NO120270B - - Google Patents

Description

Process for the production of therapeutically effective benzofuran derivatives.

The present invention relates to a process for the production of previously unknown, therapeutically effective benzofuran derivatives with the general formula

where R and Z are lower alkyl group r,

n the value 1, 2 or 3

and the dotted line a facultative bond,

and of their acid addition salts.

Lower alkyl groups preferably mean alkyl groups with no more than 4 carbon atoms. A particularly interesting class of benzofuran derivatives according to the present invention are those compounds of formula I, where Z represents the methyl group and their acid addition salts. A further interesting class of benzofuran derivatives prepareable according to the present invention are those compounds of formula I, where R means the isopropyl group and their acid addition salts.

The process according to the invention for producing benzofuran derivatives with the general formula I and their acid addition salts consists in reacting a halohydrin with the general formula

where Z and n have the above meanings and X means a chlorine or bromine atom, or an epoxide of the general formula where Z and n have the above meanings, with an amine of the general formula

where R has the above meaning,

and that a benzofuran thus obtained is optionally hydrogenated to the corresponding 2,3-dihydro-benzofuran,

or that one catalytically hydrates a compound with the general formula

where R means a lower alkyl group,

Zi chlorine or bromine in the 5- or 7-position or in the 5- and 7-position and

Z2 is a 4-, 5-, 6- or 7-lower alkyl substitution, a 4,5-, 4,6-, 5,6- or 6,7-di-lower alkyl substitution or a 4,5,6- or 4,6, 7-tri-lower alkyl- - substitution, or where

Z^ means an allyl group in the 7-position and

Zg a hydrogen atom or a lower alkyl group in the 5- or 6-position or a di-lower alkyl substitution in the 4,6- or 5,6-position, or where

Z^ and Zg each mean an allyl group in the 5,7-position,

in one or two steps

and that a base thus obtained is optionally transferred to an acid addition salt.

An embodiment of the method according to the invention consists in reacting a halohydrin of the general formula IV with an amine of the general formula III in the presence of an acid-binding agent, optionally, if desired, hydrogenating the obtained benzofuran derivative of the general formula

catalytically to the corresponding 2,3-dihydro-benzofuran derivative of formula and that, if desired, a thus obtained base of formula Ia or Ib is transferred to an acid addition salt. The halohydrins with formula IV used as starting material can be obtained by reduction of corresponding halogen ketones with the general formula

A further embodiment of the method according to the invention consists

in that one reacts an epoxide of the general formula V with an amine of the general formula III that one, if desired, hydrates the obtained benzofuran derivative with the generated fcvvn.-i lu. catalytically to the corresponding 2,3-dihydrofuran derivative of formula lo and that, if desired, a thus obtained base of formula Ia or Ib is transferred to an acid addition salt.

The epoxides of formula V used here as starting materials can be obtained by dehydrohalogenation of the halohydrins of formula IV.

The two above-mentioned method variants as well as the preparation of the starting materials with formulas IV and V are prepared in the following reaction scheme.

The haloketones of formula II can e.g. is achieved by transferring a suitable lower alkyl-substituted salicylaldehyde to an alkali metal salt, reacting this salt with chloroacetone and chlorinating or brominating the lower alkyl-substituted 2-acetyl-benzofuran thus obtained. The conversion of the salicylaldehyde to an alkali metal salt can take place by treating the salicylaldehyde with a solution of an alkali metal hydroxide to a lower aliphatic alcohol, e.g. with an ethanolic potassium hydroxide solution. The reaction of the salt with chloroacetone is preferably carried out in an inert organic solvent, e.g. in a lower aliphatic alcohol, such as ethanol. The chlorination preferably takes place by treatment with sulfuryl chloride and the bromination by treatment with bromine in an inert organic solvent, such as ether or by treatment with cupric bromide in a mixture of ethyl acetate and chloroform. Particularly interesting halogen ketones of the general formula II are those in which Z is the methyl group, in particular 2-chloroacetyl-5,6-dimethyl-benzofuran, 2-chloroacetyl-6,7-dimethyl-benzofuran, 2-chloroacetyl-4,6 -dimethyl-benzofuran, 2-chloroacetyl-5,7-dimethyl-benzofuran and 2-chloroacetyl-6-methyl-benzofuran.

The reduction of the halogen ketones of formula II is preferably carried out using an alkali metal borohydride at a temperature of 20°C or above. The halogen ketone is preferably dissolved in a lower aliphatic alcohol, such as e.g. in ethanol or in aqueous dioxane; however, other solvents inert under the reaction conditions can also be used. The reduction can also be carried out using aluminum isopropoxide in isopropanol, whereby work is preferably done at an elevated temperature.

The reaction of a halohydrin of formula IV with an amine of formula III is preferably carried out by heating the halohydrin with at least 1 mol of the amine, e.g. at 50 - 100°C, in the presence of an acid-binding agent. Suitable acid binding agents are e.g. alkali metal carbonates, pyridine or preferably an excess of amine of formula III. The reaction is carried out in a similar manner, preferably using at least 2 mol of the amine of formula III per mol of halohydrin of formula IV. The heating of the reaction mixture can be carried out in the presence of an inert organic solvent, e.g. in the presence of ethanol. However, in each case where it is not necessary to dissolve the acid-binding agent, a solvent is not absolutely necessary. Furthermore, the heating can be carried out in a closed vessel and then this is particularly advantageous when highly volatile amines are used as starting materials with formula III.

In the same way as in corresponding, known benzofuran derivatives in which the benzene ring is unsubstituted, the compounds of formula I in which R is an isopropyl group exhibit a particularly advantageous combination of properties. The amine with formula III is therefore preferably used isopropylamine. However, other lower alkylamines can also be used, such as e.g. isobutylamine.

The dehydrohalogenation of a halohydrin of formula IV to form an epoxide of formula V is preferably carried out by treating the halohydrin at room temperature with an alkali metal hydroxide, e.g. with potassium hydroxide, which is dissolved in a lower aliphatic alcohol, in particular in methanol or is suspended in a non-polar organic solvent, such as benzene.

The reaction of an epoxide of formula V with an amine of formula III, in particular with isopropylamine, can take place by heating the epoxide together with the amine to e.g. 50 - 100°C. Preferably, an excess of the amine of formula III is used here. But this reaction can also be carried out in an inert organic solvent, e.g. in benzene, at room temperature and in the presence of boron trifluoride etherate.

The products obtained by the reaction of the halohydrins of formula IV or the epoxides of formula V with the amines of formula III are lower alkyl-substituted 2-[2-(lower alkyl)-amino-1-hydroxy-ethyl]-benzofurans of formula I, which exhibits a 2,3-double bond, i.e. the compounds of formula Ia. In many cases, the product thus obtained may also contain the corresponding isomeric 2-[1-(lower alkyl)amino-2-hydroxyethyl]-compound as a by-product. This by-product can be separated by usual methods, e.g. by chromatography on aluminum oxide or by fractional crystallization of the bases or their acid addition salts.

The catalytic hydrogenation of the compounds of formula Ia to form compounds of formula Ib is preferably carried out using a palladium-charcoal catalyst at room temperature and normal pressure.

Following a further embodiment of the method according to the invention, compounds of formula Ia are obtained, where the symbol (Z)n denotes a 4-, 5-, 6- or 7-lower alkyl substitution, a 4,5-, 4,6-, 4,7-, 5,6- or 6,7-dilower alkyl substitution, or a 4,5,6- or 4,6,7-tri-lower alkyl substitution by one-stage or two-stage catalytic hydrogenation of compounds of the general formula

where R means a lower alkyl group,

Z^chlorine or bromine in the 5- or 7-position or in the 5- and 7-position and

Z2 is a 4-, 5-, 6- or 7-lower alkyl substitution, a 4,5-, 4,6-, 5,6- or 6,7-di-lower alkyl substitution or a 4,5,6- or 4,6, 7-tri-lower alkyl substitution, or where

Zjmeans an allyl group in the 7-position and

Z 2 a hydrogen atom or a lower alkyl group in the 5- or 6-position or a di-lower alkyl substitution in the 4,6- or 5,6-position, or where Zi and Z 2 each mean an allyl group in the 5,7-position.

