NO125821B - - Google Patents

Description

Process for the production of benzodiazepine derivatives.

The invention relates to a process for the production of 1,3,4,5-tetrahydro-5-phenyl-2H-1,4-benzodiazepine-2-ones with the general formula where R, and R 4 means hydrogen or lower alkyl, R 2 hydrogen , halogen, nitro or trifluoromethyl, R.j hydrogen, halogen, trifluoromethyl, nitro or cyano.

All methods that have been described so far for the production of such compounds show as a common basic principle first the production of a 1,2-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one (DAS 1145 625), which is then converted to the desired 1,3,4,5-tetrahydro-5-phenyl-2H-1,4-benzodiazepine-2-one by catalytic hydrogenation [j. Org. Chem. 26, 4936 (1961)]. According to the present invention, compounds of formula I are prepared directly from non-heterocyclic compounds. Thus, the present invention contains a method which explains the production of such 1,3,4,5-tetrahydro-5-phenyl-2H-1,4-benzodiazepine-2-ones exceptionally well, as the expensive hydration on noble metal contact is omitted . Furthermore, the method according to the invention is more general than the state of the art, since also e.g. compounds bearing nitro groups can be prepared. This compound class shows advantageous properties with regard to its reactivity, so that new and therapeutically valuable compounds can easily be prepared from it.

The method according to the invention consists in intramolecularly condensing a compound with the general formula where R^, R£, Rj and R^ have the meaning given in formula I and

R^ is lower alkoxy, hydroxy, aryloxy or

amino,

in the presence of an inert organic solvent by heating to a temperature between 80 and 300°, preferably 80 - 200° and, if desired, transferring the obtained compounds with an acid to an acid addition salt.

The term lower alkyl, as used here, refers to straight-chain or branched saturated hydrocarbon radicals, such as e.g. methyl, ethyl, propyl, isopropyl, etc. The term halogen refers to all four halogens, i.e. iodine, fluorine, bromine and chlorine. However, chlorine, fluorine, bromine are particularly preferred. The term amino includes unsubstituted and substituted amino groups such as e.g. -NH2, -NH(lower alkyl) and -N(lower alkyl)2" Aryloxy includes aromatic, cyclic hydrocarbons with oxy groups, such as, for example, phenoxy etc.

As stated above in the present invention, the preparation of compounds of formula I by intramolecular condensation of compounds of formula III. The compounds of formula III are derivatives of aminoacetic acid. The intra-molecular condensation is a dehydration. It can conveniently be carried out by heating a compound of formula III in an inert organic solvent. This dehydration can be carried out by any suitable method, but is preferably carried out by heating in an inert organic solvent. This heating can be carried out at temperatures of approx. 80° to approx. 300°C, but temperatures of approx. 80°C to approx. 200°C is particularly preferred. Suitable organic solvents are e.g. hydrocarbons such as aromatic hydrocarbons of the xylene type, etc., halogen-containing hydrocarbons, such as methylene chloride, etc., ethers, such as e.g. ethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, etc. and heterocyclic compounds containing a basic nitrogen atom, such as pyridine, piperidine, etc. Mixtures of such inert organic solvents can also be used with advantage.

Compounds with formula III, which are 2-aminobenzhydrylamino-acetic acid derivatives, are starting materials for the method described in more detail above and can be prepared by a number of methods. In particular, they can be prepared by hydrolysis of the corresponding esters or amides of compounds of formula where R^, R^/ and R^ have the same meaning as in formula III and

Rg' is a lower alkoxy, amino or aryloxy group.

Compounds of formula IV can be prepared by reacting the corresponding 2-aminobenzhydrylamines with a lower alkyl or aryl haloacetic acid ester (bromo- and chloroacetic acid esters are particularly preferred), a haloacetamide or a haloacetic acid. This reaction can be carried out at room temperature or also above or below room temperature. Appropriately, it is carried out in an inert organic solvent, e.g. in hydrocarbons such as benzene, toluene, etc., preferably in the presence of an acid-binding material, inorganic as well as organic acid-binding materials can be used, e.g. carbonates, such as sodium carbonate, amines such as lower alkyl amines, e.g. triethylamine, etc.

In a further embodiment, compounds of formula IV can be prepared from benzhydryl halides of formula V where R^, <R>2/ and <R>^ have the same meaning as in

formula 1,

by reaction with a glycine compound of formula VI

where R^ and R^<1> have the same meaning as in formula IV.

