Ammonium Hydroxide → N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide

HRID 2045885Notes

Reaction equation

HRID 2045885 reaction equation
[F:1][CH2:2][C:3]1[N:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:33])=[C:17]([C@:19]23[CH2:27][O:26][C@H:25]([C:28]([F:31])([F:30])[F:29])[C@H:24]2[CH2:23][S:22][C:21]([NH2:32])=[N:20]3)[CH:18]=1.[OH-].[NH4+]>CCOC(C)=O.O>[NH2:32][C:21]1[S:22][CH2:23][C@@H:24]2[C@@H:25]([C:28]([F:31])([F:29])[F:30])[O:26][CH2:27][C@:19]2([C:17]2[CH:18]=[C:13]([NH:12][C:9]([C:6]3[CH:5]=[N:4][C:3]([CH2:2][F:1])=[CH:8][N:7]=3)=[O:11])[CH:14]=[CH:15][C:16]=2[F:33])[N:20]=1

Participants

6

Reactant 3

HCID 14923Ammonium HydroxideHCID 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-amineHCID 668695845-(Fluoromethyl)pyrazine-2-carboxylic acid

Product 1

HCID 70495913N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamideYield 70.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
42.5 °C

Procedure

5-(Fluoromethyl)pyrazine-2-carboxylic acid (32.6 g, 1.05 equiv) and (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 (70.0 g, 1.0 equiv)1 were charged to a reactor and ethyl acetate (EtOAc, 630 mL) was added to the mixture to give a suspension. A solution of n-propane phosphonic acid anhydride (T3P, 146 g, 1.10 equiv, 50 wt % in EtOAc) was added at ambient temperature while controlling the internal temperature below 30° C. The reaction mixture was stirred at 40-45° C.>3 hours and monitored by HPLC. The reaction mixture was cooled to 15-20° C. and water (140 mL) was charged. After 10-15 minutes charged 28% ammonium hydroxide (175 mL) while controlling the temperature below 30° C. EtOAc (245 mL0 was added and the reaction mixture was stirred for 30 minutes at ambient temperature. The aqueous phase was separated and back-extracted with EtOAc (490 mL). The organic phases were combined and washed with 15% aq. NaCl (140 mL) and water (140 mL). The organic layer was filtered over Celite (1.0 Wt) and rinsed with EtOAc (140 mL). The solution was concentrated under vacuum to obtain a beige solid (quantitative crude yield) which was recrystallized from 1-propanol to afford N-(3-((4aS,5S,7aS)-2-amino-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-(fluoromethyl)pyrazine-2-carboxamide as a white solid (70.0 g). 1H NMR (500 MHz, DMSO) δ 10.89 (s, 1H), 9.30 (s, 1H), 8.89 (s, 1H), 7.95 (dd, J=7.3, 2.7 Hz, 1H), 7.94-7.89 (m, 1H), 7.21 (dd, J=12.0, 8.8 Hz, 1H), 6.22 (s, 2H), 5.71 (d, J=46.3 Hz, 2H), 4.77-4.61 (m, 1H), 4.37 (d, J=8.1 Hz, 1H), 3.87 (dd, J=8.0, 2.7 Hz, 1H), 3.20 (dt, J=7.0, 3.5 Hz, 1H), 3.15 (dd, J=13.9, 3.1 Hz, 1H), 2.91 (dd, J=13.8, 3.8 Hz, 1H). 13C NMR (126 MHz, DMSO) δ161.32 (s), 155.82 (d, J=243.4 Hz), 153.71 (d, J=18.7 Hz), 148.77 (s), 144.71 (d, J=1.9 Hz), 143.30 (s), 141.01 (d, J=5.6 Hz), 134.36 (d, J=2.0 Hz), 128.20 (d, J=12.1 Hz), 125.57 (q, J=283.0 Hz), 123.12 (d, J=3.6 Hz), 121.64 (d, J=8.6 Hz), 116.35 (d, J=25.2 Hz), 82.55 (d, J=165.8 Hz), 78.37 (s), 76.44 (q, J=30.6 Hz), 65.89 (d, J=5.3 Hz), 35.89 (s), 23.01 (s).

Workup

  1. customto give a suspension
  2. customthe internal temperature below 30° C
  3. temperatureThe reaction mixture was cooled to 15-20° C.
  4. customthe temperature below 30° C
  5. stirringthe reaction mixture was stirred for 30 minutes at ambient temperature
  6. customThe aqueous phase was separated
  7. extractionback-extracted with EtOAc (490 mL)
  8. washwashed with 15% aq. NaCl (140 mL) and water (140 mL)
  9. filtrationThe organic layer was filtered over Celite (1.0 Wt)
  10. washrinsed with EtOAc (140 mL)
  11. concentrationThe solution was concentrated under vacuum
  12. customto obtain
  13. customa beige solid (quantitative crude yield) which
  14. customwas recrystallized from 1-propanol

Sources & evidence

ORD record
ord-40f58808c83f4c3d8482ee0e6c64096c
Source dataset
uspto-grants-2013_11
Patent number
US08592408B2

Reaction notes

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