NO131814B - - Google Patents

Description

Process for the preparation of a ring-tri-substituted aniline.

This invention relates to the preparation of ring-tri-substituted aniline derivatives.

The invention consists in the preparation of a compound in which a primary amino substituent is connected to a benzene ring which is further substituted with lower hydrocarbyloxy, halogen and certain lower tertiary amino (polycarbon-lower alkoxy) radicals. The invention thus relates to (a) ring-tri-substituted anilines in which the substituents are a halogen atom, resp. a lower hydrocarbyloxy radical and a lower tertiary-amino-substituted polycarbory-lower alkoxy radical, as well as (b) addition salts thereof.

Halogen-(lower hydrocarbyloxy)-

[lower-tertiary-amino(polycarbon-lower-alkoxy)]-aniline derivatives in free base form have the formula (I)

where the halogen radical is bromine, chlorine, iodine or fluorine, R is a lower alkyl or benzyl radical in the description called a hydrocarbyl radical, X is a polycarbon lower alkylene radical whose free valences are attached to different carbon atoms, Y is hydrogen or lower acyl and NB is a lower-tertiary-amino radical, such as di-(lower-alkyl)amino, 1-piperidyl, (lower-alkylated}-1-piperidyl, 1-pyrrolidyl and (lower-alkylated)-1-pyrro-

lidyl radicals. The halogen, lower hydrocarbyloxy and lower-tertiary-amino(polycarbon-lower-alkoxy) substituents can be in any of the available ring positions relative to each other.

These compounds and their addition salt derivatives have strong local anesthetic activity and are mildly irritating. In general, the acute toxicity of these compounds proceeds in parallel with their activity.

Among the particularly preferred compounds which are produced according to the invention are 3-halo-4-[lower-tertiary-amino(polycarbon-lower- alkoxy)]-5-(lower-alkoxy) anilines whose free base has the formula (II)

where X, Y and NB have the meanings given above, the halogen is bromine or chlorine, and R is a lower alkyl radical.

In the above general formula II, the polycarbon lower alkylene radical denoted by X preferably has from two to four carbon atoms and its two free valences bound to different carbon atoms. Thus, X preferably includes such groups as -CH2CH2-, -CH2CH2CH2-, -CH2

-CH(CH:j), -CH2CH2CH2CH2-, CH2CH2(CH3)CH2-, and the like. The above stated la-

vere-tertiary-amino-radical NB comprises di-(lower-alkyl)amino-radicals where the lower alkyl groups are the same or different and each alkyl group preferably has one to six carbon atoms, such as e.g. di-(lower-alkyl)amino radicals containing dimethylamino, diethylamino, ethylmethylamino, diisopropylamino, ethyl-n-propylamino, di-n-butylamino, di-n-hexylamino, and the like. Furthermore, the lower-tertiary-amino radical called NB includes certain saturated N-heteromonocyclic radicals with five to six ring atoms, e.g. 1-piperidyl; (lower-alkylated)-1-piperidyl such as 2-methyl-1-piperidyl, 3-ethyl-1-piperidyl, 4-methyl-1-piperidyl, 2,6-dimethyl-1-piperidyl; 1-pyrroli-

dyl; (lower-alkylated)-1-pyrrolidyl such as e.g. 2-methyl-1-pyrrolidyl, 2,5-dimethyl-1-pyrrolidyl, and the like. When the lower-hydrocarbyl radical R is lower-alkyl it has one to eight carbon atoms and includes such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, n-amyl, isoamyl, 2 -amyl, n-hexyl, n-heptyl, n-octyl, and the like.

According to the invention, the compounds are preferably prepared by the method represented by the following equations, where X, NB and R have the above-mentioned meanings and Hal is chloride, bromide or iodide.

In step I, a halogen-(lower-hydrocarbyloxy)-nitro-phenol (III) is converted to a halogen-[lower-tertiary-amino(polycarbon-lower-alkoxy)]-(lower-hydrocarbyloxy)-nitrobenzene (V) by reaction with a tertiary aminoalkyl halide (IV). In step 2, the tri-substituted nitrobenzene (V) is reduced to the corresponding tri-substituted aniline (I). A specific example of this procedure is the formation of 3-bromo-4-(2-diethylaminoethoxy)-5-ethoxyaniline by allowing 2-bromo-4-nitro-6-ethoxyphenol, preferably in the form of an alkali salt, to react with a 2 -diethylaminoethyl halide, preferably the chloride, to give 3-bromo-4-(2-diethylaminoethoxy)-5-ethoxynitrobenzene, and reduce this tri-substituted nitrobenzene to the corresponding 3-bromo-4-(2-diethylaminoethoxy)-5 -ethoxyaniline.

Step 1 is preferably carried out by reacting a halogen-nitro-(lower-hydrocarbyloxy)phenol (III) in the form of a metal-. derivative, e.g. of an alkali metal, with a tertiary aminoalkyl halide (IV). Alternatively, step 1 can be carried out using a halo-nitro-(lower-hydrocarbyloxy)phenol as such, but this entails a lower yield of tri-substituted-nitrobenzene (V).

Reduction step 2 is preferably carried out by chemical methods, or, alternatively, by catalytic hydrogenation, although the latter method is less desirable where the halogen substituent is bromine or iodine. Suitable chemical reducing agents include iron and hydrochloric acid, ferrous sulphate and ammonia, tin and hydrochloric acid, sodium hydrosulphite, etc. Iron and hydrochloric acid are preferably used. Suitable catalysts for catalytic hydrogenation include Raney nickel, platinum, palladium and other catalysts which are generally effective for catalyzing the hydrogenation of nitro groups to amino groups.

Step 1 can also be carried out stepwise, namely by first haloalkylating a halo-nitro-(lower-hydrocarbyloxy)phenol (III) to form a halo-halo-alkoxyhydrocarbyloxynitrobenzene, which is then treated with a secondary amine of the formula HNB . The first step can be carried out by reacting a halo-nitro-(lower-hydrocarbyloxy)phenol or a metal derivative thereof with a haloalkylating agent, preferably with a haloalkyl ester of a strong inorganic acid or of an organic sulphonic acid, e.g. e.g. haloalkyl-para-toluenesulfonate, haloalkyl-benzenesulfonate, haloalkyl halide, and the like. An example of this stepwise procedure consists in halogenating 2-chloro-4-nitro-6-n-propoxyphenol by treating its potassium salt with 3-chloropropyl-paratoluene-sulfonate to form 3-chloro-4-(3- chloro-propoxy)-5-n-propoxynitrobenzene which is then treated with dimethylamine or piperidine to form 3-chloro-4-(3-diethyl-aminopropoxy)-5-n-propoxyaniline resp. 3-chloro-4-[3-(1-piperidyl)-propoxy]-5-n-propoxyaniline.

Meilomstof f one halogen- (lower-hydrocarbyloxy)-nitro-phenols (III) are generally known, and different methods for their preparation are also known. The inventors have prepared these intermediates, in which the halogen substituent is chlorine, bromine or iodine, by reacting the corresponding (lower-hydrocarbyloxy)-nitrophenols with a halogenating agent, e.g. bromine, pyridinium bromide-perbromide, sulfuryl chloride, chlorine, iodine monochloride, etc. Alternatively, these halo-(lower-hydrocarbyloxy)-nitrof enols can be prepared by nitrating a halo-(lower-hydrocarbyloxy)^-phenol, or by other published methods well known to chemists (see Examples IA and 2B). A method for the preparation of fluoro-(lower-hydrocarbyloxy)-nitrophenols consists in diazotizing an amino-(lower-hydrocarbyloxy)-nitrophenol, allowing the diazonium salt to react with fluoroboric acid to form diazonium fluoroborate, and heating the latter , whereby the desired fluoro-(lower-hydrocarbyloxy)-nitrophenol is formed.

