反应详情

(5-Cyano-2-nitro-phenyl)-(5-morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester hydrochloride salt (100 g, 223.7 mmol) was slurried in toluene at room temperature and a solution of sodium hydrogen carbonate (47 g, 559 mmol) in water (500 ml) was added and the reaction mixture stirred at room temperature for 45 mins. The organic phase was separated and washed twice with water (500 ml) then concentrated by distillation under vacuum to 229 ml. Dimethylformamide (846 ml) was then added followed by Degussa® [CF1082 RV/W®; Platinum (3%) and Vanadium (0.6%)] on active carbon (20 g, 20 w/w %) and the reaction mixture degassed with nitrogen followed by heating to 40° C. then hydrogen (g) was added to a pressure of 3-4 bar g and left for 30 min then heated to 70° C. and stirred for 6 hrs under an atmosphere of hydrogen. After cooling to room temperature the reaction mixture was purged with nitrogen and the catalyst filtered off and the filtrate concentrated to 395 ml. (The solution was used in the next step; Example 12). An aliquot was taken out and purified by column chromatography on silica eluting with dichloromethane/methanol (1% ammonium hydroxide) (25:1) gave (2-Amino-5-cyano-phenyl)-(5-morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester as a pale orange oil.

1. customThe organic phase was separated
2. washwashed twice with water (500 ml)
3. concentrationthen concentrated by distillation under vacuum to 229 ml
4. additionDimethylformamide (846 ml) was then added
5. customthe reaction mixture degassed with nitrogen
6. temperatureby heating to 40° C.
7. additionhydrogen (g) was added to a pressure of 3-4 bar g
8. waitleft for 30 min
9. temperaturethen heated to 70° C.
10. stirringstirred for 6 hrs under an atmosphere of hydrogen
11. temperatureAfter cooling to room temperature the reaction mixture
12. customwas purged with nitrogen
13. filtrationthe catalyst filtered off
14. concentrationthe filtrate concentrated to 395 ml
15. custompurified by column chromatography on silica eluting with dichloromethane/methanol (1% ammonium hydroxide) (25:1)