NO158505B - ANALOGY PROCEDURE FOR THE PREPARATION OF A THERAPEUTIC ACTIVE 7BETA-SUBSTITUTED MALONAMIDO-1-OXADADIA 7ALFA-METOXY-3- (1-METHYLTETRAZOL-5-YL) -TYOMETHYL CEPHALOSPORIN. - Google Patents

Description

Process for the production of benzodiazepine derivatives.

The present invention relates to a process for the preparation of benzodiazepine derivatives with the general formula I in which R1 means hydrogen, halogen, especially chlorine, trifluoromethyl, lower alkyl, lower alkoxy, nitro or amino, R 2 means furyl, thienyl, lower alkyl, lower cycloalkyl or a optionally with halogen, trifluoromethyl, lower alkyl or lower alkoxy substituted aryl radical, in particular phenyl, R^ means hydrogen or lower alkyl and R^ means hydrogen, lower caralkyloxy, alkyl or a carbamoyl residue which optionally exhibits one or two lower alkyl residues or a lower dialkylaminoalkyl residue, or the remainder means COOKat, with Kat representing an alkali or alkaline earth cation.

The peculiarity of the method according to the invention is that

an imine of the general formula II

in which R1 , R2 , R^ and R^ have the above meaning and R^ means lower alkyl or, if R^ stands for COOKat, means Kat, with Kat representing an alkali or alkaline earth cation, subjected to a ring closure by acid treatment.

The alkyl residues, also those in alkoxy groups and aralkyl groups, display 1-7 carbon atoms in a straight or branched chain. It concerns e.g. about methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl and hexyl residues.

The starting materials for the present process can be prepared by starting from o-aminoarylketimines of the general formula III

in which R.j , R.sub.2 and R.sub.^ have the meaning stated above, which compound can in turn be prepared by reacting a suitable o-aminobenzonitrile (depending on the meaning of R.sub.1 and R.sub.2) with an alkylmagnesium halide or an arylmagnesium halide with the general formula R2MgX , in which R 2 has the above meaning and X is a halogen, especially bromine. The Grignard reagent R^MgX is used in ample excess, preferably about 3_L|" m°l per mol of o-aminobenzonitrile used. • It can be worked in anhydrous ether. The reaction components can be reacted in the boiling solvent for up to 15 hours. After cooling, the magnesium complex is split with an aqueous solution of ammonium chloride and the solvent is evaporated. The o-aminoarylketimine crystallizes out spontaneously in most cases, and can be purified by recrystallization in a suitable solvent, for example in a hydrocarbon such as hexane or cyclohexane.

The o-aminoarylketimines are available in the form of well-crystallized pale yellow substances. The yield from the turnover is usually very high and often of the order of 80-90#. The infrared spectra of certain compounds agree with the given structure, which is strongly confirmed by elemental analysis. Among other things, they exhibit two characteristic oscillation bands for the valence N-H, namely a sharp band at 31+80 cm _ -1 (which is missing when the aromatic amine is secondary) and a broad band at 3270-3300 cm due to N-H in the imine and■ cherlat-NH in the NH0 (or NH-R) residue. Otherwise, the infrared spectra show two oscillation bands at 1600 cm<-1 >(1610-1580 cm" ) as a result of the aromatic ^>C = N conjugated ^> C = C<^ configuration.

The following table I shows as examples a number of imines of formula III, all of which are new and which can be prepared by means of the method described in the previous section, reference being made to the following examples.

The substituted imines corresponding to formula II (with the exception of the salts of the carboxyl derivatives) can be prepared by reacting o-aminoarylketimines of formula III with an ester of the general formula

wherein R^ and R^ have the above

meaning, but does not mean C00 Kat or Kat. This ester can in the simplest case be an ester of glycol, but can also be an ester of another naturally optically active or racemic α-amino acid, such as e.g. alanine or leucine. This ester can also be formed from aminomalonic acid, in particular from dimethyl or diethyl aminomalonate.

These esters can be used in the form of bases or preferably in the form of the salts which are easier to handle than the bases, particularly in the form of the hydrochloric acid. In the process, ammonia is released by splitting or bound as salt.

The reaction can be carried out in a solvent which does not

reacts with the imine of formula III, and in particular using a lower aliphatic alcohol or hydrocarbon, such as benzene or toluene. You can work at a temperature that is in the range of the room temperature and the return temperature for diluting the compound. The reaction time can be from 1 to approximately 12

hours and is all the shorter the higher the temperature at which it is worked. In certain cases, the product formed by the reaction separates spontaneously from the alcoholic solution at room temperature. In any case, it is advantageous after completion of the reaction to evaporate the solvent, extract the product with an inert solvent and complete the isolation by crystallising

ing in a suitable solvent.

The substituted imines of formula II (with ester function) pre-

is in the form of pale yellow substances which are in most cases crystallized, but many times also in the form of oils. Their structure is demonstrated by elemental analysis and from their infrared

spectrum and from the result of their acid hydrolysis.

As could be expected theoretically, these substituted imines can

exist in two stereoisomeric forms, one of which, which is usually obtained in predominant quantity, is characterized by an intramolecular hydrogen bond N-H between the hydrogen in the amine group and the nitrogen in the imine group (forming a chelate ring). These two forms could be isolated from each other by fractional crystallization in two examples (for comparison examples 1a' and 2a). In the other cases, a crystallized product corresponding to the chelate form could usually be isolated.

The infrared spectra of the chelate forms, determined in methylene chloride, exhibit a vibrational band for the valence N-H at 31+o>0 cm~^

(a peak which disappears in the case of a secondary amine) and a broad band at 31^0-3300 cm<-1> as a result of the N-H chelate in NH0

(or NHR-) residue. Furthermore, an oscillation band at 1730-17^0 cm

for ]>C = 0 in the residual test. At 1610 - 1620 cm _ -1 a band ■ corresponding to the aromatic ^> C = C <^ configuration ( and^ > C = N-). At 1200 -1180 cm"<1> a band for C-O-C (ester) as for the malonic acid esters is shifted to 1220 cm 1. The non-chelate forms differ from the substances described above by the presence of a doublet, formed by the two tips, corresponding the oscillation for the valence N-H in NH2 (a single peak at 3^00 cm in the case of secondary amines) and in the absence of absorption between 3150 and 3300 cm"<1>.

Table II contains a number of exemplary substituted imines corresponding to formula II, where R 1 is an alkyl radical.

These imines are all new.

The salts according to formula II can be obtained by saponification of the imines with a double ester function according to formula II corresponding to the following reaction:

The infrared spectra of the compounds of formula IVa, determined

in potassium bromide, Dverens agrees with the structure, especially as a result of the lack of the bands ^> C = 0 (amide, acid or ester) between 1650 and 1750 cm . In addition to this, they exhibit, among other things, a very broad and intense absorption at approximately 3^00 cm<-1 > (fluctuations for the valence N-H in NH5 in essentially chelated form) and

a broad and complex absorption approximately at 1600-1550 cm ( >C = C <^ (aromatic) > C = N-,>C = 0 (in the carboxylations).