The benzhy/dryl halides of formula V can be prepared by treating the corresponding benzhydrols with a halogenating agent (iodinating, chlorinating and brominating agents are particularly preferred). For example allows as halogenating agent thionyl halides, such as thionyl chloride and thionyl bromide, phosphorus trihalides or -pentahalides,

such as phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride, or hydrogen halides such as hydrogen chloride or hydrogen bromide etc. can be used. The thus produced benzhydryl halides can then be isolated (advantageously as an acid addition salt, e.g. as the acid addition salt formed during the halogenation reaction) or preferably reacted further directly by adding the glycine compound of formula VI to the reaction mixture, in which the benzhydryl halide of formula V was prepared. One

preferred embodiment of the reaction with a benzhydryl halide of formula V consists in using the glycine compound of formula VI as glycine-

ester (i.e. R5<1>means alkoxy or aryloxy).

The hydrolysis of the aminoacetic acid ester or the aminoacetamides

of formula IV to the acetic acid derivatives of formula III

is conveniently carried out either by alkaline or acid hydrolysis and can either be carried out at room temperature or above or below room temperature. Preferably, you work above room temperature while heating

the ester of formula XV either in acidic or basic aqueous medium under reflux.

The products available by the method according to the invention are valuable as sedatives, tranquilizers, anticonvulsants and muscle relaxants.

The following examples illustrate the invention, all temperatures are given in °C and all melting points are corrected.

EXAMPLE 1

A solution of 1 g of 2-[i-(2-amino-5-chlorophenyl)-1-phenyl-methylamino-acetic acid in 10 ml of anhydrous pyridine and 0.02 ml of piperidine is heated for 17 hours under reflux. The mixture is evaporated in vacuo and the residue is shaken out with a mixture of dilute hydrochloric acid and ether. The aqueous acid layer is made alkaline with sodium hydroxide solution and the precipitate that precipitates is filtered off and recrystallized from ethanol.

7-Chloro-1,3,4,5-tetrahydro-5-phenyl-2H-1,4-benzodiazepine-2-one is obtained in the form of fine prisms which melt

at 183 - 185°C.

The starting material can be produced in the following way:

in 30.6 g of 2-amino-5-chlorobenzhydrylamine dihydrochloride is dissolved in 150 ml of water and rendered alkaline with a 20% sodium hydroxide solution. Extraction of this mixture with methyl chloride ] gives 2-amino-5-chloro-benzhydrylamine as a pale yellow viscous oil. 11.64 g (0.050 mol) of 2-amino-5-chloro-benzhydrylamine are dissolved in 1,100 ml of dry benzene and treated with 10.1 g (0.100 mol) of triethylamine. The reaction mixture is added dropwise while stirring and cooling with an ice bath at 0 - 5°c (over the course of 20 - 30 minutes) a solution of 8.35 g (0.050 mol) bromoacetic acid ethyl ester in 20 ml of dry benzene. The reaction mixture is stirred for 16 hours at room temperature, then heated for one hour in a steam bath under reflux. After cooling, the reaction mixture is poured into water, extracted with methylene chloride and a light yellow oil is obtained. This oil is treated with a mixture of dilute hydrochloric acid and ether, the aqueous layer is made alkaline with sodium hydroxide solution and then extracted with methylene chloride and the crude product is obtained in the form of a viscous yellow gum. Trituration with hexane followed by several recrystallizations from hexane and ethanol gives 2 -[1-(2-amino-5-chlorophenyl)-1-phenylmethylamino] acetic acid ethyl ester in the form of fine small rods, melting at 103 - 104°C. 1.81 g of 2-[1-(2-amino-5-chlorophenyl)-1-phenylmethylamino]-acetic acid ethyl ester is heated in a mixture of 30 ml (approx. 1-n) saturated methanolic barium hydroxide solution and 10 ml of water for 17 hours under reflux. After cooling the solution, the separated barium salt is filtered off, recrystallized from water and fine needles with a melting point of 206 - 210° are obtained. The barium salt is then dissolved in 20 ml of dimethylformamide, by adding the calculated amount of 1-n sulfuric acid, the acid is set free and the precipitated barium sulphate is removed by filtration. The filtrate is concentrated and diluted with water. 2-[1-(2-amino-S-chlorophenyl)-1-phenylmethylamino]acetic acid is obtained in the form of yellow prisms, which are recrystallized from methanol. The melting point is rather undefined and the substance decomposes at approx. 234 - 242°C.

EXAMPLE 2

A suspension of 1 g of 2-[1-(2-amino-5-chlorophenyl)-1-phenyl-methylamino]acetic acid in 20 ml of dry xylene is heated with stirring for 6 hours under reflux. Some of the solid material remains undissolved. The mixture is cooled and filtered. 7-chloro-1,3,4,5-tetrahydro-5-phenyl-2H-1,4-benzodiazepine-2-ones are obtained in the form of fine prisms melting at 181 - 185°.

