CH626076A5 - Process for the preparation of 2-substituted 1,4-benzodiazepine derivatives - Google Patents

Description

The present invention relates to processes for the preparation of 2-substituted 1,4-benzodiazepines of the general formula I.

ch2-or3

tu and their acid addition compounds, where Ri is a hydrogen or a halogen atom,

R2 represents a hydrogen or a halogen atom or the trifluoromethyl group, and

R3 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.

Halogen atoms are preferably chlorine, bromine or iodine for R 1, fluorine, bromine and iodine for R 2. Suitable alkyl groups are in particular methyl, ethyl, propyl, isopropyl, butyl or sec-butyl, but also amyl or hexyl. Part of these compounds are new 1,4-benzodiazepines.

Compounds of the general formula I and processes for their preparation are described for the first time in CH-PS 605,834. These substances of the general formula I have valuable pharmacological properties, such as, for example, anticonvulsive, sedative and muscle relaxant and pronounced anxiolytic and anti-aggression effects which justify therapeutic use as tranquilizers, hypnotics and antiepileptics.

It has been proposed to make these compounds e.g. Compounds of the general formula II

ch "-x

40

45

[ii]

in which R 1 and R 2 have the meaning given above and X represents a reactive group, preferably a chlorine atom, at elevated temperature with alkali metal hydroxides or alkali metal carbonates in suitable solvents in the 2-hydroxymethyl compounds I or with alkali metal oxides in the corresponding alcohols in the 2- Transfer alkoxymethyl compounds.

According to a further proposal, you can inter alia the compounds of general formula III

[iii]

in which R 1 and R 2 have the meaning given above and X is a reactive group, preferably a chlorine atom,

626 076

represents, convert with alkali metal hydroxides or alkali metal alkoxides into the corresponding compounds of formula I. The starting products for the abovementioned compounds of the general formulas II and III are acyl diamines of the general formula IV

n_ch9_ ch. ch7-nh. | |

Oh

[iv]

in which Ri and R2 have the meaning given above. With POCb, they can be converted into the substances of the general formula II or the general formula III while observing certain reaction temperatures and, if appropriate, in the presence of suitable solvents. The type of substituents Ri and R2 has a significant influence on the reaction conditions to be observed. The reaction procedure generally requires a very precise and complex control.

In order to obtain compounds of the general formula II, acyldiamines of the general formula IV are reacted with preferably phosphorus oxychloride by the known method. By suitable choice of the proportions of the reactants, it can be achieved that the reaction temperature which is most favorable for the formation of the 1,4-benzodiazepines is established in the reaction mixture. In this way, in particular compounds of the general formula II in which R2 is a hydrogen atom can preferably be prepared in good yields at temperatures between about 115 and 125 ° C. A disadvantage of this method is the relatively long reaction times required. When using a number of substituted acyldiamines of the general formula IV, these reaction conditions can give rise to the formation of resinified by-products, so that working up the reaction mixture is difficult and the process becomes unprofitable.

In the preparation of the compounds of general formula III, which are 1,5-benzodiazocines, it is possible to work at temperatures around 100 ° C .; However, in order to obtain sufficient yields, one must work in solvents such as nitrobenzene and also use relatively long reaction times. In addition, the use of toxic nitrobenzene makes processing more difficult, particularly when working on a technical scale. In order to eliminate the formation of by-products as far as possible, it has also been proposed to convert the hydroxyl group in the acyldiamines of the general formula IV into an acyloxy group; however, the reaction temperatures required for the reaction of these compounds and the likewise relatively long reaction times can in turn reduce the yields.

In order to avoid these difficulties and to improve the yields of compounds of the general formula II, it has already been proposed to carry out the conversion of the acyldiamines of the general formula IV into the 1,4-benzodiazepines in several stages, for example by first using the acyldiamines with PCI5 in dichloroethane to give the corresponding imidoyl halides and then carry out the ring closure with AlCb in nitrobenzene. It has been shown that the ring closure of the midicoyl halides can in many cases be carried out under milder reaction conditions. In particular when R2 is a fluorine atom, better yields are obtained by this process than by the former process. However, it is disadvantageous that the step-by-step work with different solvents and reagents is time-consuming and labor-intensive.

It has now been found that, starting from the acyldiamines of the general formula IV, the 2-substituted 1,4-benzodiazepines of the general formula I can be obtained 20 without the compounds of the general formula II or III being used as complex control procedures Intermediates isolated in the purest form possible and the 2-halomethyl-l, 4-benzodiazepines obtained or the 3-halo-l, 5-benzdiazocines converted into the desired 25 compounds. Surprisingly, it was found that when the acyldiamines of the general formula IV are reacted with phosphorus oxychloride within a short time, generally within a few hours, the cyclization takes place completely with the formation of a mixture of the compounds 30 II and III if the amount of excess in the reaction mixture Phosphorus oxychloride is chosen so that its boiling temperature is set and maintained during the reaction.

It was also found that this mixture of isomers can be converted directly into the desired compounds of the general formula I without separation into the individual components.

The process for the preparation of 2-substituted 1,4-benzodiazepines of the general formula I.

ch2or3

[I]

60 and their acid addition compounds, where Ri is a hydrogen atom or a halogen atom, R2 is a hydrogen atom, a halogen atom or the trifluoromethyl group and R3 is an alkyl group having 1 to 6 carbon atoms, is defined in claim 1. Compounds 65 of the formula I, in which R3 is hydrogen, are prepared as described in claim 5.

