3-(5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazol-1-yl)-N,N-dimethylpropan-1-amine → 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

HRID 246740노트

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HRID 246740 반응식
[F:1][CH:2]([F:32])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13]CCN(C)C)[N:8]=[C:7]2[Sn](CCCC)(CCCC)CCCC.Br[C:34]1[N:39]=[C:38]2[C:40]([C:43]([NH:45][CH:46]([CH3:48])[CH3:47])=[O:44])=[CH:41][NH:42][C:37]2=[N:36][CH:35]=1>CN(C=O)C.[Cu]I.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>[F:32][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[C:34]1[N:39]=[C:38]2[C:40]([C:43]([NH:45][CH:46]([CH3:48])[CH3:47])=[O:44])=[CH:41][NH:42][C:37]2=[N:36][CH:35]=1

참가 물질

6

반응물 2

HCID 712800443-(5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazol-1-yl)-N,N-dimethylpropan-1-amineHCID 866780102-Bromo-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

생성물 1

HCID 712799912-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide수율 9%

시약·촉매·용매 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)촉매HCID 178418397HCID 178418397, 화합물촉매HCID 6228Dimethylformamide용매

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온도
80 °C

실험 절차

To a solution of 3-(5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazol-1-yl)-N,N-dimethylpropan-1-amine (200 mg, 0.36 mmol) and 2-bromo-N-isopropyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (180 mg, 0.43 mmol) in DMF (10 mL) were added CuI (18 mg, 0.08 mmol) and Pd(PPh3)4 (14 mg, 0.014 mmol), Then the reaction mixture was degassed by bubbling nitrogen for 3 minutes and refilled with nitrogen. The mixture was heated to 80° C. for 5 hours under nitrogen, after cooling to room temperature, water (50 mL) was added and product extracted with EtOAc (3×40 mL), the combined organic layers were dried over Na2SO4, concentrated under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% trifluoroacetic acid V/V) initially, and then proceed to 50% acetonitrile/50% water (0.1% trifluoroacetic acid V/V) in a linear fashion after just 9 min) to afford 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-isopropyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide as yellow solid (13 mg, 9%). LCMS: (M+H)+=472; 1H NMR (300 MHz, CD3OD): δ 9.11 (s, 1H), 8.24 (s, 1H), 8.11 (s, 1H), 7.69 (d, 1H, J=9.0 Hz), 7.38 (d, 1H, J=8.7 Hz), 6.85 (t, 1H, J=74.1 Hz), 4.85-4.78 (m, 2H), 4.65-4.60 (m, 1H), 3.34-3.32 (m, 2H), 2.89 (s, 6H), 2.50-2.40 (m, 2H), 1.43 (s, 3H), 1.40 (s, 3H).

후처리

  1. customthe reaction mixture was degassed
  2. customby bubbling nitrogen for 3 minutes
  3. additionrefilled with nitrogen
  4. temperatureafter cooling to room temperature
  5. additionwater (50 mL) was added
  6. extractionproduct extracted with EtOAc (3×40 mL)
  7. dry with materialthe combined organic layers were dried over Na2SO4
  8. concentrationconcentrated under reduced pressure
  9. customthe residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm

출처 및 근거

ORD 기록
ord-c8f37d7a99c44bc3b9ef47dd7f7e2c20
출처 데이터셋
uspto-grants-2014_02
특허 번호
US08658646B2

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