SU333763A1 - METHOD OF OBTAINING TRICYCLIC COMPOUNDS The invention relates to the production of new tricyclic compounds with a new arrangement of substituents, their pharmacological activity. A method for the preparation of tricyclic compounds of the general formula of hydrogen atoms based on the reaction of halocyclic compounds with amino compounds is described. A— ^ B are radicals. —N = C = or R "—CH — CH—, where R" has the indicated meanings. The method is that compound 5 of the formula YNH- (CHg) p-CoAHal I / ^ yA-Wu / H, Y- {T jVxЦЛ.ГА ^ '10 - Google Patents

Description

where -11; R is hydrogen, straight chained or branched lower alkyl containing from one to five carbon atoms; X and Y can have the same or different values - hydrogen, halogen atom, straight or branched lower alkyl containing up to five carbon atoms, -OR, -SR, -SOaR group, in which R is alkyl containing up to five atoms carbon, trifluoromethyl, nitro or cyano; Z is an oxygen atom, a sulfur atom, an oxide or sulfur dioxide or СНН groups, -CO-, NR, CHR, in which R is hydrogen, lower alkyl, branched or unbranched, containing

where A-B, Y, X, Z have the indicated meanings, they are reacted with the amino ester of the general formula H2N- (CH2) p -COOR, where R, p have the indicated meanings, in the presence of an acid-binding agent.

The resulting product, in the case of R - "extra alkyl, is subjected to hydrolysis in a well-known manner, for example, by treatment with an alkaline or acidic aqueous-alcoholic solution.

The process is preferably carried out in an organic solvent at a temperature from

20 to 100 ° C. Products are isolated

stereoisomers or on optical antipodes by well-known techniques.

The solvent used in this process is usually alcohol, nitromethane, acetonitrile, or an aprotic solvent, for example, dimethylformamide, dimethylacetamide, hexamethyltriphosphoramide.

As an acid acceptor, either an excess of the amino ester used, or a tertiary amine, or an alkali or alkaline earth metal carbonate or bicarbonate can be used.

The hydrolysis of the resulting ester is carried out in an acidic or alkaline medium. Moreover, the choice of medium depends on the stability of the heterocyclic or homocyclic ring.

The invention is illustrated by examples. Except for some cases during the course of all experiments, the melting point of the products is determined using a Kofler block. In fact, these temperatures are decomposition temperatures, the process of determining which turned out to be less accurate.

Example 1. 8-trifluoromethyl b hemihydrate, dibenzo-1,4-oxazepin-11-yl-7-amino-enanthic acid

21 g of o-4-trifluoromethyl-2-amino-phenyloxybenzoate is subjected to heating in a stream of nitrogen at a temperature of from 200 to 220 ° C for 7 hours. As a result, 18.6 g of 8-trifluoromethyl-L-dibenzo-1,4-oxazepin-11-one are obtained, which is a crude product, the melting point of which is in the range of 245 to 250 ° C.

Thereafter, 16.4 g of said oxazepinone is added to 130 ml of phosphorus oxychloride, which is subjected to two preliminary distillation. Next, 5 ml of dimethylaniline was added to the mixture prepared in this way and the mixture was heated under conditions of intensive evaporation using a reflux condenser for 4 hours with continuous stirring. The final mass is then evaporated to dryness. The residue obtained is redissolved in sulfuric ether. After that, the ether phase is quickly washed with water and dried. After evaporation, 16 g of 8-trifluoromethyl-11 chloro-b, -dibenzo-1,4-oxazepine, which is a crude product, are obtained.

Then, to a mixture of 13.7 g of 8-trifluoromethyl-11-chloro-b, C-dibenzo-1,4-oxazepine, which is obtained, as indicated, with 50 ml of dry nitromethane, 16 g of 7-aminoheptanatethyl, which is directly added, is added in one portion before this operation is subjected to double distillation. When this occurs, the spontaneous heating of the reaction mixture to a temperature of 35-40 ° C. Continuous stirring was continued for 1 hour, as a result of which the temperature of the reaction mixture was lowered to room temperature, after which the mixture was kept at rest for 15 hours. Next, from the resulting mixture

the solvent is removed by evaporation in vacuo. The residue is extracted with chloroform and water. After that, the chloroform layer is washed several times with water. The solvent is then removed simultaneously with water, as a result of which 17.5 g of 8-trifluoromethyl-b, -dibenzo-1,4-oxazepin-11-yl-7-aminoheptaiethyl are obtained, the content of the pure product in which is determined by dosing during the titration of chlorine chloride. acid in acetic acid medium is 95%.

