Isopropyl Acetate → 2-((R)-((3-Methyl-4-nitro-2-pyridinyl)methyl)sulfinyl)-1H-benzimidazole

HRID 218449Notes

Reaction equation

HRID 218449 reaction equation
[CH3:1][C:2]1[C:3]([CH2:11][S:12][C:13]2[NH:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C([C@@](C([O-])=O)(O)[C@@](CC)(O)C([O-])=[O:27])C.C(N(C(C)C)CC)(C)C.[O-]O.C1(C(C)C)C=CC=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+].[OH-].[Na+].C(OC(C)C)(=O)C.S(=O)(O)[O-].[Na+]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O>[CH3:1][C:2]1[C:3]([CH2:11][S@:12]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)=[O:27])=[N:4][CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]

Participants

12

Reactant 8

HCID 7915Isopropyl AcetateHCID 14798Sodium HydroxideHCID 24477Sodium ThiosulfateHCID 81531DiisopropylethylamineHCID 114721032-[[(3-Methyl-4-nitro-2-pyridinyl)methyl]thio]-1H-benzimidazoleHCID 23665763Sodium BisulfiteHCID 29414057diethyl-L(+)-tartrateHCID 53627471Cumen hydroperoxide2×

Product 1

HCID 469475292-((R)-((3-Methyl-4-nitro-2-pyridinyl)methyl)sulfinyl)-1H-benzimidazoleYield 80%

Reagents, catalysts & solvents 3

HCID 11026Titanium isopropoxideCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

A mixture of 2-[[3-methyl-4-nitro-2-piridyl]methylthio]benzimidazole (10 g, 33 mmoles, containing 70 mg of water) and (+)-diethyl-L-tartrate (3.02 g, 14.6 mmoles), in THF (100 ml) is brought to reflux temperature and maintained under stirring for 30 minutes. Titanium isopropoxide (1.89 g, 6.66 mmoles) is added and the mixture is maintained under stirring at reflux temperature till the formation of a clear solution is achieved. The solution is then cooled and added with diisopropylethylamine (1.42 g, 10.9 mmoles). After having achieved the range temperature between −5° C. and 0° C., the solution is treated by slow cooling with cumene hydroperoxide 88% (17.3 g, 100 mmoles). The reaction mixture is maintained under stirring for 3 hours at about 0° C., then treated with a 30% sodium thiosulphate solution to decompose the residue of cumene hydroperoxide. After the separation of the phases the aqueous phase is washed with toluene, and the gathered up organic phases and concentrated under reduced pressure. The oily residue so obtained is taken up with water and treated with sodium hydroxide 30% till pH 12. The so obtained mixture is treated with isopropyl acetate and a solution of sodium bisulfite 25% till pH 9 is added. The precipitated solid is then filtered off and washed with isopropyl acetate and copious water. 9.2 g of product are recovered with a yield of 80% and a chemical and stereochemical purity (determined by HPLC and chiral HPLC) equal to or higher than 98%.

Workup

  1. temperatureto reflux temperature
  2. temperaturemaintained
  3. temperaturethe mixture is maintained
  4. stirringunder stirring
  5. temperatureat reflux temperature till the formation of a clear solution
  6. temperatureThe solution is then cooled
  7. customthe range temperature between −5° C. and 0° C.
  8. additionthe solution is treated
  9. temperatureThe reaction mixture is maintained
  10. stirringunder stirring for 3 hours at about 0° C.
  11. customAfter the separation of the phases the aqueous phase
  12. washis washed with toluene
  13. concentrationconcentrated under reduced pressure
  14. customThe oily residue so obtained
  15. customThe so obtained mixture
  16. filtrationThe precipitated solid is then filtered off
  17. washwashed with isopropyl acetate and copious water
  18. custom9.2 g of product are recovered with a yield of 80%

Sources & evidence

ORD record
ord-77762fe0ea0b42919686e65eab98a63e
Source dataset
uspto-grants-2012_06
Patent number
US08198455B2

Reaction notes

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