TECHNICAL FIELD

The present invention relates to a novel process for preparation of 7-chloro-l -methyl - 5-phenyl-l,5-dihydro-benzo[b][l,4]diazepine-2,4-dione (Clobazam). The present invention also relates to the novel intermediates and its use in preparation of clobazam.

BACKGROUND

Clobazam is an antiepileptic drug of the benzodiazepine class. Clobazam is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older. Clobazam is chemically known as 7-chloro-l -methyl-5- phenyl-l,5-dihydro-benzo[b][l,4]diazepine-2,4-dione, represented by the following structure formula:

Clobazam (I)

Clobazam has been marketed worldwide since 1970' s for the treatment of seizures associated with Lennox Gastaut syndrome (LGS) in patients 2 years or above. Currently, clobazam is marketed as ONFI ^® by Lundbeck LLC. Clobazam was granted orphan drug designation by the US FDA.

U.S. Patent No. 3,984,398 first disclosed clobazam and related compounds, its therapeutic uses as well as a process for its preparation. The process for preparation of clobazam described in U.S. Patent No. 3,984,398 is shown below in Scheme-I. It describes reaction of N-(5-chloro-2-nitrophenyl) phenylamine with malonic acid monoethyl ester using benzene and phosphorus pentachloride to obtain N-carbethoxy acetyl 2-nitro 5-chloro diphenylamine. The obtained compound was cyclized in presence of ethanol, hydrochloric acid and zinc powder to yield 8-chloro-l-phenyl-l,5-dihydro-benzo[b][l,4]diazepine-2,4- dione. Crude clobazam (I) was obtained by methylation of 8-chloro-l -phenyl- 1,5-dihydro- benzo[b][l,4]diazepine-2,4-dione using methyl halide and sodium ethoxide. It also discloses purification of clobazam from 50% ethanol.

The process of US'398 has several disadvantages such as formation of by-products, poor yield and unwanted side reactions. The side reactions results in a final product of low purity which makes multiple purification unavoidable. Reduction and simultaneous cyclization of N-carbethoxy acetyl 2-nitro 5-chloro diphenylamine produces a major byproduct, (6-chloro-l-phenyl-lH-benzoimidazol-2-yl)-acetic acid ethyl ester and a very low yield of desired compound, 8-chloro-l-phenyl-l,5-dihydro-benzo[b][l,4]diazepine-2,4-dio ne as depicted in Scheme-II. Additionally, this process involves use of benzene as a solvent, which is a well known carcinogen. Thus, the process of the US'398 patent is not feasible on an industrial scale.

Scheme-II

Indian Patent Application No. 1320/MUM/2009 publication discloses N-methylation of various benzodiazepine derivatives. It describes N-methylation of benzodiazepine derivatives in biphasic solvent system such as methylene chloride and alkaline water in presence of phase transfer catalyst like tetra butyl ammonium bromide. It discloses preparation of clobazam by reacting 8-chloro-l -phenyl- l,5-dihydro-benzo[b][l,4]diazepine- 2,4-dione with dimethyl sulphate using methylene chloride, TBAB and aq. sodium hydroxide solution to provide crude clobazam. It also discloses purification of clobazam from ethyl acetate.

Another process for the preparation of clobazam is described in PCT publication number WO 2011/100838 (herein, "the '838 patent"), as depicted in Scheme-Ill. In the process of '838 patent, 4-chloro 2-fluoro nitrobenzene is reacted with aniline using DMSO and triethyl amine to yield N-(5-chloro-2-nitrophenyl)phenylamine which is further reduced with iron powder using ethanol, water and aq. hydrochloric acid solution and then resulting crude material is purified by CombiFlash. Purified diamine compound is reacted with malonyl dichloride to provide crude 8-chloro-l-phenyl-l,5-dihydro-benzo[b][l,4]diazepine- 2,4-dione, which was purified by chloroform and hexane. The resulting pure 8-chloro-l - phenyl-l,5-dihydro-benzo[b][l,4]diazepine-2,4-dione is reacted with methyl iodide using tetrahydrofuran and sodium hydride (60% in oil) to provide crude clobazam, which was further purified by methylene dichloride and diethyl ether.

Malonyl dichloride

Scheme III

The drawback of this process is repeated purifications of the product and intermediates rendering the process quite expensive and cumbersome on commercial scale. Further, maintenance of anhydrous condition may be the limiting factor on large scale preparation.

