DK155326B - METHOD FOR PREPARING 1,4-BENZODIAZEPIN-2-ON DERIVATIVES - Google Patents

Description

DK 155326 B

The present invention relates to a particular process for the preparation of 1,4-benzodiazepine-2-one derivatives of general formula 5 wherein R 1 represents hydrogen, halogen, nitro or trifluoromethyl, R 2 represents hydrogen or alkyl of 1 to 5 carbon atoms and R 3 represents phenyl, o-halophenyl or 2- 15 pyridyl, by reacting a compound of the general formula o

R 0 N-C-CH 2 X

II

Wherein R 1, R 2 and R 3 are as defined above, and X represents chlorine, bromine or iodine, preferably chlorine, with hexamethylenetetramine in an inert organic solvent, optionally while isolating an intermediate of the general formula 30 p R C-CH2N4® (CH2) 6 β ^ I 111 R1 2

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in which R 1, R 2, R 3 and X have the meaning given above, and subsequent cyclization thereof to the corresponding compound of general formula I, and this process is characterized in that 5 (a) during the direct execution of the process (II) - 'I) or - in the case of isolation of the intermediate of formula (III) - in the step (III-> I) and / or in the step (II-' III) working under the supply of ammonia, and that 10 (b) per. moles of the compound of formula (II) use hexamethylenetetramine.

Said alkyl groups may be straight or branched chain, such as methyl, ethyl, propyl and butyl. If R 2 is alkyl, then a methyl group is preferred. The term 15 '"halogen" means the four halogens bromine, chlorine, fluorine and iodine, unless otherwise indicated. If R1 is halogen, then chlorine and bromine are preferred, especially chlorine. If R3 is o-halogenophenyl, o-chlorophenyl and o are preferred. -fluoro-phenyl, especially o-fluorophenyl.

In the process of the invention, the following compounds are preferably prepared: 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one, 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one, 7-chloro-5 - (2-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one, 5- (2-fluoro-phenyl) -1,3-dihydro-7-nitro-2H - 1,4-Benzodiazepin-2-one, 5- (2-chlorophenyl) -1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one, 7-bromo-1,3-dihydro-2-one 5- (2-pyridyl) -2H-1,4-benzodiazepin-2-one as well as the 1-methyl derivatives of these compounds.

A process for the preparation of benzodiazepines of general formula I is known using a compound of general formula II as starting material and hexamethylenetetramine. However, in this known process, very good yields are not obtained when R 2 in the starting material represents hydrogen; an in-depth study of the synthesis has revealed that it is only applicable to 3

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preparing the compounds with a substituent in the 1 position. The unsubstituted compounds in the 1-position cannot be produced in practically usable quantities by the known method; this contrasts with the statement 5 on page 1174, column 2, second paragraph of the Journal of Heterocyclic Chemistry, 7, 1173 et seq. (1970), where it is claimed that such compounds can be produced in 70-80% yield.

Thus, the known method has very limited utility, while in the process of the present invention the compounds I are obtained in high yield and independent of the starting material. Thus, the process of the invention enables the preparation of different, commercially important benzodiazepines by one and the same method; moreover, the compounds are obtained in higher yields than by the known method and also with greater purity.

In one embodiment of the 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 any inert organic solvent suitable for the purpose of the invention. Such suitable inert organic solvents include lower alkanols such as methanol, ethanol and n-butanol, dimethylformamide and similar inert organic solvents as well as aqueous mixtures thereof, e.g. aqueous ethanol (95%) and aqueous butanol. The solvent must be selected such that the starting material is soluble therein and that the solvent does not interfere with the reaction. It is preferred to use lower alkanols such as methanol and ethanol. Further, the solvent must be selected such that it has the property of dissolving ammonia so that the reaction can be carried out. Temperatures and pressures are not critical to the successful implementation of the process in question. However, the reaction is preferably carried out at a temperature between approximate room temperature and approximate reflux temperature of the reaction mixture. It is particularly preferred to use elevated temperatures. Particularly suitable is a temperature 4

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at the approximate reflux temperature of the reaction mixture. Furthermore, the reaction can also be carried out under pressure to increase the ammonia concentration in the reaction mixture.

Preferably, the ammonia is added in such amounts to the reaction medium 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, since then less ammonia is generally required to saturate a solvent 10 at elevated temperatures. For the successful completion of the reaction of a compound of formula II with hexamethylentetramine, only a small molar amount of ammonia is usually required. Thus, in the preferred embodiment, a solvent is selected which has the property of dissolving the starting material but is already superimposed with ammonia using relatively small molar amounts.

