SE186227C1 - - Google Patents

Description

CLASS INTERNATIONAL SWEDISH C 07 c12o: PATENT AND REGISTRATION AGENCY Ans. 2816/1961, March 16, 1961, SMITH KLINE Sc FRENCH LABORATORIES, PHILADELPHIA, PENN. new annealed cyclopropylamine derivatives, in particular 1-aminocycloprop [a] indene, 1-aminocyclopropa [Mbensofurans and 1-aminocyclopropambenzothiophenes with valuable pharmacodynamic activity.

More specifically, the compounds of the present invention specifically alter or modify the compounds of the present invention and are particularly useful as antidepressants, ataractics and hypotensive agents for living beings. Some of these associations have the valuable property of having a quick-acting effect. The compounds of the invention also provide potent inhibition of monoamine oxidase which property is associated with antidepressant activity.

The novel 1-aminocycloprop [a] indenes, 1-aminocyclopropa [b] benzofurans and 1-aminocyclopropa [b] benzothiophenes of the invention are represented by the following structural formula: Formula I CH 2; CH N, / 112 where Y is CH S or SO 2; 111 Orthate, chlorine, bromine, fluorine, trifluoromethyl, methyl or methoxy; and R 1 and R 2 are arovate, lower alkyl or, taken together with N, piperidino, N-pyrrolidinyl or morpholino.

By the term "lower alkylh" is meant in the present context groups having 1-4, preferably 1-2 carbon atoms.

Preferably, compounds of the invention are represented by the following structural formula; Dupl. at 12 q: 1/01; 12 q: 24; 12 q: 26 Formula II (\ CHR \ / 2 R1 I CH — N, I CH / \ Ft, where Y Or CH and R 1 and R 2 are aro vate, methyl or, taken together with N, piperidino.

A particularly advantageous and non-breathable compound according to the invention is 1-amino-1,1a, 6,6atetrahydro cyclopropyl [alindene.

The invention includes non-toxic, pharmaceutically acceptable acid addition salts of bases defined above formed with organic and inorganic acids. Sadana salts Ora easy to present using kanda methods. The base is reacted either with the stoichiometric amount of organic or inorganic acid in a water-soluble solvent, for example acetone or ethanol, with isolation of the salt by concentration or cooling or with an excess of the acid in water-insoluble solvent, for example ethyl ether or chloroform, separating the desired salt. Immediately.

Examples of such organic salts are those with maleic acid, fumaric acid, benzoic acid, ascorbic acid, pamic acid, succinic acid, bismethylene salicylic acid, methanesulfonic acid, ethanedisulfonic acid, attic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, sulfonic acid, (amino succinic acid), stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid and theophyllinacetic acid as well as / 8 Examples of intended inorganic salts are those obtained by the addition of chlorine, bromine, sulfuric acid, sulphamic acid, phosphoric acid and nitric acid.

These salts can also be produced on the edge of salt by double reaction of suitable salts.

The compounds of the invention are prepared according to the following scheme: / CH 2 R 1 CH-CH, CH 2 CH CH — COOH CH \ y / A CH \ I \ CH — N = C = 0 u + "CH \ i; CH cli CH \ Ri; CH — 00C1 CH / \ / \ Y / CHR, R, I \ CH — N / CH / \ R 3 / \ CH, \, CH — CON, in which formulas Y, R1, R, and R, have the meanings given above.

The starting material anyLinda, typically substituted inner, the benzofuran or benzothiophene is reacted with at least one molar equivalent of ethyl diazoacetate at high temperature, preferably at the reflux temperature of the mixture. The resulting ethyl -1-cycloprop [a] indene carboxylic acid ester or the corresponding benzofuran or benzothiophene compound is hydrolyzed with an alkali metal hydroxide, for example potassium or sodium hydroxide, to give the carboxylic acid. By treating this carboxylic acid with a chlorinating agent, for example phosphorus trichloride, phosphorus pentachloride or preferably thionyl chloride, the corresponding acid chloride is obtained.

The acid chloride is cooled to about 0-15 ° C in an inert water-soluble organic solvent, for example acetone, tetrahydrofuran or dioxane, and treated with an excess of sodium azide in cold aqueous solution. Extraction with a water-insoluble organic solvent, for example ether or benzene, and evaporation of the extracts give the acid azide. By heating the azide with an organic solvent, for example toluene or xylene, at 90 DEG-100 DEG C. for about 30-90 minutes and evaporating the solution, the isocyanate is obtained.

By treatment with the isocyanate with concentrated hydrochloric acid at high temperature, even at reflux temperature, for about 5-15 hours, evaporation of 1-amino-1,1a, 6,6atetrahydrocycloprop [a] lindene hydrochloride or the corresponding benzofuran or benzothiophene compound according to the invention is obtained, i.e. . 1-amino-1α, 6α-dihydro-1H-cyclopropa [13] benzofuran hydrochloride or 1-amino-1α, 6α-dihydro-1H-cyclopropane [Nbenzothiophene hydrochloride. The free base is obtained by dissolving the hydrochloride salt in water, neutralizing with alkali metal hydroxide or carbonate, for example sodium hydroxide or potassium carbonate, and extraction with a water-insoluble organic solvent, for example ether or chloroform. Evaporation of the solvent from the extracts gives the 1-amino-1,1a, 6,6a-tetrahydrocycloprop [a] indenes, 1-amino1a, 6a-dihydro-1H-cyclopropa [1)] benzofurans and 1-amino-1a, The 6α-dihydro-1H-diclopropa [1)] benzothiophenes of the invention.

