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

HRID 707709Notes

Reaction equation

HRID 707709 reaction equation
[F:1][C:2]1[C:7]([F:8])=[CH:6][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.[N+:26]([O-])([OH:28])=[O:27].[OH-].[Na+]>FC(F)(F)C(O)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:26]([O-:28])=[O:27])=[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

Participants

6

Reactant 4

HCID 944Nitric AcidHCID 1118Sulfuric AcidHCID 14798Sodium HydroxideHCID 60168237(4aS,5S,7aS)-7a-(2,3-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine

Product 1

HCID 60168239(4aS,5S,7aS)-7a-(2,3-difluoro-5-nitrophenyl)-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
0 °C

Procedure

(4aS,5S,7aS)-7a-(2,3-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (9.10 g, 0.03 mol, 1.0 equiv.) was dissolved in trifluoroacetic acid (36.4 mL), and the solution was cooled to 0° C. Sulfuric acid (conc., 12.0 mL) was added, followed by fuming nitric acid (6.9 mL) dropwise while maintaining the temperature below 5° C. After stirring at 0-5° C. for 4 h, the reaction mixture was slowly charged into a vigorously stirred solution of aq.NaOH (43.3 g in 273 mL water) while maintaining a temperature below 20° C. The mixture was extracted with CH2Cl2 (1×94 ml, and 2×64 mL), and the combined organic phases were washed with sat. aq. NaCl (46 mL). Celite (15.0 g) was added to the organics, and the mixture was filtered rinsing with CH2Cl2 (40 mL). The solvents were evaporated to afford the title compound (8.3 g) which was used in the subsequent step without purification. 1H NMR (500 MHz, DMSO) δ ppm 8.41-8.30 (m, 1H), 8.22-8.13 (m, 1H), 6.36 (s, 2H), 4.70-4.46 (m, 2H), 4.43-4.31 (m, 1H), 4.35 (d, J=8.7 Hz, 1H), 3.69 (dd, J=8.5, 1.6 Hz, 1H), 3.04-2.91 (m, 2H), 2.86-2.76 (m, 1H); 13C NMR (125 MHz, DMSO) δ ppm 152.36 (dd, JCF=246.8, 12.3 Hz), 151.13, 150.32 (dd, JCF=238.2, 12.2 Hz), 143.25 (dd, JCF=7.9, 2.5 Hz), 134.70 (d, JCF=9.5 Hz), 121.28, 113.02 (d, JCF=22.3 Hz), 83.74 (d, JCF=170.1 Hz), 79.44 (d, JCF=18.3 Hz), 78.02 (d, J=3.9 Hz), 36.96, 23.28.

Workup

  1. temperaturewhile maintaining the temperature below 5° C
  2. additionthe reaction mixture was slowly charged into a vigorously stirred solution of aq
  3. extractionThe mixture was extracted with CH2Cl2 (1×94 ml, and 2×64 mL)
  4. washthe combined organic phases were washed with sat. aq. NaCl (46 mL)
  5. additionCelite (15.0 g) was added to the organics, and the mixture
  6. filtrationwas filtered
  7. washrinsing with CH2Cl2 (40 mL)
  8. customThe solvents were evaporated

Sources & evidence

ORD record
ord-41187163ffb64d8cbadbebc7b7a92164
Source dataset
uspto-grants-2015_11
Patent number
US09175013B2

Reaction notes

Loading…