Methanol → 4-(2-cyano-4-(trifluoromethyl)phenyl)-8-fluoro-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide

HRID 528608Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 528608
COC1C=CC(C[NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:26]([C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[N:38]1[CH2:43][CH2:42][O:41][C:40]2[C:44]([F:52])=[C:45]([S:48](Cl)(=[O:50])=[O:49])[CH:46]=[CH:47][C:39]1=2)#[N:27].CO>C1COCC1.CO.O>[C:26]([C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[N:38]1[CH2:43][CH2:42][O:41][C:40]2[C:44]([F:52])=[C:45]([S:48]([NH:8][C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:50])=[O:49])[CH:46]=[CH:47][C:39]1=2)#[N:27]

Komponenten

7

Edukt 4

HCID 887MethanolHCID 578640N-[(4-methoxyphenyl)methyl]-1,3-thiazol-2-amineHCID 2733832Lithium HexamethyldisilazideHCID 897617434-(2-cyano-4-(trifluoromethyl)phenyl)-8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride

Produkt 1

HCID 897617044-(2-cyano-4-(trifluoromethyl)phenyl)-8-fluoro-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamideAusbeute 56,5 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 8028TetrahydrofuranLösungsmittel3×HCID 22242641Methanol--water (1/1)Lösungsmittel

Versuchsvorschrift

To a vial charged with N-(4-methoxybenzyl)thiazol-2-amine (0.036 g, 0.162 mmol) was added THF (0.482 ml) and the mixture cooled in an ice water bath prior to the addition of lithium bis(trimethylsilyl)amide, 1.0M solution in tetrahydrofuran (0.177 ml, 0.177 mmol), faster than dropwise. After 15 mins of stirring a solution of 4-(2-cyano-4-(trifluoromethyl)phenyl)-8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (0.062 g, 0.147 mmol) in THF (0.5 ml) was added dropwise, then washed with 0.2 ml THF and added. The mixture was allowed to warm to rt over 1 hr providing a turbid brown mixture with product as the primary species according to LC-MS (m/z=605). To the turbid brown solution was added MeOH and the mixture concentrated under reduced pressure. To the crude residue was added DCM (2 ml) and TFA (0.2 ml). After 2 hr, the mixture was concentrated under reduced pressure and purified with a 25 g SNAP column ramping EtOAc in heptane (0-75%, 10% DCM throughout) to yield product as a sticky white solid, which was lyophilized from MeOH/H2O affording product as a fluffy white solid, 4-(2-cyano-4-(trifluoromethyl)phenyl)-8-fluoro-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.04 g, 0.083 mmol, 56.0% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.83-3.95 (m, 2 H) 4.34-4.46 (m, 2 H) 6.56 (dd, J=8.90, 1.27 Hz, 1 H) 6.84 (d, J=4.60 Hz, 1 H) 7.17 (dd, J=8.85, 7.29 Hz, 1 H) 7.27 (d, J=4.60 Hz, 1 H) 7.76 (d, J=8.61 Hz, 1 H) 8.11 (dd, J=8.80, 2.05 Hz, 1 H) 8.42 (d, J=1.76 Hz, 1 H) 12.80 (br. s., 1 H). m/z (ESI) 485.2 (M+H)+.

Aufarbeitung

  1. temperaturethe mixture cooled in an ice water bath
  2. additionwas added dropwise
  3. washwashed with 0.2 ml THF
  4. additionadded
  5. customproviding a turbid brown mixture with product as the primary species
  6. concentrationthe mixture concentrated under reduced pressure
  7. additionTo the crude residue was added DCM (2 ml) and TFA (0.2 ml)
  8. concentrationthe mixture was concentrated under reduced pressure
  9. custompurified with a 25 g SNAP column
  10. customto yield product as a sticky white solid, which

Quellen und Nachweise

ORD-Eintrag
ord-46d8fb9e633f47fab39807196ad3053b
Quelldatensatz
uspto-grants-2016_05
Patentnummer
US09346798B2

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