KR790001983B1 - Process for preparation of benzojuran derivatives - Google Patents

Abstract

Benzofuran derivs. (I, A = hydroxymethylene, carbonyl), useful as β-adrenergic blocking agent, were prepd. by several methods. I(A = hydroxymethylene) was prepd. by reaction of II (R = H, lower alkanoyl; X = C1, Br; Y = H, OH) with Me3CNH2 in dil. NaOH or by redn. of II(R = lower alkanoyl; X = Me3CNH; Y = O) with NaBH4 in EtOH, or by Haddition to II(R = H; X= Me3CNH ; Y = H, OH). I (A = carbonyl) was prepd. by reaction of III with base or by oxidn. of I(A = hydroxymethylene) with Cr oxidizer.

Description

Method for preparing benzofuran derivative

The present invention relates to a benzofuran derivative besides the following structural formula (I) having an β-adrenergic dentition action, an acid addition salt thereof, and a preparation method thereof.

In the above structural formula

A represents a hydroxymethylene or carbonyl group.

The compound of formula (I) and acid addition salts thereof are prepared by the following method.

The compound of formula (I) wherein A is a hydroxymethylene group can be treated by tert-butylamine with the compound of formula (II) or by reducing the compound of formula (III) with alkali metal borhydride or ) And the compound by catalytic hydrogenation

In the above structural formula

R is hydrogen or a lower alkanoyl group

× is chlorine or bromine atom

R ¹ is a lower alkanoyl group.

Compounds of formula (I) in which A is a carbonyl group are prepared by treating a compound of formula (V) with a base or optionally oxidizing a compound of formula (I) in which A is a hydroxymethylene group with a chromium oxidant.

If necessary, the compound of formula (I) obtained above is converted to its acid addition salt.

As used herein, the term lower alkanoyl means an alkanoyl group containing up to 7 carbon atoms, such as acetyl, propionyl, butynyl, and among these, an acetyl group is preferred. In the formula (II), x is preferably a bromine atom.

Treatment of the compound of formula (II) with tert-butylamine raises the compound of formula (II) in an inert organic solvent (a polar solvent such as lower alkanols such as methanol, ethanol, acetonitrile or dimethylformamide is preferred). It is suitably carried out by heating with tertiary butylamine at an elevated temperature (eg the reflux temperature of the mixture). This treatment can be carried out in the presence of an acid binder if necessary and suitable acid binders include alkali metal carbonates such as sodium carbonate, tertiary organic amines such as pyridine and the like. Excess tert-butylamine can also be used as acid binder.

The treatment as above gives a mixture of the desired structural formula (I) compound and the following structural formula (II) compound, wherein A is a hydroxyethylene group.

This mixture can be easily separated into its components by conventional techniques, for example by fractionation with an appropriate salt such as oxalate.

The reduction of the compound of formula (III) may be performed using an alkali metal borohydride (particularly sodium borohydride). This reduction reaction may be at or about 20 ° C. or lower. It is preferable to carry out in a lower alkanol or dioxane aqueous solution such as ethanol, and other solvents which are inert under the reaction conditions may be used.

For catalytic hydrogenation of the compound of formula (IV), it is preferable to use a compound in which X is bromine. Catalytic hydrogenation is conveniently carried out in the presence of a palladium catalyst (eg palladium / carbon) at room temperature and atmospheric pressure. Catalytic hydrogenation ends after the bromine or chlorine represented by X is removed but before the hydrogenation of the 2,3-2 double bond or benzylcarbinol group takes place.

Suitable bases for the treatment of the compound of formula (V) are alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, which reaction is preferably carried out using alcoholic or aqueous-alcoholic potassium hydroxide at about room temperature. Oxidation of the compound of formula (I) wherein A is a hydroxymethylene group is conveniently carried out using chromium trioxide in a solvent such as pyridan, glacial acetic acid, acetone, water or mixtures thereof, preferably trioxide in aqueous acetone. It is better to use chromium / sulfuric acid. Suitable temperatures for oxidation are about −20 ° C. to room temperature.

