反应详情

温度

2.5 °C

4-Cyanophenylhydrazine hydrochloride (26.24 kg) and the Amine Ketal hydrochloride (1 mol equiv. 38.57 kg) were charged to the reaction vessel (RV3; nominal capacity 250 L; working capacity ca300 L) followed by water (92 L) and conc. hydrochloric acid (65.6 L). The reaction mixture was stirred and heated to 80-90° for up to ca 5 h and monitored by proton NMR (see note below). When the reaction was deemed to be complete, the reaction mixture was cooled to 0-5° C. and aged for 1 hour at this temperature. The racemic Indole Nitrile Hydrochloride was filtered using a 27″ nutsche filter and washed thoroughly with water (3×26 L or until the washing is >pH5). The damp racemic Indole Nitrile Hydrochloride was then charged back into RV3, followed by water (164.5 L) and THF (66 L). The pH was adjusted to pH 13 with 6M NaOH (ca 30 L) and the reaction mixture stirred for 30 min. A sample was removed, the solid filtered off and checked by proton NMR (see note be low) to ensure the free base had been generated. The THF was then distilled off in vacuo at <40° C., the aqueous reaction mixture cooled to 0-5° C. and aged for a further 1 h. The solid was isolated by filtration using a 27″ nutsche filter, washed by displacement with water (2×33 L or until the washings are <pH9) and dried in vacuo at 55-60° C. to constant weight to give the racemic Indole Nitrile as an off-white solid (25.13 kg corrected for water content, 72.2% th, 65%w/w vs the Hydrazine hydrochloride input).

1. temperatureheated to 80-90° for up to ca 5 h
2. filtrationThe racemic Indole Nitrile Hydrochloride was filtered
3. filtrationfilter
4. washwashed thoroughly with water (3×26 L
5. additionThe damp racemic Indole Nitrile Hydrochloride was then charged back into RV3
6. stirringthe reaction mixture stirred for 30 min
7. customA sample was removed
8. filtrationthe solid filtered off
9. distillationThe THF was then distilled off in vacuo at <40° C.
10. temperaturethe aqueous reaction mixture cooled to 0-5° C.
11. customThe solid was isolated by filtration
12. filtrationfilter
13. washwashed by displacement with water (2×33 L
14. customdried in vacuo at 55-60° C. to constant weight