Triethylamine → 3-[(7R,8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl]-6-[(E)-(3-fluoro-6H-benzo[c][1]benzoxepin-11-ylidene)methyl]-1H-benzimidazol-2-one

HRID 244354Notes

Reaction equation

HRID 244354 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:36]=1)[O:7][CH2:8][C:9]1[CH:35]=[CH:34][CH:33]=[CH:32][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C@H:20]2[CH2:28][N:27]3[C@@H:22]([CH2:23][O:24][CH2:25][CH2:26]3)[CH2:21]2)=[C:15]([N+:29]([O-])=O)[CH:14]=1.C(N(CC)CC)C.Cl[C:45](Cl)([O:47]C(=O)OC(Cl)(Cl)Cl)Cl>[Pt].O1CCCC1.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:36]=1)[O:7][CH2:8][C:9]1[CH:35]=[CH:34][CH:33]=[CH:32][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]2[N:19]([C@H:20]3[CH2:28][N:27]4[C@@H:22]([CH2:23][O:24][CH2:25][CH2:26]4)[CH2:21]3)[C:45](=[O:47])[NH:29][C:15]=2[CH:14]=1

Participants

7

Reactant 3

HCID 8471TriethylamineHCID 94429TriphosgeneHCID 58564433(E)-[4-(3-Fluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-2-nitro-phenyl]-((7R, 8aR)-hexahydro-pyrrolo[2,1-c][1,4]oxazin-7-yl)-amine

Product 1

HCID 468941193-[(7R,8aR)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-7-yl]-6-[(E)-(3-fluoro-6H-benzo[c][1]benzoxepin-11-ylidene)methyl]-1H-benzimidazol-2-oneYield 74.3%

Reagents, catalysts & solvents 3

HCID 23939PlatinumCatalystHCID 8028TetrahydrofuranSolvent3×HCID 516892Sodium BicarbonateSolvent

Procedure

Hydrogenate a mixture of (E)-[4-(3-fluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-2-nitro-phenyl]-((7R,8aR)-hexahydro-pyrrolo[2,1-c][1,4]oxazin-7-yl)-amine (52 g, 0.107 mol), triethylamine (33 mL, 0.237 mol) and 5% platinum on carbon (18 g) in tetrahydrofuran (450 mL) at room temperature at 50 psi for 2 h. Filter off the catalyst, rinse with tetrahydrofuran, and concentrate to obtain a brown foam. Dissolve the foam in anhydrous tetrahydrofuran (500 mL) and cool in an ice bath. Add triphosgene (31.5 g, 0.106 mol) in tetrahydrofuran (450 mL) dropwise over 30 min and stir at room temperature for 16 h. Concentrate the solution, dissolve in 5% methanol in dichloromethane and purify through a short silica gel plug. Concentrate to obtain a brown solid. Suspend the solid in saturated sodium bicarbonate (1.5 L) and stir on the rotary evaporator for one hour. Filter and dry in vacuo. Dissolve in warm 1:1 methanol/dichloromethane (approximately 6 L) and treat with poly (4-vinylpyridine) 2% cross-linked resin (170 g). Stir the slurry for 30 min and filter through diatomaceous earth. Concentrate the filtrate to approximately 1.5 L volume and collect the resulting solids by filtration. Dry at 80° C./20 mm Hg overnight to obtain the title compound as a white solid (38.1 g, 74%). [α]D20−20.5 (c=1.0 in DMSO). 1H NMR (400 MHz, DMSO-d6) δ 1.48 (m, 1H), 2.02 (m, 1H), 2.19 (m, 2H), 2.52 (m, 1H), 2.91 (d, 1H), 3.03 (d, 1H), 3.25 (t, 1H), 3.50 (t, 1H), 3.79 (d, 1H), 3.88 (d, 1H), 4.95 (m, 1H), 5.03 (broad s, 1H), 5.60 (broad s, 1H), 6.59 (m, 2H), 6.78 (m, 2H), 6.97 (s, 1H), 7.02 (d, 1H), 7.25 (t, 1H), 7.38 (t, 1H), 7.48-7.61 (m, 3H), 10.72 (s, 1H, NH). LC-MS m/z 484.0 [M+H]+.

Workup

  1. filtrationFilter off the catalyst
  2. washrinse with tetrahydrofuran
  3. concentrationconcentrate
  4. customto obtain a brown foam
  5. temperaturecool in an ice bath
  6. concentrationConcentrate the solution
  7. dissolutiondissolve in 5% methanol in dichloromethane
  8. custompurify through a short silica gel plug
  9. concentrationConcentrate
  10. customto obtain a brown solid
  11. stirringstir on the rotary evaporator for one hour
  12. filtrationFilter
  13. customdry in vacuo
  14. dissolutionDissolve
  15. temperaturein warm 1:1 methanol/dichloromethane (approximately 6 L)
  16. additiontreat with poly (4-vinylpyridine) 2% cross-linked resin (170 g)
  17. stirringStir the slurry for 30 min
  18. filtrationfilter through diatomaceous earth
  19. concentrationConcentrate the filtrate to approximately 1.5 L volume
  20. customcollect the resulting solids
  21. filtrationby filtration
  22. customDry at 80° C./20 mm Hg overnight

Sources & evidence

ORD record
ord-48ef3fe3273d4ac2968e2ccab9575794
Source dataset
uspto-grants-2014_02
Patent number
US08658638B2

Reaction notes

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