Potassium Carbonate → (3S,4s)-4-(4-((E)-(3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)methyl)-2-nitrophenylamino)-1-methylpyrrolidin-3-ol

HRID 1670645Notes

Reaction equation

HRID 1670645 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]2[CH2:13][N:12]([CH3:14])[CH2:11][C@@H:10]2[OH:15])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[F:19][C:20]1[CH:21]=[CH:22][C:23]2=[C:24]([CH:44]=1)[O:25][CH2:26][C:27]1[CH:43]=[CH:42][CH:41]=[CH:40][C:28]=1/[C:29]/2=[CH:30]\B1OC(C)(C)C(C)(C)O1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.O.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]2=[C:24]([CH:44]=1)[O:25][CH2:26][C:27]1[CH:43]=[CH:42][CH:41]=[CH:40][C:28]=1/[C:29]/2=[CH:30]\[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]2[CH2:13][N:12]([CH3:14])[CH2:11][C@@H:10]2[OH:15])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1

Participants

9

Reactant 4

HCID 11430Potassium CarbonateHCID 11776TriphenylphosphineHCID 57748725(3S,4S)-4-(4-bromo-2-nitrophenylamino)-1-methylpyrrolidin-3-olHCID 57748738(E)-2-((3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Product 1

HCID 57748760(3S,4s)-4-(4-((E)-(3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)methyl)-2-nitrophenylamino)-1-methylpyrrolidin-3-olYield 56%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 218864351,4-Dioxane--water (1/1)Solvent

Conditions

Temperature
82 °C

Procedure

Combine (3S,4S)-4-(4-bromo-2-nitrophenylamino)-1-methylpyrrolidin-3-ol (17.6 mmol, 5.55 g), (E)-2-((3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (16.0 mmol, 5.62 g), triphenylphosphine (2.87 mmol, 0.75 g), and K2CO3 (44.7 mmol, 6.18 g) in 110 mL of dioxane:water (3:1). Degas the mixture by bubbling with nitrogen for five min, add palladium (II) acetate (0.48 mmol, 322 mg), and heat at 82° C. under nitrogen for 3.5 h. Cool to room temperature, dilute with water and dichloromethane and then pass through a pad of diatomaceous earth. Separate the phases and extract the aqueous phase with dichloromethane twice. Combine the organic phases, wash with brine, dry over anhydrous sodium sulfate, filter, and remove the solvent in vacuo. Dissolve in 4:1 CH2Cl2/MeOH and pass through a plug of silica using the same solvent. Concentrate the filtrate and triturate with methanol. Collect the resulting solid by filtration to obtain the title compound as a red solid (4.12 g, 56%): 1H NMR (300 MHz, CDCl3) δ 2.23 (dd, J=9.9, 5.6 Hz, 1H), 2.38 (s, 3H), 2.28-2.26 (m, 1H), 2.70 (d, J=3.5 Hz, 2H), 3.36 (dd, J=9.8, 7.1 Hz, 1H), 3.91-3.87 (m, 1H), 4.01 (br s, 1H), 5.00-4.80 (m, 1H), 5.70-5.50 (m, 1H), 6.52 (dd, J=10.3, 2.6 Hz, 1H), 6.68-6.64 (m, 1H), 6.78-6.75 (m, 2H), 7.01 (d, J=7.7 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 7.24-7.22 (m, 1H), 7.35 (dt, J=7.5, 1.2 Hz, 1H), 7.42 (dd, J=8.7, 6.6 Hz, 1H), 7.47 (d, J=7.4 Hz, 1H), 7.94 (s, 1H), 8.00 (d, J=6.2 Hz, 1H).

Workup

  1. customDegas the mixture
  2. customby bubbling with nitrogen for five min
  3. temperatureCool to room temperature
  4. customSeparate the phases
  5. extractionextract the aqueous phase with dichloromethane twice
  6. washwash with brine
  7. dry with materialdry over anhydrous sodium sulfate
  8. filtrationfilter
  9. customremove the solvent in vacuo
  10. dissolutionDissolve in 4:1 CH2Cl2/MeOH and pass through a plug of silica using the same solvent
  11. concentrationConcentrate the filtrate
  12. customtriturate with methanol
  13. customCollect the resulting solid
  14. filtrationby filtration

Sources & evidence

ORD record
ord-b968b0c276ae49e1880df1c8fcc550e5
Source dataset
uspto-grants-2011_08
Patent number
US07994164B2

Reaction notes

Loading…