The compound of formula (II), which is the starting material, is prepared according to the following scheme. Here, R, R ¹ and X are as described above.

In reaction (i) of the above scheme, the compound of formula (VIII) is ketalized with ethylene glycol in the presence of a suitable inert solvent such as P-toluenesulfonic acid and toluene to prepare ethylene ketal of formula (VIII). . Next, in the reaction (ii), the ethylene ketal is preferably N- (chloro or bromo) succinimide (N-bromosuccinimide) in the presence of an inert organic solvent (for example, a chlorinated hydrocarbon such as carbon tetrachloride). To react with a suitable lower alkanoic acid in the presence of the corresponding corresponding alkali metal acylate (e.g. sodium acetate) to prepare a compound of formula (IX). . In reaction (IV), the compound of formula (X) is then deketalized with a suitable aromatic sulfonic acid (eg benzenesulfonic acid) in a ketone solvent (eg acetone). The resulting compound of formula (XI) is chlorinated or brominated with sulfuryl chloride or bromine in an organic solvent such as ether in reaction (V), or cuprous bromide, or tetrahydrobutane in ethyl acetate / chloroform. The haloketone of formula (XII) is prepared by bromination using trimethylphenyl ammoniumtri bromide. Next, the haloketone of the formula (XII) is converted into an alkali metal cyanoborohydride (e.g., nitrile cyanoborohydride) under acidic conditions (pH 4 is suitable) in an inert organic solvent (e.g., a lower alkanol such as methanol). Reduction to obtain the desired compound of formula (II), wherein R is a lower alkanoyl group. The haloketone of formula (XII) is also reduced using an alkali metal hydride in the presence of a lower alkanol (eg ethanol) to obtain the starting material of formula (II), where R is a hydrogen atom.

The above-mentioned starting material, the compound of formula (III) may be prepared by reacting the halohydrin of the above-mentioned formula (XII) with t-butylamine in the presence of an inert organic solvent such as ether (e.g., diethyl ether, tetrahydrofuran or dioxane). It is made by reaction.

The starting material of the above formula (IV) is prepared according to the following reaction scheme. Wherein R, R ¹ and X are the same.

In the reaction scheme (i) to (v), the reaction is carried out in a manner similar to that described in the schemes (i) to (v) when preparing the starting material (II) compound. The haloketone of the structural formula (XIII) obtained by the reaction (y) of this scheme can be changed to the desired starting material of the structural formula (IV) in two ways.

One method is the structural formula (XIX) obtained by reacting the haloketone in reaction (vi) with tert-butylamine in the presence of an inert organic solvent such as ether (e.g., diethyl ether, tetrahydrofuran or dioxane). The compound is reduced using an alkali metal borohydride (eg sodium borohydride) in the presence of lower alkanols (eg ethanol). Another method reduces the above haloketone to the compound of formula XX in reaction (vii). This reduction reaction is carried out using alkali metal cyanoborohydride or alkali metal borohydride in the same manner as described for the reduction of the compound of formula (XII). Next, the compound of formula (XX) obtained above is reacted in the same manner as in the reaction of the compound of formula (II) with tert-butylamine.

In the latter method, a mixture of the starting material of the formula (IV) and the compound of formula (XXI) is obtained.

In the above structural formula, X is as described above.

This mixture can be easily separated into its components according to conventional methods such as fractional determination of suitable salts such as oxalate.

The starting material of formula (V) is reacted with a compound of formula (I) (where A is a hydroxy methylene group) in the presence of an inert organic solvent such as phosgene and an aromatic hydrocarbon (e.g. toluene). Oxyzolidone of)) is prepared, which is oxidized using manganese dioxide in the presence of an inert organic solvent such as chlorinated hydrocarbons (e.g. chloroform, carbon tetrachloride, etc.).

The compound of formula (I) is treated with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and the like, and organic acids such as acetic acid, tartaric acid, citric acid, maleic acid, oxalic acid, benzoic acid, P-toluenesulfonic acid, and the like to be converted into acid addition salts thereof. Pharmaceutically nontoxic acid addition salts are preferred.