Thereafter, 17 g of the obtained ester is added to 40 ml of 1N. sodium hydroxide solution and 80 ml of ethanol.

Next, the prepared mixture is heated under conditions of intensive evaporation using a reflux condenser for 30 minutes. The solvent is then removed by evaporation in vacuo and the residue is extracted with 100 ml of water, after which the resulting solution is extracted with ether. Thereafter, the aqueous phase is acidified by the addition of 40 ml of 1N. hydrochloric acid solution. Organic

the acid, which then precipitates as an oil-like product, is extracted with ether. Then the ether phase is washed with water, dried and evaporated. As a result, 11.8 g of 8-trifluoromethyl-b, α-dibenzo-1,4-oxazepin-11-yl-7-amino-enanthic acid are obtained in the form of its hemihydrate, the melting point of which (instant melting point) is 90 ° C and the content pure substance is 98.5%.

This acid can be recrystallized from benzene. The acid is in the form of a hemihydrate, which is resistant to air; the anhydrous product is hygroscopic, so that in the open air this acid quickly turns into hemihydrate.

Example 2. Chlorohydrate-8-nitro {b, G-dibenzo-1, 4-thiazepin-11-yl-7 - amino-enanthic acid

To 80 ml of phosphorus oxychloride and 3 ml of dimethyl aniline were added 12 g of 8-nitro {b, dibenzo-1, 4-thiazepin-11-one, the melting point of which (determined in accordance with the 1 Kofler micro method) is within from 300 to 303 ° C, and the product melts

with simultaneous sublimation. Thereafter, the mixture thus prepared is heated using a reflux condenser under intensive evaporation conditions for 5 hours with continuous stirring. The product slowly dissolves with evolution of gaseous hydrogen chloride. After the heating time has elapsed (using a reflux condenser), excess phosphorus oxychloride is evaporated in a vacuum. Next, the residue is washed with water, and then it is dried in a vacuum oven or a desiccator, from which air is pumped out. Thus, 12.2 g of 8-nitro-11-chloro-b, G-dibenzo-1,4-thiazepine are obtained,

the range is from 145 to 146 ° C, and after recrystallization of the said final product from nitromethane, its melting point (determined in accordance with the Kofler micromethod) ranges from 146 to 147 ° C.

After that, similarly to the method described in β-example 1, using 6.7 g of 8-nitro-11-chloro-b, dibenzo-1, 4-thiazepine as the starting material, 8.7 g of 8-nitro b are obtained, {-dibenzo- [1,4-thiazepin-11-yl-7-aminoheptane-ethyl, the melting point of which, after recrystallization of isometh nitromethane, is in the range from 97 to 98 ° C.

Next, 7.4 g of the ester thus obtained is subjected to saponification using 18 ml of 1N for this purpose. sodium hydroxide solution and 50 ml of ethanol. Then, the final mixture thus prepared is subjected to heating using a reflux condenser under intensive evaporation conditions for 15 minutes, after which the reaction mixture is evaporated to dryness in vacuo and the residue is extracted with water. Thereafter, the aqueous phase is acidified by the addition of excess hydrochloric acid. The final precipitate is drained, washed with a small amount of ice-cold water and subjected to recrystallization from 90 ml of a 20% ethyl alcohol solution. 5 g of hydrochloride, 8-nitro, G-dibenzo-1,4-thiazepin-11 - yl-7-amino-enanthic acid, melting point of which is 170 ° C, are thus obtained.

Similarly to examples 1 and 2, the proposed compounds are obtained, the substituents in the molecules of which and the melting points of which are listed in Table. one.

Table 1

With the sword ail and: 1) AB is everywhere group, 2) X is everywhere N. Example 24. 11-oxo-b hydrochloride, e-dibenzo-6-azepinyl-6-aminocaproic acid A mixture of 44.6 g 5, 6-dihydro-6,11-morphanthidinedione, 13 ml of dimethylaniline and 300 ml of chlorine vigorous evaporation within 4 hours and 30 min. Thereafter, said reaction mixture is evaporated to dryness in vacuo,

ice, followed by rapid extraction with chloroform. The chloroform solution is then washed with hydrochloric acid, followed by washing with water. Next, the organic phase is present and then subjected to evaporation to dryness under reduced pressure. Thus, 26 g of b-chloro-11-oxo b, e -dibenzoazepine are obtained as a crude product, the melting point of which ranges from 109 to 110 ° C.