The amount of phosphorus oxychloride used to adjust the boiling point of the same in the reaction mixture

626076

can be determined without difficulty, as the attached examples show. The reaction of the isomer mixture to give the corresponding 2-hydroxymethyl- or 2-alkoxymethyl-1,4-benzodiazepines of the general formula I takes place, if necessary after rough cleaning, generally under reaction conditions as used in the preparation of these compounds from the isolated compounds II and III with the corresponding nucleophilic reagents: alkali alkoxides, alkali carbonates, alkali hydroxides or alkali acetates. In general, the sodium or potassium compounds are preferred. The appropriate alcohols are suitable as solvents when using the alkali alkoxides. But you can also work in other suitable proton-free solvents such as dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide. Alkali hydroxides or alkali carbonates are generally used in the form of their aqueous solutions, optionally in the presence of a water-miscible solvent, such as dioxane or tetrahydrofuran. A suitable solvent for the reaction with sodium acetate is, for example, dimethylformamide. If necessary, these reactions can also be carried out in two-phase systems. The reflux temperatures which are established are suitable as reaction temperatures.

The acyl diamines of the general formula IV, in which the phenyl rings may already have the substituents which are to be contained in the end product, serve as starting materials. However, it is also possible to add the substituent Ri subsequently, if it has the meaning chlorine, bromine or iodine, i.e. following the cyclization reaction or after obtaining the 2-substituted 1,4-benzodiazepine of the general formula I, in which Ri is a hydrogen atom, by reaction with a suitable halogenating agent. N-bromine and N-chlorosuccinimide or iodine monochloride are particularly suitable for the introduction of iodine. The process has the advantage that the preparation of the 2-substituted 1,4-benzodiazepines with little labor, i.e. can be done without complex reaction control and cleaning procedures with short reaction times. In general, higher yields are also achieved than with the known processes. This method is particularly suitable for the preparation of the compounds in which R2 is a halogen atom or a trifluoromethyl group. This was all the less predictable since the cyclization has hitherto required long reaction times both in the direction of the compounds of the general formula II and of the general formula III and a number of R2-substituted compounds of the general formula I could only be obtained with unsatisfactory yields. The good yields achieved and the wide range of variation in the preparation of the desired compounds according to the invention is also surprising because it can generally be observed in preparative organic chemistry that losses in yield are tolerated when mixtures or only roughly purified crude products are used as a result of complicated side reactions Need to become.

In the reactions described, the compounds of the general formula I can be obtained as free bases either directly from the reaction mixture or in a known manner from the acid addition compounds, preferably the hydrochlorides, by hydrolysis using bases, such as sodium hydroxide, sodium carbonate, ammonia solution . Starting from the free bases, the desired acid addition compounds can be prepared by known chemical processes.

If the compounds are to be used as intermediates in the manufacture of other compounds or for any other non-pharmaceutical purposes, the toxicity or non-toxicity of the salts is of no concern. When the compounds are to be used for pharmaceutical purposes, they are preferably used as their non-toxic acid addition compounds. Thus, more toxic and non-toxic salts are included in the scope of the invention.

Acids which can be used to prepare the preferred non-toxic acid addition compounds are those which, together with the free bases, form salts, the anions of which, in therapeutic doses of the salts, are harmless to humans, so that the useful physiological properties of the bases are not accompanied by side effects of the acid components are questioned. To obtain the salts, the bases are advantageously reacted with the calculated amount of organic or inorganic acids in a water-miscible solvent, such as ethanol or isopropanol, the salts being isolated by concentration and cooling, or the bases are reacted with an excess of acid a water-immiscible solvent such as diethyl ether or diisopropyl ether, whereby the desired salt separates immediately. For example, such organic acid addition salts with maleic, fumaric, benzoic, ascorbic, amber, methane sulfonic, vinegar, propionic, wine, lemon, milk, apple, cyclohexane sulfamine, p-aminobenzoic - Toluene sulfonic, glutamic or stearic acid are formed. Inorganic salts can be formed, for example, with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric or nitric acid.

The use of the non-toxic salts of the compounds of the general formula I in pharmaceutical preparations has the advantage over the bases that the salts are generally water-soluble.

The 2-substituted 1,4-benzodiazepines of the general formula I 'shown in the present application

CH_ CH0 — O-R-

! / - 2 5

€ H

CH

=. N

Br and their acid addition compounds, in which R3 is an alkyl group with 1 to 3 carbon atoms and R2 is a halogen atom or the trifluoromethyl group, are new compounds which, surprisingly, differ from previously known substances which have a chlorine atom in the 7-position of this benzodiazepine skeleton , differentiate by a new, favorable effect profile. For example, with comparable toxicity, the new compounds are characterized in particular by a clear dose interval between the anxiolytic and sedative components, a fact that identifies the new compounds as valuable, particularly for the treatment of anxiety, tension, stress, neuroses and pathological aggressive behavior. The beneficial therapeutic properties can be exploited in particular for day tranquilizers without the disadvantage of severe sedation, which often leads to impaired wakefulness. In addition, the new compounds compared to those in the above-mentioned patent

