Patent GB-797740-A (GB)
Title: Novel ethers and derivatives and the manufacture of same
IPC: C07C39/215
Filed: 1956-02-08
Abstract: The invention comprises ethers of the general formula <FORM:0797740/IV (b)/1> (wherein R represents a methylene, ethylene or ethenylene group which may contain an alkyl substituent which does not bring the total number of carbon atoms in R to more than 4, R1 represents hydrogen or (except when R is ethenylene or alkyl-substituted ethenylene) a phenyl group or an alkyl group of 2-6 carbon atoms and R3 and R4 each represent an alkyl group of 1-6 carbon atoms) and their acid addition and quaternary salts, and the preparation thereof by the following processes: (a) (when R1 is phenyl or alkyl) treating a ketone of the general formula <FORM:0797740/IV (b)/2> (wherein R is a methylene, ethylene or alkylsubstituted methylene or ethylene group) with a phenyl or alkyl organo-metallic compound (e.g. phenyl-lithium or an alkyl-lithium) followed by hydrolysis to a tertiary carbinol, dehydrating this (e.g. by the action of hot acetic anhydride), catalytically hydrogenating a salt of the resulting olefinic compound and, if desired, converting the resulting salt of the saturated compound into the base by treatment with alkali, and, if further desired, quaternizing the base by the action of a quaternizing agent; (b) (when R1 is hydrogen) reducing a ketone of formula (II) (wherein R may have any of the meanings given for it in formula (I)) by the Huang-Minlon modification of the Wolff-Kishner reaction (e.g. by heating it in di- or tri-ethylene glycol with 85 per cent hydrazine hydrate in the presence of sodium or potassium hydroxide, distilling off the water formed and excess hydrazine hydrate and then refluxing at about 200 DEG  C. for several hours), followed, if desired, by conversion of the product to a salt by treatment with an acid or a quaternizing agent.  The products are useful as antifungal and antiprotozoal agents.  Example (1) describes the preparation by method (a) of compounds in which R is -CH2CH2-, -CH(C2H5)-CH2-, -CH2-CH(CH3)-or -CH2-, R1 is CH3, C2H5, n-C3H7, n-C4H9 or C6H5, R2 is -CH2CH2- or -CH2CH2CH2-and R3 and R4 are each CH3 or C2H5.  The citrates of the final products and olefinic intermediates and of all but one of the intermediate carbinols, and the ethiodides of some of the final products are described.  Example (2) describes the preparation by method (b) of compounds in which R is -CH(CH3)-CH2-, -CH(C2H5)-CH2-, -CH2-CH(CH3)-, -CH2CH2-, -CH2- or -CH=CH-, R1 is H, R2 is -CH2CH2- or -CH2CH2CH2- and R3 and R4 are each CH3 or C2H5, citrates and some ethiodides being again described.  Additional salt-forming agents specified are hydrochloric, hydrobromic, hydriodic, sulphuric, phosphoric, oxalic, acetic, lactic, tartaric, and benzenesulphonic acids, methyl bromide, butyl chloride, dimethyl sulphate and benzyl bromide.  Starting materials.  Ketones of formula (II) are prepared as follows: (i) an alkali metal derivative of p-hydroxyphenyl styryl ketone, or a derivative thereof having an alkyl substituent in the aliphatic portion of the molecule, is condensed with a dialkylaminoalkyl halide of the formula <FORM:0797740/IV (b)/3> (wherein X represents a halogen atom) to give the compounds in which R is ethenylene or alkylsubstituted ethenylene; (ii) the products of (i) are catalytically hydrogenated to give compounds in which R is ethylene or alkyl-substituted ethylene; (iii) an alkyl substituent may be introduced in a -position to the keto group in the saturated ketones by metallating it with sodium amide and treating the sodio compound with an alkyl halide; (iv) an alkyl substituent may be introduced in b -position to the keto group by treating an a  : b -unsaturated ketone with an alkyl magnesium halide.  Details are given of the preparation of p-(g -diethylaminopropoxy)-phenyl b -phenylethyl ketone and p - (b -dimethylaminoethoxy) -phenyl b phenylethyl ketone (the citrates of which are described) by method (ii), of 1-p-(b - diethylaminoethoxy) - phenyl - 2 - methyl - 3 - phenylpropanone-1 by method (iii), and of p-(b -diethylaminoethoxy)-phenyl b -phenylbutyl ketone and p-(b -diethylaminoethoxy)-phenyl b -phenylpropyl ketone (citrates described) by method (iv).  p-(g -Diethylaminopropoxy)-phenyl benzyl ketone (citrate described) is prepared by heating p-hydroxyphenyl benzyl ketone with sodium methoxide in chlorobenzene and refluxing the resulting solution with g -diethylaminopropyl chloride.