Trifluoroacetic acid → 4-(2-methoxy-4-(trifluoromethyl)phenyl)-3-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide

HRID 528641노트

반응식

HRID 528641 반응식
[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[C:18](=[O:19])[CH2:17][O:16][C:15]2[CH:20]=[C:21]([S:24](Cl)(=[O:26])=[O:25])[CH:22]=[CH:23][C:14]1=2.COC1C=CC(C[NH:35][C:36]2[S:40][N:39]=[CH:38][N:37]=2)=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(O)(C(F)(F)F)=O>CCOC(C)=O.[Cl-].[Na+].O.C(Cl)Cl.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[C:18](=[O:19])[CH2:17][O:16][C:15]2[CH:20]=[C:21]([S:24]([NH:35][C:36]3[S:40][N:39]=[CH:38][N:37]=3)(=[O:26])=[O:25])[CH:22]=[CH:23][C:14]1=2

참가 물질

9

반응물 4

HCID 6422Trifluoroacetic acidHCID 2733832Lithium HexamethyldisilazideHCID 65271538N-(4-Methoxybenzyl)-1,2,4-thiadiazol-5-amineHCID 897619204-(2-methoxy-4-(trifluoromethyl)phenyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride

생성물 1

HCID 897616294-(2-methoxy-4-(trifluoromethyl)phenyl)-3-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide수율 57.5%

시약·촉매·용매 4

HCID 6344Dichloromethane용매HCID 8028Tetrahydrofuran용매HCID 8857Ethyl Acetate용매HCID 57417360Sodium chloride; water용매

실험 절차

To a vial charged with 4-(2-methoxy-4-(trifluoromethyl)phenyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (120 mg, 0.285 mmol) and N-(4-methoxybenzyl)-1,2,4-thiadiazol-5-amine (69.3 mg, 0.313 mmol) was added THF (948 μl) and the mixture cooled in a dry ice bath at −78 C. Then lithium bis(trimethylsilyl)amide (341 μl, 0.341 mmol) was added dropwise. The mixture was stirred at −78 C for 30 min, then warmed to 0 C for 30 min until conversion to the product by LCMS. The solution was added to ice, diluted with EtOAc (5 mL) and brine (5 mL) and extracted three times with EtOAc (3×5 mL). The combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. To the crude material was added DCM (1 ml) and TFA (548 μl, 7.11 mmol) and the mixture stirred at rt for 1 hr until deprotection occurred by LCMS. The mixture was concentrated and purified using reverse-phase HPLC with a Waters-Xbridge C18, 19×100 mm, 10 m column with a gradient 5-95% acetonitrile and water with 0.1% TFA to give 4-(2-methoxy-4-(trifluoromethyl)phenyl)-3-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (80 mg, 0.164 mmol, 57.0% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.81 (s, 3 H) 4.89 (s, 2 H) 6.38 (d, J=8.42 Hz, 1 H) 7.31 (dd, J=8.45, 1.86 Hz, 1 H) 7.36 (d, J=1.89 Hz, 1 H) 7.50 (d, J=8.08 Hz, 1 H) 7.55-7.62 (m, 2 H) 8.15 (s, 1 H). m/z ESI 485.0 (M−H)−.

후처리

  1. temperaturethe mixture cooled in a dry ice bath at −78 C
  2. temperaturewarmed to 0 C for 30 min until conversion to the product by LCMS
  3. additionThe solution was added to ice
  4. extractionextracted three times with EtOAc (3×5 mL)
  5. dry with materialThe combined organics were dried with Na2SO4
  6. filtrationfiltered
  7. customdried under reduced pressure
  8. stirringthe mixture stirred at rt for 1 hr until deprotection
  9. concentrationThe mixture was concentrated
  10. custompurified

출처 및 근거

ORD 기록
ord-da3e2a80effa4bb29670980802a98e61
출처 데이터셋
uspto-grants-2016_05
특허 번호
US09346798B2

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