Triethylamine → 7-((4-methoxybenzyl)oxy)-2-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,8(2H)-dione

HRID 525855Notes

Reaction equation

HRID 525855 reaction equation
[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:20])[CH:11]=[C:12]3[C:17](=[O:18])[NH:16][CH2:15][CH2:14][N:13]3[CH:19]=2)=[CH:5][CH:4]=1.[H-].[Na+].Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:20])[CH:11]=[C:12]3[C:17](=[O:18])[N:16]([CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH2:15][CH2:14][N:13]3[CH:19]=2)=[CH:21][CH:22]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 24758Sodium hydrideHCID 816681-(2-Chloroethyl)pyrrolidine hydrochlorideHCID 867327207-((4-methoxybenzyl)oxy)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,8(2H)-dione

Product 1

HCID 867327217-((4-methoxybenzyl)oxy)-2-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,8(2H)-dioneYield 54.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

To a solution of 7-((4-methoxybenzyl)oxy)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,8(2H)-dione (4.15 g, 13.82 mmol) in N,N-dimethylformamide (DMF) (50 mL) was added sodium hydride (1.382 g, 34.5 mmol) at 0° C., and the mixture was stirred at room temperature for 30 min. Then the mixture of 1-(2-chloroethyl)pyrrolidine, hydrochloride (Aldrich) (2.90 g, 17.03 mmol) and triethylamine (2.438 mL, 17.49 mmol) in N,N-dimethylformamide (DMF) (25.00 mL) was added. The reaction was stirred at 50° C. for 30 h. The solvent was evaporated and the residue was dissolved in water (50 mL) and extracted with dichloromethane (50 mL) three times. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to afford light yellow crude product, which was then purified by normal phase automatic silica column chromatography (Combiflash RF), eluting with dichloromethane/methanol/ammonium hydroxide (v:v:v=80:20:2) over 16 min to afford 7-((4-methoxybenzyl)oxy)-2-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,8(2H)-dione (3 g, 7.55 mmol, 54.6% yield) as light yellow solid. LCMS (M+H)+: 398.0.

Workup

  1. additionwas added
  2. stirringThe reaction was stirred at 50° C. for 30 h
  3. customThe solvent was evaporated
  4. dissolutionthe residue was dissolved in water (50 mL)
  5. extractionextracted with dichloromethane (50 mL) three times
  6. dry with materialThe organic phase was dried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. customevaporated
  9. customto afford light yellow crude product, which
  10. customwas then purified by normal phase automatic silica column chromatography (Combiflash RF)
  11. washeluting with dichloromethane/methanol/ammonium hydroxide (v:v:v=80:20:2) over 16 min

Sources & evidence

ORD record
ord-f6829467c70846f58b6a6c908fd44bdb
Source dataset
uspto-grants-2016_05
Patent number
US09340556B2

Reaction notes

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