Sulfuric Acid → (4aS,5S,7aS)-7a-(5-bromo-2,4-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine

HRID 68378Notes

Reaction equation

HRID 68378 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18][F:19])[C@H:14]1[CH2:13][S:12][C:11]([NH2:20])=[N:10]2.S(=O)(=O)(O)O.C1C(=O)N([Br:33])C(=O)C1.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[Br:33][C:5]1[C:6]([F:8])=[CH:7][C:2]([F:1])=[C:3]([C@:9]23[CH2:17][O:16][C@H:15]([CH2:18][F:19])[C@H:14]2[CH2:13][S:12][C:11]([NH2:20])=[N:10]3)[CH:4]=1

Participants

6

Reactant 4

HCID 1118Sulfuric AcidHCID 14798Sodium HydroxideHCID 67184N-bromobutanimideHCID 86707817(4aS,5S,7aS)-7a-(2,4-Difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine

Product 1

HCID 86707818(4aS,5S,7aS)-7a-(5-bromo-2,4-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine

Reagents, catalysts & solvents 1

HCID 6422Trifluoroacetic acidSolvent

Conditions

Temperature
60 °C

Procedure

(4aS,5S,7aS)-7a-(2,4-Difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (700 mg, 2.32 mmol) was dissolved in TFA (2.1 mL) and sulfuric acid (864 μL, 16.2 mmol). NBS (453 mg, 2.55 mmol) was added and the reaction was stirred at 60° C. for 45 minutes. The reaction was cooled to room temperature and basified with 2N NaOH. The mixture was then extracted with EtOAc (×3). The combined organics were dried (MgSO4) and concentrated in vacuo. The residue was purified using column chromatography, eluting with 20-80% EtOAc in n-hexane to give the title compound. (620 mg). 1H NMR (400 MHz, CDCl3) δ ppm: 7.67 (t, J=8.13 Hz, 1H), 6.94 (dd, J=8.01, 11.55 Hz, 1H), 4.65 (d, J=4.16 Hz, 1H), 4.47-4.57 (m, 3H), 3.84-3.98 (m, 1H), 3.01-3.20 (m, 2H), 2.77-2.91 (m, J=13.40 Hz, 1H).

Workup

  1. extractionThe mixture was then extracted with EtOAc (×3)
  2. dry with materialThe combined organics were dried (MgSO4)
  3. concentrationconcentrated in vacuo
  4. customThe residue was purified
  5. washeluting with 20-80% EtOAc in n-hexane

Sources & evidence

ORD record
ord-51d40b39f41e4a1cbae23e41d2231a1d
Source dataset
uspto-grants-2014_09
Patent number
US08822455B2

Reaction notes

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