반응 #67074

반응 방정식

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

수율 50.2%

용매

ethanol

brine

water

N,N-dimethylformamide

반응 조건

후처리

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
   추출extracting with a mixed solvent of chloroform
5. 5
   건조The obtained organic layer was dried over anhydrous magnesium sulfate
6. 6
   기타the solvent was evaporated
7. 7
   기타The obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol:28% aqueous ammonia=10:1:0.1)
8. 8
   기타to obtain a colorless oily substance (207 mg)
9. 9
   workup.STIRRINGby stirring at an external temperature of 80° C. for 1 hour
10. 10
    온도The 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
    여과the obtained colorless solid was collected by filtration
14. 14
    세척washed with ethanol
15. 15
    기타dried

실험 절차

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).

출처