The starting material can be produced in the following way:

a solution of 23.4 g (0.100 mol) of 2-amino-5-chloro-benzhydrol in 250 ml of dichloroethane is treated under stirring with dry hydrogen chloride, which is passed through the mixture until an excess is present. Then, 2 drops of pyridine and 23.8 g (0.200 mol) of thionyl chloride are added and the mixture is heated under reflux until the evolution of sulfur dioxide has practically come to a standstill (0.5 hours). The mixture is evaporated in a vacuum, whereby it is protected from humidity. The residue is dissolved in 200 ml of methylene chloride and concentrated

again, to remove excess thionyl chloride. The residue obtained in this way by evaporation of the reaction mixture is taken up in 60 ml of methylene chloride. The solution is stirred in an ice bath while cooling and a solution of 10.3 g (100 mol) of freshly distilled aminoacetic acid ethyl ester in 25 ml of methylene chloride is added dropwise over a period of 30 minutes. The reaction mixture is stirred for one hour at room temperature and then poured into water. The organic layer is evaporated and the crude product is obtained in the form of a brown partially crystalline residue. This is distributed between ether and dilute hydrochloric acid: the acidic layer is rendered alkaline with sodium hydroxide solution, extracted with methylene chloride and a solid pure product of 2-[1-(2-amino-5-chlorophenyl)-1-phenylmethylamino]acetic acid ethyl ester is obtained in the form of a brown crystalline residue. After recrystallization from a methylene chloride-hexane mixture, fine prisms are obtained, which melt at 102 - 105°. The ester can be hydrolyzed as described in the last paragraph of the preceding example.

' EXAMPLE 3

30.6 g (0.100 mol) 2-amino-5-chlorobenzhydrylamine dihydrochloride

suspended in ethanol and treated with 21.2 g (0.200 mol) of anhydrous sodium carbonate. The mixture is heated under reflux and a solution of 16.7 g of bromoacetic acid ethyl ester in 25 ml of ethanol is added dropwise over a period of one hour. The mixture is heated under stirring for a further 24 hours

under reflux, then filtered and the combined filtrates concentrated in vacuo. The residue is worked up in the manner described in example 2 and 25.1 g of 2-[1-(2-amino-5-chlorophenyl)-1-phenylmethylamino] acetic acid ethyl ester is obtained in the form of a yellow oil. This compound is hydrolysed by refluxing with a mixture of 120 ml of 1-1 aqueous sodium hydroxide solution and 240 ml of ethanol for 3 hours. The solution thus obtained is concentrated in vacuo, diluted with water and acidified with 3-n acetic acid (pH 5 - 6). Cream-colored prisms of 2-[1-(2-amino-5-chloro-phenyl)-1-phenylmethylamine] acetic acid are obtained. The product thus obtained is cyclized to 7-chloro-1,3,4,5-tetrahydro-5-phenyl-2H-1,4-benzodiazepine-2-one by treatment with refluxing xylene as described in example 2 and one obtains brown colored prisms with a melting point of 182 - 186°.

Analogously to example 1, 1st section, 5-phenyl-1,3,4,5-tetrahydro is obtained from 2-[l-(2-aminophenyl)-1-phenylmethylamino]-acetic acid (m.p.: 160 - 162°) -2H-1,4-benzodiazepine-2-one. Recrystallization from a mixture of acetone/petroleum ether, farewell needles, m.p. 147 - 148°.

Analogously to example 1, 1st section, one obtains from 2-[1-(2-amino-5-nitrophenyl)-1-phenylmethylamino]-acetic acid (m.p.: 193 - 196°) 7-nitro-1,3,4 ,5-tetrahydrb-2H-5-phenyl-1,4-benzodiazepine-2-one, recrystallization from a mixture of dimethylformamide/water, farewell needles, m.p. 236 - 237°

(fission).

Analogously to example 1, 1st section, 2-[1-(2-amino-5-chlorophenyl)-1-(2-fluorophenyl)methylamino]acetic acid is obtained (m.p.: 160 - 161°).

7-chloro-1,3,4,5-tetrahydro-2H-5-(2-fluorophenyl)-1,4-benzodiazepine-2-one; recrystallization from a mixture of acetic acid/water, m.p. 214-215°.

Claims (1)

Process for the preparation of benzodeazepine derivatives of the general formula where R1 and R4 mean hydrogen or lower alkyl, R2 hydrogen, halogen, nitro or trifluoromethyl, R^ hydrogen, halogen, trifluoromethyl, nitro or cyano, characterized by intramolecularly condensing a compound with the general formula where R , R 2 , R 4 and R 4 have the above meaning and R,, is lower alkoxy, hydroxy, aryloxy or amino, in the presence of an organic solvent by heating to a temperature between 80 and 300°, preferably 80 - 200°, and, if desired, transferring the obtained compounds with an acid to an acid addition salt. Cited publications: J. Org. Chem. 26, 4936/41 (1961) and 2 T <_> , 562-66 (1962).