Patent GB-585994-A (GB)
Title: Manufacture of aminoalkyl ethers and of quaternary ammonium compounds formed therefrom
IPC: C07D295/088
Filed: 1943-09-22
Abstract: Aminoalkyl ethers of general formula <FORM:0585994/IV/1> wherein Ar represents an aromatic residue, Y represents a hydrocarbon radical and Z represents an N-disubstituted aminoalkyl residue, are obtained by etherifying an alcohol of general formula <FORM:0585994/IV/2> wherein Ar and Y are as above-defined, or a functional derivative thereof, with an N-disubstituted amino alcohol or its functional derivative.  Quaternary ammonium derivatives thereof may be obtained. The process is effected by treating (a) reactive esters of a -substituted benzyl alcohols with amino alcohols disubstituted at the nitrogen atom, in presence of hydrogen halide-binding agents; (b) metal compounds, particularly the alkali salts, of a -substituted benzyl alcohols with reactive esters of the foregoing amino-alcohols, preferably while heating and stirring in an inert medium, e.g. benzene; (c) corresponding esterified a -substituted benzyl hydroxyalkyl ethers, e.g. halogenalkyl ethers, with secondary or tertiary amines (the latter leading to the quarternary ammonium compounds, which are also obtained by adding reactive esters such as alkyl, aralkyl and alkinyl halides, e.g. allyl bromide; aryl sulphonic esters and dialkyl sulphates.  Halogenalkyl ethers of a -substituted benzyl alcohols are obtained by treating (a) reactive esters of such alcohols with alkylene halogen hydrins in presence of an acid-binding agent, or (b) a -substituted araliphatic alcohols with reactive esters of alkylene halogen hydrins.  The term "a -substituted benzyl alcohols" implies the secondary alcohols obtained by introducing aliphatic, araliphatic, hydroaromatic or aromatic substituents into the CH2- group of benzyl alcohol, e.g. (a) by catalytically reducing the corresponding aralkylketones, or (b) by reacting the corresponding aldehydes and suitable halides in a Grignard synthesis.  In examples: (1) pulverised sodamide in absolute benzene is heated at 60 DEG  C. with n-propyl-phenyl-carbinol, prior to heating under reflux with b -chlorethyl diethylamine, treating with water and 10 per cent hydrochloric acid, basifying with potassium carbonate and distilling the ethereal extract in vacuo. The product is also obtained by treating sodium in a mixture of benzene and diethylamino ethanol with a -n-propyl-benzyl chloride, heating under reflux and processing to isolate the corresponding base; similar products are obtained, using methyl-, ethyl-, isopropyl-, isopentyl- and allyl phenyl-carbinol; (2) a -isobutyl-benzyl-(chlorethyl) ether is heated with excess diethylamine at 100-120 DEG  C. in a sealed vessel to obtain a -isobutyl-benzyl-(diethylamino ethyl) - ether; (3) n - propyl - benzyl-(diethylamino ethyl)-ether and benzyl chloride are heated in chlorobenzene to obtain the corresponding quaternary salt, and a similar product is obtained, using ethyl iodide; (4) crude b -chloroethyl piperidine is heated with sodamide and n-propyl phenyl carbinol in absolute benzene, and the mixture is processed in the usual way to isolate the product; (5) g -chloropropyl diethylamine is heated with the sodium salt of isobutyl-phenyl-carbinol or sec.-butyl-phenyl-carbinol to isolate the corresponding bases; (6) b -chlorethyl diethylamine is heated at 90-100 DEG  C. with sodium and benzohydrol to yield the corresponding ether, which is neutralized to obtain its hydrochloride; the corresponding cyclohexyl-phenyl-, and cycloheptyl-phenyl ethers are described; (7) isobutyl-o-methyl-phenyl-carbinol or sec.-butyl-o-methyl-phenyl-carbinol is added to sodamide in benzene, followed by b -chlorethyl diethylamine and heating under reflux to isolate the corresponding ethers.  A table is appended, listing the physical properties of similar compounds according to the formula <FORM:0585994/IV/3> (8) n-propyl benzyl-carbinol, in benzene, is added to a suspension of sodamide in benzene, heating at 60 DEG  C. and treating with b -chlorethyl diethylamine with subsequent refluxing to obtain the corresponding product.  Analogously, phenyl-benzylcarbinyl-diethylaminoethyl ether is isolated. Further examples of products obtained by the processes of the invention are: styryl-benzyl- or chlorobenzyl-carbinyl-diethylaminoethyl ether, o- or p-tolyl benzyl carbinyldiethylamino or dimethylamino-ethyl ether and cyclohexyl- or cyclo - pentyl - benzylcarbinyl - diethyl- or dimethyl-amino ethyl ether.  Iso-butyl-o-methyl-phenyl-carbinol is obtained from o-toluyl aldehyde and isobutyl bromide, applying a Grignard synthesis.  The Specification as open to inspection under Sect. 91 comprises the manufacture of aminoalkyl ethers of the general formula <FORM:0585994/IV/4> (wherein X is the direct bond, or an organic residue which may contain hetero atoms; Y1 is hydrogen or as Y2, a hydrocarbon radical, and Ar and Z are as defined above), by etherifying an alcohol of the general formula <FORM:0585994/IV/5> (wherein Ar, X, Y1 and Y2 are as defined) in the manner set out above; it includes the following additional subject-matter: (1) producing a -isobutyl-benzyl-(chloro-ethyl)-ether, from (a) probutyl-phenyl-carbinol and ethylene dichloride, (b) glycol and a -isobutyl-benzyl chloride; (2) reacting sodamide, n-propyl-(phenylethenyl) - carbinol and b  - chlorethyl - diethylamine and hydrogenating the product to obtain n-propyl-(phenylethyl)-carbin ether; (3) reacting sodamide, n - propyl - (phenoxy - methyl)-carbinol and b -chlorethyldiethylamine; (4) reacting sodamide, a -phenyl-b -cyclohexylethylalcohol and b  - chlorethyldiethylamine.  This subject-matter does not appear in the Specification as accepted.