DD153682A1 - PROCESS FOR PRODUCING NEW ALKANOLAMINE - Google Patents

Abstract

The invention relates to processes for preparing racemic and optically active alkanolamines, their esters and acid addition salts with beta-adrenolytic action. The new compounds correspond to the general formula wherein: x deep 1 is a halogen atom, x deep 2 is a hydrogen atom, if y is a halogen atom or a halogen atom, if y is another of the groups listed, y is a hydrogen atom, a halogen atom, an amino group, the acylamino group R 1 deep-CO-NH-, the alkoxycarbonylamino R deep 1 -O-CO-NH-, or the ureido group R deep 1 -NH-CO-NH- (where R deep 1 is a branched or unbranched, optionally by a Phenyl group substituted alkyl group having 1-10 C atoms) and z represents the groups -CH (OH) -or-OCH deep 2 -CH (OH) - represent. Some of the compounds of the present invention selectively block d .beta. Deep heart receptors and at the same time stimulate the beta deep2 receptors of the bronchial musculature and peripheral vessels. The compounds according to the invention have the same indications as the already known beta-adrenergic blockers and can additionally be used in patients with obstructive respiratory diseases.

Description

Dr, Horst Bercher

Prof. Dr. Adolf Grisk

Process for the preparation of new alkanolamines Field of application of the invention

The invention relates to processes for the preparation of racemic or optically active alkanolamines, their esters and acid addition salts, the general Forniel I (for formulas see Appendix 1), wherein

X _{1 is} a halogen atom,

X 2 represents a hydrogen atom when у represents a halogen atom or a halogen atom when у represents another of the listed groups,

a hydrogen atom, a halogen atom, an amino group, the acylamino group R ₁ -CO-NH-, the alkoxycarbonylamino group R ₁ -O-CO-NH- or the ureido group R ₁ -NH-CO-NH- (where R _{1 is} a branched or is unbranched, optionally substituted by a phenyl radical alkyl group having 1-10 C atoms) and

ζ the groups represent -CH (OH) - or -CCH ₂ -CH (OH) -.

These compounds are novel and useful as medicaments for the therapy and prophylaxis of angina pectoria, cardiac arrhythmias, hyperkinetic heart syndrome, hypertension, among others; Field of application is the pharmaceutical industry _o

Characteristic of the known technical solutions

Methods for Preparing Similar Compounds are Now Known. Thus, processes for preparing halo-substituted i-phenyl-2-alkylaminoethanols by reacting the corresponding i-phenyl-2-chloroethanols with a primary aliphatic amine have been disclosed (see USP 2938921 (1960). J. Prakt. Chem. 315 » 1169 (1973) Pharmacie ^ 1_, 35I (1976)), by reductive amination of a corresponding phenylglyoxal (see Farmaco, Ediz., 1 £ 3> 871 (1963)) and by reduction a corresponding -N-alkylaminoacetophenone (see J. Amer.Chem.Soc.68 , 840 (19 ^ 6)), which is also used for the preparation of the inventive 1-phenyl-2- (3,4-dimethoxy-ß-phenäthylamino ) -äthanole (formula I, ζ = -CH (OH) -, ^X 1 » ^X 2 * У - ^ sit the meaning given above) are suitable. The preparation of monosubstituted 1-phenoxy-3 ~ (3> 4-dimethoxy-phenethylamino) -propanol- (2) by reacting a 1-phenoxy-3-chloropropanol (2) or a 1-phenoxy-2,3 -epoxy-propane with 3,4-dimethoxy-.beta.-phenethylamine is described in BRD patent 2259489. The 1- (2,5-dichloro-phenoxy) -3-t-butylamino-propanol (2) can be, inter alia, to German Patent 2213044 by reacting sodium 2,5-dichlorophenolate with 1 ^ -Epoxy ^ -t -butylamino-propane or 1-chloro-3-t-butylamino-propanol- (2). Alkanolamines can also be prepared by hydrolysis of an oxazolidone (compare J. Med. Chem. 11, 1121 (1968) and NE 6409883).

Object of the invention

The aim of the invention is to develop methods for the synthesis of novel biologically active alkanolamines of general formula I.

