NO135364B - - Google Patents

Description

The present invention relates to a method for

preparation of 4-substituted 4H-benzo-/3,cyclohepta/l,2-b/thiophene-10(9H)-one derivatives of formula I

in which

stands for hydrogen, halogen or a lower alkoxy group,

1*2 means hydrogen

R- and R^ each stand for hydrogen or the methyl group and

R^ either stands for lower alkyl or forms together with R2 an ethylene chain or together with R^ an ethylene or trimethylene chain or together with R^ a trimethylene or tetramethylene chain and R& means a lower alkyl group,

and acid addition salts thereof, and the distinctive feature of the method according to the invention is that a compound of formula II or III

in which R^, R2, R3, R4, R1, and R& have the above meaning and X stands for chlorine or bromine, is treated with a strong aqueous, non-oxidizing acid after which, if desired, the base obtained is converted into an acid addition salt.

If R^ stands for a lower alkoxy group, this contains from 1

to 4 carbon atoms. The symbol R^, when it means halogen, stands especially for chlorine and bromine, preferably for chlorine. If Rc is a lower alkyl group, then this contains from 1 to 4 carbon atoms.

The symbol Rfi stands for a lower alkyl group with especially 1 to 4 carbon atoms.

The acid addition salts can be prepared in a known manner from the free bases and vice versa.

Strong non-oxidizing acids can be used as well as inorganic acids, such as e.g. hydrobromic acid, sulfuric acid, hydrochloric acid, phosphoric acid, etc., as well as organic acids, such as aliphatic and aromatic sulphonic acids, trifluoroacetic acid, trichloroacetic acid, etc.

One proceeds, for example, in such a way that a solution of one of the compounds of formula II or III is heated in a 20 - 70% aqueous strong solution to approx. 80 to 120°C.-

Depending on the nature and concentration of the acid and the reaction temperature, the reaction time ranges from 1.5 to approx. 15 hours.

When using extremely diluted acid, work is usually done at higher temperatures, e.g. at approx. 200 to 230°C and in an autoclave.

The compounds of formula II or III are moderately to well soluble in aqueous acids. It is therefore usually not necessary to add a solvent. If a solvent is used, such as sn alkanol, it is recommended that the percentage of this solvent be kept as low as possible.

The compounds of formula Ia,

in which R^ and R^ have the above-mentioned meaning, and the analogous methods for preparing these compounds of formula Ia are the subject of Norwegian Patent Document 133,838. The compounds of formula Ia are obtained in two steps from the corresponding compounds of formula II by reaction with primary or secondary amines in the presence of an acid-binding agent, respectively reaction with potassium alcoholates and final hydrolysis of the thus obtained secondary or tertiary amine, respectively cleavage of the thus obtained ethers using acids.

These analogous methods have the disadvantage that when preparing the amines or the ethers, a mixture of 4H-benzo/4~, 5_7 cyclohepta^, 2-bJ7 thiophene which is substituted in the 9-position with 4H-benzo5j7cyclohepta/I, 2-b_7 thiophene which is substituted in the 10-position, in a ratio of about 2:1.

When using the method, according to the present invention, 10-keto compounds are finally obtained whereby, in comparison with the previously known methods, a doubling of the yield and a significantly better quality can be achieved.

Furthermore, one can assume, due to literature information regarding the conversion ability of halogen into vinylogenic halides, that X

(in formulas II and III) would remain practically indifferent to acids. Contrary to expectations, not only is the reaction according to the invention feasible, but proceeds easily and gives excellent yields.

The compounds of formula Ib,

in which R1 and R& have the above-mentioned meaning, R2' stands for hydrogen, R3<1> and R^' stand for. hydrogen or a methyl group and

R5' means a lower alkyl, or R5'/ when at least one of the substituents ' and R^' stands for a methyl group, forms together with R„<1> an ethylene group, or R^' forms together with R^1 a ethylene or trimethylene group, or R^' forms together with R^' a trimethylene or tetramethylene group, are new compounds.

Some of the compounds of formula II, which when treated with strong, aqueous, non-oxidizing acids can surprisingly be transferred into the compounds of formula I, are also new.

They can e.g. are prepared from compounds of formula III,

in which X, R^, R^, R^, R4/R5 and Rg have the above-mentioned meaning, by splitting off water.

The compounds of formula IIa,

in which X, Rlt R2<1>/ R3', R4<1> R5 1 and Rg have the above-mentioned meaning, has not been described so far. They are produced by starting from the compounds of formula Illa,

wherein X, R^ R2 1, R3 1, R4'/R5' and Rg have the above-mentioned meaning, splits off water.

For the water separation, it can e.g. mineral acids/such as sulfuric acid, ethanolic hydrochloric acid, hydrobromic acid, but also

strong organic acids, acetic anhydride or inorganic acid halide as a water-splitting agent.

By corresponding choice of a water-splitting agent - strong aqueous non-oxidizing acids - the compounds of formula III can also be directly, i.e. without isolation of the compounds of formula II, is transferred into the compounds of formula I. Also with this direct process variant, it is recommended that the percentage of any solvent be kept as low as possible.

Some of the starting compounds with formula III are also new and can e.g. is produced by the compounds of formula IV. wherein and X has the above-mentioned meaning, is reacted with an organomagnesium compound of the formula V, in which R^ t R^ > R^ r R^ 0<3 Rg has the above-mentioned meaning and Hal stands for chlorine, bromine or iodine, and the reaction mixture is hydrolyzed to a compound of formula III.

In practice, the preparation of compounds of the formula III is carried out by dissolving a compound of the formula IV in an absolute organic solvent inert to the reaction conditions, e.g. a straight-chain or cyclic ether, such as tetrahydrofuran or diethyl ether, is added dropwise to an organomagnesium halogen compound of formula V, in the same solvent, and the mixture is preferably stirred for approx. lh hour at room temperature» Finally hydrolysed. the mixture in a cooled state with an aqueous ammonium chloride solution and is then extracted with an organic solvent inert to the reaction conditions, which is not miscible with water, e.g. with a chlorinated, aliphatic hydrocarbon such as e.g. methylene chloride or chloroform etc.

For the preparation of compounds of formula IV, cleavage is carried out

from the compounds of formula VI,

in which and X has the above-mentioned meaning, halogen hydrogen (HX, in which X has the above-mentioned meaning). This cleavage is carried out under alkaline conditions, e.g. by impact of

a solution of potassium hydroxide in an organic solvent inert to the reaction conditions, such as e.g. methanol, or by the action of aqueous lye with the addition of lower alcohols as a solvent and the reaction is accelerated by heating the reaction mixture.

