CH651565A5 - PROCESS FOR THE PREPARATION OF IMIDAZOBENZODIAZEPINES AND THEIR SALTS. - Google Patents

Description

The present invention relates to a new process for the preparation of imidazobenzo-diazepines, as well as their addition salts with acids.

The object of the invention is more precisely a new process for preparing the products of general formula:

in which R] represents a hydrogen atom, a halogen atom, a nitro radical or a trifluoromethyl radical, R2 represents a hydrogen atom or a halogen atom, R3 and R4 together represent with the atom nitrogen to which they are linked a 4-alkyl-piperazin-1-yl radical, 4-cyclo alkyl alkyl alkyl piperazin-1-yl, 4-phenyl-piperazin-1-yl or piperidino, as well as their addition salts with mineral or organic acids.

In formula I e in the following,

When R] represents a halogen atom, it is preferably a fluorine, chlorine or bromine atom and more particularly a chlorine atom;

when R2 represents a halogen atom, it is preferably a fluorine, chlorine or bromine atom, and more particularly a fluorine or chlorine atom; moreover, when R2 is a halogen atom, it is preferably in the ortho position;

when R3 and R4 together with the nitrogen atom to which they are bonded represent a 4-alkyl-piperazin-1-yl radical, it is preferably a 4-menthyl-piperazin-1-yl 4 radical -ethyl-piperazin-1-yl or 4-propyl-piperazin-1-yl and more particularly of the 4-menthyl-piperazin-1-yl radical,

when R3 and R4 together with the nitrogen atom to which they are linked represent a 4-cyclo alkyl-alkyl-pipê-40 razin-1-yl radical, it is preferably a cyclo alkyl radical comprising from 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl or cyclophentyl radicals. Among the 4-cycloalkylalkyl-piperazin-1-yl radicals, the 4-cyclopropyl methyl-piperazin-1-yl radical is more particularly retained.

The addition salts with mineral or organic acids can be, for example, the salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, formic, benzoin, maleic, fumaric acids. , succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulfonic such as methane sulfonic acid and arylsufonic, such as benzene sulfonic acid.

The products of general formula (I) and their salts as well as a process for their preparation have been described in French patent No. 2,300,569 filed by the holder. As indicated in this patent, the products of general formula (I) have interesting sedative, hypnotic, anxiolytic, tranquilizing, anticonvulsant and muscle relaxant properties.

The new process of the invention makes it possible to prepare the products of formula (I) with good yields in a number of stages lower than that of the processes described in the aforementioned French patent.

The subject of the present invention is therefore a new process pro-65 for preparing the products of general formula I, as well as their addition salts with mineral or organic acids, characterized in that a product of • is reacted. formula:

45

3

651,565

Dehydration can advantageously be carried out using a carbodiimide such as dicyclohexyl carbo-diimide.

The products of formula (III) when they are not known (II) 5 Can be prepared by reaction of a product of formula:

in which R] and R2 have the meaning already indicated, with an amine of formula:

alcQ

alpo

(III)

in which aie represents an alkyl radical containing from 1 to 3 carbon atoms, R3 and R4 have the meaning already indicated, within an organic solvent, to obtain the desired product of formula I, which can be salified in the case if necessary.

Under preferential conditions for implementing the process of the invention, the reaction of the product of formula (II) with the product of formula (III) is carried out in an organic solvent such as methylene chloride and in the presence an amine such as triethylamine.

The acid addition salts of the products of formula I can be prepared by reacting the said products of formula I with a stoichiometric amount of a mineral or organic acid. The reaction is preferably carried out in an organic solvent or a mixture of organic solvents such as alcohols, for example methanol or ethanol, alkyl halides, for example methylene chloride.

As indicated in French Patent No. 2,300,569, the products of formula II can be prepared from a product of formula:

(IV)

in which R] and R2 have the meaning already indicated, by reaction with glycine, to obtain a product of formula:

"H-CHg-COOH

(V)

in which R] and R2 have the meaning already indicated, which is dried to obtain the desired product of formula (II).

(VI)

in which R3 and R4 have the meaning already indicated, with an alkyl ketal of dimethyl formamide. An example of such a preparation is given in the experimental part.

An example of implementation of the invention will now be given without implied limitation.

Example

2o8-nitro 1,2-dyhidro2- (N-menthyl-piperazin-1-yl) methylene

6- (o-chlorophenyl) 1H, 4H-imidazo [1,2-a] [1,4] benzodi-azepine-1-one.

Stage A: 2-carboxymethylamino-7-nitro 5- (o-chlorophenyl) 3H- [1,4] -benzodiazepine.

25 In 3 liters of demineralized water, 1.360 kg of glycine are introduced and then gradually, 1.459 kg of sodium bicarbonate. The mixture is stirred for 30 minutes at room temperature, 15 liters of ethanol are introduced and then, in approximately 5 minutes, 3 kg of

7-nitro 1,3-dihydro 5- (o-chlorophenyl) -2H- [1,4] -benzodi-30 azepine 2-thione.

