KR850000944B1 - Process for preparing 5-carbamoyl-10,11-dihydro 5h-dibenz(b,f)azepine - Google Patents

Abstract

The novel prepn. of 5-carbamoyl-10-oxo-10,11-dihydro-5Hdibenz [b,f azepine of formula (III) comprises (a) nitrating 5-cyano-5H-dibenz [b,f azepine of formula (I) with a nitrating agent in a solvent at 0-120≰C to give 5-cyano-10-nitro-5H-dibenz [b,f azepine of formula (II); (b) reducing the 10-nitro gp. of (II) with a reducing agent at 10-100≰C in the presence of a hydrogenating catalyst; (c) hydrolyzing the prod. with water to give 5-cyano-10-oxo-10,11-dihydro-5H-dibenz [b,f azepine of formula (V); and (d) hydrolyzing the 5-cyano gp. with an acetic reagent at -5 150≰C to obtatin (III). The nitrating agent in (a) is N2O3, N2O4, or NHO3.

Description

5-carbamoyl-10-oxo-10, 11-dihydro-5H-dibenz [b, f] azepine

The present invention relates to a novel process for preparing 5-carbamoyl-10-oxo-10, 11-dihydro-5H-dibenz [b, f] azepine of formula (III).

The process of the present invention is represented by the following scheme.

Hydrolysis of 10-methoxy-5H-dibenz [b, f] azepine-5-carboxamide with aqueous inorganic acid to yield 5-carbamoyl-10-oxo-10, 11-dihydro-5H-di The process for preparing benz [b, f] azepine is described in Federal Republic of Germany Patent Application No. 2, 011, 087. The method by which this starting material can be obtained is described in Belgian Patent Specification No. 597,793, according to this method, for example, by brominating 5-acetyl-5H-dibenz [b, f] azepine to give 5- Acetyl-5H-dihydro-10, 11-dibromo-5H-dibenz [b, f] azepine was produced and 5-acetyl-10-bromo-5H-dibenz [b, f] azepine Conversion results in 10-methoxy-5H-dibenz [b, f] azepine. It is then treated with phosgene to convert to the corresponding carbonyl chloride which is reacted with ammonia to give 10-methoxy-5H-dibenz [b, f] azepine-5-carboxamide. Compared with this production method, which is difficult to carry out due to the relatively large number of intermediate steps and which is disadvantageous due to the large consumption of bromine used only for the intermediate conversion of intermediate products, the preparation according to the invention comprises only a few production steps, which are monitored. It can be carried out in a simple manner since it does not require the use of easy, expensive reactants, and furthermore, it is possible to obtain the final product of the formula (III) in a high purity form and in high yield.

The process of nitrating the compound of formula (I) with the compound of formula (II) according to the invention is carried out using conventional nitrating agents, for example nitrogen trioxide (N) optionally mixed with oxygen (eg air). ₂ O ₂ ), dinitrogen tetraoxide (N ₂ O ₄ ) or mixtures thereof, or nitric acid. The reaction is carried out in a suitable solvent, in particular this solvent is stable under nitration conditions and should not cause unwanted reactions with the nitrating agent. In particular lower alkanes of up to 4 carbon atoms or halo-lower alkanes, such as acetic acid, propionic acid, n-butyric acid or isobutyric acid, optionally mixed with water, and trifluoroacetic acid or trichloroacetic acid or acetic acid, propionic acid, n-butyric acid , Anhydrides thereof such as isobutyric acid or trifluoroacetic anhydride or mixtures of such carboxylic acids with the corresponding anhydrides are suitable. The solvent used in the preferred process of the preparation according to the invention is acetic anhydride optionally mixed with the anhydrides of the lower alkanecarboxylic acids mentioned, for example lower alkane carboxylic acids (eg acetic acid).

The ratio of the starting material to the amount of solvent used (weight / volume) can vary within wide limits. The starting material: solvent ratio is advantageously in the range of 1: 3 to 1:30. The reaction temperature is carried out in the range of about 0 to 120 ° C., in particular 40 to 80 ° C. According to Chemical Reviews 36, (1945) pages 211-212, styrene is reacted with nitrogen trioxide to produce a mixture of nitroso and nitro compounds. Moreover, distillation of the reaction product of styrene and nitrogen trioxide with steam produces 1-nitro-2-phenylethylene. In addition, the reaction of styrene with nitrogen tetraoxide gives 1, 2-dinitro-1, 2-diphenyl ether. According to page 218 of the literature, the reaction of cyclohexene with anhydrous nitrogen tetraoxide in cold petroleum ether yields the corresponding bis-nitroso-nitro derivatives and oily by-products.

J. Org. Chem. 28, (1963), pages 125-129, the reaction products of olefins and nitrogen tetraoxide essentially contain nitro and nitroso groups and the conversion of this product to nitro-olefin compounds requires the addition of triethylamine. Thus, for example, cyclooctene is reacted with nitrogen tetraoxide and the reaction product is then treated with triethylamine to give 1-nitrocyclooctene.

In contrast, in the case of nitration according to the present invention, additional operations such as distillation by steam or treatment of the reaction mixture with triethyl amine are not required, and the completion of the reaction operation can be carried out very simply. Nitro compound is produced in extremely good yield. This compound is novel and not described in the literature.

