NO121545B - - Google Patents

Description

Process for the production of benzodiazepine derivatives.

The invention relates to a new chemical process for the production of benzodiazepine derivatives with muscle relaxant, sedative and anticonvulsant effects. These derivatives have the general formula

where B means carbonyl or methylene,

halogen, preferably chlorine or bromine,

R2hydrogen or lower alkyl and

R^hydrogen or halogen.

The term "halogen" refers to all forms, i.e. chlorine, bromine, fluorine and iodine, except where specifically stated. The term "lower alkyl" (either alone or in combination with other radicals) refers to straight-chain or branched hydrocarbon groups with 1-7 carbon atoms. Examples of such lower alkyl groups are methyl, ethyl, isopropyl, tert.butyl and the like. The term "aryl", as used in the following, refers to phenyl groups, substituted phenyl groups, e.g. lower alkyl-phenyl, such as tolyl and the like.

The method according to the invention consists in treating a compound with the general formula where B, , R 2 and R 2 have the above meaning and X means an arylsulfonyl, lower alkylsulfonyl or a lower alkanoyl group,

with a base in the presence of an inert organic solvent.

French patent no. 1,405,699 describes the preparation of compounds of formula I, where B means carbonyl, by oxidation of corresponding 1,2,3,4-tetrahydro derivatives. However, this method is only applicable to 1-unsubstituted compounds. If a 1-alkyl-substituted compound is desired, this alkyl group must be introduced afterwards. According to the invention, 1-substituted compounds can also be obtained, whereby the yield of these compounds is also significantly improved.

US Patent No. 3,243,427 describes compounds of formula I, where B is methylene, as well as methods for their preparation. One method involves the reduction of a corresponding benzodiazepine-2-one, whereby, however, to a large extent the corresponding 1,2,3,4-tetrahydro compound also falls out as a by-product that is not further applicable. The present invention now ensures an opportunity for further processing of these by-products into the desired compounds of formula I. The further reaction described in this patent document of 2-aminobenzophenone with ethyleneimine and the desulphurisation of a corresponding 1,4-benzodiazepine-2-thione also have disadvantages, whereby on the one hand the use of the highly toxic ethyleneimine, on the other hand the dehalogenation of a halogen substituent in the 5-phenyl ring, which always occurs simultaneously with the desulphurisation with Raney nickel, is to be considered undesirable. The reaction of a 2-halogenophenone with ethylenediamine has the disadvantage that only in the 1-position unsubstituted compounds are obtained, whereby, if 1-substituted derivatives are desired, a subsequent alkylation must take place, whereby the yield is reduced considerably. The reaction of a 2-amino-benzophenone with a p-acylamino-alkyl halide and subsequent hydrolysis of the protecting group finally has the disadvantage that the alkylation of the aniline nitrogen atom, in the case that 1-substituted compounds are desired, proceeds with very poor yields. The subsequent alkylation, as already mentioned, also significantly reduces the yield.

As said, the method according to the invention is carried out in the presence of a base and an inert organic solvent. The requirements set for the base consist exclusively in that it effects the conversion of a compound of formula II into the corresponding compound of formula I. Examples of such bases are lower alkali alkylates, such as sodium methoxide, potassium tertiary butoxide and the like, alkali hydrides, such as sodium hydride; aqueous alkali hydroxides, such as aqueous sodium hydroxide and aqueous potassium hydroxide and the like can also be used with advantage when X is arylsulfonyl or alkylsulfonyl. One or another commonly available inert organic solvent can be used in the conversion of compounds of formula II to the corresponding compounds of formula I. Examples include: dimethylformamide, dimethylsulfoxide, tetrahydrofuran and the like. Temperature and pressure are not critical factors in this transformation. However, it was determined that temperatures between approx. 0° and approx. 80°, suitable between approx. 25° and approx. 80° is advantageous, as they ensure high yields of the desired end product.

When a corresponding compound of formula I, where B denotes a carbonyl group, is prepared with one base from a compound of formula II, where B denotes a carbonyl group, it is established that a compound of formula appears as an intermediate product

where ^, R 2 and have the above meaning.

It can, with or without isolation from the reaction medium, where it is obtained, be transferred to the corresponding compound of formula I by treatment with a base.