The starting materials of formula VI can be obtained by reduction of a corresponding substituted haloketone with an alkali metal borohydride and the reaction of the resulting halohydrin with an amine of formula III in the presence of an acid scavenger. An interesting class of the starting materials of formula VI are those compounds where the symbol Zg means a mono- or dialkyl substitution, where the alkyl groups are in particular methyl and ethyl groups. A further interesting class of starting materials of formula VI are those compounds where the symbol Z^ is a bromine substitution.

Particularly interesting starting materials of formula VI are 5-bromo-2-(2-iso-propylamino-1-hydroxy-ethyl)-6,7-dimethyl-benzofuran, 5-bromo-2-(2-isopropylamino-1-hydroxy- ethyl)-7-methyl-benzofuran, 7-bromo-2-(2-isopropylamino-1-hydroxy-ethyl) - 5- methyl- benzofuran, 5,7- dibrom- 2- (2- isopropylamino -1-hydroxy-ethyl)-4-methyl-benzofuran and 5-brom-2-(2-isopropylamino-1-hydroxy-ethyl)-7-ethyl-benzofuran.

The catalytic hydrogenation is preferably carried out using a palladium catalyst (e.g. a palladium-charcoal catalyst) at room temperature and normal pressure. Furthermore, the hydration is preferably carried out in an alkaline medium, e.g. in an alcoholic, in particular a methanolic solution of an alkali metal hydroxide, e.g. potassium hydroxide. During the hydrogenation, the parent or bromine atoms of the compounds of formula VI are split off first, after which the hydrogenation almost comes to a standstill. The thereby obtained compounds of formula I, where (Z)n has the meaning of Zg and where a 2,3-double bond is present, can be isolated and can - if desired - be subjected in a separate step to a further catalytic hydrogenation, whereby one obtains they formed 2,3-dihydro compounds. But the catalytic hydrogenation can also be carried on immediately after the removal of the respective chlorine or bromine atoms, whereby the 2,3-dihydro compounds are directly obtained. The hydrogenation of the 2,3-double bond takes place more slowly than the cleavage of the respective chlorine or bromine atoms. The products obtained in this way can - if desired - be transferred to acid addition salts.

The compounds of formula I, which exhibit a 2,3-double bond, contain an asymmetric carbon atom and are therefore obtained in the form of a stereoisomeric racemate. The compounds of formula I, where the carbon atoms in positions 2 and 3 are connected to each other by a single bond, contain two asymmetric carbon atoms and therefore occur in the form of 2 stereoisomeric racemates. These racemates can, if desired, be cleaved according to methods known per se, e.g. by fractional crystallization of the salts in the optical isomers.

The benzofuran derivatives of the general formula I form acid addition salts with inorganic acids, e.g. with hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid as well as with organic acids, e.g. with acetic acid, tartaric acid, citric acid, toluene sulphonic acids and the like.

The compounds obtained according to the method according to the invention, in contrast to the corresponding compounds unsubstituted in the benzene ring, have a strong β-adrenergic blocking effect without exhibiting sympathomimetic properties, as well as a lower toxicity. They are therefore applicable for the treatment of heart diseases, such as cardiac arrhythmia and Angina pectoris.

The previously known compounds unsubstituted by the benzene ring induce, in contrast to the compounds obtained according to the method according to the invention, an increase in heart rate and thus possess sympathomimetic properties, which antagonize the /3-blocking effect and render these compounds clinically worthless.

Particularly preferred compounds are A) 2-(2-isopropylamino-1-hydroxy-ethyl)-7-ethyl-benzofuran, B) 2-(2-isopropylamino-1-hydroxy-ethyl)-6,7-dimethylbenzofuran, C) 2-{2-isopropylamino-1-hydroxy-ethyl)-5-methyl-benzofuran and D) 2-(2-isopropyl-amino-1-hydroxy-ethyl)-7-propyl-benzofuran. Compounds A and B have a particularly strong β-adrenergic effect without influence on the heart rate. Compounds C and D likewise have a strong β-adrenergic effect and induce a reduction in heart rate.

Example 1.

A solution of 15 g (0.066 mol) of 2-(2-chloro-1-hydroxy-ethyl)-5,6-dimethyl-benzofuran and 12 g (0.2 mol) of isopropylamine in 40 ml of ethanol is heated under reflux for 18 hours. The solvent and excess isopropylamine are then distilled off under reduced pressure, and the syrup-like residue is dissolved in ether. The ethereal solution is treated with aqueous 2-n potassium hydroxide solution, and the resulting aqueous phase is extracted with ether. The ether extract is washed with water and dried over anhydrous sodium sulfate. The dry solution is then filtered, and the filtrate is evaporated, whereby a syrup-like mass is obtained, which consists of 2-(2-isopropylamino-1-hydroxy-ethyl)-5,6-dimethyl-benzofuran and the isomeric 2-(1-iso -propylamino-2-hydroxy-ethyl)-5,6-dimethyl-benzofuran. This product is transferred by treatment with hydrochloric acid to the hydrochloride and brought to crystallization. This first obtains 3.8 g of 2-(2-isopropylamino-1-hydroxy-ethyl)-5,6-dimethyl-benzofuran hydrochloride with a melting point of 168 - 171°C; the product obtained by further crystallization is contaminated with 2-(1-isopropylamino-2-hydroxy-ethyl)-5,6-dimethyl-benzo-

furan hydrochloride.

The 2-(2-chloro-1-hydroxy-ethyl)-5,6-dimethyl-benzofuran used here as starting material can be prepared in the following way: A solution of 18.3 g of potassium hydroxide in 150 ml of ethanol is added dropwise and while stirring in 1/4 hour to a solution of 45 g (0.3 mol) of 4,5-dimethyl-salicylaldehyde in 200 ml of ethanol, whereby a yellow precipitate of the potassium salt is obtained. 24.15 ml (27.8 g, 0.3 mol) of chloroacetone are then added over 1/4 hour with stirring, whereby the temperature rises to 40°C. The mixture is stirred at 20°C for 20 hours, whereby a fine white precipitate falls out. 350 ml of water are then added to the reaction mixture, and the ethyl alcohol is distilled off under reduced pressure. The residue is extracted three times with ether, the combined extracts are washed once with water and dried over sodium sulphate. The dry solution is filtered, evaporated to a syrup-like consistency and distilled, thereby obtaining 43.3 g of a main fraction with a boiling point of 120 - 145°C/ 0.7 mm. Crystallization of the distillate from petroleum ether (boiling range 60 - 80°C) yields 18 g of 2-acetyl-5,6-dimethyl-benzofuran in the form of white prisms with a melting point of 85 - 88°C. The product obtained by continued crystallization is contaminated with 4,5-dimethyl salicylaldehyde and can therefore, after dissolution in ether, be purified with 2-n sodium hydroxide solution and recrystallization. In this way, a further amount of 6.2 g of 2-acetyl-5,6-dimethyl-benzofuran with a melting point of 79 - 85°C is obtained.

