NO117866B - - Google Patents

Description

Process for the production of anesthetically effective amides of N-alkylpiperidine-monocarboxylic acid and N-alkylpyrrolidine-«-monocarboxylic acid.

The present invention relates to a

method for the production of amides

of N-alkylpiperidine monocarboxylic acid and

of N-alkylpyrrolidine-α-monocarboxylic acid,

which amides have the general formulas:

In these formulas R denotes an alkyl group with less than 10 carbon atoms, R 2 denotes a lower alkyl group or a chlorine atom, R 1 denotes a hydrogen atom, a hydroxyl group, a lower alkyl group or an alkoxy group and R 4 a hydrogen atom, a

chlorine atom, a lower alkyl group or a

alkoxy group. Alternatively, R2, R3 and

R4 can all be hydrogen in one and the same compound. The carboxylic acid amide group can

be attached to the piperidine ring in alpha-,

the beta or gamma position.

These amides have been shown to be very

good local anesthetics with toxicity that is very small compared to the activity of the compounds.

The main characteristic features of the method according to the invention are that one leaves an aniline magnesium halide with the general formula:

in which X denotes halogen and R 2 , R 3 and R 4 have the meanings given above, react with a pyridine monocarboxylic acid ester or with a piperidine monocarboxylic acid ester or a pyrrole α-monocarboxylic acid ester or a pyrrolidine α-monocarboxylic acid ester, which esters can be hydrogenated or not hydrogenated, alkylated or not alkylated at the nitrogen atom of the heterocyclic ring, after which the reaction product obtained is hydrolysed with an acid and in the case where the starting material is a pyridine monocarboxylic acid ester or a pyrrbl-α-monocarboxylic acid ester the heterocyclic ring is subjected to a hydrogenation with subsequent alkylation of the nitrogen in the heterocyclic ring, e.g. with a dialkyl sulfate or alkyl halide. The hydrogenation can be carried out with metallic sodium or preferably with ordinary hydrogenation catalysts.

In the following, it is described as an example

shows some embodiments of the invention.

Example 1:

Ethylmagnesium bromide is produced on

usual way by allowing 185 parts by weight of ethyl

bromide in 100 parts of anhydrous ether react with 37 parts of magnesium turnings. With vigorous stirring, 121 is then added

splits 2,6-dimethylaniline at a rate that depends on the violence of gas evolution

sameness. When gas development has ceased,

is added to the suspension of 2,6-dimethylaniline-magnesium bromide 85 parts of N-methyl-pipecolic acid ethyl ester. The mixture up-

is heated under reflux cooling for 2 hours with constant stirring, after which the

cooled. Diluted hydrochloric acid is added to ensure

to dissolve and hydrolyze the resulting

nende magnesium compounds. The pH value is set to 5.5, the aqueous phase separates

read and extracted with additional amounts of

there ether to remove the excess of dime-

tylaniline. After adding an excess of ammonia to the solution, the reaction product, N-methylpipecolic acid-2,6-dimethylanilide, is recovered by extraction with isoamyl alcohol. isoamyl alcohol

the solution is evaporated to dryness, the residue is dissolved in dilute hydrochloric acid, treated with charcoal and combined again with NaOH.

This gives N-methyl-pipecolic acid-2,6-dimethylanilide in crystalline form.

Example 2:

In a way similar to the one in the example

1 described, 2-ethylaniline-magnesium bromide is prepared from 121 parts by weight 2-

ethylaniline, and the 2-ethylaniline magnesium bromide is allowed to react with 78 parts of ni-pecotic acid ethyl ester. After applying the procedure described in example 1,

method one obtains nipecotic acid-2-ethylanilide.

10 parts of this anilide are dissolved in 16 parts of isopropyl alcohol and 5.3 parts of isopropyl bro-

mld, - and 5 parts of potassium carbo- are added

night The mixture is heated under reflux

continuous cooling for 12 hours while stirring, felt-

stirred and evaporated to dryness. One up-

dissolves the residue in dilute hydrochloric acid and precipitates again with alkali, whereby N-iso-propylnipecotic acid-2-ethylanilide is obtained in the form of the free base.

