DD143249A1 - PROCESS FOR PREPARING 2-SUBSTITUTED 1- (2,6-D - Google Patents

Description

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Process for the preparation of 2-substituted 1- (2,6-dimethylphenoxy) -propanes

Field of application of the invention:

The invention relates to a novel process for the preparation of compounds of general formula I, wherein A is a hydroxyl, acyloxy, alkylsulforiyloxy, arylsulfonyloxy, azido or amino group, as well as pharmaceutically acceptable salts of these compounds.

Characteristic of the well-known technical solutions :

Of the compounds of the general formula 1 which can be prepared according to the invention, only those known which contain an amino or a hydroxyl group at the point of A are known from the previous literature; the others, the obi

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according to definition "compounds of the general formula I are new, not previously described in the literature products.

Numerous compounds of the general formula I show valuable pharmacological properties, but they can also be used as valuable key products for the preparation of further compounds likewise corresponding to the above-defined general formula I.

Thus, for example, the compound of the general formula I which contains an amino group in the place of A and the pharmaceutically usable acid addition salts thereof, for example the 1- (2,6-dimethylphenoxy) -2-amino-propane hydrochloride known by the name of MMILETIHS suitable for the treatment of ventricular arrhythmias, and thus can be advantageous in therapy! especially for the treatment of ischemic heart diseases, myocardial. Infarct, ventricular fibrillation and tachycardia are used / cf. Brit. Heart J., 2 £, 558, 559 (1973); Lancet. 1973/11, 339-403, 404-407; Brit. J. Clin. Pharmacol., 1_, 86-87, 229-232 (1974) _7.

Similar üharmakologische effects also shows the A at the place of A Äzido group containing new compound of general formula I, ie the 1- (2,6-dimethylphenoxy) -2-azido-propane. The antifibrillatory activity of this compound measured according to the method of 3. Vargaftig and JD Coignet / "see Eur. J. of Pharmacol., 6, 49-55 (1969) is po EDc ₀ = 150 mg / kg, ie it is the same size , as measured under the same conditions .Wirkung of the above-mentioned known 1- (2, IT-dimethyl phenoxy) ~ 2-aminc-per pan- hydrochiorids, but the new 2-azido compound also a beneficial, for example by the method by S. Irvin / Science, 123 (19δ2) __ 7 shows a measurable sedative effect.

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Similar sedative properties detectable by the mentioned test method of Irwin were also found in the compound of the general formula I which contains at the site of A p-toluenesulfonyloxy group, ie in the 1- (2, G-dimethylphenoxy) -2- (p-toluenesulfonyloxy) -propane detected.

For the preparation of the amino group-containing compound of the general formula I, several processes are described in British Patent Specification 1,205,958. Thus, this compound E.E. from compounds of the general formula II in which B represents an amino group which is substituted by one or two protective groups, by cleavage of the protective groups. getting produced. As protective groups usable in the compounds of the general formula II, benzyl, phthalyl, toluenesulfonyl and formyl groups are mentioned in the cited patent, but only the application of the benzyl group is exemplified by examples.

The starting compounds of the general formula II are prepared according to this patent from compounds of the general formula II in which Hal represents a halogen atom, by reacting with compounds of the general formula IV in which B has the meaning indicated above.

According to another method, likewise described in the cited British patent specification, the starting compounds of the general formula II can also be prepared from the ketone of the formula V by reacting under reductive conditions with compounds of the general formula VI in which R 3 in the substituted amino group B of the compounds of the general formula II present protective group (s). getting produced.

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The methods described in the British patent cited above have the following disadvantages:

The hydrogenation of the benzyl protecting group-containing compounds of the general formula II must be under a pressure of at least 5 atm, to be carried out at about 8O ⁰ G, and the desired, containing an amino group in the place of A compound of general formula I is obtained in a yield obtained from only about 50-55 % .

It is also the preparation of the starting compounds. , The general formula II quite cumbersome, as in the reaction of the compounds of general formula II with bensylamine as the compound of general formula IV, due to the large reactivity of the benzylamine in addition to the desired reaction product of general formula II by a double alkylation and a compound of formula VII , So a bis derivative is formed as an undesirable by-product. In addition, the lifting reaction which occurs with the excess of the amine is also accompanied by a hydrogen halide elimination, and the dearth of the occurrence of these body reactions also makes the purification of the desired product quite difficult, which naturally results in a reduction of the yield.

