DE971836C - Process for the preparation of p-aminobenzoic acid esters which are effective as infiltration anesthetics - Google Patents

Description

Issued on the basis of the First Overhead Line Act of July 8, 194-9

(WiGBl. P. 175)

FEDERAL REPUBLIC OF GERMANY

ISSUED APRIL 9, 1959

GERMAN PATENT OFFICE

PATENT LETTERING

CLASS 12 q GROUP 602 INTERNAT. CLASS C 07 c

H 7,534 IVb 112 q

Max Matter, Worb, Bern (Switzerland)

has been named as the inventor

CIBA Aktiengesellschaft, Basel (Switzerland)

Process for the preparation of effective as infiltration anesthetics

ρ-aminobenzoic acid esters

Patented in the territory of the Federal Republic of Germany on February 13, 1951

Patent application published April 30, 1952

Patent issued March 19, 1959

The priority of the registration in Switzerland of February 15, 1950 has been claimed

Esters from higher fatty acids and polyethylene glycols or polyethylene glycol monoalkyl ethers are known. These are surface-active and are used as network, Detergents and emulsifiers used in technology.

So far, esters of p-aminobenzoic acids and polyethylene glycols or are not known Polyethylene glycol monoalkyl ethers, since there are apparently no special properties of such compounds expected. However, it has been shown that the representatives of this class of substances are very excellent have pharmacological properties and z. B. can be used as infiltration anesthetics. Such surprising effects are noteworthy because one has hitherto been building up Esters with anesthetic effect on the co-use of amino alcohols or other nitrogen » 765/40

substance-containing compounds did not believe to be able to do without.

The new compounds correspond to the following general formula

R'-NH-

CH ₈ -CH ₂ - (O-CH ₂ -CHa) ₅₁ -OR

where R 'is hydrogen or butyl, η is an integer from 4 to 50 and R is hydrogen or a hydrocarbon radical with at most 6 carbon atoms.

These new compounds are obtained according to the invention by p-aminobenzoic acid or p-Butylaminobenzoic acid or an ester, a chloride or an acid anhydride thereof with a polyether alcohol the general formula

HO - CH ₂ - CH ₂ - (O - CH ₂ - CH ₂ ) _Ä - OR

where η and R have the abovementioned meaning, preferably esterified in the presence of an esterification catalyst or an acid-binding agent, in a manner known per se, for example according to Schotten-Baum ann, or in the presence of pyridine. In other cases it is more appropriate to use the transesterification method.

The substituted alcohols used as starting materials are known or can easily be traced Analogy procedure can be obtained.

For example, if R = isobutyl, the polyethylene glycol derivative is obtained by ethylene-

glycol monoisobutyl ether is reacted with η mol of ethylene oxide in a pressure ^{vessel at 160 to 170 0} C in the presence of catalytic amounts of potassium hydroxide.

example 1

8.25 Gewichtsteüe p-Aminobenzoesäureäthylester, 35 Gewichtsteüe technical polyethylene glycol monomethyl ether of average molecular weight 350, dried under high vacuum at 110 ⁰ C, and 4 parts by volume of a 2normalen sodium methoxide in methanol for 16 hours in a vacuum of 12 mm mercury at 100 ° C heated. A sample of the light brown oil is almost quantitatively water-soluble after this time. It is all poured into 250 parts by volume of water to which 5 parts by volume of 2η hydrochloric acid have been added. After adding ι part by volume of a saturated sodium bisulfite solution, the pH is adjusted to 7.5 and the mixture is shaken with 6 parts by weight of animal charcoal for one hour.

After the carbon has been nitrated, the filtrate is extracted several times with benzene. All benzene extracts are washed three times with saturated sodium hydrogen carbonate solution and evaporated. Of the Excess polyethylene glycol monomethyl ether is in the aqueous layers and from the When evaporated, benzene solutions become p-aminobenzoic acid ester in the form of a light yellow Haxen oil of polyethylene glycol monomethyl ether obtained. The new ester is soluble in water and can be used as a local anesthetic.

