IL29501A - Process for the manufacture of benzodiazepine derivatives - Google Patents

Description

Process for the manufcature of benzodiazepine derivatives SPARAMEDICA A.G., C.27945 f ' RAN 4008/110 This invention is directed to a novel method for directly converting l,4-benzodiazepin-2-ones to 2-amino-l,4-benzodiazepines . ' Both 1, 4-benzodiazepin-2-ohes of the general formula wherein A represents the group R^ represents hydrogen, lower alkyl or lower alkoxy- lower alkylj R≥ represents phenyl, lower alkyl substituted phenyl, nitro substituted phenyl, halo substituted phenyl or pyridyl, and represents hydrogen, halogen, nitro, lower alkyl or trifluoromethyl, and 2-amino-l,4-benzodiazepines of the general formula wherein A, R^, and R have the meaning indicated above and R^ and R,_ represent hydrogen or lower alkyl and ^ and when taken together with their attached nitrogen atom form a '5 or 6 membered heterocyclic ring, are well known as' being useful as sedatives, muscle relaxants and anti-convulsants . However, up until the present, the compounds of formula I above and formula II above have- been prepared by separate synthetic routes utilizing different reactants. Therefore, it has long been desired to provide a synthesis whereby compounds of formula I can be converted into the compounds of formula II above, thereby eliminating the necessity of utilizing separate synthetic routes for the production of these compounds.

/ It has been found that the l,4-benzodiazepin-2-ones of formula I above can be directly converted into the 2-amino- 1,4-benzodiazepines of formula II above by reacting the compounds of formula I above with the- compound of the general formula wherein R.. and R-. have the meaning indicated above.

The reaction being' erformed in the presence of an acid catalyst in case of using a 1, -benzodiazepln-2-one starting materi and/or R^ represents nitro. In this manner, a method is provided for directly converting 1, 4-benzodiazepin-2-ones into 2-amino-l, ^-benzodiazepines thereby eliminating the necessity for providing two separate reaction routes for synthesizing the. compounds of formula I above and the compounds of formula II above. Furthermore, it has been found that yields . as high as 70 per ■ cent by weight of theoretical or higher can be obtained by this conversion.

In case of using a 1, 4-benzodiazepin-2-one of formula I, wherein A represents the group and represents hydrogen, lower alkyl, halogen or tri-fluoromethyl, and R, R, and R have the meaning indicated ' above, the reaction can be simply carried out without the necessity of utilizing an acid catalyst. However, if desired, an acid catalyst can be utilized also for such embodiment of the present invention. u ed thr u hout t fi at th term lower having from 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, and the like. In like manner, the term lower alkoxy includes all alkoxy radicals having from 1 to 7 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, etc. The term halogen includes all four halogens, i.e., iodine, bromine, chlorine and fluorine, with chlorine, fluorine and bromine being the preferred halogens.

The preferred l,4-benzodiazepin-2-ones of formula I above which are utilized as the starting materials in the reactions of this invention are those l,4-benzodiazepin-2-ones wherein is either hydrogen or methyl, and R2 is either phenyl, 2-pyridyl or phenyl substituted on the two position with a halo such as chlorine or fluorine. In formula I above, R-. is preferably either a halogen such as chlorine or fluorine, a trifluoromethyl, or a nitro group, and is attached to the 7-position of the benzodiazepin-2-one ring. If A in formula I above represents the group , is pre- ferably a chlorine or bromine radical substituted on the -7-position of the benzodiazepine ring.

The preferred organic amines which are utilized in ■ carrying out these reactions are primary amines such as methylamine, ethylamine, isopropyl amine, propyl amine, butyl-amine,etc. While it is preferred to utilize primary amines in carrying out the process of this invention, secondary amines can be utilized as well as the aforementioned primary ventional secondary amines which can be' utilized in this invention are included diethylamine, dimethylamine, N,N-propyl-butylamine, pyrrolidine, piperidine, etc.