The compounds of formula IVa can also be obtained by saponification

of 3-Alkoxycarbonylbenzodiazepines of formula I by means of alkali hydroxide, preferably potassium hydroxide, in an alcoholic medium. Thereby there occurs both a saponification of the free ester function and also an opening of the ring in the benzodiazepine for the lactam function. Practically, you work with good results - in 95$ ethyl alcohol. The temperature is between room temperature and the boiling point. The purest products are obtained when working at room temperature. The turnover begins with a transient yellowing. For rapid decolourisation, it is advantageous to use at least three equivalents of kalilut. The yield of di-salt is almost quantitative. These di-salts (IVa), a number of which are listed further down in Table III, are colorless powders (with the exception of the nitrated and aminated derivatives, which are yellow), are easily soluble in water with a

strong alkaline reaction. The infrared spectra of the di-salts of potassium prepared in this way practically agree with the spectra of the corresponding salts, prepared by saponification of the diester of formula II.

For formula IV A, it should be noted that the analytical results, . which is stated in the following, can be understood more easily when, instead of the structure IV A, a cyclic structure IV"B or IV C is assumed for these compounds

The analytical investigation was carried out in particular with the compound V306 CB (the compound of formula IV with R1 = Cl, R2 = C6H5' R3 = H^'

Even after long drying of this substance at 50°C under extensive vacuum, the products obtained contain approximately ^[ 0% of the solvent (ethyl alcohol with 10% water) in which the preparation took place:

For the determination of ethyl alcohol, the substance is dissolved in water and the solution obtained is distilled. The distillate is oxidized with a chromium nitrogen reagent and the excess of the reagent is titrated using a ferrocyanide solution in the presence of diphenylbenzidine.

For the determination of water, Karl Fischer's method is not applicable due to the strong basic nature of the product, it is carried out with a suspension in xylene and the water is removed azeotropically.

The determination of ethanol and water, carried out as indicated above, shows that in addition to the 10% of retained solvent, the product by azeotropic extraction can release a molecule of water, which indicates that it is a structure IV B or IV C.

The elemental analysis of the product dried at 50°C takes into account the amount of crystallization solvent present in accordance with the calculated values for one of the three basically identical formulas IV A, IV B, IV C.

The determination of the basic functions in the molecule leads to interesting results, especially when the potentiometric diagrams obtained for ^306 CB are compared for the potassium salt of (7-chloro-5-phenyl-2-oxo-2,3-dihydro-1H- benzo(f/-1,^-diazepine)-3-carboxylic acid (V311 CB) and for 7-chloro-5-phenyl-2-oxo-2,3-dihydro-1H-benzo/f7-1,^-diazepine (above and in Example I denoted as A).

In an anhydrous environment formed by a mixture of chloroform (3 parts by volume) and acetic acid (1 part by volume), the titration with perchloric acid in acetic acid solution gives the values shown in the curve sheet: for the compound <>>+306 CB (full drawn curve) a first potential jump with an equivalence point at ~370mV and another potential jump with an equivalence point at -600mV. The total volume of titrant added to achieve this second equivalence point amounts to 1.5 times the volume that was necessary to achieve the first point\ - for the compound *+311 CB (dashed-dotted curve) a first potential jump at an equivalence point of -360mV and another potential jump with the equivalence point at -590 mV, as the volume of the titrant added to achieve the second equivalence point was twice the volume that was added to achieve the first point\

for compound (A) (dotted curve) a potential jump with the equivalence point at -580mV.

Proceeding from these experimentally established facts and from the known formulas for the compound >+311 CB and the compound (A), it is obvious that the second potential jump, obtained in the titration of the compound V306 CB, corresponds to the neutralization of the imine function, and that the first jump corresponds to a neutralization of the other two functions, i.e.: when assuming the cyclic formulas IV B or IV C, namely the alcoholate or enolate function as well as the carboxylate function,

when assuming formula IV A, one of the carboxylate functions and

the aminated group. The second carboxylate function is added

as a result of the proximity of the first function a pH value which

is too small to be measured.

Protometry in an anhydrous environment is therefore not suitable for determining the possible structures. On the contrary, the result in an aqueous environment corresponds to more than a cyclic structure. In reality, when working in this way, measurement below the pH value of 7 is not possible, because the compound V311 CB and the compound (A.) precipitate out. Only the functions with a higher pH value can therefore be measured. The compound ^-306 CB, measured in an aqueous medium with hydrochloric acid, gives an equivalence point at the pH value 9?5? to which one could assign the alcoholate or enulate function, although more difficult than the functions for the isomeric IV A.

It is not excluded that it chose connection as an example

^306 CB according to the process conditions can assume one of the isomeric forms preferred in relation to the other. In particular, the prolonged heating at 100°C of the compound in the solid state, as shown by the protometry in an alkaline environment, seems to favor the formation of the isomeric IV A besides a certain change of the product.

The infrared spectra of the compound of type IV A, IV B or IV C, especially of the compounds ^306 CB and <>>+335 CB, shall be brought into conformity with the three proposed formulas.

Table III shows some exemplary potassium di-salts, prepared according to the above tasks.

The method according to the invention is effected as stated

a cyclization of the imine of formula II by acid treatment. A preferred embodiment consists in the action of a lower anhydrous aliphatic acid, especially glacial acetic acid, on one or the other of the two stereoisomeric forms of the substituted imines of formula II or on a mixture thereof, the corresponding benzodiazepines of formula I being practically completely obtained.

A warm-up for a few minutes to an hour is beneficial. After removal of the reaction acid in vacuum and dilution using a suitable solvent, especially ethyl ether or isopropyl ether, the benzodiazepine derivative is obtained directly in a crystallized state.

Thus, e.g. 7-Chloro-5-phenyl-2,3-dihydro-1H-benzo-[f/l], k-diazepine (compound A) was described by L.H. Sternbach and E. Reeder (Journal of Organic Chemistry 1961, 26, ^936) are prepared in two steps with a total yield of & 0% starting from the unsubstituted imine <*>+356 CB, without the need with separation of the two stereoisomeric forms of the intermediate formed substituted imine ^292 CB. The N-methyl derivative (B) of compound A, which is also known, is formed in practical quantitative yield when the substituted imine V36I CB is subjected to the action of acetic acid for a few minutes.

In the same way, the 3-carbon derivatives of compound A are obtained.

It is first sufficient to react the free imine V356 CB and the hydrochloride of an oc-aminoacetic acid ester and without isolating the substituted imine intermediate and carry out the treatment with acetic acid, as mentioned above. Application is mentioned as an example

of the chlorhydrates of alanine and leucine as reaction components and production of 7-chloro-3-methyl and 3-isobutyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo-/f7-1,U-diazepine ( compounds C and D). The yields vary, but are in any case superior to the dividends

as indicated in the literature for the preparation of the same compounds.

(L.H. Sternbach, R.I. Fryer, W. Metlesics, E. Reeder, G. Sach,

G. Saucy and A. Stempel, Journal of Organic Chemistry, 1962, 27,

page 3788).

