Dichloromethane → (4aS,5S,7aS)-7a-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine

HRID 68380ノート

反応式

HRID 68380 の反応式
Br[C:2]1[C:3]([F:28])=[CH:4][C:5]([F:27])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([CH2:17][F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:19]C(=O)OC(C)(C)C)=[N:9]3)[CH:7]=1.[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl.C(O)(C(F)(F)F)=O>COCCOC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.CCO>[F:27][C:5]1[CH:4]=[C:3]([F:28])[C:2]([C:33]2[CH:34]=[N:29][CH:30]=[N:31][CH:32]=2)=[CH:7][C:6]=1[C@:8]12[CH2:16][O:15][C@H:14]([CH2:17][F:18])[C@H:13]1[CH2:12][S:11][C:10]([NH2:19])=[N:9]2

参加物

10

反応物 5

HCID 6344DichloromethaneHCID 6422Trifluoroacetic acidHCID 10796Cesium carbonateHCID 2795193(Pyrimidin-5-yl)boronic acidHCID 86707819tert-Butyl ((4aS,5S,7aS)-7a-(5-bromo-2,4-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate

生成物 1

HCID 57415617(4aS,5S,7aS)-7a-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine

試薬・触媒・溶媒 4

HCID 6102075Dichlorobis(triphenylphosphine)palladium触媒HCID 702Ethanol溶媒HCID 962Water溶媒HCID 80711,2-Dimethoxyethane溶媒

反応条件

温度
100 °C

実験手順

tert-Butyl ((4aS,5S,7aS)-7a-(5-bromo-2,4-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate (100 mg, 0.21 mmol) was dissolved in DME (1.5 mL), EtOH (0.7 mL) and water (0.5 mL). The solution was heated to 100° C. Pyrimidin-5-ylboronic acid (51.5 mg, 0.416 mmol), bis(triphenylphosphine)palladium (II) chloride (29.2 mg, 0.042 mmol) and cesium carbonate (406 mg, 1.25 mmol) were added and the reaction was stirred at 100° C. for 45 minutes. The reaction was cooled to room temperature and partitioned between DCM and saturated aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with DCM (×2). The organic layers were combined, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (Biotage SNAP 10 g, 12 mL/min eluting with 20-80% EtOAc in n-hexane). The material was stirred in DCM (2 mL, 31.08 mmol) and TFA (2 mL) for 1 hour at room temperature. The solvents were removed in vacuo. The residue was passed over a 5 g SCX cartridge, washing with MeOH then 2N NH3/MeOH. The basic fractions were concentrated in vacuo and the residue was purified by column chromatography (Biotage SNAP 10 g, 12 mL/min gradient 0-20% MeOH in EtOAc) to leave the title compound as a white solid.

後処理

  1. temperatureThe reaction was cooled to room temperature
  2. custompartitioned between DCM and saturated aqueous NaHCO3
  3. customThe layers were separated
  4. extractionthe aqueous layer was extracted with DCM (×2)
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by column chromatography (Biotage SNAP 10 g, 12 mL/min eluting with 20-80% EtOAc in n-hexane)
  8. customThe solvents were removed in vacuo
  9. washwashing with MeOH
  10. concentrationThe basic fractions were concentrated in vacuo
  11. customthe residue was purified by column chromatography (Biotage SNAP 10 g, 12 mL/min gradient 0-20% MeOH in EtOAc)

出典と根拠

ORDレコード
ord-0e899d999aaf4afeb40170a2ad1d28b4
出典データセット
uspto-grants-2014_09
特許番号
US08822455B2

反応ノート

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