The l,4-benzodiazepin-2-ones of formula I above can be converted to the 2-amino-l, -benzodiazepines of formula II above, in accordance with one embodiment of this invention, by treatment with an amino compound such as pyrrolidine, ammonia or any of the aforementioned primary or secondary lower alkyl amines, in the presence of an acid catalyst. In carrying out this reaction, any conventional acid catalyst can be utilized. Typical acid catalysts which may be utilized in carrying out this reaction include p-toluenesulfonic acid, Lewis acids such as titanium tetrachloride, aluminum trichloride, stannic tetrafluoride, ferric chloride, arsenic trichloride, antimony trichloride, boron trifluoride, etc.

The preferred acid catalysts which are utilized in accordance with this invention are p-toluene sulfonic acid and titanium tetrachloride. The conversion of the compounds of the formula I above into compounds of the formula II above preferably is carried out in the presence of an inert organic solvent. Any conventional inert organic solvent can be utilized in carrying out this reaction. Typical inert organic solvents which can be utilized in accordance with this invention include diethylether, tetrahydrof ran, - benzene, hexane, pentane, ethylpropylether and mixture thereof. In carrying out this reaction, temperature and pressure are not critical and this reaction can be effected at room temperature or below, and elevated pressure. Generally, it is preferred to carry out this reaction at a temperature of from about 0°C to about 25°C While it is generally preferable to utilize these low temperatures, temperatures as high as the reflux temperature. of the solvent can be utilized.

In cases as defined above where l, -benzodiazepin-2-ones of formula I bove are converted to the 2-amino-l, -benzodiazepinesof formula II above without utilizing an acid catalyst, this reaction is conveniently effected at elevated temperatures and pressures in the presence of an inert organic solvent. Any of the conventional inert organic solvents such as those hereinbefore mentioned can be utilized in carrying out this reaction. However, the preferred organic solvents are dimethylformamide and dimethylsulfoxide. In carrying out ■ this reaction, it is generally preferred to utilize temperatures of from about 100°C to about 175°C and pressures of from about 50 atmospheres to about 75 atmospheres. While this reaction can advantageously proceed without the use of an acid catalyst, such as hereinbefore mentioned, an acid catalyst ■· can, if desired, be utilized in this reaction. However, since no additional beneficial results are achieved by utilizing an acid catalyst, it is seldom necessary to. utilize an acid catalyst ' in this reaction.

If A in formula II is -^H-NH- such compound can be ■p easily converted into a 2 corresponding compound of s it-formula II, wherein A is - =N- by treatment with an oxidizing conventional oxidizin ' agent . Typical oxidizing agents which can be utilized are manganese dioxide, selenium dioxide, silver oxide, azodicarboxylicaeid ester, etc. Generally, it is preferred to carry out this reaction in a suitable organic solvent. Typical organic solvents which can be utilized in this oxidation reaction include benzene, toluene, acetic acid, butanol, pyridine, etc. In carrying out the oxidation reaction, temperature and pressure are not critical and the oxidation reaction can be carried out at room temperature or at elevated or reduced temperatures. Generally, it is preferred to carry out this oxidation reaction at a temperature of from 10°C to about 4o°C. The concentration of the reactants in the oxidation reaction is not critical but the oxidizing agent should preferably be used in stoichometrie excess of the compound which is being oxidized. By a stoichiometric excess it is meant an amount of in excess of stoichometrie equivalent but less than two stoichometrie equivalents..

The invention is furthe illustrated by the followin examples. In the examples, all temperatures are given in degrees centigrade.

Example 1 * A solution of .75 g of 7-chloro-l,3-dihydro-5-phenyl-2H-l, -benzodiazepin-2-one in 250 ml of Ν,Ν-dimethylformamide ■ at 10° was saturated with methylamine. The reaction mixture was placed in a pressure vessel which was then charged with / heated at 150° for 24 hours, cooled and vented to the atmosphere. The solution was poured Into 4 liters of water. The aqueous mixture was adjusted to pH 6 with hydrochloric acid and filtered. The precipitate was dissolved in 1 liter of dichloromethane which was then extracted with 3 N hydrochloric acid (3 x 250 ml). The acid extracts were combined, washed with dichloromethane (1 x 250 ml) made basic with ammonium hydroxide and extracted with dichloromethane (3 x 50 ml). The organic layers were combined, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was boiled with three 150 ml portions of benzene. The hot benzene fractions were combined and concentrated to give on cooling the crude 7-chloro-2-methylamino-5-phenyl-3H-l,4- ' benzodiazepine. Recrystallizations of the product from a mixture of dichloromethane and methanol gave 7-chloro-2-methyl amino-5-phenyl-3H-l,4-benzodiazepine as pale yellow prisms, m.p. 248-249°.

