Trifluoroacetic acid → 4-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide 2,2,2-trifluoroacetate

HRID 528560Notes

Reaction equation

HRID 528560 reaction equation
Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([NH:25][C:26]3[S:30][CH:29]=[N:28][CH:27]=3)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.CC1(C)C(C)(C)OB([C:39]2[CH2:44][CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41][CH:40]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:61]([OH:67])([C:63]([F:66])([F:65])[F:64])=[O:62]>O.O1CCOCC1>[F:64][C:63]([F:66])([F:65])[C:61]([OH:67])=[O:62].[NH:42]1[CH2:41][CH:40]=[C:39]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=2[N:12]2[CH2:17][CH2:16][O:15][C:14]3[CH:18]=[C:19]([S:22]([NH:25][C:26]4[S:30][CH:29]=[N:28][CH:27]=4)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]2=3)[CH2:44][CH2:43]1

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 62657Potassium Phosphate, TribasicHCID 4642098Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylateHCID 897614214-(2-bromo-4-(trifluoromethyl)phenyl)-N-(thiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide

Product 1

HCID 897618814-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide 2,2,2-trifluoroacetateYield 74%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
50 °C

Procedure

A microwave vial was charged with 4-(2-bromo-4-(trifluoromethyl)phenyl)-N-(thiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.076 g, 0.146 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2 H)-carboxylate (0.068 g, 0.219 mmol), Pd(AmPhos2)Cl2 (10.34 mg, 0.015 mmol), and potassium phosphate (0.093 g, 0.438 mmol). Dioxane (0.649 mL) and water (0.325 mL) were added, the vial was flushed with argon and sealed, and microwaved at 100° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was dissolved in DCM and TFA (0.1 mL, 1.298 mmol) was added. The reaction was stirred at 50° C. for one hour. The reaction was concentrated and the material was purified via silica gel column chromatography (12 g, gradient elution 0 to 10% MeOH:DCM) to afford 4-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide 2,2,2-trifluoroacetate (0.069 g, 0.108 mmol) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.71 (br. s., 1 H), 8.81 (br. s., 2 H), 8.70 (s, 1 H), 7.81-7.75 (m, 1 H), 7.63 (s, 1 H), 7.58 (d, J=8.2 Hz, 1 H), 7.35 (s, 1 H), 7.11 (d, J=2.2 Hz, 1 H), 7.06 (dd, J=2.1, 8.6 Hz, 1 H), 6.46 (d, J=8.6 Hz, 1 H), 5.86 (br. s., 1 H), 4.31 (d, J=4.1 Hz, 2 H), 3.66 (br. s., 2 H), 3.62 (t, J=4.1 Hz, 2 H), 3.17 (br. s., 3H), 2.42 (br. s., 1 H). m/z (ESI) 523.4 (M+H)+.

Workup

  1. customthe vial was flushed with argon
  2. customsealed
  3. custommicrowaved at 100° C. for 30 minutes
  4. additionThe reaction was diluted with ethyl acetate
  5. washwashed with water
  6. extractionThe aqueous layer was extracted with ethyl acetate
  7. dry with materialthe combined organic layers were dried with sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated
  10. dissolutionThe material was dissolved in DCM
  11. concentrationThe reaction was concentrated
  12. customthe material was purified via silica gel column chromatography (12 g, gradient elution 0 to 10% MeOH:DCM)

Sources & evidence

ORD record
ord-bccea0b7a4d44e8bb040a01614789c70
Source dataset
uspto-grants-2016_05
Patent number
US09346798B2

Reaction notes

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