US3202665A

US3202665A - 5-piperidino-and 5-diloweralkylamino-2-amino-benzophenones

Info

Publication number: US3202665A
Application number: US178566A
Authority: US
Inventors: Metlesics Werner; Sternbach Leo Henryk
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG; Hoffmann La Roche Inc
Priority date: 1962-03-09
Filing date: 1962-03-09
Publication date: 1965-08-24
Anticipated expiration: 1982-08-24
Also published as: SE317681B; CH457462A; CH440298A; DE1445871A1; ES285855A1; GB984707A; AT242157B; SE318885B

Description

United States Patent This invention relates to novel 7-(N-substituted-amino) -aryl-3H-1,4-benzo'diazepin 2(1H) ones, novel derivatives thereof and novel intermediates therefor; and processes of making the foregoing.

'The novel 7-('N-substituted-amino)-5-aryl-3H-1,4=ben zodiazepin-2(1H)'-ones andderiva-tives thereof to which the invention relates are selected from the group consisting of compounds of the, formula and pharmaceutically acceptable salts thereof; wherein A is selected from the group consisting of R and R are selected from the group consisting of individually lower .alkyl and, taken together with the nitrogen atom, a mon-oheterocycli-c containing at the most one further hetero atomfselected from the group consisting of nitrogen :and oxygen; R and R are each selected from the group consisting of'hydrogen and lower alkyl; and R is selected from thegroup' consisting of hydrogen, halogen, lower alkoxy, lower alkyl, and trican be referred to as 4,5-dihydro derivatives of those compounds wherein A is The symbols R have the following significance. R and R can each be straight or branched chain lower alkyl ternatively R and R taken together with the 7-position nitrogen atomgcan form a m-onoheterocyclic ring containing at the most one further hetero atom selected from 3,262,665 Patented Aug. Z4, 1965 p we;

such as methoxy and the like, lower alkyl such as methyl and the like, trifiuoromethyl or halogen. The term halogen included all four halogens and especially preferred are fluorine and chlorine.

- In addition to the compounds within the scope of Formula I above, there are also encompassed within this invention the pharmaceutically acceptable salts of said compounds. The compounds of Formula I form pharmaceutically acceptable acid addition salts with pharmaceutically acceptable organicand inorganic acids; such as hydrochloric acid, hydrobrornic acid, sulfuric acid, phosphoric .acid, nitric acid, tartaric acid, citric acid, camphor sulfonic acid, ethane sulfonic acid, toluene 'sulfonic acid, ascorbic acid, salicylic acid, maleic acid, succinic acid, mandelic acid, formic acid, acetic acid and the like. Also, inasmuch as the 7-positi-on nitrogen atom is a tertiary amino nitrogen atom, compounds of Formula I above form pharmacentically acceptable quaternary ammonium salts with conventional quaternizing agents, such as lower alkyl halides, lower alkylsulf-ates, aralkyl halides'and closed herein in order that the present disclosure may be complete. These 5-halo:2 nitrobenzophenones upon treatment with the appropriate secondary amine yield compounds of the formula NO: N

wherein R R and R have the same meaning as above;

' 5-(N-substituted-zamino)-2-nitrobenzophenone is reduced such as methyl, ethyl, propyl, is opropyl or the like. Al- I '70 In those compounds wherein R is hydrogen, the e amino.

the group consisting of nitnogenand oxygen." Especially A benzophenone.

to the corresponding 5-(N-substituted-amino)-2-amino- This reduction can conveniently be effected via hydrogenation in the presence of a hydrogenation catalyst, such as :Raney nickel, and in the presence of a conventional inert organic solvent, such as ethanol, or the like. The so-obtained S-(N-substituted-amino)-2- aminobenzophenone can be isolated in form of a mineral acid salt and can then be reacted with an u-amino acid to directly prepare compounds of Formulal above where.- inAis; 1

acid utilized is glycine, where R; is lower alkyl a-arnin-o acids having the formula R CH(NH )COOH are used to introduce the group K; into the final compound. Alanine for example is exemplary of such a-amino acids. In the preferred embodiment, the reaction of the 5-substituted amino-2-aminobenzophenones with an a-amino acid is carried out with an a-amino acid ester, such as a lower alkyl ester of an u-amino acid, and is preferably effected in the presence of an inert organic solvent such as pyridine, dimet-hylformamide, or the like. It is also preferable to utilize one of the materials, or a fraction thereof, present in the form of the salt of a strong organic or inorganic acid such as glycine hydrochloride, glycine ethyl ester hydrochloride, pyridine hydrochloride, or the like.