The benzofuran derivatives prepared by the present invention (eg, the compound of formula (I) and acid addition salts thereof) have a β-adrenergic blocking action.

Β-adorenergic blocking action of the benzofuran derivative of the present invention is measured by a well-known method.

In one method, 0.05 μg of isoprenin is injected intravenously into mice and the increased heart rate is examined by intraperitoneal injection of the test compound. The dose of test substance required to reduce the increased heart rate by 50% is recorded as PD ₅₀ . Hydrogen oxalate of 7- (1-hydroxymethyl) -α- (tert-butylaminotyl) -2-benzofuranmethanol with LD ₅₀ of 200 to 800 mg / kg (oral) in mice was tested in this test When used as a substance, PD ₅₀ is 0.08 mg / kg and the amount of 7-acetyl-α- (tert-butylaminomethyl) -2-benzofuran methanol with LD ₅₀ of 200-800 mg / kg (oral) in mice. When neutral oxalate is used, the PD ₅₀ is 0.20 mg / kg.

The compound of formula (I) and pharmaceutically toxic acid addition salts thereof can be used in medicine in the form of pharmaceutical agents together with pharmaceutically toxic carriers. These carriers are suitable organic or inorganic carriers for enteral (eg oral) administration or parenteral administration, and examples of such carriers are water, gelatin, lactose, starch, gum arabic, magnesium stearate, talc, vegetable oil, purified Petroleum jelly, and the like. Pharmaceutical formulations may be prepared in solid form (eg tablets, dragees, suppositories or capsules) or in liquid form (eg liquids, suspensions or emulsifiers) and may be sterilized or preservatives, stabilizers, emulsifiers, wetting systems, osmotic pressures. It may also contain excipients such as changing salts or buffers.

The dosage of the structural formula (I) compound and its pharmaceutically toxic acid addition salt administered to the human body may vary depending on the therapeutic conditions and the doctor's instructions. Generally, however, an amount of 0.75 mg / kg body weight to 1.25 mg / kg body weight, preferably 1.0 mg per kg body weight, may be administered once per day or dividedly.

Example 1

5.0 g of tert-butylamine was dissolved in 50 ml of acetonitrile in about 1.6 g of 7- (1'-acetoxyethyl) -2- (1'-hydroxy-2'-bromoethyl) benzofuran. After heating, reflux for 16 hours. The cooled mixture is evaporated under reduced pressure and the residue is partitioned between diethyl ether and dilute sodium hydroxide solution. The diethyl ether layer is extracted twice with dilute hydrochloric acid, the acid extract is basified with an aqueous sodium hydroxide solution and then extracted twice with diethyl ether. The ether extracts are combined, washed with water, washed again with brine and dehydrated over anhydrous sodium sulfate. Sodium sulfate is filtered off and the filtrate is evaporated under reduced pressure to give a viscous oil. The residue was treated with oxalic acid in isopropanol and fractionated to determine the hydrogen oxalate of 7- (1'-hydroxyethyl) -α- (tert-butylamino-methyl) -2-benzofuranmethanol having a melting point of 115 ° C and the above structural formula Hydrogen oxalate (IV) of the compound (IV) is obtained.

7- (1'-Acetoxyethyl) -2- (1'-hydroxy-2'-bromoethyl) -benzofuran used as starting material is prepared as follows.

A solution of 80.1 g of 2-acetyl-5-bromo-7-ethylbenzofuran, 37.5 g of triethylamine and 5 g of 5% palladium-carbon was dissolved in 1,300 ml of methanol under reduced pressure, and 1 molar equivalent of hydrogen was added at room temperature. Hydrogen until wet. The catalyst is filtered off and the filtrate is evaporated. The residual solid is dissolved in ethyl acetate and the solution is washed with water and brine and dehydrated over anhydrous sodium sulfate. Sodium sulfate was filtered and the filtrate was distilled under reduced pressure, and the remaining solid was crystallized with petroleum ether (boiling range 60 to 80 ° C) to obtain 48.7 g of 2-acetyl-7-ethylenezofuran, a white crystalline solid having a melting point of 59 to 60 ° C. .