Explanation of the essence of the invention

According to the invention, the novel compounds of general formula I are prepared:

a) by reacting a halohydrin of the general formula II in which x, j, X ₂ , у and ζ have the abovementioned meaning

and Hal is a halogenated, preferably a chlorine or bromine atom, with 3,4-dimethoxy-.beta.-phenethylamine. In order to obtain a complete conversion of the starting materials into final product, the reaction is carried out in the presence of a base, preferably in the presence of an excess of the reactant 3,4-dimethoxy-.beta.-phenethylamine. Some examples of suitable bases are alkali hydroxides, such as potassium and sodium hydroxides, .alicarbonates, such as potassium and sodium carbonate, and tertiary amines, such as triethylamine and tripropylamine. The reaction of the reactants is conveniently carried out in the presence of an organic solvent. Examples of suitable solvents are alkanols, such as ethanol and isopropanol, ethers, such as dioxane, ketones, such as acetone and methyl ethyl ketone, hydrocarbons, such as benzene, toluene and xylene, and chlorinated hydrocarbons, such as chloroform, tetrachloromethane and tetrachloroethane. The reaction times and temperatures can be varied widely. The reaction is generally carried out within 1 to 48 hours at temperatures of 20-200 °. The reaction product is isolated directly as the free base or after treatment with an acid as an acid addition salt. Preferably, the halohydrin is dissolved with twice the equimolar amount of 3 »4-dimethoxy-ß-phenäthylaiain in isopropanol, refluxed for 16 hours and distilled off the isopropanol in vacuo. The product is extracted with an organic solvent, preferably with one that does not dissolve the formed 3> 4-dimethoxy-.beta.-phenethylamine hydrochloride. Examples of suitable solvents are acetone and ethyl acetate. The reaction may also be carried out in a water-immiscible organic solvent, e.g. Chloroform, take place and the formed 3 »4-dimethoxy-ß-phenäthylaminhydrochlorid be removed by extraction with water from the reaction mixture. The final product is isolated from the reaction mixture by treatment with isopropanolic or ethereal hydrochloric acid or by introducing anhydrous hydrogen chloride as the hydrochloride. When у represents an amino group, an acylation or a reaction with a chloroformate may then be carried out.

As the acylating agent, it is convenient to use the acid anhydride or halide of an aliphatic or aromatic carboxylic acid. Examples of suitable Acylierungsmitfeel are acetic anhydride and acetyl chloride. The reaction is optionally carried out in an organic solvent.

b) by reduction of a compound of general formula I, in which Χ /, Xp and у have the abovementioned meaning and ζ represents an -OCHp-CO- or a -СО group. Examples of suitable reducing agents are base metals such as sodium, magnesium, aluminum, amalgam, iron and zinc, hydrides such as lithium aluminum hydride, lithium hydride and sodium borohydride, and hydrogen activated with catalysts such as RANEY nickel, platinum and palladium. Preferably, the reduction is carried out in methanolic solution with sodium borohydride.

c) by reductive amination of a phenylglyoxal of general formula III, in which x ^, x ~ and у have the abovementioned meaning, on a suitable catalyst, such as RANEY nickel or palladium, in the presence of 3i ^z l-dimethoxy-ß- phenethylamine, wherein ζ in the general formula I is a -CH (OH) group and x ^, Xp and у have the abovementioned meaning. The reaction may optionally be carried out in a solvent and at elevated temperature and pressure. Examples of suitable solvents are alkenols, such as methanol and ethanol, esters, such as ethyl acetate and ethers, such as dioxane. In general, the reaction at a temperature of 20 - 200 ° and a pressure of 1 - 200 atm. carried out within 24 hours. When using dioxane as a solvent, the temperature should not exceed 200 ° due to the risk of explosion.

d) by reacting a 1-phenoxy-2,3-epoxy-propane of general formula IV in which χ ,,, x ~ and у have the abovementioned meaning, with 3f4-dimethoxy-ß-phenethylamine, wherein ζ in the general Formula I represents a -OCH ₂ -CH (0H) group and X ^, Ύ-2 and у have the abovementioned meaning. The reaction is optionally carried out in a solvent and at elevated temperature. In general, the reaction will take place within 15 minutes to 48 hours at a temperature

carried out from about 15 to I5O ^0th Examples of suitable solvents are alkenols such as methanol, ethanol and isopropanol, ethers such as dioxane, ketones such as acetone and methyl ethyl ketone, hydrocarbons such as benzene, toluene and xylene and chlorinated hydrocarbons such as chloroform, tetrachloromethane and tetrachloroethane. The reactants are preferably used in approximately equimolar amounts, although a moderate excess of each of the reactants can be used.