The compounds of formula VI can e.g. is produced by the compounds of formula VII, in which it has the meaning mentioned above, in an organic solvent inert to the reaction conditions, such as e.g. cyclohexane, are chlorinated or brominated to the corresponding 9,10-dichloro- or 9,10-dibromo compounds. The 9,10-dibromo compounds obtained above from the compounds of formula VII can e.g. also obtained by reaction, of the compounds of formula VIII,

in which R^ has the meaning mentioned above, with the calculated amount of N-bromosuccinimide in an organic solvent inert to the reaction conditions, such as e.g. a chlorinated aliphatic hydrocarbon, such as carbon tetrachloride.

The bromine or chlorine atom indicated by the symbol X is i

the compounds of formula IV, and thus also in the compounds of formula III and II, according to the NMR spectrum associated in the 9- or 10-position. Due to the good yields that the compounds of formula II when using the method according to the invention gives of the compounds of formula I, it can be assumed with greater probability

that X is fixed in the 10 position.

When the preparation of the starting compounds is not specified, this means that these are known or that they can be prepared according to known methods, respectively analogous to those described above or analogous to methods known per se.

The compounds of formula I and their pharmacologically tolerable acid addition salts have interesting pharmacodynamic properties and can therefore be used as pharmaceuticals.

Thus, the compounds of formula I bg especially the compounds of formula Ia excel in histaminolytic properties, which is evident from the results of the histamine toxicity test with guinea pigs. This histaminolytic action is specific, as it helps

of the serotonin toxicity test and the acetylcholine toxicity test on guinea pigs only insignificant serotonin antagonistic and anticholinergic properties can be established.

Due to their specific histaminolytic properties, these compounds can be used in allergic affections of various origins.

The histaminolytic properties are particularly prominent in the compounds of formula Ic, in which it has the above-mentioned meaning, which e.g. by 4-(1-methyl-4-piperidylidene)-4H-benzo-/4~,5_7cyclohepta^£ 2-b7 thiophen-10(9H)-one, 6-chloro-4-(1-methyl-4-piperidylidene )-4H-benzo-23,57-cycloheptaZT/2-b7thiophen-10(9H)-one, 7-chloro-4-(1-methyl-4-piperidylidene)-4H-benzo^/4, 57cyclohepta^, 2 -b7thiophene-10(9H)-one etc.

The doses used naturally vary in relation to the species

the substance used, the method of administration and the condition of the person being treated. Generally, however, satisfactory results are obtained in the experimental animals with a dose varying from 0.004

to 3.0 mg/kg body weight. This dose can optionally be administered in 2 to 3 parts or also in slow-release form. For large mammals, a daily dose of wood is approx. 0.5 to 200 mg. For oral use, the partial doses contain from approx. 0.15 to 100 mg of the compounds in addition to solid or liquid carriers or diluents.

The compounds of formula Ib also have local anesthetic properties

properties that appear from experiments on the Cornea in rats, and can thus be used for ocular surface anaesthesia. Generally, in the experimental animals or larger mammals, satisfactory results are obtained with 0.1 to 10% mixtures of the compounds of formula Ib with solid or liquid carrier substances.

In the following examples, the invention is described in more detail.

EXAMPLE 1: 1-Methyl-4-piperidylidene)-4H-benzo^T,S7cycloheptaZT^-b^thiophene-10(9H)-one

A mixture of 100 g of 9(10)-bromo-4-(1-methyl-4-piperidylidene)-4H-benzo^", 57cyclohepta/j[, 2-b7thiophene-base and 900 ml of 50% sulfuric acid is stirred in llj hour at 100°C (oil bath temperature 110°C). The reaction solution is finally cooled to room temperature and shaken with 3000 ml of water. The solution is then made alkaline while cooling at 20°C using 1300 ml of concentrated caustic soda. The separated base is then extracted with 1350 ml of chloroform in small portions.

The mixed chloroform extracts are washed with water, dried over sodium sulphate and evaporated in vacuo. The impure 4-(1-methyl-4-piperidylidene)-4H-benzo[T,57cyclohepta^T,2-bithiophene-10(9H)-one base thus obtained is recrystallized in 320 ml of isopropanol. In this way, the pure 4-(1-methyl-4-piperidylidene)-4H-benzo ^/J/^cyclohepta/T, 2-thi7thiophene-10 (9H)-one base is obtained, which melts at 152 - 153 °C.

The starting product used 9 (10)-bromo-4-(1-methyl-4-piperidylidene)

-4H-benzo/T, 5J7cycloheptaZT, 2-bJ7thiophene-base can e.g. is prepared as follows: A mixture of 129 g of 9,10-dihydro-4H-benzoZ3", 57cyclohepta/l^ 2-hJ~" thiophen-4-one, 214 g of N-bromosuccinimide, 1.2 g of benzoyl peroxide and 2000 ml absolute carbon tetrachloride is stirred and refluxed for 3 hours. Finally, the solution is filtered hot and the filtrate is evaporated to 1/3 of the original volume. After standing for a few hours at room temperature, the crystallisate is filtered off and dried. This impure product is recrystallized in the 7-fold amount of chloroform. In this way, the pure 9,10-dibromo-9,10-dihydro-4H-benzo/T,STcyclohepta/1^ 2-]a7thiophene-4-one is obtained, which melts during decomposition at 134 - 135°C. The microanalysis agrees with the formula C^HgB^OS. The structure is determined using the NMR spectrum.

A mixture of 70 g of 9,10-dibromo-9,10-dihydro-4H-benzo(A'/57-cyclohepta/T,2-b7"thiophen-4-one, 31.6 g of potassium hydroxide and 3200 ml of methanol is heated while stirring for 2 hours with reflux. Finally, the mixture is stirred for about 4 hours at a temperature between 0 and 5°C and the crystallisate is filtered off. After recrystallization in the 100-fold amount of methanol, the pure 9(10)- brpm-4H-benzo^, 5/cyclohepta^, 2-b7thioph en-4-one, which melts at 134 - 135° C. The microanalysis agrees with the formula C^H^BrOS. According to the NMR spectrum, the bromine atom is located in 9 - or 10 position (probably in 10 position).

5 g of magnesium, which has been activated with iodine, is poured over with 15 ml

absolute tetrahydrofuran and the mixture is heated under reflux.

Finally, 2 g of freshly distilled 1-methyl-4-chloropiperidine are added

and a few drops of 1,2-dibromoethane, whereby the Grignard reaction is set in motion. Now 22.8 g of freshly distilled 1-methyl-4-chloropiperidine, dissolved in 30 ml of absolute tetrahydrofuran, are added dropwise while heating, so quickly that the mixture is always kept boiling.

After the addition is complete, the mixture is boiled for 2 hours at reflux, after which the magnesium is practically completely converted.