The present invention also includes the production of N-(lower-acylated) derivatives of the aforementioned halogen-(lower-hydrocarbyloxy)-[lower-tertiary-amino

(polycarbon-lower-alkoxy) ] -anilines and their addition salts. Preferred compounds are the 3-halo-4-[lower-tertiary-amino(polycarbon-lower-alkoxy)]-5-(lower-alkoxy)-N-(lower-alkanoyl)-anilines, the free base of which has a formula which corresponds to the formula II in which one of the hydrogen atoms in the primary amino group is replaced by a lower-alkanoyl radical, denoted by Ac, where Ac represents

rer such a radical which preferably has one to six carbon atoms. These N-acylated derivatives also have local anesthetic activity. They are prepared by reacting a halogen-(lower-hydrocarbyloxy)-[lower-tertiary-amino(polycarbon-lower-alkoxy)]-aniline with a lower-acylating agent. The preferred substances are thus prepared by reacting a 3-halo-4-[lower-tertiary-amino (polycarbon-lower-alkoxy)]-5-(lower-alkoxy)-aniline with a lower alkanoylating agent such as e.g. . a lower alkano anhydride of the formula (Ac)2 O, a lower alkanoyl halide of the formula Ac-halogen where halogen is preferably chloride, bromide or iodide or — in the case of the formates, i.e. where Ac is HCO — the lower alkanoylating agent is formic acid.

The new halogen-(lower-hydrocarbyloxy)-[lower-tertiary-amino (polycarbon-lower-alkoxy)]-aniline derivatives can be used in the form of free base or in the form of addition salts. The acids that can be used for the production of the addition salts are preferably such that, when combined with the base, give salts whose anions are relatively harmless to the animal organism when the salts are used in therapeutic doses, so that the beneficial physiological effects of the free base are not reduced by side effects which can be attributed to the anions; in other words, the latter do not significantly affect the pharmacodynamic properties of the cations. The inventors have found it appropriate to use the hydrochloride salts, but other useful addition salts can be obtained using other mineral acids such as hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid and sulfuric acid and organic acids such as acetic acid, citric acid, tartaric acid, lactic acid, quinic acid, methanesulfonic acid, ethanesulfonic acid and similar.

The chemical structure of the halogen-(lower-hydrocarbyloxy)-[lower-tertiary-amino(polycarbon-lower-alkoxy)]anilines produced according to the invention has been determined by their method of preparation and verified by the agreement between the calculated and found values by elemental analysis of representative substances.

The following examples further illustrate the invention.

Example 1:

A. Halogen-nitro-(lower ε-alkoxy)- enols.

As noted above, these compounds are generally known from before, and various methods for their preparation are indicated in the literature. One of these methods consists in reacting a (lower alkoxy)-nitrophenol with a halogenating agent. This method is illustrated by the following synthesis of 2-bromo-4-nitro-6-n-propoxyphenol: A solution of 4.9 g of bromine in 75 ml of acetic acid was added to a stirred solution of 5.33 g of 2-n-propoxy-4-nitrophenol in 40 ml of acetic acid. The resulting solution was stirred on a water bath for an additional 2-2 hours. The reaction mixture was poured into a mixture of ice and water, whereupon a solid precipitated. This was collected and recrystallized once from ethanol water and once from isopropanol, whereby 2-bromo-4-nitro-6-n-propoxyphenol was obtained, m.p. 116.0—118.0° C (corr.).

Analysis: Calculated for CøHioBrNOé: N = 5.07; Br = 28.94. Found: N = 5.05; Br = 29.03.

The intermediate product 2-n-propoxy-4-nitrophenol was prepared from catechol (1,2-di-hydroxybenzene) by first dipropylating catechol to form 1,2-di-n-propoxybenzene and then nitrating this compound to 1,2-di-n-propoxy-4-nitrobenzene, after which the 1-ether was dealkylated. This three-step procedure was as follows: 1, 2-di-n-propoxybenzene. 343.4 g of n-propyl benzene sulphonate was slowly, under nitrogen and at a temperature range of approx. 45-80° C. was added to a solution containing 188.9 g of catechol, 111.5 g of potassium hydroxide, 650 ml of ethanol and 215 ml of water. After the reaction mixture had reacted for 1 hour under reflux cooling, a further 13 g of potassium hydroxide were added and the reaction was continued with reflux cooling for a total of 12 hours. To the resulting solution was added 98.5 g of potassium hydroxide in water, followed by the slow addition of 343.4 g of n-propylbenzenesulfonate. After 1 hour of reflux cooling, a further 15 g of potassium hydroxide were added and the reaction with reflux cooling was continued for a further 11 hours. The cooled mixture was separated in a separatory funnel and the aqueous layer was extracted with ether. The ether extracts were combined, dried and the ether removed by distillation in vacuo. After distillation of the residual material, 238.4 g of 1,2-di-n-propoxybenzene bp were obtained. 142—148° C at 30 mm. 1, 2- di- n- propoxy- 4- nitrobenzene. To a solution of 58 ml conc. nitric acid in 220 ml of acetic acid, which was kept at approx. 5-10° C, a solution of 84.3 g of 1,2-di-n-propoxybenzene in 130 ml of acetic acid was slowly added. The reaction mixture was stirred at approx. 5-10° C for approx. 20 minutes, and the temperature was then allowed to rise to room temperature during approx. 3— y2 hours. The mixture was then poured into ice water, the solid which separated was collected and recrystallized from methanol-water, thereby obtaining 97.2 g of 1,2-di-n-propoxy-4-nitrobenzene, m.p. 62.0—63.2° C. 2-n-propoxy-4-nitrophenol. A reaction mixture containing 29.1 g of 1,2-di-n-propoxy-4-nitrobenzene, 58 g of potassium hydroxide, 580 ml of water and 580 ml of ethylene glycol monomethyl ether was stirred under reflux for approx. 5 days. The mixture was evaporated to dryness in vacuo. 350 ml of water was added and the mixture was again evaporated to dryness. The rest were suspended for approx. 1 liter of water, filtered and the filtrate was acidified with conc. hydrochloric acid. The acidic aqueous solution was extracted with ether, the ether extract was evaporated in vacuo, and the residue was recrystallized from ethanol-water to give 22.6 g of crystalline 2-n-propoxy-4-nitrophenol, m.p. 81.5-82.5°C.

2-chloro-4-nitro-6-n-propoxyphenol is obtained by chlorinating 2-n-propoxy-4-nitrophenol with sulfuryl chloride as a chlorinating agent, following the procedure as in ex. 8A is indicated for the preparation of 2-chloro-4-nitro-6-methoxyphenol.

Other halo-nitro-(lower-alkoxy)phenols which can be prepared by applying the procedure indicated above for the preparation of 2-halogeno-4-nitro-6-n-propoxyphenols, using suitable reactants, are: 2-bromo-4-nitro-6-n-octoxyphenol by reacting 2-n-octoxy-4-nitrophenol with bromine; 2-nitro-4-bromo-5-isopropoxyphenol by reacting 2-nitro-5-isopropoxyphenol with bromine; 2-bromo-4-n-butoxy-6-nitrophenol by reacting 2-nitro-4-n-butoxyphenol with bromine; 2-n-propoxy-4-bromo-5-nitrophenol by reacting 2-n-propoxy-5-nitrophenol with bromine; 2-chloro-4-nitro-5-ethoxyphenol by reacting 3-ethoxy-4-nitrophenol with sufuryl chloride;

2-iodo-4-nitro-6-n-propoxyphenol by reacting 2-n-propoxy-4-nitrophenol with iodine monochloride, and the like.

