Hydrochloric Acid → (4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine

HRID 2195796Notes

Reaction equation

HRID 2195796 reaction equation
Cl.[NH4+].[Cl-].Cl.[F:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[C@:15]12[CH2:23][O:22][C@H:21]([C:24]([F:27])([F:26])[F:25])[C@H:20]1[CH2:19][S:18][C:17]([NH2:28])=[N:16]2.[OH-].[Na+]>[Fe].C(O)C>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([F:5])=[C:7]([C@:15]23[CH2:23][O:22][C@H:21]([C:24]([F:26])([F:25])[F:27])[C@H:20]2[CH2:19][S:18][C:17]([NH2:28])=[N:16]3)[CH:8]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 25517Ammonium ChlorideHCID 70496439(4aS,5S,7aS)-7a-(2-fluoro-5-nitrophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine hydrochloride

Product 1

HCID 60168330(4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amineYield 95.5%

Reagents, catalysts & solvents 2

HCID 23925IronCatalystHCID 702EthanolSolvent2×

Conditions

Temperature
65 °C

Procedure

Ethanol (0.975 L) was added to iron powder (62.5 g, 1.12 mol) under nitrogen atmosphere. Concentrated HCl (9.03 mL) was added at ambient temperature and the suspension was heated to 65° C. for 1.5 h. The suspension was then cooled to 50° C., and sat. aq. NH4Cl (299 g) were added. The temperature of the reaction mixture was allowed to reach 50° C., and (4aS,5S,7aS)-7a-(2-fluoro-5-nitrophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine hydrochloride (75.0 g, 187.0 mol) was added in portions while maintaining temperature below 68° C. After 30 min, ethanol (0.45 L) was added, and the reaction mixture was cooled to 20-25° C. over 1 h. The suspension was stirred for 2 h and filtered over Celite (75 g) rinsing with ethanol (0.972 L). The solution was concentrated under vacuum to a brown solid. Water (0.9 L) was added followed by 3.0 N NaOH (0.187 L, 560 mmol) while maintaining temperature below 35° C. The resulting suspension was stirred for 1 h at 20-25° C. The suspension was filtered, and the solid was rinsed with cold water (0.38 L). The solid was dried under vacuum at 40-45° C. over 24 h to obtain the title compound (57.7 g, 95.5%). 1H NMR (500 MHz, DMSO) δ ppm 6.81 (dd, J=12.5, 8.6 Hz, 1H), 6.62 (dd, J=7.0, 2.9 Hz, 1H), 6.50-6.42 (m, 1H), 6.16 (s, 2H), 4.96 (s, 2H), 4.72-4.54 (m, 1H), 4.35 (d, J=7.8 Hz, 1H), 3.74 (dd, J=7.8, 2.5 Hz, 1H), 3.18-3.08 (m, 1H), 3.01 (dd, J=13.9, 3.0 Hz, 1H). 2.84 (dd, J=13.8, 3.8 Hz, 1H); 13C NMR (125 MHz, DMSO) δ ppm 156.20 (d, JCF=243.0 Hz), 148.73, 145.49, 127.86 (d, JCF=11.0 Hz), 116.79 (d, JCF=24.8 Hz), 116.10 (d, JCF=3.3 Hz), 114.10 (d, JCF=8.0 Hz), 78.89, 76.57 (q, JCF=31.0 Hz), 66.35, 36.35, 23.11. HRMS Calculated for C13H13F4N3OS [M+H]+ 336.0794. found 336.0789.

Workup

  1. temperatureThe suspension was then cooled to 50° C.
  2. customto reach 50° C.
  3. temperaturewhile maintaining temperature below 68° C
  4. temperaturethe reaction mixture was cooled to 20-25° C. over 1 h
  5. filtrationfiltered over Celite (75 g)
  6. washrinsing with ethanol (0.972 L)
  7. concentrationThe solution was concentrated under vacuum to a brown solid
  8. additionWater (0.9 L) was added
  9. temperaturewhile maintaining temperature below 35° C
  10. stirringThe resulting suspension was stirred for 1 h at 20-25° C
  11. filtrationThe suspension was filtered
  12. washthe solid was rinsed with cold water (0.38 L)
  13. customThe solid was dried under vacuum at 40-45° C. over 24 h

Sources & evidence

ORD record
ord-a9a581e923204aac99e0907ca9278e80
Source dataset
uspto-grants-2012_12
Patent number
US08338407B2

Reaction notes

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