IL42947A

IL42947A - Process for the preparation of 1,3-dihydro-2h-1,4-benzodiazepin-2-ones

Info

Publication number: IL42947A
Application number: IL42947A
Authority: IL
Original assignee: Sparamedica Ag
Priority date: 1972-08-21
Filing date: 1973-08-10
Publication date: 1977-01-31
Also published as: DK155326B; IE38091B1; ES418014A1; PL99162B1; AU5918073A; IL42947A0; YU219873A; FI57939C; NL179582C; SU550980A3; FR2197003B1; DE2340159C2; CA1012535A; JPS5911589B2; LU68269A1; CH578544A5; AT341527B; FR2197003A1; DD107040A5; HU170153B

Description

42947/2 SPAfiA EDICA A.G.

C: 40991 4008/252 The present invention relates to a process for the preparation of benzodiazepine derivatives of the general formula wherein R-^ represents hydrogen, halogen, nitro or trifluoromethyl, iL, represents hydrogen or lower alkyl and represents phenyl, o-halophenyl or 2-pyridyl.

The process of the present invention comprises reacting a compound of the general formula wherein R- and R are as above and X re resents chlorine, bromine or iodine, preferably chlorine, with hexamethylenetetramine in an inert organic solvent with possible isolation of an intermediate of the general formula wherein R, , R2, R and X are as above, whereby ammonia is used in the process.

By the term "lower alkyl" as utilized herein, there is intended straight or branched chain aliphatic hydrocarbon groups such as methyl, ethyl, propyl, butyl and the like.

When is lower alkyl, it is preferably methyl. By the term "halogen" as utilized herein, the fouF-fo-rms chlorine, bromine, fluorine and iodine are contemplated, unless otherwise specified. When R^ is halogen, preferred are the halogens chlorine and bromine, with chlorine being especially preferred. When R^ is o-halophenyl preferred are o-chlorophenyl and o-fluorophenyl, with o-fluorophenyl being especially preferred.

In a preferred aspect of the present invention, the following compounds are prepared: 7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin- 2-one , 7-chloro-5- (2-chlorophenyl)-1,3-dihydro-2H-l, 4-benzodiazepin-2-one , l,3-dihydro-7-nitro-5-phenyl-2H-l,4-benzodiazepin-2-one , 7-chloro-5-( 2-fluorophenyl)-1,3-dihydro-2H-l, 4-benzodiazepin-2-one , 5-( 2-fluorophenyl)-1,3-dihydro-7-nitro-2H-l,4~ benzodiazepin-2-one, 5-( 2-chlorophenyl)-1,3-dih dro-7-nitro-2H-l, -benzodiazepin-2-one , 7-bromo~l,3-dihydro-5-(2-pyridyl)-2H-1, 4-benzo-diazepin-2-one and the 1-methyl derivatives of these compounds.

The prior art discloses the preparation of benzodiazepines of the formula I utilizing hexamethylenetetramine and a compound of the formula II. However, for example, when is the starting material is hydrogen, consistently good yields are not abtained in such prior art process.

It has been discovered that, if ammonia is present during the reaction of a compound of the formula II with hexamethylenetetramine or if this reaction in followed by treatment with ammonia, better yields of the compounds of the formula I result generally when compared with the said prior art procedure disclosed in the Journal of Heterocyclic Chemistry, 7, 1173 (1970), regardless of the character of the starting material utilized, Hence, the present invention improves upon the prior art as reflected in the aforementioned article by providing a general approach to the class of compound illustrated in formula I utilizing a compound of the formula II and hexamethylenetetramine which is simple and facile and which results in higher yields than with the aforementioned prior art process. Furthermore, a compound of the formula I of good purity is obtained when following the techniques described herein.

In one aspect of the present invention, i.e. the reaction of a compound of formula II with hexamethylenetetramine in the presence of ammonia, the reaction is effected in the presence of any inert organic solvent, which is suitable for the purposes of the present invention. Among the many such inert organic solvents so suitable,! there can be included 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$), aqueous butanol. All that is required of the solvent is that the starting materials be soluble therein and that the solvent does not interfere with the ensuing reaction. Preferred are lower alkanols, such as methanol or ethanol. Furthermore, the character of the solvent should be such that it possesses the propensity to solubilize ammonia in the form that it enters the reaction zone.

