Process for the preparation of derived from 1,4-benzodiazepine.

AS AFRICAN INDUSTRIAL PROPERTY AND THE MALAGASY PATENT

in Yaounde (Cameroon) International Patent Classification: 07 C. NO. 02385

Oo.îcm ^ w. I-REQUESTED THE 30 March 1967 to 8 hr 20 min to ro.A.M.p. 1. (G.P. no. 52,850) by

the company said: ff.hoffmann the strata & a CIE S.A..

resident of Switzerland.

PROVIDES THE 5 May 1970

PRIORITY : And patent applications filed in the United States of America under the no. 858564 10 December 1959 to names of Earl rotator, the LEO HenrykSTERNBACH, no. 2605 15 January 1960 to names LEO HenrykSTERNBACH, Bruce Saucy Jack and no. 24686 26 April 1960 to names LEO HenrykSTERNBACH OSCAR expressing Keller on, Yukiko Steiger provided.

Process for the preparation of derivatives of 1.4-benzodiazepine.

The■^; ' invention relates to a process for the preparation of 1.4-benzodiazepine derivatives of the general formula

wherein represents a hydrogen atom or an alkyl group, RG is a hydrogen atom or an alkyl group, alkoxy, trifluoromethyl or halogen, the core designated by I which can be naan-substituted, monosubstituted by trifluoromethyl or mono - or di-substituted alkyls groups, alkoxy, alkylthio, hydroxyalcoylthio, halo, nitro group, amino group, alcoylsulfinyles, alcoylsulfonyles, hydroxyl or acylamino.

In the formula, above general, preferred groups are the groups lower alkyls comprising hydrocarbons saturated aliphatic, linear or branched, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, hexyl. the preferred halogen atoms are chlorine and bromine.

The method for the preparation of the title compounds is characterized in that a quinazoline derivative of the general formula

THE II

wherein the undecoded I, where R and R ^ ^^is " ^ l.^has Βΐ℮∞℮ meaning as above and X is - halo

' gene,

with an inorganic base or a quaternary ammonium base, any product obtained can then be nitrated, any nitro group converted by reduction into an amino group and the latter can tTtre acylated.

II is preferable for reacting the starting material with an alkali hydroxide - etallic ., such as sodium hydroxide, or an alkaline earth with a hydroxide, preferably in an inert organic solvent, such as alcohol, acetone or dioxane. It is also possible to use a quaternary ammonium base, preferably in the form of an anion exchange resin with d *. By this treatment/grows the core quinazolinique derivative to form a 3h L, 4 a-benzodiazepine-2 (LHRH)- one derivatives. the nitration can be performed using nitric acid, one or two nitro groups can be introduced in this way, the reduction of nitro groups can easily be carried out catalytically in the presence of Raney nickel. An acyl group can be attached to the amino group by reaction with an acid anhydride, for example a lower alcanolque acid anhydride, such as acetic anhydride.

the quinazoline used as a starting material can be obtained from 2-amino benzophenone suitably substituted, by transforming it in its oxime with hydroxylamine. Cfette oxime is reacted with a halide of has-to-halogénoacyle, such as chloroacetyl chloride, in acetic acid to produce a derivative-halogénoacétaminé, which cyclizes in the presence of a dehydrating agent, such as hydrochloric acid, n-oxide to form a quinazoline. Some of 2-amino benzophenones used in the method of the invitation are new. How to produce such compounds spring examples, which describe in detail their synthesis.

the compounds of formula (I in) above are useful as sedatives, muscle relaxants and anticonvulsants. They can be used for down-voltage. Administered in therapeutic amounts (adjusted to administration route and individual requirements) incorporated into; * carried liquid or solid, for example % Iixirs ^ suspension, capsule, tablets, powders, and the like, according to conventional pharmaceutical practice.

Example 1

60 ml of sodium hydroxide are added to a suspension cyle ά℮ 10, 2: ' gm (30 nmol) hydrochloride 6-chloro 2-chloro-methyl-4-phenyl-quinazoline derivatives of 3-oxide in 150 ml dioxane. The mixture is left to stand for 14 hours at room temperature, concentrated in vacuo to a small volume, diluted with sodium hydroxide 1®3n chilled and extracted with methylene chloride. the methylene chloride solution is removed. The alkaline solution containing the reaction product is acidified with hydrochloric acid and extracted with methylene chloride. The methylene chloride solution is dried, concentrated in vacuo and the residue crystallized in alcohol to form the 7-chloro 5-phenyl-3h L, 4 a-benzodiazepine-2 (LHRH)- one derivatives 4-oxide.

