Claims:1. A process for the preparation of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine-4-oxide of formula-5, comprising: reacting 6-chloro-2-(chloromethyl)-4-(2-fluorophenyl) quinazoline-3-oxide of formula-4 with nitromethane in-presence of potassium hydroxide to provide 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzo diazepine-4-oxide of formula-5

2. The process as claimed in claim 1, reaction is carried out in a solvent selected from but not limited to polar-aprotic solvents selected from dimethylacetamide, dimethylformamide, dimethyl sulfoxide, N-methyl pyrrolidone or mixtures thereof.
3. A process for the preparation of Midazolam of formula-1 or its salts,
comprising:
a) reacting 6-chloro-2-(chloromethyl)-4-(2-fluoro phenyl) quinazoline-3-oxide of formula-4 with nitromethane in-presence of potassium hydroxide to provide 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzo diazepine-4-oxide of formula-5
b) converting 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzo diazepine-4-oxide of formula-5 to Midazolam of formula-1 or its salts

Formula-1.
4. The process as claimed in claim 3, in step-a) reaction is carried out in a solvent selected from but not limited to polar-aprotic solvents selected from dimethylacetamide, dimethylformamide, dimethyl sulfoxide, N-methyl pyrrolidone or mixtures thereof. , Description:Field of the invention:
The present invention relates to an improved process for the preparation of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine-4-oxide of formula-5.

Formula-5
which is a key intermediate in the synthesis of Midazolam of formula-1 or its salts

Formula-1.
Background of the invention:
Midazolam is a benzodiazepine derivative, chemically known as 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]-benzodiazepine.
Midazolam is an anesthetic pre-medicant approved in the form of Midazolam hydrochloride salt and maleate salt used as sedative and inductive agent.
US4280957 A patent discloses the process for the preparation of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine by reacting
7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one with methylamine in-presence of TiCl4 in benzene and THF to gives 7-chloro-5-(2-fluorophenyl)-2-methylamino-3H-1,4-benzodiazepine which is converted into its N-nitroso derivative by reacting with NaNO2 in acetic acid, further reaction with nitromethane and potassium tert-butoxide in DMF to produce 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine.
Process described in the above is shown in the following scheme

The above said process has some disadvantages i.e. includes the usage of Potassium tert butoxide is a costly reagent and its usage results in low yield. Moreover Potassium tert butoxide is highly hygroscopic compound and it is hydrolyzes in water to form tert-butanol and potassium hydroxide. In the above process benzene is used as a reaction solvent in stage-1. Benzene is carcinogenic in nature and usage in large scale is not acceptable. By considering the above demerits, the above said process is not viable on commercial scale.
Journal of Heterocyclic Chemistry,1976, 13(3), 433-7 discloses the process for the preparation of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine-4-oxide of formula-5 by reacting nitromethane in dimethyl sulfoxide with 6-chloro-2-(chloromethyl)-4-(2-fluoro phenyl) quinazoline-3-oxide in-presence of lithium amide to give compound of formula-5.
Process described in the above is shown in the following scheme.

The above said process has some disadvantages i.e. includes the usage of hazardous chemical lithium amide in the reaction. Handling such chemical in large scale is very difficult and unsafe.
Thus, there remains a need to develop an improved process for the preparation 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine-4-oxide of formula-5, which is simple, economic and industrially viable process with excellent yields and good quality.
The present inventors have developed an improved industrially viable process which does not involve the usage of any toxic, costly reagents and critical workup procedures. Accordingly, the present invention provides an improved process for the preparation of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine-4-oxide of formula-5 is simple, efficient, cost effective, environmentally friendly and commercially scalable for large scale operations with excellent yields and good quality.
Summary of the invention
The first embodiment of the present invention provides a process for the preparation of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine-4-oxide of formula-5.
The second embodiment of the present invention provides a process for the preparation of Midazolam of formula-1 or its salts.
Detailed description of the invention
The term "solvent" used in the present invention refers to "non polar solvents like "hydrocarbon solvent" selected from n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene or mixtures thereof; "ether solvents" selected from dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane or mixtures thereof; "ester solvents" selected from methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixtures thereof; "polar-aprotic solvents selected from dimethylacetamide, dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone or mixtures thereof; "chloro solvents" selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixtures thereof.
The term “pharmaceutically acceptable salts” or ”salts” described hereinbefore are obtained by reacting organic compound with acid selected from but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; and organic acids such as oxalic acid, maleic acid, malonic acid, tartaric acid, fumaric acid, citric acid, malic acid, succinic acid, mandelic acid, lactic acid, acetic acid, propionic acid, salicylic acid, 2-chloromandelate, para toluene sulfonic acid, ethane-1,2-disulfonic acid, camphor sulfonic acid, ethane sulfonic acid, methane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, adipic acid, glutaric acid, glutamic acid, palmitic acid or aspartic acid and thereof.
The term "room temperature" as used in the present invention herein refers to the temperature in the range from about 25-35°C.
"Substantially pure" as used in the present invention herein refers to the compound is substantially free from the impurities and having purity ranges from about 99.0% to 99.9% as measured by a liquid chromatography method.

