NO123127B

NO123127B -

Info

Publication number: NO123127B
Application number: NO0554/68A
Authority: NO
Inventors: A Noren
Original assignee: Tolerans Ab
Priority date: 1967-02-15
Filing date: 1968-02-14
Publication date: 1971-10-04
Also published as: FR1584250A; GB1220941A; US3489228A; DE1652524A1; SE330674B; ES350532A1

Description

Fremgangsmåte til fremstilling av anestetisk virksomme N-alkyl-tetrahydrokinaldinsyreamider. Process for the production of anesthetically active N-alkyl-tetrahydroquinaldic acid amides.

Foreliggende oppfinnelse angår en fremgangsmåte til fremstilling av N-alkyl-tetrahydrokinaldinsyreamlder med den generelle formel: The present invention relates to a method for the production of N-alkyl-tetrahydroquinaldinic acids with the general formula:

I denne formel betegner R en alkylgruppe og Ar en 2- eller 2,6-substituert foenzen-ring, i hvilken substituentene består av al-kylgrupper. i In this formula, R denotes an alkyl group and Ar a 2- or 2,6-substituted fenzen ring, in which the substituents consist of alkyl groups. in

Disse nye amider har vist seg å være These new amides have been shown to be

meget gode lokalanestetika som også har en god overflateanestetisk virkning. Effek-ten er i forhold til giftigheten fordelakti-gere enn prokainets. very good local anesthetics which also have a good surface anesthetic effect. In relation to the toxicity, the effect is more beneficial than that of procaine.

1 Ifølge oppfinnelsen ifremstilles disse 1 According to the invention, these are produced

amider ved hjelp av en i og for seg kjent reaksjon, idet man lar en alkylert eller ikke alkyilert itetrahydrokinaldinsyre, eller kloridet, anhydridet eller en ester eller et usub-stituert amid av en sådan syre reagere med et aromatisk amin med den generelle formel HiNAr, hvor Ar har den ovenfor angitte betydning. Fortrinsvis brukes 'kloridet av en tetrahydrokinaldinsyre, og i de tilfelle hvor utgangsmaterialet, altså tetra-hydrokinaldinsyren eller >et av dens oven- amides by means of a reaction known per se, allowing an alkylated or non-alkylated tetrahydroquinaldic acid, or the chloride, anhydride or an ester or an unsubstituted amide of such an acid to react with an aromatic amine of the general formula HiNAr, where Ar has the above meaning. Preferably, the chloride of a tetrahydroquinaldic acid is used, and in those cases where the starting material, i.e. tetrahydroquinaldic acid or >one of its above-

for angitte derivater ikke er alkylert, inn-føres alkylgnuppen (R) som er bundet til nitrogenatomet i den heterocykliske ring ved alkylering etter at den nevnte reaksjon er utført. for specified derivatives are not alkylated, the alkyl group (R) which is bound to the nitrogen atom in the heterocyclic ring is introduced by alkylation after the aforementioned reaction has been carried out.

Videre kan nevnte amider fremstilles ved reaksjon mellom en tetrahydrokinaldinsyre eller et 'av de ovenfor nevnte derivater av samme og isocyanater av aroma-tiske aminer med ,den generelle formel Hi;NAr, hvor Ar har den ovenfor angitte betydning. Dessuten kan amidene fremstilles ved hydrering av kinaldinsyreamider med amidogruppen som angitt i ovenstående generelle formel for produktet. Furthermore, said amides can be prepared by reaction between a tetrahydroquinaldic acid or one of the above-mentioned derivatives of the same and isocyanates of aromatic amines with the general formula Hi;NAr, where Ar has the above meaning. Also, the amides can be prepared by hydrogenating quinaldic acid amides with the amido group as indicated in the above general formula for the product.

De erholdte baser overføres 'fortrinsvis The obtained bases are preferentially transferred

til salter, hensiktsmessig hydroklorider. to salts, suitably hydrochlorides.

I det følgende beskrives som eksempler noen utførelsesformer for oppfinnelsen. In the following, some embodiments of the invention are described as examples.

Eksempel 1. Example 1.

Ved reaksjon mellom 191,5 vektdeler kinaldylklorid og 121 vektdeler 2,6-dimetylanilin i 500 vektdeler tørr toluen, først ved romtemperatur og deretter ved 80° C i en time fåes med nesten .kvantitativt utbytte kinaldyl-2,6-dimetyl-xylidid. Ved reduk-sjon av denne forbindelse i eddiksyre med hydrogengass i nærvær av platinaoksyd ved et trykk på 5 atm overtrykk og ved en temperatur på 80° C fåes tetrahydrokinal-dyl-2,6-dimetylxylidid. Ved alkylering med dimetylsulfat fåes N-metyltetrahydroki-naldyl-2,6-metylxylidid. By reaction between 191.5 parts by weight of quinaldyl chloride and 121 parts by weight of 2,6-dimethylaniline in 500 parts by weight of dry toluene, first at room temperature and then at 80° C. for one hour, quinaldyl-2,6-dimethyl-xylidide is obtained with an almost quantitative yield. By reducing this compound in acetic acid with hydrogen gas in the presence of platinum oxide at a pressure of 5 atm overpressure and at a temperature of 80° C, tetrahydroquinal-dyl-2,6-dimethylxylidide is obtained. By alkylation with dimethylsulphate, N-methyltetrahydroquinaldyl-2,6-methylxylidide is obtained.