In an alternative method, the 5-(N-substituted-amino)- Z-aminobenzophenone described above is reacted with an a-halo-lower .alkanoyl halide to form a S-(N-substituted-amino)-2-(a-halo lower alkanoylamino)-benzophenone which can then be reacted with ammonia to yield the final product of Formula I above wherein A is Compounds of Formula I above wherein A is -CHNH i.e., the 4,5-dihydro derivatives, can be prepared from compounds of Formula I wherein A is by reduction. For example, the latter compounds can be reduced with hydrogen in the presence of a hydrogenation catalyst such as platinum oxide to yield the former compounds.

' Another method for preparing compounds of Formula I above comprises the reductive alkylation of a compound of the formula (III) wherein A, R and R have the same meaning as above. This reductive alkylation is preferably conducted using hydrogen as a reducing agent in the presence of a hydrogenation catalyst such as Raney nickel. In a preferred embodiment of the invention, to obtain compounds of Formula I above wherein R and R are both methyl, formaldehyde is used as the alkylating agent. This reductive alkylation can be conducted at room temperature or elevated temperatures, and is preferably conducted-in the presence of conventional inert organic solvent such as methanol, ethanol, or the like.

Compounds of Formula I above, wherein R is lower alkyl can be derived from compounds of Formula III above wherein R is lower alkyl, or via condensation of 5-substituted amino-Z-lower alkylamino-benzophenones prepared from the above described 5-substituted amino-2- aminobenzophenones. Alternatively, compounds of Formula I above wherein R is lower alkyl can be prepared from corresponding compounds of Formula I above wherein R is hydrogen, by reacting the latter in the form of an alkali metal salt with di-lower alkyl sulfate, lower alkyl halide or similar alkylating agents, in an inert organic solvent medium such as ether, benzene, alcohol, dimethylformamide, dioxane, or the like, preferably at room temperature or below.

The compounds of Formula I above are useful as sedatives, muscle relaxants and anticonvulsants. The compounds of Formula I, their pharmaceutically acceptable acid addition salts, and their pharmaceutically acceptable quaternary ammonium salts, can be administered internally, i.e. parenterally or entrally, by incorporating therapeutic dosages in conventional pharmaceutical liquid or solid vehicles to provide elixirs, suspensions, tablets, capsules, and the like according to accepted pharmaceutical practice.

The following examples are illustrative but not limitative of the invention. All temperatures are in degrees centigrade.

Example 1 To a solution of 10 g. of 5-chloro-2-nitrobenzopheuone in 150 ml. of ethanol was added a solution of approximately 22 g. of dimethylamine in m1. of ethanol. The mixture was heated in an autoclave under nitrogen atmosphere to for 24 hours. The alcoholic solution was concentrated in vacuo and cooled. Yellow needles of S-dimethylamino-Z-nitrobenzophenone separated which were collected on a filter and after recrystallization from alcohol melted at -132.

The above-mentioned '5-chloro-2-nitrobenzophenone is not a part of this invention, but its preparation is disclosed hereinbelow in order that the present disclosure may be complete.

A suspension of 10.8 cc. of 90% hydrogen peroxide in 250 cc. of methylene chloride contained in a 1-liter flask fitted with a stirrer, reflux condenser and a dropping funnel was cooled with an ice bath. Trifluoroacetic anhydride (67.6 cc., 100 g.) was added over 45 minutes. After stirring for 5 minutes longer, the ice bath was removed and a solution of 23.2 g. of 2-amino-5-chlorobenzophenone in 100 cc. of methylene chloride was added over .45 minutes. The resulting warm, dark solution was stirred and refluxed (steam bath) for 1 hour. After cooling with a cold water bath, the reaction mixture was washed successively with two 200 cc. portions of ice water, two 200 cc. portions of cold 10% sodium carbonate and finally with 200 cc. of 10% sodium chloride solution. Emulsions were broken by filtration through a thin pad of diatomaceous earth. The methylene chloride solution was dried over magnesium sulfate and evaporated in vacuo (50) leaving a thick oily residue wihch soon crystallized exothermically yielding 2- nitro-S chlorobenzophenone which upon recrystallization from 30 cc. of methanol melted at 87-89.

