Triphenylphosphine → (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

HRID 244353Notes

Reaction equation

HRID 244353 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]2[CH2:17][N:16]3[C@@H:11]([CH2:12][O:13][CH2:14][CH2:15]3)[CH2:10]2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[F:21][C:22]1[CH:23]=[CH:24][C:25]2=[C:26]([CH:46]=1)[O:27][CH2:28][C:29]1[CH:45]=[CH:44][CH:43]=[CH:42][C:30]=1/[C:31]/2=[CH:32]\B1OC(C)(C)C(C)(C)O1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[O-].[Na+]>O1CCCC1.CO.C(OCC)(=O)C.[Cl-].[Na+].O.ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:21][C:22]1[CH:23]=[CH:24][C:25]2=[C:26]([CH:46]=1)[O:27][CH2:28][C:29]1[CH:45]=[CH:44][CH:43]=[CH:42][C:30]=1/[C:31]/2=[CH:32]\[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]2[CH2:17][N:16]3[C@@H:11]([CH2:12][O:13][CH2:14][CH2:15]3)[CH2:10]2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1

Participants

11

Reactant 4

HCID 11776TriphenylphosphineHCID 10942334Sodium MethoxideHCID 57748738HCID 57748738, compoundHCID 58564430(7R,8aR)-(4-bromo-2-nitro-phenyl)-(hexahydro-pyrrolo[2,1-c][1,4]oxazin-7-yl)-amine

Product 1

HCID 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)-amineYield 73%

Reagents, catalysts & solvents 6

HCID 167845palladium(II) acetateCatalystHCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolventHCID 131718255Brine ethyl acetateSolvent

Conditions

Temperature
60 °C

Procedure

Charge a flask with (7R,8aR)-(4-bromo-2-nitro-phenyl)-(hexahydro-pyrrolo[2,1-c][1,4]oxazin-7-yl)-amine (50.9 g, 0.149 mol), (E)-2-((3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (57.5 g, 0.163 mol), triphenylphosphine (10.1 g, 39 mmol) and sodium methoxide (19.7 g, 0.346 mol) in tetrahydrofuran (1 L) and methanol (500 mL). Bubble nitrogen through the mixture for 30 min. Add palladium (II) acetate (3.00 g, 13 mmol) and bubble nitrogen through the mixture for an additional 30 min. Heat at reflux (60° C.) under nitrogen for 16 h. Cool to room temperature, filter through diatomaceous earth and concentrate in vacuo to obtain a solid. Dissolve in 1:1 ethyl acetate/brine (2 L) and pass through a pad of diatomaceous earth. Wash the pad with 1:1 ethyl acetate/brine (2×1 L) and then with 10% methanol in dichloromethane (4×1 L). Separate the layers and combine the organic phases. Dry the organic portion over sodium sulfate, filter, and concentrate to obtain an oil. Dissolve the oil in dichloromethane and pass through a silica gel pad. Rinse the pad with dichloromethane until higher Rf TLC component is removed. Elute with 1% methanol in dichloromethane and concentrate in vacuo to obtain a foam. Dissolve in ethyl acetate (2 L) and concentrate to approximately 200 mL. Add hexanes (1.5 L) and allow the suspension to stand at room temperature for one hour. Collect the orange solid by filtration and dry at 50° C./20 mm Hg to obtain the title compound (53 g, 73%). [α]D20−26 (c=1.0 in DMSO). 1H NMR (400 MHz, DMSO-d6) δ 1.08 (m, 1H), 2.02 (m, 1H), 2.17 (m, 1H), 2.41 (m, 2H), 2.88 (m, 1H), 3.17 (m, 1H), 3.40 (m, 1H), 3.73 (d, 1H), 3.82 (d, 1H), 4.12 (m, 1H), 5.02 (broad s, 1H), 5.59 (broad s, 1H), 6.60 (d, 1H), 6.81 (m, 2H), 6.96 (s, 1H), 7.05 (m, 2H), 7.28 (t, 1H), 7.38 (t, 1H), 7.60 (m, 2H), 7.84 (s, 1H), 8.05 (d, 1H). LC-MS m/z 458.3 [M+H]+.

Workup

  1. temperatureHeat
  2. temperatureCool to room temperature
  3. filtrationfilter through diatomaceous earth
  4. concentrationconcentrate in vacuo
  5. customto obtain a solid
  6. washWash the pad with 1:1 ethyl acetate/brine (2×1 L)
  7. customSeparate the layers
  8. dry with materialDry the organic portion over sodium sulfate
  9. filtrationfilter
  10. concentrationconcentrate
  11. customto obtain an oil
  12. washRinse the pad with dichloromethane until higher Rf TLC component
  13. customis removed
  14. washElute with 1% methanol in dichloromethane
  15. concentrationconcentrate in vacuo
  16. customto obtain a foam
  17. concentrationconcentrate to approximately 200 mL
  18. waitto stand at room temperature for one hour
  19. customCollect the orange solid
  20. filtrationby filtration
  21. customdry at 50° C./20 mm Hg

Sources & evidence

ORD record
ord-ed4d466ac96344a0b10f9f744c6f8ee7
Source dataset
uspto-grants-2014_02
Patent number
US08658638B2

Reaction notes

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