Lithium Hexamethyldisilazide → N-(3-bromo-1,2,4-thiadiazol-5-yl)-N-(4-methoxybenzyl)-1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonamide

HRID 1524435노트

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HRID 1524435 반응식
[Br:1][C:2]1[N:6]=[C:5]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:27][N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([S:37](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:39])=[O:38])[CH:35]=2)[C:30]([C:52]2[CH:57]=[CH:56][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:54][C:53]=2[C:62]2[N:66]([CH3:67])[N:65]=[CH:64][CH:63]=2)=[CH:29]1>C1COCC1.CCOC(C)=O.CCCCCCC>[Br:1][C:2]1[N:6]=[C:5]([N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:37]([C:34]2[CH:35]=[C:36]3[C:31]([C:30]([C:52]4[CH:57]=[CH:56][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:54][C:53]=4[C:62]4[N:66]([CH3:67])[N:65]=[CH:64][CH:63]=4)=[CH:29][N:28]3[CH3:27])=[CH:32][CH:33]=2)(=[O:39])=[O:38])[S:4][N:3]=1

참가 물질

6

반응물 3

HCID 2733832Lithium HexamethyldisilazideHCID 712593363-bromo-N-(4-methoxybenzyl)-1,2,4-thiadiazol-5-amine2회HCID 89407674perfluorophenyl 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonate2회

생성물 1

HCID 71259358N-(3-bromo-1,2,4-thiadiazol-5-yl)-N-(4-methoxybenzyl)-1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonamide수율 73.2%

시약·촉매·용매 2

HCID 8028Tetrahydrofuran용매2회HCID 21899848Ethylacetate heptane용매

실험 절차

A 25-mL round-bottom flask was charged with 3-bromo-N-(4-methoxybenzyl)-1,2,4-thiadiazol-5-amine (INTERMEDIATE K) (157 mg, 0.522 mmol) and THF (2.6 mL) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (653 μl, 0.653 mmol) was added dropwise. The resulting clear solution was stirred for 20 min, then a solution perfluorophenyl 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonate (INTERMEDIATE E) (157 mg, 0.261 mmol) in THF (1 mL with a 0.5 mL vial/syringe wash) was added dropwise over 1 min. The resulting solution was stirred for 10 min, then the flask was lowered into an ice bath for 2.5 h. The reaction mixture was quenched with saturated aq ammonium chloride solution, diluted with water, and extracted with EtOAc (2×). The combined organic extracts were concentrated, and the crude product was purified by chromatography on silica gel (0 to 60% EtOAc/Heptane) N-(3-bromo-1,2,4-thiadiazol-5-yl)-N-(4-methoxybenzyl)-1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonamide (136.87 mg, 0.191 mmol, 73.1% yield) as a white foam. 1H NMR (400 MHz, DMSO-d6) δ=8.09 (d, J=1.8 Hz, 1 H), 7.96-7.83 (m, 2 H), 7.79 (d, J=1.4 Hz, 1 H), 7.66-7.49 (m, 2 H), 7.39 (d, J=1.9 Hz, 1 H), 7.31 (s, 1 H), 7.26 (d, J=8.8 Hz, 2 H), 6.86-6.79 (m, 2 H), 6.33 (d, J=1.9 Hz, 1 H), 5.08 (s, 2 H), 3.83 (s, 3 H), 3.68 (s, 3 H), 3.24 (s, 3H). m/z (ESI) 717.2 (M+H)+.

후처리

  1. customto give a clear solution
  2. temperatureThe flask was cooled in a dry ice-acetone bath for 10 min
  3. stirringThe resulting solution was stirred for 10 min
  4. waitthe flask was lowered into an ice bath for 2.5 h
  5. customThe reaction mixture was quenched with saturated aq ammonium chloride solution
  6. additiondiluted with water
  7. extractionextracted with EtOAc (2×)
  8. concentrationThe combined organic extracts were concentrated

출처 및 근거

ORD 기록
ord-7c206e0aa8e74e22af062abec48d6c00
출처 데이터셋
uspto-grants-2015_07
특허 번호
US09079902B2

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