For example, in a preferred embodiment, ethanol is used. This is saturated when there are approx. 1 mole percent of ammonia present. This percentage is calculated after 20 fractions whose numerator is the molar amount of ammonia required for supersaturation of the solvent and whose divisor is the sum of molar amounts of hexamethylenetetramine, the compound of formula II and the ammonia present in the reaction mixture. The solubility of ammonia in any of the inert organic solvents suitable for the invention can be readily determined by known reference works. With this assay, the most suitable inert organic solvent can also be readily obtained.

As indicated above, the use of pressure causes an increase in the concentration of ammonia in the reaction medium in addition to the concentration normally required for saturation of the inert organic solvent. Thus, the reaction is carried out in a particular embodiment under a pressure of approx.

1-2 atmospheres. Higher ammonia concentrations can easily be obtained by using a suitable aqueous inert organic solvent.

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It is observed that in carrying out the process of this invention, an intermediate of the formula III shown above is formed. This intermediate can be reacted with or without isolation from the reaction medium in which it is formed with ammonia to the desired compound of the general formula I.

Thus, a compound of formula III, especially one in which R 2 represents alkyl, can be isolated from the reaction mixture and treated with ammonia to give a corresponding compound of formula I. On the other hand, a compound of the formula II and hexamethylenetetramine to the solvent and first add the ammonia thereafter, i. without isolating the compound of formula III. In a preferred embodiment, the intermediate of formula III is not isolated but reacted with ammonia without isolation from the reaction medium. This is primarily done when R 2 represents hydrogen.

A compound of formula III may also be prepared by other means than described above. For example, one can analogously, e.g. as described in the said article in the Journal of Heterocyclic Chemistry, adding a compound of formula II and hexamethylenetetramine with stirring at room temperature to a lower polarity solvent, e.g. acetonitrile, and isolate the intermediate of formula 25 III. The compound of formula III thus obtained is reacted with ammonia after isolation from the solvent in which it is prepared to give a compound of formula I in good yield and with high purity. As is apparent to one skilled in the art, the reaction between a compound of formula III and ammonia proceeds under the same reaction conditions described above in the preparation of a compound of formula I from a compound of formula II from hexamethylenetetramine and ammonia. Thus, for the reaction of an intermediate 35 of formula III with ammonia, the same reaction conditions and solvents mentioned above in compound 6 can be used.

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with the preparation of a compound of formula I, except that hexamethylene tetramine is not used for the reaction.

As is clear from the foregoing, the process of the invention consists in adding ammonia to the reaction medium containing hexamethylenetramine and a compound of formula II and an intermediate of formula III, respectively. moles of the compound of formula II use at least 0.1 mole of hexamethylene tetramine. The way in which the ammonia is added to the reaction mixture is not critical. Eg. For example, the hexa-methylenetetramine and ammonia can be added to the inert organic solvent and only then the compound of formula II is added. On the other hand, one can also dissolve the ammonia in an inert organic solvent and then add a compound of formula II and hexamethylene tetramine or the intermediate of formula III to the reaction mixture.

As already mentioned above, the manner in which the ammonia is added is not critical. In a preferred embodiment, the ammonia is added by 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 an ammonia-supplying reagent, e.g. ammonium carbonate which in the solvent medium, e.g. ethanol, which is heated to reflux, decomposes to ammonia. When using an ammonia-supplying reagent instead of ammonia itself, the yields are usually not as good.

30 A particularly notable feature of the process at issue here is that no greater molar excess of hexamethylenetetramine is required to achieve a successful implementation of the process. Thus one gets e.g. already using only 0.1 moles per moles of starting material of formula II, the desired compound of formula I. Preferably, however, approx. 0.5 mol 7

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hexamethylenetetramine per mole of compound II. Thus, the present invention provides a further and particularly noteworthy advantage in that the amount of hexamethylenetetramine required for the reactions is reduced to a minimum, and consequently a reduction in the cost of manufacture of the final product can be obtained without having to take a corresponding yield reduction. Because of this remarkable advantage, the process of the present invention is of particular commercial interest. It is noted that the yields become somewhat inferior when less than 0.5 mole of hexamethylenetetramine is used. However, if 0.5 mole of hexamethylenetetramine is used, the desired compounds of formula I are obtained in excellent yields and in particularly good quality.

