FIELD OF THE INVENTION
The present invention relates to a process for the preparation of N-(5-Chloro-2-nitrophenyl) phenyl amine, compound of formula (I) with high purity and good yield, which is a key intermediate for the preparation of Clobazam.
BACKGROUND OF THE INVENTION
Clobazam is an antiepileptic drug of the benzodiazepine class. It is chemically known as 7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione, represented by the following structure formula.
Its empirical formula is C16H13O2N2Cl with a molecular weight of 300.74 (free base). Clobazam is commercially marketed under the trade name of ONFI® in United States and under the trade name of FRISIUM® in Australia and Canada.
The active compound, Clobazam has been disclosed in US 3,984,398 (herein after referred to as US ‘398). The patent US ‘398 also discloses a process for the preparation of Clobazam, which comprises the reaction of N-(5-Chloro-2-nitrophenyl) phenyl amine with monomethyl

malonate in presence of benzene and phosphorous pentachloride to produce N-carbethoxy acetyl 2-nitro 5-chloro diphenyl amine, which is further treated with zinc powder in presence of ethanol and hydrochloric acid to produce N-desmethyl Clobazam, which is finally undergoes N-methylation with methyl halide (methyl chloride in the presence of sodium ethanolate) to produce Clobazam.
US ‘398 do not disclose the process for preparing the intermediate, N-(5-Chloro-2-nitrophenyl) phenyl amine, used in the process for the preparation of Clobazam.
Zhurnal Prikladnoi Khimii (Sankt-Peterburg, Russian Federation) (1948), 21, 987-94 discloses chloro derivatives of 2-nitro diphenylamine, which comprises the reaction of 2,4-dichloro-1-nitro benzene with aniline in presence of sodium acetate (NaOAc) to produce N-(5-Chloro-2-nitrophenyl) phenyl amine, which is depicted in scheme-I as given below.
DE 2,553,566 B1 discloses a process for the preparation of N-(5-Chloro-2-nitrophenyl) phenyl amine, which comprises reacting 2,4-dichloro-1-nitro benzene with aniline in a molar ratio of at least 1:2 at 100 to 180o C, which is depicted in scheme-II given below.

DE 2,648,944 C3 discloses a process for the preparation of N-(5-Chloro-2-nitrophenyl) phenyl amine, which comprises by reacting 2,4-dichloro-1-nitro benzene with at least one molar equivalent of aniline in presence of at least one molar equivalent of a tertiary organic amine like N,N-dialkylated anilines such as N,N-dimethylaniline or N, N-diethylaniline are suitable; aliphatic tertiary amines such as tripropylamine, tributylamine or triisobutylamine, and mixtures of said tertiary amines, which is depicted in scheme-III given below.
The disadvantage of above said processes is long duration of reaction conversion time, due to that the product decomposition rate is high by formation of unrelated impurities, hence obtained low yield.
Hence, there is consequently a need for a process for the preparation of N-(5-Chloro-2-nitrophenyl) phenyl amine which does not involves the problems described above. So, the inventors of the present invention have developed a process for preparation of N-(5-Chloro-2-nitrophenyl) phenyl amine using phase transfer catalyst, an intermediate of high purity and good yield, used in the process for the preparation of Clobazam.
SUMMARY OF THE INVENTION
The present invention is relates to a process for the preparation of N-(5-Chloro-2-nitrophenyl) phenyl amine, compound of formula (I) with high purity and good yield.
In one aspect of the present invention provides a process for the preparation of N-(5-Chloro-2-nitrophenyl) phenyl amine, compound of formula (I),

in the presence of a mild base, phase transfer catalyst and suitable solvent to produce N-(5-Chloro-2-nitrophenyl) phenyl amine of compound of formula (I).
DETAILEDDESCRIPTION OF THE INVENTION
The main objective of the present invention is relates to a process for the preparation of N-(5-Chloro-2-nitrophenyl) phenyl amine, compound of formula (I) with high purity and good yield.
In one embodiment of the present invention is relates to a process for the preparation of N-(5-Chloro-2-nitrophenyl) phenyl amine, compound of formula (I),

