DE1036258B - Process for the production of locally anesthetically effective basic ethers and their salts - Google Patents

Description

Process for the preparation of local anesthetically effective basic ethers and their salts The subject matter of the invention are processes for the preparation of new, locally anesthetically effective basic ethers of the general formula in which R represents an alkyl or aralkyl radical which contains 6 to 8 carbon atoms, and in which Y stands in place of a branched alkylene radical which contains 3 to 6, preferably 3 to 4 carbon atoms, as well as salts of such compounds with inorganic and organic acids.

The preparation of the new compounds can advantageously be carried out in various ways known per se. They are most easily obtained by etherifying the 4-morpholino-alkanols with reactive esters of strong inorganic or organic acids, for example in accordance with the reaction scheme where here and in the following reaction schemes the symbols R and Y are assigned the meanings defined at the outset and X is a reactive acid radical and Me is an alkali or alkaline earth metal.

The etherification can also be carried out with exchanged reaction groups, according to the reaction scheme The morpholino group can also be formed only afterwards from a primary amino group according to the reaction scheme This conversion is expediently carried out in the presence of acid-binding agents (excess base, potash, etc.).

In this reaction, H atoms of the primary amino group can also pass through Be replaced by benzyl groups. These are z. B. with ß, ß'-dichloro diethyl ether split off [(see example 2, b) 1.

The preparation of the new compounds can expediently also be carried out in such a way that the morpholino group is introduced in a last reaction stage, e.g. B. by reacting reactive alkoxy (or aralkoxy) alkyl esters with morpholine, expediently in the presence of acid-binding agents, according to reaction scheme V or by incorporation of morpholine in alkoxy (aralkoxy) alkenes z. B. in the presence of basic condensing agents or catalysts, according to reaction scheme VI: where n is an integer from 3 to 6.

Finally, the compounds in which the alkylene radical Y is in the a-position is unbranched to the morpholino group can also be correspondingly reduced by reductions Alkoxy- or aralkoxyalkylcarboxylic acid morpholides with lithium-aluminum hydride or win similar strong reducing agents.

It has been found that the compounds of the structure defined above are very valuable and effective local anesthetics. This The finding is unusual because most of the known ones are generally usable Local anesthetics have a very different chemical structure (see for example Jenkins and Hartung: The Chemistry of organic medicinal products [John Wiley, 1945], P. 358 ff.); Loefgren: Studies an Local Anesthetics, Diss. Stockholm, 1948; Loefgren: Arkiv None. Miner. Geol., 18, p.221 f1946]; Büchi: drug research, 1952, P.65).

Thanks to their simple chemical structure - basic body with aliphatic Ether group - the new compounds show an unlimited for practical use Resistance, which of today's most common local anesthetics, which hydrolyzable Containing ester or amide groups is not the case.

In addition to the strong, anesthetic effect in the infiltration, Conduction and surface anesthesia are still a part of the substances according to the invention very welcome additional effect own.

Namely, they show a strong anemic or vasoconstrictor Effect. This anemic effect can be seen particularly well in rabbit eyes follow the corneal microscope. The effect is roughly equivalent to that of four times more dilute adrenaline solution. The effects last longer than adrenaline. at Wheal and mucosal anesthesia tests were also anemic clear. The alveolus bled remarkably little during extractions.

This advantageous property is very surprising since the previously known Local anesthetics just show an opposite effect. They seem ordinary hyperaemic. The vasoconstrictive effect mostly necessary for use must with them by special additives such. B. adrenaline added. These However, additives cause a significant reduction in the pH value of the injection solution, causing severe pain when injected. The additives are also dangerous and due to their side effects, they often give rise to incidents (heart collapse) given.

Local anesthetics - like those according to the invention - with their own anemic Effect therefore corresponds to a distinct practical need. The present Invention therefore represents a considerable advance compared to the current state of technology.