2 xenole

10 ml sodium hydroxide In are added at room temperature to a solution of 2.84 grams (10 mmol) of 6-methyl 2-chloromethyl-4 a-phényi-quinazoline derivatives 3-oxide in 75 ml of dioxane. After 15 hours, the mixture is diluted with ice water and extracted with 1' ether compounds. The ethereal extracts of the starting substance containing unreacted is removed. The aqueous layer is acidified with dilute hydrochloric acid and extracted with methylene chloride. The methylene chloride solution is dried, concentrated in vacuo and the residue crystallized in a mixture of methylene chloride and petroleum ether. The 7-me-to-polyethylene resins and 5-phenyl-3h L, 4 a-benzodiazepine-2 (LHRH)- one derivatives 4-oxide forms colorless rhombic plates melts at 226 - 227 degrees.

Example 3

20 ml of sodium hydroxide In are added to a suspension of 7 grams (20 mmol) of 6 a-bromo 2-chloromethyl-4-phenyl-quinazoline derivatives 3-oxide in 75 ml of dioxane. The mixture is left to stand for 14 hours at room temperature, concentrated in vacuo to a small volume, diluted with 1' 3n sodium hydroxide and extracted with methylene chloride. The methylene chloride solution is discarded. The alkaline solution containing the reaction product is acidified with hydrochloric acid and extracted with methylene chloride. The methylene chloride solution is dried, concentrated in vacuo and the residue crystallized in a mixture of methylene chloride and petroleum ether. The 7 a-bromo 5-phenyl-3h L, 4 a-benzodiazepine-2 (LHRH)- one derivatives 4-oxide thus obtained bottom has 230 - 231 degrees.

Example 4

538 mg of 2-chloromethyl-4-phenyl-6 a-îrifluorméthyl-quinazoline derivatives 3-oxide are dissolved in 20 ml of ethanol and, after addition of 5 ml of sodium hydroxide 3n, the solution is maintained at 4 hours to 25°. After acidification with hydrochloric acid 6 ml 3n>the reaction product is extracted with ether. The ethereal solution is concentrated in vacuo and the residue crystallized in benzene. The 7-trifluoromethyl-5-phenyl-3h L, 4-benzodiazepine - 2 * (1 Η) - οη℮ 4-oxide pure resulting melts at 211 - 212 degrees.

By working according to the method described above, but using the 2 a-chiorométhyl-a 4 a-phph.ényl and 7' a-trifluorométhylquinazoiine 3-oxide retort starting substance, obtained the 8 tri-fluoromethyl-5-phenyl-3h L, 4 a-benzodiazepine-2 (LHRH)- one derivatives 4-oxide.

The 2-chloromethyl-4-phenyl-6-trifluoromethyl-quinazoline derivatives 3-oxide can be produced as follows:

80 g of sodium nitrite were added slowly to a solution stirred of 460 ml of concentrated sulfuric acid. After heating to 70 degrees, a clear solution is obtained. This solution is cooled slowly and added 200 g of 2-chloro 5-trifluoromethyl-aniline is at a temperature between 10 and 20°. The reaction mixture is stirred for 1 hour to 20 degrees, and then poured into a mixture of 200 g of sodium chloride and 1.6 kg of ice.

Excess sodium chloride is separated by filtration. A solution of 280 g of zinc chloride in 300 ml of water is added to the filtrate, after which a zinc chloride double salt of the diazonium compound corresponding precipitates. After allowing to stand up overnight 0 degrees, the double salt is separated by filtration and washed with a cold solution saturated with sodium chloride.

To a solution of 120 g of sodium cyanide and 72 g of cuprous cyanide in 300 ml of water, are added with stirring and ice cooling to 291 g of the wet double salt. After the addition of 24 g of sodium carbonate, the mixture is stirred for 1 hour at first to 20 degrees, and then for another 30 minutes to 70°. The reaction mixture is cooled and extracted with ether to.

obtain the 2-chloro 5-trifluoromethyl-benzonitrile are crude. The product is purified by distillation in the steam is crystallization of the organic part of the distillate in 1' normal hexane; the pure compound melts at 39 - 40 degrees.

