NO139481B - PROCEDURES FOR THE PREPARATION OF BENZODIAZEPINE DERIVATIVES - Google Patents

Description

The present invention relates to a method for the production of benzodiazepine derivatives with the general formula

where R1 means hydrogen, halogen or nitro or R2 hydrogen or lower alkyl and

R 3 phenyl, o-halophenyl or 2-pyridyl.

The method according to the invention comprises the reaction of a compound with the general formula

where R1? R2 and R3 have the meanings given above, and where X means chlorine, bromine or iodine, and then preferably chlorine,

with hexamethylenetetramine in an inert organic solvent, possibly during isolation of an intermediate with the general formula

where R^, R2, R^ and X have the meanings given above,

and is characterized by the fact that ammonia is used when carrying out the method.

The term "lower alkyl" used in this description denotes straight-chain or branched hydrocarbon groups, such as e.g. methyl, ethyl, propyl, butyl etc. If R 2 means lower alkyl, then methyl is preferred. The term "halogen" denotes bromine, chlorine, fluorine and iodine unless otherwise indicated. When R^ means halogen, the halogens chlorine and bromine are preferred, and then especially chlorine. When R 1 means o-halophenyl, then o-chlorophenyl and o-fluorophenyl are preferred, and then especially o-fluorophenyl.

The state of the art according to J.Het.Chem ]_ [1970] page 1173 specifies a method for the preparation of benzodiazepines of formula I using a compound of formula II as starting material and hexamethylenetetramine. By this known procedure! is however obtained, e.g. when R2 in the starting material means hydrogen, contrary to what is stated in the aforementioned literature quote, no yields that can be used practically.

The present invention now enables the production of compounds of formula I from compounds of formula II and hexamethylenetetramine in a simple and easily implementable method, which has the advantage over the stated state of the art that it gives higher yields and/or has a larger area of application.

In addition, the compounds of formula I are obtained with high purity when the process conditions described subsequently are followed.

According to a process aspect of the present invention, namely the reaction of a compound of formula II with hexamethylene-tetramine in the presence of ammonia, the reaction is carried out in the presence of an inert organic solvent suitable for the purpose according to the present invention. Such suitable inert organic solvents include lower alkanols, such as methanol, ethanol, n-butanol and the like, dimethylformamide and similar inert organic solvents, as well as aqueous mixtures thereof, e.g. aqueous ethanol (95%), and aqueous butanol. The solvent must be chosen so that the starting material is dissolved in the solvent,

and so that the solvent does not interfere with the reaction. Lower alkanols, such as methanol or ethanol, are preferred. Furthermore, the solvent must be chosen so that it has the property that it dissolves ammonia and thus enables its supply to the reaction. Temperature and pressure are not critical for a successful implementation of the method according to the invention. However, the reaction is preferably carried out at a temperature between approx. room temperature and approx. the reflux temperature of the reaction mixture. One particularly prefers to use higher temperatures. A temperature around the reflux temperature of the reaction mixture is particularly suitable. Furthermore, the reaction can also be carried out under pressure to increase the ammonia concentration in the reaction mixture.

Ammonia is preferably added to the reaction medium in such quantities that the inert organic solvent is saturated with ammonia. As indicated above, the reaction is preferably carried out at the reflux temperature of the reaction mixture, as it is usually necessary to use less ammonia to saturate a solvent at higher temperatures. For a successful completion of the reaction of a compound of formula II with hexamethylenetetramine, it is usually only necessary to use a smaller molar amount of ammonia. According to a preferred method aspect, a solvent is thus selected which has the property that it dissolves the starting material, and which is already supersaturated at relatively small molar amounts of ammonia.

E.g. ethanol is used according to a preferred aspect. This is saturated when approx. 1 mol% ammonia is present. This percentage is calculated according to a fraction, the denominator of which indicates the molar amount of ammonia required to supersaturate the solvent,, and. whose numerator indicates the sum of the molar amount of hexamethylenetetramine, compounds according to formula II and ammonia present in the reaction mixture. The solubility of ammonia in any inert organic solvent which is suitable for the purpose according to the present invention can be determined with the help of known encyclopedias. With this determination, one can also easily find the suitable, inert organic solvent. As indicated above, the application of pressure causes the ammonia concentration in the reaction medium to rise beyond the concentration normally required to saturate the inert organic solvent. Thus, the reaction is carried out according to a specific form of expansion under pressure of approx. 1 to approx. 2 atmospheres. Higher ammonia concentrations can easily be achieved by using a suitable, aqueous, inert organic solvent.