e) by reacting a phenol of the general formula V in which Xy, t Xp and ω have the abovementioned meaning, with 1,2-epoxy-3- (3 »4-dimethoxy-.beta.-phenethylamino) -propane or a 1- Halo-3- (3 ', 4-dimethoxy-.beta.-phenethylamirio) propanol (2), preferably 1-chloro-3 (3,4-di-ethoxy-.beta.-phenethylamino) -propanol (2), or 1-bromo-3- (3 ₎ -dimethoxy-.beta.-phenethylamino) -propanol- (2), wherein ζ in the general formula I is an -OC ^ -CH (OH) group and X /, Xp and The reaction may suitably be carried out in the presence of an acid-binding agent, for example potassium or sodium hydroxide. On the other hand, an alkali phenolate may be used as starting material. The reaction may optionally be carried out in a solvent and at elevated temperature, for example the boiling point of the solvent. Examples of suitable solvents are alkenols, such as ethanol and isopropanol, hydrocarbons, such as benzene, toluene and xylene, and chlorinated hydrocarbons, such as chloroform, tetrachloromethane and tetrachloroethane.

f) by hydrolysis of an oxazolidone of the general formula VI and VI, in which x ^ ,, Xp U- ³³ ^ У have the abovementioned meaning. The hydrolysis of the oxazolidone is conveniently carried out with an alkali metal hydroxide, such as z.3. aqueous solutions of sodium or potassium hydroxide, by. Optionally, an organic solvent may also be included in this reaction. Suitable solvents include alkenols such as ethanol and methanol.

g) by hydrolytic cleavage of the protective group A of compounds of general formula I in which x ^, X ₂ and у are as defined above and ζ is a -CH (OA) - or an -OCH ₂ -CH (OA) group. Suitable protecting groups include acyl groups such as the acetyl, benzoyl and hexanoyl groups or acetal groups such as the tetrahydropyranyl group. The cleavage is conveniently carried out by heating with aqueous or alkanolic alkali or preferably acetals with an acid such as hydrochloric acid.

The starting substances required for carrying out the processes a to g are currently available. already known, z.T. They can be prepared by conventional methods. The compounds according to the invention have an asymmetric carbon atom on the --CH (OH) - group and therefore come as racemate as well as in the form of

optical antipodes. The latter can be prepared in a manner known per se in addition to the use of optically active starting material also by resolution with conventional auxiliary acids, such as, for example, the (+) or (-) form of tartaric acid, O-dibenzoyltartaric acid, mandelic acid, 3-bi'omcampher-8-sulphonic acid and camphor-10-sulphonic acid.

The compounds of the invention can be converted in the usual way in their physiologically acceptable acid addition salts and esters. Examples of suitable acids for obtaining the acid addition salts are hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, oxalic, methanesulfonic, lactic, tartaric, malic and maleic acids. The conversion of the compounds of the invention into their esters can be e.g. by reaction with acyl halides or acyl anhydrides, e.g. Acetyl chloride, acetic anhydride and butyryl chloride, take place.

The compounds according to the invention surprisingly show superior pharmacological properties in animal experiments compared with the known β-receptor blockers propranolol (Obsidan®), talinolol (Cordanum®), Practolol and CI 775. Examples of the advantageous pharmacological effects of some of the compounds according to the invention are listed in Table 1 (Appendix 2). Some of the compounds of the invention block the Q 1 receptors more than usual

