SE191321C1

SE191321C1 -

Info

Publication number: SE191321C1
Authority: SE
Publication date: 1964-01-01

Description

Uppfinnare: B T at Ekenstam, B P H Egner och B G Pettersson Fareliggande uppf inning avser ett Ott att framstalla hydrerade N-alkyl-alkyl-piperidinmonokarbonsyraamider och N-alkyl-alkyl-pyrrolidinmonokarbonsyraamider enligt formlerna: R, /\ R H --C—NH—Ar \N/ R, 0 3\I 11 R H I—C—NH—Ar \N/ I ovannamnda formler betecknar R1 en alkylgrupp. R2 och R, kunna antingen var och en utgoras av en alkylgrupp med max. 2 kolatomer eller ocksa utgores den ena av dem av en alkylgrupp med max. 2 kolatomer och den andra av en vateatom. Substituenterna R, och R, kunna arrangeras pa ett godtyckligt satt i forhallande till kvaveringens kolatomer. Detta kan ske genom lampligt val av utgangsprodukter. I formlerna är Ar en osubstituerad eller substituerad bensolkarna. Namnda bensolkarna kan vara substituerad med en alkylgrupp eller en kloratom i 2-stallning, i 4-staining med en alkylgrupp eller en alkoxygrupp och i 6-staining med en kloratom, en alkylgrupp eller en alkoxygrupp. Alkyl- och alkoxigrupperna har max. 2 kolatomer. Inventors: BT at Ekenstam, BPH Egner and BG Pettersson The present invention relates to a process for producing hydrogenated N-alkyl-alkyl-piperidine monocarboxylic acid amides and N-alkyl-alkyl-pyrrolidine monocarboxylic acid amides according to the formulas: R, / \ RH --C — NH — Ar R 11 represents the above formulas: R 1 represents an alkyl group. R 2 and R 3 can either each consist of an alkyl group with max. 2 carbon atoms or also one of them consists of an alkyl group with max. 2 carbon atoms and the other of a hydrogen atom. The substituents R 1 and R 2 can be arranged in any manner relative to the carbon atoms of the suffocation. This can be done through appropriate selection of starting products. In the formulas, Ar is an unsubstituted or substituted benzole. The benzole nuclei may be substituted by an alkyl group or a chlorine atom in 2-position, in 4-staining with an alkyl group or an alkoxy group and in 6-staining with a chlorine atom, an alkyl group or an alkoxy group. The alkyl and alkoxy groups have max. 2 carbon atoms.

Ovannamnda amider har visat sig vara synnerligen goda lokalbedovningsmedel och dt speciellt for ytanestesi. Ingaende forst& liar gjorts med fiireningen N-ety1-5-etyl-piperidin-2-karbonsyra2,6-xylidid. Preparatet som kan steriliseras vid 130° C utan att sonderfalla har vidare den fordelen att vara vavnadsvanligt och har stor stabilitet. LD-vardet är vid injektion a mus 7 milligram. The above-mentioned amides have been found to be extremely good local anesthetics and especially for surface anesthesia. Compound N-ethyl-5-ethyl-piperidine-2-carbonic acid 2,6-xylidide was first prepared. The preparation, which can be sterilized at 130 ° C without probing, further has the advantage of being conventional and has great stability. The LD value when injected into a mouse is 7 milligrams.

Lampligast slier framstallningen av ifragavarande amider genom en koppling av en alkylerad eller icke alkylerad N-alkylpiperidin-monokarbonsyra eller en alkylerad eller icke alkylerad N-alkylpyrrolidinmonokarbonsyra, en sadan syras anhydrid, ester eller hakgenid med en aromatisk amin med formeln Ar • NH, dar Ar har ovan an-given betydelse eller med ett mot aminen korresponderande lisocyanat och genom att i forekommande fall erhallen amid utsattes Mr en alkylering av det ringbundna kvavet. Most conveniently, the preparation of the amides in question is by a coupling of an alkylated or non-alkylated N-alkylpiperidine monocarboxylic acid or an alkylated or non-alkylated N-alkylpyrrolidine monocarboxylic acid, the anhydride, ester or chakgenide of such an acid with an aromatic amine of the formula Ar • NH, where Ar has the meaning given above or with a lysocyanate corresponding to the amine and by subjecting, where appropriate, the amide obtained to Mr, an alkylation of the ring-bonded nitrogen is subjected.