The special, valuable properties of the compounds according to the invention are strikingly closely related to the precisely defined structure of the residue R (the general formula I) linked. It was z. B. surprisingly found that replacement the n-hexyl group through an n-butoxy-ethyl group leads to a compound which the vascular-contracting (anemic) effect of the starting substance completely has lost and only has a slight local anesthetic effect (e.g. a quarter of that of p-aminobenzoic acid diethy-l-aminoethyl ester hydrochloride) having. Similar relationships also arise when replacing, for example, the n-hexyl-oxy-iso-propyl or benzyloxy-isopropyl group through a 4 n-butoxyphenoxypropyl group (see Wright et al., J. Amer Chem. Soc., 76 [19541, pp. 4396 to 4398, S c h m i d t et a1., Anesthesia and Analgesia, 32 11953], p. 418). Even with this replacement the vascular contracting (anemic) effect is lost, and the usability of the resulting product is caused by the appearance of irritations, tissue damage etc. severely restricted.

EXAMPLE 1 18.4 g of sodium are added to 700 cc of dry, hot xylene (0.8 mol) dispersed into small droplets by vigorous stirring. Heating bath temperature about 130 to 140 ° C. This sodium suspension becomes a solution rather quickly of 116 g of 1- (4'-morpholino) propanol- (2) (0.8 mol) - obtained from propylene oxide and Morpholine, b.p. 89 ° C / 9 mm - allowed to run into 150 cc of xylene. The forming Sodium alcoholate from morpholinopropanol is completely soluble in hot xylene. After about 2 hours of stirring at 130 to 140 ° C on the reflux condenser, all of the sodium is implemented. A concentrated solution of 134 g of n-hexyl bromide (0.8 Mol) flow in xylene to the alcoholate solution and holds the reaction solution for about 3 hours with stirring at 130 to 140 ° C.

It is now cooled, regardless of the sodium bromide excreted with 500 cc of 2N hydrochloric acid and then extracted twice with 100 cc of 2N hydrochloric acid each time. The extract is washed with ether and then with an excess of concentrated Sodium hydroxide solution added. The excreted, light oil is in fresh ether taken up, the ether solution is dried and the solvent evaporated. Of the The residue is distilled in vacuo. Bp 78'C, 1,05 mm. Quantity 144 g, that is 79 ° / o of theory. The new 1- (4'-morpholino) -2-hexyloxy-propane is a colorless, easily mobile liquid, which can be found in all common organic solvents, dilute aqueous mineral acids, aqueous citric and lactic acids easily, in Water, on the other hand, hardly dissolves.

Microanalysis for C13 H21 OZN (229.35) Calculated ...... C 68.07 I / "H 11.870 /" N 6.11 Ojo; found ........ C 68.16 ° / 0, H 11.65 ° / "N 6.29 ° / 0. By adding ether-hydrochloric acid to an ethereal solution of the base, one gets that which immediately crystallizes nicely Hydrochloride of the base. This can be recrystallized from benzene, a lot of gasoline, from benzene-gasoline or, best of all, from a relatively small amount of ethyl acetate. It melts at 134 to 135 ° C and is in almost all common organic solvents except in hydrocarbons, ethers and esters and also easily soluble in water.

Example 2 a) 178 g (1.08 mol) of 1-benzylaminopropanol (2) - obtained by reductive conversion of 100 g of isopropanolamine with 141 g of benzaldehyde in 200 cc of ethanol in the presence of Raney nickel in an autoclave at a hydrogen pressure of 100 to 140 atmospheres , Kp.3 ,,; s ,, 106 to 108 ° C - 25 g (1.09 mol) of finely divided sodium in hot, almost boiling xylene are allowed to run in quickly. The sodium is almost completely converted after about 1/2 hour. The alcoholate formed is dissolved in hot xylene. 178 g (1.08 mol) of n-hexyl bromide are then added dropwise over the course of one hour. The reaction mixture is refluxed for a further 4 hours. After cooling, the sodium bromide is filtered off with suction. The xylene solution is shaken vigorously with about 500 cc of 2N hydrochloric acid and the aqueous solution is separated off. After standing for a while, 1-benzylamino-2-hexyloxypropane hydrochloride begins to separate out of the xylene solution. One sucks off and recrystallizes a sample from light gasoline. Melting point 100 to 101 ° C.

