DE1695223A1 - Process for the preparation of benzodiazepine derivatives - Google Patents

Description

RAH 4008/109

F. HofFmann-La Roche & Co. Aktiengesellschaft, Basel / Switzerland

Process for the preparation of Benzodlazepln-Derlvaten

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

(D

wherein A is phenyl, pyridyl or halophenyl, B carbonyl or Γ-'ethylene, R and R, hydrogen, halogen, preferably

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as chlorine or bromine, nitro or trifluoromethyl, R _{2 is} hydrogen, lower alkyl or lower alkenyl and FU is hydrogen or lower alkyl.

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

In a preferred embodiment of the method erfindungsge- W extent provides compounds of the above general formula I here, wherein R is hydrogen and R is connected to the 7-position of Benzodiazepinkemes. If A represents a pyridyl group, it is advantageously linked to the benzodlaze pink nucleus in the 2-position. If A represents a halophenyl group, the halogen atom is advantageously bonded to the 2-position of the phenyl radical. In a particularly advantageous embodiment, R and R are each hydrogen, R _{p is} hydrogen or lower alkyl, R. is halogen, conveniently chlorine or bromine, this halogen atom in the 7-position

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BAD OWG'iNAL

■ - 3 -

of the benzodiazepine ring, and A is phenyl.

The inventive method consists in that one compound of the general formula

(II)

wherein A, B, R, R ,, R ₂ and R, have the above meaning and X is an arylsulfonyl, lower alkylsulfonyl or a lower alkanoyl group,

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

As stated, the process according to the invention is carried out in the presence of a base and an inert organic solvent. The requirements that are placed on the base consist only in the fact that it brings about the conversion of a compound of the formula II into the corresponding compound of the formula I. Examples of such bases are lower alkali metal 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

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bath

The like. Can also be used to advantage if X is arylsulfonyl or alkylsulfonyl. Any commonly available inert organic solvent can be used in the conversion of compounds of the formula II into the corresponding compounds of formula I can be used. Examples include: dimethylformamide, dimethyl sulfoxide, tetrahydrofuran and the like. Temperature and pressure are not critical factors in this conversion. However, it was found that temperatures between about 0 ° and about 80 °, expediently between about 25 ° and about 80 °, are advantageous because they are high Ensure yields of the desired end product.

If from a compound of the formula II in which 3 is a carbonyl group, with a 3ase a corresponding Compound of the formula I, in which 3 is a carbonyl group, it has been found that the intermediate is a Compound of formula

(III)

wherein A, R, R ₁ , Rp and R, have the above meaning, occurs. It can be with or without isolation from the. Reaction medium, in which it was poured, converted into the corresponding compound of the formula I by treatment with a base

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BATH ORIGINAL

From the above it follows that a compound of the formula II, wherein B is a carbonyl group, with a React base according to the above information in an inert organic solvent and the reaction after formation a compound of formula III can interrupt. This compound of the formula III can then further with a base, preferably in the presence of a polar solvent such as water,

a lower alkanol, e.g. ethanol or the like be, this base can be identical to or different from the base used first, where one finally a compound of the formula I in which B is a carbonyl group is obtained. On the other hand, it is also possible a compound of formula II wherein B is a carbonyl group with a base until the compound of formula I is formed to implement without interrupting the reaction or isolating the., Intermediate of the formula III. These variations are explained in the examples. The isolation of a compound of the formula III can be achieved in a simple manner if one anhydrous medium is used as the reaction medium.

Compounds of the formula II can be prepared by reacting a compound of the general formula

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(IV)

where A, B, R, R ,, Rp and R, have the above meaning

P with an aryl sulfonyl halide, a lower alkyl sulfonyl halide or a lower alkanoyl group introducing agent. Examples of arylsulfonyl halides, which can be used for this purpose are Tosjjrlhalogenide, such as p-toluenesulfonyl chloride and benzenesulfonyl chloride. Suitable lower alkyl sulfonyl halides are e.g. Mesyl halides such as methanesulfonyl chloride. Suitable lower Alkanoyl group-introducing agents are, for example, acetic anhydride, acetyl chloride and the like "Preparation of compounds of the formula II arylsulfonyl halides and use lower alkyl sulfonyl halides. Especially preferred are tosyl chloride and mesyl chloride.

