反应详情

To 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine (IV, J. Heterocyclic Chem., 13, 433 (1976)--compound 4b, 40 g, 115 mmol) and sodium borohydride (6.68 g, 176 mmol, 10 mesh) is added THF (100 ml) and i-propyl alcohol (50 ml). The resulting slurry is treated with a slow addition of water (3.1 ml, 176 mmol) while the temperature is maintained at about 23°. The reaction mixture is stirred for 2 hr. Water (9.3 ml) is added slowly to quench the reaction mixture. Methanol (50 ml) is used to facilitate transfer of the reaction mixture to a 500 ml capacity stainless steel Buchi hydrogenator. Raney nickel (40 g of water wet material) is added and the hydrogenation is preformed at 5° and 60 psig pressure. After 17 hr, HPLC showed the reduction is complete. The reaction mixture is removed from the Buchi and the hydrogenator is rinsed with methanol (200 ml). The combined reaction mixture and rinses are filtered through a 5 g pad of solka floc to remove spent catalyst. The catalyst cake is then rinsed with methanol (200 ml). The combined filtrate and rinses are concentrated. Water is added to the concentrate. The product is extracted from the aqueous layer using ethyl acetate (200 ml). The ethyl acetate extract is concentrated to near dryness to azeotrope any residual water. Finally, ethyl acetate (600 ml) is used to dissolve the crude product and the mixture is heated to 50°-60°. Then oxalic acid (10.36 g, 115 mmol) is added. The slurry that forms is stirred overnight at 20°-25° and is then cooled to 0° for 1 hr and the product is collected by vacuum filtration. The product is washed with ethyl acetate (100 ml) and dried at 40° in a vacuum oven to give the title compound as the oxalic salt, mp =144°-148°; TLC (methylene chloride/methanol/ammonium hydroxide, 90/10/1) Rf =0.17.

1. temperatureis maintained at about 23°
2. customto quench the reaction mixture
3. additionRaney nickel (40 g of water wet material) is added
4. customis preformed at 5°
5. waitAfter 17 hr
6. customThe reaction mixture is removed from the Buchi
7. washthe hydrogenator is rinsed with methanol (200 ml)
8. customThe combined reaction mixture and rinses
9. filtrationare filtered through a 5 g pad of solka floc
10. customto remove
11. washThe catalyst cake is then rinsed with methanol (200 ml)
12. concentrationThe combined filtrate and rinses are concentrated
13. additionWater is added to the concentrate
14. extractionThe product is extracted from the aqueous layer
15. extractionThe ethyl acetate extract
16. concentrationis concentrated
17. dissolutionto dissolve the crude product
18. temperaturethe mixture is heated to 50°-60°
19. stirringThe slurry that forms is stirred overnight at 20°-25°
20. temperatureis then cooled to 0° for 1 hr
21. filtrationthe product is collected by vacuum filtration
22. washThe product is washed with ethyl acetate (100 ml)
23. customdried at 40° in a vacuum oven