Ci content, calculated for 1-benzylamino-2-hexyloxypropane hydrochloride = 12.410 / "found 12.48%.

The main amount of the suction filtered hydrochloride is with the aqueous hydrochloric acid Solution combined, mixed with a little water and heated until dissolution. Now the solution is made strongly alkaline by adding sodium hydroxide solution and the the base which separated out was taken up in ether. The ethereal solution is dried and evaporates. The residue is distilled in vacuo.

Bp. 134 to 135 ° C / 2 to 3 mm. The yield is 189 g, that is 70 0/0 of theory. The pure base is easily soluble in common organic ones Solvents and dilute mineral acids, on the other hand only slightly soluble in water. This base serves as the starting material for the following reaction stage b).

b) By heating 7.2 g (0.05 mol) of β, ß'-dichlorodiethyl ether with 38 g (0.15 mol) of free 1-benzylamino-2-hexyl-oxypropane at 150 to 160 ° C. for 6 to 7 hours or at 100 ° C. for 48 hours, a reaction mixture is obtained which, in addition to the calculated amount (28 g) of 1-benzylamino-2-hexyloxy-propane hydrochloride and somewhat unchanged base, mainly consists of 1- (4'-morpholino) -2 -hexyloxy-propane. This is obtained after treating the reaction mass - a crystal slurry - with ether, filtering off the hydrochloride mentioned and evaporating the solvent by distillation. The distillate - boiling point 70 to 90 ° C, 10.1 to 0.2 mm - is dissolved in ether and treated with ether-HCl, the nicely crystallizing hydrochloride of 1- (4'-morpholino) -2-hexyloxypropane immediately fails. After recrystallizing once from a little benzene, the product melts at 135 to 136.degree. Microanalysis for C "H" 02NC1 (265.82): Calculated ... C 58.74, H 10.62, N 5.27, chlorine 13.34, active H 0.38%; found .... C 58.68, H 10.56, N 5.27, Cl 13.38, active H 0.38 0/0. 1- (4'-Morpholino) -2-hexyloxy-propane is also obtained by heating 50 g of 1-amino-2-hexyloxypropane (0.314 mol) - obtained by the hydrogenolytic cleavage of 1-benzylamino-2-hexyloxy-propane hydrochloride (see Example 2, a), in ethanol and in the presence of 50% palladium carbon in the shaking duck at a hydrogen pressure of about 2.5 atmospheres, boiling point of the base: - 95 ° C / 12 mm - with 50 g ß, ß'-dichloro diethyl ether and 50 g potash. Yield 31 g, that is 43% of theory.

Example 3 a) 15 g of 1- (4'-morpholino) propanol- (2) - obtained from propylene oxide and morpholine - are carefully converted into 15 cc of thionyl chloride in 150 ml up to 200 cc of chloroform were added dropwise. The reaction mixture is then 2 to 3 Boiled under reflux on the water bath for hours. Now a volume of about Concentrated to 100 ccm and pour the dark reaction solution into 500 poured up to 600 ccm of dry ether. The resulting crystalline precipitate is sucked off, washed with ether and then made from about 400 to 500 cc of acetone using recrystallized from some activated charcoal. Virtually colorless crystals of are obtained new 1- (4'-morpholino) -2-chloropropane hydrochlorides with a melting point of 173 to 174 ° C. yield 12g, that's - 600,; 0 of theory.

Microanalysis for C, H15 ON C12: Calculated ...... C42.010 / 0, H7.560 / 0, N7.0011 / 0; found ........ C42.380 / 0, H7.61 (11'0, N6.780; 0. Ionogenically bound Cl: Calculated 17.720 / 0, found 17.410 / 0.