While temperature and pressure are not critical to a successful performance of this process aspect, it is preferred to perform the reaction at a temperature of from about room temperature to about the reflux temperature of the reaction medium. Most preferably, elevated temperatures are utilized, most suitably, a temperature at about the reflux temperature of the reaction medium. Furthermore, in one embodiment, the reaction is performed under pressure to increase the concentration- of ammonia present in the reaction zone.

Preferably, the ammonia is added to' the reaction medium in such amounts as to saturate the inert organic solvent. As noted above, it is preferable to carry out this reaction at the reflux temperature of the solvent, since in general less ammonia will be required to saturate the solvent when elevated temperatures are employed. Usually, only minor molar amounts of ammonia are required to effect a successful performance of the desired reaction of a compound of the formula II above with hexamethylenetetramine. Thus, in a preferred aspect, a solvent is selected which will solubilize the starting materials but will become supersaturated with ammonia when relatively minor molar amounts of it are added thereto.

For example, in one preferred embodiment, ethanol is utilized. It is saturated when about a 1% molar quantity of ammonia is present in the reaction zone, such percentile being determined by a ratio, the numerator of which is the molar amount of ammonia required to supersaturate the solvent medium and the denominator of which is the sum of the molar amounts of hexamethylenetetramine, a compound of the formula II and ammonia present in the reaction zone. The solubility of ammonia in any inert organic solvent useable for the purposes of the present invention can be easily determined by reference to conventional texts. Prom this determination, the appropriate inert organic solvents can be readily ascertained. The use of pressure, as is noted above, will increase the concentration of ammonia present in the reaction zone over that required to normally saturate the inert organic solvent. Thus, in one embodiment, the reaction is performed under a pressure of from about 1 to about 2 atms. Higher amounts of ammonia can be provided to the reaction zone by the simple expedient of using appropriate aqueous inert organic solvents.

It has been observed that when performing the process of the present invention, there is obtained an intermediate of the formula III, above. This intermediate can be reacted with ammonia with or without isolation from the reaction medium in which it is prepared to obtain the desired compound of the formula I above.

Thus, a compund of the formula III, particularly wherein is lower alkyl, can be isolated from the reaction medium and treated with ammonia whereby to obtain the corresponding compound of the formula I. Alternatively, a compound of the f mu a II above a h a e h lene a a reaction medium and there can be provided ammonia thereto without isolating a compound of the formula III. In a preferred embodiment, the intermediate of the formula III is not isolated but is reacted with ammonia without isolation from the reaction medium in which it is prepared. This is particularly true when It, in formula III above is hydrogen.

A compound of the formula III can also be prepared by techniques other than that described herein. For example, in an analogous manner as described in the above mentioned Journal of Heterocyclic Chemistry article, a compound of the formula II above and hexamethylenetetramine can be added to a solvent of low polarity such as acetonitrile with stirring at room temperature and the intermediate of the formula III above can be isolated. The so-obtained compound of the formula III after isolation from the solvent in which it is prepared, can be reacted with ammonia whereby a compound, of the formula I above results in good yields and of high purity. The reaction of a compound of the formula III with ammonia proceeds under the same reaction conditions as described hereinabove for the preparation of a compound of the formula I via the treatment of a compound of the formula II with hexamethylenetetramine and ammonia as should be obvious to one of ordinary skill in the art. Thus, all of the reaction conditions and solvents specified above in connection with the preparation of a compound of the formula I with the use of hexamethylenetetramine apply with equal efficacy to the treatment of the intermediate of the formula III with ammonia exce t that hexameth lene- tetramine is not added to the reaction zone As should he apparent from the above, the invention resides in adding ammonia to a reaction medium in which hexa-methylenetetramine and a compound of the formula II, or an intermediate of formula III are to! be present. The manner of adding ammonia to the reaction zone is not critical. For example, the hexamethylenetetramine can be added to an inert organic solvent of the type referred to above and the ammonia can then be added to reaction zone prior to the addition of the compound of a formula II above. Alternatively, the ammonia can be dissolved in an inert organic solvent and subsequently a compound of the formula II above and hexamethylenetetramine, or an intermediate of the formula III above can be added to the reaction zone.

Furthermore, the manner by which ammonia is introduced into the reaction zone is not critical. In one preferred process aspect, ammonia is provided to the reaction zone simply by bubbling gaseous ammonia therethrough. The ammonia can also be provided to the reaction zone in a less preferred embodi-ment by utilizing an ammonia generating reagent, e.g. ammonium carbonate which dissociates into ammonia when present in a solvent medium such as ethanol which is heated to reflux.

