Sodium Iodide → Clopidogrel

HRID 1828900Notes

Reaction equation

HRID 1828900 reaction equation
[I-].[Na+].Cl[Si](C)(C)C.[CH3:8][O:9][C:10](=[O:29])[C@H:11]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])[N:12]1[CH2:17][CH:16](O)[C:15]2[S:19][CH:20]=[CH:21][C:14]=2[CH2:13]1.C(=O)(O)[O-].[Na+]>C(#N)C.C1(C)C=CC=CC=1.O>[CH3:8][O:9][C:10]([C@@H:11]([N:12]1[CH2:13][C:14]2[CH:21]=[CH:20][S:19][C:15]=2[CH2:16][CH2:17]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])=[O:29]

Participants

8

Reactant 4

HCID 5238Sodium IodideHCID 6397ChlorotrimethylsilaneHCID 516892Sodium BicarbonateHCID 11325212HCID 11325212, compound

Product 1

HCID 60606Clopidogrel

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolventHCID 6342AcetonitrileSolvent2×

Procedure

To a mixture of sodium iodide in acetonitrile is added chlorotrimethylsilane. The mixture is stirred at room temperature under nitrogen for 30 minutes. A solution of (αS,7RS)-methyl-α-(7-hydroxy-4,5,6,7-tetrahydro-5-thieno[3,2-c]pyridyl)-o-chlorophenylacetate (9) (23.4 g, 69.3 mmol) in toluene and acetonitrile is added to the mixture at 0–5° C. After the addition is complete the mixture is warmed to room temperature and stirred for 2 hours. Water is then added to the mixture at 0–5° C. The mixture is then warmed again to room temperature and stirred for an additional 4 hours. The reaction mixture is then basified with aqueous sodium bicarbonate solution. The organic layer is then washed with aqueous sodium thiosulfate solution, followed by water, then brine. The organic layer is then dried, filtered and concentrated to provide clopidogrel free base as an oil product (21.4 g). 1H-NMR (CDCl3, ppm) 7.7 (1H, dd), 7.35 (1H, m), 7.2–7.35 (2H, m), 7.2 (1H, d), 6.68 (1H, dd), 4.95 (1H, s) 3.5–4.0 (2H, m), 3.75 (3H, s), 2.9 (4H, s); chiral HPLC 99:1 enantiomeric ratio.

Workup

  1. additionAfter the addition
  2. temperatureis warmed to room temperature
  3. stirringstirred for 2 hours
  4. temperatureThe mixture is then warmed again to room temperature
  5. stirringstirred for an additional 4 hours
  6. washThe organic layer is then washed with aqueous sodium thiosulfate solution
  7. customThe organic layer is then dried
  8. filtrationfiltered
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-717800f1d40e4034abe0208153f7c1dd
Source dataset
uspto-grants-2006_06
Patent number
US07060831B2

Reaction notes

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