2-Bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]amide → 2-(6-tert-butyl-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide

HRID 246028노트

반응식

HRID 246028 반응식
[C:1]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([Sn](CCCC)(CCCC)CCCC)=[N:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:28]([CH:30]1[CH2:33][N:32]([C:34](=[O:58])[C@H:35]([NH:37][C:38]([C:40]2[C:48]3[C:43](=[N:44][CH:45]=[C:46](Br)[N:47]=3)[N:42]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[CH:41]=2)=[O:39])[CH3:36])[CH2:31]1)#[N:29]>CN(C=O)C.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.[Cu]I>[C:28]([CH:30]1[CH2:31][N:32]([C:34](=[O:58])[C@H:35]([NH:37][C:38]([C:40]2[C:48]3[C:43](=[N:44][CH:45]=[C:46]([C:9]4[C:8]5[C:12](=[CH:13][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=5)[N:11]([CH3:14])[N:10]=4)[N:47]=3)[N:42]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[CH:41]=2)=[O:39])[CH3:36])[CH2:33]1)#[N:29]

참가 물질

6

반응물 2

HCID 584386122-Bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]amideHCID 712801066-tert-butyl-1-methyl-3-tributylstannanyl-1H-indazole

생성물 1

HCID 712889062-(6-tert-butyl-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide수율 85%

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 6-tert-butyl-1-methyl-3-tributylstannyl-1H-indazole (crude from Step 5, 217 mg, 0.45 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (125 mg, 0.25 mmol) in DMF (1.5 mL) were added Pd(PPh3)4 (14 mg, 0.012 mmol) and copper(I) iodide (9 mg, 0.05 mmol). The yellow reaction mixture was purged with argon then heated at 80° C. for 1.5 h then cooled to room temperature, quenched with sat NH4Cl and extracted with EtOAc (2×). The combined organics were washed with sat LiCl and brine then dried over MgSO4 and concentrated. The crude residue was purified by silica gel chromatography with 50% to 100% EtOAc/heptane to isolate 129 mg (85%) of 2-(6-tert-butyl-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a white solid.

후처리

  1. customThe yellow reaction mixture was purged with argon
  2. temperaturethen cooled to room temperature
  3. customquenched with sat NH4Cl
  4. extractionextracted with EtOAc (2×)
  5. washThe combined organics were washed with sat LiCl and brine
  6. dry with materialthen dried over MgSO4
  7. concentrationconcentrated
  8. customThe crude residue was purified by silica gel chromatography with 50% to 100% EtOAc/heptane

출처 및 근거

ORD 기록
ord-18c7db87151e41bd900ecdc9360d8162
출처 데이터셋
uspto-grants-2014_02
특허 번호
US08658646B2

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