Patent GB-758313-A (GB)
Title: Manufacture of 4-aminochromanes
IPC: C07D311/68
Filed: 1954-11-12
Abstract: The invention comprises 4-aminochromanes of the formula: <FORM:0758313/IV(a)/1> (in which R1, R2, R4 and R5 each represent hydrogen or an alkyl group and may be the same or different, also R1 and R2 may together with the N atom form the residue of a heterocyclic ring, and R3 is an alkyl or a phenyl group) together with their salts, and a process for their preparation by converting the keto group of the corresponding 4-chromanone, if necessary or desired after intermediate conversion via the 4-chromanol into the group > CH Halogen, by treatment with an aminating agent into a 4-amino group, and if required converting said amino group with an N-alkylating agent into a substituted or further substituted 4-amino group.  The intermediate 4-chromanol may also be prepared by reduction of the corresponding chromone.  Direct amination of the chromanone is preferably effected by catalytic hydrogenation in the presence of ammonia or a primary or secondary amine, or by treatment with hydroxylamine and hydrogenation of the oxime produced, whilst amination of the 4-halo intermediate is effected with ammonia, or a primary or secondary amine.  In examples: (1) 8-phenyl-4-chromanone (prepared from o-hydroxydiphenyl and b -halogenpropionyl chloride) is hydrogenated in methanol over Raney nickel, and the resulting chromanol treated with thionyl chloride in chloroform yielding 8-phenyl-4-chlorochromane, which is then treated overnight with dimethylamine and 4-dimethylamino-8-phenylchromane isolated as its hydrochloride; 4-diethylamino 8-phenylchromane is similarly prepared; (2) 8-phenyl-4-chromanone is converted to its oxime and then hydrogenated over palladium charcoal yielding 8 - phenyl - 4 - aminochromane hydrochloride, which is alkylated with formaldehyde-formic acid to 8 - phenyl - 4 - dimethylaminochromane hydrochloride; (3) 8-phenyl-4-chlorochromane with ethylamine gives 4-ethylamino-8-phenylchromane characterized as its tartrate and hydrochloride; (4) 8-phenyl-4-chromanone in methanol is hydrogenated over Raney nickel in the presence of ethylamine giving 8-phenyl-4-ethylaminochromane hydrochloride; (5) 2,6,8-trimethyl-4-chromanone (prepared from 2,6,8-trimethyl-4-chromone by selective hydrogenation over Raney nickel), is hydrogenated over Raney nickel to the corresponding chromanol, which is treated (a) with thionyl chloride, and the resulting 4-chloro derivative reacted with dimethylamine to give 2,6,8-trimethyl-4-dimethylaminochromane hydrochloride; (b) with phosphorus tribromide, and the resulting 4-bromo derivative reacted with piperidine to give 2,6,8 - trimethyl - 4 - piperidinochromane, precipitated as its hydrochloride; (6) 8-phenyl-4-chromanol is treated with phosphorus tribromide, and the 4-bromo derivative treated (a) with pyrrolidine to give 8-phenyl-4-pyrrolidinochromane, precipitated as its hydrochloride, (b) with morpholine to give 8-phenyl-4-morpholinochromane as its hydrochloride.  Starting material.  2,6,8-trimethylchromone is prepared from 1,3,4-xylenol by acetylation with acetic acid and phosphorus oxychloride, Fries re-arrangement and treatment of the 2-hydroxy-3,5-dimethylacetophenone produced with ethyl acetate and sodium ethoxide and then ring-closure of the diketone with ethanolic HCl.