Framstallningen belyses med fbljande exempel: Exempel 1. Syrakloriden av -etylpiperidin-2- karbonsyrahydroklorid framstalles lampligast med fosforpentaklorid i acetylklorid. 211 viktsdelar 5-etylpiperidin-2- karbonsyraklorid - hydroklorid far reagera i aceton med 121 viktsdelar 2,6-xylidin. Blandningen varmes 1/2 timme pa vattenbad. Ac,etonen avdestilleras i vakuurn och resten loses i vatten. pH installes med lut pa 5,5. Oreagerad xylidin avlagsnas genom extraktion med eter. Vattenlosningen kolbehandlas, och basen utfalles med lut. Kristallerna avsugas och tvattas med vatten samt torkas i vakuum. 2 delar dietylsulfat tillfores och losningen varmes vid 100° C under 4 tim. Vatten tillsattes och overskottet av clietylsulfat extraheras med eter. Losningen kolbehandlas och basen, som bestar av N-ety1-5-etylpiperidin-2-karbonsyra-2,6-xylidid, utfalles med list. Basen avnutschas och tvattas med vatten. Sianpunkt 123-124° C. Utbyte 70 %. och 2— — Exempel 2. 197 viktsdelar 6-metylpiperidin-3- karbonsyrakloridhydroklorid far reagera I aceton med 121 viktsdelar 2,6-xylidin. Efter upparbetning och alkylering enligt exernpel 1 erhalles Nety1-6-metyl-piperidin-3-karbonsyra-2,6-xylidid, Smaltpunkt 93-95° C. Utbyte 73 %. The preparation is illustrated by the following examples: Example 1. The acid chloride of -ethylpiperidine-2-carboxylic acid hydrochloride is most conveniently prepared with phosphorus pentachloride in acetyl chloride. 211 parts by weight of 5-ethylpiperidine-2-carboxylic acid chloride - hydrochloride are reacted in acetone with 121 parts by weight of 2,6-xylidine. The mixture is heated for 1/2 hour in a water bath. Ac, the ethone is distilled off in a vacuum and the rest is dissolved in water. The pH is installed with 5.5 lye. Unreacted xylidine is removed by extraction with ether. The aqueous solution is charred, and the base is precipitated with lye. The crystals are sucked off and washed with water and dried in vacuo. 2 parts of diethyl sulphate are added and the solution is heated at 100 ° C for 4 hours. Water was added and the excess clietyl sulfate was extracted with ether. The solution is carbon treated and the base, which consists of N-ethyl-5-ethylpiperidine-2-carboxylic acid 2,6-xylidide, is precipitated with a strip. The base is washed off and washed with water. Melting point 123-124 ° C. Yield 70%. and 2 - Example 2. 197 parts by weight of 6-methylpiperidine-3-carbonic acid chloride hydrochloride are reacted in acetone with 121 parts by weight of 2,6-xylidine. After work-up and alkylation according to Example 1, Nethyl-6-methyl-piperidine-3-carboxylic acid 2,6-xylidide is obtained, m.p. 93-95 ° C. Yield 73%.

Exempel 3. 211 viktsdelar 2,6-dimetylpiperidin4-karbonsyrakloridhydroklorid far reagera i ace-ton med 121 viktsdelar 2-etylanilin. Efter upparbetning enl. exempel 1 och alkylering med dimetylsulf at erhalles N-mety1-2,6-dimetylpiperidin4-karbonsyra-2-etylanilid. Olja • Utbyte 65 %. Example 3. 211 parts by weight of 2,6-dimethylpiperidine-4-carbonic acid hydrochloride are reacted in acetone with 121 parts by weight of 2-ethylaniline. After processing according to Example 1 and alkylation with dimethyl sulfate to give N-methyl-2,6-dimethylpiperidine-4-carbonic acid-2-ethylanilide. Oil • Yield 65%.

