Title of Invention	IMIDAZODIAZEPINE DERIVATIVE
Abstract	The present invention relates to a process for manufacturing diazepine derivatives of the general formula I wherein R<SUP>1</SUP> is lower alkyl and R<SUP>2</SUP> is hydrogen, or R<SUP>1</SUP>and R<SUP>2</SUP> are together -(CH<SUB>2</SUB>)<SUB>n</SUB>- and n is 2 or 3; R<SUP>3</SUP> is halogen, lower alkyl, lower alkoxy and m is 0, 1 or 2; R<SUP>4</SUP> is hydrogen or lower alkyl. The compounds of general formula (I) are valuable intermediate products for the manufacture of imidazo[1,5-a][1,4]diazepine derivatives, like for instance 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[1,5-a][1,4]benzodiazepin-6-one, which diazepine derivatives show excellent psychopharmacological properties as agonists of the central benzodiazepine receptors.

Title of Invention

IMIDAZODIAZEPINE DERIVATIVE

Abstract

The present invention relates to a process for manufacturing diazepine derivatives of the general formula I wherein R1 is lower alkyl and R2 is hydrogen, or R1and R2 are together -(CH2)n- and n is 2 or 3; R3 is halogen, lower alkyl, lower alkoxy and m is 0, 1 or 2; R4 is hydrogen or lower alkyl. The compounds of general formula (I) are valuable intermediate products for the manufacture of imidazo[1,5-a][1,4]diazepine derivatives, like for instance 7-chloro-3-(5-dimethylaminomethyl-[1,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[1,5-a][1,4]benzodiazepin-6-one, which diazepine derivatives show excellent psychopharmacological properties as agonists of the central benzodiazepine receptors.