The first embodiment of the present invention provides a process for the preparation of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine-4-oxide of formula-5, comprising: reacting 6-chloro-2-(chloromethyl)-4-(2-fluoro phenyl) quinazoline-3-oxide of formula-4 with nitromethane in-presence of potassium hydroxide to provide 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine-4-oxide of formula-5

and optionally purifying the compound to provide substantially pure compound of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzo diazepine-4-oxide of formula-5.
In first aspect of first embodiment, wherein the reaction is carried out in presence of solvent selected from but not limited to polar-aprotic solvents selected from dimethylacetamide, dimethylformamide, dimethyl sulfoxide, N-methyl pyrrolidone or mixtures thereof. Reaction temperature ranges from about 0°C to 30°C. Preferably from about 0°C to 15°C.
In second aspect of first embodiment of the present invention provides a process for the preparation of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine-4-oxide of formula-5, comprising: reacting 6-chloro-2-(chloromethyl)-4-(2-fluoro phenyl) quinazoline-3-oxide of formula-4 with nitromethane in-presence of potassium hydroxide in dimethyl sulfoxide to provide 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine-4-oxide of formula-5.

The second embodiment of the present invention provides a process for the preparation of Midazolam of formula-1 or its salts, comprising:
a) reacting 6-chloro-2-(chloromethyl)-4-(2-fluoro phenyl) quinazoline-3-oxide of formula-4 with nitromethane in-presence of potassium hydroxide to provide 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzo diazepine-4-oxide of formula-5

b) converting 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzo diazepine-4-oxide of formula-5 to Midazolam of formula-1 or its salts

Formula-1.
In first aspect of second embodiment, wherein the reaction is carried out in presence of solvent selected from but not limited to polar-aprotic solvents selected from dimethylacetamide, dimethylformamide, dimethyl sulfoxide, N-methyl pyrrolidone or mixtures thereof. Reaction temperature ranges from about 0°C to 30°C. Preferably from about 0°C to 15°C.
In second aspect of second embodiment 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzo diazepine-4-oxide of formula-5 can be converted to Midazolam of formula-1 or its salts by different processes known in the art.
In third aspect of second embodiment of the present invention provides a process for the preparation of Midazolam of formula-1 or its salts, comprising, comprising:
a) reacting 6-chloro-2-(chloromethyl)-4-(2-fluoro phenyl) quinazoline-3-oxide of formula-4 with nitromethane in-presence of potassium hydroxide in dimethyl sulfoxide to provide 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitro methylene-2H-1,4-benzodiazepine-4-oxide of formula-5,
b) converting 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzo diazepine-4-oxide of formula-5 to Midazolam of formula-1 or its salts.

The inventors of present invention have also carried out the
preparation of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitro methylene-2H-1,4-benzodiazepine-4-oxide of formula-5 in-presence of several bases includes sodium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide and potassium tert-butoxide. But these reactions have some disadvantages. The reactions carried out in-presence of sodium hydroxide or sodium carbonate or potassium carbonate independently has no product formation. Whereas the reactions carried out in-presence sodium methoxide or potassium tert-butoxide independently are low yield reactions and also formation of impurities was observed during the reaction.
Advantages of the present invention:
• The process described in the present invention is simple, safe, economic, eco-friendly and suitable for the production of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitro methylene-2H-1,4-benzodiazepine-4-oxide of formula-5 on commercial scale with a high reproducibility.
• The process described in the present invention avoids the usage of toxic and costly reagents.
• The process described in the present invention involves the usage of eco-friendly reagent potassium hydroxide which is safe and widely used in the commercial scale.
• Usage of commercially available reagents and solvent provides cost-effective process.
• Usage of low cost reactants provides cost-effective process.