In carrying out the above-described mode of action, in particular using a starting material of formula II wherein R 2 represents hydrogen, it has been observed that the reaction of hexamethylenetetramine with a compound of formula II proceeds during formation of formaldehyde. The ammonia present in the reaction mixture reacts with the formaldehyde thus formed to recreate 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 excess ammonia.

In this process aspect, anhydrous formaldehyde (paraformaldehyde) or aqueous formaldehyde (38% formalin) can be used. Temperature and pressure are not critical to the successful implementation of this process aspect. However, the reaction is preferably carried out at elevated temperature, e.g. approximately at the reflux temperature of the reaction mixture. The reaction is conveniently carried out in the presence of an inert organic solvent. The many inert organic solvents suitable for the purposes of the invention comprise the solvents mentioned above.

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s is mentioned in connection with the formation of a compound of formula I from a compound of formula II, hexamethylentetramine and ammonia. Thus, suitable solvents may be mentioned methanol, ethanol, n-butanol, dimethylformamide and similar inert organic solvents as well as aqueous mixtures thereof, e.g. aqueous ethanol or methanol. Here, too, the solvent should be selected such that the starting material is soluble therein and that the starting material does not interfere with the reaction. Methanol and / or ethanol are preferred.

It is apparent from the foregoing that, in this process aspect, the formaldehyde reacts with the ammonia present in molar excess to form hexamethylene tetramine to give a compound of Formula III, which with or without isolation, preferably without isolation. is converted into a compound of formula I. The amount and manner of ammonia added to the reaction mixture are the same as described above in the preparation of a compound of formula I using hexamethylenetetramine and ammonia. Thus, the solvent is saturated with ammonia in a preferred embodiment, preferably as the ammonia is passed through the solvent.

The following exemplary embodiments serve to elucidate more fully the process of the present invention.

Example 1 Into a 2 liter four neck flask equipped with stirrer, reflux condenser and gas supply tube for ammonia, place 600 ml of ethanol and 31.7 g of hexamethylenetetramine. Then, with stirring, ammonia is passed through the reaction solution until the reaction medium is saturated with ammonia. The saturated solution is heated to reflux while the passage of ammonia is continued. Next, 2 g of 2-bromo-2 '- (2-fluorobenzoyl) -4'-nitroacetanilide is added cautiously over 2 hours with refluxing reflux.

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the gums are again maintained. The reaction mixture is further heated for 3 hours to reflux and then evaporated under reduced pressure at 50 ° C to dryness. To the residue are added 300 ml of toluene and 0.4 g of p-toluenesulfonic acid. The resulting reaction mixture is heated to reflux for 1 hour. The mixture is then cooled to ca. 70 ° C and washed with water. The toluene layer is then cooled to room temperature and the crystalline product is separated by filtration, washed with toluene and dried to give 5- (2-fluorophenyl) -1,3-10 dihydro-7-nitro-2H-1,4-benzodiazepine 2-on with m.p. 210-215 ° C. The yield is 25.5%.

Example 2 Into a 2 liter four-necked flask equipped with 15 stirrer, reflux condenser and gas supply tube for ammonia, place 600 ml of ethanol and 31.2 hexamethylene tetramine. With stirring, ammonia is passed through the resulting reaction solution for so long that the ethanol is saturated with ammonia. The resulting reaction mixture is heated to reflux. While maintaining the reflux conditions and passing through ammonia, cautiously 40 g of 2-bromo-4 · -chloro-2 '- (2-chlorobenzoyl) -acetanilide are gently added over a period of 2 hours. The reaction mixture thus obtained is then evaporated to dryness. To the residue is added 300 ml of toluene and then 0.3 g of p-toluene sulfonic acid. The toluene solution is heated to reflux. The reaction mixture is cooled to 70 ° C. After cooling it is washed with water. The toluene extract is cooled to room temperature and after cooling to 10 ° C, the crystalline product formed is separated by filtration, washed with toluene and petroleum ether and dried overnight under reduced pressure at 100 ° C to give 7-chloro-5 - (2-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepin-2-one, m.p. 200 to 200.5 ° C. The yield is 68.3%.