When carrying out the method according to the invention, it has been observed that an intermediate product with the above formula III is formed. This intermediate product can, with or without isolation from the reaction medium in which it is formed, be reacted with ammonia to the desired compound of formula I.

Thus, a compound of formula III, and especially such a compound, where R 2 means lower alkyl, can be isolated from the reaction mixture and treated with ammonia, whereby a corresponding compound of formula I is obtained. On the other hand, a compound can also be added with formula II and hexamethylenetetramine to the solvent, and then first add the ammonia without isolating the compound with formula III. According to a preferred embodiment, the intermediate product of formula III is not isolated but reacted with ammonia without isolation from the reaction medium. This occurs above all when R 2 means hydrogen.

A compound of formula III can also be prepared in a different way than described above. For example* one can in an analogous way, and as described in the above-mentioned article in the "Journal of Hetero-cyclic Chemistry", add a compound of formula II and hexamethylenetetramine while stirring at room temperature to a solvent with low polarity, such as acetonitrile, and isolate the intermediate product with formula III. The thus obtained compound with formula III is, after isolation from the solvent in which it is prepared, reacted with ammonia, and thereby a compound with formula I is obtained in good yield and of high purity. It will be understood by a person skilled in the art that the reaction between a compound of formula III and ammonia proceeds under the same reaction conditions as described above in connection with the preparation of a compound of formula I from a compound of formula II from hexamethylenetetramine and ammonia. the reaction of an intermediate of formula III with ammonia the same reaction conditions and solvents as mentioned above in connection with m ed the preparation of a compound of formula I is used, with the exception that no hexamethylenetetramine is added during the reaction. As is clear from the above, the invention consists in adding ammonia to the reaction medium, in which hexamethylenetetramine and a compound of formula II, respectively. an intermediate of formula III is present. The manner in which ammonia is added to the reaction mixture is not critical. E.g. one can add the hexamethylenetetramine and the ammonia to the inert organic solvent, and only then add the compound of formula II. On the other hand, one can also dissolve the ammonia in an inert organic solvent, and then add a compound of formula II and hexamethylenetetramine or intermediates of formula III to the reaction mixture. As already mentioned above, it is not critical how you add the ammonia. According to a preferred embodiment, the ammonia is added while passing gaseous ammonia through the reaction mixture. According to a less preferred embodiment, ammonia can also be added to the reaction mixture by means of a reagent that gives ammonia, e.g. ammonium carbonate,; and which in a solvent medium, such as ethanol, and when heated to reflux is decomposed into ammonia. When using a reagent which gives ammonia instead of ammonia, the yields are usually not so good. A characteristic feature of the method according to the invention is the fact that a larger molar excess of hexamethylenetetramine is not necessary for a successful implementation of the method. Thus, one obtains e.g. already using only 0.1 mol per mol used starting material with formula II the desired compound with formula I, whereby one preferably uses, however, approx. 0.5 mol of hexamethylene tetramine. Thus, the present invention entails a further and particularly noteworthy advantage in that the amount of hexamethylenetetramine required for the reaction can be reduced to a minimum, and that consequently the manufacturing costs of the final product are reduced without this having a correspondingly reducing effect on the yield. Because of this remarkable advantage, the commercial side of the method according to the invention is particularly interesting. Attention should therefore be drawn to the fact that the yields become somewhat worse when less than 0.5 mol of hexamethylenetetramine is used. If, however, 0.5 mol of hexamethylenetetramine is used, the desired compounds of formula I are obtained in excellent yield and of very good quality. When carrying out the process measures described above, and especially when using a starting material of formula II, where R2 means hydrogen, it has been observed that the reaction of hexamethylenetetramine with a compound of formula II proceeds with the formation of formaldehyde. The ammonia present in the reaction mixture reacts with the formaldehyde thus formed to form new hexamethylenetetramine. Furthermore, it has also been established that the desired compounds of formula I can also be prepared