Example 2 A solution of 5 g of 7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one, 0 ml of pyrrolidine and 0,1 g of p-toluene sulfonic acid monohydrate in 100 ml of toluene was stirred- and refluxed using a water remover and a drying tube. After 22.5 hours, the distillate was discarded, and the residual solution in the reaction flask was evaporated in vacuo. The residue was extracted with a mixture of ether and 3N-aceti ' sodium hydroxide solution, to give crude 7-chloro-5-phenyl-2-pyrrolidine-3H-l, -benzodiazepine. This crude product was re-crystallized from isopropanol to yield pure 7-chloro-5-phenyl-2-pyrrolidine-3H-l, -benzodiazepine.

A solutio of 5 g (0.0184 m) of 7-chloro-l,3-dihydro-5-phenyl-2H-l, -benzodiazepin-2-one in 125 rnl of dry tetrahydro-furan was added to a solution of 15 g. of methylamine in 100 ml of dry tetrahydrofuran. The mixture was contained in a three neck round bottom flask fitted with a stirrer, dropping funnel and "dry ice" condenser. The flask was externally cooled in an ice bath and the mixture was kept under nitrogen. A tetrahydrofuran, titanium tetrachloride complex prepared by adding 1.8 g (0.01 m) of titanium tetrachloride to 60 ml of tetrahydrofuran was added slowly (20 min.) to the re-action mixture. The resulting mixture was continually stirred and allowed to reach room temperature. After 4 hours, thin layer chromatography indicated that the reaction was complete. The reaction mixture was allowed to stand overnight and then filtered. The filtrates were evaporated to. dryness, and the residue was dissolved in 500 ml of dichloromethane . The organic solution was washed with dilute ammonium hydroxide (1 x 200 ml), saturated brine solution (2 x 100 ml), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was recrys^tallized from a mixture of tetrahydrofuran and hexane to give 7-chloro-2-methylamino-5-phenyl-3H-l, -benzodiazepine .

Example A solution of 5 "g- (0.0178 m) of l,3-dihydro-7-nitro-5-phenyl-2H-l,4-benzodiazepin-2-one in 150 ml of dry tetrahydro-furan was added to a solution of 10 g of methylamine in 100 ml of dry tetrahydrofuran. The resulting solution was cooled as described in Example 3 and. treated with a solution of 2.4 g (O.OI3 m) of titanium tetrachloride in 50 ml of dry benzene. The mixture was warmed to room temperature and stirred overnight. Approximately 10 ml of water was added to decompose excess titanium tetrachloride and the solution was filtered. After the solvent was removed, the residue was treated with 0 ml of ethanol. The residue was filtered to remove solids. After filtration, the remaining liquor was concentrated to yield 2-methylamino-7-nitro-5-phenyl-3H-l, ^-benzodiazepine .

Example 5 A solution of 10 g (0.02 8 m) of 7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one 4-oxide in 400 ml of dry tetrahydrofuran was added to a solution of 20 g of methylamine in 200 ml of dry tetrahydrofuran. The resulting mixture was cooled as described in Example 3 and. then treated with a tetrahydrofuran, titanium tetrachloride complex prepared from 4.8 g (O.025 m) of titanium tetrachloride and 100 ml of dry tetrahydrofuran (addition time 20 min.) The resulting mixture was allowed to warm to room temperature, stand overnight, and 2-methylamino-5-phenyl-3H-l>4-benzodiazepin-4-oxide as pale yellow prisms.

Example 6 A solution of 10 g (0.0348 m) of 7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one 4-oxide in 400 ml of dry tetrahydrofuran was added to a solution of 20 g of dimethyl-amine in 200 ml of dry tetrahydrofuran. The solution was cooled as described in Example 3 a^d then treated with a solution of 4.8 g (0.025 m) of titanium tetrachloride in 100 ml of dr benzene (addition time 20 min.). The reaction mixture was allowed to reach room temperature, stirred for 3 hours, when 10 ml of water was added. The solution was filtered and the solvent was removed under reduced pressure. The residue was stirred in 50 ml of ethanol and then shaken vigorously with 100 ml of 0.5 N sodium hydroxide solution to remove starting material. The mixture was diluted with 400 ml of water and then filtered. The precipitate was washed with water and re-crystallized from ethanol to give 7-chloro-2-dimethylamino-5-phenyl-3H-l,4-benzodiazepine 4-oxide.