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Example 3 Into a 2 liter four neck flask equipped with a stirrer, a gas introductory tube for ammonia and reflux condenser, place 600 ml of ethanol and 30.4 g of hexamethylene tetramine. Ammonia is passed through the reaction mixture for so long that the ethanol is supersaturated. The reaction mixture is heated to reflux and gently added 40 g of 2-bromo-2 · - (2-chlorobenzoyl) -4'-nitro-acetanilide over 3½ hours. The reflux heating and the passage of ammonia through the reaction mixture is continued for the next 3 hours, after which the reaction mixture is evaporated to dryness. To the residue are added 250 ml of toluene and 0.04 g of p-toluenesulfonic acid. The mixture is heated to reflux for 1 hour and the toluene phase is cooled to 70 ° C. The resulting solution is washed with water and the toluene phase is then cooled to room temperature. The product crystallizes from the reaction mixture. The crystals are separated by filtration, washed once with toluene and once with petroleum ether to give 5- (2-chlorophenyl) -1,3-dihydro-7-nitro-2H-1,4-benzodiaziazepine-2 -on with m.p. 203-204 ° C. The yield is 62.9%.

Example 4 Into a 12 liter three-neck flask equipped with a cooler and an ammonia gas inlet tube are charged 7.2 liters of ethanol and 470.4 g of hexamethylenetetramine. With stirring, ammonia is passed through the reaction solution until it is supersaturated. During reflux heating, 480 g of 2-chloro-acetamido-5-chlorobenzophenone is gently added over 4 hours. The resulting reaction mixture is heated for an additional 2 hours to reflux, as well as the passage of ammonia is continued. The resulting reaction mixture is then left overnight and then evaporated to dryness under reduced pressure. 2.4 liters of toluene are added to the residue and the resulting reaction mixture is heated to reflux. Then 0.5 g of p-toluenesulfonic acid is added and the reflux heating is continued

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set for 1 hour. After cooling the reaction mixture to 70 ° C, 1.5 liters of hot water are added. The product precipitated by cooling to 20 ° C is filtered off, washed and dried under reduced pressure to give 7-5 chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one with m.p. 213-214 ° C. The yield is 80.3%.

By analogy as described above, 2-bromo-1,3-dihydro-5- (2-pyridyl) -2H-1,4-benzodiazepin-2-one can be prepared with m.p. 225-235 ° C from the compound 2- (2-chloroacet-10-amido-5-bromobenzoyl) -pyridine.

Example 5

A 12-liter three-neck flask equipped with a sealed stirrer, reflux condenser and a gas inlet 15 for ammonia is charged with 7.2 liters of ethanol. The alcohol is heated under stirring in a reflux steam bath. The solvent is then saturated with ammonia to a concentration of approx. 0.6-0.7% by weight. After removing the heat bath, 493 g of hexamethylenetetramine are added. The heating is resumed and 480 g of 2-chloroacetamido-5-chlorobenzophenone are added slowly and in small portions. The ammonia is still passed through the refluxed solution. The addition of the chloroacetamido compound lasts approx. 3-4 hours. After completion of the addition, the reaction mixture is further heated for 2 hours to reflux. The flow of ammonia flow is interrupted and the alcohol removed by vacuum distillation.

The residue is slurried in 2.4 liters of toluene and heated to reflux. At reflux temperature, 0.5 g of p-toluenesulfonic acid is added twice over 15 minutes.

A small amount of water (about 1-2 ml) is excreted. The crystal lysate is then cooled to 70 ° C and the water-soluble fraction dissolved by the addition of 1.5 liters of hot water (70 ° C).

The heterogeneous mixture is stirred overnight, allowing it to cool to room temperature. The separated product is separated by filtration and washed once with 250 ml of cold 12

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water and once with 250 ml of cold toluene (o ° C). The product is then dried to constant weight at 80 ° C to give 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, mp 213-214 ° C. 80.7%.

5

Example 6 Into a 2 liter four neck flask equipped with a stirrer, reflux condenser and a gas introductory tube for ammonia, place 600 ml of ethanol and 37.9 g of hexa-methylene tetramine under stirring. Then ammonia is passed through the resulting reaction solution with heating and stirring until the reaction mixture has reached the reflux temperature. Next, 40 g of 2-chloroacetamido-5-nitro-benzophenone are carefully added to the boiling solution.

