Ethyl Acetate → Tert-butyl 4-[2-(5,7-dioxo-[1,3]dioxolo[4,5-f]isoindol-6-yl) ethyl]piperidine-1-carboxylate

HRID 528501Notes

Reaction equation

HRID 528501 reaction equation
[O:1]1[C:5]2=[CH:6][C:7]3[C:8](=[O:14])[NH:9][C:10](=[O:13])[C:11]=3[CH:12]=[C:4]2[O:3][CH2:2]1.[OH-].[K+].S(O[CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)(C1C=CC(C)=CC=1)(=O)=O.C(OCC)(=O)C>C(O)C.CS(C)=O.O>[O:14]=[C:8]1[C:7]2[CH:6]=[C:5]3[O:1][CH2:2][O:3][C:4]3=[CH:12][C:11]=2[C:10](=[O:13])[N:9]1[CH2:28][CH2:29][CH:30]1[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:34][CH2:35]1

Participants

8

Reactant 4

HCID 8857Ethyl AcetateHCID 14797Potassium HydroxideHCID 3223665H-1,3-Dioxolo[4,5-f]isoindole-5,7(6H)-dioneHCID 21936070N-Boc-4-[2-(4-Toluenesulfonyloxy)ethyl]piperidine

Product 1

HCID 90064408Tert-butyl 4-[2-(5,7-dioxo-[1,3]dioxolo[4,5-f]isoindol-6-yl) ethyl]piperidine-1-carboxylateYield 66.3%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolvent2×HCID 702EthanolSolventHCID 962WaterSolvent

Conditions

Temperature
60 °C

Procedure

To a 1 L reaction vessel, 52 g (0.27 mol) of [1,3]dioxolo[4,5-f]isoindole-5,7-dione (compound V-1, synthesized according to the method in the references: J. Am. Chem. Soc., 1951, 73, 1371 and J. Am. Chem. Soc., 1963, 85, 473) and 320 ml dimethyl sulfoxide was added, and the mixture was stirred and heated to 60° C., 110 ml solution of 23.4 g (0.42 mol) of potassium hydroxide in ethanol was added after the solid was completely dissolved, the resulting mixture was stirred for 15 min, and then 160 ml solution of 117 g (0.31 mol) of tert-butyl 4-[2-(tosyloxy)ethyl]piperidine-1-carboxylate (compound VI-1, synthesized according to the method disclosed in the PCT application WO2007082731) in dimethyl sulfoxide was added, after addition, the reaction was kept at 60° C. for 5 h until the reaction was completed, 500 ml ethyl acetate and 300 ml water were added, extraction was carried out and the organic layer was collected, dried over sodium sulfate, filtered, the filtrate was concentrated to dry, and 102.2 g crude product was obtained, it was separated by column chromatography, and 72 g compound XI was obtained, with yield of 65.8%. 1H NMR (DMSO-d6): δ 0.90-1.00 (m, 2H), 1.36 (s, 10H), 1.46 (q, 2H, J=7.0 Hz), 1.66 (d, 2H, J=11.9 Hz), 2.62 (br s, 2H), 3.51 (t, 2H, J=7.0 Hz), 3.88 (d, 2H, J=11.5 Hz), 6.24 (s, 2H), 7.32 (s, 2H); MS (ESI): m/z 425 [M+Na]+.

Workup

  1. customsynthesized
  2. dissolutionwas completely dissolved
  3. stirringthe resulting mixture was stirred for 15 min
  4. additionwas added
  5. additionafter addition
  6. extractionextraction
  7. customthe organic layer was collected
  8. dry with materialdried over sodium sulfate
  9. filtrationfiltered
  10. concentrationthe filtrate was concentrated
  11. customto dry
  12. custom102.2 g crude product was obtained
  13. customit was separated by column chromatography

Sources & evidence

ORD record
ord-abd31c84142a4786bf45146cf3292162
Source dataset
uspto-grants-2016_05
Patent number
US09346818B2

Reaction notes

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