The preparation of compounds of formula II is expedient in the presence of an inert organic solvent such as an alkanol, e.g. ethanol, methanol, a Ethers such as diethyl ether or tetrahydrofuran, dimethylformamide, Pyridine, a tertiary amine ,, such as tertiary butylamine or

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Triethylamine and the like. Performed. It is useful to have one Provide acid acceptor in the reaction medium in order to absorb the hydrochloric acid formed, which is when used of a halide as a reagent. Suitable acid acceptors are tertiary amines, pyridine and the like. In one preferred embodiment, the acid acceptor is used in large excess, serving two purposes, one as a solvent and the other as an acid acceptor. Also for pyridine is preferred for this purpose. Temperature and pressure are not critical in this preparation of compounds of the Formula II; it is expedient to work at about room temperature or above.

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

example 1

A solution of 3.0 g (0.007 col) of 7-chloro-2,3,4,5-tetrahydro-1-methyl-S-phenyl-Jl-fc-toluenesulf onyl) -IH-1,4-benzodiazepine in 35 ml of dry Ν, Ν-dimethylformamide treated with 0.3 g (0.008 mol) of a 6o strength sodium hydride dispersion in a mineral oil. The reaction mixture is at Stirred at room temperature for 2 hours and then left to stand for 48 hours. The reaction mixture is in 100 ml of water poured and extracted 2 times with 75 ml of dichloromethane each time. the

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Dichloromethane extracts are combined, washed 3 times with 200 ml of water each time 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 -JO 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, 7-chloro- ψ 2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzadiazepiri-hydrochlQri & in the form of yellow prisms from the melting point. 240-250 °.

The starting material can be produced as follows:

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 at reflux temperature with a solution 11.7 g (0,06l5 koi) of p-toluenesulfonyl chloride in 50 ml of pyridine (Dosage W 20 minutes), and then heated to reflux for 1.5 hours. The hot reaction mixture is poured into 500 ml of water, a black oil separating out. The water is decanted off and the oil is dissolved in 200 ml of dichloromethane. The dichloromethane solution is washed 3 times with 400 ml of water each time and once with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to almost dryness. Benzene is added and the solution is evaporated again, a dark oil being obtained. The remaining OeI

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BATH ORIGINAL

is dissolved in a small volume from the benzene and replaced by a See Plorisil, filtered, which is moistened with hexane has .. A pale yellow solution is obtained after continuing line with benzene * The solution is then evaporated to an oil. After crystallization from ether / tiexane, 7-chloro-2 is obtained jj5 * 4,5-tsrtrahydro-1-methyl-5-phßnyl-4. (p-toluenesulfonyl) -IH-l * 4-benj & oäl «azepln iaa. "Farm of white crystals from the melting point 110-117 °. Nacto the recrystallization from dichloromethane / ^ Hexane sctaüxts the product at 127-110 °.

Example 2

A solution of 4.0 g (0.009 mol) of 7-chloro-1,3,4,5-tetrahydro-1-methyl-S-phenyl ^ - (ptoluolsulf any I) -2H-1,4-benzodiazepine-2 -one in 35 ml Ν, Ν-dimethylformamide is treated with 0.4 g (0.01 mol) of a 60 # strength sodium hydride dispersion in a mineral oil. The reaction mixture obtained in this way is left 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 J times with 100 ml of water and with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. The oil obtained is crystallized from acetone / hexane and gives 7-chloro, 3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one in the form of white prisms with a melting point of 127-150 °.

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The starting material can be produced as follows:

A solution of 50.0 g (0.184 mol) of 7-chloro-1,3,4,5-tetrahydro-5-phenyl-2H-1,4-benzodiazepin-2 ~ one in 100 ml of pyridine is heated to reflux. A warm solution of 42.0 g (0.22 mol) p-toluenesulfonyl chloride in 100 ml of pyridine is im Added to the reaction mixture over 20 minutes. The reaction mixture is then refluxed for 1.5 hours

P and then poured into 1 liter v / ater. One stirs until a brown precipitate has formed. This is separated off by filtration and 4 times with 500 ml of water each time, and 2 times with 500 ml each of ethanol and washed with 200 ml of ether. The precipitation is then recrystallized from a mixture of chloroform and ethanol, 7-chloro-l, j5,4,5-tetrahydro ~ 5-phenyl-4- (p-toluenesulfonyl) -2H-1,4-benzodiazepin-2-one in Obtains the shape of white prisms with a melting point of 244-250 °. Recrystallization from chloroform / ethanol is obtained

"white prisms with a melting point of 246-252 °.