According to the invention, next, the compound of formula (II) is converted into the compound of formula (III). For this purpose, the 10-nitro group in the compound of formula (II) is reduced, the reduction product is hydrolyzed and 5-cyano-10-oxo-10, 11-dihydro-5H of formula (V) is produced. -Dibenz [b, f] azepine is hydrolyzed and the final product of formula III is separated in pure form. This method involves converting a compound of formula (II) to a compound of formula (V) and producing a final product of formula (III) therefrom. Thus, the nitro group in 5-cyano-10-nitro-5H-dibenz [b, f] azepine of formula (II) is reduced according to one of the methods described above and the intermediate forming the reaction mixture is hydrolyzed. To a compound of formula (V). Reduction can be effected with a suitable solvent, for example lower alkanols of up to 4 carbon atoms, by catalytically activated hydrogen such as hydrogenation catalysts such as nickel or noble metal catalysts such as Raney Nickel or hydrogen in the presence of a palladium / carbon catalyst. Eg by methanol or ethanol) or by hydrogen or zinc, if necessary, zinc amalgam or, in particular, by the action of hydrogen in acids (e.g., inorganic acids such as gray sulfuric acid or concentrated hydrochloric acid or lower alkane carboxylic acids such as acetic acid) or It can be carried out with a compound reducing agent such as tin (II) .2H ₂ O. Further solvents, for example lower alkanols having 1 to 4 carbon atoms (e.g. ethanol) or lower alkoxy-lower alkanols having up to 4 carbon atoms in each lower alkoxy or lower alkanol group (e.g. 2-methoxy Ethanol or 2-ethoxy ethanol) and / or aromatic solvents such as optionally loweralkylated (eg methylated) or halogenated (chlorinated) benzene (eg benzene, toluene or chlorobenzene) and the like can be used. The reaction temperature is 10 to 100 °, preferably 30 to 70 °. The reaction mixture is hydrolyzed by removing water-insoluble components and then reacting with water. When the reaction is completed, 5-cyano-10-oxo-10, 11-dihydro-5H-dibenz [b, f] ase of formula (V) is completed. The pins are separated in pure form and are obtained in good yield and good purity. This compound is novel and not described in the literature. Preferred processes for converting the compound of formula (II) to the compound of formula (V) include a solvent which maintains the metal salts produced for reduction as described above, e. The use of a solvent that actually prevents the production of precipitates that are difficult to filter is included. Solvents of this type are strong polar organic solvents, for example lower alkyl ethers of ethylene glycol, wherein lower alkyl contains up to 4 carbon atoms, for example methyl or ethyl, and thus may be ethylene glycol monoethyl ester.

The cyano group in the compound of formula (V) is then converted to a carboxamide group in the final product of formula (III) by hydrolysis. This can be done using basic reagents or acidic reagents. Examples of suitable basic reagents include alkaline earth metal oxides or hydroxides (such as magnesium hydroxide or calcium hydroxide and sodium hydroxide) or alkali metal bicarbonates such as sodium bicarbonate in a mixture with hydrogen peroxide, optionally in the presence of a peroxide such as hydrogen peroxide. Examples include inorganic acids such as sulfuric acid or polyvalent phosphoric acid and lower alkanes containing 4 carbon atoms or halo-lower alkanes such as formic acid, acetic acid or mixtures of inorganic acids such as trifluoroacetic acid and concentrated sulfuric acid. have. Another example of an acidic reagent is Lewis acid, such as boron fluoride, which may be present in the form of a solution of lower alkanecarboxylic acids of the type described above, for example acetic acid, or alternatively for example BF _3. It may be present as a complex such as 2CH ₃ COOH. Another solvent, such as chlorobenzene, may optionally be added to the reaction mixture. The reaction temperature is in the range of -5 to 150 °, preferably in the range of 0 to 40 °.

An alternative to this method is to reduce the 10-nitro group in the compound of formula (II) and to produce 5-cyano-10-isonotros-10, 11 of formula (VI) to produce the intermediate of formula (V). 5-Cyano-10-oxo-10, 11-dihydro-5H- of formula (V) wherein the dihydro-5H-dibenz [b, f] azepine is isolated in pure form and then separated in pure form. Hydrolysis of dibenz [b, f] azepine. This method uses a zinc powder in acid such as lower alkanecarboxylic acid such as acetic acid in the presence of an inert solvent such as lower alkanol such as ethanol or the nitro group in the formula (II) or palladium in an appropriate solvent such as an aromatic solvent such as pyridine. Reduction with hydrogen in the presence of a hydrogenation catalyst, such as a noble metal catalyst such as a carbon catalyst, to give the corresponding 10-isononitroso compound of formula VI, followed by 5-cyano-10-iso of formula VI Nitroso-10, 11-dihydro-5H-dibenz [b, f] azepine is isolated in pure form. This compound is novel and not described in the literature. The compound of formula (VI) is hydrolyzed using an inorganic acid such as hydrochloric acid or sulfuric acid, or an acidic reagent such as acetic acid or trifluoroacetic acid in the presence of water, and is converted into a compound of formula (V). Additional solvents in the reaction mixture, for example benzene optionally substituted by lower alkyl up to 4 carbon atoms such as ethyl or halogen such as chlorine, for example benzene, toluene or chlorobenzene or lower alkanols having 4 carbon atoms May be optionally added. The compound of formula (V) is separated in pure form from the reaction mixture and converted to the final product of formula (III) as described above.