Full Text	Process for manufacturing diazepine derivatives The present invention relates to a process for manufacturing diazepine derivatives of the general formula wherein Rl is lower alkyl and R2 is hydrogen, or R1 and R: are together -(CHi)n- and n is 2 or 3; R3 is halogen, lower alkyl, lower alkoxy and m is 0,1 or 2; R4 is hydrogen or lower alkyl. The compounds of general formula I are valuable intermediate products for the manufacture of imidazo[l,5-a][l,4]diazepine derivatives, like for instance 7-chloro-3-(5- dimethylaminomethyl-[l,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro- imidazo[ 1,5-a] [ 1,4]benzodiazepin-6-one, which diazepine derivatives show excellent psychopharmacological properties as agonists of the central benzodiazepine receptors. wherein R and R have the meaning mentioned above. This reaction step takes place in a polar solvent such as for instance DMF, under atmospheric pressure and at a temperature between 110°C and the boiling point of the reaction mixture. The compounds of formula II can be obtained, on their turn, by reacting a compound of formula wherein R3 and m have the meaning mentioned above, with: a) phosgene and hydrochloric acid in THF; or b) ethyl haloformiate, e.g. ethyl chloroformiate, in dioxane and subsequent treatment with acetylchloride. Both steps take place in a batch system, under atmospheric pressure and at the boiling temperature of the reaction mixture (see e.g. G. M. Coppola, "The Chemistry of Isatoic Anhydride", Synthesis, Georg Thieme Verlag, (1980), pp 505-535). The last step of the mentioned production pathway is characterised by low yields. This is mainly due to a low conversion of the reactants and, in certain cases, also to a low selectivity towards the desired product because of the formation of a side product of general formula f These low yield and selectivity imply higher costs for the production of the compounds of formula I and lead to important disposal problems since the compounds of formula V cannot be used for other purposes and must be therefore destroyed or recycled. The problem at the root of the present invention is therefore to provide a process for manufacturing the compounds of general formula I which can overcome the disadvantages mentioned above. The problem is solved, according to the present invention, by a process for manufacturing diazepine derivatives of the general formula I, comprising the step of reacting a compound of general formula II with a compound of general formula III, characterised in that said compound of general formula II and said compound of general formula III undergo chemical reaction in the absence of a solvent or in the presence of an apolar solvent. It has been surprisingly found that the conversion, and in certain cases also the selectivity, towards the compound of formula I strongly increases if the reaction components (i.e. compounds of formula II and III) are not solvated in the reaction mixture. This situation can take place only if no solvent at all is added to the reaction mixture or if the reactants and/or products are not soluble in a given solvent. Being the present compounds of polar nature, apolar solvents can be used in the process of the invention for achieving the wished results. Particularly preferred solvents are substituted benzene rings, such as xylenes, mesitylene, ethylbenzene, isopropylbenzene, etc. Most preferably, p-xylene or a mixture of xylenes are used as solvent for carrying out the process according to the present invention. The reaction temperature is preferably set from 0 to 30°C under the boiling temperature of the reaction mixture. The process of the present invention is particularly suitable for the manufacture of 6-Chloro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2,5(lH)-dione. By way of examples, preferred embodiments of the present invention will now be described. Comparative tests were made in which the compounds of formulae II and III underwent reaction in the conventional manner, i.e. using DMF as (polar) solvent. The yields of compound I (Y(CI)) depicted in Table 1 were measured on the purified product. The ratios of compounds I and V depicted in Table 2 (R(CI) and R(CV)) were directly obtained from the HPLC measurements (HP 1050, column CC70/4 nucleosil 100-5C18HD), and refer to the molar percentage of CI and CV in the crude product of the reaction. Y(CI) = 100* [mol Cl/mol CII] CI, CII, CV = compound of general formula I, II, V Example 1 6-Chloro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2>5(lH)-dione. 25.0 g (126 mMol) 5-chloro-lH-benzo[d][l,3]xazin-2,4-dione and 12.4 g (139 mMol) sarcosine were suspended in 100 mlp-xylene and heated at reflux (oil bath temperature (Text) MS (EI): 224 (M'+, 52); 153 (68); 44(100). Example 2 6-Methyl-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2)5(lH)-dione. 