Dimethyl Sulfoxide → (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

HRID 468541Notes

Reaction equation

HRID 468541 reaction equation
Br[C:2]1[C:3](=[O:27])[C:4]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:5]2[C:10](=[O:11])[N:9]3[CH2:12][C@H:13]4[CH2:17][CH2:16][CH2:15][N:14]4[C@@H:8]3[CH2:7][N:6]2[CH:18]=1.[F:28][C:29]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33]C=1CN.CC[N:40]([CH:44]([CH3:46])C)[CH:41](C)C.CS(C)=[O:49]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[F:28][C:29]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:46]=1[CH2:44][NH:40][C:41]([C:2]1[C:3](=[O:27])[C:4]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:5]2[C:10](=[O:11])[N:9]3[CH2:12][C@H:13]4[CH2:17][CH2:16][CH2:15][N:14]4[C@@H:8]3[CH2:7][N:6]2[CH:18]=1)=[O:49]

Participants

6

Reactant 4

HCID 679Dimethyl SulfoxideHCID 81531DiisopropylethylamineHCID 27332442,4-DifluorobenzylamineHCID 46239162(4aS,13aR)-8-bromo-10-[(phenylmethyl)oxy]-2,3,4a,5,13,13a-hexahydro-1H-pyrido[1,2-a]pyrrolo[1',2':3,4]imidazo[1,2-d]pyrazine-9,11-dione

Product 1

HCID 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-carboxamideYield 56%

Reagents, catalysts & solvents 1

HCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)Catalyst

Conditions

Temperature
80 °C

Procedure

A reaction vessel was charged with (4aS,13aR)-8-bromo-10-[(phenylmethyl)oxy]-2,3,4a,5,13,13a-hexahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-9,11-dione (1.4 kg), 2,4-difluorobenzylamine (705 g), Hunigs base (1.4 L), dppf (60 g) and DMSO (12 L). The mixture was degassed with high purity nitrogen 4 times. To this mixture was added palladium (II) trifluoroacetate (18 g) in DMSO (2 L). The mixture was again degassed 3 times with high purity nitrogen and then purged with CO 3 times and left under a 45 psi atmosphere of CO. The mixture was heated at 80° C. under 45 psi CO until the reaction appeared complete by HPLC (24 hrs). The mixture was cooled to rt and slowly transferred to an ice slurry of ammonium chloride. The mixture was filtered and washed with water and isopropanol. The residue was recrystallized from isopropanol to provide (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 (952 g, 56%). Recrystallization of the mother liquor from isopropanol produced a second crop of crystals of the desired product in the amount of 327 g (19%).

Workup

  1. customThe mixture was degassed with high purity nitrogen 4 times
  2. additionTo this mixture was added palladium (II) trifluoroacetate (18 g) in DMSO (2 L)
  3. customThe mixture was again degassed 3 times with high purity nitrogen
  4. custompurged with CO 3 times
  5. waitleft under a 45 psi atmosphere of CO
  6. customappeared complete by HPLC (24 hrs)
  7. temperatureThe mixture was cooled to rt
  8. filtrationThe mixture was filtered
  9. washwashed with water and isopropanol
  10. customThe residue was recrystallized from isopropanol

Sources & evidence

ORD record
ord-0365b59549514bcfab2f9f248d807b1a
Source dataset
uspto-grants-2014_01
Patent number
US08624023B2

Reaction notes

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