Ammonium Chloride → N-((4aS,5S,7aS)-7a-(2,3-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide

HRID 707707Notes

Reaction equation

HRID 707707 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]O)[C@H:14]1[CH2:13][S:12][C:11]([NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N:10]2.C(N(CC)C(C)C)(C)C.F.F.F.C(N(CC)CC)C.[F:48]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.[NH4+].[Cl-]>C1COCC1.COC(C)(C)C>[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:48])[C@H:14]1[CH2:13][S:12][C:11]([NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N:10]2

Participants

8

Reactant 5

HCID 25517Ammonium ChlorideHCID 67814Perfluoro-1-butanesulfonyl fluorideHCID 81531DiisopropylethylamineHCID 175505N,N-Diethylethanamine trihydrofluorideHCID 68173766N-((4aS,5S,7aS)-7a-(2,3-difluorophenyl)-5-(hydroxymethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide

Product 1

HCID 60169628N-((4aS,5S,7aS)-7a-(2,3-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamideYield 38.2%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 15413tert-Butyl methyl etherSolvent

Conditions

Temperature
0 °C

Procedure

N-((4aS,5S,7aS)-7a-(2,3-difluorophenyl)-5-(hydroxymethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (21.0 g, 0.519 mol, 1.0 equiv.) was dissolved in dry THF (105 mL) under a nitrogen atmosphere and the solution was cooled at 0° C. N,N-diisopropylethylamine (40.7 mL, 0.234 mol, 4.50 equiv.), triethylamine trihydrofluoride (14.0 mL, 0.0857 mol, 1.65 equiv.) and perfluorobutanesulfonyl fluoride (22.4 mL, 0.125 mol, 2.40 equiv.) were added while maintaining temperature under 5° C. The reaction was stirred for 3 h at 0° C. then slowly warmed to RT and stirred for 11 h. To the reaction mixture was charged sat.NH4Cl (100 mL) followed by 2-methoxy-2-methylpropane (100 mL). The organic phase was isolated and washed with aq. HCl (1.0 M, 100 ml), concentrated and redissolved in 2-methoxy-2-methylpropane (301 ml). The organic phase was then washed with aq.HCl (1M, 63 mL), sat aq.NaHCO3 (100 mL). The last aqueous layer was extracted with 2-methoxy-2-methylpropane. The combined organic phase was washed with 18% aq.NaCl (63 mL) and concentrated under reduced pressure to afford title compound (19.40 g) as a foam. 1H NMR (500 MHz, DMSO) δ ppm 8.02 (s, 2H), 7.61-7.51 (m, 1H), 7.51-7.38 (m, 3H), 7.39-7.18 (m, 2H), 4.72-4.49 (m, 2H), 4.48-4.37 (m, 1H), 4.41 (d, J=9.1 Hz, 21H), 3.04 (s, 2H); 13C NMR (125 MHz, DMSO) δ ppm 150.92 (dd, JCF=245.5, 13.3 Hz), 148.11 (dd, JCF=248.2, 13.4 Hz), 132.40, 128.99, 128.63, 125.16, 124.94, 117.61, 83.64 (d, JCF=170.2 Hz), 79.51 (d, JCF=18.4 Hz), 76.17, 66.27, 23.67.

Workup

  1. temperaturewhile maintaining temperature under 5° C
  2. temperaturethen slowly warmed to RT
  3. stirringstirred for 11 h
  4. additionTo the reaction mixture was charged
  5. customThe organic phase was isolated
  6. washwashed with aq. HCl (1.0 M, 100 ml)
  7. concentrationconcentrated
  8. dissolutionredissolved in 2-methoxy-2-methylpropane (301 ml)
  9. washThe organic phase was then washed with aq
  10. extractionThe last aqueous layer was extracted with 2-methoxy-2-methylpropane
  11. washThe combined organic phase was washed with 18% aq
  12. concentrationNaCl (63 mL) and concentrated under reduced pressure

Sources & evidence

ORD record
ord-e9a085302f83418895b2db33ef785786
Source dataset
uspto-grants-2015_11
Patent number
US09175013B2

Reaction notes

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