CH485663A - 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:
EMI1.1
 in the form of the base or of addition salts with acids, in which:
 R represents a halogen atom or a nitro, aryl, alkanoylamino, alkyl or alkyloxy radical;
 Rl represents a hydrogen atom or a radical
 methyl;
 R2 represents a cycloalkyl, aralkyl, al
 coyl, alkyl substituted by one or more ha atoms
   logene or hydroxyl group;
   R3 represents an alkyl or aryl radical which can
 be substituted;

   aralkyl, the aryl radical of which can be
 substituted by one or more halogen atoms, radicals
 alkyl, alkyloxyl or cyano, a heterocyclic radical
 5- or 6-membered linked by a carbon atom of the heterocycle to the carbon atom connected to the nucleus
 benzene;
   R4 represents a group OR5 (in which R5 is a hydrogen atom or an alkyl, aryl or aralkyl radical), an NHRss group in which R6 represents a hydrogen atom, a carboxylic or sulfonic acyl radical derived from an aliphatic acid -araliphatic or aryl carboxylic or sulfonic,

      of a heterocyclic carboxylic or sulfonic acid in which the heterocyclic radical comprises 5 or 6 members and in which the group
 carboxylic or sulfonyl is attached to a carbon atom
 bone of the heterocycle; aryl groups included in
 the definition of carboxylic or sulfonic acids
 falling within the definition of Ra being possibly
 substituted by one or more halogen atoms, or
 alkyl, aryl, alkyloxy, aryloxy, hydroxy,
 nitro, amino, dialkoylamino, alkanoylamino, alkanesul-
   fonamido, sulfamoyl, cyano:

   a group
 NHC (= Z) NH R7 in which Z represents an oxygen or sulfur atom, or an NH group and R7 represents a hydrogen atom, an alkyl, alkyloxyalkyl, aryl, aralkyl or aralkyl radical substituted on the ring by a alkyloxy radical or a 5- or 6-membered heterocyclic radical linked to the nitrogen atom by a carbon atom of the heterocycle and n has the value 0, 1 or 2.



   In the present text, the alkyl, alkenyl, alkanoyl, alkyloxy radicals included in the definitions of the symbols R, RI, R2, R3, R4, RÏs R ,, R7 or which are part of the groups defined under these symbols as well as the alkane portion alkanesulfamido groups included in the definition of R do not contain more than 6 carbon atoms and can be straight or branched; the cycloalkyl groups included in the definition of R2 contain from 3 to 6 carbon atoms.



   The compounds of formula I exist in stereoisomeric forms, these naturally form part of the invention.



   As preferred compounds, mention may be made of: -semicarbazone of DL (o-acetylphenoxy) -l hydroxy-2
 isopropylamino-3 propane, -p-chlorobenzene sulfonhydrazone from DL (o-acetyl-
   phenoxy) -l 2-hydroxy isopropylamino-3 propane, -benzenesulfonylhydrazone of DL (o-acetylphenoxy) -l
 2-hydroxy isopropylamino-3 propane, -p-hydroxybenzoylhydrazone from DL (o-acetylphé
 noxy) -1 hydroxy-2 isopropylamino-3 propane.



   The compounds of formula I and their addition salts with non-toxic acids have interesting pharmacological properties, in particular they combat certain effects of adrenaline and noradrenaline, sympathetic stimulation of the heart muscle, and exhibit effects anti. arrhythmic. They can therefore be used to combat various cardiac disorders such as coronary diseases, angina pectoris, cardiac arrhythmias.



   In addition, certain compounds such as DL (o-acetylphenoxy) -1 hydroxy-2-isopropylaminopropane α-naphthalen-sulfonylhydrazone exhibit hypotensive action.



   The derivatives of formula I are prepared by reaction of an amine of general formula: HNR, (II) with a compound of general formula:
EMI2.1

 X represents the acid residue of a reactive ester such as a halogen atom or a p radical. toluenesulfonyl, R, R "R2, R3, R4 and n being defined as above.



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



   The epoxide of formula III can be obtained (optionally in situ) from a compound of general formula:
EMI2.2
 by reaction with a compound of formula: HsNR4 (Vl) (R, R3, R4 and n being defined as above).



   The reaction can be carried out in an organic solvent, inert, for example dimethylformamide, at a temperature between 00C and 1000C.



