Potassium Phosphate, Tribasic → Methyl 2-[4-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl]-3-chlorophenyl]acetate

HRID 1930189ノート

反応式

HRID 1930189 の反応式
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.[Cl: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+].[Cl-].[Li+]>COCCOC.CO.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[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[Cl:27])=[C:8]([F:24])[CH:9]=2)[C:18]([CH3:19])=[N:17][C:16]=1[CH3:20])(=[O:23])[NH2:22]

参加物

9

反応物 4

HCID 62657Potassium Phosphate, TribasicHCID 433294Lithium ChlorideHCID 58464478Benzeneacetic acid, 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-, methyl ester2 回HCID 59627655HCID 59627655、化合物2 回

生成物 1

HCID 59627722Methyl 2-[4-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl]-3-chlorophenyl]acetate収率 49%

試薬・触媒・溶媒 4

HCID 53485975CID 53485975触媒HCID 887Methanol溶媒HCID 962Water溶媒HCID 80711,2-Dimethoxyethane溶媒

実験手順

Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (68.2 g, 83.5 mmol) was added in one go to a stirred mixture, which had been degassed for 30 minutes with nitrogen, of 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl trifluoromethanesulfonate (Intermediate 31-6; 730 g, 1856 mmol), methyl 2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (Intermediate 31-3; 1164 g, 1948 mmol) (52% strength by proton NMR), tripotassium phosphate (690 g, 3248 mmol) and lithium chloride (138 g, 3248 mmol) in DME (5 L), methanol (2.5 L) and water (2.5 L) at 20° C. The reaction was heated to reflux and stirred under a nitrogen atmosphere overnight. The reaction was cooled to room temperature. The organic layer was filtered through a glass sinter. Ethyl acetate (10.0 L) and 30% brine/water (5.0 L) were added. The aqueous layer was separated and extracted with ethyl acetate (5.0 L), the organic layers were combined, washed with 50% brine/water (10.0 L), dried (magnesium sulphate), filtered and the solvents removed in vacuo. The crude product was dissolved in dichloromethane and then chromatographed on silica (5 Kg of Merck lichro prep silica 15-25 μm, 200 mm diameter column), eluting with a solvent gradient of 0-70% ethylacetate/isohexane. Pure fractions were evaporated to dryness to afford methyl 2-[4-[4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl]-3-chlorophenyl]acetate (389 g, 49%) as a white solid.

後処理

  1. temperatureThe reaction was heated
  2. temperatureto reflux
  3. filtrationThe organic layer was filtered through a glass sinter
  4. additionEthyl acetate (10.0 L) and 30% brine/water (5.0 L) were added
  5. customThe aqueous layer was separated
  6. extractionextracted with ethyl acetate (5.0 L)
  7. washwashed with 50% brine/water (10.0 L)
  8. dry with materialdried (magnesium sulphate)
  9. filtrationfiltered
  10. customthe solvents removed in vacuo
  11. dissolutionThe crude product was dissolved in dichloromethane
  12. customchromatographed on silica (5 Kg of Merck lichro prep silica 15-25 μm, 200 mm diameter column)
  13. washeluting with a solvent gradient of 0-70% ethylacetate/isohexane
  14. customPure fractions were evaporated to dryness

出典と根拠

ORDレコード
ord-5127f4b61bc547809a00bac90598d044
出典データセット
uspto-grants-2012_05
特許番号
US08188092B2

反応ノート

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