Yields are not usually as good when an ammonia generating reagent is utilized instead of ammonia per se.

A process of the present invention resides in the fact that large molar excesses of hexamethylenetetramine are not required for a successful performance thereof. Por example, by this aspect, for every one mole of the starting material of the formula II utilized, if as little as 0.10 moles is utilized, most preferably, if as little as 0.50 moles of hexamethylenetetramine is utilized, the desired compound of the formula I above is obtained. Thus, the present invention achieves an additional and particularly surprising and noteworthy end in that the amount of hexamethylenetetramine utilized is minimized and as a consequence of this, the cost of raw materials utilized in performing the process described herein is reduced without a corresponding diminution of yield. This particularly salient feature of the present invention therefore further provides a particularly commercially viable process. It should be noted that yields do begin to diminish when less than 0.50 moles of hexamethylenetetramine are utilized. However, when 0.50 moles of hexamethylenetetramine are utilized, the desired compound of the formula I is obtained in very good yields and of high quality.

When following the preparative procedure described above, particularly when utilizing a starting material of the formula II wherein R2 is hydrogen, it has been observed that the reaction of hexamethylenetetramine with the aforementioned compound of the formula II results in the evolution of formaldehyde. The ammonia that is present reacts with the formaldehyde so-formed to re enerate hexameth lenetetramine It was further discovered that the desired compound of the formula I can be prepared by treating a compound of the formula II with formaldehyde in the presence of excess ammonia.

In the last-mentioned reaction, there can be utilized anhydrous formaldehyde (paraformaldehyde) or aqueous formaldehyde (38 formalin). Temperature and pressure are not critical to a successful performance of this process aspect but it is preferred to perform the reaction at elevated temperatures, e.g. at about the reflux temperature of the reaction medium. The reaction is preferably effected in the presence of an inert organic solvent and among the many suitable organic solvents, there can be included those indentified above in connection with the formation of a compound of the formula I from a compound of the formula II with hexamethylenetetramine and ammonia. Therefore, among the many inert organic solvents suitable for the purposes of this aspect of the present invention, there can be included 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 again all that is required of the solvent is that the starting materials be soluble therein and that the solvent does not interfere with the ensuing reaction. Preferred is methanol and/or ethanol.

It can be stated therefore that in this process aspect, the formaldehyde reacts with ammonia which is resent in molar excessive amounts to form hexamethylenetetramine whereby a compound of the formula III results which with or without isolation, preferably without isolation, is converted into a compound of the formula I. The manner in which ammonia is introduced and the amount introduced is the same as described above when a compound of the formula I is prepared utilizing hexamethylenetetramine and ammonia. Thus, in a preferred aspect, the reaction solvent in this process variation is saturated with ammonia, preferably simply by bubbling ammonia through the reaction solvent.

The following examples are illustrative but do not limit the present invention. All temperatures are stated in degrees Centigrade.

Example 1 To a 2 liter, 4-necked flask equipped with a stirrer, reflux condenser and an inlet for ammonia, there are added 600 ml of ethanol and 31.7 g of hexamethylenetetramine. Ammonia is then bubbled through the resultant reaction medium with stirring until the medium is saturated with ammonia. The saturated solution is heated to reflux, while continuing the bubbling of ammonia through the reaction medium. Thereafter, 78 g of 2-bromo-2 '-(2-fluorobenzoyl)-4 '-nitroacetanilide are carefully added over a period of two hours while maintaining refluxing conditions. The reaction mixture is refluxed for three hours longer and then is concentrated in vacuo to dr ness at 50°. To the residue there are added 300 ml of toluene and 0.4 g of p-toluene sulfonic acid. The resultant medium is heated to reflux for 1 hour. The mixture is then cooled to about 70° and washed with water. The toluene layer is then permitted to cool to room temperature, the crystalline product is isolated by filtration, then washed with toluene and dried to give 5-(2-fluorophenyl)-l, 3-dihydro-7-nitro-2H-l, 4-benzodiazepin-2-one,m.p. 210-215° . (Yield 25.¾Q Example 2 To a 2-liter, 4-necked flask equipped with a stirrer, reflux condenser and inlet for ammonia, there are added 600 ml of ethanol and 31·2 g of hexamethylenetetramine. With agitation, ammonia is bubbled through the resultant reaction medium until the ethanol is saturated with ammonia. The resultant medium is heated to reflux. While maintaining the reaction under refluxing- conditions and bubbling ammonia therethrough, there are carefully added 40 g of 2-bromo-4 '-chloro-2 '-(2-chlorobenzoyl)acetanilide over a period of two hours.