6

s

10th

IS

20th

25th

30th

35

40

45

50

55

60

65

7

626076

named compounds have a significantly improved anticonvulsant effect. Finally, compared to the compounds of similar structure mentioned by name in the abovementioned patent, the new compounds show a significantly more favorable dose interval between the anxiolytic and tension-releasing and anti-aggressive component and the component influencing muscle tone, a property which is also particularly psychologically ill for outpatient treatment People is of great importance. 10th

The new, unpredictable and therefore surprising favorable pharmacological properties of the new compounds mentioned are evident below from the description and explanation of the animal experimental results. The 7-chloro-l-methyl-2-methoxy-methyl-5- (2 / -chlorophenyl) -IH-2,3-dihydro-l, 4 is used as a standard substance in all experimental arrangements to clarify the situation described -benzodiazepine (in the form of its hydrochloride) from the above-mentioned patent. As a further comparative substance, diazepam 20 is given as a common means of medical practice.

Description of the pharmacological test methods

1.) Acute toxicity

The acute 7-day toxicity is determined after a single application per os and intraperitoneally on the white, fasting NMRI mouse. The LDso values were calculated by EDP using a probit analysis (Cavelli-Sforza, Gustav Fischer Verlag, 1964, basic terms in biometrics).

30th

2.) Testing for anticonvulsant properties a) Pentetrazole spasm method

The test substances are tested after oral administration to groups of 6 mice each. 60 minutes after the application of the test substances, pentetrazole 3s is injected subcutaneously in a dose of 100 mg / kg. The occurrence of clonic or tonic convulsions is monitored over a total observation time of 45 minutes. The protective effect of the test substance against convulsions is determined in comparison to control tests. The effective 40 dose EDso is logged from the probit. Dosage curves calculated. (Modified according to J.E. Blum et al. Arzneimittel-Forsch. 23, 377 [1973]).

be added spontaneously. The test substances are administered orally to the isolated mice and the dose is determined after 30 minutes, which leads to a 50% reduction in aggressive behavior. (Modified from Weischer and Opitz, Arch. Int. Pharmacodyn. 195, 252 [1972]).

The results obtained in this test arrangement allow good conclusions to be drawn about the anxiety, stress and tension-releasing properties of the substance.

4.) Testing the musculotropic properties

In the Test de la Traction, the test substance is administered orally to mice. After 120 minutes, the mice are hung with their front paws on a thin, horizontally stretched wire. The ED is the dose at which just half of the animals do not touch the wire with the hind pods within 5 seconds. (W. Theobald et al. Arzneimittel. Forsch. 17, 561 [1967]). In this test the influence of the muscle tone by the test substances is tested.

5.) Testing for central damping properties

(Hexobarbital sleep time extension)

The test substance is administered orally to the mice. After 30 minutes, the animals receive an additional IV. Injection of 64 mg / kg hexobarbital. The time of taking the side position is determined and the duration of the side position is compared with a control group treated only with hexobarbital. ED is defined as a dose at which half of the animals maintain a side position extended by a factor of 4 compared to the control group. (G.M. Everett, Nature 177, 1238 [1956]).

The following compounds were investigated using the methods described above:

b) Maximum electric shock method 45

The test substances are administered orally to the animals. 60 minutes after application, electrodes are attached to the ears of the mice and an electrical stimulus is triggered. The dose is determined which prevents the occurrence of tonic spasms on the hind limbs in half of the animals. The EDso is also calculated using the probit analysis given above. (Modified from J. Swinyard, J. Pharmacol. Exptl. The-rap. 106, 93 [1952]).

The results obtained according to the described methods show the anticonvulsive effect of the test substances and, according to the literature, are an important criterion for assessing the clinical effectiveness as a tranquilizer (A.

Suria and E. Costa, Journal de Pharmacologie, Suppl. 1, 5, 94 [1974] and G. Zbinden and L.O. Randall, Advances in 60 Pharmacol. 5, 213 [1967]).

3. Testing for anxiolytic and anti-aggressive effectiveness. Inhibition of the aggressiveness of the mouse caused by isolation. 6s

Before the experiment, the mice are kept in strict isolation in a single cage for 4 weeks. After this time, the mice kept in isolation grab mice that were not kept in isolation

Compound 1 7-bromo-l-methyl-2-methoxymethyl-5- (2'-chlorophenyl) -lH-2,3-dihydro-1,4-benzodiazepine (as hydrochloride) Compound 2 7-bromo-l-methyl- 2-ethoxymethyl-5- (2'-chlorophenyl) -lH-2,3-dihydro-l, 4-benzodiazepine (as hydrochloride) compound 3 7-bromo-l-methyl-2-methoxymethyl-5- (2'- fluorophenyl) -lH-2,3-dihydro-1,4-benzodiazepine (as hydrochloride) Standard I 7-chloro-l-methyl-2-methoxymethyl-5-

(2'-Chlorophenyl) - lH-2,3-dihydro-1,4-benzodiazepine (as hydrochloride) Standard II 7-chloro-l-methyl-5-phenyl-l, 3-dihydro-2H-1,4- benzodiazepin-2-one (diazepam)

Table 1 shows the values for the toxicity and the anticonvulsant effects of the compounds according to the invention listed above in comparison with the two standard compounds.

Table 1

substance

LD50 p.o.