Alkylation of the amino group to produce additional compounds of the invention is accomplished in many ways. Monoalkylation - -3 is carried out by reacting the primary amino compound with suitable aldehyde or ketone a lower alcohol as solvent and catalytic reduction in the resulting schiff base with a catalyst, for example palladium on trachol or platinum oxide. The dialkylamino compounds are prepared by reacting the primary amino compound with at least 2 moles of an alkyl halide, for example an idoride or bromide, in the presence of a base, such as an alkali metal hydride or an alkali metal carbonate, for example sodium hydride or potassium carbonate.

Monomethylation is conveniently carried out by refluxing the primary amine with ethyl formate and refluxing the resulting N-formyl compound with methyl iodide and a basic adjuvant, for example an alkali metal hydride such as sodium hydride. The dimethylamino derivatives are obtained by treating the primary amine with a mixture of aqueous formaldehyde and formic acid.

To prepare the piperidino, N-pyrrolidinyl or morpholino compounds of the invention, the primary amine is heated with at least one molar equivalent of a polymethylene dihalide or a bis (b-dihalethylethyl) ether and an acid scavenger, for example pyridine or an alkali metal carbonate, for example potassium carbonate. sodium carbonate.

The substituted indenes, benzofurans and benzothiophenes used as starting material (III) are either known or prepared as follows: / \ R, - —---> - R, 1 \\ // - CHO \ / - CH = CHCO 2 H -> - R 1 - L-CH, CH, COOH CH, CH, COCl OH —OCCH, R, R, R, The substituted benzaldehyde () was saturated with acetic anhydride and sodium acetate according to Perkin condensation. The cinnamic acid obtained is hydrogenated in the presence of a platinum oxide catalyst. The acid is treated with a chlorinating agent, for example thionyl chloride. The acid chloride is cyclized by treatment with aluminum chloride. The resulting ketoindane is hydrogenated to the hydroxyindane compound. The hydroxyindane is reacted with acetic anhydride and the resulting ester is converted by pyrolysis to the indene, which is used as starting material.

The benzofuran used as starting material is prepared by reacting appropriately substituted salicylaldehyde with chloroacetic acid in the presence of an alkali metal hydroxide, for example sodium or potassium hydroxide, at an Indian temperature of about 160 DEG C. and about 200 DEG C.

The benzothiophene used as starting material is prepared according to the following scheme: R, - 01-1— R,?

The substituted thiophenol is condensed with ethyl chloroacetate in the presence of a basic adjuvant, for example an alkali metal hydroxide, such as sodium or potassium hydride. The resulting ethyl ester is hydrolyzed. The acid is chlorinated and the resulting acid chloride is cyclized under Friedel-Crafts conditions with aluminum chloride and dehydrated with zinc and acetic acid to obtain the benzothiophene used as starting material.

The compounds of the invention may exist as cis- or trans-isomers and also as right- and left-handed optically active isomers. The invention encompasses all of these isomers, separated cis and trans isomers and in optically active antipodes probed racemic compounds as well as mixtures of cis and trans isomers as well as right and left turning antipodes.

The following examples illustrate and compound the compounds of the invention, but the invention is not limited to these examples. Titanium comprises all compounds of the above true formula.

Example 1.

A cold mixture of 118.2 g of indene and 121 g of ethyl diazoacetate is stirred and slowly heated to reflux temperature. Cooking was continued under reflux for 4 hours. By vacuum distillation, ethyl 1-1,1a, 6,6a-tetrahydro-1-cycloprop [a] indene carboxylic acid ester is obtained.

A mixture of 56 g of this ester in 300 ml of ethanol and 33.6 g of sodium hydroxide in 50 ml of water is boiled under reflux for 9 hours. The solvents are evaporated in vacuo and the residue is dissolved in 500 ml of water and acidified with concentrated hydrochloric acid. By extraction with ether and evaporation of the extracts, 1,1a, 6,6a-tetrahydro-1-cyclopropyl [alindene carbonic acid, the acid chloride is obtained by mixing 41 g of the acid and 111 ml of thionyl chloride, the mixture being stirred for 16 hours at room temperature, evaporate and distill (boiling point 120-131 ° C / 1.5-3.1 mm Hg).

The acid chloride (23.5 g) in 300 ml of acetone is cooled to 5 ° C. extracted with ether. The extracts are evaporated and then treated with 100 ml of dry toluene and heated at 90-95 ° C for one hour. Upon evaporation of the solvent, the isocyanate is obtained as a residue.