The invention is particularly relevant to the preparation described in the Examples.

Next, the present invention will be described. Temperature is Celsius.

Example 1

6.0 g (0.027 mol) of 5-cyano-5H-dibenz [b, f] azepine is dissolved in 80 ml of acetic anhydride and 20 ml of acetic acid mixture. The mixture is heated to 50 ° and a solution containing 5.6 g (0.08 mol) of sodium nitrite in 10 ml of water is added dropwise over an hour and a half without the temperature exceeding 55 °. The temperature of the mixture is kept at 55 ° for 2 hours and then the solvent is distilled off under pressure at 55 ° bath temperature. The residue is washed twice with 100 ml of ice water each time and dissolved in 80 ml of ethanol. After standing for several hours at 0 ° the precipitated yellow crystals are suction filtered and washed with a small amount of ethanol.

The resulting 5-cyano-10-nitro-5H-dibenz [b, f] azepine melts at 175 to 176 ° (decomposition). Yield: 5.2 g, 72% of theory

Analytical and spectroscopic data are consistent with the accepted structure.

Example 2

6.5 g (0.03 mol) of 5-cyano-5H-dibenz [b, f] azepine is dissolved in a mixture of 100 ml of acetic acid and 100 ml of acetic anhydride. The mixture is heated to 40 ° and 6.2 g (0.09 mole) of sodium nitrite is added slowly through the air through the solution over 45 minutes. The temperature is increased to 55 ° without heating and held for another hour at 55 ° at the end of nitrite addition. The solvent is distilled under vacuum at a bath temperature of 50 ° and the residue is dissolved in 300 ml of toluene and then shaken repeatedly with water to remove inorganic components and toluene is distilled off under vacuum to 40 ml. The precipitated yellow product is suction filtered and washed with a small amount of toluene. This is the same as 5-cyano-10-nitro-5H-dibenz [b, f] azepine according to Example 1.

Yield: 6.1 g, 77.5% of theory

Example 3

19.6 g (0.09 mole) of 5-cyano-5H-dibenz [b, f] azepine was reacted with 18.6 g (0.27 mole) of sodium nitrite in 300 ml of acetic acid and 300 ml of acetic anhydride as in Example 2 Let's do it. After evaporating the solvent, the remaining red-yellow syrup is stirred well with 300 ml of water until complete solidification occurs. After aspiration filtration, the filtrate was washed with water until neutralized and dried under vacuum.

The same crude product is obtained when this reaction is carried out at a temperature of 80 to 85 °.

The resulting crude product is suitable for use in the reaction but can also be purified as follows:

1. 23.7 g of crude product is recrystallized from isopropanol to give a yellow crystalline material, which is the same as 5-cyano-10-nitro-5H-dibenz [b, f] azepine according to Example 1. Yield: 18.0 g, 76.2% of theory

2. The same final product in yield and quality is obtained by dipping the crude product with acetic acid.

Example 4

By slowly dropping 20% sulfuric acid into 40.0 g (0.58 mole) of sodium nitrite concentrated solution in the flask, N ₂ O ₃ gas is produced, which is 10.9 g (0.05 mole) of 5-cyano-5H in 100 ml of toluene. -Dibenz [b, f] azepine is dissolved and slowly introduced into a solution heated to 55 °. The amount of atmospheric oxygen supplied is so low that no explosive mixture of toluene vapor and oxygen can be formed. Continue introduction until complete reaction of starting material occurs (thin layer chromatography test), excess N ₂ O ₃ builds up in a nitrogen stream and toluene is evaporated off at 40 ° under reduced pressure. The remaining red syrup is taken up in 100 ml of isopropanol. After standing at 5 ° for several hours, the crystals are suction filtered and washed with a small amount of isopropanol. The resulting 5-cyano-10-nitro-5H-dibenz [b, f] azepine is identical to the product according to Example 1. Yield: 9.4 g, 71.1% of theory

Example 5

According to the method described in Example 4, N ₂ O ₃ gas was produced from 55.0 g (0.8 mole) sodium nitrite in the flask and these were fed into a slow air stream of 10.9 g (0.05 mole) in 110 ml of acetic acid and 110 ml of acetic anhydride. 5-cyano-5H-dibenz [b, f] azine is dissolved in the solution and placed in a solution maintained at 50 °. After 3 hours, the reaction was completed, the solvent was distilled under vacuum at a bath temperature of 50 °, the residual mule was dissolved in 50 ml of isopropinol, and the crystallized material was left at 20 ° for several hours, followed by suction filtration. 5-Cyano-10-nitro-H-dibenz [b, f] azepin is obtained which is the same as the product obtained according to Example 1. Yield: 9.5 g, 72.5% of theoretical yield