The preparation of the starting compounds of general formula II likewise possible according to the cited British patent by the reaction of the ketone of formula V under reductive conditions with an amine of general formula VI substituted by corresponding protective groups is illustrated in the patent by no example; However, the method of preparing the required ketone of the formula V is in any case disadvantageous because this Plerstellung by reacting a 2,6-Dimethylpb.enolsalzes »with your known extremely toxic chloroacetone or bromoacetone [ cf. Ii. I. Sax: Hand

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book of Dangerous Materials, Reinhold Publ. Corp., Hew York 1951, pp. 94-7.

The cited patent mentions the possibility of using phthalyl, toluenesulfonyl and pormyl-scavengers, but these possibilities are neither discussed in more detail nor illustrated by examples, so that these variants of the process can not be further assessed.

In the above-cited British Patent Specification 1,205,958 there is also described a further process for the preparation of the amino group-containing compound of general formula I, according to which the ketone of Pormel V is first converted into ammonia by reaction with ammonia, hydroxylamine or hydrazine corresponding compound of the general Pormel VIII, wherein Y is hydrogen or a hydroxyl or amino group, converted, and darm it is reduced catalytically or by means of a suitable complex metal hydride to the desired end product.

This method also shows two major disadvantages; On the one hand, the hydrogenation gives only moderate yields (in the pail of oxime 51, 5 %, of Irnin 44.3 % i for the hydrogenation of the hydrazone are given no examples), and on the other hand, the production of the ketone is the Pormel V with the drawback already mentioned connected to the inconvenience.

Hach another, also in the cited British patent mentioned, but by no way exemplified method, the position of A containing an amino group-containing compound of the general formula I from 2,6-dimethylphenol also directly, by reacting with 1 -Lee - az ir id be made in. This method

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but is disadvantageous because of the use of 1-methyl-aziridine, since this compound, like the Äthylenimin, is extremely toxic (see IT, I. Sax: Handbook of Dangerous Materials, Reinhold Publ Corp., New York, 1951 , P. 328), besides, it is also highly inclined to polymerization; the polymerization can be induced both by the action of heat and by acid traces (as such, the acidic phenol can also act).

In another process, also described in the cited British patent specification, a salt of 2,6-dimethylphenol is compounded with a compound of general formula IX wherein Z is an active ester group, e.g. represents a halogen atom, reacted. The disadvantage of this method, which is likewise not illustrated by any example, lies in the use of the compounds of the general formula IZ which are difficult to access, since these tend to polymerize strongly to piperazine derivatives.

The hydroxyl group-containing compound of general formula I is disclosed in US Pat. No. 3,979,460 as an undesirable by-product formed in about 12 % yield in the preparation of the compound 4,4'-dihydroxy- which is the subject of this patent. 3> 3 ^f -tetramethyl-diphenyl sulfide mentioned. The physical data of this by-product are not given in the cited US patent.

Explanation of the invention of the invention;

It has now been found that the compounds of the general formula I corresponding to the above definition can be prepared in simple Y / e is e and in good yield, if reacting 2,6-dimethylphenol in an alkaline medium with propylene oxide and the resulting, at the Position of A containing a hydroxyl group compound of all

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of general formula I, if desired, by acylation into the corresponding compound of the general formula I containing, at the point of A, an acyloxy, alkylsulphonyloxy or arylsulphonyloxy group and, if desired, this product with an alkali metal azide in the compound containing an azido group at the position of A. If desired, this product is reduced to the corresponding, containing the amino group-containing compound of the general formula I and, if desired, the latter product is converted into an acid addition salt.

The preparation according to the invention of the hydroxyl-containing compound of the general formula I can preferably be carried out by reacting an aqueous-alkaline solution of 2,6-dimethylphenol with an excess of propylene oxide in the presence of a water-miscible solvent Stirring heated. The alkaline agent used is preferably sodium hydroxide or potassium hydroxide, since the salts of 2,6-dimethylphenol formed with these bases are readily soluble in the reaction mixture. The amount of alkali metal hydroxide to be used may be 1.05 to 10 moles, calculated on 1 mole of 2,6-dimethylphenol, but most suitably these alkali metal hydroxides are used in amounts of 1.2 moles. As the water-miscible solvents, lower aliphatic alcohols or ketones, acetonitrile, tetrahydrofuran, dioxane, etc., but especially ethanol or acetone, can be used. The reaction can be carried out at temperatures between about 20 ⁰ C and the boiling point of the reaction mixture, suitably at 5O ~ 6O ° C. If desired, the crude product obtained after work-up of the reaction mixture can be used directly for the preparation of further compounds of the general formula I which contain A acyloxy, alkylsulfonyloxy or arylsulfonyl groups instead of A.

