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 528641ノート

反応式

HRID 528641 の反応式
[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

参加物

9

反応物 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

生成物 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-sulfonamide収率 57.5%

試薬・触媒・溶媒 4

HCID 6344Dichloromethane溶媒HCID 8028Tetrahydrofuran溶媒HCID 8857Ethyl Acetate溶媒HCID 57417360Sodium chloride; water溶媒

実験手順

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)−.

後処理

  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

出典と根拠

ORDレコード
ord-da3e2a80effa4bb29670980802a98e61
出典データセット
uspto-grants-2016_05
特許番号
US09346798B2

反応ノート

読み込み中…