CH484057A - Process for the preparation of new benzene derivatives - Google Patents

Description

Process for the preparation of new benzene derivatives The present invention relates to a process for the preparation of benzene derivatives of general formula:

in the form of the base or of addition salts with acids, in which R represents a straight or branched alkanoylamino radical containing not more than 10 carbon atoms and preferably not more than 6; R represents an alkyl radical; R3 represents an alkyl, cycloalkyl or aralkyl radical (such as phenylalkyl).

In the present text, the alkyl radicals included in the definitions of the symbols R2 and R3 or which form part of the aralkyl groups included in the definition of R3 do not comprise more than 6 carbon atoms and may be straight or branched; the cycloalkyl groups included in the definition of R3 comprise from 3 to 6 carbon atoms; temperatures are in o C.

The compounds of formula (I) exist in stereoisomeric forms and the present invention naturally comprises these various forms, their mixtures as well as the corresponding addition salts.

The compounds of formula (I) and their addition salts with non-toxic acids have valuable pharmacological properties; in particular they combat the positive inotropic and chronotropic effects of adrenaline and noradrenaline, sympathetic stimulation of the heart muscle and exhibit antiarrhythmic effects. They can therefore be used to combat various cardiac disorders such as coronary affections, angina pectoris, cardiac arrhythmias.

Preferred compounds corresponding to formula (I) are those in which R3 represents an alkyl radical, more especially an isopropyl radical.

Preferred products include: (2-hydroxy-3-isopropylamino-propoxy)-2-acetamido-acetophenone, (2-hydroxy-3-isopropylamino-2-propoxy propion-5-amidopropiophenone, (2-hydroxy-3-isopropylamino-propoxy)-2 butyr amido-5 acetophenone, and their salts with non-toxic acids.

The derivatives of formula (I) are prepared by reaction of a compound of general formula:

with an amine of general formula: RgNH.

R1, Rg and R3 being defined as above.

The reaction can conveniently be carried out in an organic solvent such as dimethylformamide or a lower alcohol such as methanol or methanol at a temperature between 00 and 1000.

The compounds of formula (II) can be prepared according to known methods for preparing epoxides, in particular by reaction of epichlorohydrin with a phenol of general formula:

RI and Ra being defined as above and M representing a hydrogen or alkali metal atom.

The reaction can be carried out in an aqueous or inert organic solvent, for example dimethylformamide or a lower alcohol such as ethanol, at a temperature of between 00 and 100°.

The compounds of formula (III) in which M re has an alkali metal atom can be prepared according to the known methods for the preparation of alkaline phenates, for example by treating a compound of formula (III) in which M represents an atom of hydrogen by a solution of an alkaline alkoxide (eg sodium ethylate) in a lower alcohol (eg ethanol).

The compounds of general formula (III) in which M represents a hydrogen atom can be prepared according to known methods, for example by heating an ester of general formula:

RI and R being defined as above, in the presence of a catalyst, for example aluminum chloride, at a temperature between 130 and 180o, optionally in the presence of an inert organic solvent such as tetrachloro-1, 1, 2.2 ethane.

The compounds of general formula (IV) can be prepared according to known methods for the preparation of esters of p. alcanamidophenols.

The derivatives of formula (I) can be converted into addition salts with acids according to known methods.

They can be obtained by action of the acid on the derivative of formula (I) in an appropriate solvent such as diethyl ether. The addition salt formed is precipitated, if necessary after concentration of the solution, and is separated by filtration or decantation.

Normally the derivatives of formula (I) are used as such or in the form of addition salts with non-toxic acids, that is to say in the form of salts containing anions which are sufficiently harmless for the organism when uses the products in therapeutically active doses so that the beneficial properties due to the base are not thwarted by the side effects due to the anions.