The reaction mixture so obtained is then evaporated to dryness. To 'the residue, there are added 300 ml of toluene and then 0.3 g of para-toluene sulfonic acid. The toluene solution is heated to reflux. The reaction medium is permitted to cool to 70°. After cooling, it is washed with hot water. The toluene extract is permitted to cool to. room temperature. After cooling to 10°, the crystalline product which formed is filtered off, 40991/2 \ vacuum at 100° to give 7-chloro-5-(2-chlorophenyl)-l,3-dihydro- 2H-l,4-benzodiazpin-2-one, m.p. 200-200.5°.(Yield 68.5??) Example 3 To a 2-liter, 4-necked flask equipped with a reflux condenser, an ammonia addition tube and a stirrer, there are added 600 ml of ethanol and 30.4 g of hexamethylenetetramine.

Ammonia is bubbled through the reaction medium until the ethanol becomes supersaturated. The reaction mixture is heated to reflux while 40 g of 2-bromo-2 '-(2-chlorobenzoyl)-4'-nitro-acetanilide are carefully added to the resultant medium over a period of 3 1/2 hours. The refluxing and bubbling of ammonia through the reaction medium is continued for three hours longer and then it is evaporated to dryness. To the residue are added 250 ml of toluene and 0.4 g of para-toluene sulfonic acid.

The mixture is refluxed for 1 hour. The toluene layer is cooled to 70°. The resultant medium is washed with water. The toluene layer is then cooled to room temperature. The product crystallizes from the reaction medium. The crystals are filtered off, and washed once with toluene and once with petroleum ether and dried yielding 5-(2-chlorophenyl)-l,3-dihydro-7-nitro-2H-l,4-benzodiazepin-2-one, m.p. 203-204°.

(Yield 62.9^) ethanol and 470.4 g of hexamethylenetetramine. Ammonia is bubbled through the resultant reaction medium with stirring until the medium becomes supersaturated. With refluxing, 480.0 g of 2-chloroacetamido-5-chlorobenzophenone are carefully added over a period of 4 hours. The resultant mixture is heated at reflux for an additional 2 hours while bubbling ammonia therethrough. The resultant medium is then left to stand overnight and then concentrated to dryness in vacuo. To the concentrate there are added 2.4 liters of toluene and the resultant medium is heated to reflux. 0.5 g of para-toluene sulfonic acid are then added. The refluxing is x continued for a period of one hour. After cooling the medium to 70°, 1.5 liters of hot water are added. The product which separated is cooled to 20° and isolated by filtration, washed and dried in vacuo yielding 7-chlor0-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one, m.p. 213-214°. (Yield 80.3 ) In a similar manner as described above, there can be prepared 7-bromo-l,3-dihydro-5-(2-pyridyl)-2H-l,4-benzodiazep 2-one melting at 225-235° from 2-(2-chloroacetamido-5-bromo benzoyl)pyridine . once with 250 ml of cold (0°) toluene. The product is then dried to constant weight at 80° yielding 7-chloro-l, 3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one, m.p. 213-214°.(Yield 80.7 ) • : \ Example 6 To a 2-liter, 4-necked flask equipped with a stirrer, a reflux condenser and an ammonia tube, there are added 600 ml of ethanol and 37.9 g of hexamethylenetetramine with stirring. Ammonia is bubbled through the resultant reaction medium with stirring until reflux temperature is reached. Then there are carefully added to the refluxing solution 40.0 g of 2-chloro-acetamido-5-nitro-benzophenone . Ammonia is steadily bubbled into the reaction mixture while continuing to reflux for three hours. The resultant solution is cooled, evaporated to dryness at 50°. The residue is dissblved in 300 ml of toluene. 0.3 g of para-toluene sulfonic acid are added to the resultant solution. The solution is heated to reflux. The refluxing is continued for 1 hour. The reaction medium is then permitted to cool to room temperature. The product which separates is filtered off, washed with water and dried. This material is taken up in- 35 -ml -of methylene chloride. It is then filtered through Hyflo. Upon the addition of 90 ml of 3N nitric acid to the filtrate, crystals appeare. They are filtered off, washed with methylene chloride and dried for 15 minutes. The crystals are added to 1 liter of water with stirring.