A solution of 17 g (0.904 mol) of the thus obtained 2-acetyl-5,6-dimethyl-benzofuran in 90 ml of chloroform is added dropwise to 8.8 ml (14.64 g, 0.1085 mol) of sulfuryl chloride during of a period of 1/4 hour and while stirring. The mixture is then slowly heated over 20 minutes to reflux temperature and then kept below reflux temperature for 2 1/2 hours. The reaction mixture is then cooled and poured into an ice-water mixture. The two phases thus obtained are separated, the aqueous phase is extracted twice with chloroform, and the combined extracts are combined with the organic phase. The combined chloroform solutions are washed twice with 2-n sodium carbonate solution and once with water and then dried over sodium sulfate. The dry solution is filtered, the filtrate is evaporated, and the residue crystallizes from ethanol, whereby 18.0 g of 2-chloro-acetyl-5,6-dimethyl-benzofuran is obtained in the form of yellow-brown needles with a melting point of 115 - 120°C . 17 g (0.076 mol) of the thus obtained 2-chloroacetyl-5,6-dimethyl-benzofuran is dissolved in 100 ml of dioxane, and the solution obtained is cooled and 18 ml of water is added. Then add 18 ml of water. 1.80 g (0.048 mol) of sodium borohydride are then added in portions over 1/2 hour while stirring and cooling with ice. The reaction mixture is then stirred for 2 hours at 20°C, after which the solvent is evaporated at 40°C under reduced pressure. 100 ml of water is added,

and the solution is extracted three times with ether. The ethereal solutions are washed with water, dried and evaporated, whereby 18.5 g of 2-(2-chloro-1-hydroxy-ethyl)-5,6-dimethyl-benzofuran is obtained in the form of an orange-coloured syrup-like mass.

Example 2.

A solution of 6.4 g (0.034 mol) of 2-epoxyethyl-5,6-dimethyl-benzofuran and 4.02 g (0.068 mol) of isopropylamine in 25 ml of berizol is treated with 10 drops of boron trifluoride etherate and then allowed to stand at 20°C for 136 hours. The 2-(2-isopropylamino-1-hydroxy-ethyl)-5,6-dimethyl-benzofuran thereby separated in the form of a white solid is filtered off and transferred by treatment with hydrochloric acid to the hydrochloride. By crystallization from a mixture of methanol and ether, 2.5 g of hydrochloride of 2-(2-isopropylamino-1-hydroxy-ethyl)-5,6-dimethyl-benzofuran is obtained in the form of colorless prisms with a melting point of 175 - 177 °C.

By concentrating the mother liquors, a syrup-like mass is obtained, which consists of the isomeric 2-(1-isopropylamino-2-hydroxy-ethyl)-5,6-dimethyl-benzofuran. This syrup-like mass gives 3.0 g of the crude hydrochloride of this base and after several recrystallizations of this by-product, 0.8 g of pure 2-(1-isopropylamino-2-hydroxy-ethyl)-5,6-dimethyl-benzofuran is obtained -hydrochloride with a melting point of 216 - 219°C.

The 2-epoxyethyl-5,6-dimethyl-benzofuran used here as starting material can be prepared in the following way: A solution of 18.5 g of 2-(2-chloro-1-hydroxy-ethyl)-5,6-dimethyl-benzofuran (prepared according to the corresponding instructions in example 1) in 50 ml of benzene is added while cooling over 1/2 hour and with stirring to a suspension of 14 g of powdered potassium hydroxide in 25 ml of benzene. The reaction mixture is stirred for 2 1/2 hours at 0 - 10°C, diluted with 25 ml of benzene and filtered through diatomaceous earth. The filtrate is washed neutrally with water and dried over anhydrous sodium sulfate. The dry solution is filtered and evaporated, and the residue is distilled, whereby 6.4 g of 2-epoxyethyl-5,6-dimethyl-benzofuran is obtained in the form of a yellow syrup-like mass with a boiling point of 120°C/0.25 mm.

Example 3.

A solution of 1.42 g (0.005 mol) of the 2-(2-isopropylamino-1-hydroxy-ethyl)-5,6-dimethyl-benzofuran hydrochloride obtained according to the instructions in example 1 or 2 in 20 ml of methanol is hydrated at 20°C and normal pressure in the presence of 0.5 g of a 5% palladium-charcoal catalyst. After the hydrogen absorption, the solution is filtered, and the filtrate is evaporated. By treatment with ether, 1.2 g of a diastereomeric mixture of 2-(2-isopropylamino-1-hydroxy-ethyl)-5,6-dimethyl-2,3-dihydro-benzofuran hydrochloride is obtained in the form of colorless prisms. By fractional crystallization from a mixture of ethanol and ether, two racemates are obtained, one of which melts at 219°C and the other at 173 - 175°C.

Example 4.

11.22 g (0.05 mol) of the 2-(2-chloro-1-hydroxy-ethyl)-5,6-dimethyl-benzofuran obtained according to the instructions in example 1 and 22 g (0.3 mol) isobutylamine dissolve in 75 ml isopropanol. The solution is heated for 24 hours under reflux and then evaporated

on a water bath at 50°C under a pressure of 15 mm. The remaining syrup-like mass is treated with 2-n etheric hydrochloric acid, after which the resulting precipitate is filtered off and recrystallized from ethanol, thereby obtaining 5.4 g of 2-(2-isobutyl-amino-1-hydroxy-ethyl)-5,6 -dimethyl-benzofuran-hydrochloride in the form of colorless prisms with a melting point of 192 - 193°C. By thin-layer chromatography, it was determined that this is a uniform product. The structure of this compound was confirmed by the nuclear resonance spectrum of the free base.

Example 5.

11.15 g (0.05 mol) 2-(2-chloro-1-hydroxy-ethyl)-4,6-dimethyl-benzofuran and

45 g (0.75 mol) isopropylamine is heated in a steel autoclave for 10 hours at 80°C.

The cooled reaction mixture is dissolved in dilute hydrochloric acid, and the solution is extracted twice with ether. The aqueous solution is made alkaline with potassium hydroxide and extracted three times with ether. The ethereal solution is washed with water, dried over anhydrous sodium sulphate, filtered and the filtrate evaporated, thereby obtaining 12.4 g of a syrup-like mass. This mass is dissolved in methanol, and the solution is treated with ethereal hydrochloric acid and ether, whereby a crystalline precipitate with a melting point of 180 - 190°C is obtained. Recrystallization of this precipitate from ethyl acetate, ethanol and ether yields 1.3 g of the unwanted isomeric 2-(1-isopropylamino-2-hydroxy-ethyl)-4,6-dimethyl-benzofuran hydrochloride with a melting point of 193 - 194°C. After concentration of the mother liquors to a syrup-like mass, these are treated with caustic liquor to release the bases. These bases are extracted three times with ether, and the combined ether extracts are washed with water, dried over anhydrous sodium sulfate and evaporated to a syrup-like mass. By crystallization from a mixture of petroleum ether (boiling range 60 - 80°C) and benzene, 1.9 g of the desired 2-(2-isopropylamine-1-hydroxy-ethyl)-4,6-dimethyl-benzofuran is obtained in the form of yellow-brown needle-shaped crystals with a melting point of 100 - 102°C. The hydrochloride thus obtained by treatment with ethyl acetate, ethereal hydrochloric acid and ether forms, after recrystallization from a mixture of ethyl acetate and ether, cream-coloured prisms with a melting point of 139 - 141°C.

The 2-(2-chloro-1-hydroxy-ethyl)-4,6-dimethyl-benzofuran used here as starting material can be obtained in the following way: To a solution of 45 g (0.3 mol) 4,6-dimethyl- salicylaldehyde in 200 ml of ethanol is added dropwise in a nitrogen atmosphere and with stirring during 1/4 hour a solution of 18.3 g of potassium hydroxide in 150 ml of ethanol. A yellow precipitate of the potassium salt is thereby formed. Then 28.9 ml (33.3 g, 0.36 mol) of chloroacetone are added dropwise over the course of 30 minutes and with stirring, whereby the reaction temperature rises to 40°C. The reaction mixture is stirred at 20°C in a nitrogen atmosphere for a further 19 hours. 350 ml of water are then added, and the ethyl alcohol is evaporated under reduced pressure. The residue is extracted three times with chloroform, and the combined organic phases are washed once with water and dried over anhydrous sodium sulfate. The dry solution is filtered, and the filtrate is evaporated to a syrup-like mass. This is distilled, whereby a main fraction with a boiling point of 120 - 135°C/l .2 mm is obtained. Crystallization from petroleum ether yields 25.8 g of 2-acetyl-4,6-dimethyl-benzofuran with a melting point of 94 - 96°C.