These halogen-nitro-(lower-alkyl)-phenol intermediates can also be prepared by other known methods, such as nitration of halogen-(lower-alkyl)-phenols, e.g. preparation of 2-nitro-3-chloro-5-methoxyphenol by nitrating 3-chloro-5-methoxyphenol (Hodgson and Batty, J. Chem. Soc. 1934, 1433), or by reacting a halogen-hydroxy- (lower -Alkoxy)-benzaldehyde with cold, fuming nitric acid, e.g. preparation of 2-nitro-4-bromo-5-methoxyphenol by reacting 2-hydroxy-4-methoxy-5-bromobenzaldehyde with cold, fuming nitric acid (Srikantia et al., J. Chem. Soc.

1932, 524), or other methods. Illustrative of the preparation of a fluoro-nitro-(lower-alkoxy)-phenol is the preparation of 2-fluoro-4-nitro-6-methoxyphenol by diazotizing 2-amino-4-nitro-6-methoxyphenol, allowing the resulting diazo -nium salt react with fluoroboric acid so that the corresponding diazonium fluoroborate is formed and heat the fluoroborate so that 2-fluoro-4-nitro-6-methoxy enol is formed!. Other syntheses of halo-nitro-(lower-alkoxy)-phenols are given in Examples 2A and 2B.

B. Halogen-(lower- alkoxy)-[lower-tertiary-amino(polycarbon- lower- alkoxy) J-nitrobenzenes.

The preparation of these compounds is illustrated by the following preparation of 3-bromo-4-(2-diethylaminoethoxy)-5-n-propoxynitrobenzene: A solution of sodium ethoxide was obtained by reacting 0.5 g of sodium with 20 ml of absolute alcohol, add 5 ml of toluene and remove the excess of ethanol by distillation. To this solution was added 6.1 g of 2-bromo-4-nitro-6-n-propoxyphenol to convert it to its sodium salt. A solution of 2.98 g of 2-diethylaminoethyl chloride in 50 ml of toluene was then added, and the resulting reaction mixture was stirred under reflux for approx. 87 hours under water-free conditions. The solid sodium chloride was filtered off, the solvent removed by distillation in vacuo, and the remaining oily material 3-bromo-4-(2-diethylaminoethoxy)-5-n-propoxynitrobenzene, in its free form base, was taken up in ether and treated with an excess of ethereal hydrogen chloride to give a light brown solid. This was dissolved in water and treated with an aqueous solution of potassium carbonate. The oily product which separated was taken up in ether and the ethereal solution was treated with an excess of ethereal hydrogen chloride to give the solid hydrochloride. This salt was recrystallized three times from ethanol-ether, whereby 3-bromo-4-(2-diethylaminoethoxy)-5-n-propoxynitrobenzene was obtained in the purified state in the form of its monohydrochloride salt, m.p. 148.6—151.2° C (corr.).

j Analysis: Calculated for CiBH2:tBrN204.HCl:

Cl- = 8.61; N = 6.80. Found: Cl- 8.61; N = 6.63. c Other halogeno-(lower-alkoxy)-[lower-tertiaryamino-(polycarbon-lower-alkoxy)]-nitrobenzenes which can be prepared read according to the preceding method for the preparation of 3-bromo-4-(2-diethylaminoethoxy)-5-n-prop-oxynitrobenzene by using the appropriate halogen-(lower-alkoxy)-nitroph enol and lower-tertiary-amino-( polycarbon-lower-alkyl)halide is: 3-bromo-4-(2-dimethylaminoethoxy)-5-n-propoxy-nitrobenzene using 2-bromo-4-nitro-6-n-propoxyphenol and 2-dimethylaminoethyl chloride ; 3-chloro-4-(2-diethylaminoethoxy)-5-n-propoxynitrobenzene using 2-chloro-4-nitro-6-n-propoxyphenol and 2-diethylaminoethyl bromide; 3-bromo-4-(2-di-n-butylaminoethoxy)-5-n-propoxynitro-benzene using 2-bromo-4-nitro-6-n-propoxyphenol and 2-di-n-butylaminoethyl-iotyl. d; 3-bromo-4-(4-diethylaminobutoxy0;-5-n-propoxynitrobenzene using 2-bromo-4-nitro-6-n-propoxyphenol and 4-diethylaminobutyl chloride; 3-bromo-4- [2- ( N-methyl-N-ethyl)-aminoethoxy]-5-n-propoxy-synnitrobenzene using 2-bromo-4-nitro-6-n-propoxyphenol and 2-(N-methyl-N-ethyl)-aminoethyl chloride; 3-bromo-4-(3-diethylamino-2-propoxy)-5-n-propoxynitrobenzene using 2-bromo-4-nitro-6-n-propoxyphenol and 3-diethylamino-2-propyl chloride; 3-bromo-4-(2-diethylaminoethoxy)-5-n-octoxynitrobenzene using 2-bromo-4-nitro-6-n-octoxyphenol and 2-diethylaminoethyl chloride; 2-(2-diethylaminoethoxy)-4-isopropoxy- 5-bromonitrobenzene using 2-nitro-4-bromo-5-isopropoxyphenol and 2-diethylaminoethyl chloride; 2-(2-diethylaminoethoxy)-3-bromo-5-n-butoxynitrobenzene using 2- bromo-4-n-butoc-sy-6-nitrophenol and 2-diethylaminoethyl chloride; 2-bromo-4-n-propoxy-5-[3-(1-piperidyl)-propoxy]-nitrobenzene using 2-n- propoxy-4-bromo-5-nitrophenol and 3-(1-piperidyl) propyl chloride; 2-ethoxy-4-[2-(3-ethyl-1-piper idyl)ethoxy]-5-chloronitrobenzene using 2-chloro-4-nitro-5-ethoxyphenol and 2-(3-ethyl-1-piperidyl)ethyl chloride; 2-chloro-4-methoxy-6-[3-(1-pyrrolidyl)propyl]nitrobenzene using 2-nitro-3-chloro-5-methoxyphenol and 3-(1-pyrrolidyl)propyl chloride; 2-[2-(2,5-dimethyl-1-pyrroly-yl)ethoxy]-4-methoxy-5-bromonitrobenzene by using 2-nitro-4-bromo-5-methoxyphenol and 2- (2,5-dimethyl-1-pyrrolidyl)-ethyl chloride; 3-iodo-4-(2-diethylaminoethoxy)-i-n-propoxynitrobenzene using 2-od-4-nitro-6-n-propoxyphenol and 2-diethyliminoethyl chloride; 3-fluoro-4-(2-diethylamino-:thoxy)-5-methoxynitrobenzene by adding 2-fluoro-4-nitro-6-methoxyphenol and 2-liethylaminoethyl chloride; and similar. These >asian ethers can be isolated as free base or form of addition salts, preferably as lydrochlorides. C. Halogen- ( lower- alkoxy) - { lower- tertiary- amino ( polycarbon- lower- alkoxy)] - anilines.

The preparation of these compounds is illustrated by the following preparation of 3-bromo-4-(2-diethylaminoethoxy)-5-n-propoxyaniline: A solution containing 4.1 g of 3-bromo-4-(2-diethylaminoethoxy)- 5-n-propoxynitrobenzene monohydrochloride, 35 ml of ethanol and 35 ml of water were added slowly under stirring and under an atmosphere of nitrogen and using reflux cooling to a mixture containing 3.3 g of iron powder, 0.3 ml of conc. hydrochloric acid, 50 ml of ethanol and 50 ml of water. The reaction mixture was heated with reflux and stirring for a further two hours. It was then basified with sodium bicarbonate, the solid that separated was filtered off, and the filter cake was washed well with hot ethanol. The filtrate was evaporated to dryness in vacuo, the residue was dissolved in water, and the aqueous solution was made strongly basic with potassium hydroxide, whereby 3-bromo-4-(2-diethylaminoethoxy)-5-n-propoxyaniline was liberated, which was recorded on air. The ether solution was dried over anhydrous sodium sulfate, treated with decolorizing charcoal and filtered. A small excess of ethereal hydrogen chloride was added to the second filtrate. The resulting precipitate was recrystallized from ethanol-ether to give, as fine needles, 3-bromo-4-(2-diethylaminoethoxy)-5-n-propoxyaniline in the form of its dihydrochloride salt, m.p. 146.4° C — undetermined (corr.).

