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

HRID 528546

Reaction equation

HRID 528546 reaction equation
COC1C=CC(C[N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=CC=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:72]1[CH:79]=[CH:78][C:77]([C:80]([F:83])([F:82])[F:81])=[CH:76][C:73]=1[C:74]#[N:75].CC(C)([O-])C.[Na+].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:74]([C:73]1[CH:76]=[C:77]([C:80]([F:81])([F:82])[F:83])[CH:78]=[CH:79][C:72]=1[N:20]1[CH2:19][CH2:18][O:17][C:16]2[CH:21]=[C:12]([S:9]([NH:8][C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:10])=[O:11])[CH:13]=[CH:14][C:15]1=2)#[N:75]

Participants

9

Reactant 5

HCID 6422Trifluoroacetic acidHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 122239802-Bromo-5-(trifluoromethyl)benzonitrileHCID 23676156Sodium t-butoxideHCID 89761436N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide2×

Product 1

HCID 897612814-(2-cyano-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamideYield 26.7%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
130 °C

Procedure

A microwave vial was charged with N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIATE M, 0.150 g, 0.359 mmol), xantphos (0.042 g, 0.072 mmol), 2-bromo-5-(trifluoromethyl)benzonitrile (Apollo Scientific) (0.135 g, 0.539 mmol), Pd2(dba)3 (0.033 g, 0.036 mmol) and sodium tert-butoxide (0.069 g, 0.719 mmol). The mixture was diluted with toluene (3.59 mL), purged with nitrogen, and heated at 130° C. in the microwave for 1.5 h. After cooling to rt, trifluoroacetic acid (0.554 mL, 7.19 mmol) was carefully added and the reaction was stirred for 1 h. The reaction mixture was diluted with water, and washed with DCM (×2). organics were dried via phase separator, and concentrated under a vacuum. The material was then purified via reverse-phase preparative HPLC, 0.1% TFA in CH3CN/H2O, gradient 25% to 90% over 25 min to provide 4-(2-cyano-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.045 g, 0.096 mmol) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.82-3.91 (m, 2 H) 4.28-4.39 (m, 2 H) 6.76-6.85 (m, 2 H) 7.18 (dd, J=8.56, 2.10 Hz, 1 H) 7.21-7.28 (m, 2 H) 7.71 (d, J=8.70 Hz, 1 H) 8.06 (dd, J=8.71, 2.15 Hz, 1 H) 8.40 (d, J=1.27 Hz, 1 H) 12.66 (br. s., 1 H). m/z (ESI) 467.0 (M+H)+.

Workup

  1. custompurged with nitrogen
  2. temperatureAfter cooling to rt
  3. washwashed with DCM (×2)
  4. customorganics were dried via phase separator
  5. concentrationconcentrated under a vacuum
  6. customThe material was then purified via reverse-phase preparative HPLC, 0.1% TFA in CH3CN/H2O, gradient 25% to 90% over 25 min

Sources & evidence

ORD record
ord-9b3057913b7644eeb7b9af5ba7e1e1a9
Source dataset
uspto-grants-2016_05
Patent number
US09346798B2

Linked notes

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