From the foregoing it follows that one can react a compound of formula II, where B means a carbonyl group, with a base corresponding to the above indications in an inert organic solvent and interrupt the reaction after formation of a compound of formula III. This compound of formula III can then be reacted with a base, preferably in the presence of a polar solvent, such as water, a lower alkano1, e.g. ethanol or the like, as this base may be identical to the first base used or different from this, whereby a compound of formula I is finally obtained, where B means a carbonyl group. On the other hand, it is also possible to react a compound of formula II, where B is a carbonyl group, with a base until the compound of formula I is formed, without interrupting the reaction or isolating the intermediate product of formula III. These variations are explained in the examples. The isolation of a compound of formula III is achieved in a simple way, when an anhydrous medium is used as reaction medium.

The preparation of compounds of formula II can be effected by reacting a compound of the general formula

where B, , R2 and R^ have the above meaning,

with an arylsulfonyl halide, a lower alkylsulfonyl halide or an agent introducing a lower alkanoyl group. Examples of arylsulfonyl halides, which can be used for this purpose, are tosyl halides, such as p-toluenesulfonyl chloride and benzenesulfonyl chloride. Suitable lower alkylsulfonyl halides are

e.g. mesyl halides, such as methanesulfonyl chloride. Suitable agents which introduce lower alkanoyl groups are e.g. acetic anhydride, acetyl chloride and the like. Appropriately, arylsulfonyl halides and lower alkylsulfonyl halides are used for this preparation of compounds of formula II. Particularly preferred are tosyl chloride and mesyl chloride.

The preparation of compounds of formula II is conveniently carried out in the presence of an inert organic solvent, such as an alkanol, e.g. ethanol, methanol, an ether, such as diethyl ether or tetrahydrofuran, dimethylformamide, pyridine, a tertiary amine, such as tertiary butylamine or triethylamine and the like.

It is appropriate to provide an acid acceptor in the reaction environment to absorb the formed hydrochloric acid, which is formed when a halide is used as a reagent. Suitable acid acceptors are tertiary amines, pyridine and the like. In a preferred form of expansion, the acid acceptor is used in large excess, as it serves two purposes, firstly as a solvent and secondly as an acid acceptor. Also for this purpose, pyridine is preferred. Temperature and pressure are not critical in this • preparation of compounds with formula 11 $ expediently work at approx. room temperature or above.

The following examples illustrate the method according to the invention. All temperatures are given in degrees Celsius.

EXAMPLE 1

A solution of 3.0 g (0.007 mol) of 7-chloro-2,3,4,5-tetrahydro-1-methyl-5-phenyl-4-(p-toluenesulfonyl)-1H-1,4-benzodiazepine in 35 ml of dry N,N-dimethylformamide is treated with 0.3 g (0.008 mol) of a 60%{iq sodium hydride dispersion in a mineral oil. The reaction mixture is stirred at room temperature for 2 hours and then allowed to stand

for a grace period of 48 hours. The reaction mixture is poured into 100 ml of water and extracted twice each time with 75 ml of dichloromethane. The dichloromethane extracts are combined, washed three times each time with 200 ml of water and once with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The yellow oil formed is dissolved in 30 ml of absolute ethanol and treated with 1.2 ml of a 5.56-n solution of hydrogen chloride in ethanol. The ethanol is evaporated and the remaining oil is crystallized from a mixture of isopropanol and ether, whereby 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine hydrochloride is obtained in the form of yellow prisms with melting point 240 - 250°.

The starting material can be produced in the following way:

A solution of 14.0 g (0.051 mol) of 7-chloro-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine in 50 ml of pyridine is treated at reflux temperature with a solution of 11.7 g (0.0615 mol) of p-toluenesulfonyl chloride in 50 ml of pyridine (addition time 20 minutes) and then heated for 1.5 hours under reflux. The hot reaction mixture is poured into 500 ml of water, whereby a black oil separates. The water is decanted off, and the oil is dissolved in 200 ml of dichloromethane. The dichloromethane solution is washed three times each time with 400 ml of water and once with 100 ml saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated almost to dryness. Benzene is added and the solution is evaporated once more, whereby a dark oil is obtained. The remaining oil is dissolved in a small volume of benzene and filtered through a layer of Florisil, which has been moistened with hexane. A faint yellow solution is obtained after continued elution with benzene. The solution is then evaporated to an oil. After crystallization from ether/hexane, 7-chloro-2,3,4,5-tetrahydro-1-methyl-5-phenyl-4-(p-toluenesulfonyl)-1H-1,4-benzodiazepine is obtained in the form of white crystals with melting point 110 - 117°. After recrystallization from dichloromethane/hexane, the product melts at 127 - 130°.

