Patent GB-565573-A (GB)
Title: Manufacture of dioxane derivatives
IPC: C07D319/20
Filed: 1943-01-04
Abstract: 2-Hydroxymethyl arylene-dioxanes, substituted in the aromatic nucleus are manufactured by reacting epihalogen hydrin with p  alkaline solutions of ortho dihydric phenols containing at least one of the following nuclear substituents or a condensed ring; alkyl, alkoxy, carboxy, carbalkoxy, aminoalkyl and alkylamino. The 2-hydroxy group may be replaced by halogen which can be exchanged for an amino or other group, or other, e.g. acylated, derivatives may be produced. In examples: (1) o-methyl catechol in potash is mixed with epichlorhydrin to form 2 - hydroxymethyl - 5 - methyl - benzodioxane. Reaction with thionyl chloride gives the 2-chlormethyl compound which is heated with morpholine under pressure to produce 2-morpholinylmethyl - 5 - methyl - benzodioxane.  The starting product is made by reduction of o-vanillin to o-methyl guaiacol and dimethylation with HBr or HCl in presence of a tertiary base. Vanillin similarly yields 1-methyl-3,4-dihydroxy-benzene which can be used for preparing an isomeric methyl-hydroxymethylbenzodioxane; (2) 1 - propyl - 3,4 - dihydroxy - benzene, made by catalytic hydrogenation of isoeugenol and demethylation, similarly yields 2-hydroxymethyl-6-propyl-benzodioxane which is converted to the chlorine and then to the morpholine derivative; (3) o-vanillin with dilute hydrogen peroxide gives pyrogallol-1-methyl ether which yields, by reaction with epichlorhydrin, 2-hydroxymethyl - 5 - methoxy-benzodioxane which can be converted to the chlormethyl and thence to the morpholine derivative.  Other alkoxy benzodioxanes are obtained from the corresponding pyrogallol derivatives, e.g. the 1-ethyl ether; (4) 2-chlormethyl - 5 - methoxy - benzodioxane obtained as in (3) is heated with diethylamine to give the 2-diethylamino-methyl derivative. Piperidine, tetrahydroquinoline or isoquinoline give the corresponding 2-aminomethyl derivatives; (5) the same intermediate is heated with n-butylamine to give the 2-butylaminomethyl derivative.  Homologues of butylamine up to stearylamine react similarly; (6) the product of (5) in benzene is treated with calcined sodium carbonate and dimethyl sulphate to produce the tertiary base.  Diethyl sulphate yields the corresponding ethylbutylamino compound; (7) 2,3-dihydroxy-naphthalene in caustic potash is treated with epichlorhydrin to give 2-hydroxymethyl-naphthodioxane which with thionyl chloride forms the 2-chlormethyl compound, yielding the 2-morpholinylmethyl derivative with morpholine.  Other o-dihydroxynaphthalenes, dihydroxyanthracenes and their derivatives such as dihydroxyanthraquinones react similarly; (8) 2-hydroxymethyl-naphthodioxane is hydrogenated in the presence of Raney nickel to give the tetrahydronaphthodioxane derivative which is converted to the 2-chlormethyl and thence to the 2-morpholinylmethyl compound; (9) 2-morpholinyl-methyl-5-methoxy-benzodioxane produced as in (3) is refluxed with hydrobromic acid with demethylation to the 5-hydroxy compound.  The same compound can be made from pyrogallol and epichlorhydrin and exchange of the hydroxyl in the 2-hydroxymethyl group for chlorine and then for morpholinyl; (10) morpholine is treated with formaldehyde solution to form hydroxymethyl-morpholine which reacts with catechol to give morpholinylmethyl-dihydroxybenzene.  Epichlorhydrin with this yields 2-hydroxymethyl - ar - morpholinylmethyl - benzodioxane; (11) 2-morpholinylmethyl-5-hydroxybenzodioxane produced as in (9) is heated with acetic anhydride to give the 5-acetoxy derivative.