反応 #10420

反応方程式

sodium tert-butoxide

chlorosulfonyl isocyanate

sodium acetate

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

→

title compound

収率 18.5%

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

収率 18.5%

溶媒

dichloromethane

反応条件

後処理

1. 1
   workup.WAITto come to room temperature overnight
2. 2
   その他is recooled to −20° C.
3. 3
   workup.STIRRINGAfter stirring for 1 hour
4. 4
   温度without cooling
5. 5
   その他the solvent is removed in vacuo
6. 6
   温度without heating
7. 7
   その他The residue is triturated with a saturated solution of sodium acetate in brine
8. 8
   抽出extracted with ethyl acetate (3×75 mL)
9. 9
   乾燥The combined organic layers are dried (MgSO4)
10. 10
    ろ過filtered
11. 11
    その他evaporated in vacuo
12. 12
    workup.STIRRINGstirred at room temperature for 36 hours
13. 13
    その他The solvent is removed in vacuo
14. 14
    その他the residue triturated with 100 mL of 0.1 M formic acid
15. 15
    抽出extracted with ethyl acetate (3×100 mL)
16. 16
    洗浄The combined organic layers are washed with water
17. 17
    乾燥dried (MgSO4)
18. 18
    ろ過filtered
19. 19
    その他evaporated in vacuo
20. 20
    その他to give a residue which
21. 21
    その他is chromatographed over flash grade silica gel (230–400 mesh)
22. 22
    洗浄eluting with dichloromethane

実験手順

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.

出典