by treating a compound of formula II with formaldehyde in the presence of an excess of ammonia. According to this procedural aspect, anhydrous formaldehyde (paraformaldehyde) or aqueous formaldehyde (38% formalin) can be used. Temperature and pressure are not critical for a successful implementation of this process aspect. However, the reaction is preferably carried out at a higher temperature, e.g. at the reflux temperature of the reaction mixture. The reaction conveniently takes place in the presence of an inert organic solvent. The many inert organic solvents suitable for the purpose according to the present invention include the solvents mentioned earlier in connection with the formation of a compound of formula I from a compound of formula II, hexamethylenetetramine and ammonia. Generally, the following can be mentioned as suitable solvents: methanol, ethanol, n-butanol and the like, dimethylformamide and similar inert organic solvents, as well as aqueous mixtures thereof, e.g. aqueous ethanol or methanol. Here, too, the solvent must be selected so that the starting material is soluble in the solvent, and so that the solvent does not intervene in the reaction. Methanol and/or ethanol are preferred. It follows from the above that the formaldehyde in this process aspect reacts with ammonia, which is present in molar excess, to form hexamethylenetetramine, whereby a compound of formula III is obtained, which with or without isolation, preferably without isolation, is transferred into a compound of formula I. The amount and manner in which ammonia is added to the reaction mixture is the same as stated above in connection with the preparation of a compound of formula I using hexamethylenetetramine and ammonia. Accordingly, according to a preferred embodiment, the solvent will be saturated with ammonia, preferably by passing ammonia through the solvent. The following examples illustrate the method according to the invention. All temperatures are given in degrees Celsius. EXAMPLE 1 600 ml of ethanol and 31.7 g of hexamethylenetetramine are added to a 2 liter 4-necked flask, which is equipped with a stirrer, reflux skirts and a gas inlet port for ammonia. Ammonia is then introduced with stirring through the reaction solution until the reaction medium is saturated with ammonia. The saturated solution is heated to reflux while ammonia is still passed through. Then 78 g of 2-bromo-2'-(2-fluorobenzoyl)-4'-nitroacetanilide are carefully added over a period of . 2 hours, while the reflux conditions are still maintained. The reaction mixture is heated to reflux for a further 3 hours, after which it is evaporated to dryness under reduced pressure at 50°. 300 ml of toluene and 0.4 g of p-toluenesulfonic acid are added to the remaining residue. The resulting reaction mixture is heated to reflux for 1 hour. The mixture is then cooled to approx. 70° and washed with water. The toluene layer is then cooled to room temperature, and the crystalline product separated by filtration, washed with toluene and dried. This gave 5-(2-fluorophenyl)-1,3-dihydro-7-nitro-2H-1,4^benzodiazepine-2-one with m.p. 210 - 215°, yield 25.5% of theoretical. ;EXAMPLE 2 ;1 600 ml of ethanol and 31.2 g of hexamethylenetetramine are added to a 2 liter 4-necked flask, which is equipped with a stirrer, reflux skirts and a gas introduction tube for ammonia. During stirring, ammonia is introduced through the obtained reaction solution until the ethanol is saturated with ammonia. The resulting reaction mixture is heated to reflux. While the reflux conditions are maintained and ammonia is passed through, 40 g of 2-bromo-4'-chloro-2'-(2-chlorobenzoyl)- are carefully added over a time interval of 2 hours. The reaction mixture thus obtained is evaporated to dryness. To the remaining residue, 300 ml of toluene and then 0.3 g of p-toluenesulfonic acid are added. The toluene solution is heated to reflux. The reaction mixture is cooled to 70°. After cooling, it is washed with water. The toluene extract is cooled to room temperature. After cooling to 10°, the crystalline product formed is filtered off, washed with toluene and petroleum ether and dried overnight under reduced pressure. This gave 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one, with m.p. ;200 - 200.5°, yield 68.3% of theoretical. EXAMPLE 3 600 ml of ethanol and 30.4 g of hexamethylenetetramine are added to a 2 liter 4-necked flask, equipped with reflux skirts, a gas introduction tube for ammonia and stirrer. Ammonia is passed through the reaction solution for so long that the ethanol is supersaturated. The reaction mixture is heated to reflux and 40 g of 2-bromo-2'-(2-chlorobenzoyl)-4'-nitroacetanilide are carefully added over a period of 3 1/2 hours. The heating to reflux and the passage of ammonia through the reaction mixture are continued for the next 3 hours and then the reaction mixture is evaporated to dryness. 