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

HRID 1162798Notes

Reaction equation

HRID 1162798 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

To 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 eluting with dichloromethane and then 5% ethyl acetate in dichloromethane. Appropriate fractions were collected and concentrated under vacuum. Residual ethyl acetate and dichloromethane were removed by co-evaporation with toluene 3 times, for the subsequent hydrogenation. The residue was triturated with hexane, and filtered to provide the cyclization product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.37 (br s, 5H), 7.23 (m, 2H), 7.02 (t, J=8.6 Hz, 2H), 6.44 (d, J=6.0 Hz, ½H), 6.32 (d, J=6.0 Hz, ½H), 5.53 (d, J=6.0 Hz, ½H), 5.42 (d, J=6.0 Hz, ½H), 5.21 (s, 2H), 4.65 (s, 2H), 4.38 (s, 2H); ES MS (M+1)=341.

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. customAppropriate fractions were collected
  10. concentrationconcentrated under vacuum
  11. customResidual ethyl acetate and dichloromethane were removed by co-evaporation with toluene 3 times, for the subsequent hydrogenation
  12. customThe residue was triturated with hexane
  13. filtrationfiltered

Sources & evidence

ORD record
ord-f6be1d82317c41549750d0e18e01cb43
Source dataset
uspto-grants-2010_10
Patent number
US07820680B2

Reaction notes

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