A solution of 10 g (0.0234 moles) of 7-chloro-1,3,4,5-tetrahydro-5-phenyl-4- (p-toluenesulf onyl) -2H-l, 4-benzodiazepin-2-one in 65 ml Ν, Ν-dimethylformamide is mixed with a solution of sodium methoxide treated 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 10 minutes at 5-10 ° and then for 1.5 hours at room

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BATH ORIGINAL

temperature stirred. The reaction mixture is then poured into 200 ml of water and extracted with 200 ml of dichloromethane. The dichloromethane is washed 3 times with 500 ml v / water each time and with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. The yellow oil obtained is recrystallized from dichloromethane / ether and yields
7-chloro-l, 3,4,5-tetrahydro-l-diethyl-5-phenyl-4- (p-toluenesulfonyl) -2H-1,4-benzodiazepin-2-one in the form of white needles from
Melting point 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) -2R-1,4-benzodlazepin-£ - one in 150 ml of dry benzene is 4.0 g (0.10 mol) of one
60 # sodium hydride dispersion treated in a mineral oil. The reaction mixture is refluxed for 20 hours
and then poured into 300 ml of water. Hydrochloric acid is added until the pH is about 7. The layers are separated and the aqueous layer 2 times with 1 each
Liter of dichloromethane extracted. The organic layers are combined, washed 3 times with 500 ml of water each time 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 / hexane and gives 7-chloro-l, 5-dihydro-5-phenyl-2H-l, 4-benzo-

diazepin-2-one in the form of white prisms with a melting point of 202-210?

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BATH ORIGINAL

A solution of 0.5 g (0.002 mol) 7-chloro-1,5-dihydro-5-phenyl-2H-1,4-benzQdiazepin-2-one in 15 ml Ν, Ν-dimethylformamide is mixed with a solution of sodium methoxide in methanol (G, QIl. Mol NaOCH-) treated. The reaction mixture becomes free for 1/2 hour Let room temperature stefaen and then poured into 50 ml of water. Hydrochloric acid is added until the pH value is reached has reached about 7 and then extracts the reaction crack

2 times with 40 ml di chloromethane each time. They united you! poor ethan— Extracts are mixed 3 times with 60 ml of water each and 1 time with 30 ml saturated brine, washed over anhydrous sodium sulfate dried, filtered and evaporated to dryness. That Remaining oil is crystallized from a mixture of dichloromethane and hexane and gives 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-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-benzodiazep'ine -2-on in 35 ml of N, N-dimethylformamide, 1.0 g (0.026 mol) treated a 60 # strength sodium hydride dispersion in a mineral oil. The brown colored 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 100 ml Dichloromethane extracted. The dichloromethane extracts are

3 times with 500 ml of water each and with 100 ml of saturated sodium chloride

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solution washed, dried over anhydrous sodium sulfate and evaporated to dryness. The oil obtained is dissolved in diehlomethane and the solution obtained is concentrated and cooled. The concentrate obtained is filtered and recrystallized from acetone, giving 7-chloro-1,3-aihydro-5-phenyl-2H-1 _J 4-benzodiazep ± n-2 ~ one in the form of white prisms with a melting point of 212-214 » ,

Example 5

A solution of 30 g (Q. 007 mol) 7-chloro-1,4,5-tetrahydro-5-phenyl-4- (p-toluenesulfonyl) -2H-1,4-benzodiazepin-2-one in 55 ml Ν, Ν-dimethylformamide is cooled to 5 ° and with a Solution of sodium methoxide in methanol (0.0154 mol NaOCH,) treated. The reaction mixture is left to stand for 79 hours then pour into 200 ml of water. The pH is brought to about 7 with hydrochloric acid and the solution is then extracted with 100 ml dichloromethane. The organic layer is separated and 3 times with 300 ml of water each time and with 100 ml of saturated water Washed brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The received OeI is crystallized from a mixture of dichloromethane and hexane and 7-chloro-1,5-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one is obtained in the form of white prisms with a melting point of 213-217 °.

