Methanol → HCID 89761608, compound

HRID 528614Notes

Reaction equation

HRID 528614 reaction equation
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[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[C:47]([F:48])[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[CH:44]=[C:45]([S:49]([NH:8][C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:51])=[O:50])[CH:46]=[C:47]([F:48])[C:39]1=2)#[N:27]

Participants

7

Reactant 4

HCID 887MethanolHCID 578640N-[(4-methoxyphenyl)methyl]-1,3-thiazol-2-amineHCID 2733832Lithium HexamethyldisilazideHCID 89761958HCID 89761958, compound

Product 1

HCID 89761608HCID 89761608, compoundYield 52.4%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent3×HCID 22242641Methanol--water (1/1)Solvent

Procedure

To a vial charged with N-(4-methoxybenzyl)thiazol-2-amine (0.071 g, 0.322 mmol) was added THF (0.955 ml) and the mixture cooled in an ice water bath prior to the addition of lithium bis(trimethylsilyl)amide, 1.0M solution in tetrahydrofuran (0.351 ml, 0.351 mmol), faster than dropwise. After 15 mins of stirring a solution of 4-(2-cyano-4-(trifluoromethyl)phenyl)-5-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (0.123 g, 0.292 mmol) in THF (0.5 ml) was added dropwise, then washed with 0.2 ml THF and added. The mixture was stirred for 1 hr (ice melt) 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 dried under reduced pressure. To the crude residue was added DCM (2 ml) and TFA (0.2 ml). After 2 hr the mixture was dried 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)-5-fluoro-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.074 g, 0.153 mmol, 52.3% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.39 (br. s., 2 H) 3.80-4.20 (m, 2 H) 6.87 (d, J=4.50 Hz, 1 H) 7.12 (dd, J=10.71, 2.01 Hz, 1 H) 7.20 (t, J=1.66 Hz, 1 H) 7.30 (d, J=4.69 Hz, 1 H) 7.41 (d, J=8.80 Hz, 1 H) 7.91-7.96 (m, 1 H) 8.35 (d, J=2.15 Hz, 1 H) 12.83 (br. s., 1 H). m/z (ESI) 485.2 (M+H)+.

Workup

  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. customthe mixture dried under reduced pressure
  7. additionTo the crude residue was added DCM (2 ml) and TFA (0.2 ml)
  8. customAfter 2 hr the mixture was dried under reduced pressure
  9. custompurified with a 25 g SNAP column
  10. customto yield product as a sticky white solid which

Sources & evidence

ORD record
ord-fca0f8255e224fcaa8c8071f5fe2bc44
Source dataset
uspto-grants-2016_05
Patent number
US09346798B2

Reaction notes

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