Dichloromethane → 4-{3-[4-Amino-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester

HRID 1972801노트

반응식

HRID 1972801 반응식
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:28]4[C:23]([C:24]([NH2:29])=[N:25][CH:26]=[N:27]4)=[C:22](Br)[CH:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:31]([N:38]1[CH:46]=[C:45]2[C:40]([CH:41]=[C:42](B3OC(C)(C)C(C)(C)O3)[CH:43]=[CH:44]2)=[N:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:28]4[C:23]([C:24]([NH2:29])=[N:25][CH:26]=[N:27]4)=[C:22]([C:42]4[CH:43]=[CH:44][C:45]5[C:40]([CH:41]=4)=[N:39][N:38]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:46]=5)[CH:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

참가 물질

6

반응물 4

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 585293132-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-IndazoleHCID 585297564-[3-(4-Amino-5-bromo-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-Phenyl]-piperazine-1-carboxylic acid tert-butyl ester

생성물 1

HCID 585292904-{3-[4-Amino-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester수율 40.1%

시약·촉매·용매 1

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)촉매

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온도
80 °C

실험 절차

The product from step 4 (150 mg, 0.32 mmol) and Intermediate C (138 mg, 0.41 mmol) were dissolved in 2 mL of 1:1-toluene:dioxane and degassed with a vacuum/N2 purge sequence (3×). 1,1′-Bis(diphenylphosphino)ferrocenepalladium(II) chloride-complex with methylene chloride (12 mg, 0.02 mmol) was added followed by 1 mL of 2M aqueous Na2CO3 solution and the mixture heated to 80° C. overnight. The heating bath was removed and the mixture diluted with water and EtOAc (5 mL each). The layers were separated and the aqueous phase was extracted with EtOAc and the combined organic phases were washed with water and brine, dried (Na2SO4), filtered and concentrated in, vacuo. The residue was purified by Isco® (Red-sep 12 eluting with 70%—100% EtOAc/hexanes) to give 77 mg (40%) of the title compound as a tan solid. 1H-NMR (DMSO-d6) 8.33 (s, 1H), 7.61 (s, 1H), 7.57 (bs, 2H), 7.40-7.24 (m, 7H), 7.22 (s, 1H), 7.08, (d, 1H), 7.06 (s, 1H), 6.77 (d, 1H), 6.58 (d, 1H), 6.25 (d, 1H), 5.55 (s, 2H), 3.47 (m, 4H), 3.18 (m, 4H), 1.42 (s, 9H); LC-MS [M+H]+=601.3, RT=3.12 min.

후처리

  1. custom1-toluene:dioxane and degassed with a vacuum/N2
  2. custompurge sequence (3×)
  3. customThe heating bath was removed
  4. additionthe mixture diluted with water and EtOAc (5 mL each)
  5. customThe layers were separated
  6. extractionthe aqueous phase was extracted with EtOAc
  7. washthe combined organic phases were washed with water and brine
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated in, vacuo
  11. customThe residue was purified by Isco® (Red-sep 12 eluting with 70%—100% EtOAc/hexanes)

출처 및 근거

ORD 기록
ord-f4a2ba77a3944ff1915b1dc8614301cf
출처 데이터셋
uspto-grants-2013_04
특허 번호
US08431695B2

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