1,200 ml of toluene was removed by heating azeotropically for 12 hours under reflux while stirring a solution in which 50 g of 2-acetyl-7-ethylbenzofuran, 3.0 g of P-toluenesulfonic acid and 45.0 g of ethylene glycol were dissolved. The solution is cooled, washed sequentially with dilute sodium hydroxide solution, water and brine, and then dehydrated over anhydrous sodium sulfate. Sodium sulfate was filtered and the filtrate was evaporated, and the free yellow oil was distilled under nitrogen stream to obtain a melting point of 86-88 ° C. 10.05 mmHg of 7-ethyl-2- (2-methyl-1,3-dioxolan-2-yl) benzo Obtain 48.6 g of furans.

28.0 g of recrystallized N-bromosuccinimido was added to a solution obtained by dissolving 32.5 g of 7-ethyl-2- (2-methyl-1,3-dioxolane-2-yne) benzofuran in 480 ml of carbon tetrachloride. The suspension obtained is then heated under reflux for 12 hours. The mixture is cooled at 0 ° C. overnight, the precipitated succinimido is filtered off and the filtrate is evaporated under reduced pressure at 30 ° C. The resulting impure 7- (1'-bromoethyl) -2- (2-methyl-1,3-dioxolan-2-yl) benzofuran is used immediately in the next step.

The structure of this compound is confirmed by the spectrum.

60 g of anhydrous sodium acetate is added to a solution of 43 g of 7- (1'-bromoethyl) -2- (2-methyl-1,3-dioxolan-2-yl) benzofuran dissolved in 600 ml of glacial acetic acid. The mixture is heated, stirred and cooled at 60 ° C. for 5 hours and then poured into 600 ml of water. The product is extracted with diethyl ether and the extract is washed three times with water, followed by brine and dehydrated with anhydrous sodium sulfate. Sodium sulfate is filtered and the filtrate is evaporated under reduced pressure. The oily 7- (1'-acetoxyethyl) -2- (2-methyl-1,3-dioxolan-2-yl) benzofuran thus obtained is used in the next reaction without further purification.

Approximately 30 g of impure 7- (1'-acetoxyethyl) -2- (2-methyl-1,3-dioxolane-2-arm) benzobutane is dissolved in 200 ml of acetone and 2 ml of an aqueous 33% benzenesulfonic acid solution is added thereto. The solution obtained after addition to the solution is heated under reflux for 3 hours, cooled and then concentrated under reduced pressure. The residual oil is dissolved in diethyl ether and the solution is washed with water and brine and then dehydrated with anhydrous sodium sulfate. Sodium sulfate is then filtered, and the filtrate is distilled off under reduced pressure. The product is purified by column chromatography on silica gel and crystallized with cyclohexanone to give 2-acetyl-7- (1'-acetoxyethyl) benzofuran at a melting point of 82-83 ° C. as a creamy crystalline solid.

25.1 g of trimethylphenylammonium tribromide are added to a solution in which 16.4 g of 2-acetyl-7- (1'-acetoxyethyl) benzofuran is dissolved in 250 ml of anhydrous tetrahydrofuran at 20 to 25 ° C. The resulting solution is stirred for 6 hours to complete the precipitation of trimethylphenyl ammonium monobromide. The mixture is poured into 1,000 ml of water and saturated with sodium chloride. The product is extracted with diethyl ether and the diethyl ether extract is washed with water and then again with brine and dehydrated over anhydrous sodium sulfate. After sodium sulfate was filtered and the filtrate was evaporated, the remaining solid was crystallized with diethyl ether to obtain 8.7 g of pale yellow crystalline 7- (1'acetoxyethyl) -2-bromo acetylbenzofuran having a melting point of 86 to 88 占 폚.