This method has been extended to the production of new benzodiazepines

which on the 3-carbon atom carries an alkoxycarbonyl residue. It is sufficient to subject compounds of formula II, which are derived from malonic acid, such as those in Table II, to treatment with an aliphatic acid. The derivatives obtained by reacting a free imine of formula III with a chlorohydrate of an alkylaminomalonate

can be insulated, or the insulation can be sloyed. By the way, the yields are particularly high when crystallized substituted imines of formula II are used for the reaction with acetic acid.

In addition to this, an advantageous variant was found for the preparation of the benzodiazepine of formula I without isolation of the substituted imines of formula II, and also a variant which is particularly advantageous when it concerns substances of formula I, in which R2 is phenyl, R ^ hydrogen and R^ an alkoxycarbonyl residue. The

The production methods indicated above then lead easily and with medium yields by starting from the letimines of formula III, which e.g. the compound ^356 CB, to these substances, but they are difficult to reproduce when the quantity of the used reaction components is increased, and the complete purification of the products by crystallization is, moreover, often cumbersome. According to these variants, the substituted imine of formula II is prepared,

like for example. the compound ^292 CB, by the action of the hydrochloride of ethyl aminomalonate on the free imine of formula III, which e.g.

the compound ^356 CB, during the work in a hydrocarbon, preferably benzene or toluene and subsequent introduction of hydrogen chloride gas into the reaction medium to complete the crystallization without prior isolation of the intermediate product. The benzodiazepine derivative formed is then isolated, which e.g. the compound ^279 CB, as chlorohydrate, which can be split into practically pure benzodiazepine.

This complete preparation or this preferred embodiment is suitable for the preparation of other benzodiazepines of formula I, especially those listed in Table IV, whether they are substituted on the 3-carbon atom in the heterocyclic ring or not. It is sufficient to replace the hydrochloride of the ethyl aminomalonate with the hydrochloride of the ethyl glycolate substituted or unsubstituted on the methylene carboatom.

Thus, the synthesis of larger quantities of the substance M-190 CB (formula

I with R2 = cyclohexyl, FU = H, R^ = H) to recommend according

tfl. this method variant. The use of substituted or unsubstituted esters of aminomalonic acid or aminoacetic acid is not limited to the ethyl ester.

The structure of the new 3- alkoxycarbonyl benzodiazepines with

formula I appears not only from their elemental analysis, but beyond this also from their infrared spectrum and the results of their hydrolysis. The infrared spectra of 3-Alkoxycarbonylbenzodiazepines of formula I, dissolved in methyl chloride, give: Vibrational band for the valence N-H of the lactan group without substituents (when this is the case): namely a peak (N-H free) at 3<l>f00 cm"<1> and a broad band (N-H bonded) at 3200 cm"<1>. In potassium bromide, the absorption attributed to the N-H bond is often more complex and can be seen by the presence of several bands between 3100 and 3^00 cm"<1>.

- Characteristic bands for the ester group at 1730-1.755

( > C = 0) and at 1200 cm"<1> (C-0-C),

A characteristic band for the secondary amine at 1660-1700 cm<-1>

(absence of the second amine band between 1510 and 1550 cm _ -I),

- a band at 1590-1610 cm<-1> (aromatic .'^> C = C < and ^ C = N-) flanked by a less intensive band at 1560-1580

cm"'' for the compounds with two of the ^> C = N-conjugated phenyl groups.

If the method according to the invention allows

a strong mineral acid, especially hydrochloric acid, act on an imine of formula II, this leads to different results depending on the presence or absence of the internal hydrogen bond. When there is no chelate form, the action of hydrochloric acid leads for the most part to the corresponding o-amino ketone as a result of cleavage of the imine bond, when an internal chelate is present, the corresponding benzodiazepine is produced without cleavage of the imine bond, whose configuration otherwise favors ring closure.

Aqueous solutions of di-salts of the formula II lead by the action of dilute hydrochloric acid by decarboxylation and cyclization to benzodiazepine derivatives, e.g. leads the compound >+306 CB by such treatment to the benzodiazepine compound (A) in Table IV. This di-salt can also be produced in situ and further processed. The Treatment of 3-Alkoxycarbonyl Benzodiazepines of Formula I

with a saponification agent (e.g. an alkali hydroxide, preferably alcoholic or aqueous potassium hydroxide) and then with a dilute acid (e.g. acetic acid) leads to hydrolysis and decarboxylation and finally leads to benzodiazepines unsubstituted at the 3-carbon atom, e.g. .ex. to the compound A, when one uses for the reaction stef f et ^-279 CB, which completely confirms the stated'structure. The treatment of the 3-Alkoxycarbonyl benzodiazepines of formula I with an alkaline agent such as alcoholic or aqueous potassium chloride and then with an alkylating agent such as dimethylsulphate leads after treatment with a dilute acid such as acetic acid to 1-alkyl benzodiazepines, e.g. to the compound B (diazepan) when the compound <*>+279 CB is used.

3-Alkoxycarbonyl-benzodiazepines of formula I usually have et

higher melting point than the corresponding benzodiazepines without substituents on the 3-carbon atom. Their solubility in organic solvents is relatively low.

Table IV shows a number of exemplary new benzodiazepines

(those denoted by a number) with a substituent in the 3-position, which can be prepared by the method according to the invention.

Furthermore, it was found that the di-salts as indicated in Table III under very strict conditions can be converted into benzodiazepine derivatives of formula V, which exhibit a carboxylic acid function on the 3-carbon atom with the original cation as salt.

It is sufficient for this to treat the aqueous solution

of the product used at room temperature with a slightly acidic reagent, (ie an acid just sufficient to release only the weaker of the two carboxylic acid functions), preferably monopotassium orthophosphate or also carbonic acid. The monosalts of formula V usually crystallize easily, provided that the process was carried out in a sufficiently concentrated solution, as their solubility in water is less than that of the starting products of formula IV. Usually they can be obtained with a higher yield.

Their formula was confirmed by elemental analysis. Their structure emerges from the infrared spectrum and their chemical properties. The infrared spectra (determined in potassium bromide) correspond to the structure of formula V and, moreover, in contrast to the structure of formula IV, show a band at 1690 cm"<1>, which is due to C=0 in the cyffic amide. The absence of the second amide band between 1510 and 1550 cm"<1>, which is characteristic of non-cyclic secondary amides. Only the group N02, when present, gives a band in this region. Otherwise, the oscillation for valerene NH in the lactan group appears in two very broad bands at 3^00 cm and 3100 cm -1 . An intensive and complex band at 1600-1620 cm-1 can be attributed to the oscillations of the aromatic \aLens

^> C = C<^ , > C = N- and > C = 0 for the carboxylation.

The aqueous solutions of the compounds of formula V usually have a pH value close to the neutral point. The stability of these products in aqueous solution is less than for the starting compound with two carboxylic acid groups. After a few hours at room temperature or rapidly by boiling or also under the action of acetic acid at room temperature, the aqueous solutions give the corresponding benzodiazepine derivatives without a substituent on the free 3-carbon atom.