therapeutically used ß-receptor blockers propranolol, talinolol, practolol and CI 775 and show a greater specificity in blocking the ß, - receptors of the heart against the blocking of the B ₂ receptors of the peripheral. Blood vessels as well as the bronchial musculature. At the same time stimulate some substances, such as the alkanolamines of the general formula I in which x ^ = 2-Cl, X ₂ = H, у = Cl and ζ = -OCH ₂ -CH (OH) -, or X ₁ = 2- Cl, X ₂ = 5-Cl, у = h and ζ = -OCH ₂ -CH (OH) - represent the ß ₂ receptors of the bronchial musculature. This manifests itself in the anesthetized cat in an increase in the respiratory time and in the awake guinea pig in an increase in the protective effect of isoproterenol against the histamine-induced asthma attack bzv /. by a spasmolytic effect on the bronchial muscles of the whole animal and on the isolated tracheal muscle. On the other hand, the known β-receptor blockers reduce the respiratory time volume, abolish the protective effect of isoproterenol over the asthma-inducing histamine and contract the bronchial musculature. For this reason, the use of nonselective β-receptor blocking agents in patients with obstructive pulmonary disease is contraindicated. But the use of the so-called cardioselective ß-receptor blockers, such as Practolol, talinolol and CI 775 »is questionable in these patients, since they can trigger an asthma attack with appropriate dosage or sensitivity of the patient. In contrast, the compounds according to the invention show qualitatively new pharmacological properties, since they selectively block the β 1 receptors of the heart and at the same time stimulate the β ₂ receptors of the bronchial musculature and the peripheral vessels. As a result, they can be advantageously used without the risk of increasing airway resistance or triggering asthma bronchial attacks. In addition, some of the compounds according to the invention show pronounced and therapeutically significant antiarrhythmic effects which exceed those of propranolol, talinolol, practolol and the known antiarrhythmic tachmalin, as well as a lower one

Toxicity as propranolol and talinolol _e Compounds of the invention have the same indications as the already known beta-adrenergic receptor blocker and can be used with obstructive airway diseases in addition and in patients. They can therefore be used advantageously for the treatment of cardiovascular diseases, such as, for example, angina pectoris, hyperkinetic heart syndrome, cardiac arrhythmias, hypertension and for the treatment of central nervous disorders, such as tremor, migraine, psychosis and drug addiction.

The therapeutic single dose of the compounds according to the invention is between 1 and 20 mg when administered intravenously and between 1 and 300 mg when administered orally.

The eri'indungsgemaßen compounds can be in the usual galenic application forms, such as tablets, capsules, dragees, powders, solutions, emulsions or depot forms, brought, with their preparation, the usual pharmaceutical excipients and the usual production methods can be used «The compounds of the invention Advantageously used in combination with other pharmacodynamically active substances. Examples of substances suitable for combination are sympathomimetics such as salbutamol and terbutaline, antianginal drugs such as propanetriol trinitrate, pentaerythrityl tetranitrate and dipyridamole, cardiac glycosides such as digitoxin and digoxin, antihypertensives such as clonidine and dihydralazine, diuretics such as furosemide and hydrochlorothiazide, and centrally acting drugs. like diazepam and lepinal.

embodiments

example 1

6.4 g of 1- (2,5-difluoro-phenyl) -2-chloro-ethanol are dissolved in 10 ml of isopropanol, treated with 12 _$ 1 g of 3 »4-dimethoxy-ß-phenethylamine in 5 ^{ml of} isopropanol and Heated under reflux for 8 hours. The precipitated 3> 4-dimethoxy-ß-phenethylamine hydrochloride is filtered off with suction and the isopropanol i.Vak. distilled off. The residue is taken up in ether and the ethereal

Solution washed with water. It is then dried over sodium sulfate, filtered off and evaporated. The 1- (2,5-difluoro-phenyl) -2- (3,4-dimethoxy-.beta.-phenethylamino) -ethanol is obtained as a yellowish oil, which solidifies after prolonged standing to give colorless crystals. Y. 6.6 g (59 % of theory).

hydrochloride

6.6 g of 1- (2,5-difluoro-phenyl) -2- (3,4-dimethoxy-.beta.-phenethylamino) -ethanol are dissolved in excess isopropanolic hydrochloric acid. The reaction mixture is evaporated and the residue recrystallized in ethyl acetate / ethanol. Colorless, fine crystalline powder of mp. 126-27 °. Y. 3.1 g (43 % of theory ),

Example 2

22.6 g ^/ l- (2,5-dichloro-phenyl) -2-chloro-ethanol are reacted with 36.2 g of 3,4-dimethoxy-ß-phenäthylsmin under the conditions mentioned in Example 1. The 1- (2,5-dichloro-phenyl) -2- (3,4-dimethoxy-.beta.-phenethylamino) -ethanol is obtained as a colorless oil, which solidifies after prolonged standing to crystals. Y. 32 g (86 % of theory ).

hydrochloride

32 g of 1- (2,5-dichloro-phenyl) -2- (3,4-dimethoxy-ß-phenethylamino) -ethanol are dissolved in absolute ether and introduced into the ethereal solution of dry hydrogen chloride. It forms a precipitate, which is filtered off, washed with ether and recrystallized from ethyl acetate / ethanol. Colorless, finely crystalline powder from Schmp, 181-82 °. Y. ЗО g (85 % of th.).