Ammonium hydroxide is then carefully added to the resultant medium until a pH of about 8 is reached. After stirring the resultant medium for 1/2 hour, the crystalline precipitate which has formed is filtered off, washed with cold water and dried at 80° for 8 hours yielding l,3-dihydro-7-nitro^5- \phenyl-2H-l,4-benzodiazepin-2-οηβ of melting point 217-219°. (Yield 27.25 Example 7 To 1350 ml of ethanol there are added 90 g of 2-chloro- acetamido-5-chlorobenzophenone and 92,5 g of hexamethylene- tetramine. Ammonia is bubbled through the resultant medium under a pressure. The resultant medium is heated to reflux. The resultant reaction medium is evaporated in vacuum to dryness. It is triturated then with 250 ml of hot water twice on a steam bath. The aqueous phase is removed by decan- tation. 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 which have formed are filtered, washed twice with 25 ml of toluene and 25 ml of petroleum ether and dried to constant weight yielding 7-chloro-l,3- dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one of melting point 213-215°.(Yield l&,) Example 8 13,5 liters of 95% ethanol, 900 g of 2-chloroacetamido- 5-chlorobenzophenone and 925 g of hexamethylenetetramine are charged to a stirred pressure vessel. The medium is saturated with ammonia gas with stirring. The ammonia supply is turned off. The resultant medium is heated for three hours at 78-80°. After cooling and venting the ammonia, the batch is removed from the preeaure vessel to a vacuum etill. The batch is concentrated to dryness in vacuo from a steam bath. To the residue are added 2 1/2 liters of toluene and 5.0 g of p-toluenesulfonlc acid and the resultant mixture is heated to reflux. Ca. 5 nil of water formed are removed by azeotropism. After cooling to 70° three liters of water at 70° are added. The crystal slurry so obtained is cooled for one hour at +10° to +15°. After filtering, washing the product with 2 x 250 ml of tap water and once with 250 ml of cold (10°) toluene and drying to constant weight, 7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one is obtained, m.p. 211-213,5°. (Yield 66$) Example 9 „ ■' A mixture of 17,5 g of hexamethylenetetramine (0.125 mol) 135 ,5mlofmethanol and 80,5 g of 2-(2-chloro-N-methylacetamido)-5-chloro-benzophenone (0.25 mol) is saturated with ammonia.

The stirred mixture is slowly heated to reflux with a steady stream of ammonia flowing through the mixture. During the course of the reaction r is prepared. This product is not isolated. The reaction mixture is hold at reflux for 6 hours. The flow of ammonia is stopped and the solvent removed under vacuum. The residue is taken up in a mixture of 500 ml of toluene and 500 ml of hot water.

The toluene phase is separated and with stirring, 169 ml of 3N nitric acid are added. The crystals which separate are filtered, washed with 50 ml of toluene and resuspended in a mixture of 250 ml of toluene and 250 ml of water. 30 ml of concentrated ammonia are added to pH 8. The toluene phase is separated, washed with 250 ml of water and then distilled to dryness in vacuo yielding 7-chloro-l-methyl-l,3-dihydro- 5-phenyl-2H-l,4-benzodiazepin-2-one, melting point 125-127°. (Yield 96.15Q Example 10 A mixture of 600 ml of ethanol and 39,1 g of hexamethyl-enetetramine (0.279 mol) is stirred and saturated with ammonia. With ammonia bubbling into 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-chlorobenzop enone (0.124 mol) are added in increments yielding which is not isolated. Refluxing is continued for 2 hours longer. The reaction mixture is then distilled to dryness in vacuo at 50°. The residue is stirred with 250 ml of toluene, heated to reflux and heated with two increments of para-toluene sulfonic acid. Reflux is continued for one hour. After cooling to 70°, the toluene solution is washed with hot water to remove soluble salts and distilled to dryness in vacuo.

The residue is dissolved in hot ethanol (111 mol) and the solution cooled at -10° for one hour. The crystalline 7-chloro- 1,3-dihydro l-methyl-5-phenyl-2H-l,4-benzodiazepin-2-one obtained is isolated/, melting point 129-131°. Concentration of the (2g) mother liq.uor by ca. 5095 gives a second croj, melting at 127°.