Example 6

Similar to the method described in Example 4, N ₂ O ₃ gas was produced from 30.0 g (0.43 mole) sodium nitrite in a flask and 10.9 g (0.05 mole) 5-cyano-5H-dibenz [b, f ] Azepine is dissolved in 110 ml of acetic anhydride and slowly pushed by air stream into a solution maintained at 55 °. Upon completion of the reaction (thin layer chromatography test), the reaction mixture is concentrated by evaporation under vacuum at 50 ° bath temperature and the remaining mule is dissolved in 20 ml of acetic acid. The mixture is left for 2 hours at 20 ° and the crystals are suction filtered and washed with a small amount of acetic acid. The same 5-cyano-10-nitro-5H-dibenz [b, f] azepine is obtained which is identical to the product obtained according to Example 1. Yield: 9.1 g, 69.4% of theory

Example 7

10.0 g (0.046 mol) of 5-cyano-5H-dibenz [b, f] azepine is dissolved in 100 ml of toluene at 55 °. The temperature was raised to 60 ° and 5.0 g (0.054 mole) of N ₂ O ₄ was slowly introduced from the pressurized vessel into the solution with stirring, until the reaction mixture reacted with all the starting materials (thin layer chromatography). After cooling, the toluene layer is dried over sodium sulfate. Concentration in vacuo gave a red oil which was dissolved in 50 ml of isopropanol. After several hours at 20 °, the crystals are aspirated and washed with a small amount of isopropanol. The resulting 5-cyano-10-nitro-5H-dibenz [b, f] azepine is identical to the product obtained according to Example 1. Yield: 6.7 g, 56% of theory

Example 8

43.6 g (0.2 moles) of 5-cyano-5H-dibenz [b, f] azepine was dissolved in 250 ml of acetic acid at 55 ° and N ₂ O ₄ was introduced into the solution from the pressure vessel with stirring for 2 hours. The temperature is then kept at 55 ° by cooling from time to time. The termination of the reaction can be seen by the green coloration of the solution (excess N ₂ O ₄ ) and thin layer chromatography tests. The mixture is cooled and stirred for several hours at room temperature. The resulting precipitate is filtered off and washed with a small amount of acetic acid. The filtrate was concentrated and dissolved in acetonitrile to give another crystal, 5-cyano-10-nitro-5H-dibenz [b, f] azepine, which is identical to the product obtained according to Example 1. Total yield: 19.5g, 37% of theory

Example 9

43.6 g (0.2 moles) of 5-cyano-5H-dibenz [b, f] azepine is dissolved in 250 ml of acetic acid at 55 °. 60 ml of water is added dropwise to the solution until the solution starts to become cloudy and then slowly introduced N ₂ O ₄ from the pressure vessel until no further starting material can be detected by thin layer chromatography. The mixture is cooled to 5 ° and stirred at this temperature for 2 hours, after which the crystals are filtered off and washed with 80% acetic acid. The same 5-cyano-10-nitro-dibenz [b, f] azepine is obtained which is identical to the product obtained according to Example 1. Yield: 42.1 g, 80% of theory

Example 10

43.6 g (0.2 mole) of 5-cyano-5H-dibenz [b, f] azepine is dissolved in 175 ml of acetic acid at 55 °. At this temperature, the starting materials are all reacted (thin layer chromatography test) and N ₂ O ₄ is introduced into the solution from the pressure vessel until the product precipitates. 16.4 g (0.2 moles) of sodium acetate are added in small portions with occasional cooling and the temperature is maintained between 50 and 55 °. The mixture is stirred filtered at room temperature for 3 hours and the crystals are washed with acetic acid and water. The same 5-cyano-10-nitro-5H-dibenz [b, f] azepine is obtained which is identical to the product obtained according to Example 1. Yield: 36.1 g, 68.6% of theory

Example 11

21.8 g (0.1 mole) of 5-cyano-5H-dibenz [b, f] azepine is dissolved in 110 ml of acetic anhydride at 55 °. Slowly introduce 10.0 g (0.1 mol) of N ₂ O ₄ into this solution from the pressure vessel to prevent dark brown gas from leaking, and occasionally cool to maintain the temperature at 55 °. Upon completion of the reaction, a stream of strong nitrogen is passed for 1 hour, after which the mixture is cooled to -20 ° and held at this temperature for 2 hours. The yellow crystals are suction filtered and washed with a small amount of acetonitrile to yield the same 5-cyano-10-nitro-5H-dibenz [b, f] azepin as the product obtained according to Example 1. The filtrate is concentrated by evaporation in vacuo at a bath temperature of 50 ° to give a red oil. It is dissolved in 10 ml of acetonitrile, left at 5 ° for 2 hours, and the second crystal is suction filtered. Total yield 19.5g, 74.1% of theory

Example 12

21.8 g (0.1 mole) of 5-cyano-5H-dibenz [b, f] azepine is dissolved in 140 ml of acetic anhydride at 50 °. 12.0 g (0.13 mol) of N ₂ O ₄ is introduced into the solution while stirring, followed by cooling to maintain a temperature of 50 to 55 °. The mixture is allowed to react for 1 hour, followed by a strong stream of nitrogen, and slowly cooled with 60 ml of water to maintain 50 to 55 °. The mixture is cooled to 5 °, crystallized for 1 hour and then filtered.

