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Potassium Phosphate, Tribasic → (R,E)-ethyl 4-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhex-2-enoate

HRID 2171846
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HRID 2171846 반응식
[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[C:10]1[N:15]=[C:14]([NH:16][C@@H:17]([C:25]([CH3:28])([CH3:27])[CH3:26])/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]([F:29])=[CH:12][N:11]=1.[F:30][C:31]1[CH:32]=[C:33]2[C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][N:37]([S:49]([C:52]3[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=3)(=[O:51])=[O:50])[C:34]2=[N:35][CH:36]=1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[F:29][C:13]1[C:14]([NH:16][C@@H:17]([C:25]([CH3:28])([CH3:27])[CH3:26])/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:15][C:10]([C:39]2[C:33]3[C:34](=[N:35][CH:36]=[C:31]([F:30])[CH:32]=3)[N:37]([S:49]([C:52]3[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=3)(=[O:50])=[O:51])[CH:38]=2)=[N:11][CH:12]=1
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참가 물질

7

반응물 3

HCID 62657Potassium Phosphate, TribasicHCID 672856905-fluoro-1-((4-methylphenyl)sulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo(2,3-b)pyridine2회HCID 86714739(R,E)-ethyl 4-((2-chloro-5-fluoropyrimidin-4-yl)amino)-5,5-dimethylhex-2-enoate2회

생성물 1

HCID 71251331(R,E)-ethyl 4-((5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhex-2-enoate

시약·촉매·용매 3

HCID 9811564Bis(dibenzylideneacetone)palladium촉매HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl촉매HCID 962Water용매2회

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온도
80 °C

실험 절차

K3PO4 (1.078 g, 5.079 mmol) was dissolved in water (3.2 mL) and added to a solution of (R,E)-ethyl 4-((2-chloro-5-fluoropyrimidin-4-yl)amino)-5,5-dimethylhex-2-enoate, 37a, (0.534 g, 1.693 mmol) in 2-methyl-THF (10.7 mL) and the mixture was purged with nitrogen for 30 minutes. 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 7a, (0.775 g, 1.862 mmol) was added and the nitrogen purging was continued for an additional 15 min. X-Phos (0.048 g, 0.102 mmol) and Pd2(dba)3 (0.031 g, 0.034 mmol) were added and the mixture was heated at 80° C. overnight. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The layers were separated and the organic phase was washed with brine, dried over MgSO4, filtered and evaporated to dryness. The crude residue was dissolved in a minimum volume of dichloromethane and purified by silica gel chromatography (0-100% EtOAc/hexanes gradient) to afford 650 mg of desired product: 1H NMR (400 MHz, CDCl3) δ 8.57-8.38 (m, 2H), 8.30 (s, 1H), 8.11 (dd, J=10.5, 5.5 Hz, 3H), 7.08 (dt, J=36.7, 18.3 Hz, 1H), 6.01 (d, J=15.7 Hz, 1H), 5.11 (d, J=8.7 Hz, 1H), 4.97-4.77 (m, 1H), 4.19 (q, J=7.1 Hz, 2H), 2.39 (d, J=10.7 Hz, 3H), 1.27 (q, J=7.4 Hz, 4H), 1.10 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=3.99 minutes (M+H) 570.01.

후처리

  1. customthe mixture was purged with nitrogen for 30 minutes
  2. temperatureAfter cooling to room temperature
  3. extractionextracted with EtOAc
  4. customThe layers were separated
  5. washthe organic phase was washed with brine
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. customevaporated to dryness
  9. dissolutionThe crude residue was dissolved in a minimum volume of dichloromethane
  10. custompurified by silica gel chromatography (0-100% EtOAc/hexanes gradient)

출처 및 근거

ORD 기록
ord-03c8e0bb0cb245458847ffb4e313b7a7
출처 데이터셋
uspto-grants-2015_06
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US09051319B2

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