Analysis: Calculated for CioHMBrN2O2.2HCl: Cl- = 16.96; C = 43.08; H = 6.51. Found: Cl- = 16.91; C = 42.92; H = 6.27.

Pharmacological testing of 3-bromo-4-(2-diethylaminoethoxy)-5-n-propoxyaniline dihydrochloride in aqueous solution given to guinea pigs intradermally according to the method indicated by Bulbring and Wajda [J. Phar-macol. & Exptl. Therapy. 85, 78 (1945)] has shown that this compound (calculated as free base) is about 15 times more active as a local anesthetic than procaine hydrochloride. When using the trypan blue irritation test, which is described by Hoppe et al. [J. Am. Pharm. Assoc. 39, 147 (1950) modified by Luduena and Hoppe [J. Pharm & Exptl. Therapy. 104, 40 (1952)] it was found that this compound is only approx. 4 times as irritating as procaine hydrochloride.

Other halogen- (lower-alkoxy)- [lower-tertiary-amino (polycarbon-lower-alk-

oxy)]-anilines which can be prepared according to the preceding method for the preparation of 3-bromo-4-(2-diethylaminoethoxy)-5-n-propoxy-aniline specified method using the corresponding halogen-(lower-alkoxy)-[ lower-tertiary-amino-(polycarbon-lower-alkoxy) ] -nitrobenzene is: 3-bromo-4-(2-dimethylaminoethoxy)-5-n-propoxyaniline, 3-chloro-4-(2-diethylaminoethoxy)-5- n-propoxyaniline, 3-bromo-4-(2-di-n-butylaminoethoxy)-5-n-propoxyaniline, 3-bromo-4- [2-(N-methyl-N-ethyl)- aminoethoxy] - 5-n-propoxyaniline, 3-bromo-4-(3-diethylamino-2-propoxy)-5-n-propoxyaniline, 3-bromo-4-(2-diethylaminoethoxy)-5-n-octoxyaniline, 2- (2-diethylaminoethoxy)-4-isopropoxy-5-bromoaniline, 2-(2-diethylaminoethoxy)-3-bromo-5-n-butoxyaniline, 2-ethoxy-4-[2-(3-ethyl- l-piperidyl)-ethoxy]-5-chloroaniline, 2-chloro-4-methoxy-6-[3-(l-pyrrolidyl)propyl]-aniline, 2-[2-(2,5-dimethyl-l-pyrrolidyl )ethoxy]-4-methoxy-5-bromoaniline, 3-iodo-4-(2-diethylaminoethoxy)-5-n-propoxyaniline, 3-fluoro-4-(2-diethylaminoethoxy)-5-methoxyaniline n, and similar. These ethers can be isolated as a free base or in the form of addition salts, preferably as hydrochlorides.

Example 2:

A. 2- bromo- 4- nitro- 6- methoxyphenol.

The inventors have prepared this compound [Robertson, J. Chem. Soc. 93, 792

(1908)] by the one in ex. IA described process for the preparation of the corresponding 2-bromo-4-nitro-6-n-propoxyphenol, using 33.8 g of 2-methoxy-4-nitrophenol, 300 ml of acetic acid and 35.2 g of bromine in 250 ml acetic acid. 43.1 g of 2-bromo-4-nitro-6-methoxyphenol were obtained, m.p. 159.7—160.3° C. The same tri-substituted phenol was obtained by slow addition of 8.0 g of bromine in 100 ml of methanol to 6.22 g of the potassium salt of 2-methoxy-4-nitrophenol in 125 ml of water , whereby 3.03 g of product is obtained. 2-Bromo-4-nitro-6-methoxyphenol was also obtained by using pyridinium bromide-perbromide as brominating agent in the following way: To a solution containing 8.5 g of 2-methoxy-4-nitrophenol in 75 ml of acetic acid and 0.6 ml of 30% hydrogen bromide in acetic acid, a warm solution containing 20.5 g of pyridinium bromide-perbromide and 4.51 g of molten sodium acetate in 200 ml of acetic acid was added dropwise and with stirring over the course of 30 minutes. Stirring was continued for a further 40 minutes, after which the reaction mixture, while stirring, was poured into 2 liters of a mixture of ice and water. The precipitated product was collected and recrystallized from ethanol water. 2-Methoxy-4-nitrophenol was produced from 1,2-dimethoxybenzene as starting material by the working method as in ex. IA is indicated for the preparation of 2-n-propoxy-4-nitrophenol. In this way, 61.1 g of 1,2-dimethoxy-4-nitrobenzene, m.p. 97.3—98.0° C, by using 50 g of 1,2-dimethoxybenzene in 50 ml of acetic acid, 60 ml of conc. nitric acid and 100 ml of water. 2- methoxy- 4- nitrophenol, m.p. 100-100.5° C, was obtained in an amount of 3.9 g by using 5.0 g of 1,2-dimethoxy-4-nitrobenzene, 10 g of potassium hydroxide, 100 ml of water and a reflux period of approx. 15 hours.

B. Halogen-methoxy-[lower-tertiary- amino-polycarbon lower- alkoxy)]-nitrobenzenes.

The preparation of these compounds is illustrated by the preparation of 3-bromo-4-(2-diethylaminoethoxy)-5-methoxynitrobenzene by the method in ex. IB stated procedure using 9.9 g of 2-bromo-4-nitro-6-methoxyphenol, 0.9 g of sodium, 20 ml of ethanol, 75 ml of toluene and 5.4 g of 2-diethylaminoethyl chloride in 75 ml of toluene. 8.24 g of 3-bromo-4-(2-diethylaminoethoxy)-5-methoxynitrobenzene were obtained in the form of its monohydrochloride, m.p. 170.4—172.6° C (corr.). Analysis: Calculated for CiHHioBrN2O4.HCl: Cl- = 9.24; NTi = 3.65.

Found: Cl- = 9.17; NTi = 3.63.

NTi here denotes nitro-nitrogen determined by titration with standard titano-chloride in glacial acetic acid solution.

Other halo-methoxy- [lower-tertiary-amino (polycarbon-lower- alkoxy) ] -

nitrobenzenes which can be prepared by the method described above for the preparation of 3-bromo-4-(2-diethylaminoethoxy)-5-methoxynitrobenzene using the appropriate halo-methoxynitro-phenol and lower-tertiary-amino(polycarbon-lower-alkyl )-halide is: 3-bromo-4-[3-(1-piperidyl)propoxy]-5-methoxynitrobenzene using 2-bromo-4-nitro-6-methoxyphenol and 3-(1-piperidyl)propylchloro - ride; 2-(2-diethylaminoethoxy)-3-methoxy-5-bromonitrobenzene using 2-methoxy-4-bromo-6-nitrophenol [Robertson, J. Chem. Soc. 93, 791 (1908)] and 2-diethylaminoethyl bromide; 2-Bromo-3-(2-diethylaminoethoxy)-4-methoxynitrobenzene using 2-bromo-3-nitro-6-methoxyphenol [Jones and Robinson, J. Chem. Soc. 111, 917 (1916)] and 2-diethylaminoethyl chloride; 2-bromo-4-methoxy-

5-(2-diethylaminoethoxy)nitrobenzene using 2-methoxy-4-bromo-5-nitrophenol [Raiford and Silker, J. Org. Chem. 2, 346