Dissolve 1.625 g of 7- (1'-acetoxyethyl) -2-bromoacetyl benzofuran in 50 ml of methanol, add methanolic hydrogen chloride to pH 4, and add 0.375 g of sodium cyanoborohydride. The mixture is stirred at 20-25 ° C. for 18 hours, 50 ml of water is added and methanol is distilled off under reduced pressure. The resulting 7- (1'-acetoxyethyl) -2- (1'-hydroxy-2'-bromoethyl) benzofuran was extracted with diethyl ether and the diethyl ether extract was washed with water and brine. It is then dehydrated over anhydrous sodium sulfate. Sodium sulfate is filtered and the filtrate is evaporated under reduced pressure to afford the bromohydrin described above. It is used for the next reaction without further purification.

Example 2

Impure 7- (1'-acetoxyethyl) -2- (tert-butylaminomethyl) -benzofuranyl ketone prepared as described below is dissolved in 15 ml of anhydrous ethanol, and 0.2 g of sodium borohydride while stirring the solution. Add. The mixture is stirred at 20-25 ° C. for 20 hours, 30 ml of water is added, and then distilled off under reduced pressure to remove ethanol. The residue is extracted with diethyl ether, the diethyl ether extract is washed with water and then again with brine and dehydrated with anhydrous sodium sulfate. Sodium sulfate is filtered and the filtrate is distilled under reduced pressure to give a viscous oil. This oil is treated with oxalic acid in isopropanol to give crystalline hydrogen oxalate of 7- (1'-hydroxyethyl) -α- (tert-butylaminomethyl) -2-benzofuranmethanol at a melting point of 115 ° C.

7- (1'-acetoxyethyl) -2- (t-butylaminomethyl) benzofuranyl-ketone used as starting material was prepared as follows.

0.9 g of tert-butylamine was dissolved in 20 ml of anhydrous diethyl ether at a temperature of 10 ° C. and 0.975 g of 7- (1′-acetoxyethyl) -2-bromo-acetylbenzofuran (Example 1) was dissolved. It is added to the stirred solution. The mixture is left at 0 ° C. for 20 hours, filtered through a cold solution, and extracted with diluted hydrochloric acid. The acidic extract is basified with dilute sodium hydroxide solution and extracted twice with diethyl ether. The extracts are combined, washed with water and brine and then dehydrated with anhydrous sodium sulfate. Sodium sulfate was filtered and the filtrate was evaporated under reduced pressure to give an unstable and impure 7- (1'-acetoxyethyl) -2- (tert-butylaminomethyl) benzofuranyl ketone which was used for the next reaction without further purification. .

Example 3

A mixture of 2.3 ml of concentrated sulfuric acid and 7.7 ml of water at 25 ° C. was mixed in a solution of 1.7 g of 7- (1′-hydroxymethyl) -α- (tert-butylaminomethyl) -2-benzofuranmethanol dissolved in 20 ml of acetone. 3.2 ml of a solution (Jones reagent) prepared by dissolving 2.667 g of chromium trioxide was added dropwise. After 5 minutes, 1 ml of methanol is added, 50 ml of water is added, and the mixture is basified with dilute sodium hydroxide solution and extracted twice with diethyl ether. The combined diethyl ether was washed with water and then dehydrated over anhydrous sodium sulfate. The dehydrating agent was filtered off and the filtrate was evaporated. The residue was dissolved in isopropanol and treated with excess oxalic acid in isopropanol to give 7-acetyl-α- (tert-butylaminometal) -2-benzofuranmethanol at a melting point of 220 to 210 ° C. Crystalline neutral oxalate is obtained.

Example 4

Tablets containing the following ingredients are prepared in a conventional manner.

Example 5

Ampoules containing the following components are prepared in a conventional manner.

Claims (1)

A is a hydroxymethylene group by treating the following compound of formula (II) with tertiary butylamine, or reducing the compound of formula (III) to alkali metal borohydride, or catalytically hydrogenating the following compound of formula (IV) And optionally oxidizing the compound with a chromium oxidizing agent or treating the compound of formula (V) with a base to make a compound having A is a carbonyl group, wherein the compound of formula (I) and an acid addition salt thereof are prepared. .

In the above structural formula A is a hydroxymethylene or carbonyl group R is a hydrogen atom or an alkanoyl group X is chlorine or bromine atom R 'is a lower alkanoyl group.