Methanol → Methyl 1-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)cyclopropanecarboxylate

HRID 1930141노트

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HRID 1930141 반응식
FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([CH3:19])=[N:17][C:16]([CH3:20])=[C:15]([C:21](=[O:23])[NH2:22])[N:14]=2)=[CH:9][CH:8]=1)(=O)=O.[Cl:26][C:27]1[CH:28]=[C:29]([C:42]2([C:45]([O:47][CH3:48])=[O:46])[CH2:44][CH2:43]2)[CH:30]=[CH:31][C:32]=1B1OC(C)(C)C(C)(C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>COCCOC.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(Cl)Cl.O>[C:21]([C:15]1[N:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:32]3[CH:31]=[CH:30][C:29]([C:42]4([C:45]([O:47][CH3:48])=[O:46])[CH2:44][CH2:43]4)=[CH:28][C:27]=3[Cl:26])=[CH:8][CH:9]=2)[C:18]([CH3:19])=[N:17][C:16]=1[CH3:20])(=[O:23])[NH2:22]

참가 물질

8

반응물 4

HCID 887MethanolHCID 62657Potassium Phosphate, TribasicHCID 59627717Methyl 1-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carboxylate2회HCID 596277294-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl trifluoromethanesulfonate2회

생성물 1

HCID 59627667Methyl 1-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)cyclopropanecarboxylate수율 49.8%

시약·촉매·용매 3

HCID 178418807HCID 178418807, 화합물촉매HCID 962Water용매HCID 80711,2-Dimethoxyethane용매

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온도
90 °C

실험 절차

A solution of 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenyl trifluoromethanesulfonate (Intermediate 7-4; 245 mg, 0.65 mmol) and methyl 1-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxylate (Intermediate 10-2; 220 mg, 0.65 mmol) and potassium phosphate, tri-basic (166 mg, 0.78 mmol) in DME (4 mL), methanol (2 mL) and water (1 mL) was thoughroughly degassed. The mixture was treated with PdCl2(dppf)-DCM adduct (26.7 mg, 0.03 mmol), degassed again and the atmosphere replaced with nitrogen before being heated to 90° C. for 4 hours in the microwave. The reaction mixture was allowed to cool to room temperature and then evaporated. The crude product was partitioned between EtOAc (75 mL), and saturated brine (75 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 70% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 1-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)cyclopropanecarboxylate (141 mg, 49.5%) as a colourless gum.

후처리

  1. customdegassed again
  2. temperatureto cool to room temperature
  3. customevaporated
  4. customThe crude product was partitioned between EtOAc (75 mL), and saturated brine (75 mL)
  5. dry with materialThe organic layer was dried over MgSO4
  6. filtrationfiltered
  7. customevaporated
  8. customto afford crude product
  9. customThe crude product was purified by flash silica chromatography, elution gradient 0 to 70% EtOAc in isohexane
  10. customPure fractions were evaporated to dryness

출처 및 근거

ORD 기록
ord-b3aaec71b9b84addaf4cb48a88887d0b
출처 데이터셋
uspto-grants-2012_05
특허 번호
US08188092B2

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