(1937)] and 2-diethylaminoethyl chloride; 2-[2-(1-pyrrolidyl)ethoxy]-3-chloro-6-methoxy-nitrobenzene using 2-nitro-3-methoxy-6-chlorophenol [Meldola and Eyre, J. Chem. Soc. 81, 999 (1902)] and 2-(1-pyrrolidyl)-ethyl chloride; 2-Methoxy-4-chloro-6-(2-diethyl-aminoethoxy)nitrobenzene using 2-nitro-3-methoxy-5-chlorophenol (Hodgson and Batty, J. Chem. Soc. 1934, 1433) and 2- diethylaminoethyl chloride; 2-chloro-4-methoxy-6-(2-diethylaminoethoxy)nitrobenzene using 2-nitro-3-chloro-5-methoxyphenol (Hodgson and Hignall, J. Chem. Soc. 1928, 329) and 2-diethylaminoethyl chloride; 2-(2-diethylaminoethoxy)-4-methoxy-5-bromonitrobenzene using 2-nitro-4-bromo-5-methoxyphenol (Hodgson and Dyson, J. Chem. Soc. 1935, 946) and 2-diethylaminoethyl chloride ;

2-(2-diethylaminoethoxy)-4-methoxy-5-chloronitrobenzene using 2-nitro-4-chloro-5-methoxyphenol [Beilstein, 6 (404)] and 2-diethylaminoethyl chloride; 2-methoxy-4-bromo-5-(2-diethylaminoethoxy)nitrobenzene using 2-bromo-4-methoxy-5-nitrophenol and 2-diethylaminoethyl chloride; 2-(2-Diethylaminoethoxy)-4-methoxy-5-iodnitrobenzene using 2-nitro-4-iodo-5-methoxyphenol [Stephens, J. Chem. Soc. 87, 1201 (1905)] and 2-diethylaminoethyl chloride; 2-(2-Diethylaminoethoxy)-3-iodo-6-methoxy-nitrobenzene using 2-nitro-3-methoxy-6-iodophenol [Meldola and Hay, J. Chem. Soc. 91, 1484 (1907)] and 2-diethylaminoethyl chloride; and similar. C. Halogen-methoxy-{lower-tertiary-amino(polycarbon-lower- alkoxy)]-anilines.

The preparation of these compounds is illustrated by the preparation of 3-bromo-4-(2-diethylaminoethoxy)-5-methoxyaniline according to the method indicated in ex. 1C using 23.0 g of 3-bromo-4-(2-diethylaminoethoxy)-5-methoxynitrobenzene hydrochloride, 420 ml of a mixture containing equal parts of ethanol and water, 19.9 g of iron powder and 1.5 ml of hydrochloric acid in 600 ml of 1:1 ethanol-water mixture. 23.3 g of 3-bromo-4-(2-diethylaminoethoxy)-5-methoxyaniline were obtained in the form of its dihydrochloride, m.p. 175-180° C. When it had been found in a previous experiment that this dihydrochloride loses part of a hydrogen chloride equivalent on drying, it was converted to monohydrochloride by first converting more than half of the dihydrochloride salt to the free base by treating a aqueous solution of it with alkali and extract the base either with ether or with ethyl acetate, and add the remaining dihydrochloride salt dissolved in absolute ethanol. The precipitated monochloride salt was collected and recrystallized from ethanol-ether, whereby 15.4 g of 3-bromo-4-(2-diethylaminoethoxy)-5-methoxyaniline monohydrochloride was obtained, m.p. 220.8—224.6° C (corr.).

Analysis: Calculated for Ci3H2iBrN220.HCl: C = 44.14; H = 6.27; Cl- = 10.02. Found: C = 44.24; H = 6.36; Cl- = 10.02.

Pharmacological testing of 3-bromo-4-(2-diethylamino-ethoxy)-5-methoxyaniline monohydrochloride by the methods described in ex. 1C has shown that this compound, considered as a base, is an approx. 3 times more active local anesthetic than procaine hydrochloride and is approx. 1— y2 times as annoying.

Other halogeno-methoxy- [lower-tertiary-amino (polycarbon-lower-alkoxy) ] - anilines which can be prepared by the above-described working method for the preparation of 3-bromo-4-(2-diethylaminoethoxy)-5-methoxyaniline by use of the corresponding halo-methoxy-[lower-tertiary-amino-(polycarbon-lower-alkoxy)]nitrobenzene is: 3-bromo-4-[3-(1-piperidyl)propoxy]-5-methoxyaniline, 2-( 2-diethylaminoethoxy)-3-methoxy-5-bromoaniline, 2-bromo-3-(2-diethylaminoethoxy)-4-methoxyaniline, 2-bromo-4-methoxy-5-(2-diethylaminoethoxy)-aniline, 2- [ 2-(1-pyrrolidyl)ethoxy]-3-chloro-6-methoxyaniline, 2-methoxy-4-chloro-6-(2-diethylaminoethoxy)aniline, 2-chloro-4-methoxy-6-(2-diethylaminoethoxy) aniline, 2-(2-diethylaminoethoxy)-4-methoxy-5-bromoaniline, 2-(2-diethylaminoethoxy)-4-methoxy-5-chloroaniline, 2-methoxy-4-bromo-5-(2-diethylaminoethoxy)- aniline, 2-(2-diethylaminoethoxy)-4-methoxy-5-iodoaniline, 2-(2-diethylaminoethoxy)-3-iodo-6-methoxyaniline, and the like. These basic ethers can be isolated as free bases or in the form of addition salts, preferably as monohydrochlorides.

Example 3:

A. 2- bromo- 4- nitro- 6- ethoxyphenol.

This compound was produced by the method described in ex. IA for the preparation of the corresponding 2-bromo-4-nitro-6-n-propoxyphenol, using 36.6 g of 2-ethoxy-4-nitrophenol, 250 ml of acetic acid and 35.2 g of bromine in 160 ml of acetic acid. 39.5 g of 2-bromo-4-nitro-6-ethoxyphenol were then obtained, m.p. 160.2—161.8° C (corr.). Analysis: Calculated for C<g>HsBrNCU: N = 5.34; Br = 30.50.

Found: N = 5.32; Br = 30.85.

2-ethoxy-4-nitrophenol was prepared from catechol by the method indicated in ex. IA for the preparation of 2-n-propoxy-4-nitrophenol. 1, 2- Diethoxybenzene was prepared in the following way: To a solution of 220.2 g of catechol, 171.5 g of sodium hydroxide and 1 liter of water, slowly, under a nitrogen atmosphere and with rapid stirring at approx. 10° C put 524 ml of diethyl sulfate. The temperature of the resulting suspension was allowed to rise to room temperature, which took approx. 4 hours, after which the suspension was heated to approx. 70-80° C for a further 2y2 hours. The mixture was steam distilled, the distillate was cooled and the precipitate was collected. The latter was recrystallized from methanol-water, whereby 207.1 g of 1,2-diethoxybenzene was obtained, m.p. 41.3—42.1° C. A yield of 240.1 g l, 2-diethoxy-4-nitrobenzene, m.p. 72.0-73.4° C was obtained by using 199.5 g of 1,2-diethoxybenzene in 400 ml of acetic acid and 190 ml of conc. nitric acid in a mixture of 330 ml water and 250 ml acetic acid. 2- ethoxy- 4- nitrophenol, m.p. 95.5-97.5°C was obtained in an amount of 50.5 g using 63.3 g of 1,2-diethoxy-4-nitrobenzene, 127 g of potassium hydroxide, 800 ml of water, 800 ml of ethylene glycol monomethyl ether and reaction with reflux for about. 3 days.

