Ammonium Hydroxide → HCID 57827725, compound

HRID 1855248Notes

Reaction equation

HRID 1855248 reaction equation
[F:1][CH:2]([F:12])[C:3]1[N:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([F:32])=[C:18]([C@:20]23[CH2:28][O:27][C@H:26]([CH2:29][F:30])[C@H:25]2[CH2:24][S:23][C:22]([NH2:31])=[N:21]3)[CH:19]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[NH4+]>CCOC(C)=O.O>[NH2:31][C:22]1[S:23][CH2:24][C@@H:25]2[C@@H:26]([CH2:29][F:30])[O:27][CH2:28][C@:20]2([C:18]2[CH:19]=[C:14]([NH:13][C:9]([C:6]3[CH:5]=[N:4][C:3]([CH:2]([F:1])[F:12])=[CH:8][N:7]=3)=[O:11])[CH:15]=[CH:16][C:17]=2[F:32])[N:21]=1

Participants

7

Reactant 4

HCID 14923Ammonium HydroxideHCID 111923Propylphosphonic anhydrideHCID 574685755-Difluoromethympyrazine-2-carboxylic acidHCID 68150583HCID 68150583, compound

Product 1

HCID 57827725HCID 57827725, compoundYield 72.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
42.5 °C

Procedure

5-(Difluoromethyl)pyrazine-2-carboxylic acid (30.0 g, 1.05 equiv) and (4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (49.2 g, 1.00 equiv.) were charged to a reactor and EtOAc (443 mL) was added to the mixture to give a suspension. A solution of ®T3P (105 g, 1.10 equiv, 50 wt % in EtOAc) (Archimica, Germany) 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 ambient temperature and water (98 mL) was charged. After 10-15 minutes charged 28% ammonium hydroxide (137 mL) while controlling the temperature below 30° C. Additional EtOAc (172 mL) was added and the reaction mixture was stirred for 30 minutes at ambient temperature. The aqueous phase was separated and back-extracted with EtOAc (246 mL). The organic phases were combined and washed with 15% aq. NaCl (98 mL) and water (98 mL). The organic layer was filtered over Celite (0.5 Wt) and 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-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-(difluoromethyl)pyrazine-2-carboxamide as a tan solid (54.2 g).

Workup

  1. customto give a suspension
  2. customthe internal temperature below 30° C
  3. temperatureThe reaction mixture was cooled to ambient temperature
  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 (246 mL)
  8. washwashed with 15% aq. NaCl (98 mL) and water (98 mL)
  9. filtrationThe organic layer was filtered over Celite (0.5 Wt)
  10. concentrationconcentrated under vacuum
  11. customto obtain
  12. customa beige solid (quantitative crude yield) which
  13. customwas recrystallized from 1-propanol

Sources & evidence

ORD record
ord-0a1184604e924cd4b14febdadb947acf
Source dataset
uspto-grants-2015_02
Patent number
US08962858B2

Reaction notes

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