SU512709A3 - Method for preparing benzopyran derivatives - Google Patents

Description

The method is based on the holune derivatives known in organic synthesis, for example, by condensation of the corresponding acetophenone derivatives.

The proposed method is that the compound of formula II

R5

L ii

I

R,

Bg

where iRs, Re, R and Rs are as defined above and

AI and A2 are pairs of -COCHsCOCOR and -OM or H and -OC (COOM) CH-COOM groups

in which R means a group-O or a group that forms-O as a result of hydrolysis, and M is a hydrogen atom or an alkali metal,

cyclized and isolate the product or translate it into a compound of formula I; or a compound of formula I is converted into its functional derivative by conventional methods.

The cyclization is usually carried out in the presence of an acid in a solvent inert under the reaction conditions, although it can also be carried out in a basic or neutral medium.

For example, cyclization is carried out in the presence of hydrochloric acid in ethanol.

The reaction can be carried out at a temperature of 20-150 ° C. Preferably, the group —COR means an ester group, for example, R means a lower alkoxy group.

The cyclization can be accomplished by treating the corresponding compound of formula II with a cyclizing agent, for example a dehydrating agent, such as chlorsulfonic, polyphosphoric or sulfuric acid. The reaction is carried out preferably in an anhydrous medium at a temperature from 0 to 100 ° C. The cyclization can be accomplished by converting the free carboxyl groups of the compound of formula II into haloacyl groups, which are then subjected to an intramolecular Friedel-Crafts reaction.

Functional derivatives of the compound of formula I are salts, esters and amides. Salts include ammonium, alkali metal, e.g. sodium, potassium, lithium, alkaline earth metal, e.g. calcium or magnesium salts, as well as organic base salts, nitrile lower alkylamines, such as methylamine or ethylamine, substituted lower alkylamines, e.g. oxy substituted alkyl amines, or salts of simple monocyclic nitrogen-containing or heterocyclic compounds, for example, piperidine or morpholine. Esters are lower alkyl esters, esters derived from alcohols containing basic groups, for example, di-lower alkylamino-substituted alkanols, and acyloxyalkyl esters, for example, lower acyl or alkyl ester, or diester, obtained from dioxo compounds, for example di (oxyply, alkyl) ester.

In the examples below, methods are described for the preparation of both target products and their functional derivatives, as well as starting products.

Example 8. Allyl - 5- (2-hydroxypropoxy) 4-oxo - 4H - 1 - beisopyran - 2 - carboxylic acid.

A. 3-Allyl - 2 - hydroxy-6- (2-hydroxypropoxy) acetophenone.

Mixture 58 wt. including 3-allyl-2,6-dioxyacetophenone, 22.5 weight. including propylene oxide and 0.25 weight. including 40% aqueous solution of benzyltrimethylammonium hydroxide in 70 weight. hours of dioxane is heated in a closed vessel at 100 ° C for

20 hours The mixture is cooled, the vessel is opened and the dioxap is evaporated. In the distillation of residual oil receive 33 weight. including 3-allyl-2-hydroxy-6- (2-hydroxypropoxy) acetophenone with a boiling point of 158-168 ° C at

pressure of 0.5-1.0 mm Hg. Art. and melting point 45-51 ° C.

Found,%: C 67.1; H 7.20.

Cl4Hi8O4.

Calculated,%: C 67.2; H 7.20.

B. A solution of 50 parts of 3-allyl-2-hydroxy-6- (2-oxypropoxy) -acetophenone in 75 parts of diethyl oxalate is added to a stirred solution of sodium ethylate prepared by dissolving 18.5 parts of sodium in 320 parts

ethanol. The mixture was stirred and heated in a steam bath for 3.5 hours, then most of the ethanol was evaporated, the residue was diluted with 1000 parts of water and washed with ether. The aqueous solution is acidified.

concentrated hydrochloric acid and then extracted with 3 portions of 250 parts of chloroform. After evaporation of the chloroform extract, the residue is refluxed for 30 minutes with 320 parts

ethanol and 5 parts of concentrated hydrochloric acid. The mixture is evaporated and the residue is stirred with 60 parts of ether until a solid precipitates, which is filtered off, dissolved in a solution of bicarbonate.

and precipitated again after acidification. The crude product is then dissolved in a mixture of 9: 1 ether and gasoline (m.p. 40-60 ° C), from which 7.4 parts of 8-allyl-5- (2-hydroxypropoxy) - 4-oxo-4H-1-benzopyran-2 - carboxylic

acids with a melting point of 75-80 ° C.

Found,%: C 60.9; H 5.46 (mol. Weight 340).

C1bN, bb-1 / 2H20.

Calculated,%: C, 61.3; H 5.43. Mol weight 304.