A mixture of 20.7 g of this isoeyanate and 350 ml of concentrated hydrochloric acid is boiled under Ater-Rode for 5 hours and then evaporated in vacuo. The residue is dissolved in water and made alkaline. Extraction with ether and evaporation of the extracts give 1-amino-1,1a, 6,6a-tetrahydrocycloprop [a] indene.

An ethanol solution of 1-amino-1,1a-6,6a-tetrahydrocycloprop [a] was reacted with an excess of hydrochloric acid to separate the hydrochloric acid salt, and this was recrystallized from ethanol-ether to give crystals, m.p. 183,184 ° C.

Example 2.

A solution of 14.5 g of 1-amino-1,1a, 6,6a-tetrahydrocycloprop [a] indene, prepared in the manner set forth in Example 1, and 100 ml of ethyl formate is boiled under reflux for 17 hours and then evaporated in vacuo. leaving 1-formyl-amino-1,1a, 6,6a-tetrahydro-cycloprop as a residue.

To a crude solution of 17.3 g of 1-formylamino1,1a, 6,6a-tetrahydrocycloprop [a] within 150 ml of diethylene glycol dimethyl ether was added 5.2 g of a 54.5% suspension of sodium hydride in mineral oil. The mixture is boiled under reflux for 2 hours, then cooled and further treated with 5.2 g of sodium hydride suspension. The reflux was continued for 2 hours and then 87 ml of methyl iodide were added. The mixture is allowed to stand at room temperature for 16 hours and then boiled for at least 12 hours. The mixture is filtered and evaporated, and the residue is poured into 1 liter of ice water. Extraction with methylene chloride and evaporation of the extracts give 1,1a, 6,6a-tetrahydro-1- (N-methyl-N-formyl) amino-cycloprop [a] indene.

By refluxing the above-prepared N-formyl compound with 150 ml of 37% hydrochloric acid, washing with ether, evaporating, dissolving the residue in water, adding sodium hydroxide solution to alkaline reaction, extraction with ether and evaporating the ether extracts are obtained as residue 1,1a, 6,6a-tetrahydro-1-methylamino cyclopropane.

The maleic acid salt is obtained by treating an ethyl ether reading of the base with a molar equivalent amount of maleic acid in ethyl acetate.

Example 3.

A mixture of 6.0 g of 1-amino-1,1a, 6,6a-tetrahydrocycloprop [a] indene prepared in the manner set forth in Example 1, 10 ml of 40% formaldehyde and 15 ml of 90% formic acid is boiled under reflux. 18 hours. The cooled reaction mixture is treated with 5.5 ml of concentrated hydrochloric acid and the solution is evaporated in vacuo. The residue is made alkaline with potassium hydroxide and extracted with ether. The extracts are evaporated to give 1,1a, 6,6a-tetrahydrodimethylaminocycloprop [a] indene.

An ethanol solution of the free base is treated with an excess of hydrochloric acid dissolved in ether, whereby the hydrochloric acid salt is obtained. —0> R, \ / s R, - - Example 4.

A mixture of 30.0 g of 5-chloroindene and 24.0 g of ethyl diazoacetate is boiled for 4 hours under reflux, after which ethyl 3-chloro-1,1a, 6,6a-tetrahydro-1-cycloprop [a] is obtained by distillation. inner carbacetic acid ester.

Hydrolysis of this ester by refluxing with sodium hydroxide in aqueous ethanol for 8 hours and working up the reaction product as described in Example 1 gives 3-chloro-1,1a, 6,6a-tetrahydro-1-cycloprop [a] indene carboxylic acid , which is treated with an excess of thionyl chloride at room temperature, whereby after evaporation and destination the acid chloride is obtained. 27 g of the acid chloride in 250 ml of acetone are treated with 16.0 g of sodium azide in aqueous solution, the temperature being between 5 and 10 ° C. By pouring the mixture into ice water, extracting with ether, evaporating the extracts and heating the residue in toluene at 90 ° C. 1 hour after evaporation of the icing, the corresponding isocyanate is obtained.

By boiling this isocyanate with 300 ml of concentrated hydrochloric acid for 5 hours and working up the product in the manner set forth in Example 1, 1-amino-3-chloro-1,1a, 6,6a-tetrahydrocyclopropane is obtained.

An ethanol solution of the free base is treated with excess hydrochloric acid solution in ether, thereby obtaining the hydrochloride salt.

Example By boiling a mixture of 13.0 g of 6-methylindene and 12.0 g of ethyl diazoacetate for 4 hours and distilling in vacuo, ethyl 1-1.1a, 6,6atetrahydro-4-methyl-1-cycloprop [a] indene carbonic acid ester are obtained. which is hydrolyzed by refluxing with sodium hydroxide in aqueous ethanol to give 1,1a, 6,6a-tetrahydro-4-methyl-1-cycloprop [a] indene carboxylic acid Treatment of this carbonic acid with excess thionyl chloride gives the acid chloride which is reacted with sodium azide and then heated in toluene to give the isoeyanate.