Example 2 Example 3 A mixture of 6.2g. of 2-nitro-S-piperidinobenzophene, 50 ml. of morpholine was refluxed for 18hours. Excess morpholine was removed in vacuo yielding an oil which was poured into ice water. Crystals formed which werecollected on a filter and recrystallized from methanol. Yellow leaflets of 5 morpholine 2 -nitrobenzophenone melting at 152-154 were obtained,

tional 4 hours.

Example 4 A mixture of 6.2 g. of 2-nit-ro5-piperidinobenzophenone, 1500 ml. of ethanol and approximately 0.5 g. of Raney nickel was shaken at 25 and normal pressure under an atmosphere of hydrogen. The uptake was 1450 ml. of hydrogen (ca. 0.06 mole). After filtering from the catalyst the solution was concentrated in vacuo to a volume of 100 ml. and ml. of a 4 N solution of hydrogen chloride in ethanol was added. Slow addition of ether to this solution precipitated crystals of 2-amino- 5-piperidinobenzophenone monohydrochloride, which upon recrystallization from a mixture of ethanol and ether yielded yellow needles melting at 227-240 (dec Example 5 A mixture of 5 g. of Z-amino-S-pipetidinobenzophenone monohydrochloride and 35 g. of glycine ethyl ester hydrochloride was refluxed for 17 hours in 100 ml. of pyridine. The pyridine was removed in vacuo and the residue stirred with water. The solid was collected on a filter and recrystallized from ethanol. Yellow prisms of 5-phenyl-7-piperidino-3H-1,4-benzodiazepin-2 1H) -one melting at 250252 were obtained.

Example 6 To a solution of 56 g. of 7-nitro-5-phenyl-3H-1,4-benzodiazepin-2( 1H)-one in 800 ml. of methanol was added 80 ml. of a 37% aqueous solution of formaldehyde and ca. 8 g. of Raney nickel. This mixture was shaken for 22 hours and ca. atm. of hydrogen pressure. The solution was filtered from the catalyst and concentrated yielding yellow needles of 7-dimethylamino-5-phenyl-3H- .1,4-benzodiazepin-2(1H)-one, which upon recrystallization from ethyl acetate gave crystalsmelting at 245-247".

The above-mentioned 7-nitro-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one is not a part of this invention but its preparation is disclosed hereinbelow in order that the present disclosure may be complete.

A mixture of 16.8 g. of Z-aminobenzophenone, 11.9 g. of glycine ethyl ester hydrochloride and 200v cc. of pyridine was heated to reflux. After one hour, 20 cc. of pyridine was distilled ofl The solution was refluxed for 15 hours, then 11.9 g. of glycine ethyl ester hydrochloride was added and the refluxing was continued for anraddi- The reaction mixture was concentrated in vacuo, then diluted with ether and Water. The reaction product, S-phenyl-BH-1,4-benzodiazepin-2(1H)- .one, crystallized out, was filtered OE and then recrystallized from acetone in the form of colorless rhombic prisms, M.P. 182-183".

