Hydrogen Bromide → 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide

HRID 1041449노트

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HRID 1041449 반응식
[NH2:1][C:2]1[C:11]([F:12])=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].Br.[C:15]1([CH3:21])[CH:20]=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[CH3:31][N:32]1C=C(B2OC(C)(C)C(C)(C)O2)C=[N:33]1.NC1C(F)=CC(C2C=NN(C)C=2)=CC=1C(NC)=O.CN1CCCC1=O.C(N(CC)C(C)C)(C)C.[Cl:80][C:81]1[N:86]=[C:85](Cl)[C:84]([Cl:88])=[CH:83][N:82]=1>O.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:80][C:81]1[N:86]=[C:85]([NH:1][C:2]2[C:11]([F:12])=[CH:10][C:9]([C:15]3[CH:20]=[N:33][N:32]([CH3:31])[CH:21]=3)=[CH:8][C:3]=2[C:4]([NH:6][CH3:7])=[O:5])[C:84]([Cl:88])=[CH:83][N:82]=1

참가 물질

14

반응물 10

HCID 260Hydrogen BromideHCID 702EthanolHCID 1140TolueneHCID 10340Sodium CarbonateHCID 13387N-methyl-2-pyrrolidoneHCID 81531DiisopropylethylamineHCID 2372592,4,5-TrichloropyrimidineHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 67263746HCID 67263746, 화합물HCID 672644312-amino-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide

생성물 1

HCID 866340362-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide수율 45%

시약·촉매·용매 3

HCID 178418397HCID 178418397, 화합물촉매HCID 962Water용매HCID 6344Dichloromethane용매

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온도
90 °C

실험 절차

2-Amino-5-bromo-3-fluoro-N-methyl-benzamide; hydrobromide (1.76 g, 5.38 mmol) was placed in toluene (70.5 mL, 662 mmol) and ethanol (70.7 mL, 1210 mmol). Tetrakis(triphenylphosphine)palladium(0) (622 mg, 0.538 mmol) was added followed by 1.00 M of sodium carbonate in water (32.3 mL) and 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1.567 g, 7.531 mmol). The reaction was heated at 90° C. for 3 hours and then concentrated under reduced pressure. The residue was taken up in DCM (200 mL) and washed with 1.00 M Na2CO3 (200 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain a mixture containing 2-amino-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide. This mixture was dissolved in N-methylpyrrolidinone (15.0 mL, 156 mmol) and N,N-diisopropylethylamine (1.12 mL, 6.46 mmol) was added followed by 2,4,5-trichloro-pyrimidine (1.85 mL, 16.1 mmol). The reaction was heated at 100° C. overnight and then cooled to room temperature. The mixture was diluted with DCM (75 mL) and washed with water (4×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by amine capped silica gel chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide as a yellow solid (967 mg, 45%). m.p.=220-221° C.; LCMS (m/e) 395 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 9.51 (s, 1H), 8.19 (s, 1H), 7.58 (s, 1H), 7.49 (s, 1H), 7.33-7.23 (m, 2H), 6.83-6.70 (m, 1H), 3.95 (s, 3H), 3.00 (d, 3H, J=3.6 Hz).

후처리

  1. concentrationconcentrated under reduced pressure
  2. washwashed with 1.00 M Na2CO3 (200 mL)
  3. dry with materialThe organic layer was dried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customPurification by basic alumina chromatography
  7. customto obtain a mixture
  8. temperatureThe reaction was heated at 100° C. overnight
  9. temperaturecooled to room temperature
  10. washwashed with water (4×100 mL)
  11. dry with materialThe organic layer was dried over sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated under reduced pressure
  14. customPurification by amine
  15. customcapped silica gel chromatography

출처 및 근거

ORD 기록
ord-0ee6ae120d2c442b90aff82b341b082f
출처 데이터셋
uspto-grants-2013_10
특허 번호
US08552186B2

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