Pentetrazole spasm

Electric shock

(mg / kg)

EDS0 (mg / kg)

EDS0 (mg / kg)

1

1578

0.9

3.0

2nd

> 1470

2.2

24.5

3rd

1580

0.5

5.0

Standard I

1779

2.0

26

Standard II

887

0.5

9.0

Table 2 shows the results for the anxiolytic and anti-aggressive effects.

626076

Table 2

Substance isol. Fighting mouse ED; o (mg / kg)

1 3.1

2 4.1

3 10.7 Standard I 68 Standard II 3.6

Table 3 shows the results for muscle coordination (Test de la Traction) and sedation (hexobarbital sleep time extension).

Table 3

substance

Test de la Traction EDso (mg / kg)

Hexobarbital sleep time extension EDS0 (mg / kg)

1

87

15.2

2nd

34.9

41.9

3rd

58.3

10.6

Standard I

163

11.7

Standard II

4.2

1.5

In table 4, the quotient formation EDso Hexo-barbital sleep extension / EDso isolated fighting mouse = quotient 1 and EDso Test de la Traction / EDso isolated fighting mouse = quotient 2 shows the superiority of the new compounds in the distance between sedative to anxiolytic components and the favorable relation between muscle relaxation and anxiolytic effects.

Table 4

substance

Quotient 1

Quotient 2

1

4.9

28.1

2nd

10.2

8.5

3rd

0.9

5.4

Standard I

0.17

2.4

Standard II

0.42

1.2

This fact is additionally illustrated by Table 5, which is shown in Table 4, by setting Standard 1 = 1.

Table 5

substance

Quotient 1 standard 1 = 1

Quotient 2 standard 1 = 1

1

28.8

11.7

2nd

60

3.5

3rd

5.3

2.3

Standard I

1

1

Standard II

2.4

0.5

The pharmacological results listed in Tables 1 to 5 show very clearly the superiority of the new compounds according to the invention over the standard compounds. The new compounds according to the invention have, in particular, superior anticonvulsant properties and a marked reduction in the sedative and muscle-relaxing components in favor of the anxiolytic and anti-aggressive properties. The new compounds according to the invention are therefore distinguished by a novel activity profile and thus represent anxiolytics which are clearly superior to known compounds in this area of indication.

The compounds of general formula I and their pharmaceutically usable acid addition compounds can thus be used as medicaments, for example in the form of pharmaceutical preparations, which compounds of formula I or their acid addition compounds in a mixture with an inorganic or organic, inert pharmaceutical carrier material suitable for enteral or parenteral administration , such as Contain water, gelatin, milk sugar, starch, magnesium stearate, talc, vegetable oils, rubber, polyalkylene glycols, petroleum jelly and the like. The pharmaceutical preparations can be in solid form (e.g. as tablets, dragees, suppositories, capsules) or in liquid form (e.g. as solutions, suspensions or emulsions). If necessary, they are sterilized and / or contain additives such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers. They can also contain other therapeutically valuable substances.

The following examples serve to illustrate the invention.

example 1

70 g of Ni-phenyl-Ni-methyl-N2- (2'-chlorobenzoyl) -2-hydroxy-1,3-diaminopropane are heated under reflux in 350 ml of phosphorus oxychloride for 2.5 hours. The excess phosphorus oxychloride is then distilled off in vacuo, the residue is taken up in 500 ml of chloroform and well-stirred with 200 g of ice, 200 ml of water and 200 ml of concentrated sodium hydroxide solution. The organic phase is separated off, washed neutral with water, dried over sodium sulfate and evaporated. The residue is stirred for three hours with 250 ml of ether, mixed with 100 g of Y-alumina and filtered.

After the ether has been distilled off, 50 g of crude product remain, which consists of a mixture of l-methyl-2-chloromethyl-5- (2'-chlorophenyl) -2,3-dihydro-lH-l, 4-benzodiazepine and 1-methyl- 3-chloro-6- (2'-chlorophenyl) -l, 2,3,4-tetrahydro-l, 5-benzodiazocin. The crude product is taken up in 750 ml of methanol, in which 4 g of sodium have previously been dissolved, and heated under reflux for five hours. After this time, the solvent is distilled off, the residue is dissolved in 250 ml of toluene and washed neutral with water. The organic phase is thoroughly stirred with 200 g of Al2O3 activity level II-III, basic (standard from Merck) and filtered. The solvent is distilled off. The residue (43 g), which consists of l-methyl-2-methoxymethyl-5- (2'-chloro-phenyl) -2,3-dihydro-lH-l, 4-benzodiazepine, is dissolved in 800 ml of methylene chloride and heated under reflux with 24.5 g of N-bromosuccinimide for 24 hours. The solvent is then distilled off and the residue is dissolved in a mixture of 125 ml of ether and 125 ml of toluene. The base is extracted with a sufficient amount of dilute hydrochloric acid (20%). The base is then separated off by adding concentrated sodium hydroxide solution and extracted with 125 ml of ether. The addition of a solution of hydrochloric acid gas in ether precipitates the hydrochloride and recrystallizes it from 150 to 250 ml of ethanol.

The yield is 25.3 g of 7-bromo-l-methyl-2-methoxy-methyl-5- (2'-chlorophenyl) -2,3-dihydro-lH-l, 4-benzodiazepine as the hydrochloride. Melting point: 193-196 ° C.