Example 3

21 »9 g of 1- (2,4-dichloro-phenoxy) -2» 3-epoxy-propane are dissolved in 50 ml of isopropanol, treated with 18.1 g of 3,4-dimethoxy-ß-phenethylamine in 50 ml of isopropanol and Heated under reflux for 10 hours. The isopropanol is distilled in vacuo, the residue is taken up in ether and the ethereal solution is washed with water. The ethereal solution is dried over sodium sulfate, filtered off and evaporated. This gives the 1- (2,4-Dichloi "-phenoxy) -3- (3 _s 4-dii3ethoxy-ß-phenethylamino) -propanol- (2) as a colorless, crystalline residue, which

Ethyl acetate / ethanol is recrystallized. Colorless, finely crystalline powder from! Y. 38 g (95 % of theory )

crystalline powder of mp 120-121 °.

Example 4

3.2 g of 1- (3,4-dichloro-phenoxy) -2,3-epoxy-propane are dissolved in 4 ml of chloroform, treated with 2.7 g of 3> 4-dimethoxy-ß-phenethylamine in 2 ml of chloroform and Heated under reflux for 8 hours. The reaction mixture is extracted with water and the organic phase dried over sodium sulfate. After filtration, ether is added to the solution and dry hydrogen chloride is introduced. A precipitate forms, which is filtered off, washed with ether and recrystallized from ethyl acetate / ethanol. Alane gives the hydrochloride of 1- (3 »4-dichlorophenoxy) -3- (3,4-dimethoxy-β-phenethylamino) -propanol (2) as a colorless, finely crystalline powder of mp 148-49 °. Y. 5.1 g (80 % of theory ).

Example 5

5.1 g of 1- (2,5-dichlorophenoxy) -3-chloropropanol (2) and 7 _} 2 g of 3,4-dimethoxy-.beta.-phenätbylamin are dissolved in 15 ml of ethyl acetate and 20 hours under reflux heated. The precipitated 3,4 ~ dimethoxy-.beta.-phenethylamine hydrochloride is filtered off with suction, the reaction mixture is extracted with water and the organic phase is dried over sodium sulfate. The residue obtained after evaporation is dissolved in excess isopropanolic hydrochloric acid. The reaction mixture is evaporated, the residue washed with ether and recrystallized from ethyl acetate / ethanol. The hydrochloride of 1- (2,5-dichlorophenoxy) -3- (3 »4-dimethoxy-.beta.-phenethylamino) propanol (2) is obtained as colorless crystals of mp. 154- 3 ^х ? ⁰ * yield, 6.2 g (71% of theory).

Example 6

6 g of 2,5-difluoro-phenylglyoxal and 6.4 g of 3 »4-dimethoxy-.beta.-phenethylamine are dissolved in 150 ml of ethanol and hydrogenated over RANEY nickel at room temperature and NormalduPVk. After taking up the theoretical amount of hydrogen, the catalyst is

vacuumed and the ethanol i. Vak. distilled off. The residue is taken up in ether and the ethereal solution is washed with water. After drying the organic phase over sodium sulfate is filtered off and introduced dry hydrogen chloride. The precipitate formed is filtered off, washed with ether and recrystallized from ethyl acetate / ethanol. The hydrochloride of 1- (2,5-difluorophenyl) -2- (3,4-dimethoxy-.beta.-phenethylamino) ethanol is obtained as. colorless, finely crystalline powder of mp. 126 - 127 °. Y. 7.2 g (55% d. Th.).

Example 7

5 g of 3- (3 »4-dimethoxy-β-phenethyl) 5- (2,4-dichloro-phenoxymethyl) oxazolidone (2) are dissolved in 20 ml of methanol and treated with 20 ml of 50% sodium hydroxide solution for 3 hours heated to reflux. The methanol is distilled off and acidified with hydrochloric acid. The mixture is then extracted with ether and the aqueous phase is alkalized with sodium hydroxide solution. The precipitated 1- (2,4-dichlorophenoxy) -3- (3 »4-dimethoxy-ß-phenethylamino) -propanol- (2) is filtered off and recrystallized from ethyl acetate / ethanol. Colorless, finely crystalline powder of mp 120-121 °. Y. 2.8 g (60% of theory).