Finally, add dropwise while cooling at 20 to 25°C

a hot solution of 30 g of 9 (10)-bromo-4H-benzo^T, 57cyclohepta/T, 2- h? thiophen-4-one in 160 ml of absolute tetrahydrofuran over a period of 1 hour. After stirring for 1 hour at 20 to 25°C, the reaction mass is poured into a mixture of 250 g of ice-mixed water and 35 g of ammonium chloride and the separated base is extracted in portions with a total of 600 ml of chloroform. The mixed chloroform phases are washed with 50 ml of water, dried over sodium sulphate and evaporated in vacuo. As a residue, the impure 9(10)-bromo-4-(1-methyl-4-piperidyl)-4H-benzo / T,5yekloheptaZT# 2-b7thiophen-4-ol base is obtained, which is directly further processed.

A solution of 51 g of impure 9(10)-bromo-4-(1-methyl-4-piperidyl)-4H-benzo/5",^7cyclohepta/T,2-b7thiophen-4-ol and 420 ml of 14% ethanolic hydrobromic acid is heated for 1 hour in an oil bath of 100°C and refluxed.Finally, the solution is evaporated in vacuum and the residue is dissolved

in 100 ml of water. After alkalization with concentrated caustic soda, the separated base is extracted three times with 100 ml of chloroform. The mixed chloroform extracts are washed with 50 ml of water, dried over sodium sulphate and evaporated in vacuo. The residue is dissolved in 70 ml of chloroform, which contains 5% methanol, and absorbed on 1000 g of silica gel. It is eluted with chloroform containing 5% methanol. The first 8 1 of eluate are discarded and the following 4 1 are evaporated together. An oily is obtained

evaporation residue, which is dissolved in 50 ml of boiling isopropanol and crystallized overnight at 0 to 5°Ca. After filtering off the crystallized and drying, the pure 9 (10)-bromo-4-(1-methyl-4-piperidylidene)-.' ; 4H-benzo^T, 57cyclohepta/T, 2-b7thiophene base, melting at 149 - 150°C. The microanalysis agrees with the formula C^gHjgBrNS. The bromine atom follows

The NMR spectrum in the 9- or I-position (probably in the 10-position).

EXAMPLE 2: 4-(1-Methyl-4-piperidylidene)-4H-benzo[4~,j^cyclohepta-£[,2-thiophene-1OjQH^-one

A solution of 10 g of 9(10)-bromo-4-(1-methyl-4-piperidylidene)-4H-benzo^/4", 57cyclohepta/T,2-b7thiophen-4-ol in 100 ml of 50% sulfuric acid stirred for 1*2 hours at 100° C. The reaction solution is poured into 400 ml of ice water and finally alkalized with concentrated caustic soda. The separated base is then extracted in portions with 400 ml of chloroform.

The mixed extracts are washed with 100 ml of water and dried over sodium sulphate and evaporated in vacuo. The impure base obtained is recrystallized in 25 ml of isopropanol. The compound mentioned in the title is obtained which has a melting point of 152 153°C.

EXAMPLE 3: 6-Chloro-4-(1-methyl-4-piperidylidene^-4H-benzo</3,§7-cyclohept a/T, 2-^thiophene-10(9H)_-one

A mixture of 10 g of 9(10)-bromo-6-chloro-4-(1-methyl-4-piperidylidene)-4H-benzo[4",57cyclohepta^T/2-b7thiophene base and 110 ml of 60% sulfuric acid is stirred for 3 hours at 85 to 90° C. Finally, the reaction solution is poured into 300 g of ice and alkalized with concentrated caustic soda while cooling to 20° C. The separated base is extracted in portions with a total of 200 ml of chloroform. The mixed extracts are washed with water , dried over sodium sulfate and evaporated. The solid residue is recrystallized in 50 ml of ethyl acetate. In this way the pure 6-chloro-4-(1-methyl-4-piperidylidenej -4H-benzo^,5_7cyclohepta,/l,2-bT "-thiophene-10(9H)-one base, which melts at 168 - 169°C. The microanalysis agrees with the formula C^gHj^ClNOS. The structure is determined with the help of the H1, NMR and MS spectra.

The starting material 9(10)-bromo-6-chloro-4-(1-methyl-4-piperidylidene)-4H-benzo^4~, 5j7cyclohepta^I, 2-b7thiophene base is prepared from 6-chloro-9,10 -dihydro-4H-benzo[4", 57cyclohepta^T, 2-b_7thiophene-4-one.

In the course of the process, the following intermediate products are isolated: 6-chloro-9,10-dibromo-9,10-dihydro-4H-benzo^3,57cyclohepta^I, 2-fc>7-thiophen-4-one (decomposition point 147 to 149 C)

9 (10)-bromo-6-chloro-4H-benzo^^cyclohepta/1,2-byrthiophen-4-one

(melting point 198 to 200°C)

9 (10)-bromo-6-chloro-4-(1-methyl-4^-piperidyl)-4H-benzo^", 57cyclohepta-/ T, 2-b7thiophen-4-ol base (further treated in impure state) 9 (10)-bromo-6-chloro-4-(1-methyl-4-piperidylidene)-4H-benzo[T,57-cyclohepta],2-b7thiophene base (m.p. 193 to 195°C)

EXAMPLE 4: 7-Chloro-4-(1-methyl-4-piperidylidene)-4H-benzoZ??|2?-cycloheptayl?J", 2-b7thiophene-10(9H)-one

A mixture of 10 g of 9(10)-bromo-7-chloro-4-(1-methyl-4-piperidylidene)-4H-benzo[4<w>,_5/cyclohepta^,2-b7thiopheh base and 100 ml 60% sulfuric acid is stirred for 1*5 hours at 100 to 105°C. Finally, the solution is poured into 300 g of ice and alkalized while cooling at 20 to 25°C

with concentrated ammonia. The secreted base is extracted in portions with a total of 300 ml of chloroform. The mixed extracts are washed with water, dried over sodium sulphate and evaporated in vacuo. The evaporation residue is dissolved in chloroform and absorbed on 250 g of silica gel. It is eluted with chloroform containing 5% methanol. The first

0.6 1 of eluate is discarded and the following 0.8 1 is evaporated separately. The solid evaporation residue is recrystallized in 4 times the amount of isopropanol. In this way, the pure 7-chloro-4-(1-methyl-4-piperidylidene)-4H-benzo[4~,57cyclohepta£T,2-b7"-thiophene-10(9H)-one base is obtained, which melts at 150 to 151° C. The microanalysis agrees with the formula C^gH^gClNOS The structure is determined by the IR, NMR and MS spectra.

The starting product 9(10)-bromo-7-chloro-4-(1-methyl-4-piperidylidene) - 4H-benzo^, 57cycloheptaZT, 2-b7thiophene-base is obtained from 7-chloro-9,10-dihydro- 4H-benzoZ?"/ STcyclohepta/T, 2-b7thioph en-4-one.

