反应详情

491 mg (1.8 mmol, 80% purity) of the compound from Example 3A and 289 mg (1.6 mmol) 6-hydrazinonicotinic acid ethyl ester [for the preparation see WO 2006/114213] are stirred in 10 ml acetic acid at RT for 12 h. Thereafter, 120 mg (0.7 mmol) 6-hydrazinonicotinic acid ethyl ester are again added to the reaction mixture and the mixture is stirred again at RT for 13 h. After standing at RT for a further two days, the reaction solution is concentrated in vacuo, the residue is taken up in ethyl acetate, the mixture is washed neutral with saturated sodium bicarbonate solution and the organic phase is dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The intermediate product obtained in this way is dissolved in 10 ml ethanol, 0.3 ml (1.8 mmol) of a 30% strength sodium methylate solution in methanol are added and the mixture is stirred at RT for 17 h. The reaction solution is adjusted to pH 5 with 1 N hydrochloric acid and is subsequently stirred at RT for a further 2 h. It is concentrated in vacuo, acetonitrile is added to the residue, the precipitate which has separated out is filtered off and the residue on the filter is washed with diethyl ether and dried in vacuo. 9.4 ml 0.1 M ethanolic potassium hydroxide solution are added to the ester obtained in this way and the mixture is stirred at RT for 16 h. The reaction solution is adjusted to pH 2 with 1 N hydrochloric acid, the solvent is removed on a rotary evaporator, the residue is taken up in water and the mixture is extracted with ethyl acetate. The crystals which have precipitated out from the aqueous phase are filtered off, the residue on the filter is washed with diethyl ether and the product is dried in vacuo.

1. waitAfter standing at RT for a further two days
2. concentrationthe reaction solution is concentrated in vacuo
3. washthe mixture is washed neutral with saturated sodium bicarbonate solution
4. dry with materialthe organic phase is dried over sodium sulfate
5. filtrationfiltered
6. concentrationconcentrated on a rotary evaporator
7. customThe intermediate product obtained in this way
8. stirringthe mixture is stirred at RT for 17 h
9. stirringis subsequently stirred at RT for a further 2 h
10. concentrationIt is concentrated in vacuo, acetonitrile
11. additionis added to the residue
12. customthe precipitate which has separated out
13. filtrationis filtered off
14. washthe residue on the filter is washed with diethyl ether
15. customdried in vacuo
16. addition9.4 ml 0.1 M ethanolic potassium hydroxide solution are added to the ester
17. customobtained in this way
18. stirringthe mixture is stirred at RT for 16 h
19. customthe solvent is removed on a rotary evaporator
20. extractionthe mixture is extracted with ethyl acetate
21. customThe crystals which have precipitated out from the aqueous phase
22. filtrationare filtered off
23. washthe residue on the filter is washed with diethyl ether
24. customthe product is dried in vacuo