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

HRID 707710Notes

Reaction equation

HRID 707710 reaction equation
Cl.[NH4+].[Cl-].[F:4][C:5]1[C:10]([F:11])=[CH:9][C:8]([N+:12]([O-])=O)=[CH:7][C:6]=1[C@:15]12[CH2:23][O:22][C@H:21]([CH2:24][F:25])[C@H:20]1[CH2:19][S:18][C:17]([NH2:26])=[N:16]2.[OH-].[Na+]>C(O)C.[Fe]>[NH2:12][C:8]1[CH:9]=[C:10]([F:11])[C:5]([F:4])=[C:6]([C@:15]23[CH2:23][O:22][C@H:21]([CH2:24][F:25])[C@H:20]2[CH2:19][S:18][C:17]([NH2:26])=[N:16]3)[CH:7]=1

Participants

7

Reactant 4

HCID 313Hydrochloric Acid2×HCID 14798Sodium HydroxideHCID 25517Ammonium ChlorideHCID 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

Product 1

HCID 60168329(4aS,5S,7aS)-7a-(5-amino-2,3-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amineYield 99.8%

Reagents, catalysts & solvents 2

HCID 23925IronCatalyst2×HCID 702EthanolSolvent3×

Conditions

Temperature
65 °C

Procedure

To iron (8.03 g, 0.144 mol, 6.0 equiv.) was added ethanol (66.56 mL), followed by conc. HCl (62%, 1.2 mL, 0.014 mol, 0.60 equiv.). The mixture was heated to 65° C. for 2 h, and then sat NH4Cl (33%, 33.3 mL) was added and the reaction temperature was maintained at 55° C. A solution of (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 (8.32 g, 0.024 mol, 1.0 equiv.) and conc. HCl (1.93 mL, 0.024 mol, 1.0 equiv.) in ethanol (41.6 mL) was added to the iron suspension. The reaction was stirred for 30 min at 55° C., then ethanol (50 mL) was added and the suspension was allowed to cool down to 20° C., filtered through celite (8.3 g) and rinsed with ethanol (125 mL). The filtrate was concentrated under reduced pressure then water (66 mL) was added, followed by 3.0 M aq.NaOH (24 mL, 0.0179 mol, 3.0 equiv.). The resulting mixture was extracted with CH2Cl2 (2×83 mL). The organics phases were combined and filtered over celite and concentrated under reduce pressure to give the title compound (7.60 g). 1H NMR (500 MHz, DMSO) δ ppm 6.42-6.35 (m, 2H), 6.02 (brs, 2H), 4.66-4.41 (m, 2H), 4.37-4.25 (m, 1H), 4.21 (d, J=8.0 Hz, 1H), 3.69 (dd, J=7.8, 2.2 Hz, 1H), 2.97 (qd, J=13.5, 3.4 Hz, 3H), 2.74-2.64 (m, 1H); 13C NMR (125 MHz, DMSO) δ ppm 151.08 (dd, JCF=240.1, 14.8 Hz), 148.88, 145.40 (d, JCF=10.7 Hz), 139.33 (dd, JCF=233.5, 13.8 Hz), 132.53 (d, JCF=8.1 Hz), 109.90, 100.70 (d, JCF=20.0 Hz), 83.99 (d, JCF=169.9 Hz), 78.79 (d, JCF=18.3 Hz), 77.99 (d, JCF=5.5 Hz), 66.22, 36.24, 23.14.

Workup

  1. additionwas added
  2. temperaturethe reaction temperature was maintained at 55° C
  3. temperatureto cool down to 20° C.
  4. filtrationfiltered through celite (8.3 g)
  5. washrinsed with ethanol (125 mL)
  6. concentrationThe filtrate was concentrated under reduced pressure
  7. additionwater (66 mL) was added
  8. extractionThe resulting mixture was extracted with CH2Cl2 (2×83 mL)
  9. filtrationfiltered over celite
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-7d12c6afd2804f17b9805fdce41c9f43
Source dataset
uspto-grants-2015_11
Patent number
US09175013B2

Reaction notes

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