6-bromo-4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide → 6-Cyano-4-(2-Methoxy-4-(Trifluoromethyl)Phenyl)-N-(Thiazol-2-Yl)-3,4-Dihydro-2H-Benzo[B][1,4]Oxazine-7-Sulfonamide

HRID 528601Notes

Reaction equation

HRID 528601 reaction equation
Br[C:2]1[C:23]([S:24]([N:27](CC2C=CC(OC)=CC=2)[C:28]2[S:29][CH:30]=[CH:31][N:32]=2)(=[O:26])=[O:25])=[CH:22][C:5]2[O:6][CH2:7][CH2:8][N:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=3[O:20][CH3:21])[C:4]=2[CH:3]=1.[C:42]([Zn]C#N)#[N:43]>CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.[Zn]>[C:42]([C:2]1[C:23]([S:24]([NH:27][C:28]2[S:29][CH:30]=[CH:31][N:32]=2)(=[O:26])=[O:25])=[CH:22][C:5]2[O:6][CH2:7][CH2:8][N:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:17])[F:19])=[CH:12][C:11]=3[O:20][CH3:21])[C:4]=2[CH:3]=1)#[N:43]

Participants

6

Reactant 2

HCID 897619566-bromo-4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamideHCID 178514179HCID 178514179, compound2×

Product 1

HCID 897620466-Cyano-4-(2-Methoxy-4-(Trifluoromethyl)Phenyl)-N-(Thiazol-2-Yl)-3,4-Dihydro-2H-Benzo[B][1,4]Oxazine-7-SulfonamideYield 32.2%

Reagents, catalysts & solvents 3

HCID 23994ZincCatalystHCID 178418851HCID 178418851, compoundCatalyst2×HCID 8857Ethyl AcetateSolvent

Procedure

A vial was charged with 6-bromo-4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (67 mg, 0.100 mmol), dicyanozinc (23.46 mg, 0.200 mmol), bis(tri-t-butylphosphine)palladium(0) (5.11 mg, 9.99 μmol), and zinc (1.960 mg, 0.030 mmol). The vial was flushed with Ar (g), then N,N-dimethylacetamide (500 μl) was added. The vial was sealed and placed in a 60° C. heating bath for 5 h. Additional portions of dicyanozinc (23.46 mg, 0.200 mmol) and bis(tri-t-butylphosphine)palladium(0) (ca. 8.5 mg) were added, and the vial was returned to the heat for 2 h. The mixture was diluted with EtOAc, then washed with water (2×), washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was taken up in DCM (1 mL) and TFA (0.5 mL). After 35 min, the mixture was diluted with MeOH and concentrated. The residue was purified by chromatography on 12-g Redi-Sep Gold column (20-70% EtOAc/Heptane, product eluted late) to give ca. 16 mg of a white solid. The material was rechromatographed twice on 12-g Redi-Sep Gold columns, once with 3% MeOH/DCM, then with 0-4% MeOH/DCM to give 6-cyano-4-(2-methoxy-4-(trifluoromethyl)phenyl)-n-(thiazol-2-yl)-3,4-dihydro-2h-benzo[b][1,4]oxazine-7-sulfonamide as a white solid that was about 91% pure by LCMS and NMR: 1H NMR (400 MHz, DMSO-d6) δ=12.91 (br. s., 1 H), 7.56 (d, J=8.1 Hz, 1 H), 7.49-7.40 (m, 2 H), 7.36 (s, 1 H), 7.28 (d, J=4.6 Hz, 1 H), 6.87 (d, J=4.6 Hz, 1 H), 6.60 (s, 1 H), 4.43-4.38 (m, 2 H), 3.87 (s, 3 H), 3.71 (t, J=4.3 Hz, 2 H); m/z (ESI) 497.2 (M+H)+.

Workup

  1. customThe vial was flushed with Ar (g)
  2. additionN,N-dimethylacetamide (500 μl) was added
  3. customThe vial was sealed
  4. customplaced in a 60° C.
  5. temperatureheating bath for 5 h
  6. temperatureheat for 2 h
  7. washwashed with water (2×)
  8. washwashed with brine
  9. dry with materialdried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated
  12. additionthe mixture was diluted with MeOH
  13. concentrationconcentrated
  14. customThe residue was purified by chromatography on 12-g Redi-Sep Gold column (20-70% EtOAc/Heptane, product eluted late)

Sources & evidence

ORD record
ord-6ab3c42f86c748fb8b4626f555a7f12f
Source dataset
uspto-grants-2016_05
Patent number
US09346798B2

Reaction notes

Loading…