Iodine → Hydroxy-di-thiophen-2-yl-acetic acid (R)-1-methyl-piperidin-3-yl ester

HRID 551379Notes

Reaction equation

HRID 551379 reaction equation
Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Mg].II.[CH3:10][N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([O:17][C:18](=[O:26])[C:19](=[O:25])[C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[CH2:12]1.[Cl-].[NH4+]>C1COCC1.O>[CH3:10][N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([O:17][C:18](=[O:26])[C:19]([OH:25])([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[CH2:12]1

Participants

8

Reactant 5

HCID 807IodineHCID 138512-Bromothiophene2×HCID 25517Ammonium ChlorideHCID 5462224MagnesiumHCID 67194971Oxo-thiophen-2-yl-acetic acid (R)-1-methyl-piperidin-3-yl ester

Product 1

HCID 67199874Hydroxy-di-thiophen-2-yl-acetic acid (R)-1-methyl-piperidin-3-yl ester

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent3×

Procedure

A solution of 2-bromothiophene (0.092 ml, 0.94 mmol) in THF (2 ml) is added to magnesium (0.576 g, 23.7 mmol) followed by a single crystal of iodine. Additional 2-bromothiophene (2.2 ml, 22.8 mmol) in THF (48 ml) is then added dropwise whilst maintaining a gentle reflux. After the addition is completed the reaction mixture is heated to reflux for 1 hour. This mixture is then added to a solution of oxo-thiophen-2-yl-acetic acid (R)-1-methyl-piperidin-3-yl ester (6 g, 23.7 mmol) in THF dropwise with stirring. After the addition is completed the reaction mixture is heated to reflux for 2 hours. After cooling to room temperature saturated aqueous ammonium chloride solution (100 ml) is added followed by water (100 ml). The resulting solution is extracted with ethylacetate (200 ml) and the resulting organic phase extracted with 1 Molar hydrochloric acid (100 ml). Basification of the aqueous layer with sodium carbonate, extraction with ethylacetate, drying over magnesium sulphate, filtration and concentration gives the title product as a brown oil which crystallises on standing.

Workup

  1. temperaturewhilst maintaining a gentle reflux
  2. additionAfter the addition
  3. temperatureis heated
  4. temperatureto reflux for 1 hour
  5. additionAfter the addition
  6. temperatureis heated
  7. temperatureto reflux for 2 hours
  8. additionis added
  9. extractionThe resulting solution is extracted with ethylacetate (200 ml)
  10. extractionthe resulting organic phase extracted with 1 Molar hydrochloric acid (100 ml)
  11. extractionBasification of the aqueous layer with sodium carbonate, extraction with ethylacetate
  12. dry with materialdrying over magnesium sulphate, filtration and concentration

Sources & evidence

ORD record
ord-c0dbfb6ff6514df8b3775a29a8bec5e7
Source dataset
uspto-grants-2011_05
Patent number
US07947730B2

Reaction notes

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