1.0 g (5.6 mMol) 5-methyl-lH-benzo[d][l,3]xazin-2,4-dione and 0.57 g (6.4 mMol) sarcosine were suspended in 4 ml p-xylene and heated at reflux (Tcxt Example 3 7-Fluoro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2,5(lH)-dione. 1.0 g (5.5 mMol) 6-fluoro-lH-benzo[d][l,3]xazin-2>4-dione and 0.54 g (6.1 mMol) sarcosine were suspended in 4.0 ml p-xylene and heated to reflux for 4 hours. The suspension was cooled to r.t. and the precipitate filtered off. The solid obtained was digested 30 minutes at 0°C in 5 ml deionised water, filtered off and dried for 16 hours at 60°C under vacuum to yield 0.92 g (80% mol) of 7-fluoro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2,5(lH)-dioneofm.p. > 250°C. MS (EI): 208 (NT, 94); 179 (100); 137(92). Example 4 7-Chloro-6-fluoro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2)5(lH)-dione. 1.0 g (4.6 mMol) 5-chloro-6-fluoro-lH-benzo[d][l)3]xazin-2,4-dione and 0.45 g (5.0 mMol) sarcosine were suspended in 4.0 mlp-xylene and heated to reflux (Text = 145°C) for 7 hours. Solvent was removed under reduced pressure and the residue was digested in 2.0 ml deionised water 1 hour at r.t. The precipitate was filtered off and crystallized from 10 ml methanol and 10 ml diethylether to give 0.63 g (56% mol) of 7-chloro-6-fluoro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2,5(lH)-dione of m.p. > 250°C. Concentration of the mother liquors and crystallization from 3 ml methanol and 9 ml diethylether gave an additional 0.13 g (11%) of 7-chloro-6-fluoro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2,5(lH)-dione of m.p. > 250°C. Example 5 (S)-6-Chloro-l,2,3Jla-tetrahydro-5H-pyrrolo[2,l-c][l>4]-benzodiazepine-5,ll(10H)-dione. 0.50 g (2.5 mMol) 5-chloro-lH-benzo[d][l,3]xazin-2,4-dione and 0,32 g (2.8mMol) L-proline were suspended in 4.0 ml p-xylene and heated at reflux (Text 250°C. Example 6 (S)-l,10a-5-Chloro-2H-azeto[2,l-c][l,4]benzodiazepine-4,10(9H)-dione. 1.0 g (5.1 mMol) 5-chloro-lH-benzo[d] [l,3]xazin-2,4-dione and 0.56 g (5.6 mMol) (S)-azetidine-2-carboxylic acid were suspended in 6.0 mlp-xylene arid heated to reflux for 24 hours. p-Xylene was removed under reduced pressure and the residue was partitioned between dichloromethane and water and the aqueous phase extracted with dichloromethane. The combined organic extracts were dried (Na2SO,) and the solvent removed under reduced pressure. The brown solid obtained was digested in 5 ml tert-butyl-methylether for 16 hours at r.t., filtered and dried under reduced pressure to give 0.99 g (82% mol) of (S)-l,10a-5-chloro-2H-azeto[2,l-c][l>4]benzodiazepine-4>10(9H)-dione as a beige powder of m. p. = 180-198°C Example 7 (S)-l-Methyl-l>2>3Jla-tetrahydro-5H-pyrrolo[24-c][l,4]-benzodiazepine-5,ll(10H)-dione. 0.5 g (2.82 mMol) N-metyI-lH-benzo[d][l,3]xazin-2,4-dione and 0.36 g (3.1 mMol) L-proline were suspended in 1.0 ml p-xylene and heated to reflux for 1 hour (goes into solution upon heating). After cooling to r.t., the reaction mixture was diluted with 10 ml dichloromethane and 5 ml deionised water and the phases separated. The aqueous phase was extracted with 8 ml dichloromethane twice. The combined organic extracts were dried (Na2S04) and evaporated. The residue was digested in 2 ml fert-butyl-methylether for 2 hours at r.t. to give 0.53 g (81.5% mol) of (S)-l-methyl-l,2,3,lla-tetrahydro-5H-pyrrolo[2,l-c][l,4]-benzodiazepine-5,ll(10H)-dione as beige crystals of m. p. = 117-118.5°C. MS (EI): 230 (M+, 56); 161 (99); 133 (90); 105 (88); 70(100). Example 8 6-Chloro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2,5(lH)-dione. 1.0 g (5.0 mMol) 5-chloro-lH-benzo[d][l,3]xazin-2,4-dione and 0.50 g (5.56 mMol) sarcosine were suspended in 4.0 ml of a mixture of xylenes and heated at reflux (Text MS (EI): 224 (M\48); 195(34); 153(60) 126(36), 44(100). Example 9 7-Chloro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2)5(lH)-dione. 1.0 g (5.06 mMol) 6-chloro-lH-benzo[d][l,3]xazin-2,4-dione and 0.67 g (7.59 mMol) sarcosine were thoroughly mixed and heated to 140°C for 2 hours then 150°C for 20 hours. The brown powder obtained was cooled to r.t. and digested in 4.0 ml water at 0°C for 1 hour, filtered and washed with 1.0 ml water. After drying under vacuum, 1.0 g (88% mol) 7-chloro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2,5(lH)-dione was obtained as a beige powder of m. p. > 250°C. MS (EI): 224 (M",78); 195 (86); 153(80), 44(100). conventional processes. Therefore, the process according to the present invention enables an increase of the productivity, thereby decreasing costs and disposal problems. As stated above, the products obtained with the process according to the invention can be used for manufacturing imidazo[l,5-a] [l,4]diazepine derivatives with excellent psychopharmacological properties. Example 11 illustrates a possible method for producing one of such diazepine derivatives. Example 11 7-chloro-3-(5-dimethylaminomethyl-[l,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro- imidazo[l,5-a][l,4]benzodiazepin-6-one. Ethyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[l,5-a][li4]benzodiazepine- 3-carboxylate. 