To a solution of phenyl magnesium bromide, prepared with 9.5 g of magnesium, 58.5 g of bromobenzene and 500 ml of anhydrous ether, is added with stirring a solution of 39 g of 2-chloro 5 a-trifluoromethyl-benzonitrile in 200 ml of benzene. 400 ml of solvent are removed by distillation and the reaction mixture is then heated for 16 hours under reflux. The Grignard complex is decomposed with 40 g of ammonium chloride and 200 g of ice, the mixture is then extracted with benzene. Hydrochloride 2-chloro 5-trifluoromethyl-benzophenone imine is precipitated from the solution by the addition of 40 ml benzene of concentrated hydrochloric acid. The product is separated by filtration, washed with benzene and dried in the vacuum; melting point 248 - 251 degrees,

60 g of the product obtained are heated to reflux overnight with a mixture of 300 ml of toluene and 300 ml of sulfuric acid at 25 $, while being stirred. The toluene layer is separated, washed with water, dried and concentrated in vacuo, then the residue EE; cdsiallisé in 1' normal hexane. The 2-chloro 5-trifluoromethyl-benzophenone resulting pure melts at 39 - 40 degrees.

50 g of this product and 500 ml of concentrated ammonia are reacted, retorting, during 10 hours in the presence of 10 140° g of cuprous chloride as catalyst. The reaction product is extracted with ether and the ethereal extract concentrate in vacuum. The residue is dissolved in 1' normal hexane, and then purified by chromatography has an amount tenfold neutral aluminum oxide (Brockmann, the II activity). By eluting with a mixture of hexane and ether * (1:1) and evaporating the solvent, the obtained 2-amino 5-trifluoromethyl-benzophenone, which recrystallizes in 1' hexane to form yellow crystals melts at 81 - 82 degrees.

15.5 g of the product obtained in 60 ml of ethanol are heated to reflux for 24 hours with 6 g of hydrochloride

d.' hydroxyl amine. The pH of the above reaction mixture is adjusted to about 6 by adding a solution of 12 g of sodium acetate in 100 ml of water. By extracting the reaction mixture with ether, giving an oil is obtained, after repeated crystallization in a mixture of ether and hexane, . the 2-amino 5-trifluoromethyl-substituted benzo-phenone oxime melts at 175 - 177 degrees.

2.8 g of the product obtained are dissolved in 15 ml of acetic acid and, after addition of 1.5 ml of chloroacetyl chloride, held one hour to 20 degrees, then 2 hours at 70°. The mixture is diluted with ether and washed with water, the ethereal solution concentrated in vacuo giving a solid residue, crystallized in a mixture of methylene chloride and ether to obtain the 2-chloromethyl-4-phenyl-6-trifluoromethyl-quinazoline derivatives 5-oxide melts at 149 - 150° to pure yellow.

1 Ξχ℮ π ΐρ ℮ 5

\ Mth slurry, of 3.2 grams (0.01 moles) of 6 a-méth.ylmercap to head 2-chloromethyl-4-phenyl-quinazoline derivatives 3-oxide in 20 ml of ethanol, are added dropwise to 12 ml (0,012 moles) of sodium hydroxide IN the mixture is heated to 45 degrees, and cooled to 25 degrees. 10 ml of acetone are added, then the reaction mixture is stirred for 3 hours and allowed to stand for 15 hours at room temperature. The mixture is cooled in ice, the precipitate separated by filtration, washed with a small amount of cold ethanol and dried.

The 7-metylmercapto-5-phenyl-3h L, 4 a-benzodiazepine-2 - one derivatives (lïï) 4 a-c2jde pure crystallizes in the form of needles in water containing a few drops of alcohol; melting point 191 - 193 degrees.

The starting material can be obtained as follows:

137 grams (1 moles) of anthranilic acid are dissolved in 250 ml of dimethylformamide. The solution is cooled to 0° and added drop ' to drop of 85 ml (155 g=1.3 mole) of thionyl chloride, the temperature of the reaction mixture is maintained below 40°. After allowing the mixture to cool to room temperature, 750 ml of acetone are added, then allowing to cool to 0°. White acid hydrochloride 2 a-diméthylformamidino-anthranilic acid which separates out is isolated by filtration through a sintered glass filter, washed with 300 ml of acetone cold and dried by suction; melting point 215 - 217 degrees.