12.6 ml (0.17 mol ) sulfuryl chloride. The reaction mixture is then slowly heated over 1/2 hour to reflux temperature and held at reflux temperature for 2 1/2 hours. The reaction mixture is then cooled and poured into 200 ml of an ice-water mixture. The organic phase, which thereby forms, is separated; the aqueous phase is extracted twice with chloroform, and the extracts are combined with the organic phase. The combined chloroform solutions are washed once with water and dried over sodium sulfate. The dry solution is filtered, and the filtrate is evaporated, whereby 2-chloro-acetyl-4,6-dimethyl-benzofuran is obtained in the form of a pink colored solid. Crystallization from ethanol yields 24.9 g of the product with a melting point of 121 - 124°C. 23 g (0.103 mol) of the thus obtained 2-chloro-acetyl-4,6-dimethyl-benzofuran are dissolved in 150 ml of dioxane. The resulting solution is added to 23 ml of water, whereupon 2.45 g (0.06 mol) of sodium borohydride is added in portions and while cooling with ice over the course of 1/2 hour. The reaction mixture is stirred for 2 3/4 hours at 20°C, after which the solvent is evaporated at 40°C under reduced pressure. The evaporation residue is added to 250 ml of water, and the mixture thus obtained is extracted three times with ether. The combined ethereal solutions are washed once with water and dried over anhydrous sodium sulfate. The dry solution is filtered, and the filtrate is evaporated, whereby 23.5 g of 2-(2-chloro-1-hydroxy-ethyl)-4,6-dimethyl-benzofuran is obtained in the form of a yellow-brown colored oil.

Example 6.

A solution of 18.8 g (0.1 mol) of 2-epoxyethyl-5,7-dimethyl-benzofuran and

11.8 g (0.2 mol) of isopropylamine in 500 ml of benzene are added to 10 drops of boron trifluoride etherate, after which the mixture is allowed to stand for 72 hours at 20°C. The mixture is then evaporated to a syrup-like mass, which is transferred to the hydrochloride. In this way, no crystallization occurs. The solution of the hydrochloride thus obtained is evaporated to a

syrup-like mass, which dissolves in ether. The ethereal solution is extracted with water, and the aqueous extracts are made alkaline with 2-n sodium hydroxide solution and extracted three times with ether. The extracts are dried over anhydrous sodium sulfate, and the dry solution is filtered. After evaporation of the filtrate, 14 g of a syrup-like mass is obtained, which after crystallization from ethyl acetate gives prism-shaped crystals. By recrystallization from ethyl acetate, 3.7 g of pure 2-(2-isopropylamino-1-hydroxy-ethyl)-5,7-dimethyl-benzofuran is obtained with a melting

point of 99 - 100°C. After dissolving the free base in ethyl acetate and treatment with ethereal hydrochloric acid, the crystalline hydrochloride with a melting point of 160°C is obtained. The mother liquors of the crystallization of the crude bases give, on treatment with ethereal hydrochloric acid, 1.7 g of the isomeric 2-(1-isopropylamino-2-hydroxy-ethyl)-5,7-dimethyl-benzofuran hydrochloride with a melting point of 197 - 198 °C.

The 2-epoxy-ethyl-5,7-dimethyl-benzofuran used here as starting material can be obtained in the following way: A solution of 303 g (2.02 mol) 3,5-dimethyl-salicylaldehyde in 1500 ml of ethanol is added dropwise in a nitrogen atmosphere during 1/4 hour a solution of 128.1 g of potassium hydroxide in 1050 ml of ethanol. This mixture is then added dropwise to 218.7 ml (251.5 g, 2.72 mol) of chloroacetone over the course of 45 minutes, whereby a slight heating of the reaction mixture occurs. The mixture is then stirred at 20° in a nitrogen atmosphere for 3 hours and then allowed to stand at 0°C for 48 hours. The resulting crystalline precipitate is filtered off and washed several times with water and dried. Crystallization from petroleum ether (boiling range 60 - 80°C) yields 126 g of 2-acetyl-5,7-dimethyl-benzofuran with a melting point of 76 - 79°C. By concentration of the mother liquors, distillation of the residue (boiling range 140 - 145°C/0.5 mm) and crystallization of the distillate from petroleum ether (boiling range .60 - 80°C), a further 103 g of this product is obtained. Total yield of 2-acetyl-5,7-dimethyl-benzofuran is consequently 229 g. A solution of 200 g (1.06 mol) 2-acetyl-5,7-dimethyl-benzofuran in 1200 ml of chloroform is added dropwise over 1 /4 hours and while stirring 102 ml (170 g, 1.27 mol) of sulfuryl chloride. The reaction mixture is then slowly heated to reflux temperature and kept at the reflux temperature for 2 1/2 hours. The cooled reaction mixture is then poured into 2000 ml of a mixture of ice and water, and the two phases which form are separated. The aqueous phase is extracted twice with chloroform, and the extract is combined with the organic phase. The combined chloroform solutions are washed and dried over anhydrous sodium sulfate. The dry solution is filtered, and the filtrate is evaporated. The resulting solid residue is crystallized from ethanol, whereby 192 g of 2-chloroacetyl-5,7-dimethyl-benzofuran with a melting point of 97 - 107°C is obtained. 167 g (0.75 mol) of the 2-chloroacetyl-5,7-dimethyl-benzofuran thus obtained is dissolved in 750 ml of dioxane. The cooled solution is added to 180 ml of water, after which 17.5 g of sodium borohydride is added in portions over the course of 1 hour while stirring and while cooling with ice. The reaction mixture is stirred for 2 hours at 20°C, after which the solvent is evaporated at 40°C under reduced pressure. The evaporation residue is added to 750 ml of water, and the resulting aqueous solution is extracted three times with

, ether. The ether solution is washed with water, dried over anhydrous sodium sulfate and filtered. By evaporating the filtrate, 190 g of 2-(2-chloro-1-hydroxy-ethyl)-5,7-dimethyl-benzofuran is obtained in the form of a syrup-like mass.

A solution of 190 g of the thus obtained 2-(2-chloro-1-hydroxy-ethyl)-5,7-dimethyl-benzofuran in 300 ml of dry benzene is added over 1/2 hour while cooling with ice and while stirring a suspension of 120 g of powdered potassium hydroxide in 300 ml of dry benzene. The reaction mixture is stirred for 2 1/2 hours at 0 - 10°C and then poured into 3000 ml of an ice-water mixture. The benzene layer, which is thereby formed, is separated, and the aqueous layer is extracted with benzene. The combined benzene solutions are washed neutral four times each time with 500 ml of water and dried over anhydrous sodium sulfate. The dry solution is filtered, and the filtrate is evaporated at 40°C

under reduced pressure in a steam bath. The main fraction obtained during the distillation (boiling range 140°C/0.2 mm) gives 26.2 g of 2-epoxy-ethyl-5,7-dimethyl-benzofuran in the form of a yellow syrup-like mass.

Example 7.