250 ml of toluene and 0.4 g of p-toluenesulfonic acid are added to the residue. The mixture is heated to reflux for 1 hour. The toluene phase is cooled to 70°. The solution obtained is washed with water. The toluene phase is then cooled to room temperature. The product crystallizes from the reaction mixture. The crystals are filtered off, washed once with toluene and once with petroleum ether and dried, thereby obtaining 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepine-2-one with m.p. 203 - 204°, yield 62.9% of theoretical. EXAMPLE 4 7.2 liters of ethanol and 470.4 g of hexamethylenetetramine are added to a 12 liter 3-necked flask, equipped with a separator and a gas introduction tube for ammonia. During conversion, ammonia is passed through the reaction solution until it is supersaturated. While heating to reflux, 480 g of 2-chloroacetamido-5-chlorobenzophenone are carefully added in portions over a period of 4 hours. The resulting reaction mixture is heated for a further 2 hours to reflux, whereby the passage of ammonia is continued. The resulting reaction mixture is allowed to stand overnight and is then evaporated under reduced pressure to dryness. 2.4 liters of toluene are added to the residue and the resulting reaction mixture is heated to reflux. 0.5 g of p-toluenesulfonic acid is then added and heating to reflux is continued for 1 hour. : -After cooling the reaction mixture to 70°, 1.5 liters of hot water are added. The product, which precipitates on cooling to 20°, is filtered off, washed and dried under reduced pressure, thereby obtaining 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one with m.p. 213 - 214°, yield 80.3% of theoretical. Analogously to what is described above, 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepine-2-one can be prepared, m.p. 225 - ;235° from 2-(2-chloroacetamido-5-bromo-benzoyl)pyridine. ;EXAMPLE 5 ;A 12 liter 3-necked flask, fitted with a sealed stirrer, reflux condenser and a gas introduction tube for ammonia was weighed with 7.2 liters of ethanol. The alcohol is heated with stirring on a steam bath to reflux. The solvent is then saturated with ammonia (at a concentration of about 0.6 to 0.7% by weight). After removing the hot bath, 493 g of hexamethylene tetramine are added. The heating is continued and 480 g of 2-chloroacetamido-5-chlorobenzophenone is added slowly in small portions. The ammonia is continuously passed through the reflux heated solution. The addition of the chloroacetamido compound lasts approx. 3-4 hours. After the addition is complete, the reaction mixture is heated to reflux for a further 2 hours. The passage of the ammonia stream is interrupted and the alcohol is removed by vacuum distillation. The residue is suspended in 2.4 liters of toluene and heated to reflux. At the reflux temperature, 0.5 g of p-toluenesulfonic acid is added twice over 15 minutes. A small amount of water (approx. 1 - 2 ml) is excreted. The crystallisate is then cooled to 70° and the water-soluble part is dissolved by adding 1.5 liters of warm (70°) water. The heterogeneous mixture is stirred overnight, whereby it is cooled to room temperature. The product, which separates, is separated by filtration and washed once with 250 ml of cold water and once with 250 ml of cold (0°) toluene. The product is then dried to constant weight at 80°, whereby 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one is obtained; with m.p. 213 - 214°, yield 80.7% of theoretical. ;EXAMPLE 6 ;In a 2-liter 4-necked flask, equipped with a stirrer, reflux condenser and gas introduction tube for ammonia, 600 ml of ethanol and 37.9 g of hexamethylenetetramine are added while stirring. The resulting reaction solution is then passed through ammonia while heating and stirring until the reaction mixture has reached the reflux temperature. 40 g of 2-chloroacetamido-5-nitro-benzophenone are then carefully added to the boiling solution. Ammonia is passed continuously through the reaction mixture while heating to reflux is continued for a further 3 hours. The solution obtained is cooled and evaporated to dryness at 50°. The residue is dissolved in 300 ml of toluene, 0.3 g of p-toluenesulfonic acid is added to this and the resulting reaction solution is heated to reflux for 1 hour. The reaction mixture is then cooled to room temperature and the separated substance is filtered off, washed with water and dried. The residue is dissolved in 435 ml of methylene chloride and then filtered through hyflo. After adding 90 ml of 3-n nitric acid to the filtrate, crystals separate. These are filtered off, washed with methylene chloride and dried for 15 minutes. The crystals are added while stirring to one liter of water. Ammonium hydroxide is then carefully added until the pH has reached 8. After stirring the resulting reaction mixture for half an hour, the precipitated crystals are filtered off, washed with cold water and dried for 8 hours at 80°, whereby 1,3-dihydro-7-nitro- 5-phenyl-2H-1,4-benzodiazepine-2-one with m.p. 217 - 219°, yield 27.2% of theoretical.