B. Sodium salt of 8-allyl-5- (2-hydroxypropoxy) -4-oxo-4H-1-bezopyran-2-carboxylic acid. A solution of 1.7 parts of 8-allyl-5- (2-hydroxypropoxy) -4-oxo-4H-1-benzopyran-2-carboxylic acid hemihydrate is prepared.

0,42 parts of sodium bicarbonate in 25 parts

water. The resulting solution is filtered and freeze dried. Obtain 1.8 parts of the sodium salt of 8 - allyl - 5 - (2-hydroxyroxyn) - 4 - oxo - 4H-1-beisoieran-2 - carboxylic acid.

Example 2. 6.8 - di-t / er. Butyl-4-oxo4H-1-benzoirane-2-carboxylic acid.

A. 6,8-D, and-tert. - butyl-4-oxo-4H-1-benzopyran-2-carboxylic acid. A mixture of 5 parts of 2,4-di-g; 7g. - butylphenol, 3.55 parts of dimethyl ester of acetylene carbonic acid and four caiele of beisyltrimethylammonium hydroxide are heated in a steam bath for 20 minutes. The resulting dimethyl ester of 2,4 - di - tert. - butylfeioxy fumaric acid is hydrolyzed by heating with 2.8 parts of caustic soda in 15 vol. including water and 8 vol. including methanol. The hydrolysis is complete when one layer is obtained. The methanol is evaporated, the solution is cooled and acidified with concentrated hydrochloric acid. Raw 2.4 - di - tert. - butylphenoxyfumaric nslot was isolated as an oil and extracted with ether. This acid is purified by extraction with sodium bicarbonate solution, previously washed with ether. As a result of the acidification of the sodium bicarbonate solution, purified fumaric acid is obtained, which is again extracted with ether. The dried ethereal extracts are evaporated to give fumaric acid as an oil.

Di - gret.-butylphenoxyfumaric acid is cyclized by careful addition of 11 vol. including chlorosulfonic acid at 5 ° C. The mixture was incubated for 20 minutes at room temperature and then poured onto water. The cured product is washed well with petroleum ether (bp. 40-60 ° C), then crystallized from aqueous ethanol and 2.8 parts of 6.8-di-treg-butyl-4-oxo-4H-1benzopyran-2- are added. carboxylic acid with a melting point of 230-232 ° C.

Found,%: C 71.4; H 7.42.

Cl8H2204.

Calculated,%: C 71.5; H 7.33.

B. Natrium salt 6,8-di-g / 7g. - butyl-4-oxO-4H-1 - benzonir - 2 - carboxylic acid. To 5.5 parts of 6.8 di greg. - butyl - 4-oxo4H-1-benzopyran-2-carboxylic acid, 1.4 parts of sodium bicarbonate are added in 150 vol. h of water. The mixture is slightly heated on the steam bath until almost all the acid is dissolved. The neutral solution is filtered and freeze dried. The sodium salt of 6,8-di-greg is obtained. - butyl - 4-oxo-4H-1-benzopyran-2-carboxylic acid.

Example. 3

A. Piperidine salt 6,8 - di - tert. - BUTYL-4-OXO-4N-1 - Benzopyran - 2 - carboxylic acid. A solution of 5.0 parts of 6.8-di-g / 7 (t-butyl-4-OXO-4H-1-benzoniran-2-carboxylic acid in 1.7 parts of pyeridine and 50 parts of water is filtered and freeze-dried. The resulting pale yellow powder is washed with hot chain ether.

(t. Kip. 60-80 ° C) and get 5.6 parts of the iperidine salt 6,8-di - tert. - butyl - 4-oxo4H-1-benzoniran-2 - carboxylic acid in the form of a colorless powder with melting point (with decomposition) of 191-194 ° C. Found,%: C 71.5; H 8.65; N 3.57.

C23H33NO4.

Calculated,%: C 71.29; H 8.58; N 3.61. The result of spectral analysis. NMR shows the 3-nroton of the benzonranic ring as a singlet at 3.23 tons, and broad signals at 7.05 tons and 8.69 tons were attributed to the nrotons of the piperidine ring (solvent is deuterium oxide).

B. Ethylamine salt 6,8 - di - tert. - butyl - 4 - oxo - 4H - 1 - benzopyran - 2 - carboxylic acid. 5.0 parts of 6.8-day-l / t butyl-4-oxo-4H-1-benzopyran-2-carboxylic acid is added to the mixture of 1.5 parts

70% aqueous ethylamine and 50 parts of water. The resulting pale yellow solution is filtered and the dried faded nvannem. The resulting solid is tromped with ether and 5.3 parts of ethylamine salt 6.8 - di - tert are obtained. - butyl - 4 - oxo4N-1-benzopnran - 2 - carboxylic acid in the interior of a colorless and powder with a temperature of melting (with decomposition) of 205-206 ° С. Found,%: C 69.2; H 8.72; N 3.74.