Example 7 A solution of 10 g (0.0348' m) of 7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one 4-oxide in 400 ml of dry tetrahydrofuran was treated at 0-10° first with 15 ml of isopropylamine and then with a solution of 4.8 g (0.025 m) of time 20 min.). The reaction mixture was allowed to warm to room temperature and was stirred overnight. Water (10 ml) was added and the solution was filtered · then evaporated. The residue was stirred in 50 ml of ethanol and shaken well with 100 ml of 0.5 N sodium hydroxide solution to remove starting material. The mixture was diluted with 400 ml of water and filtered. The insoluble product was washed on the filter with water and was then recrystallized from ethanol to give 7-chloro-2-isopropylamino-5-phenyl-5H-l,4-benzodiazepine 4-oxide .

Example 8 A mixture of 10 g (0.0348 m) of 7-chloro-l,3-dihydro-5- ■ phenyl-2H-l, 4-benzodiazepin-2-one 4-oxide and 15 ml of piperi-dine in 400 ml of dry tetrahydrofuran was cooled as in Example 3 and then treated with a solution of 4.8 g (0.025 rn) of titanium tetrachloride in 100 ml of dry benzene (addition time 20 min.). The mixture was allowed to warm to room temperature and stirred overnight. Water (10 ml) was added and the reaction mixture was filtered. Solvents were removed, the residue was stirred in 0 ml of ethanol and then shaken thoroughly with 100 ml of 0.5 N sodium hydroxide solution. The mixture was filtered and the precipitate was washed with water. Re-crystallization from a mixture of dichloromethane and hexane gave 7-chloro-5-phenyl-2-piperidino-^H-l,4-benzodiazepine 4-oxide as pale yellow prisms. · Example 9 -phenyl-2H-l,4-benzodiazepin-2-one 4-oxide in 400 ml of dry tetrahydrofuran- was stirred in a three neck round bottom flask fitted with a "dry ice" condenser and. dropping funnel. The flask was cooled externally with an ice bath. Ammonia gas was bubbled into the solution until liquid ammonia was rapidly condensing on the "dry ice" finger. A solution of 4.8 g (0.025 m) of titanium tetrachloride in 100 ml of benzene was next added dropwise (addition time 20 min.). The cooling bath was' removed and the reaction mixture was allowed to reach room temperature. After stirring overnight 10 ml of water was added and the solution was filtered. Removal of solvents gave a residue which was slurried with 0 ml of ethanol and then shaken vigorously with 100 ml of 0.5 N sodium hydroxide solution. The resulting mixture was diluted with 400 ml of water and the precipitate was removed by filtration and washed with water. Recrystallization from methanol gave 2-amino-7-chloro-5-phenyl-3H-l,4-benzodiazepine 4-oxide.

Example 10 To a suspension of 25 g (0.0916 m) of 7-chloro-l,3, 4,5-tetrahydro-5-phenyl-2H-l, 4-benzodiazepin-2-:one dissolved in 5OO ml of dry tetrahydrofuran (under a nitrogen atmosphere) was added a solution of J>0 g of methylamine in J>00 ml of dry tetrahydrofuran. The above mixture was cooled in an ice bath, and a solution of 12 g (0.0632 m) of. titanium tetrachloride in 100 ml of benzene was added over a 10 min. period with stirrin . The ice bath was removed, and after 4 hours 20 ml was washed v/ith tetrahydrofuran and the combined filtrates were evaporated to dryness. The oil was crystallized from a methanol/ether mixture to yield solid 7-chloro-4,5-dihydro-2-methylamino-5-phenyl-3H-l, 4-benzodiazepine as white plates, m.p. and m.m.p. 175-180°.