The same 5-cyano-10-nitro-5H-dibenz [b, f] azepine obtained in Example 1 is obtained. The filtrate was concentrated by evaporation in vacuo and the residue dissolved in 40 ml of 80% acetic acid to give another crystal. Total yield: 21.5g, 81.7% of theory

Example 13

43.6 g (0.2 mol) of 5-cyano-5H-dibenz [b, f] azepine is dissolved in 430 ml of acetic anhydride. 19.0 g (0.206 mole) of N ₂ O ₄ is introduced into the solution with occasional cold stirring at a rate such that the temperature will not exceed 25 °. At the end of the reaction the solution turns green and the product precipitates in crystalline form. The product is stirred for 1 hour while cooling with ice, passed through a strong stream of nitrogen, filtered off and washed with a small amount of ethyl acetate. The same 5-cyano-10-nitro-5H-dibenz [b, f] azepine is obtained which is identical to the product obtained according to Example 1. The filtrate was concentrated by evaporation in vacuo and added in ethyl acetate to give another crystal. Total yield: 42.3g, 80.4% of theory

Example 14

35.0 g (0.16 mole) of 5-cyano-5H-dibenz [b, f] azepine is suspended in 160 ml of acetic anhydride at 20 °. While stirring, a solution of 14.7 g (0.16 mol) of N ₂ O ₄ dissolved in 160 ml of acetic anhydride was slowly added dropwise over 5 hours, and the temperature was maintained between 20 and 25 °. After all the starting materials are reacted (thin layer chromatography test), the mixture is cooled for 1 hour and the crystal product is suction filtered. The same 5-cyano-10-nitro-5H-dibenz [b, f] azepine is obtained which is identical to the product obtained according to Example 1.

The filtrate is concentrated to 50 ml by evaporation in vacuo to afford crystals. Total yield: 34.6g, 80% of theory

Example 15

43.6 g (0.2 moles) of 5-cyano-5H-dibenz [b, f] azepine is dissolved in 175 ml of acetic anhydride at 50 °. If N ₂ O ₄ is introduced into the solution in an amount in which all of the starting materials react from the pressurized container over 2 hours, an excess of N ₂ O ₄ can be detected in the waste gas. The product is crystallized at 50 ° and then 16.5 g (0.2 mol) of sodium acetate is added in small portions.

After the heat generation has stopped, the mixture is further stirred at 50 ° for 30 minutes and then at room temperature for several hours. Filtration and washing of the crystals with acetic acid and water afforded the same 5-cyano-10-nitro-5H-dibenz [b, f] azepin as the product obtained according to Example 1. The mother liquor can be treated to further yield 3 g of the compound. Total yield: 44.1g, 83.8% of theory

Example 16

5 ml of concentrated nitric acid (approximately 64% strength) is added to 20 ml of acetic anhydride solution containing 2.0 g of 5-cyano-5H-dibenz [b, f] azepine with stirring at 20 ° and exothermic and dark yellow. Color change occurs. The mixture was allowed to react at 20 ° for 1 hour, 40 ml of water was added dropwise at 50 ° and the precipitated oil was added to ethyl acetate. After the organic layer was washed and evaporated, the remaining residue was treated with acetonitrile and left for a relatively long time. According to liquid chromatography, 78% of 5-cyano-10-nitro-5H-dibenz [b, f] azine 0.6 g of yellow crystals containing was obtained.

Example 17

7.9 g (0.03 mol) of 5-cyano-10-nitro-5H-dibenz [b, f] azepine is suspended in 150 ml of ethanol and 50 ml of concentrated hydrochloric acid are added. 15 g of iron powder is stirred vigorously for 15 minutes at a temperature of 40 ° and the temperature rises to 55 °. The mixture is stirred at 55 ° for 1 hour and the insoluble material is filtered on and washed three times with 25 ml of ethanol each time. Concentrate the filtrate to 80 ml volume and add 400 ml of ice water with gentle stirring. The off-white precipitate is filtered off, washed to neutrality with water and dried at 80 ° under vacuum. After recrystallization from ethanol, 5-cyano-10-oxo-10, 11-dihydro-5H-dibenz [b, f] azepine having a melting point of 154 to 156 ° is obtained. Yield: 4.8 g, 68.4% of theory. Analytical values and spectral data are consistent with the accepted structure.

Example 18

52.6 g (0.2 mole) of 5-cyano-10-nitro-5H-dibenz [b, f] azepine is suspended in a mixture of 400 ml of toluene and 200 ml of ethanol. When 130 ml of hydrochloric acid (concentration) is added, the substance dissolves, producing mild heat. The solution is heated to 40 ° and a solution containing 113 g (0.5 mol) of SnCl ₂ · 2H ₂ O in 90 ml of concentrated hydrochloric acid is added over 10 minutes. Raise the temperature to 55 ° and hold for another 20 minutes at this temperature. The mixture is cooled, the organic layer is separated and the aqueous layer is extracted repeatedly with toluene. The toluene extracts are combined, washed with water until neutral, dried over sodium sulfate and concentrated by evaporation in vacuo. The remaining crude product is slurried using 100 ml of isopropanol, filtered and cold washed with a small amount of isopropanol. 5-Cyano-10-oxo-10, 11-dihydro-5H-dibenz [b, f] azepine is obtained which is identical to the product obtained according to Example 17. Yield: 29.0 g, 62% of theory