In view of the disadvantages associated with the methods known in the art for the preparation of clobazam, there is a need to develop a process for the preparation of clobazam which is an improvement on the pre-existing processes. The main objective of the present invention is to provide an improved process for the preparation of clobazam which is devoid of repeated purification of intermediates, cost effective, commercially viable and avoid the use of potentially hazardous and expensive chemicals thus rendering the process amenable on large scale.

SUMMARY OF THE INVENTION

The present invention relates to process for the preparation of 7-chloro-l-methyl-5- phenyl- 1 ,5-dihydro-benzo[b] [ 1 ,4]diazepine-2,4-dione (I).

In one aspect, the present invention provides a process for the preparation of clobazam (I)

(I)

comprising steps of:

a) reduction of a compound of formula (II)

using suitable reducing agent to give compound of formula (III);

b) reacting compound of formula (III) with malonic acid mono ester of formula (IV)

O O

(IV)

in presence of suitable coupling reagent and solvent to give compound of formula (V)

wherein L is a leaving group and R is acid protecting group;

c) hydrolysing compound of formula (V) in the presence of suitable acid or base in a suitable solvent to give compound of formula (VI);

(VI)

d) cyclizing compound of formula (VI) in presence of suitable cyclizing agent to give compound of formula (VII);

(VII)

e) reacting compound of formula VII with suitable methylating agent in presence of a base and solvent to provide clobazam (I).

Optionally in another aspect, compound of formula (V) can be cyclised directly to compound of formula (VII) in presence of base.

In another aspect, the present invention further provides novel intermediates of formula (V) and (VI) and their salts or solvates thereof and their use in the preparation of clobazam (I).

In yet another aspect, the present invention also provides process for the preparation of novel intermediates of formula (V) and (VI) which is useful for the preparation of clobazam.

DETAILED DESCRIPTION

As used herein, the term leaving group can be defined as part of a substrate that cleaved by the action of a nucleophile.

As used herein, the term "alkyl" by itself or as part of another substituent, means, unless otherwise stated, a saturated straight or branched chain, or cyclic hydrocarbon radical, or combination thereof having the number of carbon atoms designated (e.g. Ci_io means one to ten carbons). Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec -butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropy)methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

As used herein, the term "aryl" by itself or as part of another substituent, means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (often from 1 to 3 rings) which are fused together or linked covalently. "Aryl" includes, but is not limited to, heteroaryl groups. Non-limiting examples of aryl and heteroaryl groups include: phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridinyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl and quinolyl.

The term "substituted" as used herein means that the groups in question are substituted with one or more of the substituents selected from nitro, hydroxy, cyano, sulfanyl, oxo, halogen, amino, sulfo, alkyl, alkenyl, aryl and heteroaryl. When the groups in question are substituted with more than one substituent, the substituents may be the same or different.

As used herein, the term "halogen" refers to an atom selected from the group consisting of F, CI, Br and I. Base used in the present invention can be organic base or inorganic base. The examples of organic base includes but not limiting to amines, such as diisopropylethylamine (DIPEA), triethylamine (TEA), diethylamine (DEA), pyridine, l,8-diazabicyclo[5.4.0]undec- 7-ene (DBU), imidazole, Ν,Ν-dimethyl aniline, Ν,Ν-dimethyl amino pyridine (DMAP), 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), n-butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS); metal alkoxides, such as lithium, sodium, and potassium alkoxides including lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide and the like or mixtures thereof. The examples of inorganic base includes but not limiting to alkali or alkaline earth metal carbonate, bicarbonate, hydroxide, amide, hydride or phosphate such as potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, lithium amide, sodium amide, sodium hydride, lithium hydride, potassium hydride potassium phosphate, sodium phosphate and the like or mixtures thereof.

As used herein, the term "solvent" refers to the solvents include, but are not limited to, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol and the like; esters such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile and the like; ketones such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone, methyl isobutyl ketone and the like; ethers such as diethyl ether, diisopropylether, tetrahydrofuran, dimethoxyethane and the like; hydrocarbon such as toluene, xylene, hexane, heptane, cyclohexane and the like; chlorinated hydrocarbon such as methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform, chlorobenzene and the like; polar solvents such as water; polar aprotic solvents such as N,N- dimethylformamide (DMF), dimethyl acetamide (DMAc), dimethyl sulfoxide (DMSO) and the like or mixtures thereof.