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The conversion of the compound containing A into the hydroxyl-containing compound into the corresponding compounds of general formula I containing A, acyloxy, alkylsulfonyloxy or arylsulfonyloxy groups at the point of A can be carried out by conventional acylation methods (see Houben-Weyi: Methoden of Organic Chemistry, Georg Thieme Verlag, 1952, BcL. 8, p. 543).

The acylation is preferably in pyridine or in you! oräthan in the presence of triethylamine, carried out at temperatures below 1O ⁰ C. The acylated products are in excellent yields (at least 98%) of _t obtained in high purity and can, if desired, directly without purification to prepare the A in the place of an azido group-containing compound of the general Pormel I are used.

The further reaction of the compounds of general formula I containing Acyloxy-, Alkylsulfonyloxy- or Arylsulfonyloxy in place of A to prepare the azido-containing compound of general formula I is carried out by means of an alkali metal azide, suitably sodium azide, in a mixture of water and a water-miscible organic solvent, especially Xthyienglykol monoraethyläther or ethylene glycol monoäthyläther performed. The resulting in this reaction, containing at the point of A an asido group-containing compound of the general formula I shows a surprisingly high stability (it is distilled and is not decomposed even at temperatures of about 200 ⁰ C) and is in very good yields (about 83 to 89 %) . It is immediately obtained in sufficiently high purity to be used without further purification for the preparation of the compound of general formula I which contains an amino group in the place of A.

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-Q-

The reduction of the compound of the general formula I which contains an azido group at the point of A to the corresponding compound of general formula I which contains an amino group at the point of A can be carried out according to the known liletiodes (cf., for example, Houben-Weyl: Methods of Organic Chemistry Georg Thieme Verlag, 1957, vol. 11/1 , pp. 262, 539 and 1002), "especially by catalytic hydrogenation.

As a single reaction product, the pure, free of all · intermediates, at the point of A containing an amino group compound of the general formula I, ie the 1- (2,6-dimethylphenoxy) -2-aminopropane base in almost quantitative yield.

The course of the reaction can be followed well by thin-layer chromatography; the execution of the reaction is simple and does not require any special devices.

The erfinduigsgeraäfie process for the preparation of the compounds of general formula I shows the following particular advantages:

1) All compounds of general formula I can be prepared from simple, readily available, readily processable and non-toxic starting compounds.

2) The reactions can be easily carried out in excellent yields without the use of special equipment.

3) All compounds of general formula I are obtained in the form of stable, readily processable, pure products, which are already as crude products

51 51

can be used without further purification for any further reactions.

4) The at the location of A azido containing azido derivative of the general formula I can be converted at room temperature, without application of pressure, in virtually quantitative yield in the place of A an amino group-containing compound of general formula I, wherein the amino compound is obtained in good purity.

5) After the reduction, the compound of the general formula I containing an amino group at the point of A can be isolated from the reaction mixture in an extremely simple manner.

EXAMPLES

The process according to the invention is further illustrated by the following examples, but the invention is not limited in any way to the content of these examples. .. '. '·

Example 1:

1 - (2,6-Diynylphenoxy) -2-hydroxypropane

12.2 g (0.1 mol) of 2,6-dimethyl phenol are dissolved in 20 ml of water in a solution of 4.2 g (0.105 mol) of sodium hydroxide. To the solution are added 25 ml of ethanol and 8.7 g (0.15 mol) of propylene oxide, and the mixture is stirred with stirring at 60 ° C for 12 hours. After cooling, 200 ml of benzene and 200 ml of water are added, the organic phase is separated, and the aqueous phase is extracted by shaking with 200 ml of water. The benzene phases are combined, washed with 200 ml of benzene, dried over anhydrous sodium sulfate, then on a steam bath, under 40 mm Hg pressure

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evaporated to dryness. This gives 14.6 g of 1- (2,6-dimethylphenoxy) -2-hydroxypropane (81 % of theory ) .alpha .. Oily crude product which, without further purification, gives the same results as in Examples 2a-3d. 2d described acylation reactions can be used.