25.0 g 6-Chloro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2,5(lH)-dione were suspended under stirring and argon atmosphere in 200 ml toluene and 32.1 ml N,N-dimethyl-p-toluidine. The suspension was heated to 100°C and 11.2 ml phosphorus oxychloride were added over 30 minutes and stirring was pursued two and an half hours at 100°C. The dark-orange solution was cooled to 40°C and toluene was removed under reduced pressure to give 82 g of a dark-orange oil. Meanwhile, 81.2 ml hexamethyldisilazane and 265 ml tetrahydrofiiran were mixed and cooled to -35°C. 229.5 ml Butyllithium were added over 45 minutes and, after stirring 30 minutes at -35°C, a solution of 35.2 g ethyl(dimethylamino-methylenamino)acetate in 70.4 ml tetrahydrofiiran was added over 30 minutes. The orange solution obtained was stirred one more hour at -35°C and a solution of the crude iminochloride in 100 ml tetrahydrofuran was added over 1 hour at -15°C. The dark red solution was stirred one hour at -15°C, then 18 hours at room temperature (r.t.). 75 ml Acetic acid were added in 10 minutes, then 75 ml deionized water were added in one portion and the orange suspension was heated at reflux for two hours. Tetrahydrofiiran was removed under reduced pressure and the residue was partitioned between 200 ml dichloromethane and 100 ml deionized water. The phases were separated and the organic phase was washed with 100 ml aqueous HC1 IN twice and with 100 ml deionized water. The aqueous phases were extracted twice with 100 ml dichloromethane. The combined organic extracts were dried (Na2S04) and evaporated. The residue was digested in 200 ml n-heptane 30 minutes at r.t. and filtered off. The sticky crystals obtained were digested at reflux for 30 minutes in 213.5 ml ethanol, then stirred 3 hours to r.t. and 2 hours at -20°C. The precipitate (ethyl 7- r organic extracts were dried (Na2S04) and the solvent was removed under reduced pressure. Crude product: 8.0 g as a light yellow foam. Purification The crude product was dissolved in 40 ml ethanol at reflux and 400 mg active charcoal Darco G 60 were added. The system was stirred 1 hour at reflux, then filtered on a hot pad of Dicalit Speedex, which was washed with two portions of 40 ml hot ethanol. The filtrate was concentrated to 14 g under reduced pressure, heated to reflux and at this temperature and 40 ml ferf-butyl-methylether were added over 5 minutes. The suspension was cooled slowly to r.t., stirred 16 hours, further cooled to 2°C. After stirring 1 hour at 2°C, the precipitate was filtered off, washed with 20 ml tert-butyl-methylether and dried 1 hour at 60°C under vacuum. The so obtained powder was dissolved at reflux in 26 ml ethyl acetate. 6.5 ml Ethyl acetate were then distilled off and the turbid solution obtained was slowly cooled to r.t., then to 0°C. After 1 hour stirring at 0°C, the precipitate was filtered off, washed with 10 ml cold rerr-butyl-methylether and dried under vacuum at 60°C for 16 hours. The so obtained powder (7-chioro-3-(5-dimethylaminomethyl-[ l,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[l,5-a][l,4]benzodiazepin-6-one (I)) was crystallized a second time in 24.3 ml ethyl acetate according to the procedure described above. Product: 5.5 g as a white powder, m.p. 151.5-153°C. WE CLAIM: 1. Process for manufacturing diazepine derivatives of the general formula I wherein R1 is lower alkyl and R2 is hydrogen, or R1 and R2 are together -(CH2)n- and n is 2 or 3; R3 is halogen, lower alkyl, lower allcoxy and m is 01 1 or 2\ R4 is hydrogen or lower alkyl, comprising the step of reacting a compound of general formula 2. The process according to claim 1, wherein the solvent is a substituted benzene ring. 3. The process according to claim 2, wherein the solvent is p-xylene. 4. The process according to claim 2, wherein the solvent is a mixture of xylenes. 5. The process according to any one of claims 1 to 4, wherein the compound of formula I is 6-Chloro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2,5(lH)-dione. 6. The process according to any one of claims 1 to 5, wherein the reaction temperature is from 0 to 30°C under the boiling temperature of the reaction mixture.