B. 3-bromo-4-(2-diethylaminoethoxy)-5-ethoxynitrobenzene.

This compound was prepared by that in ex. IB indicated working method and use of 13.1 g of 2-bromo-4-nitro-6-ethoxyphenol, 1.2 g of sodium, 25 ml of ethanol, 75 ml of toluene and 6.8 g of 2-diethylamino-ethyl chloride in 70 ml of toluene. 15.8 g of 3-bromo-4-(2-diethylaminoethoxy)-5-ethoxynitrobenzene were then obtained as monohydrochloride, m.p. 167.0—168.2° C (corr.).

Analysis: Calculated for Ci4H2iBrN2C>4.HCl: Cl- = 8.92; Nti = 3.53.

Found: Cl- = 8.90; NTi = 3.32. C. 3-bromo-4-(2-diethylaminoethoxy)-5-ethoxyaniline.

This compound was prepared in the manner described in ex. 1C by using 23.9 g of 3-bromo-4-(2-diethylaminoethoxy)-5-ethoxynitrobenzene hydrochloride,

420 ml of a mixture containing equal parts of ethanol and water, 19.9 g of iron powder and 1.5 ml of hydrochloric acid in 600 ml of a 1:1 ethanol-water mixture. 22.3 g of 3-bromo-4-(2-diethylaminoethoxy)-5-ethoxyaniline were obtained in

form of its dihydrochloride salt, m.p. 148-168° C. The dihydrochloride was converted in the manner described above into 16.0 g of the corresponding monohydrochloride salt, m.p. 169.0

-173.4° C (corr.).

Analysis: Calculated for Ci4H2:iBrN2O2.HCl: C = 45.73; H = 6.58; Cl- = 9.64. Found: C = 45.43; H = 6.58 Cl - = 9.78.

Pharmacological testing of 3-bromo-4-(2-diethylaminoethoxy)-5-ethoxyanilinide hydrochloride by the ex. 1C indicated method has shown that this compound (considered as its base) is about six times as active a local anesthetic as procaine hydrochloride and is about four times as irritating:

Example 4:

A. 2- bromo- 4- nitro- 6- n- butoxyphenol.

This compound was prepared by working as described in ex. IA for the preparation of the corresponding 2-bromo-4-nitro-6-n-propoxyphenol, using 8.8 g of 2-n-butoxy-4-nitrophenol, 80 ml of acetic acid and 7.4 g of bromine in 90 ml of acetic acid . 5.9 g of 2-bromo-4-nitro-6-n-butoxyphenol was then obtained, m.p. 97.2—98.4° C (corr.).

Analysis: Calculated for CioHi2BrNC>4: N = 4.83; Br = 27.53. Found: N = 4.87; Br = 27.38.

2-n-butoxy-4-nitrophenol was produced from catechol as starting material by following the method described in ex. IA for the preparation of 2-n-propoxy-4-nitrophenol. 1,2-di-n-butoxybenzene was produced, b.p. 149-152°C at 16 mm, using 154.2 g (one portion) of n-butyl benzene sulfonate, 39.6 g of catechol, 46.9 g of potassium hydroxide, 270 ml of ethanol, 90 ml of water and an additional 5, 0 g portion of potassium hydroxide; the yield was 50.1 g. 1,2-di-n-butoxy-4-nitrobenzene, m.p. 51.5-53.0° C was obtained in a quantity of 58.0 g by using 50.1 g of 1,2-di-n-butoxybenzene in 65 ml of acetic acid and 30 ml of conc. nitric acid in 115 ml of acetic acid. 9.0 g of 2-n-but-oxy-4-nitrophenol were obtained, m.p. 38-39° C, using 13.1 g of 1,2-di-n-butoxy-4-nitrobenzene, 26 g of potassium hydroxide, 260 ml of water,

260 ml of ethylene glycol monomethyl ether and a reflux period of approx. 4 days.

B. 3-bromo-4-(2-diethylaminoethoxy)-5-n-butoxynitrobenzene.

This compound was prepared by following that in ex. IB described procedure and use 14.5 g of 2-bromo-4-nitro-6-n-butoxyphenol, 1.2 g of sodium, 5 ml of ethanol, 100 ml of toluene and 6.8 g of 2-diethylamino-ethyl chloride in 140 ml of toluene . 15.4 g of 3-bromo-4-(2-diethylaminoethoxy)-5-n-butoxy-nitrobenzene were then obtained in the form of its monohydrochloride, m.p. 98.2—100° C (corr.).

Analysis: Calculated for Ci8H2sBrN2O4.HCl: N = 6.58; Cl- = 8.33.

Found: N = 6.84; Cl- = 8.24. C. 3-bromo-4-(2-diethylaminoethoxy)-5-n-butoxyaniline.

This compound was prepared by using the method described in ex. 1C and using 5.5 g of 3-bromo-4-(2-diethylaminoethoxy)-5-n-butoxynitrobenzene hydrochloride, 90 ml of a 1:1 mixture of ethanol-water, 4.4 g of iron powder and 0.4 ml hydrochloric acid in 130 ml of a 1:1 mixture of ethanol-water. 5.0 g of 3-bromo-4-(2-diethylaminoethoxy)-5-n-butoxyaniline was obtained in the form of its dihydrochloride salt, m.p. 171.0—190.6° C (corr.).

Analysis: Calculated for Ci6H27BrN2O2.2HCl: C = 44.46; H = 6.77; Cl - = 16.41.

Found: C = 44.61; H = 6.88; Cl - = 16.29.

Pharmacological testing of 3-bromo-4-(2-diethylamino-ethoxy)-5-n-butoxyaniline dihydrochloride by the methods described in ex. 1C has shown that this compound (considered as its base) is approximately twenty times more active as a local anesthetic than procaine hydrochloride and approx. six times as annoying.

Example 5:

A. 2- bromo- 4- nitro- 6- n- hexoxyphenol.

This compound was produced by following the working method as in ex. 2A is described for the preparation of the corresponding 2-bromo-4-nitro-6-methoxyphenol and to use 2.2 g of the potassium salt of 2-n-hex-oxy-4-nitrophenol in 45 ml of acetic acid and a mixture of 3 .27 g of pyridinium bromide per-bromide and 0.2 ml of 30% HBr in acetic acid in 45 ml of acetic acid. 1.79 g of 2-bromo-4-nitro-6-n-hexoxyphenol were then obtained, m.p. 84.2

-88.2° C (corr.).

Analysis : Calculated for C^HmBrNCv.

N = 4.40; Br = 25.12. Found: N = 4.37; Br = 24.90.

2-n-hexoxy-4-nitrophenol was prepared from catechol as starting material by following the working method indicated in ex. IA for the preparation of 2-n-propoxy-4-nitrophenol. 33.8 g of 1,2-di-n-hexoxybenzene were obtained, b.p. 182-185° C at 10 mm, using 116.3 g (one portion) of n-hexylbenzenesulfonate, 22.0 g of catechol, 26.1 g of potassium hydroxide, 15 ml of ethanol, 50 ml of water and an additional portion of 9.8 g of potassium hydroxide. 39.4 g of 1,2-di-n-hexoxy-4-nitrobenzene were obtained, m.p. 48-50° C, by using 36.1 g of 1,2-di-n-hexoxybenzene in 40 ml of acetic acid and 17.3 ml of concentrated nitric acid in 65 ml of acetic acid. 2-n-hexoxy-4-nitrophenol was obtained as a reddish-brown oil by using 5.0 g of 1,2-di-n-hexoxy-4-nitrobenzene, 25 g of potassium hydroxide, 100 ml of water, 100 ml of ethylene glycol monoethyl ether and a grace period of more than 5 days; the yield was 2.73 g of the product.