A mixture of 6.8 g of isocyanate and 100 ml of concentrated hydrochloric acid is boiled under reflux for 5 hours. The mixture is evaporated in vacuo and the residue is dissolved in water and made alkaline with sodium hydroxide. Extraction with ether and removal of the ether Iran extracts gives 1-amino-1,1a, 6,6a-tetrahydro-4-methylcycloprop [a] indene.

A solution of 1.0 g of the free base in 50 ml of ether is treated with excess tartaric acid. When filtering, the tartrate is obtained.

Example 6.

A mixture of 28.0 g of 5-methoxyindene and 23.0 g of ethyl diazoacetate is heated at reflux for 5 hours and then distilled to give ethyl 14,1a, 6,6a-tetrahydro-3-methoxy-1-cycloprop [a] indene carboxylic acid ester. g of this ester is boiled under reflux with 16.0 g of sodium hydroxide in aqueous ethanol for 10 hours. By working up the product in the manner set forth in Example 1, 1,1a, 6,6a-: tetrahydro-3-methoxy-1-cycloprop [a] indene carboxylic acid is obtained, the acid is treated with 50 ml of thionyl chloride, after which the resulting mixture is distilled and 1,1a, 6,6a-tetrahydro-3-methoxy-1-cycloprop [a] indene carboxylic acid chloride.

Upon treatment of this acid chloride with 18.0 g of sodium azide at 10 ° C and heating of the obtained carboxylic acid azide with dry toluene at 90 ° C for 1 hour, the corresponding isocyanate is formed.

This isocyanate (15.0 g) is heated under reflux with 250 ml of concentrated hydrochloric acid for 5 hours. When worked up in the manner set forth in Example 5, 1-amino-1,1a, 6,6a-tetrahydro-3 toxicycloprop [a linden is obtained.

The free base (1.0 g) in ethanol solution is treated with an excess of ethereal bromine, whereby the hydrobromide salt separates.

Example 7.

A mixture of 1.7 g of 1-amino-1,1a, 6,6a-tetrahydro-3-methoxycycloprop [a] indene, prepared on salt given in Example 6, 3.0 g of n-butyl bromide, 5.0 g of potassium carbonate and 60 ml of toluene are heated under reflux for 10 hours. The cooled reaction mixture is dissolved in water and the toluene layer is separated. Evaporation of the toluene in vacuo gives a residue which is treated with attic anhydride on a steam bath for 30 minutes. Excess nitric acid hydride is deposited in vacuo and the residue is taken up in ether. The effluent is extracted with aqueous hydrochloric acid. The extract is made alkaline and extracted with ether. Evaporation with the ether gives 1-dibutylamino-1,1a, 6,6a-tetrahydro-3-methoxycycloprop [a] indene as a residue.

Example 8.

Treatment of 17.6 g of 1α, 6α-dihydro-1H-cyclopropa [b] benzofuran-1-carboxylic acid with 50 ml of thionyl chloride at room temperature for 16 hours and distillation gave the acid chloride, which was reacted with sodium azide (15.0 g) in acetone-water. at 10 ° C. By heating the resulting carboxylic acid azide in toluene, the corresponding isocyanate is obtained.

This isocyanate (8.5 g) is refluxed with 150 ml of concentrated hydrochloric acid. The mixture is evaporated in vacuo and left to rise in water, made alkaline and extracted with ether. Evaporation of the solvent from the extract gives 1-amino-1α, 6α-dihydro-1H-cyclopropa [b] benzofuran.

Dissolving the free base in ethanol and treating it with an excess of hydrochloric acid dissolved in ether gives the hydrochloride salt.

Example 9.

A mixture of 14.7 g of 1-amino-1α, 6α-dihydro-1H-cyclopropa [b] benzofuran, prepared on the basis of Example 8, 22.9 g of 1,5-dibromo-pentane and 30.0 g g of potassium carbonate in 200 ml of xylene is boiled under reflux for 14 hours. The cooled reaction mixture is treated with water. The xylene layer is separated and evaporated in vacuo to give the remaining 1α, 6α-dihydro-1-pip ericlino-1H-cyclopropa [b] benzofuran.

A solution of the free base (1.0 g) of 150 ml of ether was reacted with an excess of glacial acetic acid to give the acetate.

Example 10. 5-Chlorobenzofuran (15.2 g) and 12.0 g of ethyl diazoazetate are boiled under reflux for 4 hours. By distillation, ethyl 3-chloro-1α, 6α-dihydro-1H-cycloprop [a] benzofuran-1-carboxylic acid ester is obtained.

This ester is hydrolyzed by refluxing with sodium hydroxide and the resulting acid is chlorinated with thionyl chloride to give 3-chloro-1α, 6α-dihydro-1H-cyclopropa [b] benzofuranecarboxylic acid chloride.

A potassium solution of 11.8 g of the acid chloride thus prepared in 125 ml of acetone is treated with an aqueous solution of 8.0 g of sodium azide, the temperature being kept below 13 DEG C. The mixture is stirred for 30 minutes and then poured into 1 liter of ice water and extracted with ether. The extracts are dried, evaporated and heated with 50 ml of toluene at 90 ° C for one hour. By removing the solvent in vacuo, 1-amino-3-chlorola, 6a-dihydro-1-cyclopropa [b] b ensofuran is obtained.