Full Text

Process for manufacturing diazepine derivatives
The present invention relates to a process for manufacturing diazepine derivatives of the general formula

wherein Rl is lower alkyl and R2 is hydrogen, or R1 and R: are together -(CHi)n- and n is 2 or 3; R3 is halogen, lower alkyl, lower alkoxy and m is 0,1 or 2; R4 is hydrogen or lower alkyl.
The compounds of general formula I are valuable intermediate products for the
manufacture of imidazo[l,5-a][l,4]diazepine derivatives, like for instance 7-chloro-3-(5-
dimethylaminomethyl-[l,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-
imidazo[ 1,5-a] [ 1,4]benzodiazepin-6-one, which diazepine derivatives show excellent
psychopharmacological properties as agonists of the central benzodiazepine receptors.

wherein R and R have the meaning mentioned above. This reaction step takes place in a polar solvent such as for instance DMF, under atmospheric pressure and at a temperature between 110°C and the boiling point of the reaction mixture.
The compounds of formula II can be obtained, on their turn, by reacting a compound of formula

wherein R3 and m have the meaning mentioned above,
with:
a) phosgene and hydrochloric acid in THF; or
b) ethyl haloformiate, e.g. ethyl chloroformiate, in dioxane and subsequent treatment with acetylchloride.
Both steps take place in a batch system, under atmospheric pressure and at the boiling temperature of the reaction mixture (see e.g. G. M. Coppola, "The Chemistry of Isatoic Anhydride", Synthesis, Georg Thieme Verlag, (1980), pp 505-535).
The last step of the mentioned production pathway is characterised by low yields. This is mainly due to a low conversion of the reactants and, in certain cases, also to a low selectivity towards the desired product because of the formation of a side product of general formula

f These low yield and selectivity imply higher costs for the production of the compounds of
formula I and lead to important disposal problems since the compounds of formula V
cannot be used for other purposes and must be therefore destroyed or recycled.
The problem at the root of the present invention is therefore to provide a process for manufacturing the compounds of general formula I which can overcome the disadvantages mentioned above.
The problem is solved, according to the present invention, by a process for manufacturing diazepine derivatives of the general formula I, comprising the step of reacting a compound of general formula II with a compound of general formula III, characterised in that said compound of general formula II and said compound of general formula III undergo chemical reaction in the absence of a solvent or in the presence of an apolar solvent.
It has been surprisingly found that the conversion, and in certain cases also the selectivity, towards the compound of formula I strongly increases if the reaction components (i.e. compounds of formula II and III) are not solvated in the reaction mixture. This situation can take place only if no solvent at all is added to the reaction mixture or if the reactants and/or products are not soluble in a given solvent. Being the present compounds of polar nature, apolar solvents can be used in the process of the invention for achieving the wished results.
Particularly preferred solvents are substituted benzene rings, such as xylenes, mesitylene, ethylbenzene, isopropylbenzene, etc. Most preferably, p-xylene or a mixture of xylenes are used as solvent for carrying out the process according to the present invention.
The reaction temperature is preferably set from 0 to 30°C under the boiling temperature of the reaction mixture.
The process of the present invention is particularly suitable for the manufacture of 6-Chloro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2,5(lH)-dione.
By way of examples, preferred embodiments of the present invention will now be described. Comparative tests were made in which the compounds of formulae II and III underwent reaction in the conventional manner, i.e. using DMF as (polar) solvent.