A solution of 11.0 g (0.05 mol) of 2-(2-chloro-1-hydroxy-ethyl)-6-methyl-benzofuran and 12 g (0.2 mol) of isopropylamine in 50 ml of ethanol is heated under reflux in 24 hours. The residue obtained after evaporating the solvent and the excess of isopropylamine under reduced pressure is taken up in chloroform, and the chloroform solution is washed twice with dilute caustic soda and once with water and dried over anhydrous sodium sulfate. The dry solution is filtered, the solvent is evaporated, and the remaining brown oil-like substance is dissolved in ethanol. After adding ethanolic hydrochloric acid to this solution, 2-(2-isopropylamino-1-hydroxy-ethyl)-6-methyl-benzofuran hydrochloride is obtained. By crystallization from a mixture of ethanol and ether, 2.0 g of this product with a melting point of 182°C is obtained. 1.6 g of the isomeric 2-(1-isopropylamino-2-hydroxy-ethyl)-6-methyl-benzofuran hydrochloride with a melting point of 172 - 173°C are obtained from the mother liquors.

The 2-{chloro-1-hydroxy-ethyl)-6-methyl-benzofuran used here as starting material can be obtained in the following way: A solution of 13.6 g (0.1 mol) 4-methyl-salicylaldehyde in 70 ml of dry ethanol, a solution of 6.2 g of potassium hydroxide in 50 ml of ethanol is added during 10 minutes while stirring. To the suspension of yellow potassium salt thus formed, 9.6 g (0.1 mol) of chloroacetone are added dropwise over 10 minutes. After 20 hours of stirring at room temperature, 200 ml of water is added. The mixture is then extracted three times with chloroform, and the combined extracts are washed with water and dried over sodium sulfate, after which the dry solution is filtered. After evaporation of the solvent, the remaining oil is distilled, whereby 10.0 g of a main fraction with a boiling point of 96 - 102°C/0.2 mm is obtained. After crystallization from ethanol, white prisms of 2-acetyl-6-methyl-benzofuran with a melting point of 69 - 71°C are obtained.

A solution of 8.71 g (0.05 mol) of the thus obtained 2-acetyl-6-methyl-benzofuran in 50 ml of chloroform is added dropwise and with stirring 8.1 g (0.06 mol) of sulfuryl chloride. The reaction mixture is then slowly heated to reflux temperature and held for 2 1/2 hours at reflux temperature. After the reaction mixture has cooled, it is poured into 100 ml of an ice-water mixture, and the two phases which are thereby formed are separated. The aqueous phase is extracted with chloroform twice, the combined organic extracts are washed twice with a sodium carbonate solution and once with water, and then dried over anhydrous sodium sulfate. The dry solution is filtered, the chloroform is removed by evaporation, and the residue is crystallized from ethanol, whereby 5.5 g of gray light-sensitive crystals of 2-chloroacetyl-6-methyl-benzofuran with a melting point of 114 - 115°C are obtained. A solution of 10.43 g (0.05 mol) of the thus obtained 2-chloroacetyl-6-methyl-benzofuran in a mixture of 40 ml of dioxane and 10 ml of water is added in portions over 1/2 hour and under ice cooling and stirring 2.0 g (0.05 mol) sodium borohydride. The mixture is stirred for a further 3 hours and is then allowed to stand at room temperature for 20 hours. 100 ml of water is then added, and the mixture is extracted twice with ether. The combined extracts are washed first with water and then with sodium chloride solution and then dried over anhydrous sodium sulfate. The dry solution is filtered, and the solvent is removed by evaporation under reduced pressure, whereby 11 g of 2-(2-chloro-1-hydroxy-ethyl)-6-methyl-benzofuran is obtained in the form of a pale yellow oil.

Example 8.

A solution of 28 g (0.126 mol) 2-(2-chloro-1-hydroxy-ethyl)-6,7-dimethyl-benzofuran and 14.75 g (0.25 mol) isopropylamine in 60 ml ethanol is heated 60 hours during reflux. The reaction solution is then evaporated to a syrup-like mass, which is dissolved in ether. The solution thus obtained is treated with 2-n caustic soda and extracted with ether. The ether extract is dried over sodium sulphate, filtered and the filtrate is evaporated to a syrup-like mass. This is dissolved in the smallest possible amount of methanol, and the solution is treated with ethereal hydrochloric acid and ether, whereby 5.4 g of a crystalline hydrochloride is obtained. By recrystallization, 2 g of 2-(2-isopropylamino-1-hydroxy-ethyl)-6,7-dimethyl-benzofuran hydrochloride is obtained with a melting point of 191 - 193°C. The substance precipitated by continued crystallization is contaminated with the isomeric 2-(1-isopropylamino-2-hydroxy-ethyl)-6,7-dimethyl-benzofuran hydrochloride. By chromatography on aluminum oxide, 0.6 g of this compound is obtained in a pure state with a melting point of 190 - 192°C.

The 2-(2-chloro-1-hydroxy-ethyl)-6,7-dimethyl-benzofuran used here as starting material can be obtained in the following way: A solution of 75 g (0.5 mol) of 3,4-dimethylsalicylaldehyde in 350 ml of ethanol, a solution of 30.5 g of potassium hydroxide in 250 ml of ethanol is added dropwise over the course of 1/4 hour while stirring, whereby a yellow precipitate of potassium salt forms. 40.25 ml (46.25 g, 0.5 mol) of chloroacetone are then added during 45 minutes with stirring. This raises the temperature in the mixture from 25°C to 40°C, the yellow precipitate dissolves and a fine white precipitate forms. The reaction mixture is stirred at 20° for a further 17 hours. 600 ml of water are then added, the ethyl alcohol is evaporated under reduced pressure, and the residue is extracted three times with chloroform. The chloroform extracts are washed once with water and dried over anhydrous sodium sulfate. The dry solution is filtered, and the filtrate is evaporated. The evaporation residue is distilled, thereby obtaining 19 g of a precursor with a boiling point of 95 - 110°C/0.7 mm and 42 g of a main fraction with a boiling point of 115 - 130°C/0.5 - 0.7 mm. The process is contaminated with 3,4-dimethyl-salicylaldehyde. Both fractions are crystallized from petroleum ether (boiling range 60 - 80°C), whereby a total amount of 51.5 g of 2-acetyl-6,7-dimethyl-benzofuran with a melting point of 94.5 - 96.5°C is obtained.

A solution of 37.6 g (0.2 mol) of the thus obtained 2-acetyl-6,7-dimethyl-benzofuran in 200 ml of chloroform is added dropwise over 10 minutes to 19.4 ml (27 g, 0.24 mol) sulfuryl chloride. The reaction mixture is heated during 1/2 hour to reflux temperature and kept at the reflux temperature for a further 2 1/2 hours. After cooling the reaction mixture, this is poured into 300 ml of an ice-water mixture. The two phases that form are separated. The aqueous phase is extracted twice with chloroform, and the chloroform extracts are combined with the organic phase.

The combined chloroform solutions are washed twice with 2-n sodium carbonate solution and twice with water and dried over sodium sulfate. By evaporation of the dry solution, 50 g of crude 2-chloroacetyl-6,7-dimethyl-benzofuran is obtained, which is purified by crystallization from ethanol, thereby obtaining 43.5 g of yellowish-brown needles with a melting point of 105 - 109°C. 37 g (0.166 mol) of the thus obtained 2-chloroacetyl-6,7-dimethyl-benzofuran are dissolved in 200 ml of dioxane. The solution obtained is cooled and 40 ml of water is added. 3.85 g (0.104 mol) of sodium borohydride are then added in portions over the course of 1/2 hour while stirring and cooling with ice-water. The reaction mixture is stirred at 20°C for 2 hours, after which the dioxane is evaporated at 40° under reduced pressure. The evaporation residue is added to 300 ml of water, and the solution thus obtained is extracted three times with ether. The organic phase is washed once with water and dried over anhydrous sodium sulfate. After filtering the solution and evaporating the filtrate, 2-(2-chloro-1-hydroxy-ethyl)-6,7-dimethyl-benzofuran is obtained in the form of a yellow syrup-like mass.

Example 9.