EXAMPLE 2

A solution of 4.0 g (0.009 mol) 7-chloro-1,3,4,5-tetrahydro-1-methyl-5-phenyl-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine-2 -one in 35 ml of N,N-dimethylformamide is treated with 0.4 g (0.01 mol) of a 60% sodium hydride dispersion in a mineral oil. The reaction mixture thus obtained is allowed to stand for 55 hours at room temperature and then poured into 100 ml of water, which is then extracted with 100 ml of dichloromethane. The dichloromethane extract is washed three times each time with 100 ml of water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. The obtained oil is crystallized from acetone/hexane and gives 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one in the form of white prisms with a melting point of 127 - 130° .

The starting material can be produced in the following way:

A solution of 50.0 g (0.184 mol) of 7-chloro-1,3,4,5-tetrahydro-5-phenyl-2H-1,4-benzodiazepine-2-one in 100 ml of pyridine is heated under reflux. A hot solution of 42.0 g (0.22 mol) of p-toluenesulfonyl chloride in 100 ml of pyridine is added over 20 minutes to the reaction mixture. The reaction mixture is then heated for 1.5 hours under reflux and then poured into liters of water. Stir until a brown precipitate has formed. This is separated by filtration and washed four times each time with 500 ml of water, twice each time with 300 ml of ethanol and with 200 ml of ether. The precipitate is then recrystallized from a mixture of chloroform and ethanol, whereby 7-chloro-1,3,4,5-tetrahydro-5-phenyl-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine-2- on in the form of white prisms with a melting point of 244 - 250°. By recrystallization from chloroform/ethanol, white prisms with a melting point of 246 - 25 2° are obtained.

A solution of 10 g (0.0 234 mol) of 7-chloro-1,3,4,5-tetrahydro-5-phenyl-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine-2-one in 65 ml of N,N-dimethylformamide is treated with a solution of sodium methoxide in methanol (0.028 mol NaOCH^) at room temperature. The yellow solution obtained is stirred for 20 minutes, cooled to 5° and then treated with 2.9 ml (0.047 mol) of methyl iodide. The resulting reaction mixture is then stirred for 10 minutes at 5 - 10° and then for 1.5 hours at room temperature. The reaction mixture is then poured into 200 ml of water and extracted with 200 ml of dichloromethane. The dichloromethane is washed three times each time with 300 ml of water and with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. The yellow oil obtained is recrystallized from dichloromethane/ether to give 7-chloro-1,3,4,5-tetrahydro-1-methyl-5-phenyl-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine-2 -on in the form of white needles with a melting point of 260 - 262°.

EXAMPLE 3

A solution of 19.5 g (0.0456 mol) of 7-chloro-1,3,4,5-tetrahydro-5-phenyl-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine-2-one in 150 ml of dry benzene is treated with 4.0 g (0.10 mol) of a 60% sodium hydride dispersion in a mineral oil. The reaction mixture is heated for 20 hours under reflux and then poured into 300 ml of water. Hydrochloric acid is added until the pH value is approx. 7. The layers are separated and the aqueous layer is extracted twice each time with 1 liter of dichloromethane. The organic layers are combined, washed three times each time with 500 ml of water and with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The oil obtained is crystallized from a mixture of cyclochloromethane/hexane and gives 7-chloro-1,5-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one in the form of white

prisms with melting point 20 2 - 210°.

