Chloroacetyl chloride → HCID 67492327, compound

HRID 1921465Notes

Reaction equation

HRID 1921465 reaction equation
[NH2:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]([CH2:16][CH3:17])[C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1.ClCCl>[Cl:25][CH2:26][C:27]([NH:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]([CH2:16][CH3:17])[C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1)=[O:28]

Participants

6

Reactant 3

HCID 6577Chloroacetyl chlorideHCID 8471TriethylamineHCID 58808603HCID 58808603, compound

Product 1

HCID 67492327HCID 67492327, compoundYield 46.2%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 5-(5-aminomethylthiophen-2-yl)-3-ethyl-6-methyl-1H-pyridin-2-one (0.5 g, 2 mmol) and triethylamine (0.6 mL) in THF (5 mL) and dichloromethane (20 mL) is added chloroacetyl chloride (0.24 mL, 3 mmol) at 0° C. After 2 hr at rt, the mixture is quenched with aqueous NaHCO3 solution, and extracted with EtOAc. The extracts are washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue is chromatographed on SiO2, eluting with CH2Cl2-5% MeOH to afford 0.3 g of 2-chloro-N-[5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophen-2-ylmethyl]-acetamide. A mixture of so formed 2-chloro-N-[5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-thiophen-2-ylmethyl]-acetamide (0.15 g, 0.46 mmol), and excess of pyrrolidine and potassium carbonate in acetonitrile (10 mL) is heated for 6 hr at 75° C., and extracted with EtOAc. The extracts are washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue is chromatographed on SiO2, eluting with CH2Cl2-10% MeOH to afford the free base, which is dissolved in HCl-EtOAc and concentrated. Lyophilization in acetonitrile and water affords 60 mg (33%) of N-[5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophen-2-ylmethyl]-2-(pyrrolidin-1-yl)acetamide hydrochloride as a solid. LC/MS: RT 1.93 min; m/e 360 (M+H); 1H NMR (DMSO-d6, δ, ppm): 10.5 (1H, brs), 9.4 (1H, t), 7.2 (1H, s), 6.98 (1H, d), 6.95 (1H, d), 4.5 (2H, d), 4.1 (2H, d), 3.55 (2H, brs), 3.02 (2H, brs), 2.4 (2H, q), 2.25 (3H, s), 1.8-2.05 (4H, m), 1.22 (3H, t).

Workup

  1. customthe mixture is quenched with aqueous NaHCO3 solution
  2. extractionextracted with EtOAc
  3. washThe extracts are washed with water and brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue is chromatographed on SiO2
  8. washeluting with CH2Cl2-5% MeOH

Sources & evidence

ORD record
ord-0e81c1c52bce430db30e42c57b1f8426
Source dataset
uspto-grants-2012_05
Patent number
US08173682B2

Reaction notes

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