Hydrochloric Acid → 5-(Methanesulfonylamino-methyl)-thiophen-2-yl-acetic acid methyl ester

HRID 1595912Notes

Reaction equation

HRID 1595912 reaction equation
[CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.Cl.[CH2:12]=O.[CH3:14][S:15]([NH2:18])(=[O:17])=[O:16]>O1CCOCC1.[Cl-].[Zn+2].[Cl-].CCOC(C)=O>[CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]1[S:6][C:7]([CH2:12][NH:18][S:15]([CH3:14])(=[O:17])=[O:16])=[CH:8][CH:9]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 712FormaldehydeHCID 72879MethanesulfonamideHCID 88055Methyl thiophen-2-acetate

Product 1

HCID 544573365-(Methanesulfonylamino-methyl)-thiophen-2-yl-acetic acid methyl esterYield 69%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

To a solution of thiophen-2-yl-acetic acid methyl ester (2 mL, 12.8 mmol) in 1,4-dioxane (10 mL) was added concentrated HCl (0.4 mL, 4.8 mmol) dropwise over 10 minutes. Zinc chloride (78 mg, 0.57 mmol) was added and the reaction was lowered into a pre-heated water bath at 45° C. and was stirred for 15 minutes. HCl (g) was bubbled into the solution for 2-3 minutes. The temperature of the reaction rose to about 60° C. Upon cooling, 37% aqueous formaldehyde (1.24 mL, 16 mmol) was added dropwise and the temperature rose to 70° C. The reaction was cooled to room temperature and methanesulfonamide (1.25 g, 12.8 mmol) was added in portions. The reaction was stirred for 3 h and was poured into EtOAc (60 mL). The organic solution was washed with water and the aqueous solution was washed with EtOAc (60 mL). The combined organic solutions were washed with brine, dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (CHCl3) provided the title compound (69%) as a gold oil. 1H NMR (400 MHz, CDCl3) δ 6.85 (d, 1H), 6.70 (d, 1H), 5.20 (m, 1H), 4.40 (s, 2H), 3.80 (s, 2H), 3.70 (s, 3H), 2.80 (s, 3H).

Workup

  1. customthe reaction was lowered into a pre-heated water bath at 45° C.
  2. customHCl (g) was bubbled into the solution for 2-3 minutes
  3. customrose to about 60° C
  4. temperatureUpon cooling
  5. customrose to 70° C
  6. stirringThe reaction was stirred for 3 h
  7. washThe organic solution was washed with water
  8. washthe aqueous solution was washed with EtOAc (60 mL)
  9. washThe combined organic solutions were washed with brine
  10. dry with materialdried over MgSO4
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customPurification by flash chromatography (CHCl3)

Sources & evidence

ORD record
ord-2469a25de0c9442782ab91ed6071958c
Source dataset
uspto-grants-2001_09
Patent number
US06288120B1

Reaction notes

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