   The compounds of formula V can be prepared according to known methods for preparing epoxides, in particular by reaction of orhydrin with a phenol of general formula:
EMI3.1
 (R, R3 and n being defined as above).



   The reaction can be carried out in an inert aqueous or organic solvent, for example dimethyl formamide or a lower alcohol such as ethanol in the presence of a basic condensing agent, for example potassium carbonate, soda, I sodium ethoxide, at a temperature between (MC and 1000 C.



   The starting compounds of formula IV can be obtained by reaction of a compound of formula:
EMI3.2
 (R, Rs, X, n being defined as above) with a compound of formula VI.



   The reaction can be carried out in an aqueous or organic solvent, for example dimethylformamide or a lower alcohol such as ethanol, at a temperature between 00 ° C. and 1000 C.



   The compounds of formula I having one or more substituents determined on the benzene ring can be converted into corresponding compounds of formula I. having different substituents. For example, the compounds of formula I, for which the benzene ring is substituted by one or more nitro groups, can be converted by reduction into the corresponding amino compounds. This reduction can be carried out, for example, by hydrogenation, in the presence of a hydrogenation catalyst, such as platinum oxide, in a suitable solvent, such as aqueous methanol.



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



   They can be obtained by the action of the acid on the derivative of formula I in a suitable 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 1 are employed as such or in the form of addition salts with non-toxic acids, that is to say in the form of salts containing anions sufficiently harmless to the organism when uses the products in therapeutically active doses so that the beneficial properties due to the base are not adversely affected by side effects due to the anions.



   As addition salts of non-toxic acids, mention may be made of salts derived from inorganic acids such as hydrochlorides, hydrobromides, sulphates, nitrates or salts derived from organic acids such as oxalates, lactates, tartrates, acetates, salicylates, citrates, propionates, succinates, fumarates, maleates, methylene-bis-f3-hydroxy-naphthoate 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 I:
 23.6 g of (o-acetylphenoxy) -I epoxy-2 3 propane are treated with 8.4 g of hydroxylamine hydrochloride, and 9.85 g of anhydrous sodium acetate, in 100 cil of anhydrous dimethylformamide. After 18 hours of stirring at room temperature, the reaction mixture containing the oxime of 1 '(o-acetylphenoxy) -1 epoxy-2,3 propane is treated with 50 g of isopropylamine and 50 cob of ethanol; the mixture obtained is heated under reflux for 3 hours, then concentrated under reduced pressure: the residue obtained is treated with 250 cm3 of water and the pH is adjusted to 10.

   The mixture is extracted with chloroform and, after drying and concentrating the residual oil extracts, is taken up in a mixture of ethyl acetate and diethyl ether; we obtain 15 of oxime of
DL (o-acetylphenoxy) -1 hydroxy-2-isopropylamino-3 propane, melting point 94O C.



   The starting (o-acetylphenoxy) -1 epoxy-2,3 propane is prepared according to the Beasley method. Petronv and Stephenson, J. Pharm. Pharmacol., 1958, 10, 47.



  Example 2:
 A mixture of 19.2g of (o-acetylphenoxy) -l epoxy-2 is stirred at room temperature for 18 hours. 3 propane, 11, 16g of semicarbazide hydrochloride.



     16.4g of sodium acetate, and 75cm3 of anhydrous dimethylform-amide. The solvent is removed under reduced pressure and the residue is treated with water and extracted 3 times with chloroform. The combined extracts are dried over magnesium sulphate and then concentrated. The residual oil (24, 9) is heated under reflux for 4 hours with 100cm3 of isopropylamine and 100cm3 of anhydrous ethane. After concentration under reduced pressure.



  The residual oil obtained is treated with a mixture of diethyl ether and isopropanol; after filtration, 3 g of semicarbazone hydrochloride of D! .- (o-acetylphenoxy) -1-hydroxy-3-isopropylamino-3 prupane is obtained, melting at 194O C. The filtrate is concentrated under reduced pressure and the residual oil is dissolved. in a small quantity of anhydrous ethanol: by adding hydrochloric ether, 12.3 g of the above hydrochloride are obtained, melting at 188-1900 C.