A solution of 0.5 g (0.002 mol) of 7-chloro-1,5-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one in 15 ml of N,N-dimethylformamide is treated with a solution of sodium methoxide in methanol (0.011 mol NaOCH^). The reaction mixture is allowed to stand for 1/2 hour at room temperature and is then poured into 50 ml of water. Salt is added

acid until the pH value reaches approx. 7 and then extracts the reaction mixture twice each time with 40 ml of dichloromethane. The combined dichloromethane extracts are washed three times each time with 60 ml of water and once with 30 ml of saturated sodium chloride solution, dried

kes over anhydrous sodium sulfate, filtered and evaporated to dryness. The remaining oil is crystallized from a mixture of dichloromethane and hexane and gives 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one in the form of white prisms with a melting point of 215 - 221°.

EXAMPLE 4

A solution of 5.0 g (0.0117 mol) of 7-chloro-1,3,4,5-tetrahydro-5-phenyl-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine-2-one in 35 ml of N,N-dimethylformamide is treated with 1.0 g (0.026 mol) of a

60% sodium hydride dispersion in a mineral oil. The brown solution is stirred for 1 hour at room temperature and then left to stand for 48 hours. The reaction mixture is then poured into 200 ml of water and extracted with 100 ml of dichloromethane. The dichloromethane extracts are washed three times each time with 500 ml of water and with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. The resulting oil is dissolved in dichloromethane, and the resulting solution is concentrated and cooled. The resulting concentrate is filtered and recrystallized from acetone, whereby 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one is obtained in the form of white pris-

more with melting point 212 - 214°.

EXAMPLE 5

A solution of 3.0 g (0.007 mol) of 7-chloro-1,3,4,5-tetrahydroT5-phenyl-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine-2-one in 35 ml of N ,N-dimethylformamide is cooled to 5° and treated with a solution of sodium methoxide in methanol (0.0154 mol NaOCH^). The reaction mixture is allowed to stand for 79 hours and then in 200 ml of water. The pH value is brought with hydrochloric acid to approx. 7 and then extract the solution with 100 ml of dichloromethane. The organic layer is separated and washed three times each time with 300 ml of water and with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulphate, filtered and evaporated to dryness. The obtained oil is crystallized from a mixture of dichloromethane and hexane and 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one is obtained in the form of white prisms with a melting point of 213 - 217° .

EXAMPLE 6

A solution of 3.0 g (0.007 mol) of 7-chloro-1,3,4,5-tetrahydro-5-phenyl-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine-2-one in 35 ml of N,N-dimethylformamide is cooled to 5° and treated with 1.7 g (0.0154 mol) of potassium tertiary butoxide, whereby the solution becomes deep yellow. The reaction mixture is stirred for 1.5 hours at 5°, then allowed to warm to room temperature and allowed to stand for 79 hours. The reaction mixture is then poured into 200 ml of water and brought to a pH value of approx. 7. The solution is then extracted with 100 ml of dichloromethane. The dichloromethane layer is separated and washed four times each time with 300 ml of water and with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The obtained oil is crystallized from a mixture of dichloromethane and hexane, whereby 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one is obtained in the form of white prisms with a melting point of 212 - 216°.

EXAMPLE 7

A solution of 2.0 g (0.0047 mol) of 7-chloro-1,3,4,5-tetrahydro-5-phenyl-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine-2-one in 30 ml of N,N-dimethylformamide is treated with 0.5 ml of a 0.1-n sodium hydroxide solution. The mixture is stirred for 4 hours at room temperature and then allowed to stand for 55 hours. The reaction mixture is poured into 100 ml of water and the pH value is brought to approx. 7 with hydrochloric acid. The solution obtained is then extracted three times each time with 50 ml of dichloromethane. The combined dichloromethane extracts are washed three times each time with 200 ml of water and with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The oil obtained is crystallized from a mixture of dichloromethane and hexane. It is then recrystallized twice from acetone and 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one is obtained in the form of white prisms with a melting point of 211 - 214°.

EXAMPLE 8

A solution of 5.0 g (0.117 mol) of 7-chloro-1,3,4,5-tetrahydro-5-phenyl-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine-2-one in 40 ml of tetrahydrofuran is treated with 1.0 g (0.0258 mol) of a 60% dispersion of sodium hydride in a mineral oil. The reaction mixture is stirred first at room temperature and then for 5 hours at 60°. The reaction mixture is poured into 200 ml of water and extracted with 100 ml of dichloromethane. The dichloromethane extracts are washed three times each time with 300 ml of water and with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulphate, filtered and evaporated to dryness. The oil obtained is crystallized from dichloromethane and gives 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one in the form of white prisms with a melting point of 210 - 214°.