Upon treatment with ethanol solution of the free base with an excess of chlorine chloride dissolved in ether the hydrochloride salt separates.

Example it A mixture of 14.8 g of 7-methoxybenzofuran and 12.0 g of ethyl diazoacetate is boiled under reflux for 4 hours and then distilled to give ethyl 1α, 6α-dihydro-5-methoxy-1H-cyclopropane [b lb ensofuran]. -1-carb onsic acid ester. g of this ester in 60 ml of ethanol and 8 g of sodium hydroxide in 15 ml of water are heated under reflux for 9 hours. When worked up in the manner indicated in Example 1, the carbonic acid is obtained. By treating this acid with 30 ml of thionyl chloride at room temperature for 16 hours and then following destination, 1α, 6α-dihydro5-methoxy-1H-cyclopropa [b] benzofuran-1-carboxylic acid chloride is obtained.

An acetone solution of this acid chloride (5.0 g) is treated with 4.0 g of sodium azide in aqueous solution at 5-13 ° C. corresponding isocyanate.

Upon refluxing 2.1 g of this isocyanate with 35 ml of concentrated hydrochloric acid for hours, evaporation, dissolution of the residue in water, installation on alkaline reaction, extraction with ether and evaporation of the extract, 1-amino-1α, 6α-dihydro- 5-methoxy-1H-cyclopropa [b] benzofuran.

An ethyl acetate solution of the free base is treated with an equimolar amount of mineralic acid, the maleate being obtained after evaporation and cooling.

Example 12.

A mixture of 38.4 g of 1α, 6α-dihydro-1H-cyclopropa [b] benzothiophene-1-carboxylic acid and 100 ml of thionyl chloride is added for 16 hours and then distilled to give the carboxylic acid chloride. By treating this acid chloride in acetone solution with 30.0 g of sodium azide in water at 10 ° C, the carbonic azide is obtained. The isocyanate is prepared by heating this carboxylic acid azide in tower toluene at 90-95 ° C for one hour and removing the solvent in vacuo.

A mixture of 20.0 g of the isocyanate thus prepared and 300 ml of concentrated hydrochloric acid is boiled under reflux for 5 hours. from the extract is obtained lamina-1α, 6α-dihydro-11-1-encyclopropa [b] benzothiophene. The free base (1.0 g) in 75 ml of ethanol is treated with a supernatant of hydrogen chloride solution dissolved in ether to give the hydrochloride salt.

Example 13. 5-Chlorobenzothiophene (16.8 g) and ethyl diazoacetate (12.0 g) are heated under reflux for 4 hours, after which ethyl 3 -3-chloro-1 1-carboxylic acid ester.

By boiling this ester (15.0 g) under reflux in 100 ml of ethanol with 8.0 g of sodium hydroxide in 20 ml of water for 9 hours and working up in the manner set forth in Example 1, 3-chloro, 6a - dihydro - 1H - is obtained. cyclopropa [b Thensothiophene - 1 - carbonic acid. Treatment of this acid with 50 ml of thionyl chloride at room temperature gives the corresponding acid chloride which was reacted with 12 sodium azide. The resulting carbonic acid azide is heated in toluene at 90-100 ° C for 1 hour to give the isocyanate.

By boiling this isocyanate with 200 ml of concentrated hydrochloric acid under reflux and working up in the manner set forth in Example 12, man-amino-3-chloro-1α, 6α-dihydro-1H-cyclopropa [b] benzothiophene is obtained.

An ethanol solution of the free base is treated with an excess of hydrogen chloride solution in ether to give the hydrochloride.

Example 14.

A mixture of 21.3 g of 4-bromothianaphthene and 12.0 g of ethyl diazoacetate is boiled under reflux for 4 hours. By distillation, ethyl 2-bromo-1α, 6α-dihydro-1H-cyclopropa [b] benzothiophene-1-carboxylic acid ester is obtained.

Hydrolysis of this ester by refluxing with sodium hydroxide in an aqueous ethanol and chlorination of the resulting carbonic acid with thionyl chloride gives 2-bromo1a, 6a-dihydro-1H-cyclopropa [b] benzothiophene-1-carboxylic acid chloride.

A solution of 14.4 g of this acid chloride in 150 ml of acetone is cooled to ° C and treated with an aqueous solution of 8.0 g of sodium azide. The resulting mixture is stirred for 30 minutes and worked up on the salt given in Example 10 to give the carbonic azide, which is heated in dry toluene for 1 hour at 90-95 ° C to give the isocyanate.

By boiling this isocyanate (13.4 g) with 150 ml of concentrated hydrochloric acid for 5 hours under reflux and then evaporating the reaction mixture, dissolving Lers Loden in water, installing the solution on alkaline reaction, extracting with ether and evaporating the extract to give 1-amino 2- bromo-1α, 6α-dihydro-1H-cycloprop a [b I b ensotitiophene.

Example 15.