The yields of compound I (Y(CI)) depicted in Table 1 were measured on the purified product. The ratios of compounds I and V depicted in Table 2 (R(CI) and R(CV)) were directly obtained from the HPLC measurements (HP 1050, column CC70/4 nucleosil 100-5C18HD), and refer to the molar percentage of CI and CV in the crude product of the reaction.
Y(CI) = 100* [mol Cl/mol CII]
CI, CII, CV = compound of general formula I, II, V
Example 1 6-Chloro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2>5(lH)-dione.
25.0 g (126 mMol) 5-chloro-lH-benzo[d][l,3]xazin-2,4-dione and 12.4 g (139 mMol) sarcosine were suspended in 100 mlp-xylene and heated at reflux (oil bath temperature (Text) MS (EI): 224 (M'+, 52); 153 (68); 44(100).
Example 2 6-Methyl-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2)5(lH)-dione.
1.0 g (5.6 mMol) 5-methyl-lH-benzo[d][l,3]xazin-2,4-dione and 0.57 g (6.4 mMol) sarcosine were suspended in 4 ml p-xylene and heated at reflux (Tcxt

Example 3 7-Fluoro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2,5(lH)-dione.
1.0 g (5.5 mMol) 6-fluoro-lH-benzo[d][l,3]xazin-2>4-dione and 0.54 g (6.1 mMol) sarcosine were suspended in 4.0 ml p-xylene and heated to reflux for 4 hours. The suspension was cooled to r.t. and the precipitate filtered off. The solid obtained was digested 30 minutes at 0°C in 5 ml deionised water, filtered off and dried for 16 hours at 60°C under vacuum to yield 0.92 g (80% mol) of 7-fluoro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2,5(lH)-dioneofm.p. > 250°C.
MS (EI): 208 (NT, 94); 179 (100); 137(92).
Example 4 7-Chloro-6-fluoro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2)5(lH)-dione.
1.0 g (4.6 mMol) 5-chloro-6-fluoro-lH-benzo[d][l)3]xazin-2,4-dione and 0.45 g (5.0 mMol) sarcosine were suspended in 4.0 mlp-xylene and heated to reflux (Text = 145°C) for 7 hours. Solvent was removed under reduced pressure and the residue was digested in 2.0 ml deionised water 1 hour at r.t. The precipitate was filtered off and crystallized from 10 ml methanol and 10 ml diethylether to give 0.63 g (56% mol) of 7-chloro-6-fluoro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2,5(lH)-dione of m.p. > 250°C.
Concentration of the mother liquors and crystallization from 3 ml methanol and 9 ml diethylether gave an additional 0.13 g (11%) of 7-chloro-6-fluoro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2,5(lH)-dione of m.p. > 250°C.

Example 5
(S)-6-Chloro-l,2,3Jla-tetrahydro-5H-pyrrolo[2,l-c][l>4]-benzodiazepine-5,ll(10H)-dione.
0.50 g (2.5 mMol) 5-chloro-lH-benzo[d][l,3]xazin-2,4-dione and 0,32 g (2.8mMol) L-proline were suspended in 4.0 ml p-xylene and heated at reflux (Text 250°C.

Example 6
(S)-l,10a-5-Chloro-2H-azeto[2,l-c][l,4]benzodiazepine-4,10(9H)-dione.
1.0 g (5.1 mMol) 5-chloro-lH-benzo[d] [l,3]xazin-2,4-dione and 0.56 g (5.6 mMol) (S)-azetidine-2-carboxylic acid were suspended in 6.0 mlp-xylene arid heated to reflux for 24 hours. p-Xylene was removed under reduced pressure and the residue was partitioned between dichloromethane and water and the aqueous phase extracted with dichloromethane. The combined organic extracts were dried (Na2SO,) and the solvent removed under reduced pressure. The brown solid obtained was digested in 5 ml tert-butyl-methylether for 16 hours at r.t., filtered and dried under reduced pressure to give 0.99 g (82% mol) of (S)-l,10a-5-chloro-2H-azeto[2,l-c][l>4]benzodiazepine-4>10(9H)-dione as a beige powder of m. p. = 180-198°C

