Hydrochloric Acid → N-[2-(chloromethyl)benzyl]-gamma-valerolactam

HRID 2399374Notes

Reaction equation

HRID 2399374 reaction equation
[C:1]1(=[O:7])[NH:6][CH:4]([CH3:5])[CH2:3][CH2:2]1.Cl[C:9]1[C:10](Cl)=[C:11]([CH3:16])[C:12]([CH3:15])=[CH:13][CH:14]=1.CCOCC.[ClH:23]>C1COCC1.CS(C)=O>[Cl:23][CH2:15][C:12]1[CH:13]=[CH:14][CH:9]=[CH:10][C:11]=1[CH2:16][N:6]1[CH:4]([CH3:5])[CH2:3][CH2:2][C:1]1=[O:7]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 3283Diethyl EtherHCID 660555-Methyl-2-pyrrolidoneHCID 185652Benzene, 1,2-dichloro-3,4-dimethyl-

Product 1

HCID 19385519N-[2-(chloromethyl)benzyl]-gamma-valerolactamYield 40%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of γ-valerolactam (7 g, 70.5 mmol) in THF (150 mL) and DMSO (20 mL) was treated with Nail (2.83 g of a 60% oil dispersion) at 0° C. under nitrogen atmosphere. After a total of 15 min, α,α(-dichloro-o-xylene (25 g, 140 mmol) was added and the solution was allowed to warm and stir at room temperature. After 4 h, 100 mL of ether and 100 mL of 0.2N HCl were added. The water was withdrawn, and the organic layer was washed 2× more with water, dried (MgSO4), filtered and concentrated. This material was purified on ca. 400 g of silica gel (flash chromatography; EtOAc/hexane 7:3) to yield N-[2-(chloromethyl)benzyl]-γ-valerolactam (6.6 g, 40%). 1H NMR and mass spectral analysis supported the assigned structure. A solution of this lactam (5.0 g, 21.09 mmol), 2-(isopropoxy)phenylpiperazine fumarate (6.38 g, 18.99 mmol), and triethylamine (8.82 mL, 62.37 mmol)in DMF (75 mL) was heated for 3 h at 50°-60° C. After 3 h, the solution was added to a 3:1 solution of ether/ethyl acetate (ca. 100 mL) and extracted 3× with water, dried (MgSO4), filtered and concentrated. The residual oil was purified on ca. 400 g of silica gel (flash chromatography, EtOAc/hexane, 6:4) to give 5.41 g of white semi-solid, pure by thin layer chromatography. It was then dissolved in iPrOH, filtered through a Millipore filter, treated with 2.44 mL of conc. aqueous HCl (ca. 26 mmol), and then triturated out of solution by the addition of ether. The resultant white solid was recrystallized in MeOH/ether to give 1-[[2-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]-piperidin-2-one hydrochloride (3:2) as a white powder (5.50 g, 61%), m.p. 249.5°-252.5° C. 1H NMR and mass spectral analysis supported the assigned structure.

Workup

  1. customAfter a total of 15 min
  2. additionwas added
  3. temperatureto warm
  4. customThe water was withdrawn
  5. washthe organic layer was washed 2× more with water
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThis material was purified on ca. 400 g of silica gel (flash chromatography; EtOAc/hexane 7:3)

Sources & evidence

ORD record
ord-906c20335ef14073801b68be267f17cb
Source dataset
uspto-grants-1995_09
Patent number
US05449677

Reaction notes

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