* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With caesium carbonate; potassium iodide In acetonitrile at 80℃; Inert atmosphere
General procedure: Method C: 2-Chloromethyl-1-methyl-5-nitro-1H-imidazol (6a) (1 g, 5.7 mmol), Cs2CO3 (6.6 g, 34.2 mmol) and KI (0.095 g, 0.57 mmol) were stirred in MeCN under inert atmosphere. p-Hydroxyphenyl methyl sulfide (0.8 g, 5.7 mmol) in MeCN was added via a pressure equalized dropping funnel. The mixture was reflux at 80 °C overnight under inert atmosphere. The reaction mixture was filtered and the solvent evaporated. The residue was dissolved in CHCl3 and washed with 10percent K2CO3 (3 x 15 mL). The organic layer was collected, dried over MgSO4, concentrated to give crude in the form of yellow oil. Purification of product 7a (0.95 g, 60percent) was done by the same procedure as described in method A.
Reference:
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 3, p. 1015 - 1018
2
[ 1073-72-9 ]
[ 86990-28-5 ]
[ 59729-37-2 ]
Yield
Reaction Conditions
Operation in experiment
73.6 %Chromat.
at 28 - 50℃; for 5.83333 h;
Preparing a solution of 4-methylmercapto-phenol in acetone from 70.0 g (0.5 m) of 4- methylmercapto-phenol (purity >99.9 percent) and 70.0 g (90 ml) anhydrous acetone (100 percent pure), then adding the latter to the reaction medium of step a) over a period of 120 min while keeping the reaction mixture under constant stirring at 28 °C; stirring is performed thereafter at this temperature for 3 further hours.Heating progressively the resulting reaction medium from 28 to 50 °C over a period of 50 min; eventually keeping stirring for an additional period of maximum 60 min at 50 °C before pouring 500 ml of preheated water (68 °C) onto the above reaction mixture (quenching). Stirring the whole mass at 55 °C until complete dissolution of the components, then separating the aqueous lower phase from the acetone phase for elimination and eventually keeping the remaining acetone phase at 50 °C for the subsequent step.
EXAMPLE 1: (Method a) 1.1: 1-Methyl-2-(4-methylthiophenyl-oxymethyl)-5-nitro-imidazole 13.8 Grams (0.1 mol) of a potassium carbonate powder are added to a solution of 14.0 g (0.1 mol) of 4-methylmercapto-phenol in 30 ml of dimethylformamide; then a solution of 17.6 g (0.1 mol) of 1-methyl-2-chloromethyl-5-nitro-imidazole in 40 ml of dimethylformamide is added dropwise while stirring at 25 C. The weakly exothermic reaction is kept at a maximum temperature of 35 C. by cooling with ice water. Stirring of the mixture is continued for 1 hour at 25 C., the reaction mixture is poured onto ice/water, the precipitate is suction-filtered, washed with water and recrystallized from methanol with an addition of charcoal. In this manner, 19.5 g (70% of the theoretical yield) of 1-methyl-2-(4-methylthiophenyl-oxymethyl)-5-nitro-imidazole are obtained as light-yellow crystals, melting point: 116 C.