A solution of 4 g of 2-epoxyethyl-6,7-dimethyl-benzofuran and 3 g of isopropylamine in 20 ml of benzene is added to 10 drops of boron trifluoride etherate, after which the mixture is allowed to stand for 94 hours at 20°C. The mixture is then evaporated to a syrup-like mass, which is subjected to a two-fold co-distillation with methanol and then dissolved in a small amount of methanol. The methanolic solution is treated with ethereal hydrochloric acid and ether, whereby 3.1 g of a crystalline hydrochloride with a melting point of 175 - 180°C is obtained, which consists of the desired 2-(2-isopropylamine-1-hydroxy-ethyl)-6, 7-dimethyl-benzofuran hydrochloride. By recrystallization from a mixture of methanol and ether, 1.65 g of the pure product with a melting point of 187 - 189.5°C is obtained.

The 2-epoxyethyl-6,7-dimethyl-benzofuran used here as a starting material can be obtained in the following way: A suspension of 17.5 g of powdered potassium hydroxide in 50 ml of benzene is added with stirring and ice-cooling during 1/2 hour a solution of 13.5 g (0.603 mol) of 2-(2-chloro-1-hydroxy-ethyl)-6,7-dimethyl-benzofuran in 50 ml of benzene. The reaction mixture is stirred for a further 3 hours, whereby the temperature is kept between 0° and 5°C. The filtrate obtained after filtration through diatomaceous earth is washed neutrally with water and dried over anhydrous sodium sulfate. The dry solution is filtered, and the filtrate is evaporated. Distillation of the evaporation residue yields 4 g of 2-epoxyety 1-6,7-dimethyl-benzofuran in the form of a yellow oil with a boiling point of 110 - 115°C/0.5 mm.

Example 10.

5.44 g of 5-bromo-2-(2-isopropylamino-1-hydroxy-ethyl)-6,7-dimethyl-benzofuran are dissolved in ethanol. The reaction vessel is flushed with nitrogen and 0.5 g of a 5% palladium-charcoal catalyst is added, after which the mixture is hydrated at room temperature and normal pressure. After a hydrogen consumption of approx. 5% greater than the theoretically required amount of hydrogen, the catalyst is filtered off, the filtrate is evaporated, and the evaporation residue is treated with hydrobromic acid, whereby 2-(2-isopropylamino-1-hydroxy-ethyl)-6,7-dimethyl-benzofuran is obtained in the form of its hydrobromide. The suspension obtained by adding water is made basic by means of solid sodium carbonate. The basic mixture is extracted three times with ether, and the extracts are washed once with water and dried over sodium sulfate. The dry solution is filtered and evaporated, whereby crude 2-(2-isopropylamino-1-hydroxy-ethyl)-6,7-dimethyl-benzofuran is obtained. After recrystallization from petroleum ether (boiling range 60 - 80°C), 3.5 g of the pure substance with a melting point of 107.5 - 109°C is obtained.

The 5-bromo-2-(2-isopropylamino-1-hydroxy7-ethyl)-6,7-dimethyl-benzofuran used here as starting material can be obtained in the following way: 22.9 g (0.1 mol) of 5- bromo-3,4-dimethyl-salicylaldehyde in 100 ml of ethanol, after which a solution of 6.1 g (0.1 mol) of potassium hydroxide in 75 ml of ethanol is added dropwise and with stirring over the course of 1/4 hour to the suspension thus obtained. Subsequently, initially 5-bromo-3,4-dimethyl-salicylaldehyde dissolves, but later precipitates out again in the form of its potassium salt. 8.5 ml of chloroacetone are now added dropwise and with stirring over the course of 1/4 hour. This raises the temperature to approx. 42°C. Stirring is continued for a further 2 hours, and the solvent is then evaporated under reduced pressure. After adding water to the evaporation residue, the mixture is extracted three times with chloroform. The combined extracts are washed with water and dried over sodium sulfate. The dry solution is filtered, and the filtrate is evaporated. By crystallization of the evaporation residue from ethanol, 16 g of 2-acetyl-5-bromo-6,7-dimethyl-benzofuran is obtained in the form of crystals with a melting point of 137.5 - 139.5°C.

A solution of 13.36 g (0.05 mol) of 2-acetyl-5-bromo-6,7-dimethyl-benzofuran in 75 ml of chloroform is added to 4.3 ml of sulfuryl chloride during 10 minutes with stirring. The mixture is heated slowly over 1/2 hour to boiling and then kept

for 2 hours at reflux temperature. After cooling the mixture, it is poured into a water-ice mixture and extracted three times with chloroform. The combined extracts are washed once with 2-n sodium carbonate solution and once with water and dried over sodium sulfate. The evaporation residue remaining after evaporation of the solvent is crystallized from a mixture of ethanol and methanol, whereby 9.2 g of 2-chloroacetyl-5-bromo-6,7-dimethyl-benzofuran with a melting point of 135 - 140°C is obtained. Recrystallization from ethanol yields 7 g of a product with a melting point

at 141 - 144°C. By repeated chlorination using 60.12 g of 2-acetyl-5-bromo-6,7-dimethyl-benzofuran, a first crystal amount of 43 g of 2-chloroacetyl-5-bromo-6,7-dimethyl-benzofuran is obtained with a melting point of 139 - 143°C. 42.2 g (0.143 mol) of the 2-chloroacetyl-5-bromo-6,7-dimethyl-benzofuran obtained in this way is suspended in a mixture of 210 ml of dioxane and 35 ml of water, after which the suspension is cooled to 0° C. 3.99 g (0.072 mol plus 25%) of sodium borohydride are then added in portions over 1/2 hour at a temperature of 0 - 5°C, and the mixture is then stirred for 3 hours at 20°C. The residue obtained after evaporation of the solvent under reduced pressure is treated with water and extracted three times with ether. The combined extracts are washed once with water and dried over anhydrous sodium sulfate. The dry solution is filtered, and the filtrate is evaporated, whereby a yellowish brown substance is obtained, which after crystallization from a mixture of benzene and petroleum ether gives 35.3 g of 5-bromo-2-(2-chloro-1-hydroxy-ethyl)- 6,7-dimethyl-benzofuran in the form of colorless needles with a melting point of 100 - 102°C.

A solution of 27.27 g (0.09 mol) of 5-bromo-2-(2-chloro-1-hydroxy-ethyl)-6,7-dimethyl-benzofuran and 47 ml (0.54 mol) of isopropylamine in 180 ml of isopropanol is heated under reflux for 24 hours. The isopropanol and the excess isopropylamine are then evaporated under reduced pressure, and the solid residue is shaken with an excess of aqueous 2-n sodium carbonate solution and filtered. The filter residue is washed with water and filtered again, then washed once more with water and filtered once more and then crystallized from ethanol, thereby obtaining 16.6 g of 5-bromo-2-(2-isopropylamino-1-hydroxy-ethyl) -6,7-dimethyl-benzofuran with a melting point of

135 - 138°C.

Example 11.

2 g (0.0061 mol) of 5-bromo-2-(2-isopropylamino-1-hydroxy-ethyl)-6,7-dimethyl-benzofuran are suspended in 26 ml of a 1.5% methanolic solution of potassium hydroxide . The reaction vessel is flushed with nitrogen, after which 0.2 g of a 5% palladium-charcoal catalyst is added, and the mixture is hydrated at room temperature and normal pressure. Hydrogen consumption is approx. 4% greater than the theoretically required amount of hydrogen and decreases rapidly after absorption of one mole-equivalent of hydrogen. The filtrate obtained after filtering off the catalyst is evaporated to dryness. After adding water, the mixture is extracted three times with benzene, the extracts are washed once with 2-n sodium carbonate solution and once with water and dried over sodium sulfate. The dry solution is filtered, evaporated to dryness, and the evaporation residue is crystallized from petroleum ether (boiling range 60 - 80°C), whereby 1.3 g of 2-(2-isopropylamino-1-hydroxy-ethyl)-6,7-dimethyl- benzofuran in the form of needles with a melting point of 107 - 108°C.

