反应详情

Anhydrous zinc bromide (93.5 g, 415 mmol, 0.99 equiv.), sodium azide (29.8 g, 458 mmol, 1.1 equiv.) and water (750 ml) were added to 3,5-bis(trifluoromethyl)benzonitrile (100.0 g, 418 mmol, 1.00 equiv.). The resulting suspension was stirred for 10 days at ambient temperature. The completion of the reaction was confirmed by reversed phase HPLC on a Waters Novapak C18 column (3.9×150 mm) eluting with a linear gradient from 40% to 100% acetonitrile in 250 mM triethylammonium acetate buffer pH 6.5 in 15.00 minutes with a flow rate of 1.0 mL/min, detection at λ=270 nm, product retention time 2.0 min., educt retention time 6.5 min. Ethyl acetate (3.8 ltr.) and 10% citric acid in water were added and the resulting mixture was vigorously stirred for 15 minutes. The aqueous phase was separated and extracted with ethyl acetate (2×900 ml). The organic phases were combined and evaporated to dryness. The resulting solid was stirred in aqueous NaOH solution (0.25 M, 3.8 ltr.) for 30 minutes to give a suspension, which was filtered. The filtrate was acidified with aqueous HCl (375 ml conc. hydrochloric acid and 375 ml water) which caused the product to precipitate as a fine white powder. The product was collected by filtration after one hour, washed with cold hexanes (100 ml) and dried in a desiccator under vacuum, yield 72.7 g (62%) of compound (8) as white crystalline powder. The purified product had a purity of 100% by reversed phase HPLC as depicted in FIG. 4. 1H NMR (300 MHz, d6-DMSO) δ 8.26 (s, 1H), 8.59 (s, 1H), m.p. 179° C. The product can be recrystallized from toluene.

1. washeluting with a linear gradient from 40% to 100% acetonitrile in 250 mM triethylammonium acetate buffer pH 6.5 in 15.00 minutes with a flow rate of 1.0 mL/min, detection at λ=270 nm, product retention time 2.0 min.
2. additionEthyl acetate (3.8 ltr.) and 10% citric acid in water were added
3. stirringthe resulting mixture was vigorously stirred for 15 minutes
4. customThe aqueous phase was separated
5. extractionextracted with ethyl acetate (2×900 ml)
6. customevaporated to dryness
7. stirringThe resulting solid was stirred in aqueous NaOH solution (0.25 M, 3.8 ltr.) for 30 minutes
8. customto give a suspension, which
9. filtrationwas filtered
10. customto precipitate as a fine white powder
11. filtrationThe product was collected by filtration after one hour
12. washwashed with cold hexanes (100 ml)
13. dry with materialdried in a desiccator under vacuum, yield 72.7 g (62%) of compound (8) as white crystalline powder
14. customThe product can be recrystallized from toluene