In the course of the execution, the following intermediate products are isolated: 7-chloro-9,10^dibromo-9,10-dihydro-4H-benzo^3, SjcyclpheptaZT/ 2-Toph-thiophen-4-one (further processed in an impure state) 9(10 ) -bromo-7-chloro-4H-benzo[4,57cyclohepta<£T, 2-b7thiophen-4-one

(melting point 218 to 220°C)

9(10)-bromo-7-chloro-4-(1-methyl-4-piperidyl)-4H-benzo^3,§7cyclohepta/T", 2-b7thiophen-4-ol base (oily, further processed in impure state)

9 (10)-bromo-7-chloro-4-(1-methyl-4-piperidylidene)-4H-benzo^3", 57-cyclohepta^T", 2-b7thiophene-base (m.p. 147 to 149°C ). EXAMPLE 5: 6-bromo-4-(1-methyl-4-piperidylidene)-4H-benzo</^*, 57"- cyclohepta/1, 2-b^thiophene-10 (9H)-one A mixture of 15 g of 6,9(10)-dibromo-4-(1-methyl-4-piperidylidene)-4H-benzo,/4~ , 5j^cyclohepta/T, 2-b7thiophene-base and 160 ml of 60% sulfuric acid are stirred for 1*5 hours at a room temperature of 100°C. Finally the reaction mixture is diluted with 200 ml of water and alkalized while cooling at 20 to 25°C with concentrated ammonia. The separated base is extracted in portions with a total of 400 ml of toluene. The mixed extracts are washed with water, dried over sodium sulphate and evaporated under vacuum. The evaporation residue is dissolved in chloroform and absorbed on .500 g of silica gel. It is eluted with chloroform containing 2% methanol. The first 2.5 1 of eluate are discarded and the following 2.7 1 are evaporated separately. The solid evaporation residue is recrystallized in 8 times the amount of isopropanol. In this way, the pure 6-bromo-r4-(1-methyl-4-piperidylidene)-4H-benzo^~,57cyclohepta^T,2-b7thiophene-10(9H)-one base is obtained, which melts at 172 to 173°C. The microanalysis agrees with the formula C19H18BrNOS" the structure was determined using the IR and NMR spectra.

The starting product 6,9(10)-dibromo-4-(1-methyl-4-piperidylidene)-4H-benzo ^ T, 5_7cyclohepta^I, 2-b7thiophene base is obtained from 6-bromo-9,10-dihydro- 4H-benzOj/T, 5^cyclohepta^T, 2-b7thioph en-4-one.

In the course of the preparation, the following intermediate products are isolated: 9,10-dihydro-6,9,10-tribromo-4H-benzo/?, 5j7cycloheptaZI, 2-tjTtiofen-4-one

(further processed impure)

6,9 (10)-dibromo-4H-benzo., j£7cyclohepta/T, 2-b7thiophen-4-one

(melting point 177 to 190°C)

6,9(10)-dibromo-4-(1-methyl-4-piperidyl)-4H-benzo^4,57cyclohepta/\,2-b7thiophen-4-ol-base (oily and it is further treated impure)

6,9 (10)-dibromo-4-(1-methyl-4-piperidylidene)-4H-benzo[1,5-7cyclohepta/T,2-b_7]thiophene-base (m.p. 185 to 186°C).

EXAMPLE 6: 4-(3-Dimethylaminopropylidene)-4H-benzo/?, |7

cyclohepta^,2--b7thioph en-10 (9H)_-one

72.2 g of 9(10)-bromo-4-(3-dimethylaminopropylidene)-4H-benzoZ3,57-cyclohepta/T/2-b7thiophene base is dissolved at 50°C in 720 ml of 50% sulfuric acid and the solution is finally stirred for 1Jj hour at 100°C. The reaction mixture is then poured into 1500 ml of water and alkalized while cooling at 20 to 30°C with concentrated caustic soda. The secreted base is extracted in portions with a total of 1500 ml of chloroform. The chloroform phase is washed with water, dried over sodium sulphate and evaporated. As a residue, an oily impure base is obtained. 38 g of this impure base are dissolved in 200 ml of boiling isopropanol and acidified with isopropanolic hydrochloric acid. The crystallized hydrochloride is filtered after standing for several hours at 0 to 5°C and finally recrystallized with the 20-fold amount of isopropanol. In this way, the pure isomeric mixture of 4-(3-dimethylamino-propylidene)-4H-benzo Z4/5-7cyclohepta£T, 2-b/thiophene-10(9H)-one hydrochloride is obtained, which melts under decompression at 212 to 216°C. The microanalysis agrees with the formula C^gH^gNOSoHCl. The structure is determined using the IR and NMR spectra. According to the NMR spectrum, the isomer ratio oe;(3 is approx. 80:20. To prepare the pure α-isomer, 35 g of the oily impure base is dissolved in 350 ml of boiling methanol and mixed with a hot solution of 10.6 g of oxalic acid in 150 ml methanol. The oxalate is filtered off after standing overnight at room temperature, dissolved in 1400 ml boiling methanol, filtered and the filtrate is mixed at room temperature with 1500 ml petroleum ether. The crystallized product is filtered after standing overnight at 0 to 5°C and recrystallized once more times in 1000 ml of methanol and 1000 ml of petroleum ether.In this way the pure oc-isomer is obtained

of 4-(3-dimethylaminopropylidene)-4H-benzo^T,57cyclohepta/r,2-b7thiophene-10(9H)-one-oxalate, which has a decomp. point of 198 to 199°C. The microanalysis agrees with the formula C^gH^gNOS. CjHjO^. From this oxalate, the corresponding hydrochloride is obtained in the following way: 11 g of oxalate is suspended in 100 ml of water and alkalized with 3N caustic soda.

The free base is extracted in portions with 150 ml of chloroform. The chloroform extracts are washed with water, dried over sodium sulphate and evaporated in vacuo. As a residue, an oily ..base is obtained. 8.7 g of this base is dissolved in 80 ml of boiling isopropanol and acidified with isopropanolic hydrochloric acid. The crystallized hydrochloride is filtered off after standing overnight at 0 to 5°C and dried at 70 to 80°C in vacuum. In this way is obtained the pure ct-isomer of 4-(3-dimethylaminopropylidene)-4H-benzo/T,57cyclohepta/T,2-b7thiophene-10(9H)-one hydrochloride, which melts with decomposition at 220 to 221° C. The microanalysis agrees with the formula C^gH^gNOS. HC1. The structure was determined using the IR and NMR spectra.

