2-Methylbenzenesulfonic acid → 4-Benzyloxycarbonyl-1-(4-fluorobenzyl)-3,4-dihydropyrazin-2(1H)-one

HRID 494080Notes

Reaction equation

HRID 494080 reaction equation
[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:15]([CH2:24][CH:25](OC)OC)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH:25]=[CH:24][N:15]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[C:13](=[O:14])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 69252-Methylbenzenesulfonic acidHCID 521998p-Toluenesulfonic acid monohydrateHCID 59813049N2-Benzyloxycarbonyl-N1-(2,2-dimethoxyethyl)-N1-(4-fluorobenzyl)-glycinamide

Product 1

HCID 598130504-Benzyloxycarbonyl-1-(4-fluorobenzyl)-3,4-dihydropyrazin-2(1H)-one

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

A solution of N2-benzyloxycarbonyl-N1-(2,2-dimethoxyethyl)-N1-(4-fluorobenzyl)glycinamide (61.5 g, 152 mmol) and p-toluenesulfonic acid monohydrate (3 g) in toluene (450 mL) was stirred at 75° C. for 5 days. Each day an additional 3 g of toluenesulfonic acid was added. The resultant reaction mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated under vacuum, and the residue dissolved in dichloromethane. The organic solution was washed successively with saturated aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residual solid was subjected to column chromatography on silica gel eluted first with dichloromethane and then 5% ethyl acetate in dichloromethane. Appropriate fractions were collected and concentrated under vacuum. Residual ethyl acetate and dichloromethane was removed by co-evaporation with toluene 3 times for subsequent hydrogenation. The residue was triturated with hexane, and filtered to provide the cyclization product as an off-white solid.

Workup

  1. customThe resultant reaction mixture
  2. filtrationfiltered through a pad of Celite
  3. concentrationThe filtrate was concentrated under vacuum
  4. dissolutionthe residue dissolved in dichloromethane
  5. washThe organic solution was washed successively with saturated aqueous sodium bicarbonate, brine
  6. dry with materialdried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated under vacuum
  9. washeluted first with dichloromethane
  10. customAppropriate fractions were collected
  11. concentrationconcentrated under vacuum
  12. customResidual ethyl acetate and dichloromethane was removed by co-evaporation with toluene 3 times for subsequent hydrogenation
  13. customThe residue was triturated with hexane
  14. filtrationfiltered

Sources & evidence

ORD record
ord-4cab97877a4541a99810d400d8b87871
Source dataset
uspto-grants-2009_05
Patent number
US07538112B2

Reaction notes

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