Citric Acid → HCID 131734546, compound

HRID 592097Notes

Reaction equation

HRID 592097 reaction equation
C([Li])CCC.CCCCCC.[O:12]=[C:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19].[CH3:24][O:25][CH2:26][C:27](Cl)=O.Cl.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C1(C)C=CC=CC=1.C1CCCCC1.O>[CH3:24][O:25][CH2:26][C:27](=[C:17]1[CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[C:13]1=[O:12])[NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1

Participants

12

Reactant 7

HCID 311Citric AcidHCID 313Hydrochloric AcidHCID 6115AnilineHCID 96623Methoxyacetyl chlorideHCID 521998p-Toluenesulfonic acid monohydrateHCID 13699158HCID 13699158, compoundHCID 178418244HCID 178418244, compound

Product 1

HCID 131734546HCID 131734546, compoundYield 17.2%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 1140TolueneSolvent3×HCID 8028TetrahydrofuranSolvent3×HCID 8078CyclohexaneSolvent

Conditions

Temperature
-70 °C

Procedure

Under a nitrogen stream, into a 500 mL four-mouthed flask were added 1,1,1,3,3,3-hexamethyldisilasane (25.83 g) [mw. 161.39, 160 mmol, 1.8 eq.] and tetrahydrofuran (78 mL), and the mixture was dissolved. After cooling to −70° C., 1.6 mol/L normal butyllithium/normal hexane solution (100 mL) [160 mmol, 1.8 eq.] was added within the range of −70-−60° C. After stirring at the same temperature for 30 min, a solution (20 mL) of allyl 2-oxopyrrolidine-1-carboxylate (15.04 g) [mw. 169.18, 90 mmol] in tetrahydrofuran was added within the range of −78 to −70° C. After stirring at the same temperature for 50 min, a solution (20 mL) of methoxyacetic acid chloride (9.64 g) [mw. 108.52, 90 mmol] in tetrahydrofuran was added within the range of −78 to −62° C. After stirring at the same temperature for 30 min, 6 mol/L aqueous hydrochloric acid solution (50 mL) [300 mmol] was added at not more than −30° C. to quench the reaction. After warming to 25° C., water (25 mL) and toluene (100 mL) were added to allow for partitioning. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a yellow oil. Toluene (28 mL), aniline (4.20 g) [mw. 93.13, 45 mmol], p-toluenesulfonic acid monohydrate (170.0 mg) [mw. 190.22, 0.9 mmol] and cyclohexane (84 mL) were added thereto. Dean-Stark trap was set, and the mixture was subjected to dehydration reflux for 1.5 hr. After cooling to 25° C., 10 w/w % aqueous citric acid solution (56 mL) and toluene (28 mL) were added to allow for partitioning. Furthermore, the organic layer was washed with 5 w/w % aqueous sodium bicarbonate solution (56 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by basic silica gel. (silica gel amount: 100 g, eluent:toluene) The effective fraction was concentrated under reduced pressure, and normal hexane (56 mL) and ethyl acetate (21 mL) were added to allow for crystallization. The crystals were aged, filtered under reduced pressure, washed with a mixed solvent of normal hexane/ethyl acetate=8/3 (33 mL), and dried under reduced pressure at 50° C. Yellow crystals, 4.85 g, yield 17.2%, 1H-NMR (500 MHz, CDCl3, TMS) δ2.72-2.90 (m, 2H), 3.35 (s, 3H), 3.73-3.88 (m, 2H), 4.04 (s, 2H), 4.76 (d, J=5.7 Hz, 2H), 5.21-5.50 (m, 2H), 5.88-6.10 (m, 1H), 7.04-7.16 (m, 3H), 7.28-7.39 (m, 2H), 10.44-10.66 (s, 1H). 13C-NMR (125 MHz, CDCl3, CDCl3) 520.99, 43.61, 58.49, 66.71, 68.04, 98.71, 118.66, 122.77, 124.41, 129.21, 131.95, 139.29, 150.57, 152.27, 169.92.

Workup

  1. dissolutionthe mixture was dissolved
  2. stirringAfter stirring at the same temperature for 50 min
  3. stirringAfter stirring at the same temperature for 30 min
  4. customto quench
  5. customthe reaction
  6. temperatureAfter warming to 25° C.
  7. customfor partitioning
  8. dry with materialThe organic layer was dried over magnesium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customto give a yellow oil
  12. temperaturereflux for 1.5 hr
  13. temperatureAfter cooling to 25° C.
  14. customfor partitioning
  15. washFurthermore, the organic layer was washed with 5 w/w % aqueous sodium bicarbonate solution (56 mL)
  16. dry with materialdried over magnesium sulfate
  17. filtrationfiltered
  18. concentrationconcentrated under reduced pressure
  19. customThe concentrate was purified by basic silica gel
  20. concentration(silica gel amount: 100 g, eluent:toluene) The effective fraction was concentrated under reduced pressure, and normal hexane (56 mL) and ethyl acetate (21 mL)
  21. additionwere added
  22. customto allow for crystallization
  23. filtrationfiltered under reduced pressure
  24. washwashed with a mixed solvent of normal hexane/ethyl acetate=8/3 (33 mL)
  25. customdried under reduced pressure at 50° C

Sources & evidence

ORD record
ord-f443f131892d41c78e2ea45b1cadfaba
Source dataset
uspto-grants-2016_01
Patent number
US09238667B2

Reaction notes

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