2
[ 7440-44-0 ]
[ 59729-37-2 ]
[ 62351-99-9 ]
Yield
Reaction Conditions
Operation in experiment
73%
With 3-chloro-benzenecarboperoxoic acid; In chloroform;
EXAMPLE 2: (oxidation) 2.1: 1-Methyl-2-(4-methylsulfinyl-phenyl-oxymethyl)-5-nitro-imidazole 27.9 Grams (0.1 mol) of 1-methyl-2-(4-methylthiophenyloxymethyl)-5-nitro-imidazole are dissolved in 200 ml of chloroform, and the solution is added dropwise while stirring at 25 C. to a solution of 17.25 g (0.1 mol) of m-chloroperbenzoic acid in 70 ml of chloroform. The reaction mixture is stirred for 1 hour at 25 C., the solution is shaken with dilute sodium carbonate solution, the chloroform phase is separated, dried over sodium sulfate and evaporated. The residue is recrystallized from ethanol with the addition of charcoal. Thus, 21.5 g (73% of the theoretical yield) of 1-methyl-2-(4-methyl-sulfinylphenyl-oxymethyl)-5-nitro-imidazole are obtained as yellowish crystals, m.p. 130 C. According to the method described above, the following compound is prepared:
bis-4,4'-(1-methyl-5-nitro-imidazolyl-2-methoxy)-diphenyl disulfide[ No CAS ]
[ 77-78-1 ]
[ 67343-65-1 ]
[ 59729-37-2 ]
Yield
Reaction Conditions
Operation in experiment
With sulfuric acid;
EXAMPLE 3: (Method b) 3.1: 1-Methyl-2-(4-methylthiophenyl-oxymethyl)-5-nitro-imidazole 5.8 g (0.02 mols) of 1-methyl-2-(4-thiocyanatophenyloxymethyl)-5-nitro-imidazole are introduced portionwise while stirring, under a nitrogen atmosphere, at room temperature, into a mixture of 26.5 ml of concentrated sulfuric acid and 5.0 g (0.04 mol) of dimethylsulfate and allowed to stand overnight at room temperature. The solution is then heated to 60 C. for 30 minutes, cooled and poured onto ice/water. The precipiate is suction-filtered and washed with water. In addition to bis-4,4'-(1-methyl-5-nitro-imidazolyl-2-methoxy)-diphenyl disulfide (m.p. 160 C.), column chromatographical purification on silica gel yields the 1-methyl-2-(4-methylthiophenyl-oxymethyl)-5-nitro-imidazole, m.p. 116 C.
With caesium carbonate; potassium iodide; In acetonitrile; at 80℃;Inert atmosphere;
General procedure: Method C: 2-Chloromethyl-1-methyl-5-nitro-1H-imidazol (6a) (1 g, 5.7 mmol), Cs2CO3 (6.6 g, 34.2 mmol) and KI (0.095 g, 0.57 mmol) were stirred in MeCN under inert atmosphere. p-Hydroxyphenyl methyl sulfide (0.8 g, 5.7 mmol) in MeCN was added via a pressure equalized dropping funnel. The mixture was reflux at 80 C overnight under inert atmosphere. The reaction mixture was filtered and the solvent evaporated. The residue was dissolved in CHCl3 and washed with 10% K2CO3 (3 x 15 mL). The organic layer was collected, dried over MgSO4, concentrated to give crude in the form of yellow oil. Purification of product 7a (0.95 g, 60%) was done by the same procedure as described in method A.
Preparing a solution of 4-methylmercapto-phenol in acetone from 70.0 g (0.5 m) of 4- methylmercapto-phenol (purity >99.9 %) and 70.0 g (90 ml) anhydrous acetone (100 % pure), then adding the latter to the reaction medium of step a) over a period of 120 min while keeping the reaction mixture under constant stirring at 28 C; stirring is performed thereafter at this temperature for 3 further hours.Heating progressively the resulting reaction medium from 28 to 50 C over a period of 50 min; eventually keeping stirring for an additional period of maximum 60 min at 50 C before pouring 500 ml of preheated water (68 C) onto the above reaction mixture (quenching). Stirring the whole mass at 55 C until complete dissolution of the components, then separating the aqueous lower phase from the acetone phase for elimination and eventually keeping the remaining acetone phase at 50 C for the subsequent step.
With hydrogenchloride; In water; acetone; at 50℃; for 1.0h;
100.0 g (1.0 m) of (36.7 % volume) aqueous hydrochloric acid have been progressively added to the acetone solution of step b), i.e. over 60 min, under stirring and while still keeping the reaction mixture at 50 C. Cooling down the resulting mixture progressively from 50 to 15 C to initiate crystallization of the hydrochloride salt and keeping the whole mass under stirring over an additional period of 60 min before filtration. Washing twice the crystallized hydrochloride salt with twice 160 ml acetone to afford 148 g of "wet" <strong>[59729-37-2]fexinidazole</strong> hydrochloride - yield ca. 72 % (weight).