Methyl 3-mercaptopropionate → Methyl 3-((5-(methoxymethoxy)-1-(methoxymethyl)-6-oxo-1,6-dihydropyridin-3-yl)thio)propanoate

HRID 709031Notes

Reaction equation

HRID 709031 reaction equation
Br[C:2]1[CH:3]=[C:4]([O:12][CH2:13][O:14][CH3:15])[C:5](=[O:11])[N:6]([CH2:8][O:9][CH3:10])[CH:7]=1.CCN(C(C)C)C(C)C.[SH:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:15][O:14][CH2:13][O:12][C:4]1[C:5](=[O:11])[N:6]([CH2:8][O:9][CH3:10])[CH:7]=[C:2]([S:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:3]=1

Participants

7

Reactant 3

HCID 18050Methyl 3-mercaptopropionateHCID 81531DiisopropylethylamineHCID 867315255-bromo-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one2×

Product 1

HCID 86731526Methyl 3-((5-(methoxymethoxy)-1-(methoxymethyl)-6-oxo-1,6-dihydropyridin-3-yl)thio)propanoateYield 85%

Reagents, catalysts & solvents 3

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Procedure

A mixture of 5-bromo-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 15) (3.5 g, 12.6 mmol), Pd2(dba)3 (0.46 g, 0.50 mmol), Xantphos (0.58 g, 1.00 mmol) and DIPEA (4.40 ml, 25.2 mmol) in dioxane (60 ml) was degassed and then placed under an atmosphere of nitrogen. To this mixture was added methyl 3-mercaptopropanoate (1.66 g, 13.8 mmol) and the whole was heated under reflux for 3 hours. Upon cooling it was filtered through a pad of celite and ethyl acetate was washed through the pad of celite to recover any remaining compound. The organic filtrate was washed with water and then saturated aqueous sodium chloride solution and the organics were dried (MgSO4), filtered and concentrated under vacuum. The crude residue was purified by column chromatography (SiO2; 0-100% dichloromethane in petrol, then 0-10% methanol in dichloromethane). Product fractions were collected and concentrated in vacuo to give a yellow oil. This oil was purified further by reverse phase column chromatography (SiO2—C18; 5-95% methanol in water with 0.1% formic acid) to give methyl 3-{[5-(methoxymethoxy)-1-(methoxymethyl)-6-oxo-1,6-dihydropyridin-3-yl]sulfanyl}propanoate (3.4 g, 10.7 mmol, 85%).

Workup

  1. customwas degassed
  2. temperaturethe whole was heated
  3. temperatureunder reflux for 3 hours
  4. temperatureUpon cooling it
  5. filtrationwas filtered through a pad of celite and ethyl acetate
  6. washwas washed through the pad of celite
  7. customto recover any remaining compound
  8. washThe organic filtrate was washed with water
  9. dry with materialsaturated aqueous sodium chloride solution and the organics were dried (MgSO4)
  10. filtrationfiltered
  11. concentrationconcentrated under vacuum
  12. customThe crude residue was purified by column chromatography (SiO2
  13. customProduct fractions were collected
  14. concentrationconcentrated in vacuo
  15. customto give a yellow oil
  16. customThis oil was purified further by reverse phase column chromatography (SiO2—C18; 5-95% methanol in water with 0.1% formic acid)

Sources & evidence

ORD record
ord-6bb65ecb9c1d43959497d620aacf59fc
Source dataset
uspto-grants-2015_11
Patent number
US09180122B2

Reaction notes

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