B. 3-brom-4-(2-diethylaminoethoxy)-5-n-hexoxynitrobenzene.

This compound was prepared by following that in ex. IB described method and to use 8.0 g of 2-bromo-4-nitro-6-n-hexoxyphenol, 0.6 g of sodium, 40 ml of ethanol, 100 ml of toluene and 3.4 g of 2-diethylamino-ethyl chloride in 20 ml toluene. The yield was 8.2 g of 3-bromo-4-(2-diethylaminoethoxy)5-n-hexoxynitrobenzene in the form of its monohydrochloride, m.p. 127.6—129.0° C (corr.).

Analysis: Calculated for Ci8H2!)BrN2Oj.HCl: N'Ti = 3.09; Cl - = 7.83. Found: N'Ti = 3.04; Cl- = 7.76.

By following the above procedure and using an equivalent amount of 2-bromo-4-nitro-6-n-amoxyphenol or 2-bromo-4-nitro-6-isoamoxyphenol in place of 2-bromo-4-nitro-6- n-hexoxyphenol, is obtained in the form of the monohydrochloride salt 3-bromo-4-(2-diethylaminoethoxy)-5-n-amoxynitrobenzene or 3-Bromo-4-(2-diethylaminoethoxy)-5-isoamoxynitrobenzene. C. 3-bromo-4-(2-diethylaminoethoxy)-5-n-hexoxy'aniline.

This compound was prepared by following that in ex. 1C indicated progress

manner and use 6.1 g of 3-bromo-4-(2-diethyl-aminoethoxy)-5-n-hexoxy-nitrobenzene hydrochloride, 95 ml of a 1:1 mixture of ethanol and water, 4.6 g of iron powder and 0.4 ml of hydrochloric acid in 135 ml of a 1:1 ethanol-water mixture. 5.0 g of 3-bromo-4-(2-diethylaminoethoxy)-5-n-hexoxyaniline in

form of its dihydrochloride salt, m.p. 193.0

-196.0° C (corr.).

Analysis: Calculated for Ci8H3iBrN2O2.2HCl: C = 46.97; H = 7.21; Cl - = 15.41.

Found: C = 47.13; H = 7.56; Cl- = 15.36.

Pharmacological testing of 3-bromo-4-(2-diethylaminoethoxy)-5-n-hexoxyaniline dihydrochloride by the ex. 1C indicated method has shown that this compound (considered as its base) is approx. 39 times as active as the local anesthetic procaine hydrochloride is.

By following the above procedure and using 3-bromo-4-(2-diethylaminoethoxy)-5-n-amoxynitrobenzene hydrochloride or 3-bromo-4-(2-diethylaminoethoxy)-5-isoamoxynitrobenzene hydrochloride, one obtains in the form of the dihydrochloride 3-bromo-4-(2-diethylaminoethoxy)-5-n-amoxyaniline resp. 3-Bromo-4-(2-diethylaminoethoxy)-5-isoamoxyaniline.

Example 6:

A. 2- bromo- 4- nitro- 6- benzyloxyphenol.

This compound was prepared by following that in ex. 2A specified working method

for the preparation of the corresponding 2-bromo-4-nitro-6-methoxyphenol and use 24.5 g of 2-benzyloxy-4-nitrophenol, 3 ml of 30% HBr in acetic acid, 40.9 g of pyridinium bromide-perbromide, 8, 2 molten sodium acetate and 700

ml of acetic acid. You then get 20.2 g of 2-bromo-4-nitro-6-benzyloxyphenol, m.p. 126.0—134.4°

C (corr.).

Analysis: Calculated for CnHioBrNCU: N = 4.32; Br = 24.66.

Found: N = 4.04; Br = 24.95.

2-Benzyloxy-4-nitrophenol was prepared with catechol as starting material by

the working method described in ex. IA for the preparation of 2-n-propoxy-4-nitrophenol. 1,2-di-benzyloxybenzene was prepared as follows: A mixture containing 278.2 g of benzyl chloride, 110.1 g of catechol, 148.5 g of sodium carbonate, 16.8 g of potassium iodide, 8 ml of water (used to dissolve up the potassium iodide) and 900 ml of ethanol, was for approx.

12 hours stirred at reflux under a nitrogen atmosphere. The hot suspension was filtered and the filter cake was washed well with hot absolute ethanol. The combined filtrates were evaporated to a volume of approx. 400 ml, cooled and the precipitated substance was collected and recrystallized from ethanol, whereby 130.3 g of 1,2-dibenzyloxybenzene was obtained, m.p. 58—59° C, 1,2-dibenzyloxy-4-nitrobenzene, m.p. 98.8-99.5° C, was obtained by using 116.1 g of 1,2-dibenzyloxybenzene in 600 ml of acetic acid and 53.4 ml of conc. nitric acid in 650 ml acetic acid; the yield was 124.6 g. 2-benzyloxy-4-nitrophenol, m.p. 80.2-82.0° C, was obtained in an amount of 42.9 g by using 100.6 g of 1,2-dibenzyloxy-4-nitrobenzene, 201 g of potassium hydroxide, 1800 ml of water, 1800 ml of ethylene glycol monomethyl ether and a reflux period of about. 40 hours.

B. 3-bromo-4-(2-diethylaminoethoxy)-5-benzyloxynitrobenzene.

This compound was produced by following the working method indicated in ex. IB and using 16.2 g of 2-bromo-4-nitro-6-benzyloxyphenol, 1.2 g of sodium, 50 ml of ethanol, 100 ml of toluene and 6.8 g of 2-diethylaminoethyl chloride in 40 ml of toluene. 20.9 g of 3-bromo-4-(2-diethylaminoethoxy)-5-benzyloxynitrobenzene was then obtained in the form of its monohydrochloride, m.p. 165.8—167.0° C (corr.).

Analysis: Calculated for C19H2.iBrN2O4.HCl: NTi = 3.05; Cl - = 7.72. Found: NT1 = 2.99; Cl- = 7.69. C. 3-bromo-4-(2-diethylaminoethoxy)-5-benzyloxy aniline.

This compound was prepared by following that in ex. 1C described method and using 4.6 g of 3-bromo-4-(2-diethylaminoethoxy)-5-benzyloxynitrobenzene hydrochloride, 70 ml of a 1:1 mixture of ethanol and water, 3.3 g of iron powder and 0, 30 ml of hydrochloric acid in 100 ml of a 1:1 mixture of ethanol and water. 4.0 g of 3-bromo-4-(2-diethylaminoethoxy)-5-benzyloxyaniline was then obtained in the form of its dihydrochloride salt, m.p. 223.2—224.6° C (corr.).

Analysis: Calculated for CioH2oBrN2O2.2HCl: C = 48.94; H = 5.84; Cl- = 15.21. Found: C = 49.04; H = 5.92; Cl- = 15.11.

Pharmacological testing of 3-bromo-4-(2-diethylaminoethoxy)-5-benzyloxyaniline dihydrochloride by the ex. 1C indicated method has shown that this compound (considered as its base) is approx. 6 times more active as a local anesthetic than procaine hydrochloride and approx. 11 times as annoying.

Example 7: Halogen-(lower-alkoxy)-[lower tertiary ε-amino (polycarbon-lower-alkoxy)~\-N-acylated anilines.

The production of these compounds is illustrated by the following synthesis of 3-bromo-4-(2-diethylaminoethoxy)-5-ethoxy-acetanilide: A mixture containing 3.7 g of 3-bromo-4-(2-diethylaminoethoxy)-5- ethoxycyaniline monohydrochloride, 80 ml of pyridine and 4.17 ml of acetic anhydride were heated under reflux for approx. 30 minutes. About half of the solvent was removed by distillation in vacuo, ether was added, and the precipitate was collected. Recrystallization of this material from ethanol-ether gave 3.7 g of 3-bromo-4-(2-diethylaminoethoxy)-5-ethoxy-acetanilide monohydrochloride, m.p. 161.7— 164.0° C (corr.).