If desired, the product may be purified by distillation; Bp .: 84 ^° C / 0.4 ma Hg; R-. = 0.6 / "" in the 6: 1 mixture of benzene and pyridine, on a 0.1 - 0.3 thick layer of silica gel (Merck) _J7; Development after chlorination, by blowing off with o-toluidine / ~ cf.: Z. Anal. Chera., 148. 181 (T955) _7.

Analysis for O ₁₁ H ₁₆ O ₂ (M: 180.24): Calculated: C 73.30 % _t H 8.95 % \ Found: C 73.60 SS, H 9.07 %,

Example 2a:

1- (2,6-methylphenoxy) -2- (4-methyl-1-phenylsulfonyloxy) propane

9.0 g (0.05 mol) of crude prepared according to Example 1 1- (2,6-dimethyl phenoxy) -2-hydroxy-propane are dissolved in 50 ml of anhydrous pyridine, then the solution is cooled in ice and 19, 0 g (0.1 mol) of tosyl chloride are added in small portions, the temperature of the mixture is kept below +10 ⁰ C. Then the cooling bath is removed and the mixture stirred at 20-25 ⁰ C for one hour, llach completion of the reaction, the reaction mixture is poured onto 100 g of crushed ice, the reaction product extracted with 200 ml of benzene, the benzene layer separated, extracted with water, over dried anhydrous sodium sulfate and in vacuo, evaporated to dryness.

The crystalline product obtained as residue is recrystallized from 20 ml of isopropanol; it will be on this

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To obtain 16.5 g of 1- (2,6-dimethylphenoxy) -2- (4-methylphenylsulfonyloxy) -propane (98.7 % of theory ); P .: 59-61 ⁰ C; after recrystallization from isopropanol: 63-64 C. The product can also be used in the crude state for the further reaction according to Example 3a. L = 0.8 / "" in the 6: 1 mixture of benzene and pyridine; on a silica gel layer (Merck) of 0.1-0.3 r of starch J7; Development after chlorination, by blowing off with o-Tluidin.

Analysis for G ₁₈ H ₂₂ SO ₄ (M; 334.42): Calculated: C 64.64 %. H 6.63 %, S 9.59 % \ Found: C, 64.84. #, H 6.86 % _t S 9.86 %.

Example 2b:

1- (2,6-dimethylphenoxy) -2-methanesulfonyloxypropane

It is worked in detail according to Example 2a, with the difference that instead of tosyl chloride 11.4 g (0.1 mol) of mesyl chloride to the dissolved in pyridine starting material 1- (2,6-dimethylphenoxy) -2-hydroxy Propane be added dropwise. After working up of the reaction mixture, 12.8 g of 1 "(2,6-dimethylphenoxy) -2-methanesulphonyloxypropane (99 % 1 % el. Sh.) Of honey-like consistency are obtained; this product can be used without purification for further reaction according to Example 3b.

Rj> = 0.8 / "" in the 6: 1 mixture of benzene and pyridine; on a silica gel layer (Merck) of 0.1-0.3 mm thickness_7; Development after chlorination, by blowing off with o-toluidine.

Analysis for G ₁₂ H ₁₈ OS (M: 258.33): Calculated: C 55.78 %, H 7.02 %, S 12.41 % \ Found: C 56.20 %, H 7.52 % _t S 12.14 % ·

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Example 2c:

1 - (2,6-dimethylphenoxy) -2-trichloroacetyloxy-propane

It is worked in detail according to Example 2a, with the difference that instead of tosyl chloride 18.1 g (0.1 mol) of trichloroacetyl chloride to the dissolved in pyridine starting compound 1- - (2,6-dimethylphenoxy) -2-hydroxy-propane be dropped. Subject to the work-up of the reaction mixture as described above, 16.1 g of 1- (2,6-dimethylphenoxy) -2-.trichloroacetyloxy-propane (98.9 % of theory ) are obtained in the form of an oily crude product which can be used without cleaning for v / eiteren implementation of Example 3c.