According to one of the embodiment of the present invention, a process for preparation of clobazam (I) comprising steps of:

a) reduction of a compound of formula (II)

(Π)

using suitable reducing agent to give compound of formula (III)

(HI)

b) reacting compound of formula (III) with malonic acid mono ester of formula (IV) in presence of suitable coupling reagent and solvent to give compound of formula (V)

wherein L is a leaving group selected from halogen, hydroxyl, sulfonyloxy, imidazole, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, trihalomethoxy, N-hydroxy succinimide, N-hydroxy phthalimide, N-hydroxy benzotriazole and the like and R is acid protecting group selected from substituted or unsubstituted alkyl, aryl or arylalkyl. Solvents used for this step can be selected from, but are not limited to, nitriles, ethers, hydrocarbons, chlorinated hydrocarbons, polar solvents, polar aprotic solvents or mixtures thereof,

c) hydrolysing compound of formula (V) in the presence of suitable acid or base in a suitable solvent to give compound of formula (VI)

(VI)

wherein acid is selected from hydrochloric acid, trifhioroacetic acid, formic acid and the like; and base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. Solvents used for this step selected from, but are not limited to, alcohols, ketones, ethers, hydrocarbons, chlorinated hydrocarbons, polar solvents, polar aprotic solvents or mixtures thereof,

d) cyclizing compound of formula (VI) to give compound of formula (VII)

(VII)

wherein cyclization carried out in presence of phosphorous pentachloride, phosphorous trichloride, thionyl chloride, oxalyl chloride, phosphoric acid (H ₃ PO ₄ ) and the like.

e) reacting compound of formula VII with suitable methylating agent in the presence of base and solvent to provide clobazam (I).

(I)

wherein methylation carried out using methyl halide such as methyl iodide, dimethyl sulphate and the like. Solvents used for this step selected from, but are not limited to, nitriles, ketones, ethers, hydrocarbons, chlorinated hydrocarbons, polar solvents, polar aprotic solvents or mixtures thereof. In another aspect, the present invention provides a process for the preparation of clobazam (I) comprising steps of:

a) reduction of a compound of formula (II)

using suitable reducing agent to give compound of formula (III)

wherein reducing agent selected from a mixture of zinc and ammonium chloride, iron powder and acetic acid, sodium hydrogen sulphide and catalytic hydrogenation.

b) reacting compound of formula (III) with malonic acid monoethyl ester of formula (IVa)

o o

(IVa)

in presence of suitable coupling reagent and solvent optionally in the presence of base to give compound of formula (Va)

(Va)

c) hydrolysing compound of formula (Va) in the presence of suitable acid or base to give compound of formula (VI)

(VI)

wherein acid is selected from hydrochloric acid, trifhioroacetic acid, formic acid and the like; and base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. Solvent used for this step selected from, but are not limited to, alcohols, ketones, ethers, hydrocarbons, chlorinated hydrocarbons, polar solvents, polar aprotic solvents or mixtures thereof,

d) cyclizing compound of formula (VI) to give compound of formula (VII)

(VII)

wherein cyclization carried out in presence of phosphorous pentachloride, phosphorous trichloride, thionyl chloride, oxalyl chloride, phosphoric acid (H ₃ PO ₄ ) and the like.

e) reacting compound of formula VII with suitable methylating agent in the presence of base and solvent to provide clobazam (I).

(I)

wherein methylation carried out using methyl halide such as methyl iodide, dimethyl sulphate and the like. Solvents used for this step selected from, but are not limited to, nitriles, ketones, ethers, hydrocarbons, chlorinated hydrocarbons, polar solvents, polar aprotic solvents or mixtures thereof. Step a) involve reduction of 5-chloro-2-nitro-phenyl)-phenyl-amine using a mixture of Zn metal and ammonium chloride in a suitable solvent. Reduction of nitro intermediate can also be performed by catalytic hydrogenation using nobel metal catalyst such as Pd, Pt, Rh, Ru supported on carbon or using complex of such metal. Alternatively, nitro can also be reduced using Tin(II) chloride. Solvents used for this step include, but are not limited to, alcohols, esters, hydrocarbons, chlorinated hydrocarbons, polar solvents, polar aprotic solvents or mixtures thereof.