48 g. of 5-phenyl-3H-1,4-benzodiazepin-2(lH)-one was dissolved in 250 cc. of concentrated sulfuric acid by stirring at 15 for ?/2 hour. The solution was then cooled to 0 and a mixture of 9.1 cc. of fuming nitric acid (90% sp. gr.:=1.50) and 11.8 cc. of concentrated sul- .cc. of concentrated ammonium hydroxide was added dropwise at- 0 to pH 8. Stirring was'continued for A hour and the crude product was filtered otf, washed with a small amount of ice water and sucked dry overnight. The. crude product was suspended in a mixture of 100 cc. of methylene-chloride and 1700 cc. of alcohol. 50 g. of decolorizing charcoal was added and the mixture was refluxed with stirring for 2 hours. After standing overnight at room temperature 15 g. of diatomaceous earth filter aid was added and the refluxing was resumed for 1% hours. The mixture was filtered while hot. The clear, light-yellow filtrate was concentrated in vacuo on the steambath with stirring to about 600 cc. The concentrate was stirred and cooled in ice for about 2 hours; the precipitated crystalline product was filtered off, washed with some petroleum ether and sucked dry. The product, 7-nitro-5-phenyl-3H-1,4-bcnzodiazepin 2(1H)-one, was recrystallized from a mixture of 1000 cc. of alcohol and 50 cc. of methylene chloride to obtain white prisms melting at 224-225 Example 7 To a solution of 25 g. of l-methyl-7-nitro-5-phenyl-3H- 1,4-benzodiazepin-2(1H)-one in 600 ml. of methanol was added 50 ml. of a 37% solution of aqueous formaldehyde and ca. 8 g. of Raney nickel. This mixture was shaken under an initial pressure of 8 atm. hydrogen. After 2 to 3 hours the theoretical amount (5 moles of hydrogen per mole of substance) had been taken up and the pressure remained constant. The solution was filtered from the catalyst and the main amountof methanol was re.- moved in vacuo. Yellow prisms of 7-dimethylamino-1- methyl-S-phenyl 3H-1,4-benzodiazepin-2(1H)-one separated which after recrystallization from a mixture of ethanol, ether and hexane melted at 141-143".

The above-mentioned 7-nitro-1-methyl-3H-1,4-benzodiazepin- 2(lH)-one, intermediates thereforand the preparation thereof, are not a part of this invention, but such are. set forth hereinbelow in order that the present disclosure may be complete.

5.6g. of 7-nitro-5-phenyl-3H-l,4benzodiazepin-2(1H),- one was suspended in 75 cc. of methanol. 1.1 g. (0.022 mol.) of sodium methylate was added with stirring. The clear yellow-brown solution was concentrated to dryness in .vacuo giving the yellow sodio derivative. This sodio derivative was dissolved in 70 cc. of dimethylformamide. 3.8 cc. (8.52 g.=0.06 mol.) of methyl iodide was added dropwise, the temperature rising to 30. The reactionmixture was cooled and stirred for 1 hours. The clear brown solution was added to about 500 cc. of ice and water with stirring. Thefine yellow precipitate was filtered 01f, washed with ice water, sucked dry and dried in vacuo at 50 over sodium hydroxide. The pure l-methyl- 7-nitro-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one crystallized in needles from dilute ethanol and melted at 156- 157.

Example 8 yielded white platelets melting at 174176.

Example 9 A solution containing 5.6 g. of 7-dimethylamino-1- methyl-S-phenyl-3H-1,4-benzodiazepin-2(1H)-one and 10 g. of methyl bromide in 60 ml. of acetone was kept at room temperature for 24 hours. After this time brown crystals had separated which were collected on a filter.

.Recrystallization from methanol-ether gave colorless prisms of (1,Z-dihydro-l-methyl-2-oxo-5-phenyl-3H-1,4-

behzodiazepinJ-yl)trirnethyl-ammonium bromide melting at (dec.).

Example 10 To a solution of 10' g. of 5-(2-chlorophet1yl)-7-nitro- 3H-1,4-benzodiazepin-2(1H)-one in 275 ml; of methanol was added 20 ml. of a 37% aqueous solution of formaldehyde and ca. 5 g. of Raney nickel. This mixture was shaken overnight under an initial pressure of 5-6 atm. of hydrogen. The solution was filtered from the catalyst and evaporated in vacuo. The residue was recrystallized hours, cooled and poured on ice.

'7 from ethyl acetate to yield yellow needles of 5-(2-chlorophenyl)-7-dimethylamino 3H1,4-benzodiazepin-2(1H)- one melting at 245-248". The above mentioned 7-nitro-5-(2-chlorophenyl)-3H- 1,4-benzodiazepin-2(1H)-one, intermediates therefor and the preparation thereof, are not a part of this invention, but such are set forth hereinbelow in order that the present disclosure may be complete.