The starting product 9(10)-bromo-4-(3-dimethylaminopropylidene)-4H-benzo-57cyclohepta/T,2-b7thiophene-base is obtained in the following way: 33 g of magnesium shavings activated with iodine are poured over with 200 ml of absolute tetrahydrofuran and mixed with about. 30 ml of a solution of 217 g of freshly distilled 3-dimethylaminopropyl chloride in 200 ml of absolute tetrahydrofuran. By adding a few drops of 1,2-dibromoethane, the Grignard reaction starts. Now the remainder of the 3-dimethylaminopropyl chloride solution is added dropwise to the magnesium so quickly that the reaction mixture without external heating remains at boiling, After the end of the dropwise addition, the mixture is refluxed for 1% hour, after which the magnesium is completely dissolved. The mixture is now cooled to 10°C and at this temperature a hot solution of 200 g of 9 (10)-bromo-4H-benzo/T,57cyclohepta,/I/ 2-b7thiophene-4- is added dropwise over the course of an hour on in 1000 ml of absolute tetrahydrofuran„ Finally, the mixture is stirred for l^s hour at 15 to 20°Co Then the reaction mixture is poured into a mixture of 1500 g of ice and 200 g of ammonium chloride and extracted once with 500 ml and then three times with 200 ml chloroform» The mixed extracts are washed three times with 100 ml of water, dried over sodium sulphate and evaporated. The solid evaporation residue is recrystallized in 1500 ml of isopropanol. In this way, the pure 9(10)-bromo-4-(3-dimethylaminopropyl)-4H-benzo^,5ycycloheptaZT'2-b7thiophen-4-ol base is obtained, which melts at 127 to 128°C. The microanalysis agrees with the formula C-^gH^BrNOS.

A suspension of 227 g of 9(10)-bromo-4-(3-dimethylaminopropyl)-4H-benzo[T,5j7"cycloheptaZl"# 2-b/thiophene-4-ol in 870 ml of isopropanol is mixed while cooling at 20 °C with 250 ml of 63% aqueous hydrobromic acid. Finally, the mixture is stirred for *j hour at 60°C and then the solution is alkalized while cooling at 20°C by adding 275 ml of concentrated caustic soda. The isopropanol is then distilled off in a vacuum and the resulting aqueous suspension is extracted in portions in a total of 850 ml of chloroform. The mixed chloroform extracts are washed with water,

dried over sodium sulfate and evaporated. As a residue, the oily base is obtained, which is distilled in high vacuum. In this way is obtained the pure 9(10)-bromo-4-(3-dimethylaminopropylidene)-4H-benzo^£",§7cycloheptaZT»2-feT"-thiophene base, which has a boiling point of 168 to 174°C at 0.02 Torr. The microanalysis agrees with the formula C^gH^gBrNS. According to the NMR spectrum

it is a mixture of isomers of a- and P-form (cis/trans isomers). The ratio between a: (3 is about 60:40.

EXAMPLE 7: 7-Methoxy-4-(1-methyl-4-piperidylidene)-4H-benzo^Ti57-_

cyclohepta^^^-bTtiof en-10^9H) -one

A mixture of 8 g of oily 9(10)-bromo-7-methoxy-4-(1-methyl-4-piperidylidene)-4H-benzo/4,57cyclohepta/1'2-b7thiophene base and 250 ml of 60% sulfuric acid stirred for 1*$ hour at 100°C. Finally, the reaction mixture is poured into 600 g of ice, alkalized with concentrated ammonia and the separated base is extracted several times with chloroform. The mixed extracts are washed with water, dried over sodium sulphate and evaporated. The evaporation residue is recrystallized once in five times the amount of ethyl acetate and once in ten times the amount of isopropanol.

In this way, the pure 7-methoxy-4-(1-methyl-4-piperidylidene)-4H-benzo</T,57cyclohepta^,2-b7thiophene-10 (9H)-one base is obtained, which melts at 157 to 158°C. The microanalysis agrees with the formula C^qHjjNC^S.

The structure is determined using the IR, NMR and MS spectra.

The starting product 9(10)-bromo-7-methoxy-4-(1-methyl-4-piperidylidene) - 4H-benzo/4", SjZcyclohepta/T, 2-b7thiophene-base is prepared from 4-methoxyphthalaldehyde acid. In the course of the preparation, the following intermediate products are isolated: 4-methoxy-2-^-(2-thienyl) vinyl/benzoic acid (melting point 170 to 172°C)

4-Methoxy-2-/2-(2-thienyl)ethyl-7-benzoic acid (further processed in impure state)

9,10-dihydro-7-methoxy-4H-benzo/4/§7cyclohepta^J, 2-b2*thiophen-4-one

(further processed in an impure state)

9,10-dibromo-9,10-dihydro-7-methoxy-4H-benzo/4, j^cyclohepta,/!", 2-ib]7-thiophen-4-one (further processed in the impure state)

9 (10)-bromo-7-methoxy-4H-benzo[T,5]cyclohepta[1,2-b]thiophene-4-one

(melting point 182 to 184°C)

9 (10) -bromo-7-methoxy-4-(1-methyl-4-piperidyl)-4H-benzo,/£, §7cyclohepta-/ T,2-b7thiophen-4-ol (further processed in the impure state)

EXAMPLE 8: 6-chloro-4-[3-dimethylaminopropylidene)-4H-henzo/Z>_$ 7-cycloheptaZT", 2-b7thiophen-10(9H)-one

A mixture of 57.8 g of oily 9(10)-bromo-6-chloro-4-(3-dimethylaminopropylidene)-4H-benzo/3,$7cyclohepta(/r/ 2-bJthiophene base and 580 ml of 60% sulfuric acid is stirred for 1 hour at 100° C. Finally, the reaction mixture is poured into 2000 g of ice, alkalized with concentrated caustic soda and the free base is extracted in portions with a total of 700 ml of chloroform. The mixed extracts are washed with water, dried over sodium sulfate and evaporated. The remainder is dissolved in a small amount of chloroform and absorbed on 1000 g of silica gel. It is eluted with chloroform containing 2% methanol. The first 3.5 1 of eluate are discarded and the following 8 1 are evaporated separately. As a residue, an oily base is obtained. To prepare the hydrochloride, dissolve 30 g of this base in 120 ml of boiling isopropanol, which is acidified by the addition of isoproanolic hydrochloric acid and which crystallizes overnight at 0 to 5° C. The salt is finally filtered off and dried "in vacuum at 80° C. In this way, the pure α,β -isomer mixture of 6-chloro-4-(3-dimethylaminopropylides)-4H-bene zo/T, jj7cyclohepta^T, 2-b7thiophene-10(9H)-one hydrochloride, melting at 212 to 214°C. The microanalysis agrees with the formula <C>^<gH>^gClNOS. HC1. The structure is determined using the IR and NMR spectra. According to the NMR spectrum, the isomer ratio a:j3 is approx. 87:13.