Starting materials utilized in the present invention are commercially available in the market (or) they can be prepared according to the any of the processes known in the prior art.
The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are for illustrative purposes only and in no way limit the scope of the present invention.

Examples:
Example-1: Preparation of 6-chloro-2-(chloromethyl)-4-(2-fluorophenyl)-1,2-dihydroquinazoline-3-oxide
1.5N HCl solution (50 kg, 6.84 mole equivalent) was added to chloro acetaldehyde dimethylacetal (27.5 kg, 1.1 mole equivalent) at room temperature and stirred for 10 minutes at same temperature. Heated the reaction mixture to 100-110°C and stirred for 30 minutes at same temperature. The above mixture was added to (2-amino-5-chlorophenyl)(2-fluorophenyl) methanone (50 kg, 1 mole equivalent), hydroxylamine sulphate (36.2 kg, 1.1 mole equivalent) and methanol (100 L) at room temperature and stirred for 2 hours at same temperature. Cooled the reaction mixture to 0-5°C stirred for 10 minutes at same temperature. Filtered the solid washed with methanol and dried to get the title compound.
Yield: 60.10 Kg (92.30%)
Example-2: Preparation of 6-chloro-2-(chloromethyl)-4-(2-fluorophenyl) quinazoline-3-oxide
Manganese dioxide (12.1 kg, 0.75 mole equivalent) and 10% Conc. HCl were slowly added to the mixture of chloroform (300 L) and 6-chloro-2-(chloromethyl)-4-(2-fluoro phenyl)-1,2-dihydroquinazoline 3-oxide (60 kg, 1 mole equivalent) at room temperature and stirred for 3 hours at same temperature. Compound was extracted from Manganese dioxide using chloroform and distilled off 90% of chloroform from above obtained mixture. Cooled the mixture to 0-5°C and stirred for 2 hours at same temperature. Filtered the solid washed with methanol and water, dried to get the title compound.
Yield: 52.2 Kg (87.71%)
Example-3: Preparation of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitro methylene-2H-1,4-benzo diazepine-4-oxide
Potassium hydroxide (17.5 kg, 2 mole equivalent) was added to the mixture of dimethyl sulfoxide (100 L) and nitromethane (11.4 kg, 1.2 mole equivalent) at 0-5°C and stirred for 2 hours at same temperature. 6-chloro-2-(chloromethyl)-4-(2-fluorophenyl) quinazoline-3-oxide (50 kg, 1 mole equivalent) was added to the above reaction mixture at 10-15°C and stirred for 3 hours at same temperature. Acetic acid and methanol were added to the above reaction mixture at room temperature and stirred for 1 hour at same temperature. Filtered the solid washed with methanol and water, dried to get the title compound.
Yield: 45.96 (85.42%).
Example-4: Preparation of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitro methylene-2H-1,4-benzo diazepine-4-oxide
Potassium tert-butoxide (34.8 kg, 2 mole equivalent) was added to the mixture of dimethyl sulfoxide (100 L) and nitromethane (11.4 kg, 1.2 mole equivalent) at 0-5°C and stirred for 2 hours at same temperature. 6-chloro-2-(chloromethyl)-4-(2-fluorophenyl) quinazoline-3-oxide (50 kg, 1 mole equivalent) was added to the above reaction mixture at 0-5°C and stirred for 3 hours at same temperature. Acetic acid and methanol were added to the above reaction mixture at room temperature and stirred for 1 hour at same temperature. Filtered the solid washed with methanol and water, dried to get the title compound.
Yield: 40.52 (75.31%).
Example-5: Preparation of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitro methylene-2H-1,4-benzo diazepine-4-oxide
Sodium methoxide (16.8 kg, 2 mole equivalent) was added to the mixture of dimethyl sulfoxide (100 L) and nitromethane (11.4 kg, 1.2 mole equivalent) at 0-5°C and stirred for 2 hours at same temperature. 6-chloro-2-(chloromethyl)-4-(2-fluorophenyl) quinazoline-3-oxide (50 kg, 1 mole equivalent) was added to the above reaction mixture at 0-5°C and stirred for 3 hours at same temperature. Acetic acid and methanol were added to the above reaction mixture at room temperature and stirred for 1 hour at same temperature. Filtered the solid washed with methanol and water, dried to get the title compound.
Yield: 34.04 (63.27%).