C9H29NO4.

Calculated,%: C 69.13; H 8.41; N 4.03.

The result of seectral analysis. 3 - orozoi of the benzonranic ring for NMR singlet at 3.20 t, and the N-ethyl group gives a quartet of iri 7.00 t and a triplet of iri 8.80 g (deuterium oxide).

Example 4. 6 - Allyl - 5 - hydroxy - 4 - oxo4H-1-benzopyry - 2 - carboxylic acid.

A. 2 - Allnloxy - 6-oxyacetophenone. A mixture of 15.2 parts of 2.6-dioxyacetopheion, 12.1 parts of allylbromnd and 13.8 parts of potassium carbonate in 100 parts of acetone is stirred and boiled with an inverse fridge during

7 o'clock The acetone is evaporated and water, dilute hydrochloric acid and ether are added. The ether layer is separated, dried and evaporated to a yellow oil. This oil is not distilled. H collect the fraction that is dried at a temperature of 128-132 ° C at a pressure of 0.15 mm Hg. Art.

Chromatography of a thin layer indicates that a mixture of product and starting material is formed. Mixture and Chromatography

on alumina oxide with the use of ether as a scrubbing medium. After evaporation of the reflux, a yellow solid is obtained which is crystallized from non-ether ether. Obtain 10.0 parts of 2 - allyloxy-6oxnacetophenone in the form of yellow needles with a melting point of 45.5- 46 5 ° C

Found,%: C 68.4; H 5.95. CnHj Os.

Calcd.,%: C, 68.73; H 6.29.

nineteen

3 - ethyl - 6 - tetrahydrofurfuryloxy - 2-oxyacetophenone as an orange oil.

B. 3,5 - Diallyl - 2-oxyacetophenone. A mixture of 57.5 parts of 2 - allyloxy - 3 - allylacetophenone and 45 parts of diethylanilnium is heated in a sand bath for 4 hours at a temperature of 220 ° C. After cooling, the reaction mixture is poured into excess dilute hydrochloric acid and extracted with diethyl ether. The extract is evaporated and a red oil is obtained, the distillation of which under vacuum gives 54 parts of 3,5 - diallyl - 2 - hydroxy. Acetophenone with a boiling point of 100-120 ° C at a pressure of 1.2 mm Hg. Art.

Example 21. Hydrochloride 2 - dimethyl: ammoniaoprop - 2 - 8-sulphate of ether - allyl-5- (3methyl - n - butoxy) -4-oxo-4H-1 - bezopyrapa2 - carboxylic acid.

To a suspension of 6.76 parts of sodium solp 8 - allyl - 5 - (3 - methyl n-butoxy) - 4 - oxo4P-1 - benzopyran - 2 - carboxylic acid in 5.4 parts of dry benzene, 5.42 parts of 2 - chlorine - 2 - dimethylaminomethylpropane. The mixture is heated under reflux for 10 hours, cooled and filtered. The filtrate is evaporated to an oil, which is dissolved in diethyl ether. The ether solution is filtered and evaporated to obtain an oil, which is then maintained at a temperature of 100 ° C. Iodine vacuum for 6 hours. After the oil is dissolved in ether, an excess ethereal solution of hydrogen chloride is added to it. The resulting solid is 4 parts of 2-dimethylaminomethyl-propyl-2-yl ester of 8-allnl-5- (3-methyl-n-butoxy) -4-oxo-4P-1-benzopyra-2-carboxylic acid hydrochloride hydrochloride. After washing with effromp of crystallization from benzene, the product is a white solid with a melting point of 183-184 ° C.

Paideio,%: C, 61.75; H 8.04; N 2.82.

C24H34C1N05-H20.

Calculated,%: C, 61.4; P 7.67; N 2.98.

Example 22. 6.8 - Di - t-butyl-4-oxO-4H-1 - Beisopyrap - 2 - Carboic Acid.

A solution of 2.72 parts of 6.8 - di - tert - butyl2-methyl-4-oxo - 4H - 1 - beisopyran and 4.44 parts of selenium dioxide in a mixture of 60 parts of water and 250 parts of dioxane is heated at a slight reflux for 12 hours . After cooling, the solution is filtered and the solvent is evaporated. The residue obtained is dissolved in 250 parts by volume of chloroform and this solution is extracted with three portions (100 parts each) of a solution containing 5 parts of sodium bicarbonate in 100 parts of water. The washings from all washes are combined and acidified with concentrated hydrochloric acid. The resulting solid is crystallized from aqueous ethanol and 6.8-di-tert-butyl-4-oxo-4H-1-benzopyran-2-car 512709 is obtained.