Example 19

5.0 g (0.02 mol) of 5-cyano-10-nitro-5H-dibenz [b, f] azepine is dissolved in 80 ml of ethanol and 80 ml of acetic acid mixture. A small amount of 10 g of zinc powder was added over 10 minutes with stirring to raise the temperature to 80 °. After stopping the reaction, 40 ml of concentrated hydrochloric acid was added at room temperature. The reaction mixture is stirred for 5 hours, the insoluble material is filtered off, the filtrate is evaporated to dryness and the residue is dissolved in 50 ml of water. Repeated recrystallization of the precipitated crude product followed by the same pure 5-cyano-10-oxo-10, 11-dihydro-5H-dibenz [b, f] azepin as the product obtained according to Example 17 Is obtained. Yield: 2.3 g, 50% of theory

Example 20

26.3 g (0.1 mol) of 5-cyano-10-nitro-5H-dibenz [b, f] azepine is suspended in 150 ml of acetic acid and 100 ml of concentrated hydrochloric acid. Only 40 g of iron at 30 ° was added in small portions with stirring over 30 minutes and kept at 60 ° by cooling the temperature. The mixture is stirred for 30 minutes at 50-60 ° and the insoluble material is filtered off and washed with acetic acid. The filtrate is twice the volume of water added and extracted three times with 100 ml of methylene chloride each time. The combined organic layers are washed with water, dried over sodium sulfate and concentrated by evaporation. 100 ml of isopropanol is used as a slurry for the crystalline residue and suction filtered. The resulting 5-cyano-10-oxo-10, 11-dihydro-5H-dibenz [b, f] azepine is identical to the product obtained according to Example 17. Yield: 21.8 g, 93.2% of theory

Example 21

5.2 g (0.02 mol) of 5-cyano-10-nitro-5H-dibenz [b, f] azepine are suspended in a mixture of 100 ml of chlorobenzene and 50 ml of ethanol. Continuous addition of 50 ml of concentrated hydrochloric acid raises the temperature of the mixture to 35 °. At this temperature, 20 g of iron powder is added in small amounts with vigorous stirring for 5 minutes to raise the temperature of the reaction mixture to 60 ° within a few minutes. The mixture is then stirred for 3 hours while cooling to 25 ° and the iron slurry is filtered off and washed repeatedly with ethanol and water. The organic layer of the filtrate is washed with water, extracted, dried and concentrated by evaporation to give crystalline crude product, which is recrystallized from isopropanol. The resulting 5-cyano-10-oxo--10, 11-5H-dibenz [b, f] azepine is identical to the product obtained according to Example 17. Yield: 3.8 g, 81% of theory

In a reaction mixture similarly treated using toluene as solvent instead of chlorobenzene, the final product is obtained in 84% yield.

Example 22

26.3 g (0.1 mole) of 5-cyano-10-nitro-5H-dibenz [b, f] azepine is suspended together with 40 g of iron powder in 250 ml of toluene and 125 ml of ethanol mixture. When 100 ml of concentrated hydrochloric acid is added dropwise with vigorous stirring over 75 minutes, the temperature rises to 60 °. After stirring for 10 hours at room temperature, the reaction mixture was subjected to an operation similar to the method described in Example 21 to obtain the same 5-cyano-10-oxo--10, 11-dihydro as the product obtained according to Example 17. -5H-dibenz [b, f] azepine is obtained. Yield: 19.8 g, 84.6% of theory

Example 23

2.0 g (0.0085 mole) of 5-cyano-10-oxo-10, 11-dihydro-5H-dibenz [b, f] azepine was dissolved in 10 ml of concentrated sulfuric acid while cooling with ice and the solution was dissolved from 0 to 5 Leave at 30 ° C for 30 minutes and then add dropwise to 200 ml of ice water. The flake precipitate is suction filtered, washed to neutrality with water, dried and recrystallized from isopropanol. The same 5-carbamoyl-10-oxo-10, 11-dihydro-5H-dibenz [b, f] azepine is obtained which is certified according to the I R spectrum. Yield: 1.4 g, 65% of theory

Example 24

1.0 g (0.0043 mole) of 5-cyano-10-oxo-10, 11-dihydro-5H-dibenz [b, f] azepine, 8 ml of acetic acid and 2 ml of concentrated sulfuric acid until complete dissolution occurs Stir for 48 hours. The resulting solution is added dropwise to 100 ml of ice water with stirring, the flake precipitate is filtered off, washed with water to neutral and dried at 50 ° under vacuum. The same 5-cyano-10-carbamoyl-10-oxo-10, 11-dihydro-5H-dibenz [b, f] azepine is obtained which is identical to the certified material according to the I R spectrum. Yield: 0.9 g, 84% of theory