Step b) involves condensation of 5-chloro-Nl-phenylbenzene-l, 2-diamine with malonic acid monoethyl ester in presence of coupling reagent, solvent and optionally in presence of base. Coupling reagents used for the step can be selected from such as CDI (carbonyldiimidizole), HOBt (1-Hydroxybenzotriazole), HATU ((0-(7-azabenzotriazol-l-yl)- Ν,Ν,Ν',Ν'-tetramethyluronium hexafluorophosphate)), TATU ((0-(7-Azabenzotriazole-l-yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate)), EDC (l-Ethyl-3-(3-dimethylaminopropyl) carbodiimide), DCC (Ν,Ν'-Dicyclohexylcarbodiimide) and the like. Solvents used for this step selected from, but are not limited to, hydrocarbons, chlorinated hydrocarbons, ethers, esters, nitriles, polar solvents, polar aprotic solvents or mixtures thereof. Base used for this step selected from, but are not limited to, amines, metal alkoxides, alkali or alkaline earth metal carbonate, bicarbonate, hydroxide, amide, hydride or phosphate or mixtures thereof.

In step c), N-(4-chloro-2-phenylamino-phenyl)-malonamic acid ethyl ester is hydrolysed to N-(4-chloro-2-phenylamino-phenyl)-malonamic acid in presence of acid or base. Acid used for this step can be selected from hydrochloric acid, acetic acid, formic acid and the like. Base used for this step can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. Solvents used for this step include, but are not limited to, alcohols, hydrocarbons, chlorinated hydrocarbons, polar protic solvents, polar aprotic solvents, ethers or mixtures thereof.

In step d), N-(4-chloro-2-phenylamino-phenyl)-malonamic acid is cyclized in the presence of suitable cyclizing agent and solvent. Cyclizing agent used for this step can be selected from phosphorous pentachloride, phosphorous trichloride, thionyl chloride, oxalyl chloride, phosphoric acid (H ₃ PO ₄ ) and the like. Solvents used for this step include, but are not limited to, hydrocarbons, chlorinated hydrocarbons, polar aprotic solvents, ethers or mixtures thereof.

Step e) involves methylation of 8-chloro- 1 -phenyl- 1, 5-dihydro- benzo[b][l,4]diazepine-2,4-dione using suitable methylating agent in presence of base and solvent to give clobazam (I). Methylating agent used for this step can be selected from methyl halide such as methyl iodide, dimethyl sulphate and the like. Base used for this step selected from, but are not limited to, amines, metal alkoxides, alkali or alkaline earth metal carbonate, bicarbonate, hydroxide, amide, hydride or phosphate or mixtures thereof.

In some embodiments, compound of formula (V) can be cyclised directly to compound of formula (VII) in presence of base.

(V) (VII)

Base used for this step can be selected from potassium tertiary butoxide, sodium tertiary butoxide, sodium hydride, potassium hydride and the like.

The solvent used in this step can be selected from but are not limited to hydrocarbon such as toluene, xylene and the like; ethers such as diethyl ether, diisopropylether, tetrahydrofuran, dimethoxyethane, MTBE (methyl t-butyl ether) and the like.

In another aspects, the present invention provides purification of compound (VII) by heating with a solvent selected from alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol and the like; esters such as ethyl acetate, methyl acetate, n- butyl acetate, isobutyl acetate, sec -butyl acetate, isopropyl acetate and the like; ketones such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone, methyl isobutyl ketone and the like; ethers such as diethyl ether, diisopropylether, tetrahydrofuran, dimethoxyethane and the like; water or mixtures thereof.

In a preferred embodiment, the purification can be carried out by heating the mixture of compound (VII) and solvent at a temperature which can range upto to boiling point of the solvent. In another aspect, the present invention provides novel intermediates of formula (V) and (VI) and their salts or solvates thereof and their use in the preparation of clobazam (I).

wherein R is acid protecting group selected from substituted or unsubstituted alkyl, aryl or arylalkyl. Examples includes, but are not limited to, methyl, ethyl, n-propyl, tert-butyl, phenyl, 4-nitro phenyl, p-tolulyl, benzyl and 4-nitrobenzyl.

In another aspect, the present invention further provides a process for the preparation of a novel intermediate of formula (V) and its use in the preparation of clobazam (I). The process comprises reacting a compound of formula (III) with a compound of formula (IV) in presence of suitable coupling reagent, solvent and optionally in presence of base to give compound of formula (V).

