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Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1) → 2-(4-Fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[(1-methyl-1-oxo-phosphinan-4-yl)carbonylamino]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one

HRID 562442
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Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 562442
[NH2:1][CH2:2][CH:3]=[CH:4][C:5]1[NH:6][C:7](=[O:29])[C:8]2[C:9]3[N:18]([CH3:19])[C:17]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[CH3:28])=[N:16][C:10]=3[CH:11]=[CH:12][C:13]=2[C:14]=1[CH3:15].[CH3:30][P:31]1(=[O:40])[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(N(CC)CC)C.CN(C)C=O>[F:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:17]2[N:18]([CH3:19])[C:9]3[C:8]4[C:7](=[O:29])[NH:6][C:5]([CH:4]=[CH:3][CH2:2][NH:1][C:37]([CH:34]5[CH2:35][CH2:36][P:31]([CH3:30])(=[O:40])[CH2:32][CH2:33]5)=[O:38])=[C:14]([CH3:15])[C:13]=4[CH:12]=[CH:11][C:10]=3[N:16]=2)=[C:22]([CH3:28])[CH:23]=1
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Komponenten

6

Edukt 3

HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 579733021-Methyl-1-oxo-1lambda5-phosphinane-4-carboxylic acidHCID 668324547-(3-Amino-propenyl)-2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one

Produkt 1

HCID 66832637
2-(4-Fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[(1-methyl-1-oxo-phosphinan-4-yl)carbonylamino]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one
Ausbeute 26,2 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6228DimethylformamideLösungsmittel2×HCID 8471TriethylamineLösungsmittel2×

Versuchsvorschrift

To scintillation vial with a magnetic stir-bar was added 7-(3-amino-propenyl)-2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (68 mg, 173 μmol), followed by dimethylformamide (DMF) (1.0 mL) and triethylamine (TEA) (0.25 mL). To a separate scintillation vial was added 1-methyl-1-oxo-1λ5-phosphinane-4-carboxylic acid (130 mg, 0.74 mmol, mixture of cis/trans isomers), HATU (300 mg, 0.79 mmol), and DMF (2.0 mL), followed by TEA (0.25 mL). The solution was sonicated until most of the solids were dissolved. A solution of the activated ester (1.0 mL, or roughly half) was transferred to the solution of amine and stirred for 2.5 hours at room temperature, after which time the starting material was completely consumed as determined by LC-MS. The reaction mixture was quenched by addition of water (0.5 mL), then acidified with TFA. The mixture was filtered (syringe membrane filter) and purified directly by reverse-phase HPLC to provide 2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-{3-[(1-methyl-1-oxo-phosphinan-4-yl)carbonylamino]-propenyl}-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (24.9 mg, 26%) as a mixture of cis/trans isomers. 1H NMR (400 MHz, d6-DMSO) δ 11.12 (s, 1H), 10.55 (s, 1H), 8.21-8.17 (m, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.55 (dd, J1=5.9 Hz, J2=9.0 Hz, 1H), 7.27 (td, J1=2.7 Hz, J2=8.6 Hz, 1H), 6.66 (d, J=15 Hz, 1H), 6.55-6.49 (m, 1H), 4.18 (s, 3H), 3.92 (m, 2H), 2.31 (s, 3H), 2.30 (s, 3H), 2.35-2.30 (m, 1H), 2.08-1.90 (m, 6H), 1.78-1.65 (m, 2H), 1.52-1.47 (m, 3H); ESMS m/z: found, 550 (M+1)+.

Aufarbeitung

  1. customThe solution was sonicated until most of the solids
  2. dissolutionwere dissolved
  3. customafter which time the starting material was completely consumed
  4. customThe reaction mixture was quenched by addition of water (0.5 mL)
  5. filtrationThe mixture was filtered
  6. filtration(syringe membrane filter)
  7. custompurified directly by reverse-phase HPLC

Quellen und Nachweise

ORD-Eintrag
ord-b368a25304334ac28b3d3b476cdc3cc0
Quelldatensatz
uspto-grants-2011_11
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08067395B2

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