To a solution of 2.0 g (0.007 m) of 7-chloro-4,5-di-hydro-2-methylarnino-5-phenyl-3H-l, 4-benzodiazepine in 50 ml of dry benzene was added a solution of 1.2 g (0.007 m) of diethyl azodiacrboxylate in 10 ml of dry benzene. The re-suiting solution was refluxed for 1 hour, cooled, extracted with 50 ml of dilute ammonium hydroxide and filtered to give 7-chloro-2-methylamino-5-phenyl-3H-l, -benzodiazepine as white prisms. /

Claims (10)

1. na to de , en wherein A, R^, Rg' nd R^ have the meaning indicated above, a compound of the general formula wherein ^ and have the meaning indicated above, the reaction being performed in the presence of an acid catalyst in case of using a l, -benzodiazepin-2-one starting ■materia and/or

2. A process as claimed in Claim 1, wherein a 1,4-benzodiazepin-2-one starting material of formula I is used, wherein A represents the group * re~ presents hydrogen, lower alkyl, halogen or trifluorometh l and R, R, and R_ have the meanin indicated in Claim 1 and the reaction is performed in the presence of an acid catalyst.

3. - A process as "claimed in Claim 1 or 2 , wherein said acid catalyst is p-toluene sulfonic acid.

4. A process as claimed in Claim 1 or 2, wherein said acid catalyst is titanium tetrachloride.

5. · A process as claimed in Claim 1. or 2, wherein said acid catalyst is aluminum chloride .

6. A process as claimed in any one of Claims 1 to 5, wherein the reaction is carried out in an inert organic solvent.

7. · A process as claimed in Claim 6, wherein said inert organic solvent is tetrahydrofuran.

8. A process as claimed in Claim 1 , wherein the reaction is carried out in Ν, -dimethylformarnide without utilizing an acid catalyst.

9. · A process as claimed in Claim 1, wherein the reaction is carried out at a temperature of from about 100°C to about 175°C and at a pressure of from 50 to 75 atmospheres without utilizing an acid catalyst. 10. A process as claimed in any one of Claims 1 to 9, wherein a starting material of Formula I in Claim 1 is 7-position of the molecule. 11. A process as claimed in Claim 10, wherein a starting material of Formula I in Claim 1 is used, wherein A is the group phenyl 12. A process as claimed in any one of Claims 1 to 11, wherein the compound III is methylamine. 13. A process as claimed in any one of Claims 1 to 11, wherein the compound III is pyrrolidine or piperidine. / 1 . 14. A process for the preparation of benzodiazepine of the formula II set forth in"Claim 1. derivatives /as hereinbefore particularly described, especially with reference to the foregoing Examples. 15. Benzodiazepine derivatives of the general formula / wh R^represents hydrogen, lower alkyl or lower alkoxy- lower alkyl; Kg represents phenyl, lower alkyl substituted phenyl, nitro substituted phenyl, halo substituted phenyl pr. pyridyl; R-, .represents hydrogen, halogen, nitro, lower alkyl or trifluorometh l; ^ and Rj. represent hydrogen or .lower alkyl and ^ and R,- when taken together with their attached nitrogen. ·. atom, form a five or six membered heterocyclic ring, whenever prepared by the process of any one of Claims 1 to 9 or by an obvious chemical equivalent thereof. 16. Benzodiazepine derivatives of the formula in Claim 15, wherein is hydrogen and is chlorine and in the 7-posi-tion of the molecule, whenever prepared by the process of 17 · Benzodiazepine derivatives as claimed in Claim 16 , wherein the group in , whenever prepared by the process of Claim 11 or by an obvious chemical equivalent thereof.

10. Benzodiazepine derivatives as claimed in any one of Claims 15 to 17 bearing a methylamino group in the 2-posi-tion, whenever prepared by the process of Claim 12 or by an obvious chemical equivalent thereof. 19 · Benzodiazepine derivatives as claimed in any one of Claims 15 to 17 bearing a pyrrolidino or piperidino group in. the 2-position, whenever prepared by the process of Claim 13 or by an obvious chemical equivalent thereof. 20 . 7-Chloro-2-methylamino-5-phenyl-5H-l, 4-benzodiaze-pin-4-oxide, whenever prepared by the process of Claim 12 or by an obvious chemical equivalent thereof. Bated this 19th <¾ajf of Pebsw-fy* 19ββ