EXAMPLE 7

90 g of 2-chloroacetamido-5-chloro-benzophenone and 92.5 g of hexamethylenetetramine are added to 1350 ml of ethanol. Under pressure, ammonia is passed through the reaction mixture obtained, this is heated to reflux and then evaporated under reduced pressure to dryness. The rest is grated twice with 250 ml of warm water. The aqueous phase is decanted and the crystalline residue is heated for 30 minutes in 250 ml of toluene on a steam bath and then cooled to room temperature. The crystals formed are filtered off, washed twice with 25 ml of toluene and 25 ml of petroleum ether and then dried to constant weight, whereby 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2 is obtained -on with m.p. 213 - 215°, yield 78% of theoretical.

EXAMPLE 8

13.5 liters of 95% ethanol, 900 g of 2-chloroacetamido-5-chlorobenzophenone and 925 g of hexamethylenetetramine are added while stirring in a pressure vessel. During stirring, the reaction mixture is saturated

..with■ ammonia. ■ The ammonia addition is removed and the resulting reaction mixture is heated for 3 hours to 70 - 80°. After cooling and evaporation of the ammonia, the reaction mixture is transferred from the pressure vessel to a distillation vessel. The mixture is concentrated on a steam bath under reduced pressure to dryness. 2 1/2 liters of toluene and 5 g of p-toluenesulfonic acid are added to the residue and the resulting mixture is heated to reflux. About. 5 ml of water, which has formed, is removed by azeotropic distillation. After cooling to 70°, add 3 liters of water (70°). The crystallisate thus obtained is cooled for 1 hour at 10 to 15°. After filtering off, washing the product twice with 250 ml of water and once with 250 ml of cold (10°) toluene and drying to constant weight, 7-chloro-1,3-dihydro-5-phenyl-2H-1,4 is obtained -benzodiazepine-2-one with m.p. 211 - 213.5°, yield 66% of theoretical.

EXAMPLE 9

A mixture of 17.5 g of hexamethylenetetramine (0.125 mol), 135.5 ml of methanol and 80.5 g of 2-(2-chloro-N-methylacetamido)-5-chloro-benzophenone (0.25 mol) is saturated with ammonia. While stirring, the reaction mixture is slowly heated to reflux temperature, whereby an uninterrupted stream of ammonia is passed through the mixture. In the lab of the reaction is formed

This intermediate is not isolated. The reaction mixture is heated to reflux for 6 hours, then the ammonia flow is interrupted and the solvent is removed under reduced pressure.

The residue is taken up in a mixture of 500 ml toluene and 500 ml warm

water. The toluene phase is separated while stirring and then 169 ml of 3-n nitric acid is added. The formed crystals are filtered off, washed with 50 ml of toluene and taken up again in a mixture of 250 ml of toluene and 250 ml of water. 30 ml of concentrated ammonia is added (pH 8). The toluene phase is separated, washed with 250 ml of water and then evaporated under reduced pressure to dryness, whereby 7-chloro-1-methyl-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one is obtained with m.p. 125 - r 12 7°, yield 96.1% of theoretical.

EXAMPLE 10

A mixture of 600 ml of ethanol and 39.1 g of hexamethylenetetramine

(0.279 mol) is saturated with ammonia while stirring. While still passing ammonia through the mixture, it is slowly heated to reflux. Over a period of 4 1/2 hours, 40 g of 2-(2-chloro-N-methylacetamido)-5-chlorobenzophenone are added

(0.124 mol) in portions during the formation of

Without isolation of this intermediate, heating to reflux is continued for a further 2 hours. The reaction mixture is then evaporated under reduced pressure at 50° to dryness. The residue is stirred with 250 ml of toluene and heated to reflux. There-

then 2 portions of p-toluenesulfonic acid are added and heating to reflux is continued for 1 hour. After cooling to 70°, the toluene solution is washed with hot water to remove soluble salts and

evaporated under reduced pressure to dryness V The remainder is dissolved in

hot ethanol (111 mol) and the solution is cooled for one hour to -10°. The crystalline 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-ori thus obtained is isolated, m.p. 129 - 131°, 29 g. Concentration of the mother liquor to approx. 50% gives an additional final product with m.p. 12 7°, 2 g.