Bromine content:

Calculated: 18.6%

Found: 18.8%

Chlorine content:

Calculated: 16.4% Found: 16.1%

8th

s

10th

15

20th

25th

30th

35

40

45

SO

55

60

65

9

626 076

Similarly, using only sodium in ethanol instead of methanol, 7-bromo-l-methyl-2-ethoxymethyl-5- (2'-chlorophenyl) -2,3-dihydro-1H-1,

Prepare 4-benzodiazepine (identical to the product obtained according to Example 2).

Example 2

70 g of Ni-phenyl-Ni-methyl-N2- (2'-chlorobenzoyl) -2-hydroxy-1,3-diaminopropane are heated under reflux with 350 ml of phosphorus oxychloride for 2.5 hours. Then the excess phosphorus oxychloride is distilled off, the residue is taken up in 400 ml of chloroform and extracted with 400 ml of ice water and 200 ml of concentrated sodium hydroxide solution. The chloroform phase is washed neutral with water, dried with sodium sulfate and evaporated. The residue (74.6 g) is dissolved in 1000 ml of methylene chloride and heated under reflux with 41.6 g of N-bromosuccinimide for 24 hours. The solvent is distilled off and the residue is dissolved in a mixture of 250 ml of toluene and 250 ml of ether. The base is extracted with dilute hydrochloric acid (20%) and converted into the toluene phase by treatment with concentrated sodium hydroxide solution and toluene. The toluene phase is successively filtered through 150 g of Al 2 O 3 II-III (standard from Merck) and 150 g of Ah031 basic (standard from Merck). After evaporation of the toluene, 35.5 g of an oily mixture of 7-bromo-l-methyl-2-chloromethyl-5- (2 / -chlorophenyl) -2,3-dihydro-lH-l, 4-benzodiazepine and 8- Brom-l-methyl-3-chloro-6- (2'-chlorophenyl) -l, 2,3,4-tetrahydro-l, 5-benzodiazocin isolated. The mixture is taken up in 750 ml of ethanol in which 6.5 g of sodium have previously been dissolved and heated under reflux for 24 hours. Then the ethanol is distilled off, the residue is dissolved in 300 ml of chloroform and washed neutral with water. The organic phase is separated off and dried with sodium sulfate. The solvent is distilled off and the residue (24 g) is filtered with toluene / chloroform (9: 1) over 500 g of aluminum oxide I (standard from Merck). After the solvent has been distilled off, the residue is dissolved in acetone and a solution of hydrochloric acid gas in ether is added until an acidic reaction occurs. The hydrochloride separates out as yellow crystals, which is collected and recrystallized from ethanol (100-200 ml).

7-Bromo-l-methyl-2-ethoxymethyl-5- (2'-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine as hydrochloride is obtained in a yield of 15.6 g.

Melting point: 191-194 ° C

Bromine content:

Calculated: 18.0%

Found: 18.3%

Chlorine content:

Calculated: 15.9%

Found: 15.6%

Similarly, using a solution of sodium in methanol, the 7-bromo-l-methyl-2-methoxymethyl

5- (2 / -chlorophenyl) -2,3-dihydro-lH-1,4-benzodiazepine from the mixture of 7-bromo-l-methyl-2-chloromethyl-5- (2 / chlorophenyl) -2,3 -dihydro-lH-l, 4-benzodiazepine and 8-bromo-

1-methyl-3-chloro-6- (2'-chlorophenyl) -l, 2,3,4-tetrahydro-l, 5-benzodiazocin obtained.

Example 3

70 g Ni (4-bromophenyl) -Ni-methyl-N2- (2'-chlorobenzoyl) -

2-hydroxy-1,3-diaminopropane are heated under reflux in 250 ml of phosphorus oxychloride for 2.5 hours. The excess phosphorus oxychloride is then distilled off and the residue is stirred with 50 ml of water and 500 ml of methyl isobutyl ketone until bright red crystals have separated. The crystals are collected and, as described in the previous examples, stirred with chloroform, ice, water and sodium hydroxide solution. The residue obtained from the chloroform phase is treated with 200 ml of ether and 100 g of Y-alumina. After filtering and distilling off the solvent, an oily residue (30 g) is obtained, which consists of 7-bromo-l-methyl-2-chloromethyl-5- (2 / -chlorophenyl) -

2,3-dihydro-lH-l, 4-benzodiazepine and 8-bromo-l-methyl-3-chloro-6- (2'-chlorophenyl) -l, 2,3,4-tetrahydro-l, 5-benzodiazocin. Analogously to Example 2, the mixture can be used to obtain 7-bromo-l-methyl-2-methoxymethyl-5- (2'-chlorophenyl) -2,3-dihydro-1H- with a solution of sodium and methanol.

1.4-benzodiazepine or with sodium in ethanol, the 7-bromo-l-methyl-2-ethoxymethyl-5- (2'-chlorophenyl) -2,3-dihydro-lH-1,4-benzodiazepine.