The starting product 9(10)-bromo-6-chloro-4(3-dimethylaminopropylidene)-4H-benzo^5,57cycloheptaZI»2-b7thiophene base is prepared from 6-chloro-9,10-dihydro-4H-benzo/4 , 5ycyclohepta/T,2-b7thiophen-4-one.

In the course of the preparation, the following intermediates were isolated: 6-chloro-9,10-dibromo-9,10-dihydro-4H-benzo[4~,5]cyclohept a[T,2-b]thiophene-4-one (decomposes at 147 to 149°C)

9 (10)-bromo-6-chloro-4H-benzo[3,5]cyclohepta^I,2-bithiophene-4-one

(melting point 198 to 200°C)

9 (10)-bromo-6-chloro-4-(3-dimethylaminopropyl)-4H-benzo[4], Jj7cycloheptaZT/2-b7thiophen-4-ol (m.p. 142 to 144°C)

The pure 9(10)-bromo-6-chloro-4-(3-dimethylaminopropylidene)-4H-benzo^,5j7cyclohepta/T,2-b7thiophene base has a boiling point of 191 to 195°C at 0.06 Torr .

EXAMPLE 9: 4-(1-ethyl-4-piperidylidene)-4H-benzo[3], i[7]cyclohepta-.

/\, 2-b7tiof en-10 (9H)_-:on_

A mixture of 10 g of 4-(1-ethyl-4-piperidylidene)-9(10)-bromo-4H-benzo-S/cyclohepta/1,2-b7thiophene base and 100 ml of 50% sulfuric acid is stirred

for 1*5 hours at 100°C. The solution is then cooled to room temperature, diluted with 300 ml of water and alkalized with concentrated ammonia.

The precipitated base is extracted with chloroform. The chloroform solution is washed with water, dried over sodium sulphate and evaporated. The residue is recrystallized in three times the amount of isopropanol. In this way is obtained the pure 4-(1-ethyl-4-piperidylidene)-4H-benzoZ? S/cyclohepta^T, the 2-b7thiophen-10(9H)-one base, which melts at 113 to 115°C (the microanalysis agrees with the formula C^qE^NOS). The structure is determined using the TR and NMR spectra.

The starting product 4-(1-ethyl-4-piperidylidene)-9(10)-bromo-4H-benzo/ ?> 57cyclohepta/1,2-b7thiophene base (melting point 130 to 132°C) is prepared from 9 (10) -bromo-4H-benzo^,5J7cyclohepta^, 2-bithiophene-4-one. At the end of the preparation, 4-(1-ethyl-4-piperidyl)-9(10)-bromo-4H-benzo/T/57cyclohepta/T, 2-bZthiophen-4-ol-base is isolated, which is further processed in an impure state.

EXAMPLE 10 : 4-_(1-isopropyl-4-piperidylidene)-4H-benzo^4jL5_7cyclohepta-Æii-^thiophen-1O^H^-one

The procedure is the same as in example 9, but by application

of the 9 (10)-bromo-4-(1-isopropyl-4-piperidylidene)-4H-benzo/4",57cyclohepta-j/T,2-b7thiophene base as starting product instead of 4-(1-ethyl- 4-piperidylidene)-9(10)-bromo-4H-benzo./4,57cyclohepta^T,2-b_7thiof en-base The title hydrogen fumarate is obtained and this is recrystallized from ethanol and melts at 225 to 226°C with decomposition.

The starting product 9(10)-bromo-4-(1-isopropyl-4-piperidylidene)-4H-benzo/?, 57cyclohepta/T, 2-b7*thiophene-base is obtained from 9(10)-bromo-4H- benzo/2,5-cyclohepta/T,2-b7thiophen-4-one. In the course of the preparation, the 9(10)-bromo-4-(1-isopropyl-4-piperidyl)-4H-benzoyl/?,5/-cyclohepta/1/2-b_7thiophen-4-ol base is isolated, which is further processed in impure state.

EXAMPLE 11: 4-ZT (1-methyl-3-piperidyl^methyl^-4H-benzo^^

/T, 2-b7t iof en-10 OH^-one

A mixture of 54 g of the impure 9(10)-bromo-4-£~(1-methyl-3-piperidyl)-methylene-7-4H-benzo/?,5^cyclohepta/T,2-b_7thiophene-base and 540 ml of 50% sulfuric acid is stirred for 6 hours at 100°C. Finally, the solution is alkalized while cooling at 20 to 30°C with concentrated ammonia and the precipitated base is extracted with chloroform. The chloroform solution is washed with water, dried over sodium sulphate and evaporated. To prepare the hydrogen maleate, 37.7 g of the evaporation residue is dissolved in 280 ml of absolute ethanol and mixed with a hot solution of 14.2 g of maleic acid in 100 ml of absolute ethanol. The salt is filtered off after standing overnight at 0 to 5°C and dried in a vacuum*. In this way, the pure a, (3-isomer mixture of 4-/<_>(l-methyl-3-piperidyl-methylery7-4H-benzo-,/3,57cyclohepta/T~,2-fc7thiophen en-10 ( 9H)-one-hydrogen maleinate, which melts during decomposition at 186 to 188°C. The microanalysis agrees with the formula C2QH21NOS .C4H4O4. According to the NMR spectrum, the isomeric ratio is cc:|3 = 55:45.

The starting product 9 (10)-bromo-4-(1-methyl-3-piperidyl)methylerj7~4H-benzo,/4~,57cyclohepta/1/2-b7thiophene-base is obtained in the following way: To a mixture of 16.7 g of magnesium, activated with iodine, and 70 ml of absolute tetrahydrofuran, 15 g of 3-chloromethyl-1-methylpiperidine are added dropwise. By adding a few drops of 1,2-dibromoethane, the Grignard reaction starts. Finally, 115.3 g of 3-chloromethyl-1-methylpiperidine dissolved in 250 ml of absolute tetrahydrofuran are added dropwise to the magnesium so quickly that the reaction mass continues to reflux without external heating. Finally, the mixture is boiled in IJ5

hour with return. After cooling to lo°C, add drop by drop

in the course of ½ hour a hot solution of 100 g of 9(10)-bromo-4H-benzo/3,57cycloheptaZT,2-b7thiophen-4-one in 500 ml of absolute tetrahydrofuran while cooling at 10 to 15°C. The mixture is then stirred for 15 hours at 10 to 20°C and then poured into 700 g of ice, which contains

80 g of ammonium chloride. The product is extracted with chloroform. After washing the chloroform solution with water, this is dried over sodium sulphate and evaporated. The evaporation residue is recrystallized in 90 times the amount of acetic acid. In this way, the pure 9(10)-bromo-4/7-(1-methyl-3-piperidyl)methyl7-4H-benzoZT, 57cyclohepta/T, 2-b*7thiophen-4-ol base is obtained

which melts at 196 to 208°C. The microanalysis agrees with the formula C20H22BrNOS.