EXAMPLE 11

A mixture of 1100 ml of ethanol, 70.0 g of hexamethylenetetramine

(0.5 mol), 58 ml of 26% ammonium hydroxide solution and 308.2 g of 2-chloroacetamido-5-chlorobenzophenone (1.0 mol) are heated with stirring and introduction of ammonia slowly to reflux. Heating to reflux for 5 hours is continued, then the ammonia stream is interrupted and the reaction mixture is evaporated under reduced pressure to dryness. The residue is heated for 30 minutes in a mixture of 500 ml toluene and 500 ml water to reflux and then slowly cooled to room temperature.

The precipitated crystals are filtered off, washed with 100 ml of toluene and twice with 250 ml of hot water and then dried to constant weight. The thus obtained 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one melts at 210°, yield 83.5% of theoretical.

EXAMPLE 12

A mixture of 1100 ml of ethanol, 35 g of hexamethylenetetramine (0.25 mol), 58 ml of 26% ammonium hydroxide solution and 308.2 g of 2-chloroacetamido-5-chlorobenzophenone (1.0 mol) is reacted as described in example 11, with exception of heating the reaction mixture for 7 hours, instead of 5 hours, at reflux. The reaction product, namely 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one is isolated, as described in example 11 and melts at 208.5 - 209°, yield 81.6% of theoretical.

EXAMPLE 13

A mixture of 550 ml of methanol, 14.1 g of hexamethylene tetramine

(0.1 mol) and 308.2 g of 2-chloroacetamido-5-chloro-benzophenone are saturated at room temperature and under stirring with ammonia. The mixture is slowly heated to reflux under uninterrupted passage of ammonia. The heating to reflux is continued for 24 hours, then the ammonia drum and the obtained are removed

the crystallisate is cooled to room temperature. The product file

is filtered off, washed with twice 125 ml of methanol and four times with 500 ml of hot water and dried, thereby obtaining 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one with m.p. . 213 - 215°, yield 62.3% of theoretical.

EXAMPLE 14

A mixture of 300 ml of ethanol and 20 g of hexamethylenetetramine (0.143 mol) is saturated under stirring and heating to reflux.

with ammonia. 18.1 g of 2-chloro-acetamidobenzophenone (0.066 mol) is added in small portions in lbpet over a period of 3 to 4

hours, while a continuous stream of ammonia is passed through the reaction mixture. After the addition of 2-chloro-acetamidobenzophenone is finished, the heating to reflux is continued in 3

hours. The ammonia flow is interrupted and the ethanol is removed by distillation under reduced pressure. The residue thus obtained is taken up in 200 ml of chloroform and washed with 100 ml of 50° water. The chloroform phase is evaporated at 30° to dryness, and the oily residue crystallizes in 100 ml of toluene, whereby 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one with m.p. 184 - 186°, yield 86% of theoretical.

EXAMPLE 15

A mixture of 275 ml of methanol and 154.2 g of 2-chloroacetamido-5-chlorobenzophenone (0.5 mol) is heated under continuous passage of ammonia to reflux. At the reflux temperature, 237 ml of a 37% formaldehyde solution is added in the amount of approx. 40 minutes. The reaction mixture is heated to reflux for 5 hours. The passage of ammonia is interrupted and the crystallisate is cooled to room temperature, filtered, washed twice with 125 ml of methanol and four times with 500 ml of hot water and dried, thereby obtaining 7-chloro-1,3-dihydro-5-phenyl-2H-1 ,4-benzodiazepine-2-one with m.p. 211.5 - 214.5°, yield 77.3% of theoretical.

EXAMPLE 16

A mixture of 147.2 g of paraformaldehyde and 550 ml of methanol is heated with stirring and uninterrupted passage of ammonia to reflux. After cooling the thus obtained crystallisate of hexamethylenetetramine to room temperature, 308.2 g of 2-chloroacetamido-5-chlorobenzophenone (1.0 mol) are added in portions. When ammonia is passed through, the reaction mixture is heated to reflux for 10 hours. The passage of ammonia is interrupted and the reaction mixture is cooled to room temperature, filtered and washed twice with 125 ml of methanol and four times with 500 ml of hot water and dried, thereby obtaining 7-chloro-1,3-dihydro-5-phenyl-2H- 1,4-benzodiazepine-2-one with m.p. 212.5-215°, yield 81.4% of theoretical.