A number of 3-potassium carboxylate benzodiazepines of formula V are listed in Table V.

The following statements relate to some examples of how the diazepines that can be produced according to the invention can be converted.

The impact of ammonia or a primary or secondary

amine at room temperature in a suitable solvent, such as methanol, leads to the reaction of the 3-alkoxycarbonyl-benzodiazepine of formula I to benzodiazepines which display a substituted or unsubstituted amide function in the 3-position. Nitration of the benzodiazepine derivative ^-352 CB in sulfuric acid leads to the aromatic derivative nitrated in the 7-position (the compound <*>+353 CB). Its structure is revealed by its elemental analysis, by its infrared spectrum (NC^ bands at 1530 and 1350 cm _ -i in potassium bromide)

and by its hydrolysis followed by decarboxylation, leading to 7-nitro-5-phenyl-2,3-dihydro-1H-benzo[f/-1,^1-diazepine, which is known and is described by L.H. Sternbach, R.I. Fryer, 0. Keller, W. Metlesics, G. Sach and N. Steiger in Journal of Medicinal Chemistry, 1963, vol. 6, page 261. Reduction of the nitrated derivative M-353 CB, e.g. catalytically, leading to the corresponding aminated compound, which exhibits a 7-amino group (^35^ CB).

The following examples illustrate preferred embodiments

for the invention, the melting points are indicated by a melting point K , M or C in °C, according as they are determined in Kofler apparatus, Maquenne apparatus or in KapjlLarror. In the examples, the compounds of type IV are reproduced using formulas of the open type IV A, without this formula being particularly emphasized over the cyclic formulas IV B and IV C indicated above.

Example 1: 7-chloro-5-phenyl-2-oxo-2,3-dihydro-1H-benzo[f_/-]+-diazepine (A):

a) (2-amino-5-chloro-phenyl>phenyl-methane-imine(<l>f356)

CB (starting material), which can also be designated

as_ (^amino^-chloro-f enjrlj^f en^l-ketimine_.

To a solution of phenylmagnesium bromide, prepared from 109 g (<*>+»5 atomic grams) of magnesium shavings and 8<*>+8 g (5A mol) of bromobenzene in 36OO ml of anhydrous ether is added slowly (over the course of approximately 3^- hours) a solution of 228.7 g (1.5 mol) of 2-amino-5-chloro-benzonitrile in 1800-

ml of dry ether and then heated to reflux for 15 hours.

The complex is cleaved by adding the reaction mixture while stirring to a solution of 500 g of ammonium chloride in 2000 ml of water with 3 kg of added granulated ice. After extraction and washing, ether is evaporated in vacuum at <1>+0°C. The oily residue is taken up in 500 ml of petroleum ether and it is then crystallized by cooling to -20°C. The yellowish crystals formed (308 g) are collected. Melting point K: 7^°C Yield 92$. b) 1-phenyl-1-(2-amino-5-chloro-phenyl)-^-oxo-5-oxa-2-aza-1 - £se£ss_I!+222_cb)_.

A mixture of 27.6 g (0.12 mol) (2-amino-5-chloro-phenyl)-methane-imine and 20.7 g (0.15 mol) of the hydrochloride of ethyl glycocholate in 150 ml of methanol is stirred in 2 -g- hour at room temperature. A suspension of a pale yellow solid is obtained which consists of the mixture of the imine and the ammonium chloride formed during the reaction. The solvent is removed under vacuum, the residue is taken up in methylene chloride

and washed with an aqueous ldsnirg of sodium carbonate 10$ and then with water. It is dried over sodium sulphate and the solvent is evaporated. A yellow solid remains, which is crystallized from acetone. 32.g of the crystallized product is obtained. Melting point K is 130-135°C. Dividend 85$.

This product consists of a mixture of the two stereoisomers

forms and can be used as desired for the following reactions.

However, fractional crystallization in acetone is successful

isolate the two forms in their pure state. They have the following melting points: Chelate form: Melting point K 1<l>+8-150°C. The non-chelate form: Melting point K 1l+2-1lfV°C, and when mixed gives a lowering of the melting point.

c) 7-chloro-5-phenyl-2-oxo-2,3-dihydro-1H-benzo/T71,>+-diazepine

(A)..

Work is carried out as indicated above and the product is taken up without isolation of the compound !+292 CB in 1 50 ral of acetic acid and it is heated.' for 30 minutes to boil under reflux. The acetic acid is evaporated until a dry residue is obtained, 250 ml of isopropyl ether and 250 ml of water are added and stirred. A yellow solid separates, which is collected and washed with ether. It is recrystallized in methyl ethyl ketone. Faint yellow crystals are obtained.

Yield about 80$ calculated on the unsubstituted imine. The product is identical to the product described in the chemical literature (.L.H. Sternbach and E. Reeder, Journal of organic chemistry 1961, 26, >+936).

Example 2: 7-chloro-1-methyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo/ f. 71 A-diazepine (B).

a) (2-methylamino-5-chloro-phenyl)-phenyl-methane-imine

I^Z-CB)^

Following the tasks in example 1, by replacing 2-amino-5-chloro-benzonitrile with 2-methyl-amino-5-chloro-benzonitrile in an equimolar amount, the compound ^357 CB is obtained with a yield of 61$.

Yellow crystals with melting point K 97°C (hexane).

b) 1-phenyl-1-(2-methylamino-5-chloro-phenyl)-<>>+-oxo-5-oxa-2-aza-ll£e2ten_£tf36l_CB2.

This substance is prepared according to the instructions in example 1, replacing (2-amino-5-chloro-phenyl)-phenyl-methane-imine with (2-methyamino-5-chloro-phenyl)-phenyl-methane-imine in stdchiometric crowd.

A solid is obtained by crystallization in hexane, which constitutes a mixture of the two stereoisomeric forms. Melting point K: 70-7<5>°C Yield 82$.

This mixture can be used as is for the following reactions.

By fractional crystallization in hexane, isolation of

the two forms in their pure state.

The melting points for the two forms are:

The chelate form: Melting point K 100°C. The non-chelate form: Melting point K 85°C.

The mixture of the two forms has a distinctly lowered melting point.

c) 7-chloro-1-methyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo[yl]l,>+-5i§2§£i2_i52i 6 g of the compound ^361 CB are heated under reflux in 25 ml of acetic acid for 15 minutes. The acetic acid is driven off under vacuum, the residue is taken up in water and a little ether and a yellowish solid with a melting point K 130°C separates out. The yield is roughly quantitative. It is recrystallized from isopropyl ether. Yellow crystals are obtained (k, k g) with a melting point K 132 C. Yield $85 for the wet portion. The product is identical to the product described in the literature.

Example 3: 7-chloro-3-ethoxycarbonyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo/c71,^-diazepine C+ 279 CB).