If desired, the product may be purified by distillation; Bp .: 146 C (0.4 mm Hg. R ~ = 0.85 / in 6: 1 mixture of benzene and pyridine, on a silica gel layer (Merck) of 0.1 - 0.3 mm strength__7 »Development after chlorination by Blow off with o-toluidine.

Analysis for C ₁₃ H ₁₅ Cl ₃ O- (LI: 325.62): calculated: C 47.95 H 32.67% fo _t \ found 4.64%, Cl: C 48.12% H 4.92 ₉ %, Cl 32.48 %.

Example 2d:

1 ~ (2,6-dimethylphenoxy) -2- (4-methylphenylsulfonyloxy) -propane

9.0 (0.05 mol) of crude 1- (2,6-dimethylphenoxy) -2-hydroxypropane prepared according to Example 1 are dissolved in 100 ml of anhydrous dichloroethane, the solution is treated with 11.1 g (0, 11 mol) of triethylamine, and then the solution of 19.0 g (0.1 mol) of tosyl chloride under ice cooling in 50 ml of anhydrous dichloroethane dropwise, added with stirring.

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The cooling bath is then removed and the reaction mixture is allowed to warm to room temperature. The mixture is stirred for a further hour at room temperature, then poured onto 100 g of crushed ice. The phases are separated from each other. The Dichloräthanphase is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The crystalline product obtained as residue is recrystallized in the manner described in Example 2a; There are 16.55 g of 1- (2,6-dimethylphenoxy) -2- (4-methylphenylsulfonyloxy) -propane (.98.9 % of theory ). receive; F .: 58-61 ⁰ C. This product is identical with the compound prepared according to Example 2a, and can be used directly, without further purification for v / Eiteren reaction according to Example 3a.

Example 3a:

1- (2,6-dimethylphenoxy) -2-propane-aaido

8.36 g (0.025 mol) of crude, prepared according to Example 2a or 2d 1 - (2,6-dimethylphenoxy) -2- (4-methyl-phenylsulfonyloxy) propane are dissolved in 50 ml of ethylene glycol monomethyl ether, this solution with a solution of 3 * 25 g (0.05 mol) of sodium azide in 15 ml V / asser added at once and the mixture was refluxed for 5 hours. For cooling, 100 ml of water and 100 ml of chloroform are added. The phases are separated, the chloroform phase is washed with 200 ml of water, dried over anhydrous sodium sulfate and then evaporated to dryness under steam at 40-60 mm Hg pressure to dryness. The residue obtained is 4> 6 g of crude 1- (2,6-dimethylphenoxy) -2-azidopropane (89.6 % of theory ); This product can be processed immediately, without further purification according to Example 4.

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If desired, you can pass the product through. Clean the distillation; B.p. 106 ° C / 0.7 M Hg. R ~ = 0.75 (in the 6: 1 mixture of benzene and pyridine, on a silica gel layer of 0.1 to 0.3 mm thickness).

Analysis for C ₁₁ H ₁₅ II ₃ O (M: 205.25): calculated: C 64.37%, H 7.37%, IT 20.47%; Found: C 64.65 %, H 7.48 %, Ή 20.30 %.

Example 3b:

The procedure is as described in Seispiel 3a, with the difference that instead of 1- (2,6-dimethylphenoxy) -2- (4-methyl-phenyl sulfonyl oxy) -propane 6.46 g (0.025 MoI) according to Example 2b prepared crude 1- (2,6-dimethylphenoxy) -2-methanesulfonyloxy-propane can be used as starting compound. Each workup of the reaction mixture gives 4.3 g of crude 1- (2,6-dimethylphenoxy) -2-asido-propane (83.8 % of theory ); the product is identical to the compound prepared according to Example 3a.

Example 3c:

The procedure of Example 3a is repeated except that instead of 1- (2,6-dimethylphenoxy) -2- (4-methylsulfonyloxy) -propane, 8.14 g (0.025 mol) of crude 1 prepared according to Example 2c are used. (2,6-dimethylphenoxy) -2-trichloroacetyl-propane can be used as the starting compound. After working up the reaction mixture, 4.5 g of crude 1- (2,6-dimethylphenoxy) -2-azido-propane (87.7 % of theory ) are obtained; the product is identical to the compound prepared according to Example 3a.