EXAMPLE 17

200 g of paraformaldehyde (91% floc) is added to a vessel, equipped with agitator, reflux condenser and gas introduction tube for ammonia as well as a device for decanting

and 575 ml of methanol and then gaseous ammonia is passed through the mixture. 2 73.7 g of 2-chloroacetamido-benzophenone are then added. By passing a slow, continuous stream of ammonia, the mixture is heated to reflux for 5 hours. The crystallisate obtained is distilled to

recover the methanol again. 350 ml of toluene are then added to the crystalline residue and the water still present is removed by azeotropic distillation. The hot toluene solution is then filtered and the filtrate is cooled until crystallization, whereby 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one with m.p. 180 - 181° (not corrected), yield 84.7% of theoretical.

EXAMPLE 18

In a vessel, equipped with a stirrer, reflux condensers and a gas introduction tube for ammonia, 14 7.2 g of paraformaldehyde (91% flakes), 550 ml of methanol and 326.2 g of 2-chloroacetamido-5-chloro-2'-fluorobenzophenone are added at room temperature. The mixture is stirred and the ammonia is led below the surface. The reaction mixture is then heated under continuous passage of ammonia gas for 10 hours to reflux. It is then cooled to room temperature, and the crystalline product is filtered off. The product is washed twice with 125 ml of cold methanol (-10°) and four times with 500 ml of hot water (60°). After distillation, 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one is obtained with m.p. 205.5 - 207 (not corrected), yield 71% of theoretical.

EXAMPLE 19

In a 5 liter 3-necked flask, equipped with a stirrer and calcium chloride drying stirrer, 250 g of 2-chloroacetamido-5-chlorobenzophenone and 122.5 g of hexamethylenetetramine are added to 2.5 liters of acetonitrile. The mixture is stirred for 72 hours at room temperature, whereby both starting materials go into solution. The reaction product

then crystallizes out, is filtered, washed with a small amount of fresh solvent and dried, thereby obtaining the product with m.p. 169 - 170°.

89.7 g of the product thus obtained is dissolved in ethanol-containing ammonia. Under continuous passage of gaseous ammonia, the mixture thus obtained is heated to reflux for 5 hours, whereby 7-chloro-l>? 3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one, which is isolated according to known methods, m.p. 212 - 214°, yield 79.2% of theoretical.

EXAMPLE 20

In a 1 liter vessel, equipped with reflux condensers, add 89.7 g of the addition salt of formula

61.6 g of 2-chloroacetamido-5-chlorobenzophenone, 22.4 ml of 26% ammonium hydroxide solution and 425 ml of ethanol. When ammonia is passed through, the mixture is heated to reflux for 5 hours. The mixture is evaporated to dryness. The residue is then heated for 1 hour in a mixture of 100 ml toluene and 100 ml water to reflux and cooled to room temperature. The thus precipitated product is filtered off, washed with 20 ml of water and toluene and dried, thereby obtaining 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one with m.p. 210-213°, yield 85.4% of theoretical.

EXAMPLE 21

A mixture of 74.55 g of 2-(2-chloroacetamido-5-bromobenzoyl)pyridine, 115.4 ml of methanol and 14.96 g of hexmethylenetetramine saturated with ammonia. The reaction mixture is heated for 6 hours at reflux (62°), during which a constant stream of ammonia is passed through the mixture. Evaporation under reduced pressure and filtration after drying gives 35.7 g of 7-bromo-1,3-dihydro-5-(2-<p>yridyl)-2H-1,4-benzodiazepine-2-one, melting point 226 -227°C. Evaporation of the mother liquor gives a further 12.1 g of the desired end product. A thin-layer chromatographic examination shows that both fractions are of good quality.

Claims (2)

1. Process for the preparation of benzodiazepine derivatives with the general formula where R± means hydrogen, halogen or nitro, hydrogen or lower alkyl and R^ phenyl, o-halophenyl or 2-pyridyl, by reacting a compound with the general formula where R^, R2 and R^ have the meaning indicated above, and X means chlorine, bromine or iodine, preferably chlorine, with hexamethylenetetramine in an inert organic solvent, possibly by isolating an intermediate with the general formula where R^, R2, R^ and X have the meanings indicated above, characterized in that ammonia is used during the execution of the method. 2. Method according to claim 1, characterized in that a starting material is used, where R1 means chlorine, R2 methyl and R-j phenyl.