FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION: AN IMPROVED PROCESS FOR PREPARATION OF QUINAZOLINE COMPOUND AND APPLICATION THEREOF.
2. APPLICANT:

(a) NAME: Centaur Pharmaceuticals Pvt. Ltd.
(b) NATIONALITY: An Indian Company incorporated under the Indian Companies ACT 1956
(c) ADDRESS: Centaur House, Near Grand Hyatt, Vakola, Santacruz (East), Mumbai, Maharashtra India Pin Code: 400055.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of Quinazoline compound represented by structural formula I with high yield and high purity, is an important intermediate for synthesis of various Active Pharmaceutical Ingredients (API's) viz. Chlordiazepoxide, Lormetazepam, Midazolam, Lorazepam and Oxazepam.

FORMULA-I
wherein, R = H, F or CI.
The present invention also relates to one pot synthesis of 7-chloro-2-methylamino-5-phenyl-3H-l,4-benzodiazepine-4-oxide (Chlordiazepoxide API) compound represented by structural formula-VIII by using a Quinazoline compound represented by structural formula I.



U.S. Patent No. 2,893,992 discloses a process for the preparation of Quinazoline compound like 6-chloro-2-(Chloromethyl)-4-phenylquinazoline-3-oxide, compound represented by structural formula-P wherein, 2-amino-5-chlorobenzophenone compound represented by structural formula-IV is reacted with hydroxylamine hydrochloride or hydroxyl amine sulphate in presence of pyridine, alcoholic solvent, and recrystallized from petroleum ether to obtain 2-amino-5-chlorobenzophenone oxime compound represented by structural formula-Ill which is further treated with chloroacetyl chloride in presence of dioxane, sodium hydroxide to gives 2-chloroacetamido-5-chlorobenzophenone oxime compound represented by structural formula-IP, which is further reacted with acetic acid and HC1 gas to obtain 6-chloro-2-(Chloromethyl)-4-phenylquinazoline-3 -oxide compound represented by structural formula-P. This is further reacted with methylamine to obtain 7-chloro-2-methylamino-5-phenyl-3H-l,4-benzodiazepine-4-oxide (Chlordiazepoxide API) compound represented by structural formula-VIII. In this process HC1 gas and Acetic acid are used for Quinazoline synthesis, both are hazardous in nature and generates hazardous effluent.

U.S. Patent No. 3,932,325 discloses a process for the preparation of 6-chloro-2-(Chloromethyl)-4-phenyIquinazoline-3-oxide compound represented by structural formula-P wherein, 2-amino-5-chlorobenzophenone compound represented by structural formula-IV is reacted with chloroacetyl chloride in presence of ethyl acetate, sodium hydroxide to gives 2-Chloroacetamido-5-chlorobenzophenone compound represented by structural formula-V, which is further reacted with thionyl chloride and pyridine in presence of dichloromethane to gives 2-(l'-chloroimino-2'-chloromethyl)-5-chlorobenzophenone compound represented by

formula-VI, which is further reacted with Hydroxylamine hydrochloride in presence of pyridine obtain 6-chloro-2-(Chloromethyl)-4-phenylquinazoline-3-oxide compound represented by structural formula-F. The said process takes prolonged time for completion and gives poor yield. Further it involves use of hazardous chemicals like thionyl chloride, pyridine etc.

G.B. Patent No. 1201626 discloses a process for the preparation of 6-chloro-2-(Chloromethyl)-4-phenylquinazoline-3-oxide compound represented by structural formula-F wherein, 2-chloroacetamido ethyl ester hydrochloride compound represented by structural formula-VII reacts with 2-amino-5-chlorobenzophenone oxime compound represented by structural formula-Ill in presence of glacial acetic acid, the precipitated Ammonium chloride was filtered off, clear solution was concentrated to obtain 6-chloro-2-(Chloromethyl)-4-phenylquinazoline-3-oxide compound represented by structural formula-F. The said process requires reaction condition at lower temperature -5°C and gives poor yield.

OBJECT OF THE INVENTION:
An objective of the invention is to be provide an improved, simple, cost efficient and environment friendly process for the preparation of Quinazoline compound represented by structural formula-I, which are important intermediates of various Active Pharmaceutical Ingredients (API's) viz. Chlordiazepoxide, Lormetazepam, Midazolam, Lorazepam and Oxazepam.


wherein, R = I-I, F or CI
Another object of the invention is to provide one pot synthesis of 7-chloro-2-methylamino-5-phenyl-3H-l,4-benzodiazepine-4-oxide (Chlordiazepoxide API) compound represented by structural formula-VIII with high yield, high purity and avoiding hazardous toxic reagents.