As non-toxic acid addition salts, mention may be made of salts derived from inorganic acids such as hydrochlorides, hydrobromides, phosphates, sulfates, nitrates or salts derived from organic acids such as oxalates, lactates, tartrates, acetates , salicylates, citrates, propionates, succinates, fumarates, maleates, methylene-bis-O-hydroxynaphthoates, gentisates, D-di-p. toluyl tartrates.

By known methods is meant in the present text the methods known or described in the literature for obtaining analogous compounds.

The following examples illustrate the invention: Example 1: A mixture of 17 g of (2,3-epoxy)-2-acetamido-5-acetophenone, 100 ml of isopropylamine and 100 ml of anhydrous ethanol. The excess isopropylamine and methanol are evaporated and the residue is dissolved in chloroform.

The solution is extracted with dilute hydrochloric acid, the acid extract rendered alkaline by adding a sodium hydroxide solution and then extracted with chloroform. The chloroform solution is dried and the chloroform evaporated.

A residue is obtained which is treated with petroleum ether and a solid residue is obtained by evaporation which is recrystallized from ethyl acetate. 2-(2-hydroxy-3-isopropylaminopropoxy)-2-acetamido-5-acetophenone is obtained, melting at 131-134.

The 2-(2,3-epoxy)-5-acetamido-acetophenone used as starting material was prepared as follows: 19.6 g of 2-hydroxy-5-acetamido-acetophenone [prepared according to M. Julia and M. Baillarge-Bul. Soc. Chem.

639 (1952)] are dissolved in the minimum of anhydrous methanol.

An ethanolic solution of sodium ethoxide prepared from 2.3 g of sodium and ethanol is added. The solid which separates is collected by filtration, washed with a little anhydrous diethyl ether and dried overnight in a vacuum desiccator.

The solid is placed in a Soxhlet extractor and extracted with 28.3 g of epichlorohydrin in ethanol.

The solution is allowed to cool and diethyl ether is added. The sodium chloride which has formed is filtered off and the filtrate is evaporated. The residue is extracted with benzene and the extract evaporated. 1'(epoxy-2,3-propoxy)-2-acetamido-5-acetophenone melting at 105 1120 is obtained.

Example 2: 7 g of 2-(2,3-epoxy)-2-propionamido-5-acetophenone, 40 g of isopropylamine and 200 ml of methanol are refluxed for an hour and a half.

The reaction mixture is concentrated under reduced pressure and the residual oil is treated with normal hydrochloric acid and ethyl acetate.

The acid extract is brought to pH 11 by addition of 2N sodium hydroxide and extracted with chloroform. The chloroform extract is dried and concentrated to an oil. This oil is treated with diethyl ether, evaporated and 5.5 g of 2-(2-hydroxyisopropylamino-3-propoxy)-2-propionamido-5-acetophenone melting at 110-113 C are obtained.

The following compounds are prepared in the same way from epoxide derivatives: (2-Hydroxy-3-isopropylaminopropoxy)-2-isobutyramido-5 acetophenone melting at 102 1040.

2-Hydroxy-3-isopropylaminopropoxy)-2-valera-5-midoacetophenone melting at 129"131.

(2-Hydroxy-3-isopropylaminopropoxy)-2-isovaleramido-5 acetophenone melting at 110-111".

(2-Hydroxy-3-isopropylaminopropoxy)-2-hexan-5-amidoacetophenone melting at 141-142.

(2-Hydroxy-3-isopropylaminopropoxy)-2 octan amido-5 acetophenone melting at 117-119.

(2-Hydroxy-3-isopropylaminopropoxy)-2 nonan amido-5 acetophenone melting at 108-109.

(2-Hydroxy-3-isopropylaminopropoxy)-2-decan-amido-5-acetophenone melting at 113-114 .

(2-Hydroxy-3-isopropylaminopropoxy)-2 benz amido-5 acetophenone melting at 144-1460.

2-Hydroxy-3-methylaminopropoxy)-2-butyrami-5-do-acetophenone melting at 143-146.

(Hydroxy-2 ter. butylamino-3 propoxy)-2 butyr amido-5 acetophenone melting at 138".