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Example 4ι

1- (2,6-dimethylphenoxy) -2-amino-propane

4j1 S (0.02 mol) of crude 1- (2,6-dimethylphenoxy) -2-azido-propane prepared according to one of Examples 3a to 3c are dissolved in 100 ml of ethanol; after the addition of 1 g of palladium / carbon catalyst, a continuous slow stream of hydrogen is passed off gas in the shaken at 20-25 ° C solution for 5 hours. The course of the reaction can be monitored by thin-layer chromatography (mobile phase 6: 1 mixture of benzene and pyridine, on a 0.1 to 0.3 μ thick silica gel layer). (Azide R _f = 0.75, amine R ~ = 0.15, development after chlorination by blowing off with o-toluidine).

After completion of the reaction, the catalyst is removed by filtration and rinsed with a little 70 % aqueous ethanol. The filtrate combined with the washing liquid is acidified to pH = 1 with concentrated hydrochloric acid and evaporated to dryness on a steam bath under 40 mm Hg pressure. The residue obtained is 4.4 g of crude, crystalline 1- (2,6-dimethylphenoxy) -2-amino-propane hydrochloride (100 % of theory ). This crude product is dissolved in 10 ml of isopropanol with heating and the solution filtered. 50 ml of anhydrous diethyl ether were added to the well at about 40 ° C. After a short while, the product separates from the solution in pure crystalline form. The solution containing the crystalline product is cooled in ice, then the crystalline product is filtered off, washed with v / enig diethyl ether and dried; P .: 201-203 ° C.

CH,

O- CH ^ - CH - CH

CH,

CH,

CH-

- CH B

- CH.

U CH ^ CH

CH-

Hal

HL

B- H

CH.

CH

O-CH ₀ -C-CH-

² if ^J

H ₂ NO

CH-,

O-CH ₂ -CH - CH ₃

CH-

N - CH *

CH ₃ O-

CHO

- CH- CH

- O - CH ₂ - C - CH ₃

Z - CH ₀ - CH - CH ₀ * I J

NH.

Claims (5)

-η- 21 251i Erfaunamsams .: 1. A process for the preparation of compounds of general formula I, wherein A is a hydroxyl, acyloxy, alkyl sulfonyl oxy-, aryl sulfonyl oxy-, azido or amino group, as well as of pharmaceutically acceptable acid addition salts of the amino group at the point of A. compounds which are characterized in that 2,6-dimethylphenol is reacted with propylene oxide in an alkaline medium and the resulting compound of general formula I which contains a hydroxyl group in place of A is, if desired, converted by acylation into the corresponding CXV ^ - ox-fZ-oxY-S A transferred Ie of an acyl-f ~ A.lkylsulfonyl ^/ or arylsulfonyl i ^ group-containing compound of the general formula I, and if desired this product with ei - * - · no alkali metal azide in the containing an azido group in the place of compound A of the general formula I, if desired, the azido derivative obtained is reduced to the corresponding compound of the general formula I containing an amino group at the point of A and, if desired, converting this amino compound into a pharmaceutically acceptable acid addition salt. 2. The method according to item 1, characterized in that one carries out the reaction of 2,6-dimethylphenol with propylene oxide in the presence of an aqueous solution of ITatriumhydroxyd or potassium hydroxide and a water-miscible organic solvent. 3. The method according to item 1 _s, characterized in that the at the location of A is a hydroxyl group-containing alcohol of the general formula I by acylating with the corresponding acid halide in 21 251 Pyridine or in the presence of triethylamine base in dichloroethane, at temperatures below 10 ⁰ G in which in the place of A an acyl oxy- ,. Alkylsulfonyloxy- or aryl sulfonyl oxygruppe containing active ester of general formula I. 4. Verfaliren according to item 1, characterized in that one comprises in place of A an acyl oxy-, alkylsulfonyloxy or Arylsulfonyloxygruppe containing active esters of general formula I by reacting with sodium azide in the presence of water and a mixable with ¥ / organic solvent in the place of A contains an azido-containing Verder general formula I. 5 * _ Verfaliren according to item 1, characterized in that one reduces at the point of A an azido group-containing compound of general formula I by at normal pressure, carried out at 15 ° to 25 ⁰ C catalytic hydrogenation to the corresponding amino compound. For this __ ^ 5 soap formulas