512709

20

boom acid with a melting point of 230-223 ° C.

EXAMPLE 23 6.8 - Diethyl - 5 - hydroxy-4-oxo4H-1 - benzoiran - 2 - carboxylic acid. A mixture of 43.2 parts of 3,5-diethyl -2,6-dioxyacetophenone, 30 parts of methyl iodide, 15.2 parts of anhydrous potassium carbonate, and 300 parts of acetone is heated under reflux for two days. After cooling, the reaction mixture is filtered and the volatile components of the filtrate are removed by evaporation. Chromatography of the residue on silica gel, while extracting 4: 1 and 2: 1 light gasoline with ether, gives 32 parts of 3,5-diethyl -2 - hydroxy - 6 - methoxy acetophenone as an oil.

The results of the spectral analysis. Molecular weight 222 (determined by mass spectroscopy). For CisHisOs, molecular weight

222.

B. 6.8 - Diethyl - 5 - methoxy-4-OXO-4H-1benzoppran - 2 - carboxylic acid. A solution of 13.8 parts of sodium in 300 parts of ethanol is added with stirring to the solution

32 parts of 3,5 - diethyl 2 - hydroxy - 6 - methoxy acetophenone P 99 parts diethyl oxalate in 300 parts of ether. The reaction mixture was stirred at room temperature for 2 to 1/2 hours and then poured into a stirred mixture of 100 parts of chloroform, 300 parts of water and 60 parts of concentrated hydrochloric acid. The chloroform layer is separated and the solvent is removed by evaporation. The resulting oil was refluxed with a 95% ethanol solution containing concentrated sulfuric acid for four hours. After evaporation of the ethanol, a residue is obtained, which is refluxed for one hour with an excess of sodium bicarbonate solution. After cooling, the mixture is acidified with concentrated hydrochloric acid and extracted with chloroform. The chloroform is evaporated, the resulting residue is triturated with a light gasoline. 17.6 parts of 6.8 - dipethyl - 5 - methoxy - 4 - oxo-4H-1benzopyran - 2 - carboxylic acid are obtained with a melting point of 199-200 ° C (after crystallization from a mixture of chloroform and light gasoline).

Found,%: C 64.4; H 5.9.

CisHieOs.

Calculated,%: C 65.2; H 5.8.

The result of spectral analysis.

Molecular weight 276 (determined by mass spectroscopy). For CjeHieOs, the molecular weight is 276.

B. 6.8 - Diethyl - 5 - hydroxy - 4-oxo-4H-1-benzonrane - 2 - carboxylic acid. A mixture of 5 parts of 6.8 - diethyl - 5 - methoxy - 4-oxo-4H-1benzopyran-2-carboxylic acid and 130 parts of 48% aqueous hydrobromic acid was refluxed for seven hours. Reaction mixture

cooled n add excess solution

21

sodium bicarbonate. The solution is acidified with concentrated hydrochloric acid and extracted with chloroform. The residue was evaporated from chloroform and triturated with light gasoline to obtain 2.3 parts of 6.8-diethyl-5oxy-4-oxo-4H-1 benzopyran-2-carboxylic acid with a melting point of 218-220 ° C (crystallization from ethanol) . Found,%: C 63.8; H 5.6.

Ci4Hi405.

Calculated%: C 64.1; H 5.3.

The result of spectral analysis. Molecular weight 262 (determined by mass spectroscopy). Molecular weight is 262 for CHiaoIz.

Example 24. 5 - (/ g-hexyloxy) - 4 - oxo4H-1 - benzopyran - 2 - carboxylic acid.

A mixture of 23.4 parts of 5 - hydroxy - 4 - oxo-4H-1benzopyran - 2 - carboxylate, 200 parts of hexyl iodide, 11.65 parts of anhydrous potassium carbonate and 500 parts of acetone is heated under reflux for 13 days. After cooling, the reaction mixture was filtered and the acetone was removed from the filtrate by vacuum distillation, the residue was dissolved in chloroform, the chloroform extract was washed with cold 1N. an aqueous solution of sodium hydroxide, then with water and evaporated.

The oily residue is heated under reflux with an aqueous solution of sodium bicarbonate for 2 hours. After cooling, the solution is extracted with chloroform and the aqueous layer is separated. The aqueous phase is acidified with 2N hydrochloric acid and the mixture is extracted with chloroform. After evaporation of chloroform, 5- (p-hexyloxy) -4-oxo-4H1-benzopyran-2-carboxylic acid with m.p. 156.5-157.5 ° C.