/2-phenyl-2-(2-amino-5-chloro-phenyl)-1-aza-vinylO-^i<SiZil2J§i>2<i>}S5<_l>!l"3<i>!" §_2<§>2i

To a boiling solution of 10.6 g (0.05 mol) of the hydrochloride of ethyl aminomalonate in 30 ml of absolute ethyl alcohol is added dropwise a solution of 9.2 g (0.0*+ mol) (2-amino-5-chloro- phenyl)-phenyl-methane-imine in 16 ml of absolute ethyl alcohol. After the addition is finished, it is heated for 30 minutes to boiling under reflux and then the solvent is evaporated in a vacuum.

The residue is taken up in water and ether and the ethereal solution is decanted. It is washed with water, dried over sodium sulphate and the solvent is evaporated. It is recrystallized from isopropyl ether, "Dg yellow crystals are obtained (7.8 g, with a yield of 50$. Melting point K 106°C). b) 7-chloro-3-ethoxycarbonyl-5-phenyl-2-oxc~2,3- dihydro-1H-^enzo/fyi j^=diazepine_(^222_CB)_.

This substance is obtained according to what is indicated in example II

under replacement of the compound V36I CB with the compound ^3^6 CB in equimolar amount. Glistening colorless crystals with a melting point K 2kh°C (ethyl acetate). Yield 7k% in the first portion.

Example kt 7-chloro-3-ethoxycarbonyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo/" f_ 7l ,^-- diazepine (k279 CB).

For one hour, a mixture of 9£ g (0.05 mol) of the compound "+356 CB, 10.6 g (0.05 mol) of the hydrochloride of ethyl aminomalonate and 5 g (0.05 mol) of triethylamine in V5 ml of absolute ethyl alcohol. The solvent is evaporated in vacuo and the residue is taken up in water and ether. The ether layer is separated,

washed with water and dried over sodium sulfate. After evaporation of the solvent, the residue is dissolved in 5 ml of acetic acid and heated for 15 minutes to boiling under reflux. It is evaporated in vacuo to dryness and the residue is taken up in ether. A solid separates out, which is collected and recrystallized from ethyl acetate. Colorless glistening crystals (6.<*>+ g ) with a melting point K 2kk°C. The yield k- 7%. The product is identical to the product obtained according to example 3.

Example 5: 7-chloro-3-methyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo[f7l.^-diazepine (C).

Under reflux, the mixture of 6.9 g (0.03 mol) of the substance ^356 CB and 5.1 g (0.033 mol) of the hydrochloride of the ethyl ester of DL-alanine in kO cm^ of absolute ethyl alcohol is heated for one hour. It is evaporated to dryness and the residue is taken up in methylene chloride and a 10% sodium carbonate solution. The organic layer is separated, and washed with water, and dried over sodium sulfate. The solvent is evaporated and the residue taken up in 50 cm^ of acetic acid. It is heated for 5 minutes under reflux and the solvent is then evaporated in vacuo. Isopropyl ether is added and allowed to crystallize and light yellow crystals (5.15 g) with a melting point K 22k°C are obtained. Yield 60% in the first portion. The product is identical to the product described in the literature (Journal of Organic Chemistry 1962, 27, 3877).

Example 6: 7-chloro~3-isobutyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo/f7l.^-diazepine (D).

Proceed as in example 5, however, replacing the hydrochloride of the ethyl ester of DL-alanine with the hydrochloride of the ethyl ester of DL-leucine in an equimolar amount. The compound D is obtained in a yield of hS% and with a melting point K 213°C (ethyl acetate). The product is identical to the product described in the literature.

Example 7: 7-chloro-3-methoxycarbonyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo/ f_ 7l ,*+-diazepine (<k>^h-7 CB).

To a boiling solution of 9.2 g (0.05 mol) of the hydrochloric acid

of methylaminomalonate in 30 ml of methyl alcohol, a solution of 9.2 g (0.0^- mol) of the compound V356 CB in 20 ml of methyl alcohol is added dropwise over the course of 1-g-hour. After the addition is complete, the reflux is continued for 30 minutes and then evaporated to dryness in a vacuum. The residue is taken up in water and ether, the organic layer is separated, washed with water and dried over sodium sulphate. The solvent is evaporated in a vacuum. The residue, which consists of the methyl ester homologous to the ethyl ester described in example 1, could not be obtained in a crystallized state. It is dissolved in 25 ml of acetic acid and heated for 15 minutes under reflux. It is evaporated to dryness and the remaining oily residue is taken up in ether. A colorless solid is separated which is collected and recrystallized from methyl alcohol. Colorless crystals (k-, 7 g) with a melting point K 226°C are obtained. By concentration, a further portion is obtained, (1.5 g) with a melting point K

222°C so that the total amount amounts to 6.2 g, which corresponds to a yield of k-7%.

Example 8: 7-chloro-3-ethoxycarbonyl-1-methyl-5-phenyl-2-oxo-2. 3- dihydro- 1H- benzo/* £7l .^- diazepine ( M- 366 CB).

The product is prepared according to the procedure in example 7, replacing the methylaminomalonate and the compound M-356 CB with ethyl aminomalonate and the compound ^+375 CB in equivolar amounts. Light yellow crystals with a melting point K 180°C (ethyl alcohol,

the dividend

This compound can also be prepared starting from /2-phenyl-2-(2-methylamino-5-chloro-phenyl)-1-aza-vinylj7-

diethyl malonate (<*>+362 CB), which is obtained according to the indications in example 1 by replacing C2-amino-5-chloro-phenyl)-phenyl-methane-imine with (2-methylamino-5-chloro-phenyl)-phenyl -methane-imine in stdchiometric amount.

Yellow solid with a melting point K 88°C (isopropyl ether).

Dividend 25$.

Example 9: 3-ethoxycarbonyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo/f. 71.^-diazepine (U-352 CB).

a) 12Z§^iS2l£SD-Zi)l£§2Zilm6tan=imin_ (^3^8_CB)_.

Work is carried out as in example 1, replacing 2-amino-5-chloro-benzonitrile with 2-amino-benzonitrile in an equimolar amount. The compound <*>+358 CB is obtained in a yield of about 80$ crude product. Yellowish crystals. Melting point C: <1>f8°C (isopropyl ether). b) ^:^SZll2l&amino =phenyl2-2 =aza =vin^l) = diet^lmalonate__(^3^1_CB2_.

According to the indications in example 3, substituting (2-amino-5-chloro-phenyl)-phenyl-methane-imine with (2-amino-phenyl)-phenyl-methane-

imine in an equimolar amount, the compound <*>+35l CB is obtained in a yield of 31$. Pale yellow crystals with a melting point K:100°C (isopropyl ether).

It should be noted that in this production insulation is off

a small amount of the ring-closed product respectively 3-ethoxycarbonyl-5~phenyl-2-oxo-2,3-dihydro-1H-benzo(fl7l , U-diazepine C+352 CB) in the mother liquor next to the desired product possible .

c) 3-ethoxycarbonyl-5~phenyl-2-oxo-2,3-dihydro-1H-benzo/f/l, h-^i§2iEiD_l-^352-5?2i

This substance is obtained according to the procedure in example 2 by replacing the compound <*>+36l CB with the compound <*>+35l CB in an equimolar amount. Colorless crystals with a melting point K 226°C (ethyl acetate). Dividend 70$ in the first portion.