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Example 6

A solution of 3.0 g (0.007 moles) of 7-chloro-1,3,4,5-tetrahydro-5-phenyl-4- (p-toluenesulf onyl) -2H-1,4-benzodiazepin-2-one in 35 ml of N, N-dimethylformamide is cooled to 5 ° and with 1 * 7 S (0.0154 mol) potassium tertiary butoxide treated, whereby the Solution turns deep yellow. The reaction mixture is stirred at 5 ° for 1.5 hours and then allowed to warm to room temperature 79 hours standing. The reaction mixture is then poured into 200 ml of water and made up with hydrochloric acid brought a pH of about 7. The solution is then extracted with 100 ml of dichloromethane. The dichloromethane layer will separated and 4 times with JOO ml of water and with 100 ml of saturated Washed brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. That The oil obtained is crystallized from a mixture of dichloromethane and hexane, 7-chloro-l, 3-dihydro-5-phenyl-r 2H-1,4-benzodiazepin-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 moles) of 7-chloro-1,3,4,5-tetrahydro-5-phenyl-4- (p-toluenesulf onyl) -2H-1, 4-benzodiazepin-2-one in 30 ml of N, N-dimethylformamide is mixed with 0.5 ml of a 0.1-n Sodium hydroxide solution treated. The mixture is 4 hours

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stirred at room temperature and then left to stand for 55 hours. The reaction mixture is poured into 100 ml of water and the pH is brought to about 7 with hydrochloric acid. The received The solution is then extracted 3 times with 50 ml of dichloromethane each time. The combined dichloromethane extracts are 3 times with 200 ml of water each and with 100 ml of saturated saline solution washed, dried over anhydrous sodium sulfate, filtered evaporated to dryness. The oil obtained is crystallized from a mixture of dichloromethane and hexane. Then it is recrystallized twice from acetone and 7-chloro-1,5-dihydro-5-phenyl-2H ~ 1,4-benzodiazepin-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-S-phenyl- ^ - (p-toluenesulfonyl) -2H-1,4-benzodiazepin-2-one in 40 ml of tetrahydrofuran is treated with 1.0 g (0.0258 mol) of a 60 # strength 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 will Poured into 200 ml of water and extracted with 100 ml. dichloromethane. The dichloromethane extracts are washed 3 times with 300 ml of water each time and with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The oil obtained is made from dichloromethane

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- Eat -

16 9-223-

crystallizes and delivers. 7-Chior> 1,3-dihydr. A-5 ~ phenyL-2H-1,4-benzodiazepin-2-one in the form of white prisms from the melting point 210-214 °.

Example 9

A last of. 5.0 g (0 * 0) 117 mole) of 7-chloro - l, 3% _{i-5 i-tetr} ahydr 0-5 -phenyl-4- (ρ -toltiolstilfbny 1) -2H-I * 4-. bensodiazepine-2— ση in 40 ml of dimethylsulfoxyu is treated with 1.0 g (0.0258 mol) of an ÖÖ ^ igen dispersion of sodium hydride in a mineral oil. The reaction mixture is stirred for 1 hour at room temperature and then left to stand for 40 hours, the solution turning amber. The reaction mixture is then poured into 150 ml of water and extracted with 100 ml of dichloromethane. The dichloromethane extract is washed 5 times with 600 ml of water each time 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, 7-chloro-l, j5-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one in the form of white prisms with a melting point of 210-214 ° receives.

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-benzodiazepin-2-one in JiO ml of N, N-dimethylformamide is 0.76 g (0.019 mol) of a

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ORIGINAL INSPECTED

60 # sodium hydride dispersion in a mineral oil, heat treated. The reaction mixture is 2 hours at room temperature and then stirred 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 about 7 with hydrochloric acid set. The mixture obtained is 2 times with 75 ml each Dichloromethane extracted. The combined dichloromethane extracts are saturated 3 times with 300 ml of water and with 100 ml Washed with brine, 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, where T-chlorine-l ^ -dihydro-S-phenyl ^ H-l ^ -benzodiazepine - ^ - on in the form of white prisms with a melting point of 210-214 °.

The starting material can be produced as follows:

A suspension of 50 g (0.183 mol) of 7-chloro-1,3,4,5-tetrahydro-5-phenyl-2H-1,4-benzodlazepin-2-one in 380 ml of pyridine is cooled to 5 ° and with 15.6 ml (0.201 mol) of methanesulfonyl chloride treated for 15 minutes. The clear yellow solution is warmed to 20 ° and then at room temperature for 2.5 hours touched. The reaction mixture is then poured into 1.3 liters of water and stirred vigorously. The crystalline low

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blow is filtered off and 4 times with 300 ml of water each time and washed 2 times with 200 ml of ether each time. By recrystallization the reaction product from a mixture of chloroform and ethanol is obtained T-chloro-liJi ^ iS-tetrahydro ^ -methanesulfonyl-5-phenyl-2H-1,4-benzodiazepln-2-one as white prisms with a melting point of 205-206 °.