Example 8

5 g of 3- (3,4-dimethoxy-.beta.-phenethyl) -5- (2,5-difluoro-phenyl) -oxazolidon- (2) are hydrolyzed analogously to Example 7. The base is converted with isopropanolic hydrochloric acid into the hydrochloride. After recrystallization from ethyl acetate / ethanol, the hydrochloride of 1- (2,5-difluoro-phenyl) -2- (3,4-dimethoxy-phenethylamino) -ethanol is obtained as a colorless, finely crystalline powder of mp. 126-27 °. Y. 1.3 g (25% of theory).

Example 9

3 6 1- (3 »4-dichloro-phenoxy) -3- (3,4-dimethoxy-ß-phenethyl) -aminopropan-tetrahydropyranyl ether-oxalate v / earth dissolved in 25 ml of 2 η hydrochloric acid and heated under reflux for 15 min. The reaction mixture is extracted with ether and the aqueous phase with sodium hydroxide solution alkalized ₀ The separated oil is taken up in ether, the ethereal solution washed with water, dried over sodium sulfate, abfiltrierb and concentrated to about half. After the introduction of dry hydrogen chloride

A precipitate forms, which is filtered off, washed with ether and recrystallized from water. The hydrochloride of 1- (3> 4-dichloro-phenoxy) -3- (3> 4-dimethoxy-ß-phenethylamino) -propanols- (2) is obtained as a colorless, finely crystalline powder of mp. 148-49 °. Y. 1.5 g (55% of theory)

Example 10

29.5 g of 2,5-dichloro-o / - (3,4-dimethoxy-ß-phenethylamino) acetophenone are dissolved in 25 ml of methanol and treated with 5 »9 g Natriuniborhydrid in ЗО ml of methanol with stirring and reflux. The mixture is stirred for 1 hour and then distilled off the methanol in vacuo. The residue is poured into a mixture of ice and conc. Hydrochloric acid and alkalized with sodium hydroxide solution. It is then extracted with ether, the ethereal extract washed with water, dried over sodium sulfate, filtered off and concentrated to about 30 ml. Dry hydrogen chloride is introduced into the ethereal solution, and the precipitate formed is filtered off with suction and recrystallized from ethyl acetate / ethanol. The hydrochloride of 1 ~ (2,5-dichloro-phenyl) -2- (3,4-dimethoxy-.beta.-phenethylamino) -ethanol is obtained as a colorless, finely crystalline powder of mp. 181-182 °. Y. 9.6 g (29% of theory).

Example 11

16.3 g of 2,4-dichlorophenol and 8.0 g of sodium hydroxide are dissolved in 100 ml of ethanol and 20 ml of water and 32.9 g of 1-chloro-3- (3,4-dimethoxy-ß-phenethylamino) -propanol (2) hydrochloride added. The mixture is refluxed for 4 hours and i. Yak. evaporated to dryness. To obtain the 1- (2,4-dichloro-phenoxy) -3- (3> 4-dimethoxy-.beta.-phenethylamino) -propanol- (2), the residue was further processed as described in Example 3. Y. 11.2 g (28 % of theory ).

Example 12

16.3 g of 2,4-dichlorophenol and 4.0 g of sodium hydroxide are dissolved in 300 ml of ethanol, 28.5 g of 1,2-epoxy-3- (3,4-dimethoxy-ßphenäthylamino) -propane added and the reaction mixture Heated under reflux for hours. Thereafter, the mixture i. Vak. evaporated to dryness, the residue in 80 ml of chloroform

taken up, extracted with water and the organic phase dried over sodium sulfate. As it is filtered off, twice the amount of ether is added to the solution and dry hydrogen chloride is introduced. The precipitate formed is filtered off, washed with ether and recrystallized from dilute ethanol. This gives the hydrochloride of 1- (2,4-dichlorophenoxy) -3- (3,4-dimethoxy-.beta.-phenäthylamino) -propanols- (2) as a colorless, finely crystalline powder with mp. I5I-52 ^0th Y. 9.7 g (22% of theory).