This compound serves as the starting material for the following reaction stage b).

b) 100 ccm of dry xylene are mixed with 2.3 g of sodium metal (0.1 mol) offset. Vigorous stirring at around 120 to 130 ° C makes the sodium too small Droplets distributed. 11 g of n-hexanol (0.108 mol) are now quickly added. It kicks a moderate reaction and free hydrogen is produced. After a few minutes the solution begins to become cloudy and n-C, H "- O-Na separates as fine, white Mass off. After stirring and heating for about 1 hour, practically all of it is sodium implemented. After cooling, 10 g of solid 1- (4'-morpholino) -2-chloropropane hydrochloride are then added in the course of about 15 minutes (0.05 mol) added to the reaction mixture. The mixture is stirred for a further 30 minutes at room temperature and then 1 hour at about 100 to 120 ° C. After cooling down, as in the example l was described in more detail, worked up. Extraction of the product with 100 ccm 2 n-H Cl, ether out the extract, add an excess of sodium hydroxide solution, ether out, evaporate, distill the residue in vacuo. 8.1 g are obtained 1- (4'-Morpholino) -2-hexyloxypropane, that's 710/0 of theory.

Example 4 a) In the same way as in Examples 1 and 2, a), 75 g, that is 50 1111 ! , the theory, 1-hexyloxy-2-aminopropane obtained. This compound foams when distilled in a vacuum. Bp - 90 ° C / 16 mm.

Equivalent Weight: Calculated 159, found 161.

The new basic ether is easily soluble in organic solvents and dilute mineral acids, but only sparingly soluble in water. This connection serves as the starting material for the following reaction stage b).

b) 21 g of the 1-hexyloxy-2-aminopropane obtained by the above process (0.132 mol) with 6.5 g of ß, ß'-dichloro diethyl ether (0.0455 mol) for 7 hours heated to 150 to 160 ° C. After cooling, the dark brown liquid will turn out mixed with water and extracted repeatedly with petroleum ether. The 1-hexyloxy-2- (4'-morpholino) propane formed wanders into petroleum ether or light gasoline, which in most of the rest of the organic Solvents easily soluble hydrochloride of 1-hexyloxy-2-aminopropane, the has formed during conversion, is now in the aqueous phase. The petroleum ether or petroleum extract is evaporated and the residue is distilled in vacuo.

Bp. 123 ° C / 4 to 6 mm, amount: 5.45 g, that is 54% of theory.

Microanalysis for C13Ha702N: Calculated ...... C 68.070 / 0, H 11.870 / 0, N 6.110 / 0; Found ........ C 68.26 0/0, H 11.70 0/0, N 6.24 0/0. The new base is sparingly soluble in water, but easily soluble in organic solvents and dilute mineral acids. About 500 % of the 1-hexyloxy-2-aminopropane used can be recovered from the aqueous extract. 1-Hexyloxy-2-aminopropane can also be reacted with ß, ß'-dichlorodiethyl ether in the presence of potash analogously to Example 2 to give 1-hexyloxy-2- (4'-morpholino) propane. This process is particularly economical because it does not require the use of an excess amine to bind the hydrochloric acid formed in the reaction.

By adding a solution of 5 g of the new base to 50 cc of ether With 4.2 ccm of 5.26 normal ethereal hydrochloric acid, the hydrochloride of 1-hexyloxy-2- (4'-morpholino) propane is obtained. This can be done by dissolving it in a little warm ethyl acetate and carefully precipitating it obtained completely colorless and pure with dry ether. That Hydrochloride melts at 104 to 105 ° C. It is easily soluble in water and in most organic Solvents with the exception of gasoline and ethers.

Microanalysis for C "H" 02NC1: Calculated ..... C 58.74, H 10.62, N 5.27, Cl 13.34 °; 0; found ..... C 58.66, H 10.60, N 5.15, Cl 13.18%. Example 5 In the same way as in Examples 1 and 2, a), by reacting 58 g of 1- (4'-morpholino) -2-oxypropane (0.4 mol) with 9.3 g of sodium metal (0.404 mol) in Xylene and subsequent conversion with 51 g of benzyl chloride (0.403 mol) obtained 73.5 g of 1- (4'-morpholino) -2-benzyloxypropane, that is 78% of theory. The new compound boils at 105 ° C / 0.01 mm. It is easily soluble in all common organic solvents and dilute mineral acids, but hardly soluble in water.