115 grams (0.5 moles) of the hydrochloride thus obtained are suspended in 1500 ml of benzene free of thiophene. 119 g of phosphorus pentachloride are added and the mixture heated to reflux for about 2 steam baths τ hours until the reaction is complete, appearing as the discoloration becoming brown-yellow. The reaction mixture is then cooled to 20 - 25° to 290 g of anhydrous aluminum trichloride are added in four portions, the temperature being maintained below 40°. The mixture is then heated at reflux at steam bath during 6 hours. After cooling to room temperature, 800 g of crushed ice are added in portions of 100 grams, the temperature being maintained below 50°. The mixture is then heated at 60° and again cooled to room temperature. Then, about 1100 ml of sodium hydroxide are added 40 $confectioneries dropwise to form a pH of 11, the temperature being maintained below 50°. Once the addition has ended, the mixture is heated to reflux during 5 hours steam baths. The benzene phase is separated and the aqueous phase extracted three times with portions of 250 ml of benzene. The combined benzene solutions are concentrated in vacuo and the oily residue is heated at reflux for 20 hours with a mixture of 150 ml of sodium hydroxide to 40 $, 150 ml of water and 500 ml of alcohol. The alcohol is separated by distillation at atmospheric pressure and the aqueous residue is cooled to room temperature. 1000 ml of water are then added dropwise, the 2-amino benzophenone precipitating " the yellow product is separated by filtration, washed with cold water and dried by suction; melting point 105 - 105 degrees.

30 gm (0.15 moles) of 2-amino benzophéhone and 40 g of sodium thiocyanate are suspended in 100 ml of methanol. After cooling to 0 degrees, is added dropwise to a cold solution of 9.5 ml of " bromine (28.5 g=0.36 moles) dissolved in 35 ml of cold methanol (saturated with sodium bromide).

Once the addition is complete, the reaction mixture is stirred cold for still l/2 hour and poured into 1 liter of cold water.

After neutralization with 110 ml of sodium carbonate to 20 $, the 2-amino 5 a-thiocyano or-benzophenone thus obtained is separated by filtration and crystallized in ethanol diluted as yellow plates melts at 83 - 84 degrees.

39 grams (0.15 moles) of 2-amino 5 a-thiocyano or-benzophenone are suspended in 200 ml of ethanol. The mixture is heated to steam bath and 50° at total 55 g of sodium hydrosulfite and 250 ml sodium hydroxide 10 $are added alternately, in portions. The temperature rises to 80°. At this time, the reaction mixture gives a blue coloration with paper'd ' indanthrene yellow, indicating the presence of an excess of sodium hydrosulfite. After cooling to 40 degrees, is added dropwise to 20 ml (27 g=0.22 moles) of dimethyl sulfate.

A negative reaction with lead acetate at this time indicates the absence of free mercaptan. The reaction mixture is stirred for 1 hour at room temperature, then the ethanol is separated by distillation. The aqueous phase is diluted with 700 ml of water and the thioether oily extract with 4 portions of 300 ml of benzene. The phase benzenic is dried and the solvent removed by distillation in vacuo. The 2-amino 5-metylmercapto-benzophéju> & crude is obtained in the form of a heavy oil.

78 grams (0.32 moles) of the product obtained are heated to reflux overnight with 37 grams (0.53 moles) of hydroxylamine hydrochloride in 400 ml - alcohol. After evaporation to dryness in a vacuum, the residue is taken up in 125 ml of water. The mixture is rendered slightly acid sunflower at 40 ml of deodorized by adding sodium hydroxide 40 $and 25 ml of sodium carbonate to 20 $, followed by addition of 20 ml of glacial acetic acid. 125 ml of ether and 125 ml of Skellysolve b are then added, and the mixture is then maintained at the cooler until the following day. The supernatant is decanted off and the precipitate dissolved in 500 ml of ether gummy. After being washed with water, the ethereal solution is dried using sodium sulfate. It is then concentrated in vacuo until an oil, which is treated with 200 ml of ether and 100 ml of Skellysolve b for the 2-amino 5-me-to-thylmercapto-benzophenone oxime-crystallized. The oxime crystallizes in pure forms of yellow needles in ethanol diluted and melts at 149 - 150 degrees.

15.5 grams (0.06 moles) of 1' esont oxime derivatives thus obtained. dissolved in 150 ml of glacial acetic acid to 40°. 9.5 ml (14 g=0.125 moles) of chloroacetyl chloride are added to 55 - 60 degrees. The reaction mixture is. stirred at 50 - 60° during a VBE1 hour, and then during 4 hours at ambient temperature. The solution is concentrated in vacuo and the oily residue obtained dissolved in 150 ml of methylene chloride boiling, the solution is cooled and diluted with about 150 g of ice " ground. Added 1' 1st sodium hydroxide while stirring the mixture until an alkaline reaction to the phenolphthaléine. the methylene chloride layer is separated and dried using sodium sulfate. Concentrating the solution of methylene chloride until crystallization, obtained the 6-metylmercapto-2-chloromethyl-4-phenyl-quinazoline derivatives 3-oxide. the pure substance crystallizes in methylene chloride as yellow needles melting at 155 - 156 degrees.