A stirred solution of 75 g. of 2-amino-2'-nitrobenzophenone in 700 ml. of hot concentrated hydrochloric acid was cooled to and a solution of 21.5 g. of sodium nitrite in 50 ml. of water was added in the course of 3 hours. The temperature of the suspension was kept at 2-7 during the addition. The resulting clear solution was poured into stirred solution of 37 g. of euprous chloride in 350 ml. of hydrochloric acid 1:1. The solid which had formed after a few minutes was filtered off, washed with water and recrystallized from ethanol. Crystals of 2-chloro-2-nitrobenzophenone melting at 76-79 were obtained.

A solution of 20 g. of 2-chloro-2-nitrobenzophenone in 450 ml. of ethanol was hydrogenated at normal pressure and room temperature with Raney nickel. After uptake of ca. 6 liters of hydrogen the catalyst was filtered off, and the alcohol then removed in vacuo. The residue was distilled in a bulb tube at 0.4 mm. and a bath temperature of ISO-165 giving a yellow oil. The oil was dissolved in alcohol, and on addition of water, needles of 2-amino-2-chlorobenzophenone melting at 58-60 were obtained.

To a solution of 42 g. of 2-amino-2-chlorobenzophenone in 500 ml. of benzene, 19 ml. of bromoacetyl bromide was added dropwise. After refluxing for 2 hours, the solution was cooled, washed with 2 N sodium hydroxide and evaporated. The residue was recrystallized from methanol giving crystals of 2-bromo-2'(2-chlorobenzoyl) acetanilide melting at 119-121".

To a solution of 14.5 g. of 2-bromo-2'-(2-chlorobenzoyl)-acetanilide in 100 ml. of tetrahydrofuran, and excess of liquid ammonia (ca. 150 ml.) was added. The

ammonia was kept refluxing with a Dry Ice condenser for .3 hours after which time the ammonia was allowed to evaporate and the solution was poured into water. Crystals of 2-amino-2'-(2-chlorobenzoyl) acetanil-ide were collected, which after recrystallization from ethanol melted at 162-164".

A solution of 3 g. of 2-amino-2'-(2-chlorobenzoyl)-acetanilide in 50 ml. of pyridine was refluxed for 24 hours after which time the pyridine was removed in vacuo.

The residue was recrystallized from methanol and a mixture of dichloromethane and ether giving crystals of 5- (2-chlorophenyl)-3H-1,4-benzodiazepin-2(1H)-one melting at 212-213".

To a solution of 13.5 g. of 5-(2-chlorophenyl)-3H- 1,4-benzodiazepin-2(1H)-one in 60 ml. of concentrated sulfuric acid, a solution of 5.5 g .of potassium nitrate in 20 ml. concentrated sulfuric acid was added dropwise. The solution then was heated in a bath at 45-60? for 2% After neutralizing with ammonia, the formed precipitate was filtered off and boiled with ethanol. A small amount of white insoluble material was then filtered ofr. The alcoholic solution on concentration yielded crystals of 7-nitro-5-(2-chlorophenyl)-3H-1,4-benzodiazepin-2(1H)-one which, after recrystallization from dichloromethane, melted at 238- 240.

Example 11 To a solution of 35 g. of 7-nitro-5-(a,a,a-trifiuoro-otolyl)-3H-1,4-benzodiazepin-2(1H)-one in 800 ml. of methanol was added 50 ml. of a 37% aqueous solution of formaldehyde and ca. 8 g. of Raney nickel. This mixture was shaken overnight under an initial pressure of ca. 20 atm. of hydrogen. The solution was filtered from the catalyst and evaporated in vacuo. The residue was recrystallized from methanol to yield yellow needles of 7 dimethylamino-S (a,a,a-trifluoro-o-tolyl)-3H-l,4- benzodiazepin-2(1H)-one melting at 254256.

. The above-mentioned 7 Ilitl'O-S-(oc,o,ot-tflfiUOIO-O- t-olyl)-3H-1,4-benzodiazepin 2(1H)-one, intermediates therefor and the preparation thereof, are not a part of this invention, but such are set forth hereinbelow in order that the present disclosure may be complete.