Example 11

A solution of 5.0 g (0.0068 mol) of 7-chloro-1,5,4,5-tetrahydro-5- (2-f luophenyl) -4- (p-toluenesulfonyl) -2H-1,4-benzodiazepin-2-one in 55 ml of N, N-Dimethy 1 formamide is added 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 about with hydrochloric acid 7 set. The reaction mixture is then extracted twice with 75 ml dichloromethane. The combined dichloromethane extracts are washed 4 times with 600 ml of water and with 100 ml of saturated sodium chloride solution, over anhydrous Dried sodium sulfate, filtered and evaporated to dryness. The remaining yellow oil becomes from a mixture crystallized from dichloromethane and hexane. The mother liquors are then evaporated to dryness and made from a mixture crystallized from benzene and hexane, 7-chloro-l, 5-dihydro-5- (2-fluorophenyl) -2H-l, 4-benzodiazepin-2-one in shape

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obtained from white prisms with a melting point of 196-202 °.

The starting material can be produced as follows:

A solution of 10.0 g (0.034 mol) of 7-chloro-1,3,4,5-tetrahydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one in 100 ml of pyridine is treated with a solution of 9.5 g (0.051 mol) of p-toluenesulfonyl chloride treated in 50 ml of pyridine. The reaction mixture is heated to reflux for 2 hours and then in Poured 750 ml of water. After stirring for 1/2 hour, an oily precipitate separates out. The crystals will be filtered off and dissolved in a large amount of dichloromethane, dried over anhydrous sodium sulfate, filtered and then concentrated to a small volume on a steam bath. The resulting solution is cooled. 7-chloro-1,3,4,5-tetrahydro-5- (2-fluorophenyl) -4- (p-toluenesulfonyl) -2H-1,4-benzodiazepin-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 nmoles) of 7-chloro-1,2,3,5-tetrahydro-1-methyl-5-phenyl-4H-1,4-benzodiazepine-4-carboxaldehyde 300 mg of sodium hydride are placed in 25 ml of Ν, Ν-dimethylformamide

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(7 * 5 mmol of a 60 # strength suspension in a mineral oil). the The reaction mixture is stirred for 90 minutes under nitrogen and then poured onto ice. After the ice has melted, the obtained precipitate separated and in a 1 N acetic acid solution on slurried. The mixture is filtered off and the filtrate made alkaline with dilute sodium hydroxide solution, whereby one. crude 7-chloro-2,5-dihydro-1-methyl-5-phenyl-1H-1,4-benzo-diazepine hydrochloride in the form of an oil obtained by extraction with ether. For further cleaning, a The benzene solution of the extract is filtered through 10 g of aluminum oxide (activity III neutral). The filtrate is evaporated and obtained a gummy product which is treated with methanolic hydrochloric acid and ether, 7-chloro-2, ^ - dihydro-1methyl-S-phenyl-1H-1 ^ -benzodiazepine hydrochloride receives. By recrystallizing the hydrochloride from methanol / ether, orange-colored crystals with a melting point of 256-257 ° (closed Tube).

The starting material can be produced as follows:

A mixture of 63.8 g (0.5 mol) of p-chloroaniline and 114 g (0.6 mol) of p-toluenesulfonyl chloride in 400 ml of pyridine is stirred at room temperature overnight. Most of the pyridine is then removed in vacuo and the residue is poured into 2 liters Ice water and extracted the distillate with ether. The ether is with 1N sodium hydroxide solution, aqueous hydrochloric acid and

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Extracted water, dried over magnesium sulfate 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) of tosylamido-4-chlorobenzene, 700 ml of toluene and 0.3 mol of sodium methoxide in 200 ml of methanol is stirred and refluxed for 1 hour. Is distilled from the main amount of the methanol and treated with a 47.3 ml (0.5 mol) of dimethyl sulfate. Stirring and refluxing are continued for an additional 5 hours. The precipitated sodium salt slowly dissolves. Excess dimethyl sulfate is destroyed by heating to reflux for 1.5 hours with 400 ml of 5N sodium hydroxide solution. The phases are separated and the toluene is distilled off, a white crystalline precipitate remaining. Recrystallization from ethanol gives N-methyl-tosylamido-4-chlorobenzene with a melting point of 92-93 °