  Example 3:
 A mixture of 1.92 g of (o-acetylphenoxy) -I epoxy-2,3 propane, 1.72 g of benzenesulfonyl hydrazide and 40 cm3 of anhydrous ethanol is maintained at room temperature for 24 hours. Mixing, adding 40cm3 of isopropylamine while cooling, then maintaining the mixture again at room temperature for 24 hours. The oil obtained after concentration under reduced pressure is taken up in benzene and the solvent is azeotropically distilled. The residue is triturated with diethyl ether and the solid which appears is purified by treatment with boiling benzene.

   Benzene sulfonylhydrazone is obtained from DL- (o-acetylphenoxy) -1 hydroxy-2 isopropylamino-3 propane, melting point 161-162 C.



  Example 4:
 A mixture of 1.92 g of (o-acetylphenoxy) -I epoxy-2,3 propane, 2.06 g of p-chlorobenzenesulfonyl hydrazide and 40 cm3 of anhydrous ethanol is maintained at room temperature for 24 hours. 40 cm3 of isopropylamine are added to the mixture while cooling, then the mixture is again maintained at room temperature for 24 hours. The oil obtained after concentration under reduced pressure is taken up in benzene and the solution is concentrated to remove Fethan! and water by azeotropy. The benzene solution leaves a solid to deposit.

   By recrystallization from ethanol, p-chlorobenzenesulfonylhydrazone from DL- (o-acetylpheno) -l hydroxy-2 isopropylamino-3 propane is obtained, melting at 161-1620 C
Example 5:
 A mixture of 9.6 g of (o-acetylphenoxy) -I epoxy-2,3 propane, 5.58 g of semicarbazide hydrochloride and 100 cm3 of anhydrous ethanol is refluxed for 5 hours. By concentration, an oil is obtained which is heated under reflux for 6 hours with 50cm3 of isopropylamine and 100cm3 of anhydrous ethanol.



  The solution is concentrated under reduced pressure; the residue is taken up twice in benzene and the solution is concentrated. By recrystallization of the residue from diethyl ether containing a small amount of iso propanol, the hydrochloride of the semi-carbazone of DL- (o-acetylphenoxy) -1 hydroxy-2 isopropyl-3-amino-propane is obtained, melting at 194 -196C.


 

Claims (1)

CLAIM Process for the preparation of compounds of general formula: EMI4.1 in which : R represents a halogen atom, a nitro, aryl, alkanoylamino, alkyl or alkyloxyl radical; Rl represents a hydrogen atom or a methyl radical; RS represents a cycloalkyl, aralkyl, alkyl or alkyl radical substituted by one or more halogen atoms or hydroxy radicals: R3 represents an alkyl, aryl or aryl radical substituted by one or more halogen atoms or alkyl, alkyloxy or cyano radicals; aralkyl, aralkyl in which the aryl radical is substituted by one or more halogen atoms, alkyl, alkyloxyl or cyano radicals; a 5- or 6-membered heterocyclic radical connected through a carbon atom to the carbon atom attached to the phenyl group; R4 represents: - an ORI group, in which R represents an atom of hydrogen or an alkyl, aryl, aralkyl, -a group NHR ", in which R represents an atom of hydrogen, an acyl carboxylic or sulfo radical nique derived from an aliphatic, araliphatic, arylcarboxylic or sulfonic acid, of an arylcarb acid oxylic or sulfonic, the aryl radical of which is subs tituated by one or more halogen atoms, radicals alkyl, aryl, alkyloxy, aryloxy, hydroxy, nitro, amino, dialkoylamino, alkanoylamino, alkanesulf- amido, sulfamoyl, cyano, deterocycHic acid carboxylic or sulfonic, in which the group heterocyclic is 5 or 6 membered and the group carbonyl or sulfonyl is bonded to a carbon atom of the heterocycle, -a group NHC (= Z) NHR "in which Z represents smells of an oxygen or sulfur atom, or a NH group and R represents a hydrogen atom, an alkyl, alkyloxyalkyl, aryl or aralkyl radical, aralkyl substituted by an alkyloxy radical, a 5- or 6-membered heterocycle attached to the atom nitrogen by one of its atoms of: n is an integer from 0 to 2 inclusive; and their addition salts, characterized in that an amine HNRIR3 is heated in an inert solvent with a compound of general formula: EMI4.2 or a compound of formula: EMI4.3 X representing a halogen atom or a p-toluenesulphonic residue, R, R ,, R, - ,, R .. 3, R4, and n being defined as above.