Example 7
(S)-l-Methyl-l>2>3Jla-tetrahydro-5H-pyrrolo[24-c][l,4]-benzodiazepine-5,ll(10H)-dione.
0.5 g (2.82 mMol) N-metyI-lH-benzo[d][l,3]xazin-2,4-dione and 0.36 g (3.1 mMol) L-proline were suspended in 1.0 ml p-xylene and heated to reflux for 1 hour (goes into solution upon heating). After cooling to r.t., the reaction mixture was diluted with 10 ml

dichloromethane and 5 ml deionised water and the phases separated. The aqueous phase was extracted with 8 ml dichloromethane twice. The combined organic extracts were dried (Na2S04) and evaporated. The residue was digested in 2 ml fert-butyl-methylether for 2 hours at r.t. to give 0.53 g (81.5% mol) of (S)-l-methyl-l,2,3,lla-tetrahydro-5H-pyrrolo[2,l-c][l,4]-benzodiazepine-5,ll(10H)-dione as beige crystals of m. p. = 117-118.5°C.
MS (EI): 230 (M+, 56); 161 (99); 133 (90); 105 (88); 70(100).
Example 8 6-Chloro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2,5(lH)-dione.
1.0 g (5.0 mMol) 5-chloro-lH-benzo[d][l,3]xazin-2,4-dione and 0.50 g (5.56 mMol) sarcosine were suspended in 4.0 ml of a mixture of xylenes and heated at reflux (Text MS (EI): 224 (M\48); 195(34); 153(60) 126(36), 44(100).
Example 9 7-Chloro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2)5(lH)-dione.
1.0 g (5.06 mMol) 6-chloro-lH-benzo[d][l,3]xazin-2,4-dione and 0.67 g (7.59 mMol) sarcosine were thoroughly mixed and heated to 140°C for 2 hours then 150°C for 20 hours. The brown powder obtained was cooled to r.t. and digested in 4.0 ml water at 0°C for 1 hour, filtered and washed with 1.0 ml water. After drying under vacuum, 1.0 g (88% mol) 7-chloro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2,5(lH)-dione was obtained as a beige powder of m. p. > 250°C.
MS (EI): 224 (M",78); 195 (86); 153(80), 44(100).

conventional processes. Therefore, the process according to the present invention enables an increase of the productivity, thereby decreasing costs and disposal problems.
As stated above, the products obtained with the process according to the invention can be used for manufacturing imidazo[l,5-a] [l,4]diazepine derivatives with excellent psychopharmacological properties. Example 11 illustrates a possible method for producing one of such diazepine derivatives.
Example 11
7-chloro-3-(5-dimethylaminomethyl-[l,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-
imidazo[l,5-a][l,4]benzodiazepin-6-one.
Ethyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[l,5-a][li4]benzodiazepine- 3-carboxylate.
25.0 g 6-Chloro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2,5(lH)-dione were suspended under stirring and argon atmosphere in 200 ml toluene and 32.1 ml N,N-dimethyl-p-toluidine. The suspension was heated to 100°C and 11.2 ml phosphorus oxychloride were added over 30 minutes and stirring was pursued two and an half hours at 100°C. The dark-orange solution was cooled to 40°C and toluene was removed under reduced pressure to give 82 g of a dark-orange oil.
Meanwhile, 81.2 ml hexamethyldisilazane and 265 ml tetrahydrofiiran were mixed and cooled to -35°C. 229.5 ml Butyllithium were added over 45 minutes and, after stirring 30 minutes at -35°C, a solution of 35.2 g ethyl(dimethylamino-methylenamino)acetate in 70.4 ml tetrahydrofiiran was added over 30 minutes. The orange solution obtained was stirred one more hour at -35°C and a solution of the crude iminochloride in 100 ml tetrahydrofuran was added over 1 hour at -15°C. The dark red solution was stirred one hour at -15°C, then 18 hours at room temperature (r.t.). 75 ml Acetic acid were added in 10 minutes, then 75 ml deionized water were added in one portion and the orange suspension was heated at reflux for two hours. Tetrahydrofiiran was removed under reduced pressure and the residue was partitioned between 200 ml dichloromethane and 100 ml deionized water. The phases were separated and the organic phase was washed with 100 ml aqueous HC1 IN twice and with 100 ml deionized water. The aqueous phases were extracted twice with 100 ml dichloromethane. The combined organic extracts were dried (Na2S04) and evaporated. The residue was digested in 200 ml n-heptane 30 minutes at r.t. and filtered off. The sticky crystals obtained were digested at reflux for 30 minutes in 213.5 ml ethanol, then stirred 3 hours to r.t. and 2 hours at -20°C. The precipitate (ethyl 7-