The product obtained can be further processed in the following way: 7-nitro-3-ethoxycarbonyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo/fy 1,>+-diazepine (^353 CB).

12.3 g (0.0<*>+ mol) of the compound <*>+352 CB in a finely powdered state are slowly added to 50 ml of concentrated sulfuric acid (66° Be) while stirring in such a way that the temperature does not rise above 25 °C. To the solution thus obtained, <!>+.8 g (O.©^ mol) of powdered potassium nitrate is added at such a rate that the temperature remains below 25°C. After the addition is complete, stir for 2 hours at room temperature. The reaction mixture is poured onto granulated ice and ether and allowed to stand for half an hour. The solid material that separates is collected and washed with water and ether. It is recrystallized from a large volume of ethyl acetate. Light yellow crystals (7.7 g) with a melting point M 271°C are obtained. Dividend 55$.

7-amino-3-ethoxycarbonyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo ,^f-diazepine ( h35h CB).

A solution of h-, k8 g (0.0133 mol) of the compound >+353 CB in. 80 ml of dimethylformamide and 120 ml of ethyl alcohol are hydrated at ordinary temperature and ordinary pressure in the presence of nickel rane. The theoretical absorption is finished after approximately 3 hours.

After filtering off the catalyst and evaporating the solvent in vacuo, a solid residue is obtained which is recrystallized from a mixture of dimethylformamide-ethyl alcohol. Light yellow crystals (3.9 g) with a melting point M 305°C (cleavage) are obtained. Dividend 90$.

Example 10: 7-Chloro5-cyclohexyl-2-oxo-2,3-dihydro-1H-benzo / f7l .^- diazepine ( 1+ 190 CB). a) Cyclohexyl-(2-amino-5-chloro-phenyl)-methane-imine H+32LCB).. Work is carried out as in example 1, but with the replacement of bromobenzene with bromocyclohexane in an equimolar amount. The compound ^359 CB is obtained in a yield of $81. Yellowish crystals exhibiting a double melting point. Melting point K 65°C, then 95°C. b) 7-chloro-5-cyclohexyl-2-oxo-2,3-dihydro-1H-benzo(f7l ,*f-^ia22Ei2_1^122_CB).

This product is prepared according to the procedure in example-5, replacing the compound ^+35° CB and the hydrochloride of the ethyl ester of DL-alanine with the compound <*>+359 CB and the hydrochloride of ethyl glycocholate in an equimolecular amount. Yellow crystals with a melting point K 210°C (n-propyl alcohol). The yield 71$^calculated the simple amine. It is noted that the 1-cyclohexyl-1-(2-amino-5-chloro-phenyl)-i+-oxo-5-oxa-2-aza-1-heptene intermediate could not be isolated in the crystallized state.

Example 11: 7-chloro-3-ethoxycarbonyl-5-cyclohexyl-2-oxo-2. Vdihydro- 1H- benzoZf_ 7l .^- diazepine ( h - 370 CB).

This product is prepared according to the procedure in example 7, replacing the methylaminomalonate and the compound V356 CB with ethyl aminomalonate and the compound V3?9 CB in stoichiometric quantities.

Colorless crystals with a melting point K 208°C (ethyl acetate). Yield h0%. It is noted that the /2-cyclohexyl-2-(2-amino-5-chloro-phenyl)-1-aza-vinyl7-diethylmalonate could not be isolated in the crystallized state.

Example 12: 7-methyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo/t<7>

1 A- diazepine ( F).

a) 1-phenyl-1-(2-amino-5-methyl-phenyl)-^-oxo-5-oxa-2-aza-1-heptene__(<l>f36|f_CB)i.

This product is obtained according to the instructions in example 1 by replacing (2-amino-5-chloro-phenyl)-phenyl-methane-imine with (2-amino-5-methyl-phenyl)-phenyl-methane-imine in an equimolecular amount. Yellow crystals with a melting point K 131°C (isopropyl ether). Dividend 35$.

It is noted that according to the indications in example 1, by replacing 2-amino-5-chloro-benzonitrile with 2-amino-5-methyl-benzonitrile in an equimolecular amount, (2-amino-5-methyl-phenyl)-phenylmethane was obtained -imine could not be produced in a crystallized state. This is an oily crude product which was used in one of the following reactions as described above. b) 7-methyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo[f_71,^-diazepine in±—

This substance is obtained according to the indications in example 1 by replacing the compound ^292 CB with the compound ^36^ CB in an equivalent amount.

Yellow crystals with a melting point K 208°C (ethyl acetate).

Yield hh%. The product is identical to the product described in the literature (in example 5)•

Example " M: 7-methyl-3-ethoxycarbonyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo/ f_ 7l .^-- diazepine (h327 CB).

This substance is obtained according to the indications in example 7 by replacing the hydrochloride of methylaminomalonate and the compound ^356 CB with the hydrochloride of ethylaminomalonate and with (2-amino-5-methyl-phenyl)-phenyl-methane-imine in an equimolecular amount.

Yellow crystals with a melting point K 260°C. Dividend 25$.

Example 1**: 7-chloro-5-phenyl-2-oxo-2,3-dihydro-1H-benzo[f_71], k-diazepine (A).

a) Di-potassium salt of /2-pheny 1-2-(2-amino-5-chloro-^^SZlllll^SYiSZllSJ^^ZIS-1^Q^-CB)^ 1) Dissolve 50 g of potassium in 1350 ml of ethyl alcohol 96° and 82 g (0.25 mol) of the compound <i>+3^7 CB are then added once at 70°C.

The solid dissolves quickly to a yellow colored solution, after which the solution decolourises. At the same time, an abundant colorless precipitate is formed.

After cooling, the precipitate is collected and washed with 96$ alcohol.

It is dried at normal temperature with a long powered vacuum. A colorless solid is obtained (quantitative yield) which is completely soluble in water. The aqueous solution exhibits a strong alkaline reaction. After acidification with acetic acid on the water bath, it releases a precipitate of 7-chloro-5-phenyl-2-oxo-2,3-dihydro-1H-benzo[f_71,^-diazepine. (compound A).

Remarks:

1) The preparation can be carried out by replacing the compound ^3^-7 CB with the corresponding ethyl ester (^279 CB). The yield is the same as for the compound V3O6 CB. 2) By replacing potassium with sodium during the reaction, the corresponding disodium salt is obtained in the same way. 3) To a solution of 0.8<*>f g (0.015 mol) of potassium chloride in 1 ml of water and 25 ml of methyl alcohol, 2 g of the substance ^3^-6 CB is added and it is heated to boiling under reflux. The solid dissolves into a red solution which quickly decolourises while a precipitate appears. After cooling, the solid is collected and washed with methyl alcohol. A colorless solid is obtained (1^5 g) • This substance turns out to be identical to the substance produced according to regulation 1. - k) To a solution of 22h g (h mol) potassium in 5130 ml ethyl alcohol with 10% water, add as quickly as possible while stirring at 18-20°C 3<*>4-1.5 g (1 mol) of the compound k- 279 CB. In the course of 2 minutes, a yellow and clear liquid forms. Rowing ended. The crystallization of the compound ^306 CB begins after a few minutes, followed by a progressive decolorization. After k hours the product is collected, washed with absetyl alcohol (500 ml) and then at 50°C at 0.1 mm vacuum to constant weight. ^-22 g of pale yellow plates are obtained. b) 7-Chloro-5-phenyl-2-oxo-2,3-dihydro-1H-benzo/T71,^-diazepine (a).

