DE824202C - Process for the preparation of 3-alkyloxybenzoic acid mono- and dialkylaminoalkylamides - Google Patents

Description

A process for the preparation of 3-Alkyloxybenzoesäuremono- and -dialkylaminoalkylamiden It is known that 3-Alkoxybenzoesäuredialkylainiiioätli ## lamide as local anesthetics to be used (Act. Pharmacol. 1948, 4, 199-204).

It has now been found that very effective local anesthetics can be obtained comes when, in a known manner, mono- or dialkylaminoalkylamides, whose nitrogen atoms are separated by more than two carbon atoms, of 3-alkyloxybenzoic acids produces, the two alkyl radicals with the nitrogen atom of the amino .gruppe a heterocyclic residue, e.g. B. form a pyrrolidyl or piperidyl radical can and wherein the alkyloxy group is in the m-position to the carbonamide group and carries more than two carbon atoms. Connections of this kind show an unusual one long-lasting effect and are suitable for both surface and conduction anesthesia useful. Surprisingly, compared to the known 3-Alkoxybenzoesäuredialkylaminoäthylamiden the products produced according to the invention have the advantage of greater tissue compatibility.

The above-mentioned compounds are preferably prepared in the manner that one 3-alkyloxybenzoic acids or their functional derivatives, their Alkyloxy group containing more than two carbon atoms, with alkylbenzylaminoalkylamines or dialkylaminoalkylamines having more than two carbon atoms between the nitrogen atoms converts and, if necessary, splits off the benzyl radical. One can also proceed in such a way that.man 3-Alkyloxybenzoic acid amides, the alkyloxy group of which has more than two carbon atoms contains, on reactive esters, e.g. B. hydrogen halide esters, of alkylbenzylamino or dialkylaminoalkanols with more than two carbon atoms between nitrogen and Hydroxyl group in the presence of alkaline condensation agents and if necessary then splits off the benzyl radical. In both cases, the structure of the mono or Dialkylaminoalkylrestes also take place in stages by z. B. initially i-halopropyl-3-amide and higher haloalkylamides of 3-alkyloxybenzoic acids, the alkyloxy group of which is more contains than two carbon atoms, and then with mono- or dialkylamines implemented. Finally, alkylbenzylaminoalkylamides with more than two carbon atoms between the nitrogen atoms or the corresponding dialkylaminoalkylamides of 3-OxY-benzoic acids subjected to subsequent alkylation on the hydroxyl group the benzyl group is then split off if necessary.

The mentioned mono- and dialkylaminoalkylamides of 3-alkyloxybenzoic acids are crystalline or liquid in the form of their free bases at room temperature Substances are that with inorganic or organic acids, such as. B. hydrochloric acid, Form phosphoric acid, lactic acid, methanesulfonic acid, water-soluble salts.

Example I 21.2 9 3-n-Butyloxybenzoylchlorid be reacted in benzene solution with 13 g of diethylaminopropylamine under cooling. When the reaction has ended, it is shaken out with soda solution and then with saline solution and the benzene is expelled, finally in vacuo. The residue is dissolved in about 51% phosphoric acid, the solution is washed with ether and treated hot with charcoal. The base is precipitated from the clear, colorless solution with soda solution and taken up in ether. After drying and driving off the solvent, the residue is distilled in vacuo. To yield the 3-n-Butyloxybenzoesäurediäthylaminopropylamid as a yellowish from 01 Kp. O, oi 184-186 '.

In contrast to 3-n-Butyloxybenzoesäurediäthylaminoäthylamid is tolerated the compound in 1% solution in animal experiments without irritation.

Similarly, e.g. B. following bases were prepared: 3-ii-Butyloxybenzoesäure-3'-di-n-butylamino-i'-propylamide, almost colorless from 01 Kp = 0.15 2O6, 3-n-Butyloxybenzoesäure-3'-d i. . -isobutyl-i'-propylamide, colorless oil, bp o, iS = 200 ', which crystallizes after standing, mp 45 to 46,5-, 3 -. n - Butyloxybenzoesäure - 4'-diethylamino - i'-methyl -i'-butylamide, colorless oil, b.p. o, oi = 184 to 188 '.