Eksempel 2. Example 2.

Ved reaksjon mellom 191.5 vektdeler kinaldylklorid og 121 vektdeler 2-etylani-lin, samt behandling som angitt i eksempel 1 og påfølgende alkylering med dieitylsul-fat fåes N~etyl-tetrahydrokinaidyl-2-etyl-anilid. By reaction between 191.5 parts by weight of quinaldyl chloride and 121 parts by weight of 2-ethylaniline, as well as treatment as indicated in example 1 and subsequent alkylation with diethyl sulfate, N-ethyl-tetrahydroquinaidyl-2-ethyl-anilide is obtained.

Eksempel 3. Example 3.

Ved reaksjon mellom 191.5 vektdeler kinaldylklorid og 121 vektdeler 2,6-dimetyL anllin samt behandlinng som angitt i eksempel 1 og påfølgende alkylering med normalt-butylbromid fåes N-n-butyltetra-hydrok>inaldyl-2,6-dimatylanilin. By reaction between 191.5 parts by weight of quinaldyl chloride and 121 parts by weight of 2,6-dimethylaniline and treatment as stated in example 1 and subsequent alkylation with normal-butyl bromide, N-n-butyltetrahydroquinaldyl-2,6-dimethylaniline is obtained.

Eksempel 4. Example 4.

209,5 vektdeler N-metyl-tetrahydro-kinaldylklorid forbindes med 125 vektdeler 2,6-dimetylanilin i 500 vektdeler benzen først under avkjøling og deretter ved opp-hetning under kokning i en time. Det dan-nede N-metyl-tetrahydrokinaldyl-2,6-di-matylanilid-hydroklorid utkrystalliseres herved, avnutsj es/vaskes og renses ved omfelling. 209.5 parts by weight of N-methyl-tetrahydro-quinaldyl chloride are combined with 125 parts by weight of 2,6-dimethylaniline in 500 parts by weight of benzene first under cooling and then by heating under boiling for one hour. The formed N-methyl-tetrahydroquinaldyl-2,6-dimethylanilide hydrochloride is thereby crystallized, filtered off/washed and purified by reprecipitation.

Eksempel 5. Example 5.

177 vektdeler tetrahydrokinaldinsyre oppvarmes sammen med 295 vektdeler 2,6-dimetyl-fenylisocyanat under omrøring og god utluftning ved en temperatur på 90— I10<0> C Reaksjonen vises av en intens ut-vikling av kullsyre, og reaksjonens slutt ved at denne gassutvikling opphører. Over-skudd av isocyanat avdestilleres i vakuum. En tilsvarende mengde 10—15 pst.'s saltsy-re tilsettes reaksjonsoflandingen som kokes i 15 minutter, hvorpå den avkjøles og filt- 177 parts by weight of tetrahydroquinaldic acid are heated together with 295 parts by weight of 2,6-dimethyl-phenyl isocyanate with stirring and good aeration at a temperature of 90-110<0> C. The reaction is shown by an intense evolution of carbonic acid, and the end of the reaction when this evolution of gas ceases . Excess isocyanate is distilled off in a vacuum. A corresponding amount of 10-15% hydrochloric acid is added to the reaction mixture, which is boiled for 15 minutes, after which it is cooled and filtered.

reres. Fra filtratet utfelles tetrahydrokinal-dyl-2,6-dimetylanilid med natriumhydr-oksyd. Basen frafiltreres, vaskes med vann og tørres. Ved alkylering med dimetylsulfat får man N-metyltetrahydrokinaldyl-2,6-dimetylanilid. reres. Tetrahydroquinal-dyl-2,6-dimethylanilide is precipitated from the filtrate with sodium hydroxide. The base is filtered off, washed with water and dried. Alkylation with dimethylsulphate gives N-methyltetrahydroquinaldyl-2,6-dimethylanilide.

Claims

Process for the production of anesthetically active N-alkyl-tetrahydroquinaldonic acid amides with the general formula:

in which R denotes an alkyl group and Ar a 2-alkyl- or a 2,6-dialkylbenzene, characterized by bringing an alkylated or non-alkylated tetrahydroquinaldic acid or the chloride, anhydride, an ester or an unsubstituted amide of such an acid to to react with an aromatic amine of the general formula H2NAr (in which Ar has the above meaning), or with an isocyanate of such an aromatic amine, with subsequent alkylation of the nitrogen in the heterocyclic ring in the case where said starting material is not alkylated, or by hydrogenating a quinaldic acid amide with an amido group as indicated in the above general formula.