in the presence of a mild base, phase transfer catalyst and suitable solvent to produce N-(5-Chloro-2-nitrophenyl) phenyl amine of compound of formula (I).
According to the embodiment of the present invention, the 2,4-dichloro-1-nitro benzene is reacted with aniline in presence of a mild base, phase transfer catalyst and suitable solvent at 25-30oC to produce N-(5-Chloro-2-nitrophenyl) phenyl amine of compound of formula (I), wherein the mild base is selected from sodium acetate, potassium acetate and ammonium acetate, preferably sodium acetate; wherein the phase transfer catalyst is selected from trimethylbenzylammonium chloride, triethylbenzylammonium chloride, tetrabutylammonium bromide and tetrabutylammonium sulfate, preferably trimethylbenzylammonium chloride and wherein the suitable solvent is selected from dimethyl sulfoxide, dimethyl formamide and dimethyl acetamide, preferably dimethyl sulfoxide.
When analytical HPLC revealed completion of the reaction, aniline and solvent distilled out under reduced pressure at below 140oC and allowed to cool at 25-30o C. Add purified water, adjust the reaction mixture pH (limit pH 1.0-3.0) using hydrochloric acid, followed by addition of ethyl acetate to the reaction mixture, stir it for 15 min and settle for 20 min to separate two layers. Take aqueous layer in round bottom flask (RBF) and extract with ethyl acetate. Combine both organic layers and distilled out solvent under reduced pressure at below 65oC. Cool the reaction mixture to 40-45oC, add methanol and heat at reflux for 10-20 min. Further cool the reaction mixture 25-30oC for 30 min to obtain the compound. The obtained compound was filtered, washed with methanol.
Recrystallized the obtain solid in the mixture of ethyl acetate and methanol, heat at reflux (60-70oC) for 10-20 min to dissolve solid completely. The reaction mixture was cool to 10-15oC for 30 min, filtered the material, washed with methanol and load into tray drier. Dry the material at 25-30oC for 2-3 hrs, temperature raised to 60-70oC and maintain for 6-8 hrs to afford N-(5-Chloro-2-nitrophenyl) phenyl amine of compound of formula (I).

Advantages of the present invention:
1. The present invention has developed a process for the preparation of N-(5-Chloro-2-nitrophenyl) phenyl amine, compound of formula (I) with high purity and good yield.
2. The present invention is also provides a simple, scalable, operation friendly and industrially applicable process.
3. In the present invention, by using phase transfer catalyst reaction conversion time is very less and compare to existing processes.
4. In the present invention, by using phase transfer catalyst the product decomposition rate was very low, hence obtained high yield.
5. The present invention gives re crystallization of formula (I) in a mixture of ethyl acetate and methanol to remove dimer impurity.
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
EXPERIMENTAL PROCEDURE:
Example-1:
Synthesis of N-(5-Chloro-2-nitrophenyl) phenyl amine (I)
Charge dimethyl sulphoxide (150 ml) and aniline (327 g) in to the RB flask, added 2,4-dichloro-1-nitro benzene (100 g), sodium acetate (50 g) and trimethylbenzylammonium chloride (10 g) at 25-30°C. The reaction mixture temperature was slowly raised to 120-140°C and stir for 3-5 hrs. (Check the reaction progress by HPLC, when analytical HPLC revealed completion of the reaction) The solvents like aniline and DMSO in a reaction mixture was distilled out under reduced pressure at below 140°C and allowed to cool to 25-30°C. Charge purified water (600 ml), adjust the reaction mixture pH 1.0-3.0 using hydrochloric acid, added ethyl acetate (800 ml), stir it for 15 min and settle for 20 min to separate two layers.

