Hydrochloric Acid → 1-[(4-Methoxyphenyl)methyl]piperidine-2,4-dione

HRID 73214Notes

Reaction equation

HRID 73214 reaction equation
C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1.COC(=O)[CH2:28][C:29]([N:31]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)[CH2:32][CH2:33][C:34]([O:36]C)=O)=[O:30].Cl>C1(C)C=CC=CC=1.O>[CH3:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([CH2:38][N:31]2[CH2:32][CH2:33][C:34](=[O:36])[CH2:28][C:29]2=[O:30])=[CH:44][CH:43]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 2855718-Crown-6HCID 59752294Methyl 3-((3-methoxy-3-oxopropyl)(4-methoxybenzyl)amino)-3-oxopropanoate

Product 1

HCID 468356221-[(4-Methoxyphenyl)methyl]piperidine-2,4-dioneYield 69%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 1140TolueneSolvent2×

Procedure

A mixture of anhydrous K2CO3 (3.2 g, 23.2 mmol, 5 eq) and 18-crown-6 (azetroped several times with toluene) (122 mg, 0.464 mmol, 10 mol %) in dry toluene (4 ml), under nitrogen, was heated to reflux and then treated, dropwise, over 40 min, with a solution of N-(4-Methoxy-benzyl)-N-(2-methoxycarbonyl-ethyl)-malonamic acid methyl ester. After 7 h at reflux the reaction was diluted with water (4 ml) and toluene (4 ml), then cooled to 0° and carefully acudified to pH 1.7 with 0.1N HCl. The mixture was then extracted several times with CH2Cl2 (3×80 ml) and the combined organics dried and evaporated to a brown oil (1.33 g). The brown oil was treated with 10% aqueous oxalic acid and heated to reflux for 6.5 h. The mixture was then extracted repratedly with CH2Cl2 and the combined organics dried and evaporated to a dirty yellow oil (1.03 g). The crude material was purified on silica gel using (CH2Cl2:MeOH=30:1) as eluent to give 1-(4-Methoxy-benzyl)-piperidine-2,4-dione as a pale brown solid (750 mg, 69%); (300 MHz, CDCl3) 2.52 (t, J=5.7 HZ, 2H), 3.41 (s, 2H), 3.47 (t, J=5.7 Hz, 2H), 3.80 (s, 3H), 4.62 (s, 2H), 6.16-6.88 (m, 2H), 7.20 (m, 2H).

Workup

  1. temperatureunder nitrogen, was heated
  2. temperatureto reflux
  3. additiontreated
  4. temperatureAfter 7 h at reflux the reaction
  5. temperaturecooled to 0°
  6. extractionThe mixture was then extracted several times with CH2Cl2 (3×80 ml)
  7. customthe combined organics dried
  8. customevaporated to a brown oil (1.33 g)
  9. additionThe brown oil was treated with 10% aqueous oxalic acid
  10. temperatureheated
  11. temperatureto reflux for 6.5 h
  12. extractionThe mixture was then extracted repratedly with CH2Cl2
  13. customthe combined organics dried
  14. customevaporated to a dirty yellow oil (1.03 g)
  15. customThe crude material was purified on silica gel using (CH2Cl2:MeOH=30:1) as eluent

Sources & evidence

ORD record
ord-c8edf6f7540f4266beb720067f4d4eef
Source dataset
uspto-grants-2014_09
Patent number
US08829030B2

Reaction notes

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