Example 11 A mixture of 1100 ml of^ethanol, 70,0 g of hexamethyl-enetetramine (0.5 mol), 58 ml of 26% ammonium hydroxide solution and 308.2 g of 2-chloroacetamido-5-chlorobenzo-benzophenone (1.0 mol) is stirred and slowly heated to reflux with ammonia bubbling into the mixture. Reflux is continued for 5 hours, the flow of ammonia is interrupted, and the reaction mixture is distilled to dryness in vacuo.

The residue is heated to reflux for 30 minutes in a mixture of 500 ml of toluene and 500 ml of water and then allowed to cool slowly to room temperature. The crystalline material is filtered, washed with 100 ml of toluene and 2 x 250 ml of hot water and dried to constant weight. The product, 7-chloro-1,3-dihydro-5-phenyl-2H-l, -benzodiazepin-2-one obtained melts at 210°. (Yi&ld 83.5#) Example 12 A mixture of 1100 ml of ethanol, 35 g of hexamethylene-tetramine (0.25 mol), 58 ml of 26# ammonium hydroxide solution and 308.2 g of 2-chloroacetamido-5-e¾lorobenzophenone (1,0 mol) is permitted to react as described in Example 11 except that the reflux period is increased from 5 to 7 hours. The reaction product, 7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzo-diazpein-2-one isolated in a manner identical with Example 11, melts at 208.5 -209°. (Yield 81.656) 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 is stirred and saturated with ammonia at room temperature. The mixture is heated slowly to reflux with a steady stream of ammonia bubbling through the solution.

Refluxing is continued for 24 hours. The flow of ammonia is interrupted and the crystal slurry obtained is cooled to room temperature. The product is filtered, washed with 2 x 125 ml of methanol and 4 x 500 ml of hot water and dried to give 7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one melting at 213-215°. (Yield 62.3 ) Example 14 A mixture of 300 ml of ethanol and 20 g of hexamethylene-tetramine (0.143 mol) is stirred, heated to reflux, and saturated with ammonia. 18.1 g of 2-chloroacetamidobenzo-phenone (0.066 mol) are added in small increments over 3 to 4 hours while a steady stream of ammonia is bubbled into the reaction mixture. Refluxing is continued for 3 hours after complete addition of 2-chloroacetamidobenzophenone . The flow of ammonia is interrupted and the ethanol removed by distillation in vacuo. The residue obtained is taken up in 200 ml of chloroform and washed with 100 ml of water at 50°. The chloroform layer is evaporated to dryness at 30° and the oily solid obtained is recrystallized from 100 ml of toluene to give l,3-dihydro-5-phen l-2H-l,4-benzodiazepin-2-one, melting at 184-186°.(Yield 86?$) Example 15 \ A mixture of 275 ml of methanol and 154.2 g of 2-chloro-acetamido-5-chlorobenzophenone (0.5 mol) is heated to reflux with a steady stream of ammonia bubbling in. At reflux, 237 ml of a 37$ formaledhyde solution are fed in over ca. 40 minutes. The reaction mixture is then heated under reflux for 5 hours. The flow of ammonia is stopped and the slurry of crystals is cooled to room temperature, filtered, washed with 2 x 125 ml of methanol, 4 x 500 ml of hot water and dried.

There is obtained 7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzo-diazepin-2-one, melting at 211.5-214.5°. (Yield 77.3 ) Example 16 A mixture of 147.2 g of paraformaldehyde and.$50 ml of methanol is stirred and heated to reflux with a steady stream of ammonia bubbling in. The crystal slurry of hexa-methylenetetramine which has formed is cooled to room temperature and 308.2 g of 2-chloroacetamido-5-chlorobenzo- * phenone (1.0 mol) are -added in one portion. With ammonia bubbling in,the reaction mixture is heated at reflux for 10 hours. The flow of ammonia is interrupted and the reaction mixture is cooled to room temperature, filtered, washed with 2 x 125 ml of methanol and 4 x 500 ml of hot water and dried.