The (epoxy-2,3-propoxy)-2-propionamido-5-acetophenone used as starting material was prepared as follows: Refluxed until dissolved 82 g of p. propionamidophenol [prepared according to Fierz-David and Kuster-Helv. Chem. Acta 22.82 (1939),] 40 g of acetyl chloride, in a liter of benzene. The solution is cooled and water is added so as to obtain a solid precipitate which is isolated by filtration. It is washed with water and dried. 50 g of p acetate are obtained. propionamidophenyl melting at 100-105. A mixture of 50 g of p-propionamidophenyl acetate and 100 g of aluminum chloride is heated at 170 for 5 hours. Cool and add excess water. The precipitate formed is collected by filtration and recrystallized from aqueous methanol. 16 g of 2-hydroxy-5-propionamido acetophenone, melting at 116-1200, are obtained.

11.5 g of this 2-hydroxy-5-propionamido acetophenone are dissolved in 200 ml of ethanol and this solution is added to an ethanolic solution of sodium ethoxide prepared from 1.27 g of sodium and 200 ml of ethanol.

It is evaporated to dryness under reduced pressure. Benzene is added and then evaporated again to dryness under reduced pressure. 100 ml of dimethylformamide and 20 ml of epichlorohydrin are added and the solution is heated at 100° C. for 4 hours. The solution is concentrated under reduced pressure and a solid is obtained which, recrystallizes from ethyl acetate, gives 7.1 g of (2,3-epoxy-propoxy)-2-propionamido-5-acetophenone melting at 120-125 .

From the corresponding 2-hydroxy derivatives, the following products are prepared in the same way: (2,3-epoxy)-2-isobutyramido-5-acetophenone melting at 123-127o, (2,3-epoxy)-2 valeramido-5 acetophenone melting at 137-139 , (epoxy-2, 3 propoxy)-2 isovaleramido-5 acetophenone melting W 95-100 , (epoxy-2, 3 propoxy)-2 hexanamido-5 acetophenone melting at 136-1370, (epoxy-2, 3 propoxy)-2 octanamido-5 acetophenone melting at 133-134o, (epoxy-2, 3 propoxy)-2 nonanamido-5 crude acetophenone, (epoxy-2 , 3-propoxy)-2-decanamido-5-acetophenone melting at 113-114o.

The intermediate 2-hydroxyisobutyramidoacetophenone was prepared as follows: 17.5 g of isobutyric anhydride are added dropwise with stirring to a mixture of 13.7 g of 2-hydroxy-5-aminoacetophenone [prepared according to M. Julia and M. Baillarge, Bull. Soc. Chem. 639 (1952)], 10 g of isobutyric acid and 25 ml of water and heated in a bain-marie.

Stirring and heating are continued for a further 1 hour and the mixture is cooled. Another 25 ml of water are added. 11 separates a solid which is collected by filtration, dried and then triturated with diethyl ether. The solid is collected by filtration and dried. 14.15 g of 2-hydroxy-5-isobutyramido acetaphenone, melting at 131-132, are obtained.

The following compounds are prepared analogously starting from the raw materials: 2-Hydroxy-5-valeramido acetophenone melting at 112-1150, 2-Hydroxy-5-isovaleramido acetophenone melting at 119-120 , Hydroxy-2 hexanamido-5 acetophenone melting at 120-121e, Hydroxy-2 octanamido-5 acetophenone melting at 108-110o, 2-Hydroxy-5-nonanamido acetophenone melting at 55-600, 2-Hydroxy-5-decanamido acetophenone melting at 122-1230.

Example 3: 14 g of (2,3-epoxy)-2-propionamido-5-propiophenone, 80 g of isopropylamine and 200 ml of methanol are refluxed for one and a half hours.

The reaction mixture is concentrated under reduced pressure so as to obtain a residual oil. This oil is crystallized in ethyl acetate and 13 g of 2-(2-hydroxyisopropylamino-3-propoxy)-2-propionamido-5-propiophenone melting at 89-920 are obtained.

