Phosphorus oxybromide → 8-cyclopropyl-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine

HRID 473218노트

반응식

HRID 473218 반응식
[CH:1]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[C:11]([C:14]([F:23])([F:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[N:10]=[C:9]3O)[CH2:3][CH2:2]1.P(Br)(Br)(Br)=O.CCN(C(C)C)C(C)C.[CH3:39][C:40]1[NH:44][N:43]=[C:42]([NH2:45])[CH:41]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[C:11]([C:14]([F:23])([F:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[N:10]=[C:9]3[NH:45][C:42]2[CH:41]=[C:40]([CH3:39])[NH:44][N:43]=2)[CH2:3][CH2:2]1

참가 물질

7

반응물 4

HCID 24613Phosphorus oxybromideHCID 81531DiisopropylethylamineHCID 931461H-Pyrazol-3-amine, 5-methyl-HCID 178517773HCID 178517773, 화합물

생성물 1

HCID 568488708-cyclopropyl-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine수율 48.7%

시약·촉매·용매 2

HCID 1140Toluene용매HCID 6228Dimethylformamide용매

반응 조건

온도
95 °C

실험 절차

To 8-cyclopropyl-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4-ol (50 mg, 0.15 mmol) were added phosphoryl tribromide (0.86 g) and toluene (2 mL) followed by DIEA (0.053 mL, 0.3 mmol). The mixture was heated at 95° C. for 0.5 h. The mixture was cooled and partitioned between EtOAc and a saturated aq sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated. To the residue was added a solution of 5-methyl-1H-pyrazol-3-amine (100 mg, 1 mmol) in DMF (3 mL) and the mixture was stirred at rt overnight. The mixture was purified by preparative HPLC (Varian diphenyl reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O) to afford 8-cyclopropyl-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (30 mg, 48%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.79-0.90 (m, 2H) 1.04-1.16 (m, 2H) 2.17 (s, 3H) 2.95-3.10 (m, 1H) 5.97 (s, 1H) 7.32 (d, J=7.35 Hz, 1H) 7.52 (t, J=7.91 Hz, 1H) 7.96-8.06 (m, 2H) 8.43 (d, J=8.10 Hz, 1H) 8.67 (s, 1H) 10.57 (br s, 1H) 12.15 (br s, 1H); LC-MS (ESI) m/z 411 (M+H)+.

후처리

  1. temperatureThe mixture was cooled
  2. custompartitioned between EtOAc
  3. dry with materialThe organic layer was dried over sodium sulfate
  4. concentrationconcentrated
  5. customThe mixture was purified by preparative HPLC (Varian diphenyl reverse phase column
  6. washeluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O)

출처 및 근거

ORD 기록
ord-41dda6787df24cf7b4bc22b533ce10b3
출처 데이터셋
uspto-grants-2014_01
특허 번호
US08633207B2

반응 노트

불러오는 중…