Lithium Hexamethyldisilazide → 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

HRID 509101

반응식

HRID 509101 반응식
[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:28]([C:30]1[CH:31]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[F:36])#[N:29]>C1COCC1.C(OCC)(=O)C>[C:28]([C:30]1[CH:31]=[C:32]([S:37]([N:6]([CH2:5][C:4]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=2[O:2][CH3:1])[C:7]2[S:11][N:10]=[CH:9][N:8]=2)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[F:36])#[N:29]

참가 물질

6

반응물 3

HCID 2733832Lithium HexamethyldisilazideHCID 27789083-Cyano-4-fluorobenzenesulfonyl chlorideHCID 57732216N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine

생성물 1

HCID 580422543-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide수율 71%

시약·촉매·용매 2

HCID 8028Tetrahydrofuran용매3회HCID 8857Ethyl Acetate용매

반응 조건

온도
-78 °C

실험 절차

N-(2,4-Dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (Preparation 18, 42.8 g, 170 mmol) was dissolved in anhydrous THF (600 mL) and stirred under a nitrogen atmosphere at −78° C. A 1M solution of LiHMDS in THF (238 mL, 238 mmol) was added dropwise over 30 minutes maintaining the temperature between −65° C. and −70° C. The reaction mixture was left at −78° C. for 5 minutes, then allowed to warm to −10° C. over 1.5 hours. Upon reaching −10° C., the brown reaction mixture was cooled to −78° C. again, and a solution of 3-cyano-4-fluorobenzene sulfonyl chloride (48.6 g, 221 mmol) in THF (200 mL) was added dropwise over 30 minutes maintaining the temperature between −65° C. and −70° C. The brown solution was allowed to warm gradually to ambient temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with a saturated ammonium chloride solution, and extracting with further ethyl acetate. The combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford a brown residue. The residue was purified by silica gel column chromatography (10%-30% ethyl acetate in heptane gradient elution) to afford the title compound as a white solid (52.3 g, 71%).

후처리

  1. temperaturemaintaining the temperature between −65° C. and −70° C
  2. temperatureto warm to −10° C. over 1.5 hours
  3. customUpon reaching −10° C.
  4. temperaturethe brown reaction mixture was cooled to −78° C. again
  5. temperaturemaintaining the temperature between −65° C. and −70° C
  6. temperatureto warm gradually to ambient temperature
  7. stirringstirred overnight
  8. washwashed with a saturated ammonium chloride solution
  9. extractionextracting with further ethyl acetate
  10. dry with materialThe combined organics were dried over MgSO4
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customto afford a brown residue
  14. customThe residue was purified by silica gel column chromatography (10%-30% ethyl acetate in heptane gradient elution)

출처 및 근거

ORD 기록
ord-3668af3c47694a34a552556dad9e70d9
출처 데이터셋
uspto-grants-2015_08
특허 번호
US09096558B2

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