The mixture is refluxed for 1 hour 30 minutes, distilled under reduced pressure, 15 liters of demineralized water are added twice, then 7.5 liters of methylene chloride and the phases are separated.

The aqueous phase is re-extracted with 3 times 6 liters of methylene chloride and then the chloromethylenic phases are washed with water and all of the aqueous phases are combined. 18 liters of methylene chloride are added thereto, then at 0 °, -1- 5 ° C, 1.3 liters of 22 ° Be hydrochloric acid. A chloromethylenic solution of 2-carboxymethylamino 7-nitro 5- (o-chlorophenyl) 40 3H- [1,4] benzodiazepine is obtained which is used in the following stage.

Stage B: 8-nitro 1,2-dihydro 6- (o-chlorophenyl) 1H, 4H-imi-dazo [1,2-a] [1,4] benzodiazepine-1-one

To the chloromethylenic solution of 2-carboxy methyl-45 amino 7-nitro 5- (o-chlorophenyl) 3H- [1,4] -benzodiazepine obtained above, the solution of + is added at + 5 ° C in about 2 minutes 1.865 kg of dicyclohexylcarbodiimide in 3 liters of methylene chloride and then stirred for 30 minutes.

It is left to rest overnight and then wrung. Wash 2 times with 50 3 liters of methylene chloride and collect the chloromethylenic solution of 8-nitro 1,2-dihydro 6- (o-chlorophenyl) IH, 4H-imidazo [1,2-a] [1,4] benzodiazepine 1-one which is used in the next stage.

55 Stage C: 8-nitro 1,2-dihydro 2- (N-methyl piperazin-1-yl) methylene 6- (o-chlorophenyl) 1H, 4H-imidazo [1,2-a] [1, 4] benzodiazepine -l-one.

Ala chloromethylenic solution of 8-nitro 1,2-dihydro 6- (o-chlorophenyl) IH, 4H-imidazo [1,2-a] [1,4] benzodiazé-60 pine-1-one obtained above, we add in approximately 5 minutes and at room temperature, 650 g of triethylamine then 2.4 kg of a solution of dimethyl ketai of N-formyl N-methyl pi-perazine, the preparation of which is given below.

The mixture is stirred for 1 hour 30 minutes, concentrated to dryness under 65 reduced pressure and 6 liters of ethanol are added. It is distilled while keeping the level constant by adding ethanol until vapors are obtained at 78 ° C, then cooled to 0 ° -f 2 ° C, stirred for 2 hours and wrung. Wash with ethanol and re-

651565

picks 4.260 kg of crude product which is purified by treatment with activated carbon and then with ethanol.

Finally collected 3.362 kg of 8-nitro 1,2-dihydro 2- (N-methyl piperazin-1-yl) methlene 6- (o-chlorophenyl) 1H, 4H-imidazo [1,2-a] [1,4 ] benzodiazepine-1-one.

The product obtained is identical to that described in Example 30 of the aforementioned French patent.

The dimethyl ketai solution of N-formyl N-methyl pi-perazine can be prepared as follows:

3.3 kg of N-methyl piperazine, brought to reflux for 15 hours, are introduced into 2 kg of dimethylformamide dimethyl ketai.

The uncombined N-methyl piperazine is distilled under reduced pressure, stirred for 1 hour under reduced pressure at 115-120 ° C and then cooled to 20 ° C. 3.920 kg of a brown solution of dimethyl ketal of N-formyl N-methyl piperazine are obtained.

VS

Claims (2)

651,565 2 CLAIMS 1. Process for the preparation of products of general formula: CK - N; 'R3 © in which Ri represents a hydrogen atom, a halogen atom, a nitro radical or a trifluoro-methyl radical, R2 represents a hydrogen atom or a halogen atom, R3 and R4 together represent with the atom d nitrogen to which they are linked a radical 4-alkyl-piperazin-1-yl, 4-cyclo alkyl alkyl piperazin-1-yl, 4-phenyl-piperazin-1-yl or piperidino, as well as their addition salts with mineral or organic acids, characterized in that a product of formula is reacted: 'NOT > î. Ri have) -R2 in which Ri and R2 have the meaning already indicated, with an amine of formula: alcO. \ Ouch 0 / .CH- ■ N • r3 R4 (III) (I) in which aie represents an alkyl radical containing 1 to 3 carbon atoms, R3 and R4 have the meaning already indicated, in an organic solvent, to obtain the desired product of formula (I), which can be salified if applicable. 2. Method according to claim 1, characterized in that the reaction of the product of formula (II) with the product of formula (III) is carried out in methylene chloride and in the presence of an amine such as triethylamine.