EXAMPLE 9

A solution of 5.0 g (0.0117 mol) of 7-chloro-1,3,4,5-tetrahydro-5-phenyl-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine-2-one in 40 ml of dimethyl sulfoxide is treated with 1.0 g (0.0258 mol) of a 60% dispersion of sodium hydride in a mineral oil. The reaction mixture is stirred for 1 hour at room temperature and then allowed to stand for 40 hours, whereby the solution becomes amber colored. The reaction mixture is then poured into 150 ml of water and extracted with 100 ml of dichloromethane. The dichloromethane extract is washed three times each time with 300 ml of water and with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulphate, filtered and evaporated to dryness.

The obtained oil is crystallized from a mixture of dichloromethane and hexane, whereby 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one is obtained in the form of white prisms with a melting point of 210 - 214 °.

EXAMPLE 10

A solution of 3.0 g (0.0086 mol) of 7-chloro-1,3,4,5-tetrahydro-4-methanesulfonyl-5-phenyl-2H-1,4-benzodiazepine-2-one in 30 ml of N ,N-dimethylformamide is treated with 0.76 g (0.019 mol) of a 60% sodium hydride dispersion in a mineral oil. The reaction mixture is stirred for 2 hours at room temperature and then for 4 hours at 45°. After cooling to room temperature, the reaction mixture is poured into 200 ml of water and the pH value is adjusted to approx. 7 with hydrochloric acid. The resulting mixture is extracted twice each time with 75 ml of dichloromethane. The combined dichloromethane extracts are washed three times each time with 300 ml of water and with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The oil obtained is crystallized from a mixture of dichloromethane and hexane. The mother liquors are evaporated to dryness and crystallized from a mixture of dichloromethane and hexane, whereby 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine is obtained -2-one in the form of white prisms with a melting point of 210 - 214°.

The starting material can be produced in the following way:

A suspension of 50 g (0.183 mol) of 7-chloro-1,3,4,5-tetrahydro-5-phenyl-2H-1,4-benzodiazepine-2-one in 380 ml of pyridine is cooled to 5° and treated with 15 .6 ml (0.201 mol) of methanesulfonyl chloride for 15 minutes. The clear yellow solution is heated to 28° and then stirred at room temperature for 2.5 hours. The reaction mixture is then poured into 1.3 liters of water and stirred vigorously. The crystalline precipitate is filtered off and washed four times each time with 300 ml of water and twice each time with 200 ml of ether. By recrystallization of the reaction product from a mixture of chloroform and ethanol, 7-chloro-1,3,4,5-tetrahydro-4-methanesulfonyl-5-phenyl-2H-1,4-benzodiazepine-2-one is obtained as white prisms with melting point 203 - 206°.

EXAMPLE 11

A solution of 3.0 g (0.0068 mol) of 7-chloro-1,3,4,5-tetrahydro-5-(2-fluorophenyl)-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine -2-one in 35 ml of N,N-dimethylformamide is treated with 0.6 g (0.015 mol) of a 60% sodium hydride dispersion in a mineral oil and stirred for 19 hours at room temperature. The reaction mixture is then poured into 200 ml of water and the pH is adjusted to approx. 7 with hydrochloric acid. The reaction mixture is then extracted twice with 75 ml of dichloromethane. The combined dichloromethane extracts are washed four times each time with 600 ml of water and with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The remaining yellow oil is crystallized from a mixture of dichloromethane and hexane. The mother liquors are then evaporated to dryness and crystallized from a mixture of benzene and hexane, whereby 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-one is obtained in form of white prisms with melting point 196 - 20 2°.