Thereafter, a suspension of 14.45 g of 6-chloro-11oxo-b, e-dibenzoazepine, which is a crude product, obtained as described above, in 113 ml of dry nitromethane, is added with a solution of 19.7 g of freshly distilled b-aminocapronate-ethyl in 24 ml of dry nitromethane. Thus, a slightly exothermic reaction is carried out when the chlorine-containing derivative is dissolved. The final mass is then kept at rest overnight, followed by evaporation to dryness under reduced pressure.

The resulting residue is repeatedly extracted with water. Thus, a crude product is obtained, the melting point of which is in the range of 99 to 100 ° C, the content of the pure final product (determined by titration by dosing with perchloric acid in a medium previously acidified with acetic acid) is 99%.

Example 29. Right-levogyrate 8-methoxy-a, d-dibenzo-10-cycloheptadienyl-7-amino-enanthic acid hydrochloride

In 15 g of 8-methoxy-a, e-dibenzo-10-schicoheptandnenone, which is in suspension in 100 ml of methyl alcohol, 2.4 g of sodium borohydride are added in separate portions under conditions of continuous movement. As a result, a very high exothermic reaction takes place and the ketone dissolves. Thereafter, the reaction mixture is heated under reflux for 1 hour under intensive evaporation conditions, and then left to stand still overnight. The reaction mixture is then diluted with 200 ml of water, extracted with chloroform, washed with water, dried and evaporated to remove the solvent. As a result, 13.6 g of crude product are obtained, after nepeKp HCTavi.TH. After the subsequent recrystallization of this product from 150 ml of ethyl alcohol, 16.5 g of 11-oxo-b, e-dibenzo-azepinyl-6-aminocapronate-ethyl are obtained, the melting point is in the range from 100 to 101 ° C. Next, 8 g of the ester thus recrystallized in this way are added to 30 ml of 2N. hydrochloric acid solution. Then, the said reaction mixture is heated under reflux for 30 minutes under intensive evaporation conditions. Thereafter, a light insoluble product is filtered off, which is 6.1 Å morphantidine diphenol, the melting point of which is approximately 260 ° C. The filtrate thus obtained is then evaporated to dryness for a very short time and the residue is then recrystallized from adonitrile. As a result, 5.2 g of 11-oxo-b, e-dibenzo-b-azepinyl-b-aminocaproic acid hydrochloride are obtained, to some extent a hygroscopic product, the instantaneous melting point of which ranges from 134 to 13 b ° C.

Examples 25-28. Similarly to Example 24, the proposed compounds are prepared, the substituents in the molecules of which and the melting points of which are listed in Table. 2

table 2

From this cyclohexane, 11.7 g of 8-methoxy-a, b -dibenzo-10-cycloheptadiene are obtained, the melting point of which (determined according to Kofler's micromethod) is in the range from 85 to 8 ° C. After that, 10.5 2 of the thus obtained cycloheptadiene in solution in chloroform / chloroform is chlorinated, passing through it a stream of dry

hydrogen chloride gas. After contacting overnight with a lack of moisture, the solvent is removed by evaporation under reduced pressure. As a result of this, 9 g of 8-methoxy-10-chloro-a, d) -dibenzocycloheptadiene are obtained, the melting point of which is in the range of 96 to 99 ° C. The melting point of a sample of such a product after its recrystallization from cyclohexane (determined according to Kofler micromethod) is in the range of 98 to W2 ° C. Further, to the above 9 g of chlorine-containing derivative in 70 ml of nitromethane, 12.5 g of 7-aminoheptanateethyl are added in one portion, which is previously subjected to double distillation to 18.5 ml of nitromethane, which is then heated at 60 ° C. for 1 hour, followed by removal of nitromethane by evaporation under reduced pressure.

The residue obtained is dissolved in water and sulfuric ether. After that, the ether phase is decanted, washed with water, dried and evaporated. The residual product is crude 8-methoxy a, e-dibenzo-10-cycloheptadienyl-7-aminoheptane-ethyl, with a pure substance content of 80%.