Example 3:

In a way similar to that in ex-

pel 1 described are prepared aniline magne-

sium bromide of 93 parts of aniline, and one lets

the amine magnesium bromide reacts with 75

shares isonicotinic acid ethyl ester. The magnesium compound thus formed is dissolved and hydrolysed in dilute hydrochloric acid, after which the solutions' pH value is adjusted to about

around 7 and the ether is separated. The back-

remaining aqueous solution is extracted twice with isoamyl alcohol, and dissolve

The extract together with the ether solution is evaporated to dryness. The residue subject to

water vapor distillation is carried out until it is be-

freed from aniline. The remaining iso-nicotinic acid anilide is dissolved in dilute salt

acid, treated with charcoal, precipitated again with alkali, after which the precipitate is filtered off and dried. 99 parts of isonicotinic acid anili-

it dissolves in 240 parts alcohol and 60 parts glacial acetic acid. 2.5 parts of platinum oxide are added to the solution, and the anilide is hydrated at a pressure of 2-5 atmospheres and a temperature

temperature of 50-80° C. When it no longer ab-

hydrogen is sorbed, the catalysis is filtered off

tower. 40 parts of NaOH are added to the filtrate

dissolved in water to a 40-50 percent solvent

ning, as well as 250 parts of ether. After cooling, the precipitated sodium acetate is filtered off, and the filtrate is evaporated to crystallization or to dryness. 10 parts of the residue from the evaporation (or the crystalline pro-

duct) is dissolved in 16 parts methanol. dissolve-

5 parts of potassium carbonate and 5.2 parts of dimethylsulphate are added to the mixture. It is heated there-

for 6 hours under reflux and stirring, after which the solution is filtered and evaporated to dryness. The residue is dissolved in dilute hydrochloric acid, treated with charcoal and combined again with alkali. In this way, crystalline N-methylisonipecotin is obtained

acid anilide.

Example 4:

In a way similar to that in ex-

pel 1 described, 2-chloro-6-methyl-aniline-magnesium bromide is prepared from 141.5 parts of 2-chloro-6-methylaniline. One then lets last-

said compound react with 100 parts of N-normal-butyl-pyrrolidine-α-carboxylic acid-

ester. Using it in Example 1 be-

written procedure gives N-nor-malt-butyl-pyrrolidine-α-carboxylic acid-2-chloro-6-methylanilide.

Claims (5)

1. Process for the production of anesthetically effective amides of N-alkylpiperidine-monocarboxylic acid and of N-alkylpyrrolidine-α-monocarboxylic acid, with the general formulas: where the carboxylic acid amide group is linked to the piperidine ring in the alpha, beta, or gamma position and in which R denotes an alkyl group with less than 10 carbon atoms, R2 a lower alkyl group or a chlorine atom, R3 a hydrogen atom, a lower alkyl group or an alkoxy group , R4 denotes a hydrogen atom, a chlorine atom, a lower alkyl group or an alkoxy group, or alternatively R2, R3 and R4 can all be hydrogen in one and the same compound, characterized by allowing an aniline magnesium halide with the general formula: in which X denotes halogen and R 2 , R 3 and R 4 have the above meanings react with a pyridine monocarboxylic acid ester or with a piperidine monocarboxylic acid ester or a pyrrole α-monocarboxylic acid ester or a pyrrolidine α-monocarboxylic acid ester, which may or may not be alkylated alkylated at the nitrogen atom in the heterocyclic ring, whereupon the reaction product obtained is hydrolyzed with an acid, and in cases where the starting material is a pyridine monocarboxylic acid ester or pyrrole-a-monocarboxylic acid ester, the heterocyclic ring undergoes a preferably catalytic hydrogenation with subsequent alkylation of the nitrogen in the heterocyclic ring. 2. Process according to claim 1, characterized in that 2,6-dimethylaniline-magnesium bromide is allowed to react with N-methylpipecolic acid ethyl ester which is hydrolysed with an acid, thereby obtaining N-methylpipecolic acid-2,6-dimethylanilide. 3. Process according to claim 1, characterized in that 2-ethyl magnesium bromide is allowed to react with nipecotic acid ethyl ester, the reaction product is hydrolysed with an acid, thereby obtaining nipecotic acid 2-ethyl ester, and then this compound is allowed to react with isopropyl bromide whereby N-isopropylnipecotic acid-2-ethylanilide is obtained. 4. Process according to claim 1, characterized in that aniline magnesium bromide is allowed to react with isonicotinic acid ethyl ester, the reaction product is hydrolyzed with an acid, whereby isonicotinic acid anilide is obtained, the heterocyclic ring in this anilide is hydrogenated and then the hydrogenated product is allowed to react with dimethyl sulfate, whereby N-methylisonipecotin acid anilide is obtained. 5. Process according to claim 1, characterized in that 2-chloro-6-methyl-aniline-magnesium bromide is allowed to react with N-normal-butylpyrrolidine-α-carboxylic acid ethyl ester, the reaction product is hydrolyzed with an acid, thereby obtaining N- normal-butyl-pyrrolidine-carbonic acid-2-chloro-methylanilide.