The same ester can also be obtained by catalytic hydrogenation of the p-nitrobenzoic acid ester of polyethylene glycol monomethyl ether can be obtained.

The p-butylaminobenzoic acid ester of polyethylene glycol monomethyl ether can also be prepared using the same transesterification process can be obtained.

Example 2

11.05 parts by weight of ethyl p-butylaminobenzoate and 40 parts by weight of polyethylene glycol monomethyl ether of average molecular weight 350 are in an apparatus for vacuum distillation heated to 100 ° C, during half an hour at a vacuum of 10 to 15 mm Hg absolute Xylene drips under the surface of the mixture. This treatment removes the last traces of moisture removed .. 1 part by volume of 4N sodium methylate solution in absolute methanol is then added and again heated to 100 to 110 ° C in vacuo with simultaneous dropwise addition of absolute xylene into the mixture until the transesterification is complete. This is the case when a sample of the reaction mixture dissolves clearly in cold water. Rinses after cooling one with 200 parts by volume of benzene in a separating funnel and put in a second separating funnel 100 parts by volume of fresh benzene. The following solutions are then shaken out one after the other:

1. 50 parts by volume of water and 100 parts by volume of saturated Sodium hydrogen carbonate solution,

2. 100 parts by volume of 2N sodium carbonate solution,

3. 80 parts by volume of water and 20 parts by volume of saturated sodium chloride solution,

4. like sub 3.

The combined benzene layers are dried with sodium sulfate, evaporated and heated in vacuo from 10 to 12 mm Hg to 90 to 100 ° C. until the weight is constant. The residue weighs 26.8 parts by weight and consists of a light yellowish, viscous oil. This represents the new ester of polyethyleneglycol monomethyl ether and p-butylaminobenzoic acid. For cleaning, you can dissolve ether in 75 parts by volume and filter over 100 parts by weight of activated, neutral aluminum oxide and elute with 450 parts by volume of ether. After evaporation and drying, 24.1 parts by weight of a slightly lighter oil, which dissolves clearly in water, are obtained. The cloud point of a io ° / ₀ aqueous solution is 38 to 39 ⁰ C. The new esters has good local anesthetic effect on.

Claims (2)

Patent claims: i. Process for the production of as infiltration anesthetics effective p-aminobenzoic acid esters of the general formula R'-NH CO - O - CH ₂ - CH ₂ - (O - CH ₃ - CH ₂ ) _n - OR where R 'is hydrogen or butyl, η is an integer from 4 to 50 and R is hydrogen or a hydrocarbon radical with a maximum of 6 carbon atoms, characterized in that p-aminobenzoic acid or p-butylaminobenzoic acid or an ester, a chloride or an acid anhydride thereof with a polyether alcohol of the general formula HO - CH ₂ - CH ₂ - (O - CH ₂ - CH ₂ ) "- OR in which η and R have the abovementioned meaning, preferably in the presence of an esterification catalyst or an acid-binding agent, esterified in a manner known per se. 2. Method of making an intravenous anesthetic effective p-aminobenzoic acid ester, characterized in that the p-nitrobenzoic acid ester of technical polyethylene glycol monomethyl ether catalytically hydrogenated with an average molecular weight of 350. Considered publications: German patent application ρ 1177 IVd / i2 0 made known on February 5, 1953); German Patent Nos. 881 947, 605 973; French Patent No. 727 202; U.S. Patents Nos. 2,390,941, 2,396,513, 115,700, 2,176,070, 2,198,583, 2,417,499, 2,426,968; Zeitschrift Angewandte Chemie, 62 (1950), pp. 7 to 9; Klinische Wochenschrift, 35 (1957), pp. 1034 to 1036; British Patent Nos. 588 833, 588 834. ® 809 765/40 4.59