Patent GB-581230-A (GB)
Title: Manufacture of basic esters and amides of ª‡-substituted aryloxy acetic acids
IPC: C07D295/088
Filed: 1944-08-23
Abstract: Basic esters and amides of a -substituted aryloxy acetic acids of the formula <FORM:0581230/IV/1> where R1 is an aromatic residue, X an alkyl, cycloalkyl or aryl residue, Y hydrogen or alkyl, or X and Y form part of an alicyclic ring, and R2 is the residue of an N-disubstituted amino alcohol or alkylene diamine are manufactured as follows: convertible functional derivatives of the a -substituted aryloxy acetic acids such as their halides, esters or anhydrides, are reacted with N-disubstituted amino alcohols; reactive esters of the amino alcohols, such as hydrogen halide or aryl sulphonic esters, are reacted with the said acids or their salts; the acids are converted to their halogen alkyl esters and converted with secondary amines; the acids or their functional derivatives are converted with alkylene diamines containing a primary or secondary and a tertiary amino group; reactive esters of amino alcohols react with salts, particularly alkali salts of the corresponding carboxylic acid amides; halogen alkyl amides of the acids are reacted with secondary amines; compounds of the formula <FORM:0581230/IV/2> where Z is a reactive atom or exchangeable atom group, such as halogen, alkoxy, benzyloxy, sulphonic acid ester, are reacted with compounds R1OH or their salts.  The products have a spasmolytic, and often an analgesic action.  The neutral salts with acids are water-soluble.  In examples: (1) diethylaminoethanol is reacted with a -phenoxy-isovaleric acid chloride in ether to give the diethylaminoethanol ester of the acid.  Other aryloxy isovaleric acid chlorides may be used where R1 is <FORM:0581230/IV/3> (2) a -(m-chlorphenoxy)-isovaleric acid is reacted with b -diethylamine ethyl chloride in presence of acetic ester and potash to give the diethyl-aminoethanol ester.  Compounds can be obtained similarly, wherein R1 is methoxy-, ethoxy-, isopropoxy- or dimethyl-phenyl or <FORM:0581230/IV/4> ; (3) a -(o-cresoxy)-isovaleric acid chloride is added to glycol chlorhydrin in pyridine at below 0 DEG  C. to give the b -ethyl chloride ester which on heating with diethylamine yield a -(o-cresoxy)-isovaleric acid diethylaminoethanol ester; (4) b -ethyldiethylamine chloride is heated with a -(m-cresoxy)-cyclopentyl-sodium acetate to yield the diethylaminoethanol ester.  Compounds of the formula <FORM:0581230/IV/5> are made similarly, where R1 may be phenyl or o-tolyl, X ethyl, isopropyl, cyclohexyl or phenyl, and Y hydrogen or methyl, or X and Y both -CH2-CH2-, or -CH2-CH2-CH2-and -CH2-CH2- respectively; (5) a -(m-cresoxy)-isovaleric acid dimethylaminoethanol ester is made as in (1).  With other amino alcohols, compounds are obtained wherein R2 is <FORM:0581230/IV/6> , (6) a -phenoxy-valeric acid chloride with N.N-diethyl-ethylenediamine yields the compound <FORM:0581230/IV/7> The comcompounds <FORM:0581230/IV/8> (or C2H5)-CH2-CH2-N(C2H5)2\t are made similarly; (7) a -phenoxy-isovaleric acid amide is heated in toluene with sodium amide, and the product yields with b -diethylamine-ethyl chloride, <FORM:0581230/IV/9> ; (8) a -bromisovaleric acid-diethylaminoethanol ester is heated with potassium guaiacol to give the corresponding ester of a -(o-methoxyphenoxy)-isovaleric acid.  In place of the brom compound, the toluene sulphonic acid ester or the chlor, methoxy or benzyloxy compounds may be used.