Methanol → Methyl 2-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,2'-difluorobiphenyl-4-yl)acetate

HRID 1930129노트

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HRID 1930129 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][C:8]=1[F:24])(=O)=O.[F:27][C:28]1[CH:29]=[C:30]([CH2:43][C:44]([O:46][CH3:47])=[O:45])[CH:31]=[CH:32][C:33]=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:33]3[CH:32]=[CH:31][C:30]([CH2:43][C:44]([O:46][CH3:47])=[O:45])=[CH:29][C:28]=3[F:27])=[C:8]([F:24])[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 59627655HCID 59627655, 화합물2회HCID 59627674Methyl 2-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate2회

생성물 1

HCID 59627685Methyl 2-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,2'-difluorobiphenyl-4-yl)acetate수율 76%

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)-2-fluorophenyl trifluoromethanesulfonate (Intermediate 6-4; 302 mg, 0.77 mmol) and methyl 2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (Intermediate 6-2; 226 mg, 0.77 mmol) and potassium phosphate, tri-basic (196 mg, 0.92 mmol) in DME (10 mL), methanol (5 mL) and water (2.5 mL) was thoughroughly degassed. The mixture was treated with PdCl2(dppf)-DCM adduct (31.4 mg, 0.04 mmol), degassed again and the atmosphere replaced with nitrogen before being heated to 90° C. for 4 hours. 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 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,2′-difluorobiphenyl-4-yl)acetate (240 mg, 76%) as a cream solid.

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-35a312b0f80345faa193901673e61f69
출처 데이터셋
uspto-grants-2012_05
특허 번호
US08188092B2

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