Ethyl 3-(4-pyridyl)-3-oxopropionate → (+/-) 2-(4-Oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-1H-isoindole-1,3(2H)-dione

HRID 217884Notes

Reaction equation

HRID 217884 reaction equation
Cl.[NH2:2][C:3]1[CH:8]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH2:7][CH2:6][CH2:5][N:4]=1.C[O-].[Na+].[Na].[N:24]1[CH:29]=[CH:28][C:27]([C:30](=O)[CH2:31][C:32](OCC)=[O:33])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.CO>[O:33]=[C:32]1[N:4]2[CH2:5][CH2:6][CH2:7][CH:8]([N:9]3[C:10](=[O:19])[C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:17]3=[O:18])[C:3]2=[N:2][C:30]([C:27]2[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=2)=[CH:31]1

Participants

7

Reactant 4

HCID 2735202Ethyl 3-(4-pyridyl)-3-oxopropionateHCID 5360545SodiumHCID 10942334Sodium MethoxideHCID 67265827(+/-) 2-(2-Amino-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-dione hydrochloride

Product 1

HCID 67265728(+/-) 2-(4-Oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)-1H-isoindole-1,3(2H)-dioneYield 34.1%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 1140TolueneSolvent

Procedure

To a suspension of 9.166 g (32.77 mmol) of (+/−)2-(2-Amino-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-dione hydrochloride (1:1) in 50 mL of toluene was added sodium methanolate (freshly prepared from 0.754 g (32.77 mmol) of sodium in 10 mL of methanol and the reaction mixture was stirred at room temperature for 1 h. The mixture was evaporated to dryness, dissolved in 50 mL of toluene and 4.87 g (25.21 mmol) of ethyl 3-(pyridin-4-yl)-3-oxopropionate was added. The resulting solution was stirred under reflux for 12 h. The cooled solution was evaporated to remove solvent. The mixture was dissolved in dichloromethane, washed with a saturated aqueous solution of ammonium chloride, saturated aqueous sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 97/3/0.3 led to afford 3.2 g (34%) of the desired compound as a white powder.

Workup

  1. customThe mixture was evaporated to dryness
  2. dissolutiondissolved in 50 mL of toluene
  3. stirringThe resulting solution was stirred
  4. temperatureunder reflux for 12 h
  5. customThe cooled solution was evaporated
  6. customto remove solvent
  7. dissolutionThe mixture was dissolved in dichloromethane
  8. washwashed with a saturated aqueous solution of ammonium chloride, saturated aqueous sodium chloride
  9. dry with materialdried over sodium sulfate
  10. customevaporated to dryness
  11. customThe residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 97/3/0.3

Sources & evidence

ORD record
ord-4b088f9f6b1247588162c1ce7193caea
Source dataset
uspto-grants-2012_06
Patent number
US08198287B2

Reaction notes

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