Patent GB-625811-A (GB)
Title: Improvements in or relating to basic alkyl esters and method of preparing the same
IPC: C07D333/24
Filed: 1945-12-31
Abstract: Basic alkyl esters of the general formula <FORM:0625811/IV (b)/1> wherein m is 0-2, x is 1-8, R represents a hydrocarbon radical, an a -thienyl radical or an a -thienylalkyl radical, the group Cxh2x is a straight or branched chain, Y represents hydrogen or a hydroxy group and Z represents <FORM:0625811/IV (b)/2> (wherein n is 1-8 and X represents oxygen, sulphur, a methylene group or an imino group), are manufactured, in the form of their hydrohalides, by reacting a thienyl substituted fatty acid with a basic aliphatic halide, or (when Y is hydrogen) by reacting a thienyl substituted fatty acid halide with an aminoalkanol, the reaction in either case being advantageously effected by refluxing substantially equimolecular proportions of the reactants in an anhydrous solvent.  The free basic esters are obtained by treating the hydrohalides, preferably at low temperatures, with excess of a mild alkali, and may be converted by known methods into salts other than hydrohalides, e.g. into quaternary ammonium salts by treatment with an alkyl halide.  The products may be used for pharmaceutical purposes, especially as antispasmodics.  In examples: (1) phenyl-(a -thienyl)-hydroxyacetic acid is refluxed with y-diethylaminopropyl chloride in isopropyl alcohol to produce y-diethylaminopropyl phenyl - (a 1 - thienyl) - hydroxyacetate hydrochloride; (2) phenyl-(a -thienyl)-acetic acid is similarly treated; (3) (p-xenyl)-(a -thienyl)-acetic acid is refluxed with thionyl chloride and the resulting acid chloride is refluxed with b -diethylaminoethanol in benzene, yielding b -diethylaminoethyl (p-xenyl)-(a 1-thienyl)-acetate hydrochloride; (4) the b -diethylaminoethanol in (3) is replaced by b -morpholinoethanol; (5) the products of (1) to (4) are treated with sodium carbonate solution and the resulting free basic esters are treated in alcohol with methyl bromide to form their methobromides.  Tables give the properties of the hydrohalides and methobromides of further esters of the general formula above in which m is zero and R is methyl, cyclohexyl, phenyl, a -naphthyl, p-xenyl, benzyl or a -thienyl, and it is stated that R may also be ethyl, n- or isopropyl, n-, iso- or tert.-butyl, n-amyl, n-hexyl, n-heptyl, n-octyl, p-tolyl, chlorophenyl, phenylethyl, tolylmethyl, phenylpropyl, alkylnaphthyl, cyclopentyl, cycloheptyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl or thienylbutyl.  Samples have been furnished under Sect. 2 (5) of hydrohalides of the general formula above in which m is 1, the basic alkyl group is b -diethylaminoethyl, Y is hydrogen and R is b -(2-thienyl)-ethyl, benzyl, b -phenylethyl, a -thienyl, a -thienylmethyl, phenyl, cyclohexyl, cyclohexylmethyl, b -cyclohexylethyl and n-propyl.  A further sample was prepared by stirring b -methylaminoethanol with 2-thienylmethylbenzylacetyl chloride in aqueous caustic soda and ether to form N-methyl-N-(b -hydroxyethyl)-2-thienylmethylbenzylacetamide and heating this with aqueous alcoholic hydrochloric acid to give b -methylaminoethyl-2-thienylmethylbenzylacetate hydrochloride. Thienyl substituted fatty acids.-Starting materials for the production of esters of the general formula given above in which m is zero, are obtained by condensing ethyl oxalyl chloride in the presence of aluminium chloride with thiophene or with an aromatic substance suitable as a component in the Friedel-Crafts reaction, hydrolysing the resulting substituted glyoxylic ester, treating the free acid with a Grignard reagent, which must contain a thienyl radical if thiophene is not used in the initial condensation (e.g. a -thienyl magnesium bromide, methyl magnesium iodide or cyclohexyl, benzyl, phenyl, p-xenyl or a -naphthyl magnesium bromide), decomposing the resulting complex with an acidic reagent (e.g. hydrochloric acid, ammonium chloride or sodium bisulphate), and if desired, reducing the resulting hydroxy-acid to the corresponding hydroxyl-free acid (e.g. with stannous chloride).  When m is 1, the starting materials are obtainable by first preparing a monosubstituted malonic ester by interaction of the required ethyl arylacetate, diethyl carbonate and sodium ethoxide, or by the malonic ester synthesis, converting the product into a disubstituted malonic ester, and hydrolysing and decarboxylating the latter.  The Specification as open to inspection under Sect. 91 comprises also the manufacture of other esters of the general formula given above in which m may be any integer up to 7, R may additionally represent hydrogen and Y halogen, alkoxy, amino or substituted amino. Reference is also made to the use of other halides of alkyl esters of aliphatic dicarboxylic acids, e.g. ethyl succinyl chloride, in place of ethyl oxalyl chloride in the preparation of the starting materials.  This subject-matter does not appear in the Specification as accepted.