Example 25

A solution containing 2.0 g (0.0085 mol) of 5-cyano-10-oxo-10, 11-dihydro-5H-dibenz [b, f] azepine in 20 ml of 98% strength formic acid was 110-120. Heat for 8 hours in a bath of °. The solution is introduced into 100 ml of ice water, filtered and washed to neutral with water and dried at 50 ° under vacuum. According to the I R spectrum, 5-carbamoyl-10-oxo-10, 11-dihydro-5H-dibenz [b, f] azepine is identical to the certified material. Yield: 1.8 g, 84% of theory

Example 26

When 1.0 g (0.0043 mol) of 5-cyano-10 (11) -oxo-10, 11-dihydro-5H-dibenz [b, f] azepine is treated with 20 g of polyphosphoric acid and complete dissolution occurs It is left for several hours at room temperature. Excess water is added in small portions and the yellowish white precipitate is filtered off with suction and washed with water until neutral. After recrystallization from chlorobenzene, the same 5-carbamoyl-10-oxo-10, 11-5H-dibenz [b, f] azepine is obtained which is identical to the material certified according to the I R spectrum. Yield: 0.75 g, 70% of theory

Example 27

5.0 ml of H ₂ O ₂ (30%) was stirred at room temperature with 1.0 g (0.0043 moles) of 5-cyano-10-oxo-10, 11-dihydro-5H-dibenz [b, in 20 ml of methanol. f] Azepine is distilled into the suspended solution. After stirring for 3 hours, the insoluble material was filtered off, washed once with methanol and then repeatedly washed with water to obtain the same 5-carbamoyl-10-oxo-10, 11-dihydro-5H as the certified material according to the IR spectrum. -Dibenz [b, f] azine is obtained. Yield: 0.6 g, 55% of theory

Example 28

_Three BF gases are added to a suspension of 3.0 g (0.013 mol) of 5-cyano-10-oxo-10, 11-dihydro-5H-dibenz [b, f] azepine in a mixture of 30 ml of acetic acid and 3 ml of water. While stirring, the initial strong exothermic reaction is introduced until it stops and the temperature is maintained at 50 ° by external cooling. Cool the reaction solution, add 100 ml of water dropwise while cooling with ice to this clear solution, filter the colorless precipitate, and wash the filter residue to neutrality with water to recrystallize from acetonitrile. The resulting 5-carbamoyl-10-oxo-10, 11-dihydro-5H-dibenz [b, f] azepine is identical to the material certified according to the IR spectrum. Yield: 71% of 2.3g theory

Example 29

2.0 g (0.0085 mol) of 5-cyano-10-oxo-10, 11-dihydro-5H-dibenz [b, f] azepine were introduced into 40 ml of 10% by weight acetic acid solution in small portions with stirring and 20 Clear solution is obtained over a period of 15 minutes at °. After standing for 3 hours, 100 ml of water is added while stirring with ice, and sodium hydroxide solution is added to adjust the pH of the solution to 6. Precipitated crude 5-carbamoyl-10-oxo-10, 11-dihydro-5H-dibenz [b, f] azepine was aspirated, washed with water and dried. Same as the certified material according to the I R spectrum. Yield: 1.6 g, 74.8% of theory

Example 30

10.3 g (0.055 mol) of BF ₃ .2CH ₃ COOH complex was mixed with 11.7 g (0.05 mol) of 5-cyano-10-oxo-10, 11-dihydro-5H-dibenz [b, f in 60 ml of acetic acid. ] The starting material slowly dissolves when added to the azepine suspension and the temperature is raised to 35 ° without external cooling. After about 1 hour, the BF ₃ adduct begins to crystallize. The mixture is stirred at rt for 4 h and washed with acetic acid. The intermediate was prepared into a slurry by adding 100 ml of water, neutralized with sodium acetate to pH 6 and stirred for 1 hour. 9.0 g of 5-carbamoyl-10-oxo-10, 11-dihydro-5H-dibenz [b, f] azepin is obtained which is the same as the material certified according to the IR spectrum after washing with suction. The filtrate of the intermediate is concentrated by evaporation and fractionated from methanol / water to give 1.2 g more product. Total yield: 10.2g, 81% of theory

Example 31

50 ml of a 15% by weight solution of BF ₃ in acetic acid is suspended in 23.4 g (0.1 mole) of 5-cyano-10-oxo-10, 11-dihydro-5H-dibenz [b, f] azepine in 40 ml of acetic acid. And the mixture is stirred until heat dissipation stops. Dropping 15 ml of water raises the temperature to 40-45 ° resulting in a clear dark blue solution. The solution is held at 40 ° for 15 minutes and then slowly added 135 ml of water. The resulting crystalline precipitate is stirred for several hours at room temperature, filtered off with suction and washed until neutral with water. After drying at 50 ° in vacuo, the same 5-carbamoyl-10-oxo-10, 11-dihydro-5H-dibenz [b, f] azepine is obtained which is identical to the certified material according to the IR spectrum. Yield: 24.2 g, 96.0% of theory

