Citric Acid → HCID 131734547, compound

HRID 592099Notes

Reaction equation

HRID 592099 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]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19].[CH3:35][O:36][CH2:37][C:38](Cl)=O.Cl.[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=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>[CH3:35][O:36][CH2:37][C:38](=[C:17]1[CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][CH:22]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[C:13]1=[O:12])[NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1

Participants

12

Reactant 7

HCID 311Citric AcidHCID 313Hydrochloric AcidHCID 6115AnilineHCID 96623Methoxyacetyl chlorideHCID 521998p-Toluenesulfonic acid monohydrateHCID 117841095HCID 117841095, compoundHCID 178418244HCID 178418244, compound

Product 1

HCID 131734547HCID 131734547, compoundYield 5.7%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 1140TolueneSolvent3×HCID 8028TetrahydrofuranSolvent2×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 (27.44 g) [mw. 161.39, 170 mmol, 1.7 eq.] and tetrahydrofuran (78 mL), and the mixture was dissolved. After cooling to −70° C., 1.6 mol/L normal butyllithium/normal hexane solution (105 mL) [168 mmol, 1.7 eq.] was added within the range of −70-−60° C. After stirring at the same temperature for 30 min, a solution (50 mL) of (9H-fluoren-9-yl)methyl 2-oxopyrrolidine-1-carboxylate (30.56 g) [mw. 307.34, 99 mmol] in tetrahydrofuran was added within the range of −78 to −70° C. After stirring at the same temperature for 90 min, methoxyacetic acid chloride (9.71 g) [mw. 108.52, 89 mmol] was added within the range of −78 to −67° C. After stirring at the same temperature for 90 min, 6 mol/L aqueous hydrochloric acid solution (55 mL) [330 mmol] was added at not more than −20° C. to quench the reaction. After warming to 25° C., water (55 mL) and toluene (110 mL) were added to allow for partitioning. The organic layer was washed with water (55 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a yellow oil. Toluene (28 mL), aniline (8.40 g) [mw. 93.13, 90 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 hr. After cooling to 25° C., 10 w/w % aqueous citric acid solution (60 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 (60 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by basic silica gel. (silica gel amount: 250 g, eluent:toluene, Rf=0.9) The effective fraction was concentrated under reduced pressure, and preserved in a freezer to allow for crystallization. A mixed solvent of ethyl acetate/diisopropyl ether=1/5 (60 mL) was added, and the mixture was aged at room temperature. The crystals were collected by filtration under reduced pressure, acetone was added, and insoluble matter was filtered off. The mother liquor was concentrated under reduced pressure, a mixed solvent of ethyl acetate/diisopropyl ether=1/4 (25 mL) was added, and the mixture was suspended by stirring. After filtration under reduced pressure, the crystals were washed with a mixed solvent of ethyl acetate/diisopropyl ether=1/4, and dried under reduced pressure at 50° C. Yellow crystals, 2.60 g, yield 5.7%, 1H-NMR (500 MHz, CDCl3, TMS) δ 2.83 (m, 2H), 3.36 (s, 3H), 3.81 (m, 2H), 4.05 (s, 2H), 4.35 (m, 1H), 4.50 (d, J=7.6 Hz, 2H), 7.10-7.17 (m, 3H), 7.29-7.36 (m, 4H), 10.60 (s, 1H). 13C-NMR (125 MHz, CDCl3, CDCl3) δ21.01, 43.63, 46.85, 58.54, 68.07, 68.25, 98.67, 119.94, 122.99, 124.52, 125.40, 127.20, 127.78, 129.24, 139.30, 141.30, 143.76, 150.63, 152.44, 169.89.

Workup

  1. dissolutionthe mixture was dissolved
  2. stirringAfter stirring at the same temperature for 90 min
  3. stirringAfter stirring at the same temperature for 90 min
  4. customto quench
  5. customthe reaction
  6. temperatureAfter warming to 25° C.
  7. customfor partitioning
  8. washThe organic layer was washed with water (55 mL)
  9. dry with materialdried over magnesium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customto give a yellow oil
  13. temperaturereflux for 1 hr
  14. temperatureAfter cooling to 25° C.
  15. customfor partitioning
  16. washFurthermore, the organic layer was washed with 5 w/w % aqueous sodium bicarbonate solution (60 mL)
  17. dry with materialdried over magnesium sulfate
  18. filtrationfiltered
  19. concentrationconcentrated under reduced pressure
  20. customThe concentrate was purified by basic silica gel
  21. concentration(silica gel amount: 250 g, eluent:toluene, Rf=0.9) The effective fraction was concentrated under reduced pressure
  22. customto allow for crystallization
  23. additionA mixed solvent of ethyl acetate/diisopropyl ether=1/5 (60 mL) was added
  24. customwas aged at room temperature
  25. filtrationThe crystals were collected by filtration under reduced pressure, acetone
  26. additionwas added
  27. filtrationinsoluble matter was filtered off
  28. concentrationThe mother liquor was concentrated under reduced pressure
  29. additiona mixed solvent of ethyl acetate/diisopropyl ether=1/4 (25 mL) was added
  30. stirringby stirring
  31. filtrationAfter filtration under reduced pressure
  32. washthe crystals were washed with a mixed solvent of ethyl acetate/diisopropyl ether=1/4
  33. customdried under reduced pressure at 50° C

Sources & evidence

ORD record
ord-e1d66dab4c084d0d88e374493519ce3c
Source dataset
uspto-grants-2016_01
Patent number
US09238667B2

Reaction notes

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