Example 13

2.8 g of 1- (4-acetamino-2,6-dichloro-phenoxy) -3-chloro-propanol (2) in 200 ml of ethanol are treated with 3 »6 g of 3> 4-dimethoxy-β-phenethylamine 5 Heated under reflux for hours. The reaction mixture is evaporated to dryness, the residue is heated for 10 hours to I3O ⁰ and then washed several times with hot water. The dark brown crude product is dissolved in a little hot ethanol, heated with charcoal and filtered hot. After cooling, the product is filtered off with suction, giving 1- (4-acetamino-2,6-dichlorophenoxy) -3- (3,4-dimethoxy-β-phenethylamino) -propanol (2) as a colorless, finely crystalline powder of mp 109-110 °. Y. 1.7 g (37 % of theory ).

Example 14

4.1 g of 1- (4-amino-2,6-dichloro-phenoxy) -3- (3 »-dimethoxy: y-.beta.-phenethylamino) -propanol- (2) are suspended in 50 ml of water and stirred 1 g of acetic acid and 1.3 g of acetic anhydride are added dropwise. The mixture is stirred for about 1 hour, adjusted to ph 10-11 with 1N sodium hydroxide and extracted several times with chloroform. The organic phase is dried with sodium sulfate, filtered off and the chloroform is distilled off. From the brownish residue is the 1- (4-amino-2,6-dichlorophenoxy) -3 ~ (3,4-dimethoxy-ß-phenethylamino) propanol (2) as described in Example I3 isolated. Yield: 3.5 g (77 % d, Th.).

Example 15

5 g of 1- / 4- (3-phenylureido) -2,6-dibromo-phenoxy_7-2,3-epoxypropane are reacted with 1.96 g of 3,4-methoxy-.beta.-phenethylamine under the conditions mentioned in Example 3. To yield the 1-Д- (3-Pi ^ _ι enylureido) -2,6 dibromo ~ phenoxy_7-3- (3 '4-dimethoxy-ß ~ phenäthylamino) ~ propanol- (2) as a colorless, crystalline residue which consists of Ethyl acetate / ethanol is recrystallized. Colorless, fine crystalline powder with m.p. · 116-117 ⁰ C. Yield: 5.2 g (70% d.

Example 16

60 g of 1- (2,3-dichloro-phenoxy) -2,3-epoxypropane are reacted with 49 »5 g of 3» 4-dimethoxy-β-phenethylamine under the conditions mentioned in Example 3. The ethanol-recrystallized hydrochloride of γ- (3,4-dimethoxy-β-phenethylamino) propanol (2) is obtained as a colorless, finely crystalline powder of Si. Yield: 17 g (14 % of theory ).

fine crystalline powder of mp. 170 ~ 71 ⁰ C

Example 17

50 g of 1 ~ (2,6-dichlorophenoxy) -2,3-epoxypropane are reacted with 41 g of 3,4-methoxy-.beta.-phenethylamine under the conditions mentioned in Example 3. The hydrochloride of 1- (2,6-dichloro-phenoxy) -3- (3> 4-dime thoxy-ß-phenethylamino) -propanols- ^) is obtained as a colorless, crystalline residue which is recrystallized from ethyl acetate / ethanol. Colorless, finely crystalline powder of mp 135-36 °, Au: 44 g (44 % of theory )

Example 18

20 g of 1- (3,5-dichloro-phenoxy) -2,3-epoxypropane are reacted with 16.6 g of 3,4-dimethoxy-.beta.-phenethylamine under the conditions mentioned in Example 3. The hydrochloride of 1- (3,5-dichloro-phonoxy) ~ 3 ~ (3 »4 ~ cti! Ic іііоху-С-рлепагііу.іатіпо), recrystallized from ethyl acetate / ethanol, is obtained as" colorless, "propanol (2). fine crystalline powder of mp 171-72 ° yield: 16 g (40 % of theory ).