Example 12.

8.52 g of 2-(2-isopropylamino-1-hydroxy-ethyl)-6,7-dimethyl-benzofuran hydrochloride (obtained by treating the base obtained according to one of examples 10 and 11) are dissolved in 200 ml of methanol. The reaction vessel is flushed with nitrogen, after which 2 g of a 5% palladium-charcoal catalyst is added. The mixture is hydrated at 20°C and normal pressure, whereby after 24 hours 1 g of the catalyst is once again added to carry out a complete hydration. The total hydrogen consumption amounts to approx. 740 ml (theoretical consumption 750 ml). The filtrate obtained after removal of the catalyst is evaporated to dryness, and the evaporation residue is crystallized from a mixture of methanol and ether, whereby 4.9 g of one of the racemates of 2-(2-isopropylamino-1-hydroxy-ethyl)-6 is obtained, 7-dimethyl-2,3-dihydrobenzofuran (designated as racemate A) in the form of its hydrochloride with a melting point of 174°C (softening point at 150°C). After two recrystallizations from ethanol, 2.2 g of the hydrochloride is obtained with a melting point of 179 - 181.5°C.

The mother liquors according to the first crystallization are evaporated to a syrup-like mass, which is made alkaline and extracted with ether. The extract is evaporated again to a syrup-like mass, which is crystallized from petroleum ether (boiling range 60 - 80°C), thereby obtaining 0.6 g of the second racemate of 2-(2-isopropylamino-1-hydroxy-ethyl)-6, 7-dimethyl-2,3-dihydro-benzofuran (racemate B) in the form of crystals with a melting point of 67 - 71°C.

Example 13.

1.75 g (0.005 mol) of 5-bromo-2-(2-isopropylamino-1-hydroxy-ethyl)-7-methyl-benzofuran hydrochloride is dissolved in 50 ml of ethanol and hydrated at room temperature and normal pressure in the presence of 0.1 g of a 5% palladium-charcoal catalyst. After approx.

5% more hydrogen is consumed, which corresponds to the theoretically necessary amount of hydrogen, the speed of hydrogen absorption drops considerably. The catalyst is now filtered off, and the filtrate is evaporated to dryness. The solution obtained after absorption of the evaporation residue in water is made alkaline and extracted twice with ether. The ether extracts are washed with water and saline and dried over sodium sulphate. The dry solution is filtered and evaporated, whereby 2-(2-isopropylamino-1-hydroxy-ethyl)-7-methyl-benzofuran is obtained in the form of white crystals, which after recrystallization from petroleum ether (boiling range 60 - 80°C) give 1 .1 g of white needles with a melting point of 90 - 92°C. By thin-layer chromatography, it can be established that the product is a single substance, the structure of which can be confirmed through nuclear resonance spectroscopy. By dissolving the free base in ethanol and treating the solution with ethereal hydrochloric acid, the hydrochloride is obtained. This is recrystallized from a mixture of methanol and ether, whereby white microcrystals of 2-(2-isopropylamino-1-hydroxy-ethyl)-7-methyl-benzofuran hydrochloride with a melting point of 162 - 163°C are obtained.

In the same way, the 5-bromo-2-(2-isopropylamino-1-hydroxy-ethyl)-7-methyl-benzofuran in the form of the free base can also be hydrogenated to 2-(2-isopropylamino-1-hydroxy-ethyl) - 7- methyl-benzofuran.

The monovalent 5-bromo-2-(2-isopropylamino-1-hydroxy-ethyl)-7-methyl-benzofuran or its hydrochloride can be obtained as follows: A solution of 10.8 g (0.05 mol) 5-bromo-3-methyl-salicylaldehyde in 100 ml of ethanol is added dropwise and with stirring at room temperature over the course of 10 minutes, a solution of 3.1 g (0.05 mol) of potassium hydroxide in 30 ml of ethanol. To the yellow solution thus obtained, 4.8 g of chloroacetone are added dropwise over the course of 1/4 hour. The mixture is stirred at room temperature for 20 hours and then poured into 50 ml of water and extracted twice with chloroform. The combined extracts are washed with dilute caustic soda and with water and dried over sodium sulfate. After evaporation of the solvent, a yellow solid is obtained, which is recrystallized from ethanol, thereby obtaining 9.3 g of 2-acetyl-5-bromo-7-methyl-benzofuran in the form of fine yellow needles with a melting point of 122 - 123 °C. A solution of 7.6 g (0.03 mol) of 2-acetyl-5-bromo-7-methyl-benzofuran in 30 ml of chloroform is added dropwise with stirring over the course of 10 minutes to 4.9 g of sulphuryl chloride. The mixture is heated for 3 hours under reflux, then cooled and poured onto ice. The two phases which thereby form are separated, and the aqueous phase is extracted with chloroform. The extract is combined with the organic phase, washed with 2-n sodium carbonate solution and then with water and dried over sodium sulfate. The dry solution is filtered, and the filtrate is evaporated under reduced pressure. The solid evaporation residue is crystallized from ethanol, whereby 7.1 g of 2-chloroacetyl-5-bromo-7-methyl-benzofuran is obtained in the form of fine yellow needles with a melting point of 134 - 137°C.

14.4 g (0.05 mol) of 2-chloroacetyl-5-bromo-7-methyl-benzofuran are dissolved in a mixture of 100 ml of dioxane and 20 ml of water, and the solution thus obtained is cooled to 0°C. 1.2 g of sodium borohydride are then added in portions over the course of 1/2 hour, and the mixture is stirred at room temperature for 2 hours. The residue remaining after evaporation of dioxane under reduced pressure is diluted with 200 ml of water and extracted twice with ether. The combined extracts are washed with water and salt solution and dried over sodium sulfate. After evaporation of the solvent, crude 5-bromo-2-(2-chloro-1-hydroxy-ethyl)-7-methyl-benzofuran is obtained in almost quantitative yield in the form of a pale yellow oil.

The thus obtained crude 5-bromo-2-(2-chloro-1-hydroxy-ethyl)-7-methyl-benzofuran (0.05 mol) is heated together with 12 g (0.2 mol) of isopropylamine in 50 ml of ethanol 24 hours during reflux. The solid residue obtained after evaporation of the solvent and the excess isopropylamine under reduced pressure is distributed between ether and dilute hydrochloric acid. The aqueous acid phase is washed with ether, made alkaline with dilute caustic soda and extracted three times with ether. The combined extracts are washed with water and saline and dried over sodium sulfate. After evaporation of the solvent, a brown solid is obtained, which is recrystallized from petroleum ether (boiling range 60 - 80°C), thereby obtaining 9.0 g of 5-bromo-2-(2-isopropylamino-1-hydroxy-ethyl)-7 -methyl-benzofuran in the form of yellow-brown crystals with a melting point of 120 - 130°C. By thin-layer chromatography, it can be determined that this is a uniform product, the structure of which can be confirmed by nuclear resonance spectroscopy. The 5-bromo-2-(2-isopropylamino-1-hydroxy-ethyl)-7-methyl-benzofuran hydrochloride obtained from this base by treatment with hydrochloric acid melts after recrystallization from a mixture of ethanol and ether at 158 - 159°C .

Example 14.

7-bromo-2-(2-isopropylamino-1-hydroxy-ethyl)-5-methyl-benzofuran or its hydrochloride (prepared by reaction of 2-chloroacetyl-7-bromo-5-methyl-benzofuran and reaction of the obtained 7 -bromo-2-(2-chloro-1-hydroxy-ethyl)-5-methyl-benzofuran with isopropylamine) are transferred by hydration analogously to those in example 13 containing

indications for the 2-(2-isopropylamino-1-hydroxy-ethyl)-5-methyl-benzofuran, which is obtained in the form of white crystals with a melting point of 111 - 112°C (after crystallization from petroleum ether). The corresponding hydrochloride forms white crystals with a melting point of 174 - 176°C (after crystallization from a mixture of ethanol and ether).

