Chloromethyl chloroformate → Di-tert-butyl [4-[[4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methyl phosphate

HRID 1752993ノート

反応式

HRID 1752993 の反応式
[Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=2)=[O:7])=[C:4]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[O:27][CH3:28])[CH:3]=1.ClC([O:32][CH2:33]Cl)=O.[C:35]([O:39][P:40](O[K])([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl.CCOC(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CN(C=O)C.C1COCC1>[P:40]([O:32][CH2:33][N:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:16]=[C:17]([Cl:18])[C:2]([Cl:1])=[CH:3][C:4]=2[O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[O:27][CH3:28])=[CH:10][C:11]1=[O:15])([O:39][C:35]([CH3:38])([CH3:37])[CH3:36])([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41]

参加物

10

反応物 3

HCID 62754Chloromethyl chloroformate3 回HCID 768532154,5-Dichloro-N-(1,2-dihydro-2-oxo-4-pyridinyl)-2-(4-fluoro-2-methoxyphenoxy)benzamideHCID 178454814HCID 178454814、化合物

生成物 1

HCID 118148564Di-tert-butyl [4-[[4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methyl phosphate収率 26%

試薬・触媒・溶媒 6

HCID 67553Tetrabutylammonium Iodide触媒HCID 962Water溶媒HCID 6228Dimethylformamide溶媒2 回HCID 6344Dichloromethane溶媒HCID 8028Tetrahydrofuran溶媒HCID 8857Ethyl Acetate溶媒

実験手順

To a solution of 4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)benzamide (1a) (101 mg, 0.2386 mmol) and chloromethyl chloroformate (36.92 mg, 24.86 μL, 0.2863 mmol) in CH2Cl2 (2 mL) was added DMF (200 μL) and the reaction mixture was stirred at room temperature for 1 hour. At this time, THF (1 mL) was added followed by more chloromethyl chloroformate (36.92 mg, 24.86 μL, 0.2863 mmol) and the reaction mixture stirred at room temperature for 1 h. More DMF (1 mL) and chloromethyl chloroformate (36.92 mg, 24.86 μL, 0.2863 mmol) was added and the reaction mixture was heated to 70° C. for 15 min. The reaction mixture was diluted with EtOAc and the organic phase washed with sat. aq. NaHCO3, brine, dried with Na2SO4 and evaporated to dryness. The residue was taken up in DMF (1.010 mL), di-tert-butoxyphosphoryloxypotassium (118.5 mg, 0.4772 mmol) and tetrabutylammonium iodide (8.813 mg, 0.02386 mmol) was added and the reaction mixture stirred at 70° C. for 4 h. The reaction mixture was cooled, diluted with water and extracted with EtOAc (3×). The organic layers were combined, washed with water then brine, dried with Na2SO4 and evaporated to dryness. Purification by column chromatography (12 g silica; 0-100% EtOAc in Hx) gave di-tert-butyl [4-[[4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methyl phosphate (25) (40 mg, 0.06197 mmol, 26.0%) as a clear glass. ESI-MS m/z calc. 644.12573, found 647.3 (M+1)+; Retention time: 0.81 minutes

後処理

  1. stirringthe reaction mixture stirred at room temperature for 1 h
  2. temperaturethe reaction mixture was heated to 70° C. for 15 min
  3. washthe organic phase washed with sat. aq. NaHCO3, brine
  4. dry with materialdried with Na2SO4
  5. customevaporated to dryness
  6. stirringthe reaction mixture stirred at 70° C. for 4 h
  7. temperatureThe reaction mixture was cooled
  8. extractionextracted with EtOAc (3×)
  9. washwashed with water
  10. dry with materialbrine, dried with Na2SO4
  11. customevaporated to dryness
  12. customPurification by column chromatography (12 g silica; 0-100% EtOAc in Hx)

出典と根拠

ORDレコード
ord-2461077f1efa4ce6a8024e2421c6dccb
出典データセット
uspto-grants-2015_10
特許番号
US09163042B2

反応ノート

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