Example 4

250 g of Ni-methyl-Ni-phenyl-N2- (2'-chlorobenzoyl) -2-hydroxy-1,3-diaminopropane are refluxed in 500 ml of phosphorus oxychloride for four hours. It is poured into ice water and extracted with chloroform. The combined organic phases are washed with sodium hydroxide solution, dried over sodium sulfate and evaporated in vacuo. 255 g of crude product are obtained, which, dissolved in 300 ml of toluene, is heated under reflux together with a solution of 50 g of sodium in 1.41 methanol for 24 hours. The solution is then concentrated to about 800 ml, poured into ice water and extracted with about 41 methylene chloride. After drying over sodium sulfate, the solution is concentrated to about 3 l and refluxed with 150 g of N-bromosuccinimide for seven hours. The reaction solution is washed with dilute sodium hydroxide solution, dried over sodium sulfate and evaporated in vacuo. The residue is taken up in toluene and filtered through y-alumina. The toluene is distilled off, the residue is taken up in 2.5 l of acetone and the hydrochloride is precipitated by passing in HCl gas. 163.5 g of 7-bromo-l-methyl-2-methoxymethyl-5- (2 / -chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine hydrochloride with a melting point of 193-196 ° are obtained C.

Example

270 g of Ni-methyl-Ni (4'-chlorophenyl) -N2- (2'-chlorobenzoyl) -2-hydroxy-l, 3-diaminopropane are added to 550 ml of phosphorus oxychloride with stirring. Then heated under reflux for four hours. The mixture is allowed to cool to 80 ° C., poured into ice water and extracted with methylene chloride. The combined organic phases are shaken with sodium hydroxide solution, dried over sodium sulfate and evaporated in vacuo. 275 g of crude product are obtained, which is heated to 130 ° C. for two hours with 330 g of sodium acetate in 1.11 dimethylformamide. After filtration, the dimethylformamide is distilled off in vacuo, the residue is dissolved in 1.2 l of methanol and refluxed for 30 minutes with 240 ml of 20% sodium hydroxide solution. The mixture is filtered, the solvent is distilled off in vacuo and the residue is poured into 5 l of water. The precipitated product is filtered off, washed with water and stirred with acetone for two hours. 112 g of 7-chloro-1-methyl-2-hydroxymethyl-5 (2 / -chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine are obtained, which recrystallized from 11 isopropanol and melt at 172-174 ° C .

Example 6

600 g of Ni-methyl-Ni (4'-chlorophenyl) -N2- (2'-chlorobenzoyl) -2-hydroxy-l, 3-diaminopropane are in 2.61 phosphorus oxide

10th

15

20th

25th

30th

35

40

45

50

55

60

65

626 076

10th

chloride added and heated under reflux for 2.5 hours. The unreacted, excess phosphorus oxychloride is distilled off, the residue is taken up in chloroform and poured into ice water. The chloroform phase is separated off, dried over sodium sulfate and evaporated in vacuo. The residue is taken up in methyl isobutyl ketone for crystallization and the crystals are suction filtered. 320.7 g of a mixture of 7-chloro-1-methyl-2-chloromethyl-5- (2'-chlorophenyl) -2,3-dihydro-1H-1, 4-benzodiazepine hydrochloride and 8 are obtained -Chlor-l-methyl-3-chloro-6- (2'-chlorophenyl) -l, 2,3,4-tetrahydro-l, 5-benzodiazepine hydrochloride. A further 131 g of the hydrochloride mixture can be isolated from the mother liquor.

125 g of this mixture are refluxed in 1.2 l of dioxane and 820 ml of water with 880 ml of 20% sodium carbonate solution for one hour. The solvent is distilled off in vacuo and the aqueous phase is extracted with chloroform. The chloroform solution is dried over sodium sulfate, evaporated and the solid residue is extracted with acetone. 68.5 g of 7-chloro-l-methyl-2-hydroxy-methyl] -5- (2'-chlorophenyl) -2,3-dihydro-1H-1,4-benzodiazepine with a melting point of 172-174 ° C. are obtained .

Example 7

151 g of Ni-phenyl-Ni-methyl-N2- (2'-fluorobenzoyl) -2-hydroxy-l, 3-diaminopropane are refluxed in 430 ml of phosphorus oxychloride for 3 hours. Then the excess phosphorus oxychloride is distilled off in vacuo, the residue is taken up in 1000 ml of chloroform and concentrated with 200 g of ice, 200 ml of water and 200 ml. Sodium hydroxide solution stirred well. The organic phase is separated off, washed neutral with water, dried over sodium sulfate and evaporated. The residue is stirred for 3 hours with 500 ml of ether, mixed with 100 g "/ alumina and filtered. After evaporation of the ether, 110 g of crude product remain, which consists of a mixture of l-methyl-2-chloromethyl-5- (2 ' -fluorophenyl) -IH-2,3-dihydro-l, 4-benzodiazepine and l-methyl-3-chloro-6- (2 / -fluorophenyl) -l, 2,3,4-tetrahydro-1,5 The crude product is taken up in 1.5 l of methanol in which 8.9 g of sodium have previously been dissolved and heated under reflux for 5 hours, after which the solvent is distilled off, the residue is dissolved in 500 ml of toluene and washed neutral with water The organic phase is carried out well with 200 g of Al 2 O 3 activity stage II-III, basic (from Merck) and filtered, the solvent is distilled off and the residue (93 g), which consists of 1-methyl-2 -methoxymethyl-5 (2'-fluorophenyl) -1H-2,3-dihydro-1,4-benzodiazepine is dissolved in 1200 ml of methylene chloride and boiled under reflux with 53 g of N-bromosuccinimide for 24 hours. Dan After the solvent is distilled off and the residue is dissolved in a mixture of 250 ml of ether and 250 ml of toluene. The base is extracted with a sufficient amount of dilute hydrochloric acid (20%). Then by adding conc. Sodium hydroxide solution excreted the base and extracted with ether (250 ml). The hydrochloride is precipitated by adding a solution of hydrochloric acid gas in ether and recrystallized from 200 to 300 ml of ethanol.