Claims (3)

1. A method of producing benzoniran derivatives of the formula I soon where Rs is a hydrogen atom, oxygrunn or a group -ORs, Rs is a straight or branched hydrocarbon group which is either saturated or ethylenically unsaturated, which may be substituted with oxygrutine or five- or six-membered oxygen-containing heterocyclic ring, and Rs, together with other substituents, contains 3-8 carbon atoms; Re - hydrogen atom, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, lly phenyl; Rr is a hydrogen atom or a (lower alkoxy) lower alkoxy group; 22 RS is a hydrogen atom, alkyl with 1-6 atoms II with 2-6 carbon atoms or alkenele of the genus; and: Rg does not mean propyl, when RS is an oxynropoxy group; Re does not mean ethyl when the R5-6yT-3-eHOKCH group; two or three of the radicals Rs, Re, R and Rs do not mean a hydrogen atom in those cases where a) Rg is an alknl or an alkenyl with a straight chain with 5-7 carbon atoms or an alkyl alkenyl with a branched chain with 6-8 atoms carbon, or b) Re is phenyl, the radicals Re, Ry and Rs, or one or two of them, do not mean a hydrogen atom; Re and Rg are both ethyl or both secondary butyl, when RS does not mean a hydrogen atom; Re is alkyl with 4-6 carbon atoms, when R is (lower alkoxy) -nizia alkoxy group; at least one of the radicals Re and Rs contains two or more carbon atoms, when RS is a hydrogen atom or an oxigruine; or their functional derivatives, characterized in that the compound of the formula P P thirty where RS, Re, R and Rs are as defined above, and AI and A2 represent the bunks of the -COCHaCOCOR and -OM or -H and -OC (COOM) CH-COOM groups, in which R means the group -OM or the group forming -OM in the hydrolysis solution and M, a hydrogen or alkali metal atom, is cyclized and the product is isolated or converted into the compound of formula I, or the compound of formula I is converted into its functional derivative by conventional methods. 2. A method according to claim 1, characterized in that the cyclization is carried out in the presence of an acid in a solvent inert under the reaction conditions. 3. The method according to claim 1, characterized in that the cyclization is carried out in the presence of a dehydrating agent in an anhydrous medium. Prioritt by features: 08.23.70: RS is a hydrogen atom of hydroxy, hydroxyproxy, or 3-methyl-n-butoxy; Re is a hydrogen atom or an alkyl or alkeyl with 2-6 carbon atoms; R is a hydrogen atom or (lower alkoxy) and a lower alkoxy group; RS is a hydrogen atom or an alkyl or alkenyl with 2-6 carbon atoms, except for n-propyl; moreover, Rs is alkenyl, when Rs is hydroxypropoxy, and two or three of the radicals Rs, Ry, R and Rs do not mean a hydrogen atom, beyond is23 Including the case when Rs is a 3-methyl-n-butoxy group. 11.12.70: Kb - branched alkoxngroup with 5-8 carbon atoms or tetrahydrofurfuryloxy group; Re is a hydrogen atom or an alkyl or alkenyl with 2-6 carbon atoms; R is a hydrogen atom or a (lower alkoxy) lower alkoxy group; Rs is hydrogen or alkyl or alkenyl with 2-6 carbon atoms, except for m-propyl; moreover, two or three of the radicals Rs, Re, R and RS do not mean a hydrogen atom, with the exception of the case when Rs is alkoxy-branched chain with 5-8 carbon atoms, then one, two or three of Rs, Re, R and Rs may not represent a hydrogen atom; Rs and RS are ethyl when Rs is hydroxy; 03.06.71: RS is a hydrogen atom, hydroxy group or -ORs group, where Rs is a straight or branched ethylene bond saturated or unsaturated hydrocarbon group with 3-8 carbon atoms, unsubstituted or substituted with oxygranyl or five-membered or six-membered oxygen-containing heterocyclic ring; 24 Re - hydrogen atom, alkyl with 1-b carbon atoms or alkenyl with 2-6 carbon atoms; R is a hydrogen atom or a (lower alkoxy) lower alkoxyl; RS is a hydrogen atom, alkyl with 1-6 carbon atoms or alkenyl with 2-6 carbon atoms; moreover, RS cannot mean ethyl when RS is a but-3-enoxyl group; RS is alkenyl when Rs is an oxnproxy group; two or three of the radicals Rs, Re, R and RS do not mean a hydrogen atom, except for the case when Rs is an alkyl or alkenele with a straight chain with 5-8 carbon atoms or alkenyl with a branched chain with 6-8 carbon