A mixture of 12.1 g of 1-amino-2-bromo-1α, 6-dihydro-1H-cyclopropa [b] benzothiophene, prepared in the manner set forth in Example 14, 10.8 g of 1,4-dibromobutane and 11.0 g g of sodium carbonate in 300 ml of benzene is heated under reflux for 10 hours. The cooled reaction mixture is poured into water and the benzene layer is separated. After evaporation of the solvent in vacuo, 2-bromo-1α, 6α-dihydro- (N-pyrrolidinyl) -1H-cyclopropa [b] benzothiophene are obtained.

A solution of 2.0 g of this base in ethyl acetate is treated with excess citric acid. By evaporation and cooling, the citrate is obtained.

Example 16. 6-Methoxybenzothiophene (16.4 g) and ethyl diazoacetate (12.0 g) are boiled together for atherbide 4 hours and then distilled to give ethyl 1α, 6α-dihydro-4-methoxy-1H-cyclopropa [ bb ensothiophene-1-carboxylic acid ester. By boiling this ester under reflux with 12.0 g of sodium hydroxide in aqueous ethanol for 9 hours, the carbonic acid is obtained. This is treated with 40 ml of thionyl chloride at room temperature for 16 hours to give, after destination, 1α, 6α-dihydro-4-methoxy-1H-cyclopropa [b b ensotiophene-1-carboxylic acid chloride.

The acid chloride (12.0 g) thus prepared is stirred with 7.5 g of sodium azide in acetone water at 5-13 ° C for 30 minutes. The mixture is poured into ice water and extracted with ether. The extract is then evaporated and treated with dry toluene and heated at 90-95 ° C for 1 hour, whereby after removal of the solvent the corresponding isocyanate is obtained.

Upon boiling under Merflode the isocyanate with 100 ml of concentrated hydrochloric acid and working up as described in Example 14, 1-amino-1,6a-dihydro-4-methoxy-1H-cyclopropa [1: 1] benzothiophene is obtained.

The hydrochloride salt of this base is separated before an ethanol solution of the free base is treated with an excess of hydrochloric acid dissolved in ether.

Example 17.

A mixture of 3.9 g of 1-amino-1α, 6α-dihydro-4-methoxy-1H-cyclopropa [b] benzothiophene, which is precipitated on the salt given in Example 16, 2.8 g of bis (β-chloroethyl) ether , 5.5 g of potassium carbonate and 75 ml of xylene are boiled under reflux for 12 hours. By cooling the solution, pouring it into water and evaporating the xylene mixture in vacuo, 12,6a-dihydro-4-methoxy-1-morolino-1H-cyclopropa [b] benzothiophene is obtained as a crude product.

Example 18. p-Trifluoromethylbenzaldehyde (17.4 g) is heated with a mixture of 55 ml of acetic anhydride and 8.7 g of sodium acetate at 170-175 ° C for 8 hours. The reaction mixture is dissolved in water and acidified with concentrated hydrochloric acid. p-trifluoromethyl cinnamic acid is filtered off. g of p-trifluoromethyl cinnamic acid dissolved in 100 ml of absolute ethanol are hydrogenated with 0 g of platinum oxide at 3.5 kp / cm 2 for 7-8 hours at room temperature. The mixture is filtered and evaporated in vacuo to give p-trifluoromethyldihydrocinnamic acid.

Upon treatment of 12.0 g of the above-prepared acid with 25 ml of thionyl chloride at room temperature for 16 hours and evaporation of the mixture in vacuo, ptrifluoromethyldihydrocinnamic acid chloride is obtained.

This acid chloride is heated in light petroleum with about 12 g of anhydrous aluminum chloride until the hydrogen chloride evolution ceases. The mixture is cooled, treated with water and steam distilled. The distillate is fed with sodium sulfate and the organic layer is separated, washed with sodium carbonate ice and with water and evaporated in vacuo to give 6-trifluoromethyl-1-indanone.

This indanone (11 g) is refluxed with 2 g of lithium aluminum hydride in 500 ml of absolute ethanol for 20 minutes. The mixture was diluted with 100 ml of ether and then with 50 ml of water. The organic layer is separated and evaporated to give 6-trifluoromethyl-1-indanol.

A mixture of 9.5 g of 6-trifluoromethyl-1-indanol and 50 ml of acetic anhydride is boiled under reflux for 2 hours. the excess acetic anhydride is removed in vacuo and the residue is diluted with water and extracted with ether. By removing the solvent in vacuo, 1-acetoxy-6-trifluoromethylindane is obtained.

The 1-acetoxy-6-trifluoromethylindane prepared on the above salt is slowly dropped through a column packed with glass spirals while maintaining an internal temperature of 460 ° C. The vapors are collected in a cooled flask. Then acetoxifore-. addition, rinse the column with 5 ml of anhydrous benzene. The product collected in the flask was diluted with 200 ml of water and extracted with ether. The ether extract is washed with sodium carbonate, dried, evaporated and distilled to give the 5-trifluoromethylindene.

A mixture of 9.2 g of 5-trifluoromethylindene and 6.0 g of ethyl diazoacetate is boiled under reflux: - - 4 hours. By distillation, ethyl 1-1,1a, 6,6a-tetrahydro-3-trifluoromethyl-1-cycloprop [a] indene carboxylic acid ester is obtained.