Example 32

23.4 g (0.1 mole) of 5-cyano-10-oxo-10, 11-di in 230 ml of chlorobenzene, while stirring 15.4 ml (0.11 mole) of BF ₃ .2CH ₃ COOH complex and 38 ml of acetic acid mixture at room temperature. Quickly drain into a hydro-5H-dibenz [b, f] azepine suspension. When the transparent brown solution is gently heated, the crystalline precursor is precipitated after about 10 minutes. The temperature is kept at 5 ° for 30 minutes, then filtered and washed with chlorobenzene. 200 ml of water was added to the dried intermediate to prepare a slurry, stirred for 30 minutes, suction filtered and washed until neutral with water. After drying at 60 ° in vacuo, the same 5-carbamoyl-10-oxo-10,11-dihydro-5H-dibenz [b, f] azepine is obtained which is identical to the material certified according to the IR spectrum. Yield: 24.1 g, 95.6% of theory

Example 33

1.0 g (0.004 mole) of 5-cyano-10-nitro-5H-dibenz [b, f] azepine was dissolved in 40 ml of ethanol and 20 ml of acetic acid mixture at 60 ° and 2.0 g of zinc powder was heated. It is added over 10 minutes with stirring. Continue stirring for 15 more minutes, filter the insoluble material on, and wash with ethanol and water. The filtrate is evaporated to dryness and dissolved in 50 ml of water. After suction filtration, washing with water and drying, crude 5-cyano-10-isonitroso-10, 11-dihydro-5H-dibenz [b, f] azepine was obtained, and recrystallized from ethanol and 185 °. Dissolve and dissolve in Analytical and spectral data are consistent with the cited structures. Yield: 0.9 g, 95% of theory

Example 34

50.0 g (0.19 mole) of 5-cyano-10-nitro-5H-dibenz [b, f] azepine was dissolved in 500 ml of pyridine and 10 g of palladium / carbon (5%) was added, followed by room temperature and pressure. Hydrogenation is carried out. The catalyst was filtered off, the solvent was evaporated in vacuo and the remaining crude product was recrystallized from methanol / water to give the same 5-cyano-10-isonotros-10, 11-dihydro as the product obtained according to Example 33. -5H-dibenz [b, f] azepine is tapped.

Yield: 35.6 g, 75.2% of theory

Example 35

2.5 g (0.01 mole) of 5-cyano-10-isonitroso--10, 11-dihydro-5H-dibenz [b, f] azepine was diluted with 25 ml of toluene, 15 ml of ethanol and 10 ml of concentrated hydrochloric acid. Suspension in the mixture. The suspension is stirred at 50 ° for 30 minutes and the toluene layer is separated and then evaporated to dryness in vacuo. Slurry filtration of the crystalline residue by slurrying with 10 ml of isopropanol and washing twice with isopropanol yielded the same 5-cyano-10-oxo-10, 11-dihydro-5H-di as the product obtained according to Example 17. Benz [b, f] azepine is obtained. Yield: 0.8 g, 35% of theory

Example 36

26.3 g (0.1 mole) of 5-cyano-10-nitro-5H-dibenz [b, f] azepine is suspended in 265 ml of ethylene glycol monoethyl ether and 75 ml of concentrated hydrochloric acid. 40 g of iron powder is added in small portions over 40 minutes at 40 ° and the temperature is maintained at 40 ° by external cooling. After stirring the mixture for 2 more hours at room temperature and heating to 80 °, the precipitated product is dissolved again, which is filtered through a heated suction filter and subsequently washed with ethylene glycol monoethyl ether. Crystallization starting in the filtrate is completed by adding 200 ml of water. After cooling for 1 hour in an ice bath, filtration and washing with a mixture of ethylene glycol monoethyl ether and water 1: 1. When comparing the I R spectra, the same 5-cyano-10-oxo-10, 11-dihydro-5H-dibenz [b, f] azepin is obtained which is identical to the material obtained in Example 17. Yield: 19.0 g, 81.2% of theory

Claims (1)

5-Cyano-5H-dibenz [b, f] azepine of formula (I) was used as a lower alkane carboxylic acid up to 4 carbon atoms, a lower alkane carboxylic acid anhydride up to 4 carbon atoms, a lower alkane carboxylic acid up to 4 carbon atoms and anhydrides thereof. Nitrogenated at about 0 to 120 ° C. with a nitrating agent selected from N ₂ O ₃ · N ₂ O ₄ or nitric acid using a weight ratio of solvent 1: 3 to 1:30 (weight / volume) in a solvent selected from the mixture. 5-cyano-10-nitro-5H-dibenz [b, f] azepine of (II) is produced and then released by hydrogen in the presence of a hydrogenation catalyst or by a metal in an acid selected from inorganic or lower alkane carboxylic acids. After reducing the 10-nitro group of the compound of formula (II) at 10 to 100 ° C. with a reducing agent selected from generator hydrogen or stannous chloride, 2H ₂ O, the reaction mixture was hydrolyzed to give 5-cyano of formula (V). -10-oxo-10, 11-dihydro-5H-dibenz [ b, f] azepine is produced, and the 5-cyano group of the compound of formula (V) is present in solution form of an inorganic acid, a lower alkane carboxylic acid with up to 4 carbon atoms or a lower alkane carboxylic acid or as a complex of the formula BF ₃ .2CH ₃ COOH 5-carbamoyl-10-oxo-10, 11-dihydro-5H-di of formula (III), characterized by hydrolysis at -5 to 150 ° C by an acidic reagent selected from among boron trifluorofluoride. Method for preparing benz [b, f] azepine.