Ammonia is constantly passed through the reaction mixture while continuing to reflux for an additional 3 hours. The resulting solution is cooled and evaporated to dryness at 50 ° C. The residue is dissolved in 300 ml of toluene, 0.3 g of p-toluenesulfonic acid is added, and the resulting reaction solution is heated to reflux for 1 hour. Next, the reaction mixture is cooled to room temperature and the separated material is separated by filtration, washed with water and dried. The residue is dissolved in 435 L of methylene chloride and then filtered through Hyflo. After adding 25 ml of 90 ml of 3 N nitric acid to the filtrate, crystals are separated. These are separated by filtration, washed with methylene chloride and dried for 15 minutes. The crystals are stirred into 1 liter of water. Then ammonium hydroxide solution is gently added until the pH has reached 8. After half an hour of stirring the resulting reaction mixture, the separated crystals are separated by filtration, washed with cold water and dried for 8 hours at 80 ° C to give 1 , 3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one, m.p. 217-219 ° C. The yield is 27.2%.

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Example 7

To 1350 ml of ethanol are added 90 g of 2-chloroacetamido-5-chlorobenzophenone and 92.5 g of hexamethylenetetramine. Under pressure, ammonia is passed through the resulting reaction mixture, and the latter is heated to reflux and then evaporated to dryness under reduced pressure. The residue is then rinsed twice with 250 ml of warm water. The aqueous phase is decanted and the crystalline residue is heated on a steam bath for 30 minutes in 250 ml of toluene and then cooled to room temperature 10. The crystals formed are separated by filtration, washed twice with 25 ml of toluene and 25 ml of petroleum ether and then dried to constant weight to give 7-chloro-1,3-dihydro-5-phenyl-2H-1,4 -benzodiazepine-2-one with m.p. 213-215 ° C. The yield is 78%.

15

Example 8 13.5 liters of 95% ethanol, 900 g of 2-chloroacetamido-5-chlorobenzophenone and 925 g of hexamethylenetetramine are placed under stirring in a pressure vessel. With stirring, the reaction mixture is saturated with ammonia. The ammonia feed is removed and the resulting reaction mixture is heated to 70-80 ° C for 3 hours. After cooling and evaporating the ammonia, the reaction mixture is transferred from the pressure vessel to a distillation vessel. The mixture is evaporated on a steam bath under reduced pressure to dryness. To the residue are added 2 µl of toluene and 5 g of p-toluenesulfonic acid, and the resulting mixture is heated to reflux. Ca. 5 ml of water formed is removed by azeotropic distillation. After cooling to 70 ° C, 3 liters of water with a temperature of 30 70 ° C are added. The crystalline thus formed is cooled to 10-15 ° C for 1 hour. After filtration, washing the product with twice 250 ml of water and once 250 ml of cold (10 ° C) 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 to 213.5 ° C. The yield is 66%.

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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-chlorobenzophenone (0.25 mol) are saturated with ammonia.

While stirring, the reaction mixture is slowly heated to reflux temperature, passing through the mixture a steady stream of ammonia. During the reaction, the compound 010 - ° / chA® (CH2) 6 c1® 15 is formed

This intermediate is not isolated. The reaction mixture is heated to reflux for 6 hours, after which the ammonia stream is discontinued and the solvent is removed under reduced pressure. The residue is taken up in a mixture of 500 ml of 20 toluene and 500 ml of hot water. The toluene phase is separated off with stirring and then 169 ml of 3 N nitric acid is added.

The crystals formed are separated by filtration, washed with 50 ml of toluene and taken up again in a mixture of 250 ml of toluene and 250 ml of water. Add 30 ml of concentrated 25 ammonia (pH = 8). The toluene phase is separated, washed with 250 ml of water and then evaporated to dryness under reduced pressure to give 7-chloro-1-methyl-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine -2-on with m.p. 125-127 ° C. The yield is 96.1%.

30

Example 10

A mixture of 600 ml of ethanol and 39.1 g of hexamethylenetetramine (0.279 mol) is saturated with ammonia. While still ammonia is passed through the mixture, it is slowly heated to reflux. Over a period of 4½ hours, 40 g of 2- (2-chloro-N-methyl acetate) are added in portions.