Hydrolysis of this ester by refluxing with sodium hydroxide and chlorination by treatment with thionyl chloride gives 1,1a, 6,6a-tetrahydro-3-trifluoromethyl-1-cycloprop [a] indenecarboxylic acid chloride. This acid chloride is treated with sodium azide and the resulting carbonic azide is heated in toluene to give the corresponding isocyanate.

A mixture of 8.0 g of the isocyanate is boiled under reflux with 100 ml of concentrated hydrochloric acid for hours and then evaporated in vacuo. The residue is dissolved in water, made alkaline and extracted with ether. Evaporation of the extracts gives 1-amino-1,1a, 6,6a-tetrahydro-3-trifluoromethylcycloprop [a] indene.

The hydrochloride salt is prepared by treating an ethanol solution of the free base with excess hydrochloric acid solution in ether.

Example 19. p-trifluoromethylaniline (120.0 g) was slowly added to a mixture of 150 ml of concentrated hydrochloric acid and. 150 g crushed ice. A cold solution of sodium nitrite (49.2 g) in 124 ml of water was added slowly while the temperature was below 4 ° C. The resulting solution was slowly added to 140 g of potassium methyl xanate 1180 ml of water at 40-45 ° C. The separating trifluoromethylphenylethyl xanate is first washed with 10% sodium hydride solution and then clay with water. The xanate is dissolved in 95% ethanol. The solution is boiled under reflux with 160 g of potassium hydroxide for 8 hours. The alcohol is removed by distillation. Water is added to the residue and the aqueous solution is washed with ether. The aqueous solution Ores is strongly acidic with concentrated sulfuric acid and is then subjected to steam distillation. The lower layer is separated and redistilled to give p-trifluoromethylthiophenol.

To a mixture of 17.8 g of p-trifluoromethylthiophenol and 4.0 g of sodium hydroxide in aqueous solution was added 12.2 g of ethyl chloroacetate over 30 minutes, the temperature being measured at 20-25 ° C. The reaction mixture was extracted into ether and the extract was evaporated and distilled. to give ethyl 1-4-trifluoromethylphenyl mercaptoacetate. This ester is hydrolyzed by refluxing in sodium hydroxide solution for 5 hours, after which the whole is evaporated and the residue is dissolved in water, acidified and extracted with ether, finally the solvent is evaporated in vacuo to give 4-trifluoromethylphenylmercaptoacetic acid. The acid chloride is obtained by treating 15.0 g of the acid with 50 ml of thionyl chloride at room temperature for 16 hours. By removing the excess thionyl chloride in vacuo, 4-trifluoromethylphenyl mercaptoacetyl chloride is obtained.

Anhydrous aluminum chloride (15.0 g) was added to a benzene solution of the acetyl chloride prepared above. The mixture is heated slowly, until the chlorine water evolution stops. The mixture is cooled, carefully treated with water and steam distilled. Sodium sulfate was added to the distillate and the organic layer was separated, washed with sodium carbonate solution and with water and evaporated to give 5-trifluoromethyl-3 (2H) -benzothiophenone.

A mixture of 10.9 g of 5-trifluoromethyl-3- (2H) -benzothiophenone 60 ml of glacial acetic acid and 15 ml of zinc powder is boiled under reflux and stirring for 3 hours. The cooled solution is made alkaline with sodium hydroxide and steam distilled. The distillate is extracted with ether. Evaporation of the extract and distillation of the residue give 5-trifluoromethyl-benzothiophene.

By refluxing 10.1 g of 5-trifluoromethylthianaphthene with 6.0 g of ethyl diazoacetate for 4 hours and then distilling off, ethyl 1 -, 6a-dihydro-3-trifluoromethyl-1H-cyclopropa [b Thensothiophene-1-carboxylic acid ester is obtained. This ester is hydrolyzed by refluxing with sodium hydroxide in aqueous ethanol. The carboxylic acid thus prepared is treated with thionyl chloride to give 1α, 6α-dihydro-3-trifluoromethyl-1H-cyclopropo Then sotofen-1-carboxylic acid chloride. By reacting this acid chloride with sodium azide, the carboxylic acid azide is obtained, which is then heated in toluene at 95 ° C, which results in the formation of the isocyanate.

This isocyanate (6.0 g) and 75 ml of concentrated hydrochloric acid are heated under reflux for 5 hours. By working up in the manner set forth in Example 18, 1-amino-1α, 6α-dihydro-3-trifluoromethyl-1H-cyclopropa [b] benzothiophene is obtained.

A solution of 1.0 g of the free base in ethyl acetate was added to an ethanol solution of mandelic acid. By evaporation and cooling, the mandelate is obtained.

Example 20.

A mixture of 4.6 g of 1-amino-1α, 6α-dihydro-3-trifluoromethyl-1H-cyclopropa [13] bensothiophene, prepared in the manner set forth in Example 19, and 40 ml of acetaldehyde in ethanol is stirred at room temperature. 5 hours. The solution is evaporated in vacuo and the residue is hydrogenated with 0.2 g of palladium on tracol in ethanol solution at 3.5 kp / cm 2 for 2 hours. Upon filtration and evaporation of the solvent, 1-ethylamino-1α, 6α-dihydro-3-trifluoromethyl-1H-cyclopropa [b] benzothiophene is obtained as a residue.