The resulted organic layers was distilled out under reduced pressure at below 65°C, added methanol (200 ml) and heat at reflux for 10-20 min. Further cool the reaction mixture to 25-30°C for 30 min. The resultant solid was filtered and washed with methanol (100 ml). The obtain wet solid was added to a mixture of ethyl acetate (200 ml) / methanol (300 ml) and heat at reflux (60-70°C) for 10-20 min to dissolve solid completely. The reaction mixture was cooled to 10-15°C and maintain for 30 min at same temperature. The resultant solid was filtered, washed with methanol and dried at 6-8 hrs at 60-70°C to afford a title compound
Dry wt.: 85 gm
Example-2:
Synthesis of N-(5-Chloro-2-nitrophenyl) phenyl amine (I)
Charge dimethyl formamide (75 ml) and aniline (160 g) in to the RB flask, added 2,4-dichloro-1-nitro benzene (100 g), sodium acetate (50 g) and tetrabutylammonium bromide (5 g) at 25-30°C. The reaction mixture temperature was slowly raised to 120-140°C and stir for 3-5 hrs. (Check the reaction progress by HPLC, when analytical HPLC revealed completion of the reaction) The solvents like aniline and DMF in a reaction mixture was distilled out under reduced pressure at below 140°C and allowed to cool to 25-30°C. Charge purified water (300 ml), adjust the reaction mixture pH 1.0-3.0 using hydrochloric acid, added ethyl acetate (400 ml), stir it for 15 min and settle for 20 min to separate two layers.
The resulted organic layers was distilled out under reduced pressure at below 65°C, added methanol (100 ml) and heat at reflux for 10-20 min. Further cool the reaction mixture to 25-30°C for 30 min. The resultant solid was filtered and washed with methanol (50 ml). The obtain wet solid was added to a mixture of ethyl acetate (100 ml) / methanol (150 ml) and heat at reflux (60-70°C) for 10-20 min to dissolve solid completely. The reaction mixture was cooled to 10-15°C and maintain for 30 min at same temperature. The resultant solid was filtered, washed with methanol and dried at 6-8 hrs at 60-70°C to afford a title compound
Dry wt.: 75 gm

Example-3:
Synthesis of N-(5-Chloro-2-nitrophenyl) phenyl amine (I)
Charge dimethyl sulphoxide (75 ml) and aniline (160 g) in to the RB flask, added 2,4-dichloro-1-nitro benzene (50 g), potassium acetate (25 g) and triethylbenzylammonium chloride (5 g) at 25-30°C. The reaction mixture temperature was slowly raised to 120-140°C and stir for 3-5 hrs. (Check the reaction progress by HPLC, when analytical HPLC revealed completion of the reaction). The solvents like aniline and DMSO in a reaction mixture was distilled out under reduced pressure at below 140°C and allowed to cool to 25-30°C. Charge purified water (300 ml), adjust the reaction mixture pH 1.0-3.0 using hydrochloric acid, added ethyl acetate (400 ml), stir it for 15 min and settle for 20 min to separate two layers.
The resulted organic layers was distilled out under reduced pressure at below 65°C, added methanol (100 ml) and heat at reflux for 10-20 min. Further cool the reaction mixture to 25-30°C for 30 min. The resultant solid was filtered and washed with methanol (50 ml). The obtain wet solid was added to a mixture of ethyl acetate (100 ml) / Isopropyl alcohol (150 ml) and heat at reflux (60-70°C) for 10-20 min to dissolve solid completely. The reaction mixture was cooled to 10-15°C and maintain for 30 min at same temperature. The resultant solid was filtered, washed with methanol and dried at 6-8 hrs. at 60-70°C to afford a title compound
1H- NMR (400 MHz, DMSO-d6) : δ 9.52 (s, 1H), 8.147-8.125 (d, 1H, J = 8.8 Hz), 7.474-7.7.435 (t, 2H, J = 7.6 Hz), 7.354-7.335 (d, 2H, J = 7.6 Hz), 7.284-7.247 (t, 1H, J = 7.6 Hz), 6.993-6.988 (d, 1H, J = 2.0 Hz), 6.890-6.862 (dd, 1H, J= 2.0 &8.8 Hz).
Dry wt: 80 gm.

WE CLAIM:
1. A process for the preparation of N-(5-Chloro-2-nitrophenyl) phenyl amine, compound of formula (I),
in the presence of a mild base, phase transfer catalyst and suitable solvent to produce N-(5-Chloro-2-nitrophenyl) phenyl amine of compound of formula (I).
The process as claimed in claim 1, wherein the mild base is selected from sodium acetate, potassium acetate and ammonium acetate, preferably sodium acetate.
The process as claimed in claim 1, wherein the phase transfer catalyst is selected from
trimethylbenzylammonium chloride, triethylbenzylammonium chloride,
tetrabutylammonium bromide and tetrabutylammonium sulfate, preferably trimethylbenzylammonium chloride.
The process as claimed in claim 1, wherein the suitable solvent is selected from dimethyl sulfoxide, dimethyl formamide and dimethyl acetamide, preferably dimethyl sulfoxide.

5. The process as claimed in claim 1, N-(5-Chloro-2-nitrophenyl) phenyl amine HPLC purity is not less than 99.5%.