A mixture of 90 g of 9(10)-bromo-4-(1-methyl-3-piperidyl)methyl7-4H-benzo-3'57cyclohepta/T/2-b7thiophen-4-ol base, 400 ml of isopropanol and 160 ml

63% aqueous hydrobromic acid is stirred for Jg hour at 60°C. The solution is then alkalized while cooling at 20 to 25°C with concentrated caustic soda. After evaporation of the isopropanol, the free base is extracted with chloroform. The chloroform solution is washed with water, dried over sodium sulphate and evaporated. As a residue, the impure, oily 9 (10)-bromo-4-^T (1-methyl-3-piperidyl) methyl T74H-benzo/3/§7cyclohepta-ZX,2-b7thiophene base is obtained, which is directly further processed.

EXAMPLE 12: 4-[2=(1-methyl-2-pyrrolidyl)ethylidenej-4H-b^nzo/4\ §7-cyclohe<p>ta/<1,>2-b7thiophen-10(9H)-one

A mixture of 40 g of 9(10)-bromo-4-(2-(1-methyl-2-pyrrolidyl)-ethylidegT-4H-benzo/?,5^cyclohepta/1,2-b7thiophene base and 400 ml of 50 % sulfuric acid is stirred for 2 hours at 100°C. Finally, the solution is alkalized while cooling at 20 to 30°C with concentrated ammonia and the separated base is extracted with chloroform. The chloroform solution is washed with water, dried with sodium sulphate and evaporated. To prepare the hydrochloride, dissolve 25 g of the evaporation residue in 75 ml of isopropanol and acidify with isopropanolic hydrochloric acid. The salt is filtered off after standing overnight at 0 to 5°C and finally dried at 80°C in a vacuum. In this way, the pure oc-ros isomer mixture of 4-(2-(1-methyl-2-pyrrolidyl)-ethylidene-7-4H-benzo/4/57cyclohepta/1,2-b7thiophen-10(9H)-one- hydrochloride, melting at 218 to 220°C. The microanalysis agrees with the formula C20H21NOS * HC1* 1 f°l9e The NMR spectrum is the isomer ratio oc:|3 = 60 : 40.

The starting product 9 (10)-bromo-4-(2-(1-methyl-2-pyrrolidyl)ethylidene74H-benzo/T, 57"cyclohepta/I, 2-b7thiophene base is obtained in the following way: To a mixture of 16, 7 g of magnesium, activated with iodine, and 100 ml of absolute tetrahydrofuran are added dropwise to 10 g of 2-(2-chloroethyl)-1-methylpyrrolidine.Adding a few drops of 1,2-dibromoethane starts the Grignard reaction, finally adding dropwise 121, 8 g of 1-(2-chloroethyl)-1-methyl-pyrrolidine' dissolved in 100 ml absolute tetrahydrofuran to magnesium so quickly that the reaction mass without external heating is maintained by refluxing. Finally, the mixture is refluxed for 1% hour. After cooling to 10°C, a hot solution of 100 g of 9 (10)-bromo-4H-benzo/4~, 5_7cyclohepta/1, 2-b~/thiophene^S, 57cyclohepta/T, 2 is added dropwise over the course of % hour -&7-thiophen-4-one in 500 ml absolute tetrahydrofuran while cooling at 10 to 15° C. Then stir for 1% hour at 10 to 20° C. and the reaction mixture is poured over 700 g of ice, containing 80 g of ammonium chloride. et, is extracted with chloroform. After washing the chloroform solution with water, it is dried over sodium sulfate and evaporated. /?,57cyclohepta/T, 2-b/thiophen-4-ol base, which is directly further processed.

A mixture of 150 g of 9(10)-bromo-4-ZJ-(1-methyl-2-pyrrolidyl)ethylideneT-4H-benzo/4~,57cycloheptaZl,2-b_7thiophen-4-ol-base, 600 ml of isopropanol and 150 ml of 63% aqueous hydrobromic acid are boiled for h hour with reflux.

Finally, the solution is alkalized while cooling at 20 to 25°C

with concentrated caustic soda. After evaporation of the isopropanol, the free base is extracted with chloroform. The chloroform solution is washed with water,

dried over sodium sulfate and evaporated. The evaporation residue is distilled in high vacuum. In this way is obtained the pure, oily 9(10)-bromo-4-^-(1-methyl-2-pyrrolidyl)ethylidene7-4H-benzo/?,5J7-cyclohepta/T,2-b7thiophene base, which boils between 180 to 186°C at 0.01 Torr. The microanalysis agrees with the formula C^Q^QBrNS.

EXAMPLE 13: 4-(l-n-butyl-4-piperidylidene)-4H-benzo</3,5ycyclohepta-Æ-^Z^thiophene-1O^H^-o^

Proceeding in the same way as in example 9, merl by application

of 9(10)-bromo-4-(l-n-butyl-4-piperidylidene)-4H-benzo[3",57cyclohepta/T,2-b7thiophene base as starting product, instead of 4-(l-ethyl-4 -piperidylidene)-9(10)-bromo-4H-benzo/3,5/cyclohepta/1,2-b7thiophene base The pure title compound melts at 104 to 105°C

(from isopropanol).

The starting product 9(10)-bromo-4-(1-n-butyl-4-piperidylidene)-4H-benzo-S/cyclohepta/1,2-b7thiophene base is obtained from 9(10)-bromo-4H-benzo-57cyclohepta /T, 2-b7thiophen-4-one. In the course of the preparation, 9 (10)-bromo-4-(1-n-butyl-4-piperidyl)-4H-benzo/?, S/cyclohepta/T, 2- Td/thiophen-4-ol base is isolated, which is further processed in unclean condition.,

EXAMPLE 14: 4-(1-methyl-4-piperidylidene)-4H-benzo[i],57cycloheptaZI,2-b7thiophen-10(9H)-one

By proceeding in the same way as in example 9, mén by application

of 9(10)-bromo-4-(l-meth<y>l-4-<p>i<p>erid<y>lidene)-4H-benzo/5,5<7>cyclohepta/T,2 -b7thiophene base, instead of 4-(1-ethyl-4-piperidylidene)-9(10)-bromo-4H-benzo/4,5_7cycloheptaZl, 2-b7thiophene base as starting product and with 25% instead of 50% sulfuric acid. After 15 hours of heating, the compound mentioned in the title is obtained with a melting point of 152 to 153°C.

