GB799030A - Improvements in or relating to process of preparing 1, 3-di-substituted pyrrolidine compounds and the compounds resulting therefrom - Google Patents

Abstract

The invention comprises 3-substituted pyrrolidine compounds having the formula: <FORM:0799030/IV (b)/1> and acid addition salts and quaternary ammonium salts thereof, wherein X is a hydroxyl group or a halogen atom, preferably chlorine, and wherein R is an alkyl, alkenyl, aryl or aralkyl radical, preferably methyl, ethyl, n-propyl, isopropyl, benzyl, phenyl, allyl or butyl. The N-substituted-3-pyrrolidyl-methyl alcohols may be prepared by reacting esters of itaconic acid with an organic amine RNH2 to form an intermediate N-substituted-3-carbalkoxy-5-pyrrolidinone by ring closure and reducing the latter with a strong reducing agent, such as lithium aluminium hydride, to produce the desired carbinol. Suitable amines are methylamine, ethylamine, n-propylamine, isopropylamine, allylamine, butylamine, aniline or benzylamine. The itaconic acid esters employed may be the dimethyl, diethyl, di-n-propyl, di-isopropyl, or dibutyl. The corre-sponding halides may be obtained by reacting the carbinols with a thionyl halide, e.g. thionyl, chloride, bromide or iodide, to produce the N-substituted-3-pyrrolidylmethyl halides. The carbinol or halides may be converted into acid addition salts by treatment with organic or inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulphuric, phosphoric, maleic, acetic, citric, succinic or tartaric acid. Suitable quaternary ammonium salts are formed by the addition to the basic compounds of alkyl or aralkyl esters of inorganic acids or organic sulphonic acids, such as methyl chloride, bromide or iodide, ethyl bromide, propyl chloride, benzyl chloride, benzyl bromide, methyl sulphate, methyl benzene sulphonate or methyl-p-toluene sulphonate. In an example, an anhydrous methanol solution of dimethyl itaconate is added with stirring to a solution of ethylamine in anhydrous methanol with cooling to maintain a temperature of 5 \sB 2 DEG C.; the mixture is then allowed to warm up to room temperature and after standing the solvent is removed and the residue fractionated; an ether solution of the 1-ethyl-3-carbomethoxy-5-pyrrolidinone so formed is added to an ether solution of lithium aluminium hydride at such a rate as to maintain moderate refluxing and then the refluxing is maintained for 2 hours; the 1-ethyl-3-pyrrolidylmethyl alcohol is recovered and may be treated in chloroform with hydrochloric acid gas and then with thionyl chloride while refluxing the mixture; 1-ethyl-3-pyrrolidylmethyl chloride is recovered from the reaction mixture. The N-substituted-3-pyrrolidylmethyl alcohols may be esterified with organic acids, such as benzilic acid to produce compounds having high antispasmodic activity as described in Specification 799,032. The halides may be reacted with an amine, such as phenothiazine, as described in Specification 799,031.