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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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HRID 562442 반응식
[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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참가 물질

6

반응물 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

생성물 1

HCID 668326372-(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
수율 26.2%

시약·촉매·용매 2

HCID 6228Dimethylformamide용매2회HCID 8471Triethylamine용매2회

실험 절차

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)+.

후처리

  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

출처 및 근거

ORD 기록
ord-b368a25304334ac28b3d3b476cdc3cc0
출처 데이터셋
uspto-grants-2011_11
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US08067395B2

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