EXAMPLE 15: 4-(1-Methyl-4-piperidylidene)-^H-benzo/?^5_7cyclohepta-Al2=b7thiophene-10^9H)_;;one

By proceeding in the same way as described in example 14, but using a 50% methanesulphonic acid instead of 50% sulfuric acid, the compound mentioned in the title with a melting point of 152 to 153°C is obtained after 3 hours of heating.

EXAMPLE 16: 4-(1-methyl-4-piperidylidene)-4H-benzoZ?,57cyclohepta-£i,2-bithiophene-10_(9H)_-one

By proceeding in the same way as described in example 14, but using a 50% toluenesulfonic acid instead of 25% sulfuric acid, the compound mentioned in the title with a melting point of 152 to 153°C is obtained after 15 hours of heating.

EXAMPLE 17: 4-(1-methyl-4-piperidylidene)-4H-benzo[4",5-7cyclohepta[T,2-b7thiophen-10<9H)-one

By proceeding in the same way as described in example 14, but using an 18% hydrochloric acid instead of 25% sulfuric acid, after 3 hours of heating the compound mentioned in the title is obtained - with a melting point of 152 to 153°C.

EXAMPLE 18: 4-(1-methyl-4-piperidylidene)-4H-benzo[4,57c<y>chlohe<p>t a-Æ^z^thiophen-10 j9H)_-one

By proceeding in the same way as described in example 14, but by using a 63% hydrobromic acid instead of a 25% sulfuric acid • the compound mentioned in the title is obtained after waiting for 1 hour

•with a melting point of 152 to 153°C.

EXAMPLE 19: 4-(1-methyl-4-piperidylidene)-^H-benzo/^^cycloheptaZT' 5lSZti2ÉeI}liC1 (9H)_--one

By proceeding in the same way as described in example 14, but using a 30% hydrobromic acid instead of a 25% sulfuric acid, the compound mentioned in the title is obtained after 15 hours of heating. melting point. 152 to...153 oC.

EXAMPLE 20: 4-(1-methyl-4-piperidylidene)-4H-benzo[5,5]cycloheptaZT, 2-b7thiophen-10(9H)-one

By proceeding in the same way as described in example 14, but by using a 40% phosphoric acid instead of a 25% sulfuric acid, the compound mentioned in the title with a melting point of 152 to 153°C is obtained after 15 hours of heating.

EXAMPLE 21: A-{1-methyl-4-piperidylidene)-4H-benzoZ? /S/cyclohepta-^J, 2-b7thiophene-10 (9H)_-one

By proceeding in the same manner as described in Example 14, but using a 50% trifluoroacetic acid instead of a 25%

sulfuric acid, after 15 hours of heating to 120°C the aforementioned compound with a melting point of 152 to 153°C is obtained.

EXAMPLE 22: 4-[1-methyl-4-piperidylidene)-4H-benzo[4], 5[cyclohepta-_

Sl' 2zÉ7ti2Éenzi212Slz2n

By proceeding in the same way as described in example 14, but using a 50% trichloroacetic acid instead of 25% sulfuric acid, the aforementioned compound with a melting point of 152 to 153°C is obtained after 15 hours of heating to 100°C.

EXAMPLE 23: f-jl-methyl-4-piperidylidene-4H-benzo[3,57cyclohepta-^T,2-b7thiophen-10(9H)-one

By proceeding in the same way as described in Example 14, but using per mole of 9(10)-bromo-4-(1-methyl-4-piperidylidene)-4H-benzo[¥.57"cyclohepta/r, 2-b7tiof en-base one mole of sulfuric acid in a 20 times larger quantity of water, instead of a 25% sulfuric acid, after 6 hours of heating to 230°C at 20 atmospheres the mentioned compound with a melting point of 152 to 153°C is obtained.

EXAMPLE 24: 4-(1-methyl-4-piperidylidene)-4H-benzoZJi57cyclohepta-ZT/2-b7thiophene-10(9H)-one

By proceeding in the same way as described in example 23, but using per mole of 9(10)-bromo-4-(1-methyl-4-piperidylidene)-4H-benzo/T, 57"cyclohepta^T, 2-b7tiof en-base Jj mol of sulfuric acid in a 20 times greater amount of water is obtained after 6 hours of heating

to 230°C at 20 atmospheres the said compound with melting point 152 to 153°C.

EXAMPLE 25: 4-(1-methyl-4-piperidylidene)-4H-benzoZJ, 5<Z>cycloheptaZT, 2-b7thiophene-10(9H)-one

.. By proceeding in the same way as described in examples 14 to 24,

.but using 9(10)-chloro-4-(1-methyl-4-piperidylidene)-4H-benzo/4,S^cyclohepta/T,2-bithiophene base instead of 9(10)-bromo -4-(1-methyl-4-piperidylidene)-4H-benzo/4,57cyclohepta/T,2-b7thiophene base, the aforementioned compound with melting point 152 to 153°C is obtained.

The starting product 9(10)-chloro-4-(1-methyl-4-piperidylidene)-4H-benzo/?,_57cycloheptaZT/ 2-b7thiophene-base (m.p. 150 to 152°C)

bpp is obtained from 4H-benzo/?, 5β?cyclohepta/I, 2-b/thiophen-4-one.

In the course of the preparation, the following intermediate products are isolated: 9,10-dichloro-9,10-dihydro-4H-benzb/?, 57cycloheptaZI, 2-bJ7thiophen-4-one

(further processed in an impure state)

9 (10)-chloro-4H-benzo/?, 57cycloheptaZT, 2-b7thiophene-4-one

(melting point 124 to 126°C)

9 (10)-chloro-4-(1-methylpiperidyl)-4H-benzoZJ,J^cycloheptaZI, 2-b/- thiophen-4-ol (further processed in the impure state)

EXAMPLE 26: 4-N-Methyl-4-piperidylidene)-4H-benzo[beta],5^cyclohepta-£T,2-b]7thiophene-10(9H)_-one

By proceeding in the same way as described in example 14, but by

using a mixture of 50% sulfuric acid with n-butanol (in a weight ratio of 1:2), instead of 25% sulfuric acid, the aforementioned compound with a melting point of 152 to 153°C is obtained after 16 hours of heating to 100°C.

Claims (1)

Process for the preparation of 4-substituted 4H-benzo/?,jJ/cycloheptaj/T, 2-b7thiophene-10 (9H)-one derivatives of formula I in which R1 stands for hydrogen, halogen or a lower alkoxy group, R2 means hydrogen R 3 and R^ each stand for hydrogen or a methyl group and Rg either stands for lower alkyl or forms together with R2 a ethylene chain or together with R^ an ethylene or trimethylene chain or together with R4 a trimethylene or tetramethylene chain and Rg means a lower alkyl group, and acid addition salts thereof, characterized in that a compound of formula II or III in which R^, R^ .