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amido) -5-chlorobenzophenone (0.124 mol) to give a compound of formula H3 s 5 -C-CHA + (CH2) 6 Cl

Without isolation of this intermediate, the reflux heating is continued for an additional 2 hours. The reaction mixture is then evaporated to dryness under reduced pressure at 50 ° C. The residue is stirred with 250 ml of toluene and heated to reflux. Next, two portions of p-toluene sulfonic acid are added and heating to reflux is continued for 1 hour. After cooling to 70 ° C, the toluene solution is washed with warm water to remove the soluble salts and evaporated to dryness under reduced pressure. The residue is dissolved in hot ethanol (111 mol) and the solution is cooled to -10 ° C for 1 hour. The crystalline 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one thus obtained is isolated in an amount of 29 g and has m.p. 129-131 ° C. Evaporation of the mother liquor to approx. 50% gives an additional 2 g of final product with 25 m.p. 127 ° C.

Example 11

A mixture of 1100 ml of ethanol, 70.0 g of hexamethylene tetramine (0.5 mole), 58 ml of 26% ammonium hydroxide solution 30 and 308.2 g of 2-chloroacetamido-5-chlorobenzophenone (1.0 mole) is slowly heated to reflux while stirring and passing ammonia. The refluxing is continued for 5 hours, after which the ammonia flow is stopped and the reaction mixture is evaporated to dryness under reduced pressure. The residue is heated to reflux for 30 minutes in a mixture of 500 ml of toluene and 500 ml of water and cooled 16

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then slowly to room temperature. The separated crystals are separated by filtration, 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-5H-1,4-benzodiazepin-2-one melts at 210 ° C. The yield is 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-chloro-acetamido-5-chlorobenzophenone (1.0 mol) is reacted as described. in Example 11, with the exception that the reaction mixture is heated to reflux for 7 hours instead of 5 hours. The reaction product, namely 7-chloro-15,1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one is isolated as described in Example 11 and melts at 208.5-209 ° C. The yield is 81.6%.

Example 13 A mixture of 550 ml of methanol, 14.1 g of hexamethylene tetramine (0.1 mole) and 308.2 g of 2-chloroacetamido-5-chlorobenzophenone are saturated with stirring at room temperature with ammonia. The mixture is slowly heated to reflux while still passing through ammonia. The refluxing is continued for 24 hours, after which the ammonia stream is removed and the resulting crystalline is cooled to room temperature. The product is separated by filtration, washed with 2 times 125 ml of methanol and 4 times 500 ml of hot water and dried to give 7-chloro-1,3-dihydro-5-phenyl-2H-30,4-benzodiazepine-2 -on with m.p. 213-215eC. The yield is 62.3%.

Example 14

A mixture of 300 ml of ethanol and 20 g of hexamethylene tetramine (0.143 mol) is saturated with ammonia with stirring and reflux heating. 18.1 g of 2-chloroacetamidobenzophenone (0.066 mol) is added in small portions over 17

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3-4 hours while a steady stream of ammonia is passed through the reaction mixture. After the addition of 2-chloroacetamidobenzophenone, the heating is continued at reflux for 3 hours. The ammonia stream is stopped 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 water at a temperature of 50 ° C. The chloroform phase is evaporated to dryness at 308 C and the oily residue is crystallized from 100 ml of toluene to give 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, m.p. 184-186 ° C. Out the exchange is 86%.

Example 15

A mixture of 275 ml of methanol and 154.2 g of 2-chloro-15-acetamido-5-chlorobenzophenone (0.5 mol) is heated to reflux while still passing through ammonia. At reflux temperature, 237 ml of 37% formaldehyde solution is added over approx. 40 minutes. The reaction mixture is then heated to reflux for 5 hours. The lead-through of the ammonia is quenched and the crystalline is cooled to room temperature, filtered, washed with twice 125 ml of methanol and four times 500 ml of warm water and dried to give 7-chloro-1,3-dihydro-5-phenyl 2H-1,4-benzodiazepin-2-one with m.p. 211,5-214,58C. The yield is 77.3%.

25

Example 16

A mixture of 147.2 g of paraformaldehyde and 55o ml of methanol is heated to reflux with stirring and still passing through ammonia. After cooling the thus obtained crystallize hexamethylenetetramine to room temperature, 308.2 g of 2-chloroacetamido-5-chlorobenzophenone (1.0 mole) are added portionwise. Under the course of ammonia, the reaction mixture is heated to reflux for 10 hours. The ammonia pass-through is quenched and the reaction mixture is cooled to room temperature, filtered, washed twice with 125 ml of methanol and four times 500 ml of warm water and dried.

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to give 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, m.p. 212.5 to 215 "C. The yield is 81.4%.