Example 6

6.3 grams (0.02 moles) of 2-chloromethyl-4-phenyl-6 a-nitroquinazoline 3-oxide are suspended in 50 ml of a mixture of ethanol and 20 ml of acetone. 24 ml of sodium hydroxide In are added dropwise, the reaction mixture becomes dark brown (at pH=9 - 10). the mixture is heated to 40 degrees, then stirred at room temperature overnight, the reaction mixture is adjusted to pH 5 using dilute hydrochloric acid and concentrated in vacuo to dryness. the residue is heated at reflux with a mixture of 125 ml of ethanol and 30 ml of acetone. After filtration and concentration to 50 ml, a small portion of the original substance is separated by filtration and the reaction product is obtained by precipitation with petroleum ether; melting point 205 - 208 degrees (dec), the 7-nitrate 5-phenyl-3h L, 4 a-benzodiazepine-2 (1 Η) - οη℮ 4-oxide crystallizes precoated pure yellow prisms in a mixture of ethanol and petroleum ether; melting point 218 - 220 degrees (dec.).

The starting material can be obtained in the manner in th:

72 grams (0.30 moles) of 2-amino 5-nitrate benzophenone are suspended in a mixture of 500 ml alcohol, 25 ml of water, 34 g of hydroxylamine hydrochloride and 90 g of pulverized potassium hydroxide. The reaction mixture is heated under reflux at steam bath with stirring for 15 min. It is then cooled to ambient temperature and poured into a solution of 160 ml of concentrated hydrochloric acid in 1000 ml of water. The suspension of the substance precipitated crude is cooled in ice and separated by filtration, washed with ice water and dried with acid free suction; melting point 195 - 200 degrees.

The 2-amino 5-nitrate benzophenone oxime derivatives resulting pure crystallized in ethanol in the form of needles melting at 203 - 205 degrees.

With a suspension of 10 grams (0,039 moles) of 2-amino 5-nitrate benzophenone oxime in 100 ml of acetic acid, heated to 50 - 60 degrees, is added in small portions with stirring 6 ml (0.08 mol) of chloroacetyl chloride. The solution is stirred for 3 brown body obtained 50 - 60 degrees to hours, then left to stand until overnight at room temperature. The reaction mixture is then saturated with hydrogen chloride and concentrated in vacuo. The residue is dissolved in 200 ml of methylene chloride cooled hot 0°. 50 g of crushed ice are added to the reaction mixture, and then 30 ml sodium hydroxide In are added dropwise until a pH of 8 - 9 is reached. The mixture is placed in, a funnel in 150 ml water tap and are separated. The organic phase is separated and dried using sodium sulfate "the solution of methylene chloride is treated with char activated, filtered and evaporated to dryness in a vacuum to form a yellow residue crystallized" the crude product is purified by heating at reflux in a mixture of 200 ml of acetone and 100 ml of methylene chloride with 15 g of char activated cooling the filtered mixture, the 2-chloromethyl-4-phenyl-6 nitro--quinazoline derivatives 3-oxide pure crystallizes in the form of prisms yellow; melting point 205 - 207 degrees.

The analogous manner, the compounds can be according to formulae:

7.8-dimethyl 5-phenyl-3h L, 4 a-benzodiazepine-2 (1:00) - one derivatives 4-oxide;

colorless plates melts at 234 - 235 degrees.

7 a-bromo 5 - (P-tolyl) - 3h-to-1.4-benzodiazepine-to-2 (1:00) - one derivatives 4-oxide;

colorless plates melts at 237 - 238 degrees.

7-chloro 5 - (4 chloro-phenyl) - 3h-to-subscribes, 4 a-benzodiazepine-2 (LHRH)- one derivatives 4-oxide; colorless plates melts at 250 - 252 degrees.

7-chloro 5 - (2-chloro-phenyl) - 3h-to-1.4-benzodiazepine-a 2 - one derivatives (1 Η) 4-oxide; melting claim 248 - 249 degrees.