The yield is 60.2 g of 7-bromo-l-methyl-2-methoxy-methyl-5- (2 / -fluorophenyl) -lH-2,3-dihydro-1,4-benzodiazepine as the hydrochloride.

Melting point: 183-185 ° C.

Elemental analysis:

C H N Br Cl

Calculated: 52.3% 4.6% 6.8% 19.3% 8.6% Found: 52.3% 4.7% 6.4% 19.4% 8.3%

Example 8

70 g of Ni-phenyl-Ni-methyl-N2- (2'-chlorobenzoyl) -2-hydroxy-1,3-diaminopropane are heated under reflux with 350 ml of phosphorus oxychloride for 2.5 hours. Then the excess phosphorus oxychloride is distilled off, the residue is taken up in 400 ml of chloroform and concentrated with ice water (400 ml) and 200 ml. Sodium hydroxide solution shaken out. The chloroform phase is washed neutral with water, dried with sodium sulfate and evaporated. The residue (74.6 g) is dissolved in 1000 ml of methylene chloride and refluxed with 41.6 g of N-bromosuccinimide for 24 hours. The solvent is distilled off and the residue is dissolved in a mixture of 250 ml of toluene and 250 ml of ether. The base is extracted with dilute hydrochloric acid (20%) and treated with conc. Sodium hydroxide solution and toluene isolated. The toluene phase is filtered over 150 g of Al2O3 II-III (Merck company) and 150 g of Al2O31 basic (Merck company). After evaporation of the toluene, 35.5 g of an oily mixture of 7-bromo-l-methyl-2-chloromethyl-5- (2 / -chlorophenyl) -lH-2,3-dihydro-l, 4-benzodiapzepine and 8- Brom-l-methyl-3-chloro-6- (2'-chlorophenyl) -l, 2,3,4-tetrahydro-l, 5-benzodiazocin isolated with 750 ml of isopropanol, previously containing 6.5 g of sodium have been dissolved, heated under reflux for 24 hours. The isopropanol is then distilled off, the residue is dissolved in 300 ml of chloroform and washed neutral with water. The organic phase is separated off, dried with sodium sulfate and the solvent is distilled off. The residue (24 g) is filtered with toluene / chloroform (9: 1) over 500 g of aluminum oxide I (Merck company). After the solvent has been distilled off, the residue is dissolved in acetone and a solution of hydrochloric acid gas in ether is added until an acidic reaction occurs. The hydrochloride separates out as yellow crystals, which is collected and recrystallized from ethanol (100-200 ml).

7-Bromo-l-methyl-2-isopropoxymethyl-5- (2'-chlorophenyl) -1H-2,3-dihydro-1,4-benzodiazepine as hydrochloride is obtained in a yield of 15.6 g.

Melting point: 189-191.5 ° C

Elemental analysis:

C H N Br Cl

Calculated: 52.4% 5.1% 6.1% 17.4% 15.5% Found: 52.6% 5.0% 6.0% 17.2% 15.2%

As described in Examples 1 to 8, the compounds of the general formula I listed below in Table 6 can be obtained.

Table 6

cu-

■ ch

= n

Ilr

Elemental analysis

Mp ° C

R;

No.

calculated% found %

9 C3H7 Cl 152-154 Cl - 15.5 15.5

(Hydrochloride) Br = 17.4 17.1

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

Table 6 (continued)

No.

R3

R2

Mp ° C

Elemental analysis calculated% found. %

10th

CHs

CF3

128-130 (hydrochloride) X 1/2 H2O

Cl = 7.5 Br = 16.9

7.5 17.2

11

C2H5

CF3

102-104

Br = 18.1

18.3

12

CH3

Br

185-187 (hydrochloride)

Cl = 7.5 Br = 33.7

7.5 33.4

13

C2H5

Br

154-156 (hydrochloride)

Cl = 7.3 Br = 32.7

7.2 32.8

14

C3H7

Br

143-146 (hydrochloride)

Cl = 7.1 Br = 31.8

7.3 31.5

15

CHa

J

223-225 (hydrochloride)

Cl = 6.8 Br = 15.3

6.7 15.7

16

C2H5

J

204-207 (hydrochloride)

CI = 6.6 Br = 14.9

6.6 15.1

Claims (13)