Example 17 5 In a container equipped with stirrer, reflux condenser and gas supply tube for ammonia and a decanting device, 200 g of paraformaldehyde (91% s liquor) and 575 ml of methanol are charged and gaseous ammonia is passed through the mixture. . 10 273.7 g of 2-chloroacetamidobenzophenone are then added. Undergoing slow, continuous ammonia flow, the mixture is heated to reflux for 5 hours. The resulting crystallate is distilled to recover methanol. Next, 350 ml of toluene is added to the crystalline residue and the water still present is removed by azeotropic distillation. Next, the hot toluene solution is filtered and the filtrate is cooled to crystallize, after which 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one can be isolated with m.p. 180-181 ° C (not corrected). The yield is 84.7%.

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Example 18 In a container equipped with a stirrer, reflux condenser and a gas supply tube for ammonia, at room temperature 147.2 g of paraformaldehyde (91% 25 lb), 550 ml of methanol and 326.2 g of 2-chloroacetamido acid are charged. 5-chloro-2'-fluorobenzophenone. The mixture is stirred and ammonia is passed beneath the surface. Next, the reaction mixture is heated to reflux while still passing ammonia gas for 10 hours. Then, it is cooled to room temperature and the crystalline product is separated by filtration. The product is washed twice with 125 ml of cold methanol (-10 ° C) and four times with 500 ml of hot water (60 ° C). After drying, 7-chloro-5- (2-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiaze-pin-2-one is obtained, m.p. 205.5-207 ° C (not corrected). Yield 35 is 71%.

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Example 19 Into a 5 liter three neck flask equipped with agitator and calcium chloride drying tube are placed 250 g of 2-chloro-acetamido-5-chlorobenzophenone and 122.5 g of hexamethylene-tetramine and 2.5 liters of acetonitrile. The mixture is stirred at room temperature for 72 hours, dissolving both starting materials. The reaction product of the formula H0 - ccgif, © (ch2) 6 ci © 10 ^ CXc = o is then crystallized, filtered, washed with a small amount of fresh solvent and dried to give the product with m.p. 169-170 ° C.

89.7 g of the product thus obtained are dissolved in 20 ethanolic ammonia. With still gaseous ammonia passing through, the resulting mixture is heated to reflux for 5 hours to give 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, which is isolated by prior art. methods. Mp. 212-214 ° C. The yield is 79.2%.

25

Example 20 In a 1 liter container equipped with a reflux condenser, 89.7 g of the addition salt of formula 30 H 0 ^ ______ Jj-C-CHjMj © (CH2) 6 Cl © iXc == oo 20

DK 155326 B

61.6 g of 2-chloroacetamido-5-chlorobenzophenone, 22.4 ml of 26% ammonium hydroxide solution and 425 ml of ethanol. Under the conduction of ammonia, the mixture is heated for 5 hours to reflux. The mixture is evaporated to dryness and the residue is then heated for 1 hour in a mixture of 100 ml of toluene and 100 ml of reflux water and cooled to room temperature. The product precipitated is separated by filtration, washed with 20 ml of water and toluene and dried to give 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one with m.p. . 210-213eC. The yield is 85.4%.

Claims (3)

A process for the preparation of 1,1'-benzodiazepine-one derivatives of the general formula p 5 (- / 10 in which R 1 represents hydrogen, halogen, nitro or trifluoromethyl, R 2 represents hydrogen or alkyl of 1 to 5 carbon atoms and R 3 represents phenyl, o-halophenyl or 2-pyridyl, by reacting a compound of the general formula 2 RO ^ ___ ^ NC CH2X R 1 in which R 1, R 2 and R 3 have the meaning given above and X represents chlorine, bromine or iodine, preferably chlorine, with 25 hexamethylenetetramine in an inert organic solvent, optionally while isolating an intermediate of the general formula o RO 30 - In which R1, R2, R3 and X are as defined above, DK 155326 B and subsequent cyclization thereof to the corresponding compound of the general formula I, characterized in that (a) during the direct implementation of process 5 (II-4!) or - in the case of isolation of the intermediate of formula III - in step (III-* I) and / or in step (II-III), using ammonia and (b) at least 10 0.1 moles of hexamethylenetetramine are used per mole of the compound of formula II. Process according to claim 1, characterized in that a starting material is used, wherein R 1 is chlorine, R 2 is hydrogen and R 3 is phenyl. 3. A process according to claim 1, characterized in that a starting material is used wherein R 1 is chlorine, R 2 is methyl and R 3 is phenyl.