A solution of o-trifiuoromethyl phenyl magnesium bromide was prepared in the usual manner from 50.0 g. of o-bromo-benzotrifluoride, 5.55 g. of magnesium and ml. of anhydrous ether. The Grignard reagent can also be prepared by reacting 39.7 g. of o-chlorobenzotrifluoride with 5 .55 g. of magnesium in tetrahydrofurane. This solution was added with stirring at 20 C. over a period of 3 hours to a solution of 33.0 g. of 2-methyl- 4H-3-l-benzoxazin-4-one in 300 ml. of methylene chloride. The resulting dark but clear solution was left at room temperature for 16 hours and was then poured over a mixture of 50 g. of ammonium chloride and 600 g. of crushed ice. Extraction with ether gave a crude reaction product which was directly hydrolyzed by refluxing for one hour in a mixture of 240 ml. of ethanol and 240 ml. of 3 N sodium hydroxide. After standing overnight, the reaction mixture was extracted with ether. The ether layer was washed with water and concentrated in vacuo yielding an oil. This was purified in two portions by chromatography on the 20-fold amount of neutral alumina (activity grade III; e.g. containing 6% of water). Elution with petroleum ether (60-70) and a mixture of petroleum ether (60-70) and ether (9:1) followed by crystallization from a mixture of ether and hexane yielded 2-amino-2'-trifluoromethylbenzophenone, melting at 94- 96" (yellow prisms).

To a solution of 5.0 g. of 2-amino-2'-trifluoromethylbenzophenone in 25 ml. of anhydrous ether, cooled to 0 C., 1.7 ml. of bromoacetylbromide was added with stirring; a precipitation occurred and the yellow color of the solution gradually faded. The suspension containing 2 bromoacetamido-Z trifluoromethylbenzophenone (not isolated) was stirred for half an hour at 0 C. and for two hours at room temperature. After that, 25 ml. of liquid ammonia was condensed into the flask, by introducing ammonia gas and using an efiicient Dry Ice-acetone condenser. The resulting mixture was stirred and refluxed (B.P. of liquid ammonia) for 3 hours. After taking off the condenser, the ammonia was allowed to evaporate overnight. The reaction mixture was extracted with ether (the ether layers being washed 3 times with water) and yielded crude 2-amino-2'-(2-trifluoromethylbenzoyl) acetanilide. Recrystallization from a mixture of 15 ml. of benzene and 15 ml. of hexane gave the pure product, melting at 141-l42 C. (colorless, rhombic plates).

3.0 g. of 2-amino-2'-(3-trifluoromethylbenzoyl) acetanilide was heated in an open tube for 15 minutes to 200-205" C., using an oil bath. Water was given off. On cooling, a brown glass was obtained which, on crystallization from a mixture of methanol and ether, gave crude 5 (2 trifluoromethylphenyl) 3H-1,4-benzodiazepin- 2(1H)-one. The mother liquor was evaporated to dryness, dissolved in benzene and chromatographed on 60 g. of neutral alumina (activity grade III, e.g. containing 6% of water). Elution with benzene (300 ml.) gave a product which could be crystallized to give some starting material. Then, with a benzene-ether-(l:1)-mixture (400 ml.), a crude product could be eluted. This, on crystallization from ether-hexane, gave the pure 5-(2 trifluoromethylphenyl) 3H 1,4-benzodiazepin-2(1H)- one, melting at 187-188 (almost colorless prisms).

7.3 g. of 5-(2-trifiuoromethylphenyl)-3H-1,4-benzodiazepin-2(1H)-one were dissolved at 0 in 58.4 ml. of concentrated sulfuric acid. To this, over a period of about 15 minutes, 3.22 g. of potassium nitrate were added with stirring. After keeping the reaction mixture for 30 minutes at it was allowed to stand for one hour at 25. Finally, it was heated to 50 for 3 hours. After standing overnight at 25 the yellow solution was poured over 250 g. of ice and the precipitate obtained, filtered and thoroughly washed with diluted ammonium hydroxide solution, diluted acetic acid and water. Crystallization from acetone-benzene of the thus-obtained crude product afforded the 7-nitro-5-(2-trifluoromethylphenyl)-3H-l,4-benzodiazepin-2(1H)-one. From the mother liquor and the filtrate, a second crop could be obtained. An analytical sample was prepared by recrystallization from acetone-methanol. Slightly yellow prisms (hexagonal), melting at 233-234, were obtained.