SUMMERY OF THE INVENTION;
A first aspect of the present invention is to provide an improved, simple, cost efficient and environment friendly process for the preparation of Quinazoline compound represented by structural formula-I comprises reacting a compound represented by structural formula-II with p-toluene sulfonic acid in presence of non-polar solvents to obtain Quinazoline compound represented by structural formula-I.

wherein, R = H, F or CI
Another aspect of the present invention is to provide one pot synthesis of 7-chloro-2-methylamino-5-phenyl-3H-l,4-benzodiazepine-4-oxide (Chlordiazepoxide API) compound represented by structural formula-VIII comprises, reacting a compound represented by

structural formula-IP with p-toluene sulfonic acid in presence of non-polar solvents to obtain 6-chloro-2-(Chloromethyl)-4-phenylquinazoline-3-oxide compound represented structural formula-P, which is in situ treated with Monomethylamine to obtain 7-chloro-2-methylamino-' * 5-phenyl-3H-l,4-benzodiazepine-4-oxide (Chlordiazepoxide API) compound represented by structural formula-VIII.

DETAIL DESCRIPTION OF THE INVENTION:
In one embodiment, the present invention provides an improved, simple, cost efficient and environment friendly process for the preparation of Quinazoline compound represented by structural formula-I.

wherein, R = H, F or CI
In another embodiment, the present invention provides an improved process for the preparation of Quinazoline compound represented by structural formula-I comprises, reacting a compound represented by structural formula-II with of p-toluene sulfonic acid in presence of non-polar solvents to obtain Quinazoline compound represented by structural formula-I.


The reaction of a compound represented by structural formula-II with of p-toluene sulfonic acid is carried out at a temperature in the range of temperature 80°C to 115°C; preferably 100°C to O°C.
The examples of non-polar solvents may include but not limited to toluene, dichloromethane, chlorobenzene, and the like.
The Quinazoline compound represented by structural formula-I may be isolated by the steps of cooling, separating layers, filtration, washing, drying or the combination thereof.
The Quinazoline compound represented by structural formula-I may include 6-chloro-2-(Chloromethyl)-4-phenylquinazoline-3-oxide compound represented by structural formula-I'.

The Quinazoline compound represented by structural formula-I may include 6-chloro-2-(chloromethyl)-4-(2-fluorophenyl) quinazoline 3-oxide compound represented by structural formula-I".



The compound represented by structural formula-II may include 2-Chloro-N-(4-chloro-2-((2-fluorophenyl) (hydroxyimino) methyl) phenyl) acetamide compound represented by structural formula-II".

FORMULA-II"
In another embodiment, the present invention provides one pot synthesis of 7-chloro-2-methylamino-5-phenyl-3H-l,4-benzodiazepine-4-oxide (Chlordiazepoxide API) compound represented by structural formula-VIII comprises, reacting a compound represented by structural formula-IP with p-toluene sulfonic acid in presence of non-polar solvents to obtain 6-chloro-2-(Chloromethyl)-4-phenylquinazoline-3-oxide compound represented structural formula-P, which is in situ treated with Monomethylamine to obtain 7-chloro-2-methylamino-5-phenyl-3H-l,4-benzodiazepine-4-oxide (Chlordiazepoxide API) compound represented by structural formula-VIII.

FORMULA-II' FORMULA-!* FORMULA-VIM
The reaction of a compound represented by structural formula-IP with of p-toluene sulfonic acid is carried out at a temperature in the range of temperature 80°C to 115°C; preferably 100°C tollO°C.
The examples of non-polar solvents may include but not limited to toluene, dichloromethane, chlorobenzene, and the like.
The 6-chloro-2-(Chloromethyl)-4-phenylquinazoline-3-oxide compound represented by structural formula-P is not isolated and further can be converted to 7-chloro-2-methylamino-

5-phenyl-3H-l,4-benzodiazepine-4-oxide (Chlordiazepoxide API) compound represented by structural formula-VIII, by the process known in the art such as those described in U.S. Patent No. 2,893,992.
EXAMPLES:
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example: 1 Preparation of 6-chloro-2-(Chloromethyl)-4-phenylquinazoline-3-oxide compound represented by structural formula-P:
2-Chloro-N-(4-chloro-2-((hydroxyimino)(phenyl)methyl) phenyl) acetamide compound represented by structural formula-IF, 50 g is added in toluene, 250 mL and heated to 100-110°C for 1 to 2 hrs. Cooled at 80-85°and p-Toluene sulfonic acid, 4.0 g is added and heated to 100-110°C for 2 to 3 hours. The reaction is monitored by TLC. After completion of reaction, cooled to 25-30°C and water, 150 ml is added. Stirred and separated toluene layer from aqueous * layer. Distilled out toluene completely, cooled to 25-30°C. Methanol, 150 mL is added and cooled to 5-10°C. Maintained for 1 to 2 hours at 5-10°C. Filtered and washed with Methanol, 25 ml. Suck dried to obtain 6-chloro-2-(Chloromethyl)-4-phenylquinazoline-3-oxide compound represented by structural formula-P. Wet product is dried to obtained 43 g of 6-chloro-2-(Chloromethyl)-4-phenylquinazoline-3-oxide compound represented by structural formula-F. Yield: 91.0% (purity of 99.3% by HPLC.)
Example: 2 Preparation of 6-chloro-2-(chloromethyl)-4-(2-fluorophenyl) quinazoline 3-oxide compound represented by structural formula-I":
2-Chloro-N-(4-chloro-2-((2-fluorophenyl) (hydroxyimino) methyl) phenyl) acetamide compound represented by structural formula-II", 50 g is added in toluene, 250 mL and heated to 100-110°C for 1 to 2 hrs. Cooled at 80-85°and p-Toluene sulfonic acid, 4.0 g is added and heated to 100-110°C for 2 to 3 hours. The reaction is monitored by TLC. After completion of reaction, cooled to 25-30°C and water, 150 ml is added. Stirred and separated toluene layer from aqueous layer. Distilled out toluene completely, cooled to 25-30°C. Methanol, 150 mL is added and cooled to 5-10°C. Maintained for 1 to 2 hours at 5-10°C. Filtered and washed with Methanol, 25 ml. Suck dried to obtained 6-chloro-2-(chloromethyl)-4-(2-fluorophenyl)