To a solution of 0.^09 g (0.001 mol) of the dipotassium salt of /2-phenyl-2(2-amino-5-chloro-phenyl)-1-aza-vinyl7-malonic acid (^306 CB) in h ml distilled water, acetic acid is added in such a way that the pH value for the solution is h. It is heated for 15 minutes in a water bath and the co-extracted solid that is collected is washed with water and dried. Weight 0.216 g. Melting point K 21^-216°C. Dividend 80$. The product is identical to the product obtained according to example 1.

Example 15: 7-chloro-5-phenyl-2-oxo-2,3-dihydro-1H-benzo[beta]1,[beta]-diazepine (A).

A suspension of 6.68 g (0.02 mol) of the compound k279 CB in aqueous potassium hydroxide (5.5 g of potassium hydroxide in 5 ml of water) is heated in the water bath with stirring until complete dissolution. A yellow, strongly colored solution is obtained which becomes lighter in the course of a few minutes. The hot solution is treated with 6 ml of acetic acid.

Thereby precipitation of a paste-like product is effected while carbon dioxide gas is released. The decarboxylation is completed by brief boiling under reflux. After completion of this reaction, the product crystallizes. It is collected, washed with water and dried at 100°C in a vacuum. The yield is practically quantitative and the melting point K 212°C. A completely pure product can be prepared by crystallization as indicated in Example 1.

Instead of the aqueous kalilut, a solution can be used

of potassium hydroxide in ethyl alcohol, e.g. 95$. The hot solution is then treated with dilute acetic acid.

Example 16; 7-chloro-1-methyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo/ f_ 7l , h - diazepine ( B).

a) The dikaHum salt of /2-phenyl-2-(2-methylamino-5-1).

This product is obtained according to the procedure in example 1<*>f below

replacement of the compound ^3^7 CB by the compound ^366 CB

in stoichiometric amount. The connection constitutes a farewell,

in water slightly loaaLig powder. Dividend 71$. The aqueous solution shows a strong alkaline reaction. 2. This substance can be obtained as indicated in example 1<>>+ by replacing the compound V366 CB with the compound <*>+362 CB 1 equimolecular amount. It is available in the form of a colorless powder that is completely soluble in water and is identical to the previously mentioned product under 1). Dividend 50$.

b) 7-chloro-1-methyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo[beta]+-2^ia52EiS_i52i

To the aqueous solution of 3 g of the compound V306 CB, a solution prepared by dissolving 0.7 g of potassium hydroxide in 15 ml of water is added and then gradually (over the course of about 5 minutes) while stirring and while avoiding a temperature rise above 25°C 1 .8 g of dimethyl sulfate. After the addition, leave for approximately 2 hours at room temperature and then acidify with acetic acid. A paste-like product precipitates which is isolated with isopropyl ether. The thus formed suspension forms over the course of a few minutes (evolution of carbon dioxide gas). It is cooled, diluted with ether and the aqueous phase separated. The solvent is evaporated and the residue is crystallized from isopropyl ether. Dividend 80$. The melting point K 132°C and the product is identical to the product

from example 2.

Example 17: The potassium salt of 3-(7-chloro-5-phenyl)-oxo^-dihydro-1H-benzo[f/l]-diazepineZ-carbcksjlsye C+311

CB).

At room temperature, dissolve 2.1 g (0.005 mol) of the substance in 18 ml of water

•+306 CB and 0.68 g (0.005 mol) monopotassium phosphate. Dissolution takes place quickly and then colorless plates slowly fall out. These are collected, washed with ice-cold water and then with absolute alcohol. It is dried for 12 hours at room temperature in a high powered vacuum. 1.8 g of colourless, completely water-soluble crystals are obtained. The aqueous solution is essentially neutral

PH value. Dividend 80$. The product is decarboxylated in the course of a few minutes by heating the aqueous solution, releasing substance A in a crystallized state.

Example 18: The potassium salt of 3-^5-phenyl-2-oxo-2,3-dihydro-1H-benzo/ t7l , tf-diazepine7-carboxylic acid C+ 338 CB).

a) The dipotassium salt of /2-pheny2-(2-amino-?§5Yilzli§?§iYi5YlZi5§:lonsZ52 (^237 CB)^

This substance is produced according to the method described in example 1, replacing the compound ^+3^7 CB with the compound *+352 CB in a stoichiometric amount.

Colourless, completely soluble in water leaves that give a strong alkaline solution. The yield is almost quantitative. b) The potassium salt of 3-[5-phen<y>1-2-oxo-2,3-dihydro-1H-benzo[fJ7 1_i^=diazePin72karboksYlsy_re (1f338_CB). This substance is obtained according to the method in example 17, replacing the compound ^306 CB with the compound ^337 CB in an equivalent amount and reducing the volume of water used to half. The substance is a colorless powder that dissolves in water and exhibits an essentially neutral reaction. The dividend 7>+$.

Example 19; The potassium salt of 3-/7-methyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo/f_/1 tk-diazepine7-carboxylic acid C+ 573 CB). a) Di-potassium salt of Z2-phenyl-2-(2-amino-5-methyl-f e5Zl 1 z 1 z§ 5§ zYi^Y^^l^syr e _ L^33 9 _CB_)_.

This substance is prepared according to the method in example 1^, replacing the compound V}^7 CB with the compound V327 CB in an equimolecular amount. The substance is available in the form of a completely water-soluble colorless solid. The yield is practically quantitative.

b) Potassium salt of 3-[7-methyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo[phy2]zdiazepin7-c^rtoc^yl acid (^573 QB)-_

Work is carried out as in example 17, replacing the compound 1+306 CB with the compound 1+339 CB in a stoichiometric amount and reducing the volume of water to half.

The colorless solid obtained is soluble in water. The dividend

Example 20; Potassium salt of 3~/7-nitro-5-phenyl-2-oxo-2,3-dihydro-lH-benzo/f/l ,l+-diazepine7-carboxylic acid ( 1+ 336 CB). a) Di-potassium salt of /2-phenyl-2-(2-amino-5-_Si5?2zCS5yi2ilia5aivi5Y^"?ai2n§yre (Lt"335'_c?) • 1. The substance is obtained by the method in example 1 W - during replacement of the compound h^ h^ CB with the compound 1+353 CB in equimolecular amount. The substance precipitates as a yellow powder which dissolves completely in water to a strong alkaline solution. The yield is practically quantitative. 2. The procedure in example 1< >>+ is used while replacing the compound 1+279 CB with the compound 1+353 CB in an equimolecular amount. The reaction takes place as described above. The compound

*+335 CB is obtained in the same yield as the compound 1+306 CB.

b) Potassium salt of 3-(7-nitro-5-phenyl-2-oxo-2,3-dihydro-1H-2§5?2^^1i^z§ia52BihZz^§I!2ok§ZlsY'r2 (^3.36_CB)1

The product is produced according to the procedure in example 17, replacing the substance 1+306 CB with the substance <>>+335 CB- in a stoichiometric amount and reducing the volume of water used for the half-paite.

