Patent GB-518989-A (GB)
Title: Manufacture of acylamino-morpholine compounds
IPC: C07D295/32
Filed: 1938-09-14
Abstract: 518,989. Acylamino-morpholine compounds. GEIGY AKT.-GES., J. R. Sept. 14, 1938, No. 26800. Convention date, June 11. [Class 2 (iii)] Acylamino-morpholine compounds of high surface activity are prepared by reacting a morpholine derivative containing attached to the nuclear nitrogen atom, either directly or through an alkylene, arylene, or aralkylene group, an amino-group having at least one reactive hydrogen atom, with a carboxylic acid containing at least 6 carbon atoms or a mixture of such acids or with the anhydride or a halide or ester of such an acid or mixture of acids. In a modification, a product obtained by the reaction of an aryl-morpholine with formaldehyde and a primary aromatic amine which is not capable of forming a.stable anhydro-compound with formaldehyde, or a sulphonic acid of such an amine, is acylated by reaction with an amide of a carboxylic acid containing at least 6 carbon atoms or of a mixture of such acids. The intermediate morpholine derivatives can be prepared by converting nitroso-morpholine to N-aminomorpholine or by condensing a hydrazine having a non-substituted amino-group, e.g., phenylhydrazine with #: #<1>-dichloroethyl ether to produce phenylaminomorpholine; or by condensing a diamine, e.g., ethylene, phenylene or naphthylene diamine with #:#<1>-dichloroethyl ether ; or by condensing a monoaminoarylcompound, e.g., aniline chloraniline, nitraniline or toluidine, with #:#<1>-dichloroethyl ether and introducing a nuclear amino-group, e.g., by nitrating or nitrosating or coupling with a diazo-compound and subsequently reducing or reductively cleaving ; or by reacting the arylmorpholine with formaldehyde and a primary aromatic amine or amino-aromatic sulphonic acid, which forms no stable anhydro-compound with formaldehyde, e.g., para-toluidine or sulphanilic acid, to produce a substituted paramorphinyl - benzyl - amine. The acylaminomorpholine compounds react with known alkylating or aralkylating agents, e.g., methyl, ethyl or benzyl chloride, methyl ethyl or allyl bromide, or dimethyl sulphate to form morpholinium salts. In examples : (1) N-meta-tolylmorpholine is nitrosated and reduced and the product is heated on the water-bath with stearic acid chloride ; the acylamino compound is treated with dimethyl sulphate or allyl bromide to form (3-methyl-4-stearoylamino-phenyl)- methylmorpholinium methosulphate or the corresponding allyl-morpholinium bromide ; (ii) N-para-tolylmorpholine is nitrated, reduced and then treated with the chloride of the mixture of the fatty acids from coconut oil ; the morpholium salt is prepared using methyl chloride ; (iii) meta-aminophenyl-morpholine (prepared by condensing #:#<1>-dichlorethyl ether and meta-nitraniline and reducing) is reacted with the chloride of commercial lauric acid and then heated with dimethyl or diethyl sulphate ; (iv) the product of reaction of #:#<1>-dichlorethyl ether and para-phenylenediamine is reacted with the chloride of fermentation caproic acid and converted into the quaternary salt by means of ethyl chloride ; (v) an aqueous alcoholic solution of phenyl-morpholine sulphanilate is mixed with formaldehyde to produce N-(4- morpholinyl-benzyl)-sulphanilic acid which is heated with stearic acid chloride and ammonia in an autoclave for hours, and the product is treated with dimethyl sulphate ; (vi) phenylaminomorpholine (prepared by condensing phenylhydrazine and #:#<1>-dichlorethyl ether) is acylated with lauric acid chloride, and the product is heated with dimethyl sulphate.