The starting material can be produced in the following way:

A solution of 10.0 g (0.034 mol) of 7-chloro-1,3,4,5-tetrahydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-one in 100 ml of pyridine is treated with a solution of 9.5 g (0.051 mol) of p-toluenesulfonyl chloride in 50 ml of pyridine. The reaction mixture is heated for 2 hours under reflux and then poured into 750 ml of water. After stirring for 1/2 hour, an oily sediment separates. The crystals are filtered off and dissolved in a large amount of dichloromethane, which is dried over anhydrous sodium sulfate, filtered and then concentrated on a steam bath to a small volume. The obtained solution is cooled. 7-chloro-1,3,4,5-tetrahydro-5-(2-fluorophenyl)-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine-2-one is obtained, which is filtered off. After recrystallization from a mixture of dichloromethane/petroleum ether (boiling range 30 - 60°), the product crystallizes in the form of white prisms with a melting point of 242 - 243°.

EXAMPLE 12

To a solution of 1 g (3.3 mmol) of 7-chloro-1,2,3,5-tetrahydro-1-methyl-5-phenyl-4H-1,4-benzodiazepine-4-carboxaldehyde in 25 ml of N, 300 mg of sodium hydride (7.5 mmol of a 60% suspension in a mineral oil) is added to N-dimethylformamide. The reaction mixture is stirred under nitrogen for 90 minutes and then poured onto ice. After melting the ice, the precipitate obtained is separated and suspended in a l-n acetic acid solution. The mixture is filtered off, and the filtrate is made alkaline with dilute caustic soda, whereby crude 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine hydrochloride is obtained in the form of an oil, which by extraction is recovered with ether. For further purification, the extract is filtered from a benzene solution through 10 g of aluminum oxide (activity III neutral). The filtrate is evaporated and a gum-like product is obtained, which is treated with methanolic hydrochloric acid and ether, whereby 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine hydrochloride is obtained. On recrystallization of the hydrochloride from methanol/ether, orange-coloured crystals with a melting point of 256 - 257° (closed stirrer) are obtained.

The starting material can be produced in the following way:

A mixture of 63.8 g (0.5 mol) p-chloroaniline and 114 g (0.6 mol) p-toluenesulfonyl chloride in 400 ml pyridine is stirred at room temperature overnight. Most of the pyridine is then removed under vacuum and the remainder is poured into 2 liters of ice water and the distillate is extracted with ether. The ether is extracted with 1-1 sodium hydroxide solution, aqueous hydrochloric acid and water, dried over magnesium sulphate and concentrated. The oil obtained is recrystallized from ether and gives tosylamido-4-chlorobenzene with a melting point of 119.5-120.5.

A mixture of 70.4 g (0.25 mol) tosylamido-4-chlorobenzene,

700 ml of toluene and 0.3 mol of sodium methoxide in 200 ml of methanol are stirred and heated for 1 hour under reflux. The main amount of methanol is distilled off and 47.3 ml (0.5 mol) of dimethylsulphate is added. Stirring and heating during reflux are continued for a further 5 hours. The secreted sodium salt dissolves slowly. Excess dimethyl sulfate is decomposed by heating under reflux for 1.5 hours with 400 ml of 3-n sodium hydroxide solution. The phases are separated and the toluene is distilled off, whereby a white crystalline precipitate remains. By recrystallization from ethanol, N-methyl-tosylamido-4-chloro-benzene is obtained with a melting point of 92 - 93°.

61.5 g (0.208 mol) of N-methyl-tosylamido-4-chlorobenzene are added to 580 ml of sulfuric acid (specific gravity 1.74) at 105°. The reaction mixture is stirred, heated to 145° and kept at this temperature for 1 hour. After cooling, the solution is made strongly alkaline with 50% caustic soda, and the organic base is extracted with ether. The organic extracts are dried over potassium hydroxide granules, concentrated and the residue is distilled in vacuum, whereby p-chloro-N-methylaniline with boiling point 74 - 75<0> at 0.7 Torr is obtained.