Examples of the compound of formula (IV) include, but are not limited to, malonic acid monoethyl ester, malonic acid monomethyl ester, malonic acid monopropyl ester, malonic acid monophenyl ester, malonic acid mono-(4-nitro-phenyl) ester, malonic acid monobenzyl ester, methyl malonyl chloride, ethyl malonyl chloride and the like.

Coupling reagents used for the step can be selected from such as CDI (carbonyldiimidizole), HOBt (1-Hydroxybenzotriazole), HATU ((0-(7-azabenzotriazol-l-yl)- Ν,Ν,Ν',Ν'-tetramethyluronium hexafluorophosphate)), TATU ((0-(7-Azabenzotriazole-l-yl)- Ν,Ν,Ν',Ν'-tetramethyluronium tetrafluoroborate)), EDC (l-Ethyl-3-(3-dimethylaminopropyl) carbodiimide), DCC (Ν,Ν'-Dicyclohexylcarbodiimide) and the like. Solvents used for this step include, but are not limited to, hydrocarbons such as toluene, xylene; chlorinated hydrocarbons such as dichloromethane, ethylene dichloride, chlorobenzene, chloroform; polar aprotic solvents such as Ν,Ν-dimethylformamide (DMF), dimethyl acetamide (DMAc), dimethyl sulfoxide (DMSO), sulfolane; ethers such as diethyl ether, tetrahydrofuran (THF) or mixtures thereof.

Base used for this step can be selected from, but are not limited to, amines, metal alkoxides, alkali or alkaline earth metal carbonate, bicarbonate, hydroxide, amide, hydride or phosphate or mixtures thereof. Examples include, but are not limited to, diisopropylethylamine (DIPEA), triethylamine (TEA), diethylamine (DEA), pyridine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), imidazole, Ν,Ν-dimethyl aniline, N,N-dimethyl amino pyridine (DMAP), 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), n-butyl lithium, lithium diisopropylamide (LDA), lithium hexamethyldiSilazide (LiHMDS), sodium hexamethyldiSilazide (NaHMDS), potassium hexamethyldiSilazide (KHMDS), potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium phosphate, sodium phosphate, sodium hydride, lithium hydride or potassium hydride, sodium or potassium methoxide or ethoxide and sodium or potassium tertiary butoxide (KTB). The reaction can be carried out at any temperature ranging from about -10°C to about 160°C.

In yet another aspect, the present invention provides a process for the preparation of a novel intermediate of formula (VI) and its use in the preparation of clobazam (I). The process comprises hydrolyzing a compound of formula (V) in presence of acid or base to give the compound of formula (VI).

Acid used for this step can be selected from hydrochloric acid, acetic acid, formic acid and the like; base used for this step can be selected from alkali or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. Solvents used for this step include, but are not limited to, alcohols such as methanol, ethanol, isopropanol, n-butanol; hydrocarbon such as toluene, xylene; chlorinated hydrocarbon such as dichloromethane, ethylene dichloride, chlorobenzene, chloroform; polar aprotic solvents such as Ν,Ν-dimethylformamide (DMF), dimethyl acetamide (DM Ac), dimethyl sulfoxide (DMSO), sulfolane; ethers such as tetrahydrofuran (THF), water or mixtures thereof.

In one embodiment, the synthetic reaction scheme of the present invention is as shown in Scheme-IV.

Scheme IV

In another embodiment of the present invention, the synthetic route can be depicted as shown in Scheme-IV .

Clobazam (I) ^

Scheme IV

In one embodiment, the synthetic reaction scheme of the present invention is as shown in Scheme V.

Clobazam (I) (VII)

Scheme V

In another embodiment of the present invention, the synthetic route can be depicted as shown in Scheme V.

Clobazam (I)

Scheme V

The following examples are given for the purpose of illustrating the present invention and should not be considered as limiting the scope of the invention.