atoms, Re, R n Rs, or one or two of them, do not mean a hydrogen atom; Re and RS both are ethnl nli both are secondary butyl when the radical Rs does not surround a hydrogen atom; Re is alkyl with 4-6 carbon atoms, when Ry is (lower alkoxy) - lower alkoxy; at least one of the radicals Re and Rs contains two nly more carbon atoms, when Rs is a hydrogen or oxygrine atom. Compiled by 3. Latypova Editor L. Gerasimova Tehred 3. Taranenko Proofreaders L. Kotova and O. Tyurina Order 2540 / 4Exc. № 1808 Draw 575 Subscription TSNIIPI State Committee of the Council of Ministers of the USSR for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5 Printing house, Sapunova Ave., 2 Date: 03/08/2001 Number of pages: 4 Previous document: SU 512709 Next Document: SU 512711 DESCRIPTION OF THE INVENTION TO PATENT (61) Complementary to the patent - (22) Submitted 17.10.74 (21) 1959356 / / 2067161 / 23-4 (23) Priority 09/19/73 (32) - Published 04/30/76. Bulletin number 16 Date of publication of the description 08.12.76 (72) Author the invention (71) Claimant (54) METHOD FOR OBTAINING 4H-BENZO 4,5 CYCLOHEPT 1,2-Ü TIOPHENE OR SALTS PRODUCTS one The present invention relates to a method for preparing heterocyclic compounds of the formula I not described in literature. 512710 (AND) lgz ;; -: .r,;:, J I u; h: .----- :,: , CR k, -, -. ,-..."- .. one -. (51) M.C.2 C 07D 333/10 (53) UDC 547.732.07 (088.8) Alien Jean-Michel Basti n (Switzerland) Foreign company Sandoz AG (Switzerland) A known method for producing heterocyclic compounds of the general formula where RI is a hydrogen atom or chlorine in position 6 or ring 7; 15 R2 is lower alkyl; Rs is hydrogen or lower alkyl; A - ethylene or einilenova group, and that: kzhe their salts. The compounds of general formula I 20 and their salts with acids are pharmacologically active compounds. ten Ha where RI and R2 are H, alkyl, dehydration of the compound formula  - - hhh CH, -li, Mr. III about where RI, R :; And A has the meanings indicated above for these symbols, with the compound of Gryi-ra of formula IV Hmdch TNT where RI and Kg are as defined above, in the presence of acid catalysts in a carbon solvent environment at low temperatures, followed by isolation of the target product in a known manner. Using Q for the indicated reaction of general formula P CHj-R, where RI, Ra, R: j and A have the meaning of formula I, allows to obtain compounds of formula I. According to the invention, a method is obtained and heterocyclic compounds of formula I or their additive salts, consisting in the fact that the compound of formula II is subjected to dehydration by a known method, followed by isolation of the target product In free form or in the form of a salt, the basic method. Monsneric or strong organic acids are not used as a water withdrawal agent. Example Example Mixture of concentrated hydrochloric and glacial acetic acids, trifluoroacetic acid, benzenesulfonic acid, or anhydrides, or acid halides, for example acetic anhydride or chloride, In order to obtain heterocyclic compounds of general formula I, it is expedient to carry out the process at temperatures from 0 to 100 ° C in an organic solvent that is inert under the conditions of the process. In the proposed method, the free bases obtained can be converted into their acid addition salts with acids or free bases can be separated from the acid salts with acids. Heterocyclic compounds of the indicated general formula II can be obtained by reacting a ketone of formula III where R2 has the above value and then the resulting comylex will hydrate hydrolysis followed by isolation of the target product in a known manner. It is advisable to carry out the process in an environment of an organic solvent suitable for carrying out a Grignard reaction, for example, growth hydroxy esters, diethyl or tetrahydrofuran. The hydrolysis of the formed pa at the intermediate stage of the organometallic complex eoeppeepie can be carried out 1: in the following ways, for example, by treatment with an aqueous solution of ammonium chloride. Compounds of the formula III can be lost. For example, by reconstituting the compound of the formula V where RI, Rs and A are as defined for these