Example 21.

A mixture of 2.3 g of 1-amino-1α, 6α-dihydro-3-trifluoromethyl-1H-cyclopropa [b] benzothiophene, 2.2 g of ethyl bromide, 2.5 g of sodium carbonate and 50 ml of toluene is boiled under reflux for 6 hours. The cooled mixture Mlles in water. The organic layer is evaporated in vacuo to give 1-diethylamino-1α, 6α-dihydro-3-trifluoromethyl-1H-cyclopropa [b] benzothiophene. The free base is dissolved in ethanol and treated with excess chlorohydrate in ether to give 1-diethylamino-1,6a-dihydro-3-trifluoromethyl-1H-cyclopropa [b] -benzothiophene hydrochloride. - —9 Example 22.

A mixture of 14.0 g of 5-fluorososalicylaldehyde, 9.4 g of chloroacetic acid and 11.2 g of potassium hydroxide in aqueous ethanol is heated at 160-180 ° C for 12 hours. The mixture is then subjected to steam distillation. The distillate is extracted with ether and the extract is evaporated and distilled to give 5-fluorobenzofuran.

By boiling 13.6 g of 5-fluorobenzofuran with 12.0 g of ethyl diazoacetate for 4 hours under reflux and then distilling off, ethyl 3-fluoro1a, 6a-dihydro-1H-cyclopropa [13 Thensofuran-1-carboxylic acid ester is obtained.

This ester is hydrolyzed by refluxing with 12 g of sodium hydroxide in aqueous ethanol for 9 hours and the resulting carboxylic acid is treated with thionyl chloride at room temperature to give, after evaporation and distillation, 3-fluoro-1a, 6a-dihydro-1H-cycloprop a lb ensofuran-1-carb onsic acid chloride.

A solution of 10.6 g of the above-prepared acid chloride in acetone is cooled to ° C and treated with 14.0 g of sodium azide in aqueous solution. The mixture is stirred for 5 minutes at 5-13 ° C, dissolved in water and extracted into ether. The extract is evaporated, treated with dry toluene and heated at 90-95 ° C for 1 hour, whereby, after removal of the solvent, the corresponding isocyanate is obtained.

By refluxing 10.0 g of this isocyanate with 150 ml of concentrated hydrochloric acid and working up in the manner set forth in Example 1, 1-amino-3-fluoro-1α, 6α-dihydro-1H-cycloprop a [b] benzofuran is obtained.

The free base is treated in ethanol solution with an excess of chlorine chloride solution in ether to give the hydrochloride.

Example 23.

Ethyl diazoacetate (12.0 g) and 16.6 g of thianaphthene-1,1-dioxide are heated under reflux for 4 hours and the resulting mixture is distilled to give ethyl 1α, 6α-dihydro-6,6-dioxi-1H-cyclopropa [ 13] benzothioph and 1-carb onsic acid ester.

By boiling the ester prepared on the above salt with 20 g of sodium hydroxide in aqueous ethanol, the carbonic acid is obtained, which treated with thionyl chloride (30 ml) gives the acid chloride.

By treating this acid chloride with sodium azide in the manner set forth in Example 22, the carboxylic acid azide is obtained, which is heated in toluene at 95 ° C for one hour to prepare the isocyanate.

Heating this isocyanate (4.3 g) with 60 ml of hydrochloric acid under reflux for 5 hours and working up on the salt given in Example 1 gives 1-amino-1α, 6α-dihydro-6,6-dioxy4H-cyclopropa [b lb ensothiophene .

Claims (4)

Patent claim: A process for the preparation of therapeutically active compounds, characterized in that a annealed cyclopropylcarboxylic acid azide of the formula CH,; CH-CON, / / Y / in which Y is CH 2 O, S or SO, and R chlorine, bromine, fluorine, trifluoromethyl, methyl or methoxy, to the corresponding isocyanate and hydrolyze it to give an annealed encyclopropylamine of the formula CH, I 1 CH-NH, CH / van in Y and R, having the meanings given above, and optionally alkylating the amino group of this annealed cyclopropylamine, so as to obtain an alkylated annealed cyclopropylamine of the formula CH 2 / B-2 \ R 8 in which R 1 and Y have the meanings given above and R 1 and 1C1.3 taken together with N aro lower monoalkylamino, store dialkylamino, piperidine, N-pyrrolidinyl or morpholino. 2. Process according to claim 1, characterized in that the annealed cyclopropylcarbonic acid azide is rearranged with the isocyanate by heating in an organic solvent. 3. Process according to claim 1, characterized in that the annealed cyclopropyl isocyanate is hydrolyzed by heating in hydrochloric acid solution and that the obtained annealed cyclopropylamine hydrochloride is neutralized. Request publications: Patentslcriffer friin Sverige 166 67 4.