There is obtained 7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzo-diazepin-2-one, melting at 212,5-215°. (Yield 81.4$) X Example 17 200 g of paraformaldehyde (91 flake) are placed in a stirred reactor equipped with a reflux condenser, decanter and ammonia addition tube. 575 ml of methanol are added and then gaseous ammonia is added below the surface of the reaction mixture. 273.7 g of 2-chloroacetamidobenzophenone are then added. With a slow, continuous flow of ammonia to the reaction zone, the mixture is heated at reflux for 5 hours. The crystal slurry obtained is distilled to recover the methanol. 1350 ml of toluene are now added to the crystal residue and residual water is removed by azeotropic distillation through the decanter. When dry, the hot toluene solution is filtered, the filtrate is cooled for crystallization, and the product obtained isolated to give l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one, m.p. 180-181° (uncorr.). (Yield 84.1 ) Example 18 147.2 g of paraformaldehyde (91$ flake) are placed in a stirred reactor equipped with an ammonia addition tube and a reflux condenser. 550 ml of methanol are added, along with 326.2 g of 2-chloroacetamido-5-chloro-2'-fluorobenzo-phenone at room temperature. The reaction mixture is stirred and ammonia gas .is bubbled in below the surface of the reaction mixture. The reaction mixture is then heated at reflux for 10 hours with a steady flow of ammonia gas, cooled to room temperature and the crystalline product obtained is filtered. The product is washed with 2 x 125 ml of cold methanol (-10°), followed by 4 x 500 ml of hot water (60°).

When dry, there is obtained 7-chloro-5-(2-fluorophenyl)-l,3-dihydro-2H-l,4-benzodiazepin-2-one, m.p. 205.5-207° (uncorr.). (Yield 71 ) Example 19 250 g of 2-chloroacetamido-5-chlorobenzophenone and 122.5 g of hexamethylenetetramine are added to 2.5 liters of acetonitrile in a 5 1.» 3-neck flask, equipped with a stirrer and calcium chloride drying tube. The reactants are stirred for 72 hours at room temperature. All reactants go into solution. The product which is crystallizes out. The product is filtered, washed with a small amount of fresh solvent and dried yielding the product, m.p. 169-170". 89.7 g of the product so-obtained are dissolved in ethanolic ammonia. The so-obtained reaction mixture is heated and gaseous ammonia is bubbled into the reaction mixture continuously during the heat-up and for a 5-hour period of reflux yielding 7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one which is isolated according to conventional procedures, m.p. 212-214°. (Yield 79.2^) Example 20 In a one liter, stirred flask equipped with a reflux condenser are placed 89.7 g of 61.6 g of 2--chloroac«tamido-5-chlorobenzophenone, 22.4 ml* of 26% ammonium hydroxide and 425 ml of ethanol. Ammonia is bubbled into the reaction mixture while it is stirred and heated to reflux. Refluxing is continued for 5 hours thereafter with stirring. The reaction mixture is distilled to dryness in an evaporator. The residue is then heated at reflux for one hour in a mixture of 100 ml of toluene and 100 ml of water and cooled to room temperature yielding 7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one . The product is filtered, washed with 20 ml of water and 20 ml of toluene and dried; melting point 210-213°. (Yield 85.4 )

Claims

Having now particularly described and ascertained the nature of our said invention and in what manner the same is to be performed, we declare that what we claim is:

1. A process for preparing benzodiazepine derivatives of the general formula wherein represents hydrogen, halogen, nitro or trifluoromethyl, Rg represents hydrogen or lower alkyl and R^ represents phenyl, o-halophenyl or 2-pyridyl, which comprises reacting a compound of the general formula wherein R^, 2 and R^ are as above and X represents chlorine, bromine or iodine, with hexamethylenetetramine in an inert organic solvent with poesible isolation of an intermediate of the general formula wherein R^, Rg» R^ and X are as above, whereby ammonia is used in the process.

2. A process according to Claim 1, wherein a compound of the formula II is reacted with hexamethylenetetramine in the presence of ammonia without isolating the intermediate of the formula III.

3. A process according to Claim 1, wherein the inter-mediate of the formula III is isolated.

4. A process according to Claim 3» wherein a compound of the formula II is reacted with hexamethylenetetramine in the presence of ammonia and the so-obtained intermediate of the folmula III is treated with ammonia.

5. A process according to Claim 3» wherein a compound of the formula II ia reacted with hexamethylenetetramine in the absence of ammonia and the so-obtained intermediate of the formula III is treated with ammonia.

6. A process according to any one of Claims 1-5» wherein the ammonia is formed in situ from an ammonia generating agent.

7. A process according to any one of Claims 1-6, wherein the hexamethylenetetramine is formed in situ from formaldehyde and ammonia.

8. A process according to any one of Claims 1-7, wherein the reaction is effected under pressure.

9. A process according to any one of Claims 1-8, wherein the ammonia is provided to the reaction zone in such quantities as to saturate the inert organic solvent being employed.