61 * 5 g (0.208 mol) of N-methyl-tosylamido-4-chlorobenzene are converted to 58O ml of sulfuric acid (specific weight 1.74) at 105? set ^to ". The reaction mixture is stirred, heated to 145 ° and held for 1 hour at this temperature. After cooling, the solution of 50 $ aqueous sodium hydroxide solution is made strongly alkaline and extracted the organic base with ether. The organic extracts are Kaliumhydroxyd- Granules · dried, concentrated and the residue distilled in vacuo, whereby

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one p-chloro-N-methylaniline boiling point 74-75 ° at 0.7 Torr. receives.

In a 50 ml three-necked flask equipped with a reflux condenser> Dropping funnel and stirrer are fitted too 13 * 3 g of aluminum chloride and 20 ml of dry benzene, 14.1 g (0.1 mol) of p-chloro-N-methylaniline, carefully added while stirring

fe is dripping. When the addition is complete, the reaction mixture becomes heated to the beginning of reflux and held at this temperature for a short period. It is then freshly distilled Slowly pour distilled ethyleneimine (4.3 g> 0.1 mol) into the reaction vessel a. When the addition is complete, the reaction mixture becomes Stirred for another 30 minutes and then in 200 g of ice! poured into a 1 liter flask with a Reflux condenser is located. The solid product obtained is then mixed in small portions with 50 g of solid potassium hydroxide,

ψ observing that the material goes into solution. It is then cooled and extracted 3 times with benzene. The combined benzene extracts are dried over granules of potassium hydroxide and concentrated. The residue is distilled in vacuo through a 10 cm Vigreux column, giving N- (p-chlorophenyl) -N-methyl-ethylenediamine with a boiling point of 126-127 ° at 0.05 torr.

100 ml of 98% formic acid are stirred and added Carefully cool in an ice bath to 70 g (0.4 mol) N- (p-chlorine-

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BATH

phenyl) -N-methyl-ethylenediamine added. The reaction mixture obtained is allowed to warm to 25 ° and then 40 g (0.375 mol) of benzaldehyde are added. The mixture obtained is heated to 95 ° for 17 hours. After cooling, the reaction mixture slowly to a stirred mixture of ice, J> n sodium hydroxide solution and ether is added. The alkaline aqueous layer is separated off, extracted a further 3 times with 100 ml of ether each time and discarded. The combined ether extracts are washed with water, dried over magnesium sulfate and evaporated. An oil is obtained which is dissolved in a mixture of 500 ml of η-hydrochloric acid and 250 ml of ether. The ethereal layer is separated off and the aqueous acidic layer is extracted again with 2 times 250 ml of ether each time. The combined ether extracts are washed with saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated. Crystallization of the residue from isopropanol gives 7-chloro-1,2,3,5-tetrahydro-1-methyl-5-phenyl-4H-1,4-benzodiazepine-4-carboxaldehyde in two yields of crystals, which are at 114 -115 and melt at 120-121 °. By recrystallizing the combined crystals from hexane, cream-colored prisms with a melting point of 121-122 ° are obtained.

Example 13

A solution of 1 g (0.00318 mol) of 4-acetyl-7-chloro-2,3,4,5-tetrahydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine in

109886/1725 bad or ""! M _AL

T695223

25 ml of dry N ^ -dimethylformamide under nitrogen 'is treated with' Qi, 14 g (0.00349 mol) of a 56.9 # strength sodium hydride dispersion ¹ in a mineral oil. The reaction mixture is left 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 washed twice with j © 4Q; ml 1 η hydrochloric acid extracted. The acidic layers are combined * made basic with ammonium hydroxide and extracted with 100 * ml dichloromethane. The organic layer is washed with 50 ml of a saturated saline solution, dried over anhydrous sodium sulfate and evaporated to dryness. The oil obtained is dissolved in dichloromethane, filtered through 75 g of silica gel and eluted with 400 ml of dichloromethane and 500 ml of ethyl acetate. The ethyl acetate fraction is mixed with excess ethanolic hydrochloric acid, whereupon 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 tube).

