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Sodium Carbonate → 6-(2-fluoro-3-pyridinyl)-2-(3-{1-methyl-5-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-1,2,4-triazine-3,5(2H,4H)-dione

HRID 1513352
ノート
印刷プレビュー

反応式

HRID 1513352 の反応式
Br[C:2]1[C:3](=[O:29])[NH:4][C:5](=[O:28])[N:6]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][C:15]3([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)[C:13]([CH3:27])([CH2:14]3)[CH2:12]2)[N:7]=1.[F:30][C:31]1[C:36](B(O)O)=[CH:35][CH:34]=[CH:33][N:32]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.COCCOC>[F:30][C:31]1[C:36]([C:2]2[C:3](=[O:29])[NH:4][C:5](=[O:28])[N:6]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:16][C:15]4([C:17]5[CH:22]=[CH:21][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:19][CH:18]=5)[C:13]([CH3:27])([CH2:14]4)[CH2:12]3)[N:7]=2)=[CH:35][CH:34]=[CH:33][N:32]=1
参加物反応条件実験手順後処理出典と根拠反応ノート

参加物

9

反応物 4

HCID 10340Sodium Carbonate2 回HCID 27342162-(Dicyclohexylphosphino)biphenyl2 回HCID 27832702-Fluoropyridine-3-boronic acid2 回HCID 686531246-bromo-2-(3-{1-methyl-5-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-1,2,4-triazine-3,5(2H,4H)-dione

生成物 1

HCID 59496095
6-(2-fluoro-3-pyridinyl)-2-(3-{1-methyl-5-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-1,2,4-triazine-3,5(2H,4H)-dione
収率 28.7%

試薬・触媒・溶媒 4

HCID 178418397HCID 178418397、化合物触媒2 回HCID 962Water溶媒HCID 80711,2-Dimethoxyethane溶媒HCID 18180031Water 1,2-dimethoxyethane溶媒

反応条件

温度
90 °C

実験手順

6-bromo-2-(3-{1-methyl-5-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-1,2,4-triazine-3,5(2H,4H)-dione (P16, 48 mg, 0.101 mmol) was suspended in a degassed mixture of 1,2-Dimethoxyethane (DME) (1.725 mL)/Water (0.345 mL). Then (2-fluoro-3-pyridinyl)boronic acid (42.9 mg, 0.304 mmol), sodium carbonate (32.2 mg, 0.304 mmol), Tetrakis (23.44 mg, 0.020 mmol) and 2-biphenylyl(dicyclohexyl)phosphane (7.11 mg, 0.020 mmol) were added and the mixture was heated to 90° C. and stirred at that temperature for 3 hours. The mixture was cooled down to room temperature, diluted with 1.3 mL of a mixture of DME/Water (5:1) then 2-biphenylyl(dicyclohexyl)phosphane (7.11 mg, 0.020 mmol), (2-fluoro-3-pyridinyl)boronic acid (42.9 mg, 0.304 mmol), Tetrakis (23.44 mg, 0.020 mmol) and sodium carbonate (32.2 mg, 0.304 mmol) were added again. The reaction mixture was then heated to 90° C. and left stirring at that temperature for 40 minutes. The reaction mixture was cooled down to room temperature and evaporated under reduced pressure. The residue was partitioned between AcOEt and water and extracted. Organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. Crude product was purified by Preparative HPLC then further purified by flash chromatography (SiO2, DCM to DCM/MeOH 9:1) affording 6-(2-fluoro-3-pyridinyl)-2-(3-{1-methyl-5-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hex-3-yl}propyl)-1,2,4-triazine-3,5(2H,4H)-dione (Enantiomer 2) (E11, 14 mg, 0.029 mmol, 28.2% yield).

後処理

  1. temperatureThe mixture was cooled down to room temperature
  2. temperatureThe reaction mixture was then heated to 90° C.
  3. waitleft
  4. stirringstirring at that temperature for 40 minutes
  5. temperatureThe reaction mixture was cooled down to room temperature
  6. customevaporated under reduced pressure
  7. customThe residue was partitioned between AcOEt and water
  8. extractionextracted
  9. dry with materialOrganic phase was dried over sodium sulphate
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customCrude product was purified by Preparative HPLC
  13. customthen further purified by flash chromatography (SiO2, DCM to DCM/MeOH 9:1)

出典と根拠

ORDレコード
ord-3fa5df04a8eb49249ef5251224972176
出典データセット
uspto-grants-2012_07
DOI
10.6084/m9.figshare.5104873.v1
特許番号
US08217168B2

反応ノート

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