symbols. As reducing agents, it is advisable to use SnCU or CuCl in an acidic medium, for example, in the presence of hydrochloric acid. It is advisable to carry out the process in an organic solvent inert under the conditions of the reaction, preferably mixed with water, for example dioxane or ethyl alcohol, with the preferred process temperature being from room temperature to 80 ° C. The compounds MOJ1NO corresponding to formula V can be obtained by chloroalkylated compounds of formula VI /. A S C, X, N x x where RI and A are as indicated above for these symbols. Beginning, the interaction of a compound of formula VI with an aldehyde is formly VII. Cs-CHO, VII where Cs has the above values for this symbol, or its polymer compound in an acidic solution, for example, in an aqueous solution of hydrochloric acid in acetic acid, while passing hydrogen chloride gas or in a concentrated hydrochloric acid solution into the reaction mixture at temperatures from about 20 to + 80 ° С, preferably from -10 to + 15 ° С, 03 The flow is about 2-70 hours, preferably 8-12 hours. The following examples illustrate, but do not limit the invention. Example 1. 9,10-Dehydro-2-methyl-4- (1-methyl-4-piperidyl-idene) -4H-benzo 4,5 cyclohepta 1, 2-b is thiophene. A mixture of 5.0 g of 9,10-dehydro-2-methyl-1- (1-methyl 4-niperidyl) -5H-benzo 4,5 cyclohepta 1,2-b thiophen-4-ol with 20 ml of concentrated hydrochloric acid in 60 ml of glacial acetic acid are boiled for 2 hours, after which the reaction mixture is evaporated under reduced pressure. The residue is diluted with 200 ml of water, alkalinized with concentrated sodium hydroxide solution and then extracted with methylene chloride. The extract is washed with water to neutral wash water, dried and then evaporated. The residue is recrystallized from acetone to obtain 9,10-deg1Idro-2-methyl-4- (methyl-4-piperidylidene) -4H-benzo 4,5 cyclohepta 1,2-b thiophene with a melting point of 119-121 ° C. The starting compounds can be prepared as follows. A. A mixture of 100 g of 9,10-dehydro-4H-benzo 4,5 of cyclohepta 1,2-bb thiophen-4-one with 57 ml of a 40% form.aldehyde solution in 700 ml of concentrated hydrochloric acid at a temperature of 10-15 ° C is saturated with stirring for 8 hours with hydrogen chloride, then kept for 14-18 hours at room temperature, then poured into 2.5 liters of ice water and extracted with chloroform. The extract is dried, evaporated, the residue is recrystallized from ethnr and 2-chloromethyl-9,10-dehydro-4H-benzo 4,5 cyclohepta 1, 2-b thiofbn-4-one is obtained with a melting point of 82-83 ° C. B. To a mixture of 75 g of tin chloride (SnCb) in 400 ml of Dio-sapa with 200 ml of ivonnenTpHpOBaH hydrochloric acid, a solution of 25 g of the above product in 250 ml of dioxane is added dropwise at room temperature. The reaction mixture is stirred for 48 hours at-room temperature, then for another 10 minutes at, then cooled, diluted with water, and extracted with diethyl ether. EXTR-CT is treated with water, dried, evaporated and an oily product 9,10-dehydro-2-methyl-4H-benzo 4,5 of cyclohepta 1,2-b thiophen-4-one with temperature is obtained; Iteppe 200-21 ° C at 1-2 mm Hg. Art. C. A small amount of ethylene bromide was added to 1.9 g of α-magnesium in 15 ml of absolute tetrahydrofuran, and then with a solution of tetrahydrofuran, a solution of 10.0 g of 4-chloro-1-methyl-n-peridine in 25 ml of absolute tetrahydrofuran was added dropwise. Then the reaction mixture is boiled at a temperature of 1.5 hours, cooled to 20-25 ° C. and added dropwise over 30 minutes. 9. 5 g of 9LO-degpdro-2-methyl-4H-benzo 4,5 cyclohepta k2-l1T ofsn-4-one in 50 ml of absolute tetrahydrofuran. Then the reaction mixture is stirred for 2 hours at room temperature. After cooling, it is poured into 250 ml of a 20% solution of amdioni chloride, extracted with methylene chloride, the extract is washed with water, dried and evaporated. Received as a residue crude 9,10-dehydro-2-methyl-4- (1-methyl 4-piperidyl) -4H-benzo 4,5 cyclohepta 1,2-b TIOFSP-4-OL. At measure 2. 