quinazoline 3-oxide compound represented by structural formula-!". Wet product is dried to obtained 41.3 g of 6-chloro-2-(chloromethyl)-4-(2-fluorophenyl) quinazoline 3-oxide compound represented by structural formula-I". Yield: 88.0% (purity of 99.0% by HPLC.)
Example: 3 Preparation of 7-chloro-2-methylamino*5*phenyl=3II-l,4-benzodiazepine-4-oxide (Chlordiazepoxide API) compound represented by structural formula-VIII:
2-Chloro-N-(4-chloro-2-((hydroxyimino)(phenyl) methyl) phenyl) acetamide compound represented by structural formula-IP, 50 g is added in toluene, 250 mL and heated to 100-110°C for 1 to 2 hrs. Cooled at 80-85°and p-Toluene sulfonic acid, 4.0 g is added and heated to 100-110°C for 2 to 3 hours. The reaction is monitored by TLC. After completion of reaction, toluene is distilled out and Dichloromethane, 200 ml is added. Cooled to 25-30°C and sodium carbonate, 150 ml is added. Stirred and separated dichloromethane layer from aqueous layer. Dichloromethane layer containing 6-chloro-2-(Chloromethyl)-4-phenylquinazoline-3-oxide compound represented by structural formula-P is added in monomethyl amine solution (40%) at 10-20°C and stirred for 2 to 3 hrs. The reaction is monitored by TLC and after completion of reaction, further chilled to -5-0°C and stirred for 2 to 3 hrs. The solid is precipitated out. Filtered and washed with dichloromethane, 30 ml. Suck dried to obtained 7-chloro-2-methylamino-5-phenyl-3H-l,4-benzodiazepine-4-oxide (Chlordiazepoxide API) compound represented by structural formula-VIII. Wet product is dried to obtained 38.0 g of 7-chloro-2-methylamino-5-phenyl-3H-l,4-benzodiazepine-4-oxide (Chlordiazepoxide API) compound represented by structural formula-VIII. Yield: 81.0% (purity of 99.3% by HPLC.)

WE CLAIM:
1. An improved process for the preparation of Quinazoline compound represented by structural formula-I comprises, reacting a compound represented by structural formula-II with of p-toluene sulfonic acid in presence of non-polar solvents to obtain Quinazoline compound represented by structural formula-I.

FORMULA-II FORMULA-I
wherein, R = H, F or CI
2. The process as claimed in claim no. 1 wherein, the reaction of a compound represented by structural formula-II with of p-toluene sulfonic acid is carried out at a temperature in the range of temperature 80°C to 115°C; preferably 100°C to 110°C.
3. The process as claimed in claim no. 1 wherein, the examples of non-polar solvents is selected form the group but not limited to toluene, dichloromethane, chlorobenzene, and the like.
4. The process as claimed in claim no. 1 wherein, the Quinazoline compound represented by structural formula-I is isolated by the steps of cooling, separating layers, filtration, washing, drying or the combination thereof.
5. An one pot synthesis of 7-chloro-2-methylamino-5-phenyl-3H-l,4-benzodiazepine-4-oxide (Chlordiazepoxide API) compound represented by structural formula-VIII comprises, reacting a compound represented by structural formula-IF with p-toluene sulfonic acid in presence of non-polar solvents to obtain 6-chloro-2-(Chloromethyl)-4-phenylquinazoline-3-oxide compound represented structural formula-I', which is in situ treated with Monomethylamine to obtain 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide (Chlordiazepoxide API) compound represented by structural formula-VIII.


FORMULA-II' FORMULA-!' FORMULA-VIII
6. The process as claimed in claim no. 5 wherein, the reaction of a compound represented by structural formula-II with of p-toluene sulfonic acid is carried out at a temperature in the range of temperature 80°C to 115°C; preferably 100°C to 110°C.
7. The process as claimed in claim no. 5 wherein, the examples of non-polar solvents is selected form the group but not limited to toluene, dichloromethane, chlorobenzene, and the like.