Patent GB-715755-A (GB)
Title: Manufacture of new diketopiperidines
IPC: C07D211/88
Filed: 1951-07-06
Abstract: The invention comprises 2 : 6-dioxopiperidines of the general formula <FORM:0715755/IV (b)/1> (wherein R represents an unsaturated cyclic residue, which may contain substituents, e.g. alkyl, hydroxy or substituted hydroxy groups or halogen atoms, R1 represents an aminoalkyl residue, the amino group of which is tertiary, e.g. dialkylamino or alkyleneimino, and R2 represents hydrogen or an alkyl residue of 1-4 carbon atoms), and their salts and quaternary compounds, and the preparation thereof from 2-R,R1-disubstituted pentane-1 : 5-diacids or their functional derivatives by the following methods: (a) reaction of the acids or their functional derivatives, e.g. halides, with ammonia or amines; (b) intramolecular acylation, by the action of condensing agents, of the monoamides of the acids, which may be formed in situ, e.g. from the mono- or di-nitriles or nitrile esters; (c) heating the diamides or diammonium salts of the acids. The products, which are pharmacologically useful, are obtained as free bases, salts or quaternary compounds.  The free bases may be converted into salts (e.g. with hydrohalic acids, sulphuric, nitric, phosphoric, acetic, propionic, oxalic, malic, citric, methane-, ethane-, hydroxyethane- or p-toluene-sulphonic, benzoic, salicylic or p-aminosalicylic acid), or quaternated, e.g. by reaction with reactive esters (e.g. halides, sulphates or sulphonates) of alcohols (especially alkanols containing 1-4 carbon atoms in the molecule).  In examples (1) the potassium salt of 2-phenyl-2-(b -diethylaminoethyl) - pentane - 1 : 5 - diacid 1 - mononitrile is heated with glacial acetic acid, acetic anhydride and concentrated sulphuric acid to produce 3 - phenyl - 3 - (b  - diethylaminoethyl)-2 : 6 - dioxopiperidine, which may be converted into its hydrochloride or methiodide; the base may also be prepared by refluxing the free acid mononitrile with acetic anhydride or heating it with acetic anhydride, acetic acid and stannic chloride; (2) the corresponding b -dimethylaminoethyl compound and its hydrochloride are prepared as in the first part of (1); (3) 2 - phenyl - 2 - (g  - piperidinopropyl) - pentane - 1 : 5 - diacid 1 - mononitrile similarly yields 3 - phenyl - 3 - (g  - piperidinopropyl)-2 : 6 - dioxopiperidine; (4) the potassium salt of 2 - (p - chlorophenyl) - 2 - (b  - dimethylaminoethyl) - pentane - 1 : 5 - diacid 1 - mononitrile is heated with acetic anhydride and concentrated sulphuric acid to give 3-(p-chlorophenyl)-3-(b -dimethylaminoethyl) - 2 : 6 - dioxopiperidine; (5) the hydrochloride of 2-phenyl-2-(b -methyl-b -dimethylaminoethyl) - pentane - 1 : 5 - diacid 1-mononitrile similarly yields 3-phenyl-3-(b -methyl - b  - dimethylaminoethyl) - 2 : 6 - dioxopiperidine, which may be converted to its hydrochloride; 1-alkyl derivatives of the base are obtainable by reacting the diacid anhydride with primary amines, e.g. methylamine; (6) the potassium salt of 2-(m-methoxyphenyl)-2-(b  - diethylaminoethyl) - pentane - 1 : 5 - diacid 1-mononitrile is treated as in (4) to form 3-(m-methoxyphenyl) - 3 - (b  - diethylaminoethyl)-2 : 6 - dioxopiperidine, which may be converted into its hydrochloride; (7) the corresponding b -dimethylaminoethyl compounds are similarly prepared, except that concentrated sulphuric acid is used alone; (8) 2-phenyl-2-(g -diethylaminopropyl) - pentane - 1 : 5 - diacid dinitrile is heated with glacial acetic acid and concentrated sulphuric acid to produce 3-phenyl-3-(g -diethylaminopropyl) - 2 : 6 - dioxopiperidine, which may be converted to its hydrochloride; (9) the corresponding b -(N-methyl-N-cycloheptylamino)-ethyl compound is prepared similarly, or by hydrolysing the 5-nitrile group by boiling with concentrated hydrochloric acid in glacial acetic acid and refluxing the resulting 1-mononitrile with acetic anhydride; (10) 2-(21-thienyl) - 2 - (b  - diethylaminoethyl) - pentane-1 : 5-diacid dinitrile is treated as in the second part of (9) to give 3-(21-thienyl)-3-(b -diethylaminoethyl) - 2 : 6 - dioxopiperidine, which may be converted to its hydrochloride; (11) the hydrochloride of the anhydride of 2-phenyl-2-(b  - diethylaminoethyl) - pentane - 1 : 5 - diacid is heated with