2-Ztil-4- (1-p-butyl-4-piperndilide ") -9,10-digndro-4P-bepzo 4.5 cyclohepta | 1, 2-b thiophene. / tax; 1Ч 1o Example 1 of 5.5 g of 2-ethyl-4 (1-n-butyl-4-ninerndyl) - 9LO-dihydro-4H-benzo 4, 5 cyclohepta 1,2-b thiophene-4-ol in 60 ml of glacial acetic acid and 20 ml of concentrated hydrochloric acid, 2-ethyl-4 (1: -butyl-4-pipernd 11Lido11) - 9,10-dngidro-4Nbepzo 4, 5 cyclohepta 1,2-b thiophene is obtained. Found C, 79.0; And 8.4; N 3.9; S 8.7. Calculated,%: C 79.0; P 8.5; N 3.8; S 8.7. The starting compounds can be prepared as follows. A.2- (1-Chloroethyl) -9,10-dihydro-4H-benzo 4,5-cyclohepta 1,2-b thiophene-4-it is obtained in the same way as described in example 1 A from 20 g of 9,10-dihydro-4H-bel 13 o 4.5 cyclohepta 1,2-b thiophen-4-one, 4.0 g of paracetaldehyde, 120 ml of concentrated hydrochloric acid and hydrogen chloride. The product is unstable and is used in subsequent stages without additional clearing B.2-Ethyl-9,10-d; hydro-4P - benzo 4,5 cyclohepta 1, 2-b thiophen-4-one is obtained analogously to example 1 B. Those: a boiling temperature of 195-210 ° С (1-2 m-m Hg). C. 2-Ethyl - 4- (1-n-butyl-4-piperidyl) -9,10 dihydro-4H-benzo 4,5 cyclohepta 1,2-b thiophene-ol is prepared as in Example 1 C out of 1.5 g of activated magnesium, 10.8 g of 1-n-butyl-4-chloropiperid1 on and 5.6 g of 2-ethyl-9,10-dihydro-4H-benzo 4,5 cyclohepta 1,2-b thiophene-one a. PRI me R 3. 2-Mstil-4- (1-methyl-4-piperid)) -4H-benzo 4,5 c; 1 of the Agent 1,2-b thiophene. In analogy with Example 1, from 5.0 g of 2-methyl-4 (1-meth gl-4-piperpdil) -4P-benzo 4,5 cyclohepta 1, 2-b thiophen-4-ol in 60 ml of glacial acetic acid and 20 m, concentrated hydrophane hydrochloric acid 1 are obtained by decree ;; in the title there are sudipsnpe, which in the form of hydrochloric acid salt is recrystallized from a mixture of methyl oiirt and ethyl alcohol. Calculated,%: C 69.9; H 6.4; C1 10.3; S 9.3. Found,%: C 70.0; H 6.3; C1 10.1; S 9.3. The starting compounds can be prepared as follows. A.2-Chloromethyl-4H-benzo 4,5-cyclobpta 1,2-b thiophen-4-one is prepared analogously to Example 1 A, from 4H-beiso 4.5 cyclohepta 1,2-b thiophen-4-OTia. Melt temperature is 162-164 ° C (from a mixture of methyl and ethyl alcohol). B.2-Methyl-4H-benzo 4,5-cy1Klohepta 1,2-b thiophen-4-one. Is prepared as in Example 1 C. The melting point is 112-115 ° C (from hexane). C.2-Methyl - 4- (I-methyl - 4-p-I | Peridyl) -4Nbenzo 4, 5 q. Klogept 1,2-b thiop H-4-ol is prepared analogously to example 1 C. Example 4. 6- Chloro-2-methyl-4- (1-adetil-4piperidylidone) - 4H - benzo 4,5 cyclohepta 1,2-b thiophene. Similarly to the above example 1, from 5.0 g of 6-chloro-2-methyl-4- (1-methyl-4-pi | Peridyl) 4H-benzo 4, 5 cyclohepta 1,2-b thiophene-4-ol in 60 : ml of glacial acetic acid and 50 ml of concentrated hydrochloric acid obtain the title compound 1. Its hydrofumarate has a melting point of 221-225 ° C (from a mixture of methyl and isopropyl alcohol). The starting compounds can be prepared as follows. A. A mixture of 50 g of 6-chloro-4H-benzo 4,5 of cyclobpta-, 2-b of tiofvn-4-one and 6.1 g of paraformaldehyde in 85 ml of 1 concentrated hydrochloric acid, 56 1 ml of glacial acetic acid and 39 ml of 85% phosphoric acid, stirred for 6 hours at a temperature of 80 ° C. It is then poured into 1 liter of water, extracted with chloroform, the extract is washed with water, with a saturated solution of sodium chloride, dried, and then the solvent is distilled off. 6-chloro-2-chloromethyl-4Nbenzo 4, 5 cyclohepta 1,2-b thiophen-4-one is obtained as a residue with a melting point of 175-177 ° C (from benzene). B.6-Chloro-2-methyl-4H-benzo 4.5 cyclohepta 1,2-b thiophen-4-one is prepared as in Example 1 B with a melting point of 155-157 ° C. C.6-Chloro-2-methyl-4- (1-methyl-4-piperidyl) 4H-benzo 4, 5 cycloheptane 1,2-b thiophen-4-ol is prepared in analogy to example 1 C. Claim 1: Method obtaining 4H-benzo 4, 5 derivatives of cyclohepta 1,2-b thiophene of the general formula I where RI is a hydrogen or chlorine atom in the 6 or 7 ring position; Ra is lower alkyl; Rs is a hydrogen atom or lower alkyl; A - ethyl & nova or vinylene group, or their salts, characterized in that the compounds of the formula I and RI, Ra, Rs and A have the above values, are dehydrated in a known manner, followed by isolation of the target product in free form or in salt form tricks.