FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
"IMPROVED PROCESS FOR THE
PREPARATION OF BENZOXAZINE-1-ONE
INTERMEDIATE"
UNICHEM LABORATORIES LIMITED, A COMPANY REGISTERED UNDER THE INDIAN COMPANY ACT, 1956,
HAVING ITS REGISTERED OFFICE LOCATED AT
UNICHEM BHAVAN, PRABHAT ESTATE, OFF S. V. ROAD,
JOGESHWARI (WEST), MUMBAI -400 102,
MAHARASTRA, INDIA

TECHNICAL FIELD OF THE INVENTION:
The present invention provides an improved process for the preparation of 4-(4'-chlorophenyl)-lH-2,3-benzoxazin-l-one, an intermediate used for preparation of Chlorthalidone.
BACKGROUND OF THE INVENTION:
Chlorthalidone (CAS number: 77-36-1) chemically known as l-oxo-3-(3'-sulfamyl-4'-chlorophenyl)-3-hydroxyisoindoline and has the following structure:

Chlorthalidone is widely used as an antihypertensive, diuretic and for treatment of renal and cardiovascular disorder. Chlorthalidone and method of its preparation are disclosed in U.S. patent 3,055,904.
4-(4'-chlorophenyl)-lH-2,3-benzoxazin-l-one (CAS number: 2224-83-1) intermediate herein after referred as Benzoxazine-1-one intermediate, is a key intermediate of Chlorthalidone and has the following structure:

U.K. patent GB 1,025,904 disclosed (Page no. 4, line 65-97) the process for preparation of 4-(4'-chlorophenyl)-lH-2,3-benzoxazin-l-one intermediate comprising refluxing the mixture of 2-(4-chlorobenzoyl) benzoic acid, hydroxylamine hydrochloride, barium carbonate and ethanol. The mixture is filtered hot, the filtrate is allowed to cool and the solid thus obtained is collected by filtration. Barium carbonate is rarely used as a base in industry and also its availability is not guaranteed. Hence it is not advisable to use barium carbonate as a base.

U.S. patent 4,331,600 (Column 13, line 1-18) disclosed the process for preparation of benzoxazine-1-one wherein the 2-(4-chlorobenzoyl) benzoic acid and hydroxylamine hydrochloride are dissolved in a base such as pyridine and absolute ethanol and is heated under reflux for 5 V% hours. Then reaction mass is poured over crushed ice water and the precipitated product is collected by vacuum filtration. The second crop is also isolated from the mother liquor. Process required use of organic base like pyridine in large excess which results in a sticky mass when isolated by quenching with water and base like pyridine is not only hazardous to health but also environmentally unfriendly and difficult to

recover and recycle from the reaction mixture containing lots of water and ethanol. Use of absolute ethanol in process indicates requirement of anhydrous condition for the reaction completion.
India patent 213624 disclosed the process for preparation of benzoxazine-1-one intermediate comprising reacting 2-(4-chlorobenzoyl) benzoic acid and hydroxylamine hydrochloride in presence of an inorganic base and a protic solvent. Inorganic base used is selected from sodium hydroxide, potassium hydroxide or mixtures thereof and solvent used is selected from isopropyl alcohol, ethanol, water or their mixture thereof. This patent also disclosed that this reaction in the presence of organic base such as pyridine or triethylamine does not lead to the completion. Failure to use organic bases to produce benzoxazine-1-one is a serious drawback of this invention.

Although some processes for the synthesis of Chlorthalidone are available, there exists a need for the improved process to prepare Benzoxazine-1-one intermediate.

It is an object of the present invention to provide an improved process that overcomes at least one of the problems of the prior art processes.
SUMMARY OF THE INVENTION:
The present invention provides an improved process for the preparation of Chlorthalidone intermediate 4-(4'-chlorophenyl)-lH-2,3-benzoxazin-l-one from 2-(4-chlorobenzoyl) benzoic acid.
DETAILED DESCROPTION OF THE INVENTION:
The present invention provides an improved process for preparation of Chlorthalidone intermediate 4-(4'-chlorophenyl)-lH-2,3-benzoxazin-1-one from 2-(4-chlorobenzoyl) benzoic acid.
The process of the present invention comprises combining 2-(4-chlorobenzoyl) benzoic acid with hydroxylamine hydrochloride in solvent selected from water or alcohol or mixture thereof in the presence of triethylamine or sodium acetate as an organic base and isolating the said intermediate 4-(4'-chlorophenyl)-lH-2,3-benzoxazin-1-one.
The starting material, 2-(4-chlorobenzoy!) benzoic acid can be prepared by the methods known in the prior art (US1746736, US1699671), for example by reaction of phthalic anhydride with chlorobenzene in presence of AlCl3.

Prior art methods suggest that use of organic bases does not lead the reaction to completion. The inventors of the present invention surprisingly found that reaction of 2-(4-chlorobenzoyl) benzoic acid with hydroxylamine hydrochloride can be conveniently carried out in the presence of organic bases such as sodium acetate or triethylamine with good yield and good quality of product. The process of the present invention avoids use of hazardous organic base pyridine and also avoids stringent use of anhydrous conditions for the process, making the process of present invention better, industrially and economically. The product is obtained in good yield of at least 95% and purity of at least 95%.
The process of the present invention involves combining 2-(4-chlorobenzoyl) benzoic acid with hydroxylamine hydrochloride is used in 1.0 to 5.0 moles, more preferably 2.0 to 3.0 moles with respect to 2-(4-chlorobenzoyl) benzoic acid in solvent water or alcohol or mixture thereof.
Sodium acetate, which may be anhydrous or hydrated, and is used in molar ratio of 1.0 to 6.0, more preferably 1.5 to 2.5 with respect to 2-(4-chlorobenzoyl) benzoic acid. Triethyl amine is used in molar ratio of 1.5 to 5.0, more preferably 2.0 to 2.5 with respect to 2-(4-chlorobenzoyl) benzoic acid. The alcohol used is methanol.
The reaction in the present invention is carried out at a temperature of 40 °C to 120 °C, more preferably at a temperature of 80 °C to 100°C and completed in 1 to 6 hours.