methylamine in toluene to form 1 - methyl - 3 - phenyl - 3 - (b  - diethylaminoethyl) - 2 : 6 - dioxopiperidine; (12) 2 - (31-pyridyl) - 2 - (b  - dimethylaminoethyl) - pentane-1 : 5-diacid dinitrile is treated as in the second part of (9); (13) the potassium salt of 2-(p-chlorophenyl) - 2 - (b  - diethylaminoethyl) - pentane - 1 : 5 - diacid 1 - mononitrile is treated as in (7); (14) 2-(11-naphthyl)-2-(b -diethylaminoethyl) - pentane - 1 : 5 - diacid dinitrile is refluxed with concentrated hydrochloric acid and glacial acetic acid to yield 3-(11-naphthyl)-3-(b -diethylaminoethyl) - 2 : 6 - dioxopiperidine, which may be converted into its hydrochloride.  2 - Phenyl - 2 - (b  - diethyl - and - dimethylaminoethyl) - pentane - 1 : 5 - diacid 1 - mononitriles are prepared, in the form of their potassium salts, by hydrolysis, with methanolic caustic potash, of the corresponding ester nitriles obtained by condensing phenyl-(b -diethyl - or - dimethyl - aminoethyl) - acetonitrile with methyl acrylate.  The free acid mononitrile of the diethylamino compound is also obtainable by using acrylonitrile instead of methyl acrylate and refluxing the resulting dinitrile with acetic anhydride and concentrated acetic acid.  2 - Phenyl - 2 - (g  - piperidinopropyl) - and 2-p - chlorophenyl - 2 - (b  - dimethylaminoethyl)-pentane - 1 : 5 - diacid 1 - mononitriles are prepared by hydrolysis of the corresponding ester nitriles obtained by condensing phenyl-(g -piperdinopropyl) - or (p - chlorophenyl) - (b -dimethylaminoethyl)-acetonitrile with methyl acrylate.  2 - Phenyl - 2 - (b  - methyl - b  - dimethylaminoethyl) - pentane - 1 : 5 - diacid 1 - mononitrile is prepared by hydrolysis of the dinitrile obtained by condensing phenyl-(b -methyl-b -dimethylaminoethyl)-acetonitrile with acrylonitrile.  The potassium salts of 2-(m-methoxyphenyl)-2-(b  - diethyl - and - dimethyl - aminoethyl) - pentane - 1 : 5 - diacid 1 - mononitriles are prepared by hydrolysis, with methanolic caustic potash, of the corresponding ester nitriles obtained by condensing m-methoxyphenyl-(a -diethyl- or -dimethyl-aminoethyl)-acetonitrile with methyl acrylate.  2 - Phenyl - 2 - (g  - diethylaminopropyl) -, 2-phenyl - 2 - (b  - N - methyl - N - cycloheptylaminoethyl) -, 2 - (21 - thienyl) - 2 - (b  - diethylaminoethyl) -, 2 - (31 - pyridyl) - 2 - (b  - dimethylaminoethyl)- and 2 - (11 - naphthyl) - 2 - (b  - diethylaminoethyl) - pentane - 1 : 5 - diacid dinitriles are prepared by condensing the correspondingly disubstituted acetonitriles with acrylonitrile.  The potassium salt of 2 - (p - chlorophenyl)-2 - (b - diethylaminoethyl) - pentane - 1 : 5 - diacid 1 - mononitrile is prepared by hydrolysis, with methanolic caustic potash, of the corresponding ester nitrile obtained by condensing (p - chlorophenyl) - (b  - diethylaminoethyl)-acetonitrile with methyl acrylate.  m - Methoxyphenyl - (b  - diethyl - and - dimethyl-aminoethyl)-acetonitrile are obtainable by condensing m-methoxybenzyl cyanide in the presence of sodamide with b -chlorethyl-diethyl- or -dimethyl-amine.  Phenyl - (g  - diethylaminopropyl) - and - (b -N - methyl - N - cycloheptylaminoethyl) - acetonitrile are obtainable similarly from benzyl cyanide and g -chloropropyldiethylamine or N-b -chlorethyl-N-methyl-N-cycloheptylamine.  2 - Thienyl -, p - chlorophenyl - and 1-naphthyl - (b  - diethylaminoethyl) - acetonitrile are obtainable similarly from 2-thienylacetonitrile, p-chlorobenzyl cyanide or 1-naphthylacetonitrile and b -chlorethyldiethylamine.  3 - Pyridyl - (b  - dimethylaminoethyl) - acetonitrile is obtainable similarly from 3-pyridylacetonitrile and b -chlorethyldimethylamine.  The hydrochloride of the anhydride of 2-phenyl-2 - (b  - diethylaminoethyl) - pentane - 1 : 5 - diacid is prepared by hydrolysing phenyl-(b -diethylaminoethyl)-acetonitrile with concentrated sulphuric acid to the corresponding amide, converting this to the corresponding methyl ester by refluxing with methanol while passing dry hydrogen chloride, condensing the product with acrylonitrile to form 2-phenyl-2-(b -diethylaminoethyl) - pentane - 1 : 5 - diacid 1 - methyl ester 5-nitrile, hydrolysing this with concentrated hydrochloric acid in glacial acetic acid to the hydrochloride of the diacid, and refluxing this with acetyl chloride.