Microanalysis for C "H" 02N (235.32): Calculated ....... C 71.45 ° / 0, H 9.00 ° l0, N 5.95 ° l0 found ....... C 71.690 / 0, H 8.710 / 0, N 5.840 / 0. The hydrochloride of the new base melts at 137 to 138 ° C. It is easily soluble in water and ethanol, but only slightly soluble in ether, petroleum ether, cold benzene and ethyl acetate. It can be recrystallized from benzene, acetone or ethyl acetate.

Microanalysis for C, H "02NC1 (271.79): Calculated C 61.860 / 0, H 8.160 / 0, N 5.150 / 0, Cl 13.050 / 0; Found C 62.05 0/0, H 8.35 0/0, N 4.92 0/0, Cl 13.110J0. Example 6 a) In principle in the same way as in Examples 1 and above 2, a), were obtained by converting 46 g of 2-amino-butanol- (3) - by Reduction of the 2-nitrobutanols- (3) obtained from nitroethane and acetaldehyde - with 12 g of sodium in 600 cc of xylene for 1 hour and subsequent conversion with 87 g n-hexyl bromide 60 g, that is 67% of the theory of the new 2-hexyloxy-3-aminobutane, obtain.

This compound foams violently when distilled in a vacuum. Kp.91 up to 93 ° C / 12 mm. The new basic ether is easily soluble in organic solvents, diluted mineral acids, but not very soluble in water. This base serves as Starting material for the following reaction stage b).

b) 31 g of the 2-hexyloxy-3-aminobutane obtained by the above process (0.18 mol) with 8.6 g of ß, ß'-dichloro-diethyl ether (0.06 mol) for 6 to 7 Heated to 140 to 150 ° C for hours. : After cooling down, water is added and extracted with petroleum ether or mineral spirits. The extract contains the desired 2-hexyloxy-3- (4'-morpholino) -butane, which is purified by distilling in vacuo. Bp 85 ° C / 0.1 to 0.01 mm. The new base is easily soluble in organic solvents and dilute mineral acids. The same compound is also obtained through conversion with ß, ß'-dichloro diethyl ether in the presence of potash as in Example 2, b).

Claims (1)

PATENT CLAIM: Process for the production of local anesthetically effective basic ethers of the general formula in which R represents an alkyl or aralkyl radical which contains 6 to 8 carbon atoms, and in which Y stands in place of a branched alkylene radical which contains 3 to 6, preferably 3 to 4 carbon atoms, and their salts, characterized in that one Compound of the general formula R - X II in which X is instead of a reactive acid residue, etherified with an alkali or alkaline earth metal salt of a basic alcohol of the formula HO-YN HO 111 in a manner known per se or that the etherification is carried out with exchanged reaction groups, by reacting an alkali or alkaline earth metal salt of an alcohol of the formula R-OH IV with a compound of the general formula XY -NHOV by known methods, or that a compound of the formula ROY-NH, VI or an N-benzyl derivative of this compound is reacted with a ß, ß'-Dihalo diethyl ether in the presence of acid-binding agents in a known manner or that one morpholine with a reactive gen esters of the formula ROYX VII or with the unsaturated ether corresponding to this compound of the general formula R - O - C "H2" _1 VIII where n is an integer from 3 to 6, according to known methods, or that one for the preparation of compounds , in which the alkylene radical y is unbranched in the a-position to the morpholine ring, carboxylic acid morpholides of the general formula in which Z means a branched alkylene radical with 2 to 5, preferably 2 to 3 carbon atoms, reduced in a manner known per se, the symbols R, Y and X used in formulas II to IX having the meanings defined at the outset. References considered: British Patent No. 710,511; USA. Patent No. 2,001,584, 2 581,285th; J. Amer. chem. Soc., 73 (1951), pp. 5525, 5526. When the application was announced, 7 pages of test report were laid out.