nitrogen overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and H2O (50 mL) and the organic layer was washed with brine, dried and concentrated under reduced pressure. The residue was purified by prep-TLC to give N-(4-(2-(2-cyanoacetamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (70 mg, yield 64.5%). 1H-NMR (400 MHz, DMSO-d6): δ 10.99 (s, 1H), 10.94 (s, 1H), 9.81 (s, 1H), 8.23 (d, J=5.6 Hz, 1H), 8.08 (dd, J=12.4, 6.8 Hz, 1H), 7.59-7.55 (m, 4H), 7.15 (t, J=8.8 Hz, 2H), 6.80 (dd, J=6.0, 2.4 Hz, 1H), 3.92 (s, 2H), 1.61-1.56 (m, 4H); MS (ESI): m/z 510.2 [M+H]+.

Aufarbeitung

  1. temperatureThe reaction mixture was cooled to room temperature
  2. washthe organic layer was washed with brine
  3. customdried
  4. concentrationconcentrated under reduced pressure
  5. customThe residue was purified by prep-TLC

Quellen und Nachweise

ORD-Eintrag
ord-47b49cb258f147f2b7332d31306bc138
Quelldatensatz
uspto-grants-2014_01
Patentnummer
US08637672B2

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