Reaction #67074

Reaction equation

fumaric acid

4-{[2-chloro-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}thiomorpholine 1,1-dioxide

quinuclidin-3-ol

sodium hydride

→

3-({5-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]-4-(trifluoromethyl)pyrimidin-2-yl}oxy)quinuclidine fumarate

Yield 50.2%

Solvents

ethanol

brine

water

N,N-dimethylformamide

Conditions

Workup

1. 1
   workup.STIRRINGby stirring at room temperature for 1 hour
2. 2
   workup.WAITat 80° C. for 3 hours
3. 3
   workup.STIRRINGby stirring
4. 4
   Extractionextracting with a mixed solvent of chloroform
5. 5
   DryingThe obtained organic layer was dried over anhydrous magnesium sulfate
6. 6
   Otherthe solvent was evaporated
7. 7
   OtherThe obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol:28% aqueous ammonia=10:1:0.1)
8. 8
   Otherto obtain a colorless oily substance (207 mg)
9. 9
   workup.STIRRINGby stirring at an external temperature of 80° C. for 1 hour
10. 10
    TemperatureThe reaction mixture was cooled to room temperature
11. 11
    workup.STIRRINGunder stirring
12. 12
    workup.STIRRINGfurther stirred at room temperature for 1 hour
13. 13
    Filtrationthe obtained colorless solid was collected by filtration
14. 14
    Washwashed with ethanol
15. 15
    Otherdried

Procedure

To a solution of quinuclidin-3-ol (127 mg) in N,N-dimethylformamide (5 mL) was added 60% sodium hydride (60 mg), and the mixture was stirred at room temperature for 20 minutes. To the reaction mixture was added 4-{[2-chloro-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}thiomorpholine 1,1-dioxide (344 mg), followed by stirring at room temperature for 1 hour, and then at 80° C. for 3 hours. To the reaction mixture were added water and saturated brine, followed by stirring and then extracting with a mixed solvent of chloroform:2-propanol=3:1. The obtained organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol:28% aqueous ammonia=10:1:0.1) to obtain a colorless oily substance (207 mg). This oily substance was dissolved in ethanol (5 mL) and then fumaric acid (58 mg) was added thereto, followed by stirring at an external temperature of 80° C. for 1 hour. The reaction mixture was cooled to room temperature under stirring, and further stirred at room temperature for 1 hour, and then the obtained colorless solid was collected by filtration, washed with ethanol, and dried to obtain 3-({5-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]-4-(trifluoromethyl)pyrimidin-2-yl}oxy)quinuclidine fumarate (138 mg).

Source