Cesium fluoride → Methyl 6-amino-2-(4-chloro-2,3-difluorophenyl)pyrimidine-4-carboxylate

HRID 244306

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HRID 244306 반응식
[Cl:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[C:4]([F:17])[C:3]=1[F:18].[NH2:19][C:20]1[N:25]=[C:24](Cl)[N:23]=[C:22]([C:27]([O:29][CH3:30])=[O:28])[CH:21]=1.[F-].[Cs+].P(C1C=C(S([O-])(=O)=O)C=CC=1)(C1C=C(S([O-])(=O)=O)C=CC=1)C1C=C(S([O-])(=O)=O)C=CC=1.[Na+].[Na+].[Na+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[NH2:19][C:20]1[N:25]=[C:24]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:18])[C:4]=2[F:17])[N:23]=[C:22]([C:27]([O:29][CH3:30])=[O:28])[CH:21]=1

참가 물질

8

반응물 4

HCID 25953Cesium fluorideHCID 6099338Trisodium 3,3',3''-phosphinetriyltris(benzene-1-sulphonate)HCID 53396493Methyl 6-amino-2-chloropyrimidine-4-carboxylateHCID 569732562-(4-Chloro-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

생성물 1

HCID 70497913Methyl 6-amino-2-(4-chloro-2,3-difluorophenyl)pyrimidine-4-carboxylate수율 68.3%

시약·촉매·용매 3

HCID 167845palladium(II) acetate촉매HCID 962Water용매2회HCID 6342Acetonitrile용매

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온도
150 °C

실험 절차

2-(4-Chloro-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.4 g, 5.1 mmol, 1.2 equiv) and methyl 6-amino-2-chloropyrimidine-4-carboxylate (800 mg, 4.3 mmol, 1.0 equiv) were sequentially added to a 20 mL Biotage microwave vessel, followed by cesium fluoride (1.3 g, 8.5 mmol, 2.0 equiv), palladium(II) acetate (38 mg, 0.17 mmol, 0.04 equiv), and sodium 3,3′,3″-phosphinetriyltribenzenesulfonate (190 mg, 0.34 mmol, 0.08 equiv). A 3:1 mixture of water:acetonitrile (8.5 mL) was added and the resulting brown mixture was placed in a Biotage microwave and heated at 150° C. for 5 m. The cooled reaction mixture was diluted with water (300 mL) and extracted with dichloromethane (5×100 mL). The combined organic layers were dried (magnesium sulfate), gravity-filtered, and concentrated under vacuum. The product was purified by flash chromatography (SiO2, 40% ethyl acetate in hexane) to afford the title compound as an off-white powder (880 mg, 68% yield): mp 192-195° C.; 1H NMR (300 MHz, CDCl3) δ 7.77 (m, 1H), 7.21-7.28 (m, 2H), 7.15 (s, 1H), 5.23 (br s, 2H), 4.00 (s, 3H); IR (neat film) 3493 (w), 3393 (m), 3342 (m), 3211 (s), 1730 (m), 1649 (m); ESIMS m/z 300 ([M+H]+).

후처리

  1. customThe cooled reaction mixture
  2. extractionextracted with dichloromethane (5×100 mL)
  3. dry with materialThe combined organic layers were dried (magnesium sulfate)
  4. filtrationgravity-filtered
  5. concentrationconcentrated under vacuum
  6. customThe product was purified by flash chromatography (SiO2, 40% ethyl acetate in hexane)

출처 및 근거

ORD 기록
ord-eca781b0bcf34654873145d03134edf4
출처 데이터셋
uspto-grants-2014_02
특허 번호
US08658568B2

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