تفاعل #10420

معادلة التفاعل

sodium tert-butoxide

chlorosulfonyl isocyanate

sodium acetate

ethyl 2-cyclopropylamino-5-fluoro-6-methylsulfanylnicotinate

→

title compound

المردود 18.5%

1-Cyclopropyl-6-fluoro-7-methylsulfanyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione

المردود 18.5%

المذيبات

dichloromethane

ظروف التفاعل

المعالجة

1. 1
   workup.WAITto come to room temperature overnight
2. 2
   أخرىis recooled to −20° C.
3. 3
   workup.STIRRINGAfter stirring for 1 hour
4. 4
   درجة الحرارةwithout cooling
5. 5
   أخرىthe solvent is removed in vacuo
6. 6
   درجة الحرارةwithout heating
7. 7
   أخرىThe residue is triturated with a saturated solution of sodium acetate in brine
8. 8
   استخلاصextracted with ethyl acetate (3×75 mL)
9. 9
   تجفيفThe combined organic layers are dried (MgSO4)
10. 10
    ترشيحfiltered
11. 11
    أخرىevaporated in vacuo
12. 12
    workup.STIRRINGstirred at room temperature for 36 hours
13. 13
    أخرىThe solvent is removed in vacuo
14. 14
    أخرىthe residue triturated with 100 mL of 0.1 M formic acid
15. 15
    استخلاصextracted with ethyl acetate (3×100 mL)
16. 16
    غسيلThe combined organic layers are washed with water
17. 17
    تجفيفdried (MgSO4)
18. 18
    ترشيحfiltered
19. 19
    أخرىevaporated in vacuo
20. 20
    أخرىto give a residue which
21. 21
    أخرىis chromatographed over flash grade silica gel (230–400 mesh)
22. 22
    غسيلeluting with dichloromethane

الإجراء التجريبي

A solution of 4.1 g (15.2 mmol) of ethyl 2-cyclopropylamino-5-fluoro-6-methylsulfanylnicotinate (Example 34) in 125 mL of dichloromethane is cooled to −20° C. and treated dropwise with 5.24 g (37 mmol) of chlorosulfonyl isocyanate. The reaction is stirred at −20° C. for 3 hours and allowed to come to room temperature overnight. The mixture is recooled to −20° C. and treated with 6.8 g (80 mmol) of solid sodium acetate. After stirring for 1 hour without cooling, the solvent is removed in vacuo without heating. The residue is triturated with a saturated solution of sodium acetate in brine and extracted with ethyl acetate (3×75 mL). The combined organic layers are dried (MgSO4), filtered and evaporated in vacuo. The residue is suspended in 100 mL of tetrahydrofuran and treated with 3.6 g (32 mmol) of solid sodium tert-butoxide and stirred at room temperature for 36 hours. The solvent is removed in vacuo, the residue triturated with 100 mL of 0.1 M formic acid and extracted with ethyl acetate (3×100 mL). The combined organic layers are washed with water, dried (MgSO4), filtered and evaporated in vacuo to give a residue which is chromatographed over flash grade silica gel (230–400 mesh) eluting with dichloromethane to give 0.75 g of the title compound, mp 220–222° C.

المصدر