反应详情

温度

-10 °C

To a cooled (-10° C.) and stirred suspension of the product from Step 2 (20 g, 72.0 mmol) in concentrated hydrochloric acid (100 ml) and water (10 ml) was added dropwise a solution of sodium nitrite (5.22 g, 75.6 mmol) in water (40 ml) at such a rate as to maintain the temperature below -5° C. (ca 20 minutes). After a further 10 minutes, the mixture was quickly filtered to remove solids and the filtrate was added portionwise to a cooled (-15° C.) and stirred solution of tin (II) chloride dihydrate (81.2 g, 360 mmol) in concentrated hydrochloric acid (60 ml) at such a rate as to maintain the temperature below -10° C. (ca 15 minutes). The mixture was allowed to warm to 0° C. and it was concentrated to 50% of the volume under vacuum. The remaining acid aqueous solution was basified with 10N potassium hydroxide (temperature maintained below 30° C.) and the resulting mixture was shaken with ethyl acetate (500 ml) and filtered through Hyflo supercel filter aid. The organic phase was decanted off and the basic aqueous solution was extracted with ethyl acetate (3×250 ml). The combined organic phases were washed with brine (1×100 ml), dried (Na2SO4) and concentrated. Crystallization of the remaining residue from ethyl acetate followed by flash chromatography purification of the mother liquors (silica gel, ethyl acetate-methanol, 98:2; and dichloromethane-methanol, 95:5) gave 6.5 g (35%) of the required title compound as a yellow solid; δH (250 MHz, DMSO-d6) 7.07 (2H, d, J=8.5 Hz, Ar--H), 6.74 (2H, d, J=8.5 Hz, Ar--H), 6.70 (1H, br s, --NH--), 3.94 (2H, s, Ar--CH2 --N), 3.91 (2H, br s, --NH2), 3.23--3.05 (4H, m, N--CH2CH2 --N), 2.60 (3H, s, --NMe); m/z (EI) 256 (M+).

1. temperatureto maintain the temperature below -5° C. (ca 20 minutes)
2. filtrationthe mixture was quickly filtered
3. customto remove solids
4. additionthe filtrate was added portionwise to
5. temperaturea cooled (-15° C.)
6. temperatureto maintain the temperature below -10° C. (ca 15 minutes)
7. temperatureto warm to 0° C.
8. concentrationit was concentrated to 50% of the volume under vacuum
9. customwas basified with 10N potassium hydroxide (temperature maintained below 30° C.)
10. stirringthe resulting mixture was shaken with ethyl acetate (500 ml)
11. filtrationfiltered through Hyflo supercel
12. filtrationfilter aid
13. customThe organic phase was decanted off
14. extractionthe basic aqueous solution was extracted with ethyl acetate (3×250 ml)
15. washThe combined organic phases were washed with brine (1×100 ml)
16. dry with materialdried (Na2SO4)
17. concentrationconcentrated
18. customCrystallization of the remaining residue from ethyl acetate
19. customfollowed by flash chromatography purification of the mother liquors (silica gel, ethyl acetate-methanol, 98:2; and dichloromethane-methanol, 95:5)