The (epoxy-2, 3 propoxy)-2-propionamido-5 propiophenone used as starting product was prepared as follows: A solution of 30 g of 2-hydroxy-5-propionamido-propiophenone [prepared according to Raval and Thakor, J. Ind. Chem. Soc. 38, 421 (1961)] in 200 ml of ethanol to an ethanolic solution of sodium ethoxide prepared with 3.12 g of sodium and 200 ml of ethanol. The resulting solution is evaporated under reduced pressure.

Benzine is added and the mixture is again evaporated to dryness under reduced pressure. 200 ml of dimethylformamide and 50 ml of epichlorohydrin are added and the solution is heated at 1000 for 4 hours.

The solution is concentrated under reduced pressure and an oil is obtained which is treated with water so as to obtain a solid which is recrystallized from ethyl acetate. 18.4 g of 2-(2,3-epoxypropoxy)-5-propionamido-propiophenone melting at 114-118 are thus obtained.

Example 4: 16 g of 2,3-(epoxy-propoxy)-2-butyramido-5-acetophenone, 20 g of isopropylamine and 100 ml of ethanol are refluxed for 4 hours. The mixture is concentrated under reduced pressure and the residual oil is dissolved in N hydrochloric acid. The acid solution is extracted with ethyl acetate, discarding the ethyl acetate layers. The acid solution is brought to pH 11 by addition of 2N sodium hydroxide and extracted with chloroform. The chloroform extracts are dried and concentrated under reduced pressure. An oil is obtained which is recrystallized from an ethanol-diethyl ether mixture. 3 g of 2-(2-hydroxyisopropylamino3-propoxy)-2-butyramido-5-acetophenone, melting at 119-1230, are obtained.

The (2,3-epoxy propoxy)-2-butyramido-5-acetophenone used as starting material was prepared as follows: Refluxed until a solution is obtained (12 hours), 58 g of p. butyramidophenol [prepared according to Fierz-David and Kuster-Loc. cit.], 25.4 g of acetyl chloride and 500 ml of benzene. The solution is cooled and treated with water. The benzene layer is separated and the aqueous layer is again extracted with benzene.

The benzene extracts are combined, dried, evaporated to dryness under reduced pressure and 38 g of p acetate are obtained. butyramidophenyl, off-white solid melting at 102-1030. 38 g of acetate of p. butyramidophenyl, 80 g of aluminum chloride and 250 ml of tetrachloro-1, 1,2,2 ethane. Heat at 140 for 3 hours. The mixture is cooled and ice water added. The tetrachloroethane layer is separated and the aqueous layer is extracted with chloroform. The organic layers are combined and extracted with 2 N sodium hydroxide. The alkaline solution is acidified with concentrated hydrochloric acid to pH 5. This acid solution is extracted with chloroform, the chloroform extracts are dried and concentrated. under reduced pressure. 15.6 g of 2-hydroxy-5-butyramido-acetophenone, melting at 114-117, are obtained.

15.6 g of 2-hydroxy-5-butyramido-acetophenone are dissolved in 100 ml of methanol and added to an ethanolic solution of sodium ethoxide, prepared from 1.62 g of sodium and 100 ml of ethanol.

The resulting solution is evaporated to dryness under reduced pressure and 100 ml of dimethylformamide are added to the residual solid. About 10 ml of dimethylformamide are distilled off under reduced pressure.

25 ml of epichlorohydrin are added and the solution is heated at 100 for 4 hours. The solution is poured under reduced pressure and a residual oil is obtained which is treated with water so as to obtain a solid precipitate. The solid is collected and dissolved in ethanol. The solution is treated with charcoal, filtered and concentrated under reduced pressure. 16 g of crude 2,3-epoxy-2-butyramido-5-acetophenone, melting at 110-1160, are obtained.