Example 15.

5,7-dibromo-2-(2-isopropylamino-1-hydroxy-ethyl)-4-methyl-benzofuran (obtained by reducing 2-chloroacetyl-5,7-dibromo-4-methyl-benzofuran and reacting it thereby obtained 5,7-dibromo-2-(2-chloro-1-hydroxy-ethyl)-4-methyl-benzofuran with isopropylamine) is hydrogenated analogously to the instructions contained in example 13, whereby both bromine atoms are split off in equal mass and whereby after the consumption of the theoretical amount of hydrogen required decreases the speed of hydrogen absorption. 2-(2-isopropylamino-1-hydroxy-ethyl)-4-methyl-benzofuran is thereby obtained in the form of cream-colored crystals with a melting point of 81 - 82°C. By treating this base with ethereal hydrochloric acid, 2-(2-isopropylamino-1-hydroxy-ethyl)-4-methyl-benzofuran hydrochloride is obtained, which after recrystallization from a mixture of ethanol and ether melts at 146 - 148°C.

Example 16.

5-bromo-2-(2-isopropylamino-1-hydroxy-ethyl)-7-ethyl-benzofuran (obtained by reduction of 2-chloroacetyl-5-bromo-7-ethyl-benzofuran and conversion of the thereby obtained 5-bromo -2-(2-chloro-1-hydroxy-ethyl)-7-ethyl-benzofuran with isopropylamine) is hydrogenated analogously to the indications contained in example 13 to 2-(2-isopropylamino-1-hydroxy-ethyl)-7-ethyl- benzofuran, which precipitates as an oil. By treating this base with hydrochloric acid, the corresponding hydrochloride is obtained, which after crystallization from a mixture of ethanol and ether precipitates in the form of white crystals with a melting point of 113: - 114°C.

Example 17.

2.95 g of 2-(2-isopropylamino-1-hydroxy-ethyl)-7-allyl-benzofuran hydrochloride (obtained by reduction of 2-chloroacetyl-7-allyl-benzofuran and reaction of the thereby obtained 2-(2- chloro-1-hydroxy-ethyl)-7-allyl-benzofuran with isopropylamine and conversion of the obtained base to the hydrochloride) is hydrated in 20 ml of methanol in the presence of 0.5 g of a 5% palladium-charcoal catalyst. After the rapid absorption of 242 ml of hydrogen (within 10 minutes), the hydration is interrupted. The catalyst is filtered off, and the filtrate is evaporated, whereby 2.1 g of 2-(2-isopropylamino-1-hydroxy-ethyl)-7-propyl-benzofuran hydrochloride is obtained, which after recrystallization from a mixture of ethyl acetate and ether precipitates in form of a white crystalline powder with a melting point of 83 - 85°C.

Example 18.

A solution of 2.73 g (0.01 mol) of 2-(2-isopropylamino-1-hydroxy-ethyl)-5-methyl-7-allyl-benzofuran (obtained by reduction of 2-chloroacetyl-5-methyl-7 -allyl-benzofuran and reaction of the resulting 2-(2-chloro-1-hydroxy-ethyl)-5-methyl-7-allyl-benzofuran with isopropylamine) in 40 ml of ethanol is hydrated at room temperature and normal pressure in the presence of 0 .2 g of a 5% palladium-charcoal catalyst. After 10 minutes, the amount of hydrogen, which is necessary for the hydration of the double bond of the allyl group, is taken up, and no further hydrogen uptake takes place for the next 15 minutes. The catalyst is now filtered off and washed with ethanol. The filtrate combined with washing liquid is added while cooling with ethereal hydrochloric acid, after which dry ether is added to the mixture. The viscous oil obtained after evaporation is dissolved in the smallest possible volume of ethyl acetate, and the solution is added to dry ether and cooled to 0°C. This gives 2.6 g of 2-(2-isopropylamino-1-hydroxy-ethyl)-5-methyl-7-propyl-benzofuran hydrochloride in the form of white crystals with a melting point of 108 - 109°C.

Example 19.

0.25 g (0.000744 mol) 2-(2-isopropylamino-1-hydroxy-ethyl)-5,7-diallyl-benzofuran hydrochloride (obtained by reduction of 2-chloroacetyl-5,7-diallyl-benzofuran, reaction of the thereby formed 2-(2-chloro-1-hydroxy-ethyl)-5,7-diallyl-benzofuran with isopropylamine and conversion of the thereby obtained base to the hydrochloride) is dissolved in 15 ml of methanol. The reaction vessel, which contains the solution, is flushed with nitrogen, after which 0.05 g of a 5% palladium-charcoal catalyst is added. Now the mixture is hydrogenated at 20°C and normal pressure, whereby the theoretical amount of hydrogen is taken up within 5 minutes. The filtrate obtained after filtering off the catalyst is evaporated to a syrup-like mass. This is distilled together with ethyl acetate, and the distillate is crystallized from ethyl acetate, whereby 2-(2-isopropylamino-1-hydroxy-ethyl)-5,7-dipropyl-benzofuran hydrochloride is obtained in the form of colorless prisms with a melting point of 115 - 116 °C.

Example 20.

4.8 g of 5-bromo-2-(2-tert.butylamino-1-hydroxy-ethyl)-7-ethyl-benzofuran is hydrogenated at room temperature and normal pressure with 0.3 g of 5% palladium-charcoal catalyst in 50 ml of ethanol. After the absorption of one equivalent of hydrogen, the catalyst is filtered off, the filtrate is evaporated to dryness, the residue is made basic and extracted twice with ether. The ether extracts are combined and worked up in the usual way to give 2-(2-tert.butylamino-1-hydroxy-ethyl)-7-ethyl-benzofuran in the form of an oil. This is converted into 2.9 g of the crystalline hydrochloride with a melting point of 145 - 146°C (from a mixture of ethanol and ether)

5-bromo-2-(2-tert.butylamino-1-hydroxy-ethyl)-7-ethyl-benzofuran used as starting material can be prepared in the following way: 16.0 g of 5-bromo-2-(2-chloro-1 -hydroxy-ethyl)-7-ethyl-benzofuran is heated at 100°C in a closed autoclave for 24 hours with 37.0 g of tert-butylamine. The mixture is cooled, the excess amine is evaporated, the residue is taken up in dilute hydrochloric acid and washed twice with ether. The aqueous solution is made basic with dilute sodium hydroxide solution and extracted twice with ether. The ether extracts are combined, washed with water and sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to give a solid residue. Crystallization of this residue from petroleum ether (boiling range 60 - 80°C) gives 4.7 g of 5-bromo-2-(2-tert.butylamino-1-hydroxy-ethyl)-7-ethyl-benzofuran as brown-yellow-f argent crystals with a melting point of 101 - 103°C. This base is converted in accordance with conventional techniques to its hydrochloride,

which took the form of cream-coloured crystals with a melting point of 188 - 190°C (from a mixture of ethanol and ether).

Example 21.

In an analogous manner according to examples 1 and 2, starting from 2-(2-chloro-1-hydroxy-ethyl)-7-ethyl-benzofuran or from 2-epoxyethyl-7-ethyl-benzofuran and isopropylamine 2-(2 -isopropylamino-1-hydroxyethyl)-7-ethylbenzofuran is obtained. The hydrochloride of this compound melts at 113 - 114°C.

Claims (1)

1.. Process for the production of therapeutically active benzofuran derivatives with the general formula where R and Z are lower alkyl groups, n the value 1, 2 or 3 , and the dotted line a facultative bond, and of their acid addition salts, characterized in that a compound of the general formula is reacted where Z and n have the above meaning and X means a chlorine or bromine atom, or an epoxide of the general formula