Example 12 To a solution of 6 g. of -(2-chlorophenyl)-7-dimethylamino-BH-l,4-benzodiazepin-2(lH)-one in 100 ml. of dimethylformamide 1.25 g. of solid sodium methoxide was added with stirring. The mixture was cooled to 0 and a solution of 4 g. of methyl iodide in 50 ml. of dimethylformamide was added dropwise. The temperature was maintained between 0 and The excess of methyl iodide was removed in vacuo without heating and the solution was poured into ice water. The aqueous phase was extracted with ether, the ether was washed with Water, dried and evaporated. The residue crystallized on addition of hexane and was recrystallized from a mixture of ether and hexane. Yellow prisms of 5-(2 chlorophenyl) 7 dimethylamine 1 methyl 3H- 1,4-benzodiazepin-2(1H)-one were obtained melting at 110-115 Example 13 To a solution of 4 g. of 7-dlm6thyla1'1'llI10-5-(06,0L,0ttrifluoro o tolyl) 3H 1,4 benzodiazepin 2(1H)- one in 50 ml. of dimethylformamide was added 0.6 g. of a 50% suspension of sodium hydride in mineral oil. The mixture was stirred and heated on a steambath to complete the reaction. After cooling to 0 a solution of 4.2 g. of methyl iodide in 25 ml. of dimethylformamide was added dropwise so that the temperature did not rise above 10". After 30 minutes the excess of methyl iodide was removed in vacuo without heating and the solution was poured into ice water. The aqueous solution was extracted with ether, the ether was washed with water,

dried and evaporated. The residue crystallized on addition of hexane and was recrystallized from a mixture of ether and cyclohexane. Yellow prisms of 7-dimethylamino 1 methyl 5 (oc,ot,ot trifluoro o tolyl) 3H- l,4-benzodiazepin-2(1H)-one melting at 110-115 were obtained.

Example 14 To a solution of 7.3 g. of 1-methyl-7-nitro-S-(a,cc, xtrifluoro o tolyl) 3H 1,4 benzodiazepin 2(1H)- one in 275 ml. of methanol was added 25 ml. of a 37% aqueous solution of formaldehyde and ca. 4 g. of Raney nickel. This mixture was shaken for 4 hours and at an initial pressure of 14 atm. hydrogen. The resulting solution was filtered from the catalyst and the methanol then evaporated in vacuo. The residue was dissolved in ether and dried with sodium sulfate. On addition of cyclohexane, crystals of 7-dimethylamino-l-methyl-S-(u,a,atrifluoro o tolyl) 3H 1,4 benzodiazepin 2(1H)- one were obtained which after recrystallization from a mixture of ether and cyclohexane melted at 110-115".

The above-mentioned 1-1'Il6thYl-7-I1ltI'O-5e(00,06,0t-l1'lfll1- oro o tolyl) 3H 1,4 benzodiazepin 2(1H) one,

its preparation and intermediates therefor, are not a part vof the instant invention, but such are disclosed hereinbelow in order that the present disclosure may be complete.

4.97 g. of 7-nitro-5-(2-trifluoromethyl-phenyl)-3H-l,4- benzodiazepin-2(lH)-one was dissolved in a cold solution of sodium methoxide obtained from 350 mg. of sodium and 50 ml. of anhydrous methanol. The solution was stirred at room temperature for 30 minutes after which 5 ml. of methyl iodide was added and stirring continued for 3 hours. The solution was then permitted to stand at -15 for several hours during which time a crystalline precipitate formed. The precipitate was filtered off, washed with water and with ether, and crystallized from acetone to yield 1-methyl-7-nitro-5-(2-trifiuoromethylphenyl)-3H-1,4-benzodiazepin 2(1H) one as almost colorless prisms melting at 198-199" C.