Then, 9.4 g of the above ester, obtained above, is added to 100 lgl of aqueous

Example 32. Hydrochloride of the programe-levogyrate of 2-chloro-10,11-dihydro b, -dibenzo-10-typaninyl - 7-amino-enanthic acid

To 10 g of 7-aminoheptanateethyl, which was immediately subjected to distillation distillation, in 10 ml of nitromethane was added 7.9 g of 2,10-dichloro-10,11-dihydrob, dibenzothiepine in 50 ml of dry nitromethane. After that, the mixture thus prepared is incubated for 1 hour in a boiling bath. When this occurs, the chlorine-containing compound gradually dissolves. The final reaction mixture is then allowed to stand overnight in a calm state. Then, the light insoluble fraction was filtered and the solvent was removed by evaporation under reduced pressure, and the resulting residue was dissolved in sulfuric ether, followed by washing the organic layer several times with water, after which the layer was formed and the evaporator was evaporated. As a result of this, 11.5 g of crude 2-chloro-10,11-dihydrob) -dibenzo-10-typaninyl-7-aminoheptanateethyl are obtained, in which the concentration of pure ester is 80%.

Next, 10 g of the crude ester thus obtained is subjected to saponification by adding 24.5 ml of I to it.

hydrochloric acid solution, after which this mixture is heated for 3 hours under reflux under conditions of intensive evaporation. After that, the mixture is evaporated to dryness in vacuum. The residue thus obtained is dissolved in acetonitrile heated to boiling point. Next, the final product is recrystallized from water. In this way, 4.5 g of right-rotating-levorotatory 8-methoxy-a, d-dibo-zo-10-cycloheptadiyl-7-amino-enanthic acid hydrochloride are obtained, the melting point of which (determined according to Kofler's method) ranges from 206 to 209 ° s

Examples 30-31. Similarly to Example 29, the proposed compounds are obtained, the substituents in the molecules of which and the melting points of which are listed in Table. 3

Table 3

sodium hydroxide solution and 50 ml of ethanol. The final α-reaction mixture is then heated for 1 hour and 30 minutes using a reflux condenser under intensive evaporation, followed by

removing the ethanol by evaporation in vacuo. After that, the resulting residue is dissolved in water. Next, the aqueous solution is subjected to extraction with sulfuric ether, the organic layer is removed, and the aqueous layer is removed.

acidified by adding 1N. hydrochloric acid solution until the medium reaches 1 RP. As a result, a gummy product precipitates, which is then extracted with chloroform,

and then the extract is dried and the solvent is evaporated from it under reduced pressure. Then, the residue is recrystallized from a mixture of acetone and ethyl alcohol, resulting in 5 g of hydrochloride of the programe-levorotatory 2-chloro-10,11-dihydro b, -dibenzo-10-thiepinyl-7-amino-enanthic acid, the melting point of which is 178 ° WITH.

Examples 33-37. Similarly to Example 32, the proposed compounds are prepared, the substituents in the molecules of which and the melting points of which are listed in Table. four.

II

12

Table 4

Subject invention

1. A method of producing tricyclic compounds of general formula

g1n- (cis) p-juice

/ UA-Bx /

4 4-

where n 1 - And; R is hydrogen, lower alkyl, unbranched or branched, containing from one to five carbon atoms; X and Y may have the same or different values — hydrogen, halogen atom, straight or branched lower alkyl containing from one to five carbon atoms, the group —OR, —SR, —SOaR, in which R is alkyl containing from one up to five carbon atoms, trifluoromethyl, nitro or cyano; Z is an oxygen atom, a sulfur atom, oxide or sulfur dioxide or groups —СНОН, —CO-, —NR, CHR, in which R is hydrogen, lower alkyl, branched or unbranched, containing from one to five carbon atoms; AB - radicals -N C

or R —CH — CH—, where R has the indicated meanings, characterized in that the compound of the general formula

Hal

where AB, Y, X, Z have the indicated meanings, Hal is a chlorine or bromine atom, is reacted with an ether of the general formula

H2N- (CH2) p-OOOR, where R, p have the indicated meanings, in the presence of an acid binding agent, the products obtained therewith are selected or subjected to hydrolysis by a well-known method, for example, by treatment with an aqueous-alcoholic solution of an alkali or acid, followed by isolation products known methods in free form or in salt form. 2. The method according to claim 1, characterized in that

Processes are carried out in an organic solvent medium.