626076 2 PATENT CLAIMS 1. Process for the preparation of 2-substituted 1,4-benzodiazepines of the general formula IA ch2-or3 [ia] and their acid addition salts, where Ri represents a hydrogen atom or a halogen atom, R2 represents a hydrogen atom, a halogen atom or the trifluoro methyl group, and R3 is an alkyl group with 1 to 6 carbon atoms, characterized in that acyldiamines of the general formula IV n_ ch9— ch_ ch9 ^ nh_c - {/ i 2 i 2 ii ch, oh 0 [iv] in which R 1 and R 2 have the meaning given above, with such an excess of phosphorus oxychloride for the reaction that the boiling temperature of the latter is established during the entire reaction, the resulting mixture of the compounds of the general formulas II and III ch2-ci [ii] 60 65 [iii] and in which R 1 and R 2 have the meaning given above, separated from the unreacted phosphorus oxychloride and the other inorganic constituents and then converting the isomer mixture in suitable solvents at elevated temperature with alkali metal oxides into the compounds of the general formula IA and, if appropriate, from acid addition salts of the compounds obtained of the general formula IA by hydrolysis produces the free bases of the formula IA or produces the acid addition salts from bases of the formula IA obtained by reaction with acids. 2. The method according to claim 1, characterized in that the reaction of the isomer mixture with the alkali metal oxides in the presence of the corresponding alcohols 626076 or a suitable proton-free solvent. 3. The method according to claim 1, characterized in that from the end products obtained, in which R.2 has the above meaning and Ri is a hydrogen atom, s produces the corresponding compounds in which Ri is a halogen atom by treatment with a halogenating agent. 4th in which R 1 and R 2 have the meaning given above, separated from the unreacted phosphorus oxychloride and the other inorganic constituents and then reacting the isomer mixture in suitable solvents at elevated temperature with alkali metal hydroxides or alkali metal carbonates or the isomer mixture with alkali metal acetate and subsequently with dilute alkali metal hydroxide solution reacted and, if appropriate, produces the free bases of the formula IB from the acid addition salts of the compounds of the general formula IB obtained by hydrolysis or produces the acid addition salts from the free bases of the formula IB obtained by reaction with acids. 4. The method according to claim 1, characterized in that the corresponding compounds in which Ri is a halogen atom are prepared by treatment with a halogenating agent from the intermediates obtained, in which R2 has the above meaning and Ri is a hydrogen atom. 5. The method according to claim 3, for the preparation of is 7-bromo-l-methyl-2-methoxymethyl-5- (2 / -fluoro- phenyl) - lH-2,3-dihydro-1,4-benzodiazepine, 7-bromo-l-methyl-2-methoxymethyl-5- (2 / chlorophenyl) -lH-2,3-dihydro-l, 4-benzodiazepine, 7-bromo-l-methyl-2-ethoxymethyl-5- (2 / -chloro-20 phenyl) - lH-2,3-dihydro-1,4-benzodiazepine, 7-bromo-l-methyl-2-n-propoxymethyl-5- (2 / chlorophenyl) -lH-2,3-dihydro- 1,4-benzodiazepine, 7-bromo-l-methyl-2-isopropoxymethyl-5- (2 / chlorophenyl) -IH-2,3-dihydro-1,4-benzodiazepine, 7-bromo-l-methyl -2-methoxymethyl-5- (2'-trifluoromethylphenyl) -lH-2,3-dihydro-l, 4-benzodiazepine, 7-bromo-l-methyl-2-ethoxymethyl-5- (2 / -trifluoro- methylphenyl) -IH-2,3-dihydro-l, 4-benzodiazepine, 7-bromo-l-methyl-2-methoxymethyl-5- (2'-bromo-phenyl) -IH-2,3-dihydro-l, 4-benzodiazepine, 7-bromo-l-methyl-2-ethoxymethyl-5- (2 / -bromo-phenyl) -lH-2,3-dihydro-l, 4-benzodiazepine, 7-bromo-l-methyl-2 -n-propoxymethyl-5- (2 / -bromophenyl) -lH-2,3-dihydro-l, 4-benzodiazepine, 7-bromo-l-methyl-2-methoxymethyl-6- (2 / -iodophenyl) - 30th 35 1H-2,3-dihydro-l, 4-benzodiazepine, or 6. The method according to claim 5 for the preparation of 7-bromo-l-methyl-2-methoxymethyl-5- (2'-chlorophenyl) -lH-2,3-dihydro-l, 4-benzodiazepine. 7. Process for the preparation of 2-substituted 1,4-benzodiazepines of the general formula IB ch? -or3 r., 25th [ib] and their acid addition salts, where Ri represents a hydrogen atom or a halogen atom, R2 represents a hydrogen atom, a halogen atom or the trifluoro methyl group and R3 represents a hydrogen atom, characterized in that acyl diamines of the general formula IV _ ch "- ch_ ch" _nh_c j \ i oh [iv] in which Ri and R2 have the meaning given above, with such an excess of phosphorus oxychloride to bring about the reaction that during the entire reaction • Cl sets the boiling point of the latter, the resulting mixture of the compounds of general formulas II and III and [ii] 626 076 7-bromo-l-methyl-2-ethoxymethyl-5- (2'-iodophenyl) - 1H-2,3-dihydro-1,4-benzodiazepine. 8. The method according to claim 7, characterized in that one carries out the reaction of the isomer mixture with aqueous solutions of the alkali metal hydroxides or alkali metal carbonates in the presence of dioxane or tetrahydrofuran. 9. The method according to claim 7, characterized in that one carries out the reaction of the isomer mixture with sodium acetate in dimethylformamide and then hydrolyzed with aqueous alkali metal hydroxide solution in the presence of methanol. 10. The method according to claim 7, characterized in that from the end products obtained, in which R2 has the above meaning and Ri is a hydrogen atom, by treatment with a halogenating agent, the corresponding compounds are prepared, in which Ri is a halogen atom. 11. The method according to claim 7, characterized in that from the intermediates obtained, in which R2 has the above meaning and Ri is a hydrogen atom, by treatment with a halogenating agent, the corresponding compounds are prepared, in which Ri is a halogen atom. 12. Compounds of the formula IA, prepared by the process according to claim 5. 13. Compounds according to claim 12, produced by the method according to claim 6.