Analysis: Calculated for CioH2r,BrN2O:s.HCl: C = 46.90; H = 6.40; Cl- = 8.65.

Found: C = 46.61; H = 6.33; Cl- = 8.37.

3-Bromo-4-(2-diethylaminoethoxy)-5-ethoxyacetanilide is obtained in the form of the free base by dissolving the hydrochloride in water, making the aqueous solution alkaline with sodium hydroxide solution, extracting the free base with benzene and removing the benzene by distillation in vacuum. Alternatively, this basic ether can be prepared directly by acylating 3-bromo-4-(2-diethylaminoethoxy)-5-ethoxyaniline in free base form by following the procedure described above for the acetylation of its monohydrochloride.

Pharmacological testing of 3-bromo-4-(2-diethylaminoethoxy)-5-ethoxyacetanilide hydrochloride by the ex. 1C indicated method has shown that this compound (considered as its base) is approx. y2 more active as a local anesthetic than procaine hydrochloride.

By following the above procedure but using propionic anhydride, n-hexanoyl chloride or formic acid as acylating agent instead of acetic anhydride, the following compounds can be obtained: 3-bromo-4-(2-diethylaminoethoxy)-5-ethoxy-N-(n-propanoyl) ) aniline, 3-bromo-4-(2-diethylaminoethoxy)-5-ethoxy-N-(n-hexanoyl) aniline, resp. 3-Bromo-4-(2-diethylaminoethoxy)-5-ethoxy-N-formylaniline. These basic ethers can be isolated in free form or as acid addition salts, preferably as hydrochlorides.

Example 8:

A. 2- Chloro- 4- Nitro- 6- Methoxyphenol.

A mixture containing 12.6 g of 2-methoxy-4-nitrophenol and 65 ml of sulfuryl chloro-

rid was heated under anhydrous conditions under reflux for three hours. The excess sulfuryl chloride was cleaved by careful addition of ethanol, and the resulting solution was poured into water. The solid that precipitated was recrystallized from ethanol-water to give a crystalline material that melted over a large area, suggesting that the chlorination was incomplete. The crystalline material was dissolved in 100 ml of chloroform, 65 ml of sulfuryl chloride was added and the mixture heated at reflux for four hours. The reaction mixture was concentrated by distillation to a volume of approx. 150 ml, and an equal volume of hot water was added. The resulting precipitate was collected and recrystallized once from ethanol-water and once from isopropanol to give 3.02 g of light brown crystalline product, 2-chloro-4-nitro-6-methoxy-phenol, m.p. 146— 148.9° C.

Analysis: Calculated for C7H6CINO4:

Cl = 17.43.

Found: Cl = 16.90.

B. 3-chloro-4-(2-diethylaminoethoxy)-5-methoxynitrobenzene.

This compound was prepared according to the method in ex. 2B by using an equivalent amount of 2-chloro-4-nitro-6-methoxyphenol in place of 2-bromo-4-nitro-6-methoxyphenol. 3-chloro-4-(2-diethylaminoethoxy)-5-methoxynitrobenzene was obtained in the form of its monohydrochloride. C. 3-chloro-4-(2-diethylaminoethoxy)-5-methoxy aniline.

This compound was prepared by

to follow the method in e.g. 2C but use an equivalent amount of 3-chloro-4-(2-diethylaminoethoxy)-5-methoxynitrobenzene monohydrochloride in place of the corresponding 3-bromo compound. The product obtained is 3-chloro-4-(2-diethylaminoethoxy)-5-methoxycyaniline in the form of its monohydrochloride.

The following chloro-(lower alkoxy)-[lower-tertiary amino(polycarbon-lower-

alkoxy)]-anilines and chloro-(lower-alk

sy)-[lower-tertiary-amino(polycarbon-lower-alkoxy)]-nitrobenzenes were also prepared by the procedure of Examples IA and IB: 3-chloro-4-(2-dimethylaminoethoxy)-5-methoxyaniline hydrochloride, m.p. 162.0—164.2° C (corr.), prepared from 3-chloro-

4-(2-dimethylaminoethoxy)-5-methoxynitrobenzene, m.p. 173.4—175.4° C (corr.); 3-chloro-4-(3-dimethylaminopropoxy)-5-methoxyaniline hydrochloride, m.p. 210.8—213.2°

C (corr.) prepared from 3-chloro-4-(3-dimethylaminopropoxy)-5-methoxy-nitrobenzene hydrochloride, m.p. 179.0—181.6° C (corr.);

3-chloro-4-(3-diethylaminopropoxy)-5-methoxyaniline hydrochloride, m.p. 135.0—137.6°

C (corr.) prepared from 3-chloro-4-(3-diethylaminopropoxy)-5-methoxynitrobenzene hydrochloride, m.p. 162.8—164.4° C (corr.);

3-chloro-4-(2-diethylaminoethoxy)-5-ethoxyaniline hydrochloride, m.p. 178.2—180.8° C (corr.) prepared from 3-chloro-4-(2-diethylaminoethoxy)-5-ethoxynitrobenzene-hydrochloro-

ride, m.p. 170.0—174.4° C (corr.); 3-chloro-4-(3-diethylaminopropoxy)-5-ethoxyaniline - hydrochloride, m.p. 147.4—149.4° C (corr.) prepared from 3-chloro-4-(3-diethylaminopropoxy)-5-ethoxynitrobenzene hydrochloride,

m.p. 165.0—166.2° C (corr.); 3-chloro-4-[2-(2-methyl-1-piperidyl)-ethoxy]-5-methoxy-cyaniline hydrochloride, m.p. 208.8—216.2° C (corr.) prepared from 3-chloro-4-[2-(2-methyl-1-piperidyl)ethoxy]-5-methoxynitrobenzene hydrochloride, m.p. 170.4—171.4° C (corr.); and 3-chloro-4-[3-(2-methyl-1-piperidyl)propoxy]-5-methoxyaniline-hydrochloro-

ride, m.p. 169.2—172.4° C (corr.) prepared from 3-chloro-4-[2-(2-methyl-1-piperidyl)propoxy]-5-methoxynitrobenzene hydrochloride,

m.p. 153.2—156.4° C (corr.).

The halogen-(lower-alkyl)-[lower-tertiary-amino-(polycarbon-lower-alkyl)]-aniline derivatives produced according to the invention can be used in the manner that is customary for local anaesthetics. For example, they can be advantageously used in the form of their acid addition salts, e.g. hydrochlorides, in aqueous, liquid preparations. These preparations can be given locally or injected intramuscularly or intravenously. The compounds can also advantageously be combined with other pharmacologically active compounds, e.g. with vasoconstrictor agents.

Claims (2)

1. Process for the preparation of an anesthetically active ring-tri-substituted aniline of formula in which R is a lower alkyl or benzyl radical, X is a polycarbon lower alkylene radical whose two free valences are bonded to different carbon atoms, Y is hydrogen or lower acyl and NB is a di-(lower alkyl) amino, 1-piperidyl, (lower-alkylated) - 1-piperidyl-, 1-pyrrolidyl- or (lower-alkylated)-1-pyrrolidyl radical, or acid addition salts thereof, characterized in that reacts the corresponding ring-tri-substituted nitrobenzene with a reducing agent capable of reducing nitro groups to amino groups and, if desired, reacts the resulting product with a lower-acylating agent to obtain N-(lower -acylated) derivative, and — if desired — produces an acid addition salt. 2. Process according to claim 1, for the production of 3-chloro-4-(2-diethylaminoethoxy)-5-methoxyaniline, characterized in that 3-chloro-4-(2-diethylaminoethoxy)-5-methoxynitrobenzene is reduced.