In a 50 ml wooden-necked flask, which is equipped with reflux skirts, dropping funnel and stirrer, to 13.3 g of aluminum chloride and 20 ml of dry benzene, 14.1 g (0.1 mol) of p-chloro-N-methylaniline is carefully added dropwise while stirring. After complete addition, the reaction mixture is heated until it begins to reflux and is kept for a short period at this temperature. Freshly distilled ethyleneimine (4.3 g, 0.1 mol) is then slowly distilled into the reaction vessel. After complete addition, the reaction mixture is further stirred for 30 minutes and then poured into 200 g of ice, which is in a 1 liter flask fitted with a reflux condenser. 50 g of solid potassium hydroxide is then added in small portions to the solid product obtained, whereby it is observed that the material dissolves. It is then cooled and extracted three times with benzene. The combined benzene extracts are dried over potassium hydroxide granules and concentrated. The residue is distilled in vacuum through a 10 cm Vigreux column, whereby N-(p-chlorophenyl)-N-methyl-ethylenediamine with a boiling point of 126 - 127° at 0.05 Torr is obtained.

100 ml of 98% formic acid is carefully added while stirring and while cooling in an ice bath to 70 g (0.4 mol) of N-(p-chloro-phenyl)-N-methyl-ethylenediamine. The resulting reaction mixture is allowed to warm to 25° and then 40 g (0.375 mol) benzaldehyde is added. The resulting mixture is heated for 17 hours to 95°. After cooling, the reaction mixture is slowly added to a stirred mixture of ice, 3-n sodium hydroxide solution and ether. The alkaline aqueous layer is separated, extracted a further three times each time with 100 ml of ether and discarded.

The combined ether extracts are washed with water, dried over magnesium sulphate and evaporated. An oil is obtained, which is dissolved in a mixture of 500 ml of n-hydrochloric acid and 250 ml of ether. The ether layer is separated and the aqueous acidic layer is extracted once more with 250 ml each of ether twice. The combined ether extracts are washed with saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated. Crystallization of the residue from isopropanol yields 7-chloro-1,3,4,5-tetrahydro-1-methyl-5-phenyl-4H-1,4-benzodiazepine-4-carboxaldehyde in two yields of crystals melting at 114 - 115° and at 120 - 121°. By recrystallization of the combined crystals from hexane, cream-coloured prisms with a melting point of 121 - 122° are obtained.

EXAMPLE 13

A solution of 1 g (0.00318 mol) 4-acetyl-7-chloro-2,3,4,5-tetrahydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine in 25 ml torr N, N-dimethylformamide under nitrogen is treated with 0.14 g

(0.00349 mol) of a 56.9% sodium hydride dispersion in a mineral oil. The reaction mixture is allowed to stand for 60 hours. It is then stirred for 5 hours at 40 - 45° and the solvent is removed under reduced pressure. The residue is dissolved in 50 ml of ether and extracted twice each time with 40 ml of 1-n hydrochloric acid. The acidic layers are combined, made basic with aluminum hydroxide and extracted with 100 ml of dichloromethane. The organic layer is washed with 50 ml of a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. The oil obtained is dissolved in dichloromethane, filtered over 75 g of silica gel and eluted with 400 ml of dichloromethane and 500 ml of ethyl acetate. Excess ethanolic hydrochloric acid is added to the ethyl acetate fraction, after which it is evaporated to dryness. The reaction product is recrystallized twice from isopropanol/ether and gives 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine hydrochloride in the form of orange-colored prisms with a melting point of 250 - 254° (closed rudder).

The starting material can be produced in the following way:

To a solution of 69 g (0.25 mol) of crude 7-chloro-2,3,4,5-tetra hydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine in 200 ml of pyridine 125 ml of acetic anhydride is added. The reaction mixture stand for 15 minutes at room temperature and heat then in a steam bath for 35 minutes. Then you concentrate in vacuum to dryness. The residue is dissolved in a mixture of ether and ice-cold dilute hydrochloric acid. The ether layer is separated, washed with water and diluted ice-cold caustic soda, dried and evaporated in vacuum to dryness. The residue is crystallized into the mixture of ether and petroleum ether and gives 4-acetyl-7-chloro-2,3,4,5-tetrahydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine with melting point 106 - 108°.

Claims (1)

Process for the preparation of benzodiazepine derivatives with the general formula where B means carbonyl or methylene, R^halogen, R2hydrogen or lower alkyl and R^hydrogen or halogen, characterized by treating a for bond with the general formula where B, , R 2 and R 3 have the meanings given above and X means arylsulfonyl, lower alkylsulfonyl or lower alkanoyl, with a base in the presence of an inert organic solvent.