The light yellow powder obtained dissolves in water to a practically neutral solution. Dividend 79$.

Example 21; 7-chloro-3-ethoxycarbonyl-5-phenyl-2-oxo-2,3-dihydro

1H- benzoÆ7l .^-- diazepine ( 1+ 279 CB).

In a dress with rudder work, drop funnel and inner rudder

For the introduction of hydrogen chloride gas, a reaction vessel equipped with 23.5 g (2 mol) of the hydrochloride of ethyl aminomalonate and 1250 ml of dry benzene is filled. It is heated to boiling under reflux and added over the course of 50 min. a solution of <*>+60 g (2 mol) of the ketimine (^+356 CB) in 1250 ml of dry benzene. For the addition, one observes the precipitation of the chlorhydrate of the ketimine (^+356 CB)

in the form of orange-red crystals. Boiling is continued under reflux until the suspended precipitate is colorless (ammonium chloride),

to which it takes about 2 hours. A rapid stream of hydrogen chloride gas is then allowed to bubble through for 2 hours while maintaining reflux. A precipitate of the chlorhydrate of the compound ^+279 CB is eventually found in the form of an organge-coloured powder. It is cooled, the crystals (chloro-

the hydrate of the substance ^279 CB and ammonium chloride) are collected and washed out with benzene bg ether. For the release of the base treated with a solution of sodium carbonate in the presence of methylene chloride. The organic layer is separated, dried, the solvent is distilled off and the residue is treated with ether. A white, practically pure product is obtained in this way (M+1.5 g, yield $63.5). Temp. K = 2h3- 2kh°C.

Example 22; 3-ethoxycarbonyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzoÆ7l A-diazepine ( 1+^ 52 CB).

In the apparatus according to example 21, ^23, h g (2 mol) is introduced

of the hydrochloride of ethyl aminomalonate and 1250 ml of benzene. It is heated to boiling under reflux and over the course of 50 min.

is added a solution of 391 g (2 mol) of (2-amino-phenyl)-phenyl-

methane-imine C+358 CB) in 1250 ml of dry benzene. Before the introduction begins, the chlorhydrate of the compound V358 CB precipitates out in the form of brownish-red crystals. To facilitate the condensation, 62.5 ml of methanol are added, i.e. 2.5% of the total solvent present.

It is heated for h hours to boiling under reflux for decolourisation

of the precipitate, which at the end of the reaction consists only of ammonium chloride. Methanol is driven off by azeotropic distillation (methanol-benzene) and a rapid stream of hydrogen is then bubbled through

chloride gas for 2 hours while maintaining the reflux. A progressive precipitation of the chlorhydrate of the compound !+352 CB takes place in the form of an orange-coloured powder. It is undressed. The crystals of the chlorhydrate of the substance ^352 CB and ammonium chloride are collected and washed with benzene and ether. To liberate the base, treat - as indicated in Example 21 for the hydrochloride of the compound ^279 CB. <>>+16 g of the compound <>>+352 CB is recovered in a practically pure state. Yield 67.5%. Temp. K=22l+-225°C.

Example 23; 7-chloro-5-cyclohexyl-2-oxo-2,3-dihydro-1H-benzo-/ £71 A- diazepine ( 1+ 190 CB).

Work is carried out according to the procedure in example 21, replacing the hydrochloride of ethyl aminomalonate with the hydrochloride of ethyl glycocholate and the compound *+356 CB with the compound *+359 CB in a stoichiometric amount and benzene with toluene in an equal volume. The compound <1>+190 CB is obtained by cleavage of its red-orange carbohydrate with a yield of $66.5. Temp. K=208°C.

Example 2*+:

By using the methods described in examples 1-13, the following compounds can be prepared: 7-chloro-3-carbamoyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo[f_7-1,t+- diazepine ( h3k8 CB).

Colorless crystals (from methyl alcohol). Temp. M= 255-256°C. 7-chloro-3-methylaminocarbonyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo/£7l ,^diazepine (<I>+367 CB).

Colorless crystals (from ethyl alcohol). Temp. M=291+°C. 7-chloro-3-dimethylaminocarbonyl-5-phenyl-2-oxo-2,3-dihydro-1H-benzo/£7l ,*+-diazepine (I+368 CB).

Colorless crystals with m.p. M=297°C.

7-Chloro-3-(2-diethylamino-ethylaminocarbonyl)-5-phenyl-2-oxo-2,3-dihydro-1H-benzo//fJl,l+-diazepine (*+369 CB).

Colorless crystals (from ethyl acetate). Temp. K=220°C.

A number of the compounds described above were investigated for their effects on the central nervous system as psycholeptics, muscle relaxants and tranquilizers. Incidentally, the acute toxicity was determined for a number of these substances.

Under the same conditions, some compounds whose pharmaceutical and clinical effects are known, such as diazepam and chlordiazepoxide, were also investigated at the same time and subjected to the same tests with animals from the same origin as the new compounds. In this way, a numerical comparison of the effect of the different compounds with the different test methods used has been made possible. The overall results of these investigations are briefly summarized: 1. The two nitrated derivatives <1>+335 and <1>+336 in the para-position prove to be distinctly active in the various tests, especially as muscle relaxants and anticonvulsants and in the curiosity-hate test. In contrast, they seem to have less of an effect on the ability to change places. Finally, they significantly reduce aggressiveness (loss of combativeness). 2. The compound I+3O6, which is very similar to the compound <1>+335, is likewise very active and in most samples at least as active as diazepam and often superior.

3- The compound *+311 is likewise very rigid, although less so than the compound V3O6. Its activity is less with parenteral administration than with oral administration.

Claims (1)

Process for the preparation of benzodiazepine derivatives with the general formula I in which R^ means hydrogen, halogen, especially chlorine, trifluoromethyl, lower alkyl, lower alkoxy, nitro or amino, R 2 means furyl, thienyl, lower alkyl, lower cycloalkyl or one optionally substituted with halogen, trifluoromethyl, nitro, lower alkyl or lower alkoxy aryl residue, in particular a phenyl residue, R^ means hydrogen or lower alkyl and R^ means hydrogen, lower carbalkyloxy, alkyl or a carbamoyl residue which optionally exhibits one or two lower alkyl residues or a lower dialkylamino-alkyl residue, or the residue means COOKat, Kat representing a alkali or an alkaline earth cation, characterized in that an imine of the general formula II in which R^, R2, R^ and R^ have the above meaning and R^ means lower alkyl or, if R^ stands for -COOKat, means Kat, as Kat represents an alkali or alkaline earth cation, is subjected to a ring closure by acid treatment.