Exempel 4. 184 viktsdelar 5-metylpyrrolidin-2- karbonsyrakloridhydroklorid far reagera i aceton med 121 viktsdelar 2,6-xylidid. Efter upparbetning och alkylering en!. exempel 1 erhalles N-ety1- 5-metylpyrrolidin-2-karbonsyra-2,6-xylidid. OljaUtbyte 55 %. Example 4. 184 parts by weight of 5-methylpyrrolidine-2-carboxylic acid chloride hydrochloride are reacted in acetone with 121 parts by weight of 2,6-xylidide. After reprocessing and alkylation a !. Example 1, N-ethyl-5-methylpyrrolidine-2-carboxylic acid 2,6-xylidide is obtained. Oil Yield 55%.

Exempel 5. 198 viktsdelar 4-etylpyrrolidin-2- karbonsyrakloridhydroklorid far reagera i aceton med 137 viktsdelar 2-etoxianilin. Efter upparbetning och alkylering enl. exempel 1 med n-propylbromid erhalles N-n-propy1-5-etylpyrrolidin-2- karbonsyra-2-etoxianilid. Olja • Utbyte 52 %. Example 5. 198 parts by weight of 4-ethylpyrrolidine-2-carboxylic acid chloride hydrochloride are reacted in acetone with 137 parts by weight of 2-ethoxyaniline. After work-up and alkylation according to Example 1 with n-propyl bromide gives N-n-propyl-5-ethylpyrrolidine-2-carbonic acid-2-ethoxyanilide. Oil • Yield 52%.

Exempel 6. 143 viktsdelar 5-metylpiperidin-2- karbonsyra upphettas tillsammans med 295 viktsdelar 2,6-dimetyl-fenylisocyanat under god °mitring vid en temperatur av 90-110° C. Reaktionen kannetecknas av den starka kolsyraavspjalkningen, vars upphorande utvisar fullbordad reaktion. Overskottet isocyanat avdestilleras darefter under vakuum, Reaktionsresten fOrsattes med ekvivalent mangd 10 % saltsyra och kokas under 15 minuter, varefter kyles och filtreras. Fran filtratet utfalles 5-metylpiperidin-2-karbonsyra- 2,6 -xylidid med lut i kristallinisk form. Efter filtrering och torkning sker alkylering enligt exempel 1 med dimetylsulfat till N-mety1-5-metylpiperidin-2-karbonsyra-2,6-xylidid. Example 6. 143 parts by weight of 5-methylpiperidine-2-carboxylic acid are heated together with 295 parts by weight of 2,6-dimethyl-phenylisocyanate with good metering at a temperature of 90-110 ° C. The reaction can be characterized by the strong carbon dioxide cleavage, the cessation of which completes the reaction. . The excess isocyanate is then distilled off in vacuo. The reaction residue is provided with an equivalent amount of 10% hydrochloric acid and boiled for 15 minutes, after which it is cooled and filtered. From the filtrate, 5-methylpiperidine-2-carboxylic acid 2,6-xylidide precipitates with lye in crystalline form. After filtration and drying, alkylation according to Example 1 is carried out with dimethyl sulphate to form N-methyl-5-methylpiperidine-2-carboxylic acid 2,6-xylidide.

Claims

Patent claim:

A method of producing novel carboxylic acid amides having a therapeutic effect is characterized in that an acid of the formula or R an alkyl group with max. 2 carbon atoms or one an alkyl group with max. 2 carbon atoms and the other a hydrogen atom, an anhydride, ester or halide of such an acid are reacted with an aromatic amine of the formula ArNH, where Ar is a substituted or an unsubstituted benzene nucleus, the substituents of which are chlorine in 2 and / or 6 position , alkyl- in 2,4 and / or 6-position or alkoxy groups in 4 and / or 6-position with max. 2 carbon atoms, in order to form the anilide of the corresponding acid and that the resulting acid amide is alkylated at the edge where the substituent R is, means hydrogen.

2. The modification according to claim 1 may be characterized in that said acid of the formula stated in claim 1, its anhydride, ester or halide may react with an isocyanate of the formula Ar • NCO corresponding to said amine, where Ar has the meaning given in claim 1, in and for the formation of acid amide according to patent claim 1. Request publications: Karrer, P, Lehrbuch der organischen Chemie. 12. Aufl. Stuttgart 1954, pp. 225.