The starting material can be produced as follows:

To a solution of 69 g (0.25 mol) of crude 7-chloro-2,3,4,5-tetrahydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine 125 ml of acetic anhydride are added to 200 ml of pyridine. The reaction

109886/1725

mixture is left for 15 minutes at room temperature and then heated in a steam bath for 55 minutes. Then you narrow in a vacuum to dryness. The residue is dissolved in a mixture of ether and ice-cold dilute hydrochloric acid. the Aether vision is separated, with water and diluted ice cold Washed sodium hydroxide solution, dried and evaporated to dryness in vacuo. The residue becomes a mixture of ether and petroleum ether crystallizes and gives 4-ethyl-7-chloro-2,5 »4, S-teit ^ ahydiTO-1-methyl-S-piienyl-1H-1,4-benzodiazepine with a melting point of 106-1 ° 8 °.

109886/1725

Claims (1)

Claims 1. Process for the preparation of benzodiazepine derivatives the general formula (D wherein A is phenyl, pyridyl or halophenyl, B is carbonyl or methylene, R and R, is hydrogen, halogen, nitro or trifluoromethyl, R ₂ is hydrogen lower alkyl or lower alkenyl and R, is hydrogen or lower ^alkyl: characterized in that a compound of the general formula (II) wherein A, B, R, R-, R ₂ and R, have the above meaning and X arylsulfonyl, lower alkylsulfonyl or 109886/1725 lower alkanoyl means with a base in the presence of an inert organic solvent treated. 2. The method according to claim 1, characterized in that a starting material of the formula II is used in which B denotes a carbonyl group and that one is the compound of the general formula formed as an intermediate -Jt ₁ (III) wherein A, R, R ₁ , R ₂ and R have the meaning given in claim 1, isolated and then converted into a compound by treatment with a base in the presence of an anhydrous solvent of the general formula I converts. 3. The method according to claim 1 or 2, characterized in that a starting material of the formula II is used in which R is hydrogen and R ₁ is in the 7-position of the molecule. 109886/1725 4. The method according to claim 1 or 2, characterized in that a starting material of the formula II is used, wherein A is a pyridyl (2) radical. 5. The method according to claim 1 or 2, characterized in that that a starting material of the formula II is used in which A is a 2-halophenyl group. 6. The method according to claim 5 *, characterized in that the halogen part of the 2-halophenyl group is fluorine. 7. The method according to claim 1 or 2, characterized in that a starting material of the formula II is used in which A is phenyl, R and R, hydrogen, R _{1 is} halogen in the 7-position of the molecule and Rp is hydrogen or lower alkyl. 8. The method according to claim 7 * characterized in that the halogen substituent in the 7-position is chlorine and R _{2 is} hydrogen or methyl. 9. The method according to any one of claims 1-8, characterized in that that one uses a starting material of the formula II in which X is tosyl or mesyl. 109886/1725 10. Benzodiazepine derivatives of the general formula wherein A is phenyl, pyridyl or halophenyl, R and R _{1 are} hydrogen, halogen, nitro or trifluoromethyl, hydrogen, lower alkyl or lower alkenyl and R_ is hydrogen or lower alkyl. 11. T- 12. 7-chloro-l, 5-dihydro-5-phenyl-2H-l, 4-benzodiazepine Benzodiazepine derivatives of the general formula 109886/1725 wherein A is phenyl, pyridyl or halophenyl, B carbonyl or methylene, R and R, hydrogen, halogen, nitro or trifluoromethyl, R _{2 is} hydrogen, lower alkyl or lower alkenyl, R, hydrogen or lower alkyl and X is arylsulfonyl, lower alkylsulfonyl or lower alkanoyl mean. 14. A compound according to claim 13 .. wherein R and R, are hydrogen and X is tosyl or mesyl, 15. 7-Halo-1,3,4,5-tetrahydro-1-lower alkyl-5-phenyl-4- (p-toluenesulf onyl) -2H-1,4-benzodiazepine. 16. 7-Halo-1,3,4,5-tetrahydro-5-phenyl-4 (p-toluenesulfonyl) -2H-1,4-benzodiazepin-2-one. 17. 7-Chloro-1,3,4,5-tetrahydro-5-phenyl-4- (p ~ tcluolsuirony]) -2H-1,4-benzodiazepin-2-one. 109886/1725