The crude product can be purified by recrystallization from ethyl acetate, after treatment with decolorizing charcoal. A pure product melting at 136138 is obtained.

Example 5: 3.36 g of 2-(2-hydroxyisopropylamino-3-propoxy)-2-butyramido-5-acetophenone prepared as in Example 4 are dissolved in 50 ml of methanol and 200 ml of diethyl ether are added. We add drop fi. drop with stirring 25 ml of a saturated solution of hydrochloric gas in ether. It precipitates an oil which crystallizes on stirring. The solid is collected by filtration and recrystallized from an anhydrous methanol-anhydrous diethyl ether mixture. 2.5 g of 2-hydroxy-3-isopropylaminopropoxy)-2-butyramido5-acetophenone hydrochloride, melting at 141-1430, are obtained.

Example 6: The boiling solutions are mixed on the one hand with 3.36 g of (2-hydroxy-3-isopropylamino-propoxy)-2-butyramido-5-acetophenone (prepared as in the example in 250 ml of acetone and on the other hand with 1.5 g of D-tartaric acid in 50 ml of acetone. The mixture is left to cool and stand overnight. The solid formed is collected by filtration and 3.7 g of D-tartrate of (2-hydroxyisopropylamino-3 propoxy) are obtained. )-2-butyramido-5 acetophenone melting at 175-179.

Example 7: A mixture of 4.15 g of 2,3-(2,3-epoxypropoxy)-2-butyramido-5-acetophenone, 20 ml of 1-phenylethylamine and 100 ml of anhydrous ethanol is refluxed overnight. The methanol and almost all the excess phenyl-1 ethylamine are evaporated under vacuum. The residue is triturated several times with light petroleum ether so as to remove the last traces of 1-phenylethylamine. The residue was dissolved in ethyl acetate and the solution extracted with N hydrochloric acid. The aqueous extract was brought to pH 6.7 with sodium bicarbonate solution and stirred with acetate. of ethyl. The aqueous layer is brought to pH 10 using a sodium carbonate solution and extracted with chloroform. The chloroform solution is dried over sodium sulphate and evaporated. The residue crystallizes slowly and the solid is recrystallized from an ethyl acetate-petroleum ether mixture (fraction 80 1000). 1.3 g of [2-hydroxy(1-phenylethylamino)-3-propoxy]-2-butyramido-5-acetophenone, melting at 105-107, are obtained.

1′ (2-hydroxy-3-cyclohexylaminopropoxy)-2-butyramido-5-acetophenone, melting at 112-113, is prepared in the same way.

The products prepared according to the invention and in particular those according to the preceding examples, exhibit an effect of blocking the beta sympathetic receptors of the heart. This action is selective compared to the effect on sympathetic beta receptors in the bronchi and the vascular system. This selective action makes the products of the present application especially interesting for subjects with cardiac disorders such as coronary affections, angina pectoris, cardiac arrhythmias, for which the blocking of the sympathetic beta receptors of the bronchi is contraindicated, in particular particularly for subjects suffering from bronchial asthma or other forms of bronchospasm.

Claims (1)

CLAIM I Process for the preparation of compounds of general formula: in which: Ri represents a straight or branched alkanoylamino radical comprising at most 10 carbon atoms, R represents a straight or branched alkyl radical comprising at most 6 carbon atoms, R3 represents an alkyl, cycloalkyl or aralkyl radical in which the alkyl groups are straight or branched and contain at most 6 carbon atoms, and the cycloalkyl group comprises from 3 to 6 carbon atoms, characterized in that a compound of general formula is reacted: with an amine of formula R3 N H, R1, R2 and R3 being defined as above. SUB-CLAIM Process according to Claim I, characterized in that the operation is carried out in an inert organic solvent at a temperature of between Oo and 1000. CLAIM II Use of the compounds prepared by the process according to claim 1, for the preparation of addition salts, characterized in that a solution of the product is made to act on a solution of an acid and that the salt formed is isolated .