Example 1

Preparation of 5-chloro-Nl-phenylbenzene-l,2-diamine

To a stirred mixture of N-(5-chloro-2-nitrophenyl)phenylamine (100 g) and methanol (500 ml), a solution of ammonium chloride (107.55 g) in water (400 ml) was added at 25-35°C. Zn powder (118.27 g) was added lot wise to the reaction mixture at 50-60°C within 5 h. Exothermicity was observed during addition of Zn powder. After completion of reaction, the reaction mixture was cooled to 25-35°C and dichloromethane (1000 ml) was added. The reaction mixture was allowed to stir at 25-35°C for 1 h. Solid was filtered and washed with dichloromethane (400 ml x 2). Filtrate was allowed to settle; organic layer was separated and distilled out below 40°C under vacuum. The residue was stirred with cyclohexane (500 ml) for 1 h and resulting solid was filtered, washed with cyclohexane (100 ml x 2). The solid was dried at 25-35°C for 2 h and then at 45-55°C for 8 h to give the title product (74 g).

Yield: 84.0 %

1H NMR (DMSO)5: 6.83-6.89 (5H, m), 7.05 (lH,s), 7.22 (2H,s), 7.66 (1H, s)

Mass: 219.1 [M+H] ⁺ Example 2

Preparation of N-(4-chloro-2-phenylamino-phenyl)-malonamic acid ethyl ester

A mixture of 5-chloro-Nl-phenylbenzene-l,2-diamine (70 g), dichloromethane (350 ml) and malonic acid monoethyl ester (46.52 ml) was cooled to 5-10°C. A solution of Ν,Ν'- Dicyclohexylcarbodiimide (72.76 g) in dichloromethane (350 ml) was added to the reaction mixture at 0-10°C within 1 to 2 h. Reaction mixture was allowed to warm at room temperature and stirred for 1 h. After completion of reaction, resulting solid was filtered and washed with dichloromethane (350 ml x 2). A clear filtrate was washed with water (350 ml) and then organic layer was distilled out below 40°C under vacuum. The residue was stirred with a mixture of toluene: cyclohexane (1: 1) for lh. The solid material was filtered and washed with toluene: cyclohexane (1: 1) (35 ml x 2) followed by cyclohexane (140 ml x 2). The solid was dried at 25-35°C for 2 h and then at 45-55°C for 8 h to give the title product (60 g).

Yield: 56.3 %

1H NMR (CDC1 ₃ )5: 1.26-1.29 (3H, t), 3.46 (1H, s), 4.16-4.21 (2H, q), 5.95 (1H, s), 6.90-6.96 (3H, m), 6.99-7.01 (1H, dd), 7.24-7.29 (3H, m), 7.60-7.62(lH, d), 9.16 (lH,s)

Mass: 333.2 [M+H] ⁺

Example 3

Preparation of N-(4-chloro-2-phenylamino-phenyl)-malonamic acid

A solution of sodium hydroxide (7.26 g) in water (75 ml) was added at 25-35°C to heterogeneous reaction mixture of N-(4-chloro-2-phenylamino-phenyl)-malonamic acid ethyl ester (55 g) in methanol (275 ml) within 30 to 60 min. Reaction mixture was allowed to stir for 1 h. After completion of reaction, the reaction mixture was cooled to 10-20° and then acidified with a mixture of water (20 ml) and concentrate hydrochloric acid (20 ml) within 30 min. Water (275 ml) was added to the reaction mixture and then stirred for 1 h. The resulting suspension was filtered and washed with a mixture of methanol: water (1: 1) (27.5 ml x 2) followed by water (110 ml x 2). The filtered solid was dried at 25-35°C for 2 h and then at 45-55°C for 8 h to give the title product (45 g).

Yield: 88.9 %

1H NMR (CD ₃ OD)5: 3.45 (2H, s), 6.86-6.89 (1H, dd), 6.92-6.96 (1H, m), 7.02-7.05 (2H, m), 7.19-7.20 (1H, d), 7.24-7.29 (2H, m), 7.36-7.38 (1H, d) Mass: 285.1 [M+H] ⁺

Example 4

Preparation of 8-chloro-l -phenyl- 1, 5-dihydro-benzo[b][l,4]diazepine-2,4-dione

Phosphorus pentachloride (6.03 g) was added to a mixture of N-(4-chloro-2-phenylamino- phenyl)-malonamic acid (8.0 g) and toluene (80 ml) at 25-35°C. Exothermicity was observed. Reaction mixture was stirred for 1 h. After completion of reaction, the reaction mixture was diluted with toluene (40 ml). The reaction mixture was filtered and washed with toluene (16 ml x 2) and then with water (160 ml x 2). The solid was dried at 25-35°C for 2 h and then at 45-55°C for 8 h to give the title product (3.5 g).

