Patent GB-729453-A (GB)
Title: Manufacture of tetra-hydropyridine compounds and their salts and quaternary compounds
Filed: 1952-04-24
Abstract: The invention comprises tetrahydropyridine compounds of the formula <FORM:0729453/IV (b)/1> in which X represents oxygen or sulphur, R represents an aryl, alkyl or tertiary aminoalkyl group and R1 represents a hydrogen atom or an alkyl group, and salts and quaternary derivatives of such compounds when they contain a tertiary aminoalkyl group.  R may represent a methyl or ethyl group, or a dialkylaminoalkyl or alkylene-iminoalkyl group such as a piperidino- or morpholino-alkyl group, and R1 may represent, e.g., a methyl, ethyl or propyl group.  The compounds may be obtained by converting D 3 - 2 - aryl - pentene - 1 : 5 - diacids also containing in the 2-position an alkyl, aryl or tertiary aminoalkyl residue or a functional derivative of such acid, into their cyclic imides, e.g. the pentene diacids or functional derivative thereof such as anhydrides may be reacted with ammonia or mono-alkylamines; alternatively the conversion may be effected by treating the pentene-diacid mononitriles with a condensing agent such as concentrated sulphuric acid, acetic anhydride, tin tetrachloride, titanium tetrachloride, boron trifluoride etherates, zinc chloride, aluminium chloride or mixtures thereof.  A further method is to heat the pentene-diacid diamides or diammonium salts.  Another method consists in forming a double bond in a compound of the formula <FORM:0729453/IV (b)/2> in which of the two residues Y1 and Y2 one represents hydrogen and the other a substituent capable of being split off together with hydrogen, e.g. hydroxy or acyloxy, with the formation of a double bond.  Where R1 in the products represents hydrogen, it may be replaced by an alkyl group, e.g. by reaction with diazo-alkanes or with reactive esters of alkanols such as those of hydrohalic acids or organic sulphonic acids, preferably in the presence of a condensing agent capable of forming metal compounds with the dioxo-tetrahydropyridines. p  Compounds of the first formula in which X stands for sulphur are obtained by reacting the appropriate 2 : 6 - dioxo - 1 : 2 : 3 : 6-tetrahydropyridine with an agent capable of replacing oxygen by sulphur, e.g. phosphorus pentasulphide.  From the products with a tertiary aminoalkyl group salts with, e.g., hydrohalic, sulphuric, phosphoric, acetic, oxalic, citric, methane sulphonic, benzoic, p-aminosalicylic and toluene sulphonic acids may be prepared. Quaternary derivatives may be prepared with the esters of alcohols with, e.g., hydrohalic, sulphuric or organic sulphonic acids.  In examples: (1) 3 : 3-diphenyl-2 : 6-dioxo-1 : 2 : 3 : 6-tetrahydropyridine is prepared by heating 2 : 2-diphenylpentene-1 : 5-diacid-1-mononitrile with acetic and sulphuric acids; (2) 2 - ethyl - 2 - phenyl - pentene - 1 : 5 - diacid - 1-mononitrile heated with sulphuric and acetic acid gives 3 - ethyl - 3 - phenyl - 2 : 6 - dioxo - 1 : 2 : 3 : 6 - tetrahydropyridine which on treatment with methyl iodide in the presence of sodamide gives the corresponding 1-methyl-derivative; (3) 3 - (b  - diethylaminoethyl) - 3 - phenyl - 2 : 6 - dioxo - 1 : 2 : 3 : 6 - tetrahydro - pyridine is prepared similarly and converted to its hydrochloride; (4) 3 - ethyl - 3 - phenyl - 2 - oxo - 6 - thioketo - 1 : 2 : 3 : 6 - tetrahydro pyridine is prepared by heating the 1 : 6-diketo-derivative with phosphorus pentasulphide; (5) 3 - ethyl - 3 - phenyl - 2 : 6 - dioxo - 1 : 2 : 3 : 6-tetrahydro-piperidine is prepared by heating 2 : 6 - dioxo - 3 - ethyl - 3 - phenyl - bromopiperidine with collidine.  2 : 2 - Diphenylpentene - 1 : 5 - diacid - 1 - mononitrile is prepared by reacting diphenyl-acetonitrile and propiolic acid ethyl ester in the presence of trimethyl - benzyl - ammonium hydroxide and hydrolysing the 2 : 2-diphenyl-1 : 5-pentene-diane-5-monoethyl ester-1-nitrile obtained.  Other starting materials are obtained similarly using a -ethyl-benzyl cyanide and a  - (diethylaminoethyl) - benzyl cyanide in place of diphenyl acetonitrile.  2 : 6 - Dioxo - 3 - ethyl - 3 - phenylbromopiperidine is obtained by bromination of 2 : 6-dioxo-3-ethyl-3-phenyl-piperidine.