Cr

Example 19

50 g of 1- (2-bromo-4-chloro-phenoxy) -2,3 ~ epoxy-propane are reacted with 43.4 g of 3 »4-dimethoxy-.beta.-phenä'thylamin under the conditions mentioned in Example 3 · Man the hydrochloride of 1- (2-bromo-4-chlorophenoxy) -3- (3,4-dimethoxy-.beta.-phenethylamino) -propanols ^) as a colorless, crystalline residue, which is uracilcrystallized from ethyl acetate / ethanol. Colorless, finely crystalline powder of the mp 16O - 61 ° £. Yield: 42 G (46 % of theory ),

Example 20

29 g of 1- (4-bromo-2-chloro-phenoxy) -2,3-epoxy-propane are reacted with 19 * 9 g of 3> 4-dimethoxy-.beta.-phenethylamine under the conditions mentioned in Example 3-en. lian obtained from ethyl acetate / ethanol recrystallized hydrochloride of 1- (4-bromo-2-chloro-phenoxy) -3- (3> 4-dimethoxy-ß ~ phenäthylamino) -pr opanols- (2) as a colorless, feinkriötallines powder from SchEjp, 150 51 ⁰ C

Yield: 13 g (28 % of theory ).

Example 21

22 g of 1- (2 _s 4-dibromo-phenoxy) -2,3 ™ epoxy-propane are reacted with 12.7 g of 3,4-dimethoxy-.beta.-phenethylamine under the conditions mentioned in Example 3. One obtains the from ethyl acetate / ethanol recrystallized hydrochloride of 1- -3- (3,4-dimethoxy-.beta.-phenäthylamino) -propanols- (2) as a colorless, fine, crystalline powder having a mp 164 (2 4 ~ _{dibromophenoxy?)} -. 65 ° £ * Yield: 18 g (48 % of theory ).

Claims (2)

invention claim 1 «A process for the preparation of novel racemic or optically active alkanolamines of general formula I, wherein x ^ is a halogen atom, X _{2 represents} a hydrogen atom when у represents a halogen atom or a halogen atom when у represents another of the listed groups, у is a hydrogen atom, a halogen atom, an amino group, the acylamino group Ib-CO-NH-, the alkoxycarbonylamino group БЦ-О-СО-ГШ- or the ureido group БЦ-NH-CO-NH- (where ГЦ is a branched or unbranched, if necessary a phenyl radical substituted alkyl group having 1-10 C atoms means)
and ζ the groups represent -CH (OH) - or -OCH ₂ -CH (OH) -, characterized in that a) a halohydrin of the general formula II in which ^X 1 * ^X 2 'У ^{un <^ z} ^ ^e are as defined above and Hal represents a halogen atom, 3> 4-dimethoxy-.beta.-phenethylamine 1 to 48 hours at 20 - 200 ° C, optionally in an organic. Solvent and with the addition of a base, and that is optionally then, if у represents an amino group, with an acylating agent or a chloroformate, optionally in an organic solvent _f or that b) a compound of general formula I in which ζ is an -OCH ₂ -CO- or a -СО group and Χ /, X ₂ and у have the abovementioned meaning, reduced with base metals, hydrides or catalytically activated hydrogen _t or that one c) a phenylglyoxal of general formula III in which χ. *, X ₂ and у have the abovementioned meaning, in the presence of 3,4-dimethoxy-.beta.-phenethylamine with catalytically activated Hydrogen at 20 to 200 ° C and a pressure of 1 to 200 atm. reductive aminated, or that one d) a 1-phenoxy-2,3-epoxy-propane of the general formula IY, in which χ ,,, X ₂ and у have the abovementioned meaning, with 3 »4 ~ dimethoxy-ß-phenethylamine optionally in an organic solvent within 15 minutes or reacting to 48 hours at 15 to ⁰ I5O that e) a phenol of the general formula V in which χ, X, £ and у have the abovementioned meaning, with 1,2-epoxy-3- (3 »-4-dimethoxy-β-phenethylamino) -propane or a 1- Halogen-3- (3 »4-dimethoxy-ß-phenethylamino) -propanol- (2) optionally in the presence of an acid-binding agent and in an organic solvent or that f) an oxazolidone of the general formula VI or VII in which x, Xp and ω have the abovementioned meaning, is hydrolyzed with an alkali metal hydroxide solution or that g) of a compound of the general formula I, in which X ₂ and у have the abovementioned meaning and ζ represents a -CH (OA) or an -OCHp-CHCOA group which hydrolytically splits off protective group A, and that, if appropriate, the racemic alkanolamines obtained according to a to g are then converted into their diastereomeric salts by reaction with suitable auxiliaries and the latter is separated by fractional crystallization. 2. The method according to item 1, characterized in that starting from optically active starting materials » Rierzu..2i. Pages formulas