تفاعل #67074

معادلة التفاعل

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

المردود 50.2%

المذيبات

ethanol

brine

water

N,N-dimethylformamide

ظروف التفاعل

المعالجة

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
   استخلاصextracting with a mixed solvent of chloroform
5. 5
   تجفيفThe obtained organic layer was dried over anhydrous magnesium sulfate
6. 6
   أخرىthe solvent was evaporated
7. 7
   أخرىThe obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol:28% aqueous ammonia=10:1:0.1)
8. 8
   أخرىto obtain a colorless oily substance (207 mg)
9. 9
   workup.STIRRINGby stirring at an external temperature of 80° C. for 1 hour
10. 10
    درجة الحرارةThe 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
    ترشيحthe obtained colorless solid was collected by filtration
14. 14
    غسيلwashed with ethanol
15. 15
    أخرىdried

الإجراء التجريبي

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).

المصدر