Example 15 A solution of 8.8 g. of 7-dimethylamino-l-methyl-S- phenyl-3H-l,4-benzodiazepin-2(1H)-one in 150 ml. of acetic acid was hydrogenated with 0.3 g. of platinum oxide at 25 and 1 atm. After 1 hour the uptake of hydrogen had stopped and the solution was filtered from the catalyst. 0n neutralization with sodium hydroxide white flocks separated which were extracted with dichloromethane. The organic phase was washed with water and dried over sodium sulfate. After evaporation of the dichloromethane the residue was recrystallized twice from ethanol yielding 4,5-dihydro-7-dimethylamino-l-methyl- S-phenyl-SH 1,4 benzodiazepin 2(1H) one as white prisms melting at 152-154".

Example 16 To a solution of 8 g. of 2',S-dichloro-Z-nitrobenzophenone in 175 ml. of ethanol there was added a solution of app. 5 g. of dimethylamine in 25 ml. of ethanol. The mixture was heated in an autoclave under nitrogen atmosphere to for 20 hours and the resulting solution concentrated in vacuo and cooled. Yellow prisms of 2-chloro-5-dimethylamino-2-nitrobenzophenone separated and were collected on a filter and, after recrystallization from methanol, melted at 156-158.

The above-mentioned 2,5-dichloro-2-nitrobenzophenone, its preparation and intermediates therefor, are not a part of the instant invention, but such are disclosed here in below in order that the present disclosure may be complete.

A mixture of 10.8 cc. of 90% hydrogen peroxide and 250 cc. of methylene chloride contained in a 1-liter flask fitted with a stirrer, reflux condenser and a dropping funnel was cooled with an ice bath. Trifluoroacetic anhydride (67.6 cc., g.) was then added over 45 minutes and after stirring for 5 minutes longer, the ice bath was removed and a solution of 26.6 g. of 2-amino-2',5-dichlorobenzophenone in 100 cc. of methylene chloride was added over 45 minutes. The resulting warm, dark solution was stirred and refluxed (steambath) for 1 hour. After cooling with a cold water bath, the reaction mixture was washed successively with two 200 cc. portions of ice water, two 200 cc. portions of cold 10% sodium carbonate and finally with 200 cc. of 10% sodium chloride solution. Emulsions were broken by filtration through a thin pad of diatomaceous earth. The methylene chloride solution was dried over magnesium sulfate and evaporated in vacuo (50) leaving a thick oily residue which soon crystallized exothermically. Recrystallized first from 425 cc. of ethanol (with use of decolorizing charcoal) and then a second time from 255 cc. of ethanol (with use of decolorizing charcoal), the product, 2-nitro-2,S-dichlorobenzophenone, melted at 1l0-112.

Example 17 and after recrystallization from a mixture of ethanol and water melted at approximately 70.

1 1 12 We claim: References Cited by the Examiner A compound of the formula UNITED STATES PATENTS 2,852,510 9/58 Holfmann et a1 260-2393 5 2,893,992 7/5'9' Sternbach 260-239 NH 2,914,563 11/59 Allen et al. 260-570 R1 2,914,564 11/59' Allen et al 260-570 2,926,180 2/60 Linn 260-570 3,045,008 7/62 Lombardino et al. 260-2393 10 3,109,843 11/63 Reeder et a1. 260-239 R5 OTHER REFERENCES Atkinson et al.: Chemical Abstracts, volume 49, pages 2414-15 (1955). 15 Maron: Chemical Abstracts, volume 8, page 670 ,(1914). and pharmaceutically acceptable acid addition salts there- Maren at at Chemical Abstracts, volume 9, page of wherein R and R are selected from the group con- 307 (1915) sisting of, individually, lower alkyl and, taken together with the nitrogen atom, piperidino, and R is selected CHARLES R PARKER, primary from the group consisting of hydrogen, halogen, lower 20 alkyl, lower alkoxy and trifluoromethyl. IRVING MARCUS Exammer' UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3,202,665 August 24, 1965 Werner Metlesics et al.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 2, lines 36 to 44, the formula should appear as shown below instead of as in the patent:

column 4 line 69, strike out "A mixture of 6.2 g. of Z-nitro- 5-piperidinobenzophene," and insert instead A solution of 3 g. of S-chloro-Z-nitrobenzophenone in column 7, line 58, for "4560" read 45-50 Signed and sealed this lZt h day of April 1966.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner of Patents