Yield: 47.0 %

1H NMR (DMSO)5: 3.61 (1H, s), 6.78-6.79 (1H, d), 7.17-7.23 (2H, m), 7.25-7.28 (1H, m), 7.31-7.34 (1H, dd), 7.36-7.41 (1H, m), 7.45-7.49 (2H, m), 10.70(1H, s)

Mass: 287.1 [M+H] ⁺

Example 5

Preparation of 7-chloro-l-methyl-5-phenyl-l,5-dihydro-benzo[b][l,4]diazepin e-2,4- dione (Clobazam)

A mixture of 8-chloro-l-phenyl-l,5-dihydro-benzo[b][l,4]diazepine-2,4-dio ne (1.0 g) and methyl ethyl ketone (10 ml) was cooled to 0-5°C. A solution of sodium hydroxide (0.44 g) in water (9 ml) was added to the reaction mixture at 0-5°C within 30 min. and the reaction was allowed to proceed for 30 min. Then dimethyl sulphate (0.55 g) was added to the reaction mixture at 0-5°C and stirred for 1 h. After completion of reaction, the reaction mixture was allowed to settle. Organic phase was separated and distilled out below 50°C under vacuum. The residue was stirred with isopropyl alcohol (5 ml) for 1 h. Resulting solid was filtered, washed with isopropyl alcohol (2 ml x 2). The solid was dried at 25-35°C to give the title product (0.5 g).

Yield: 48 %

1H NMR (CDC1 ₃ )5: 3.48-3.3.56 (5H, m), 6.92-6.93 (1H, d), 7.18-7.19 (2H, m), 7.20-7.27 (1H, m), 7.29-7.31 (1H, m), 7.33-7.38 (1H, m), 7.42-7.46 (2H, m)

Mass: 301.2 [M+H] ⁺

Example 6

Preparation of 8-chloro-l-phenyl-l,5-dihydro-benzo[b][l,4]diazepine-2,4-dio ne A mixture of N-(4-chloro-2-phenylamino-phenyl)-malonamic acid ethyl ester (5.0 g), potassium tert. Butoxide (1.86 g) and toluene(25 ml) was heated to 90-100°C for 2h. After completion of reaction, the reaction mixture was cooled to 25-35°C. Water (25 ml)was added to the reaction mixture and stirred for 1 h. Solid was filtered, washed with water(2 mix 2) followed by toluene (5 ml). The solid was dried at 50-55°C to give the title product (2.5 g). Yield: 50 %

1H NMR (DMSO)5: 3.15 (1H, s),3.68(lH, s), 6.78-6.79 (1H, d), 7.14-7.27 (3H, m), 7.31-7.34 (1H, m), 7.37-7.40 (1H, m), 7.45-7.49 (2H, m), 10.70(1H, s)

Mass: 287.1 [M+H] ⁺

Example 7

Preparation of 8-chloro-l-phenyl-l,5-dihydro-benzo[b][l,4]diazepine-2,4-dio ne

A mixture of N-(4-chloro-2-phenylamino-phenyl)-malonamic acid ethylester (5.0g), potassium tert. butoxide (1.86 g) and xylene(25 ml) was heated to 90-100°C for 2h. After completion of reaction, the reaction mixture was cooled to 25-35°C. Water (25 ml)was added to the reaction mixture and stirred for 1 h. Solid was filtered, washed with water(2 ml x 2) followed by xylene (5 ml). The solid was dried at 50-55°C to give the title product (2.5 g). Yield: 50 %

1H NMR (DMSO)5: 3.15 (1H, s),3.68(lH, s), 6.78-6.79 (1H, d), 7.14-7.27 (3H, m), 7.31-7.34 (1H, m), 7.37-7.40 (1H, m), 7.45-7.49 (2H, m), 10.70(1H, s)

Mass: 287.1 [M+H] ⁺

Example 8

Purification of 7-chloro-5-phenyl-l,5-dihydro-3H-l,5-benzodiazepine-2,4-dion e or N- desmethylclobazam

A mixture of 7-chloro-5-phenyl-l,5-dihydro-3H-l,5-benzodiazepine-2,4-dion e (100 g) and isopropyl alcohol (1000 ml) was heated to 70-80°C and stirred for 1 h. Solid was filtered at 25-35° and washed with isopropyl alcohol (100 ml). The solid was dried at 55-65°C to give the title product (90 g).

Yield: 90 %