The compounds described form water-soluble, neutrally reacting salts with acids. Example 2 21.29 of 3-n-butyloxybenzoyl chloride are reacted with 14.29 of 3-pentamethyleneamino-i-propylamine in the manner described in Examplei and worked up. The residue remaining after the ether has been driven off crystallizes after a short time and can be dissolved from a ligroin / petroleum ether mixture. 3-n-Butyloxybenzoic acid-3'-pentamethyleneamino-i'-propylamide is obtained as colorless crystals from Schml) - 46 to 47.5 '. It forms water-soluble neutral salts with acids.

B ice p i el 3 20.89 3-n-Butyloxybenzoesäuremethylester and 37.2 9 3-di-isobutylamino-i-propylamine is heated in an autoclave 2o hours igo to 2ool. When the reaction has ended, the methanol formed and the excess diamine are distilled off in vacuo and the residue is dissolved in about 5% phosphoric acid. The solution is washed with ether, treated with charcoal, the base is precipitated with soda solution and taken up with ether. After driving out of the ether, the residue is distilled in vacuo and n-Butyloxybenzoesäure-3'-di-isobutylamino-i'-propylamide 3 receives the already described in Example I as a yellowish 01 of boiling o, i =:. 2oo to 205 ' , which solidifies after inoculation to a colorless crystal mass of m.p. 45 (). Example 4 21.2 9 3-n-Butyloxyl) enzoylchlorid and 22 9 3-n-Butylbenzylamino-i-propylamine were reacted in benzene solution. Working up according to Example i, 3-n-butyloxybenzoic acid-3'-n-butylbenzylamino-i'-propylamide is obtained as an almost colorless thick oil with a boiling point of o, oi = 220 to 230 '. 24 g of this product are dissolved in 220 CCM methanol and the solution is neutralized with dilute hydrochloric acid. After adding a catalyst prepared from 2 g of carbon and 5 cc of 10% strength palladium (2) chloride solution, hydrogenation is carried out at 400 and a slight excess pressure until the uptake of hydrogen has ceased. After the catalyst has been filtered off with suction, the clear, colorless solution is evaporated to dryness in vacuo. After the residue has been redissolved from acetone, the hydrochloric acid salt of 3-n-butyloxybenzoic acid-3'-n-butylamino-propylamide is obtained in colorless crystals, which dissolve in water with a neutral reaction and melt at 146 to 147 '.

Claims (1)

Claim: Process for the preparation of 3-alkyloxybenzoic acid mono- and dialkylaminoalkylamides, the alkyloxy group of which has more than two carbon atoms, characterized in that either a) 3-alkyloxybenzoic acids or their functional derivatives, the alkyloxy group of which has more than two carbon atoms, are used in a manner known per se contains, reacts with alkylbenzylaminoalkylamines or dialkylaminoalkylamines with more than two carbon atoms between the nitrogen atoms and, if necessary, splits off the benzyl radical, or b) 3-Alkylox #, benzoic acid amides, the alkyloxy group of which contains more than two carbon atoms, on reactive esters, e.g. B. hydrogen halide esters, of alkylbenzylaminoalkanols or dialkylaminoalkanols with more than two carbon atoms between the basic nitrogen atom and the hydroxyl group in the presence of alkaline condensing agents and, if necessary, then cleaves the benzyl radical, or that c) haloalkylamides of 3-alkyloxybenzoic acids, the alkyloxy group more than two Contains carbon atoms and which contain more than two carbon atoms between halogen and amide nitrogen, reacts with mono- or dialkylamines, or that d) alkylbenzylamino or dialkylaminoalkylamides with more than two carbon atoms between the nitrogen atoms of 3-oxybenzoic acids with alkylating agents which react more than contain two carbon atoms and are suitable for alkylating the oxy group, and if necessary then splitting off the benzyl radical.