r
organic extracts were dried (Na2S04) and the solvent was removed under reduced pressure. Crude product: 8.0 g as a light yellow foam.
Purification
The crude product was dissolved in 40 ml ethanol at reflux and 400 mg active charcoal Darco G 60 were added. The system was stirred 1 hour at reflux, then filtered on a hot pad of Dicalit Speedex, which was washed with two portions of 40 ml hot ethanol. The filtrate was concentrated to 14 g under reduced pressure, heated to reflux and at this temperature and 40 ml ferf-butyl-methylether were added over 5 minutes. The suspension was cooled slowly to r.t., stirred 16 hours, further cooled to 2°C. After stirring 1 hour at 2°C, the precipitate was filtered off, washed with 20 ml tert-butyl-methylether and dried 1 hour at 60°C under vacuum. The so obtained powder was dissolved at reflux in 26 ml ethyl acetate. 6.5 ml Ethyl acetate were then distilled off and the turbid solution obtained was slowly cooled to r.t., then to 0°C. After 1 hour stirring at 0°C, the precipitate was filtered off, washed with 10 ml cold rerr-butyl-methylether and dried under vacuum at 60°C for 16 hours. The so obtained powder (7-chioro-3-(5-dimethylaminomethyl-[ l,2,4]oxadiazol-3-yl)-5-methyl-4,5-dihydro-imidazo[l,5-a][l,4]benzodiazepin-6-one (I)) was crystallized a second time in 24.3 ml ethyl acetate according to the procedure described above. Product: 5.5 g as a white powder, m.p. 151.5-153°C.

WE CLAIM:
1. Process for manufacturing diazepine derivatives of the general formula I

wherein R1 is lower alkyl and R2 is hydrogen, or R1 and R2 are together -(CH2)n- and n is 2 or 3; R3 is halogen, lower alkyl, lower allcoxy and m is 01 1 or 2\ R4 is hydrogen or lower alkyl, comprising the step of reacting a compound of general formula

2. The process according to claim 1, wherein the solvent is a substituted benzene ring.
3. The process according to claim 2, wherein the solvent is p-xylene.
4. The process according to claim 2, wherein the solvent is a mixture of xylenes.
5. The process according to any one of claims 1 to 4, wherein the compound of formula I
is 6-Chloro-3,4-dihydro-4-methyl-2H-l,4-benzodiazepine-2,5(lH)-dione.

6. The process according to any one of claims 1 to 5, wherein the reaction temperature is from 0 to 30°C under the boiling temperature of the reaction mixture.

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Patent Number

272318

Indian Patent Application Number

3893/CHENP/2007

PG Journal Number

14/2016

Publication Date

01-Apr-2016

Grant Date

29-Mar-2016

Date of Filing

06-Sep-2007

Name of Patentee

F. HOFFMANN-LA ROCHE AG

Applicant Address

124 GRENZACHERSTRASSE CH-4070 BASEL

Inventors:

#	Inventor's Name	Inventor's Address
1	HOFFMANN-EMERY	FABIENNE, MUTTENZERSTRASSE 71 CH-4127 BIRSFELDEN

PCT International Classification Number

C07D 243/14

PCT International Application Number

PCT/EP00/04033

PCT International Filing date

2000-05-05

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	99109514.2	1999-05-12	EUROPEAN UNION