Ammonium Hydroxide → (4aS,13aR)-N-[(2,4-difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2': 3,4]imidazo[1,2-d]pyrazine-8-carboxamide

HRID 406926Notes

Reaction equation

HRID 406926 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:38])[C:15]([O:30]CC2C=CC=CC=2)=[C:16]2[C:21](=[O:22])[N:20]3[CH2:23][C@H:24]4[CH2:28][CH2:27][CH2:26][N:25]4[C@@H:19]3[CH2:18][N:17]2[CH:29]=1)=[O:12].[OH-].[NH4+]>[Pd].C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:38])[C:15]([OH:30])=[C:16]2[C:21](=[O:22])[N:20]3[CH2:23][C@H:24]4[CH2:28][CH2:27][CH2:26][N:25]4[C@@H:19]3[CH2:18][N:17]2[CH:29]=1)=[O:12]

Participants

5

Reactant 2

HCID 14923Ammonium HydroxideHCID 66594434(4aS,13aR)-N-[(2,4-Difluorophenyl)methyl]-9,11-dioxo-10-[(phenylmethyl)oxy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazine-8-carboxamide

Product 1

HCID 54713648(4aS,13aR)-N-[(2,4-difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1',2': 3,4]imidazo[1,2-d]pyrazine-8-carboxamideYield 78.4%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 702EthanolSolvent

Procedure

A pressure reaction vessel was charged with (4aS,13aR)—N-[(2,4-Difluorophenyl)methyl]-9,11-dioxo-10-[(phenylmethyl)oxy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide (950 g), 192 g of palladium on carbon (50% wet), ethanol (9.5 L) and concentrated ammonium hydroxide (124 mL). The mixture was degassed with nitrogen 3 times and then placed under 50 psi of hydrogen until the reaction was complete. The mixture was degassed again with nitrogen and then filtered through Celite. The cake was extracted with refluxing dichloromethane and then filtered again. The combined filtrates were concentrated to a small volume (4 L), azeotroped with ethanol (28.5 L) to a final volume of 9 L. The slurry was filtered and washed with ethanol and dried to produce (4aS,13aR)—N-[(2,4-difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide (616 g, 78.4%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.37 (m, 1H), 8.42 (s, 1H), 7.41-7.05 (m, 3H), 4.72-4.53 (m, 4H), 4.05 (m, 1H), 3.86 (m, 1H), 3.70 (m, 1H), 3.16 (m, 1H), 2.88 (m, 2H), 1.92-1.60 (m, 4H).

Workup

  1. customA pressure reaction vessel
  2. customThe mixture was degassed with nitrogen 3 times
  3. customThe mixture was degassed again with nitrogen
  4. filtrationfiltered through Celite
  5. extractionThe cake was extracted with refluxing dichloromethane
  6. filtrationfiltered again
  7. concentrationThe combined filtrates were concentrated to a small volume (4 L)
  8. customazeotroped with ethanol (28.5 L) to a final volume of 9 L
  9. filtrationThe slurry was filtered
  10. washwashed with ethanol
  11. customdried

Sources & evidence

ORD record
ord-209fa9b6a96d480fb6072b0d95a86694
Source dataset
uspto-grants-2014_06
Patent number
US08754214B2

Reaction notes

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