Potassium Phosphate, Tribasic → 6-(2'-Chloro-4'-((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)biphenyl-4-yl)-3,5-dimethylpyrazine-2-carboxamide

HRID 1930166노트

반응식

HRID 1930166 반응식
[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13](B(O)O)=[C:12](Cl)[CH:11]=2)[C:7]([CH3:20])=[N:6][C:5]=1[CH3:21])(=[O:3])[NH2:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:31]1[CH:43]=[CH:42][C:34]([CH2:35][C:36]2[NH:40][C:39](=[O:41])[O:38][N:37]=2)=[CH:33][C:32]=1[Cl:44]>COCCOC.CO.O.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:44][C:32]1[CH:33]=[C:34]([CH2:35][C:36]2[NH:40][C:39](=[O:41])[O:38][N:37]=2)[CH:42]=[CH:43][C:31]=1[C:13]1[CH:14]=[CH:15][C:10]([C:8]2[N:9]=[C:4]([C:1]([NH2:2])=[O:3])[C:5]([CH3:21])=[N:6][C:7]=2[CH3:20])=[CH:11][CH:12]=1

참가 물질

8

반응물 3

HCID 62657Potassium Phosphate, TribasicHCID 672865054-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorophenylboronic acid2회HCID 1361605583-(4-bromo-3-chlorobenzyl)-1,2,4-oxadiazol-5(4H)-one2회

생성물 1

HCID 1361605536-(2'-Chloro-4'-((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)biphenyl-4-yl)-3,5-dimethylpyrazine-2-carboxamide수율 29.8%

시약·촉매·용매 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)촉매HCID 887Methanol용매HCID 962Water용매HCID 80711,2-Dimethoxyethane용매

반응 조건

온도
80 °C

실험 절차

To a degassed solution of 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenylboronic acid (Intermediate 5-1; 562 mg, 2.07 mmol) in DME (60 mL), methanol (15 mL) and water (15 mL) was added tripotassium phosphate (660 mg, 3.11 mmol), 3-(4-bromo-3-chlorobenzyl)-1,2,4-oxadiazol-5(4H)-one (Intermediate 23-1; 600 mg, 2.07 mmol) followed by (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (DCM adduct) (341 mg, 0.41 mmol). The resulting mixture was stirred at 80° C. under nitrogen for 90 minutes. The reaction mixture was allowed to cool to ambient temperature evaporated and partitioned between DCM (100 mL) and 0.5M HCl (100 mL), the suspension was filtered (difficult as most of the material was a sticky gum) and the resultant material retained. Organic phase separated off, dried by passing through a phase seperating cartridge. Removal of the solvent under reduced pressure gave crude product which was combined with previously filtered material for chromatography. The crude product was purified by preparative HPLC (Waters—Xbridge Prep C18 5 μm), using decreasingly polar mixtures of water (containing 0.1% formic acid) and {MeOH(3):MeCN(1)} as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-(2′-chloro-4′-((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)biphenyl-4-yl)-3,5-dimethylpyrazine-2-carboxamide (269 mg, 29.8%) as a colourless solid.

후처리

  1. temperatureto cool to ambient temperature
  2. customevaporated
  3. custompartitioned between DCM (100 mL) and 0.5M HCl (100 mL)
  4. filtrationthe suspension was filtered (difficult as most of the material
  5. customOrganic phase separated off
  6. customdried
  7. customseperating cartridge
  8. customRemoval of the solvent under reduced pressure
  9. customgave crude product which
  10. customThe crude product was purified by preparative HPLC (Waters—Xbridge Prep C18 5 μm)
  11. additionFractions containing the desired compound
  12. customwere evaporated to dryness

출처 및 근거

ORD 기록
ord-dba5fb78daaf4429817b0dc0c22a4fb3
출처 데이터셋
uspto-grants-2012_05
특허 번호
US08188092B2

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