10. A process according to any one of Claims 1-9, wherein lower alkanols, dimethylformamide and aqueous mixtures thereof are utilized an inert organic solvent.

11. A process according to any one of Claims 1-10, wherein an aqueous inert organic solvent is utilized.

12. A proceea according to any one of Claims 1-11, wherein is halogen or nitro, R2 is hydrogen or methyl and R^ is phenyl, o-halophenyl or 2-pyridyl.

13. A process according to Claim 12, wherein R.^ is chlorine, bromine or nitro, Rg is hydrogen or methyl and R^ is phenyl, o-chlorophenyl, o-fluorophenyl or 2-pyridyl.

14. A process acoording to Claims 13, wherein is chlorine, R^ is hydrogen and R^ is phenyl.

15. A process according to Claim 13, wherein 1 is chlorine, Rg is methyl and is phenyl.

16. A process according to Claim 13, wherein is chlorine, R2 is hydrogen and R^ is o-fluorophenyl.

17. A process according to Claim 13, wherein R^ is chlorine, Rg is hydrogen and R^ is o-chlorophenyl.

18. A process according to Claim 13, wherein R. nitro, R is hydrogen and R, is phenyl.

19. A process according to Claim 13, wherein is nitro, R5 is hydrogen and R, is o-chlorophenyl.

20. A process according to Claim 13, wherein R nitro, R~ is methyl and R- is o-fluorophenyl.

21. A process according to Claim 13, wherein is bromine, R2 is hydrogen and is 2-pyridyl.

22. A process for the manufacture of benzodiazepine derivatives of formula I in Claim 1, substantially as hereinbefore described with reference to the foregoing Examples.

23. Benzodiazepine derivatives of the general formula wherein represents hydrogen, halogen, nitro or trifluoromethyl, R≥ represents hydrogen or lower alkyl and R^ represents phenyl, o-halophenyl or 2-pyridyl, whenever prepared by the process of any one of Claims 1 to 11 and 22 or by an obvious chemical equivalent thereof.

24. Benzodiazepine derivatives according to Claim 23, wherein is halogen or nitro, R2 is hydrogen or methyl and -j is phenyl, o-halophenyl or 2-pyridyl, whenever prepared by the process of Claim 12 or by an obvious chemical equivalent thereof.

25. Benzodiazepine derivatives according to Claim 24, wherein 1 is chlorine, bromine or nitro, R2 is hydrogen or methyl and R^ is phenyl, o-chlorophenyl, o-fluorophenyl or 2-pyridyl, whenever prepared by the process of Claim 13 or by an obvious chemical equivalent thereof.

26. 7-Chloro-l, 3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one, whenever prepared by the process of Claim 14 or by an obvious chemical equivalent thereof.

27. 7-Chloro-l, 3-dihydro-l-methyl-5-phenyl-2H-l,4-benzo diazepin-2-one, whenever prepared by the process of Claim 15 or by an obvious chemical equivalent thereof.

28. 7-Chloro-5- (2-fluorophenyl)-1, 3-dihydr0-2H-1,4-benzodiazepin-2-οηβ, whenever prepared by the process of Claim 16 or by an obvious chemical equivalent thereof.

29. 7-Chloro-5- (2-chlorophenyl)-l, 3-dihydro-2H-l,4-benzodiazepin-2-one, whenever prepared by the process of Claim 17 or by an obvious chemical equivalent thereof.

30. l,3-Dihydro-7-nitro-5-phenyl-2H-l,4-benzodiazepin-2-one, whenever prepared by the process of Claim 18 or by an obvious chemical equivalent thereof.

31. 5- (2-Chlorophenyl)-1, 3-dihydro-7-nitro-2H-l,4-benzodiazepin-2-one, whenever prepared by the procese of Claim 19 or by an obvious chemical equivalent thereof.

32. 5- (2-Fluorophenyl)-1, 3-dihydro-l-methyl-7-nitro-2H-l,4-benzodiazepin-2-one, whenever prepared by the process of Claim 20 or by an obvious chemical equivalent thereof.

33. 7-Bromo-l,3-dihydro-5-(2-pyridyl)-2H-l,4-benzo-diazepin-2-one, whenever prepared by the process of Claim 21 or by an obvious chemical equivalent thereof. Applicants OLD/ COHN AN