Benzoxazine-1-one intermediate is precipitated from the reaction mixture. Solid product is then filtered and dried to give Benzoxazine-1-one intermediate in substantially pure form. As used here in the term "substantially pure form" means Benzoxazine-1-one intermediate with at least 95% purity.
Process of the present invention is depicted in a scheme mentioned below:

This Benzoxazine-1-one intermediate is then converted to Chlorthalidone by methods known in the prior art for example by reduction of Benzoxazine-1-one intermediate to form phthalimidine intermediate, this intermediate is then converted to sulfonamide intermediate by reaction with Chlorosulfuric acid and ammonia and finally oxidizing this sulfonamide intermediate with H2O2 to give Chlorthalidone.
The following examples are for illustrative purposes only and are not intended nor should they be interpreted to, limit the scope of the invention.

EXAMPLES:
Example 1: 4-(4'-chlorophenyI)-lH-2,3-benzoxazin-l-one
In a round bottom flask was charged 1500 mL water, 150 gm of 2-(4-chlorobenzoyl) benzoic acid (I), 157 gm of Sodium acetate trihydrate and 200 gm hydroxyl amine hydrochloride. The reaction mixture was stir for 30 min at room temp and was further allowed heat at 95 to 100 °C. Reaction was maintained at this temperature till the completion (monitored by using TLC / HPLC). Cool the reaction mass to room temperature and maintain at this temp for another lhr. Filter the solid obtained and wash the wet cake with water (600ml). The product obtained was dried in an air oven at 65 to 70°C for 5 to 6hr. Dry weight of 4-(4-chlorophenyl)-lH-2,3-benzoxazin-l-one (II) obtained was 147.0gm. Yield= 95-100 %, HPLC purity is 98-100 %.
Example 2: 4-(4'-chIorophenyl)-lH-2,3-benzoxazin-l-one
In a round bottom flask was charged 500 mL water, 32 gm hydroxyl amine hydrochloride, 30 gm of triethylamine and 50 gm of 2-(4-chlorobenzoyl) benzoic acid (I). The reaction mixture was stir for 30 min at room temp and was further allowed heat at 95 to 100 °C. Reaction was maintained at this temperature till the completion (monitored by using TLC / HPLC). Cool the reaction mass to room temperature and maintain at this temp for another lhr. Filter the solid obtained and wash the wet cake with water (200ml). The product obtained was dried in an air oven at 65 to 70°C for 5 to 6hr. Dry weight of 4-(4-ch!orophenyl)-lH-2,3-

benzoxazin-1-one (II) obtained was 46.0gm. Yield = 93%, HPLC purity is 95-100%.
Example 3: 4-(4'-chlorophenyI)-lH-2,3-benzoxazin-l-one
In a round bottom flask was charged 100 mL methanol, 10 gm of 2-(4-chlorobenzoyl) benzoic acid (I), 13.8 gm of Sodium acetate trihydrate and 11.7 gm hydroxy! amine hydrochloride. The reaction mixture was stir for 30 min at room temp and was further allowed heat at 60 to 65 °C. Reaction was maintained at this temperature till the completion (monitored by using TLC / HPLC). Cool the reaction mass to room temperature and maintain at this temp for another Ihr. Filter the solid obtained and wash the wet cake with water (60ml). The product obtained was dried in an air oven at 65 to 70°C for 5 to 6hr. Dry weight of 4-(4-chlorophenyl)-lH-2,3-benzoxazin-l-one (II) obtained was 5.0gm. Yield= 50-55 %, HPLC purity is 98-100%.

CLAIMS:
We claim,
1. An improved process for the preparation of benzoxazin-1 -one intermediate 4-(4'-chIorophenyI)-lH-2,3-benzoxazin-l-one comprising combining 2-(4-chlorobertzoyl) benzoic acid with hydroxylamine hydrochloride in solvent in the presence of Sodium acetate or triethylamine.
2. The process as claimed in claim 1, wherein the solvent is selected from water or alcohol or mixture thereof.
3. The process as claimed in claim 1, wherein the said process is carried out preferably at a temperature of 40°C to 120°C, more preferably at a temperature of 80°C to 100°C.
4. The process as claimed in claim 1, wherein hydroxylamine hydrochloride is used in 1.0 to 5.0 moles, more preferably 2.0 to 3.0 moles with respect to 2-(4-chlorobenzoyl) benzoic acid.
5. The process as claimed in claim 1, wherein sodium acetate is used in molar ratio of 1.0 to 6.0, more preferably 1.5 to 2.5 with respect to 2-(4-chlorobenzoyl) benzoic acid.
6. The process as claimed in claim 1, wherein sodium acetate is used in anhydrous or hydrated form.
7. The process as claimed in claim 1, wherein Triethylamine is used in molar ratio of 1.5 to 5.0, more preferably 2.0 to 2.5 with respect to 2-(4-chlorobenzoyl) benzoic acid.

8. The process as claimed in claim 2, wherein alcohol is methanol.
9. The process as claimed in claim 1, wherein benzoxazin-1-one intermediate is obtained in at least 93% yield and at least 95% purity.
10. The process as claimed in claim 1, further comprises converting benzoxazin-1-one intermediate 4-(4'-chlorophenyl)-lH-2,3-benzoxazin-l-one to Chlorthalidone.