Title of Invention

AN IMPROVED PROCESS FOR MANUFACTURE OF 4-(4'- CHLOROPHENYL)-5,6-BENZ-2,3-OXAZINE-1-ONE

Abstract This invention describes an improved process for preparation of 4-(4'-chlorophenyl)-5,6-benz-2,3-oxazine-l-one (benzoxazine-1-one), a key intermediate of 3-hydroxy-3-(3'-sulfamyl-4'-chlorophenyl)phthalimidine {chlorthalidone) which is widely used as an antihypertensive, diuretic and for treatment of renal and cardiovascular disorder.
Full Text FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
[See section 10; rule 13]
"AN IMPROVED PROCESS FOR MANUFACTURE OF 4(4'-CHLOROPHENYL)-5,6-BENZ-2,3-OXAZINE-l-ONE"
(a) IPCA LABORATORIES LIMITED
(b) 48, Kandivli Industrial Estate, Mumbai - 400 067, Maharashtra, India
(c) Indian Company incorporated under the Companies Act 1956
The following specification describes the nature of this invention and the manner in which it is to be performed:
10 FEB 2005

Technical Field of invention:
This invention relates to an improved process for preparation of 4-(4'-chlorophenyl)-5,6-benz-2,3-oxazine-l-one (benzoxazine-1-one), a key intermediate of 3-hydroxy-3-(3'-sulfamyl-4'-chlorophenyl)phthalimidine (Chlorthalidone) which is widely used as an antihypertensive, diuretic and for treatment of renal and cardiovascular disorder.
Background and prior art:
Chlorthalidone is used in the treatment of high blood pressure and fluid retention caused by various conditions including heart diseases. It is particularly known as a "water pill" as it causes the kidneys to get rid of unneeded water and salt from the body into the urine. Chlorthalidone is also used for the treatment of diabetes insipidus and some electrolyte disturbance as well as to prevent kidney stones.
Benzoxazine-1-one is a key intermediate of Chlorthalidone. UK patent GB 1195408 describes the process for manufacture of l-keto-4-(4'-chlorophenyl)-2,3-benzoxazine which comprises refluxing the mixture of 2-(4'-chloro benzoyl) benzoic acid, hydroxylamine hydrochloride, barium carbonate and ethanol and is filtered hot and allowed to cool. The solid thus obtained is filtered off.
Another US patent US 4,331,600 (Equivalent EP0051215) and EP 0051217 reports the process for preparation of intermediates used in the preparation of other anti-hypertensive and diuretic agent. In this patent they have disclosed the process for benzoxazine-1-one wherein the 2-(4'-chlorobenzoyl) benzoic acid and hydroxylamine hydrochloride are dissolved in a base like pyridine and absolute ethanol and is heated under reflux for 5 Vi hours. Then reaction mass is poured over crushed ice water and the precipitated product of the Formula II is collected by vacuum filtration. The second crop is also isolated from the mother liquor.
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The major drawback of the processes reported in prior art is that they all lead to the product of Formula (II) having high level of impurities. The other main draw back is difficult isolation procedure from the crude sticky mass leading to poor yield.
Another drawback of the prior art is the use of organic base like pyridine which 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.
Objective of the invention
The main objective of the present invention is to provide a simple, economical and environmental friendly process for the preparation of benzoxazine-1-one derivative like 4-(4'-chlorophenyl)-5, 6-benz-2,3-oxazine-l-one of high yield and quality.
The further objective of the present invention is to avoid the use of pyridine.
Summary of the invention:
This invention relates to an improved process for preparation of 4-(4'-chlorophenyl)-5,6-benz-2,3-oxazine-l-one (benzoxazine-1-one), a key intermediate of 3-hydroxy-3-(3'-sulfamyl-4'-chlorophenyl)phthalimidine (Chlorthalidone) which is widely used as an antihypertensive, diuretic and also for treatment of renal and cardiovascular disorder.
Detailed description:
The present invention provides an improved process for the preparation of 4-(4'-chlorophenyl)-5,6-benz-oxazine-l-one (Formula II, where X denotes chlorine or bromine), a key intermediate in the synthesis of phthalimidine derivatives (e.g. Chlorthalidone). This improved process involves an inorganic base catalyzed cyclization of a compound of Formula I (where X has the same meaning as defined above) with hydroxyl amine hydrochloride in a suitable solvent. The starting material, 2-(4'-
3

chlorobenzoyl) benzoic acid, of formula I and its preparation was reported earlier in patents US 4500636, US 30555904, US 4379092, US 3764664.
'-<:>-•
o
.^^
I.
""O

.x-

"^

^>j

X * CI, Br
Formula I
V X - CI. Br
Formula II

In the prior art, this reaction was carried out in presence of pyridine base, which also acts as solvent, in a mixture of 1.25:1 proportion of pyridine and absolute ethanol. The use of pyridine in large excess results in a sticky mass when isolated by quenching with water due to the presence of pyridine. It is observed that use of molar amounts of organic bases like triethyl amine or pyridine does not lead the reaction to completion. The prior art also indicates anhydrous condition by the use of absolute ethanol (with 1:1.25 pyridine) for the reaction completion. The crude product was required to be purified from a mixture of organic solvents for example ethylacetate / dimethyl formamide / heptane mixture.
It is therefore, of interest to see the workability of employing an inorganic base for the complete transformation of compound of Formula I to Formula II and to employ a simple isolation procedure which is environmental friendly unlike pyridine process to get pure product.
According to the present invention, it is found that an inorganic base such as potassium hydroxide or sodium hydroxide catalyzes this reaction and the reaction completes in a lesser period of time under suitable conditions.
In this aspect, according to the present invention, the reaction of compound of formula (I) with hydroxyl amine hydrochloride is performed in solvent selected from water, ethanol,
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isopropanol or their mixture thereof in any proportions, preferably in the range of 1 to 99. It is advantageous to perform the reaction in these solvents as the product can be directly isolated after completion of reaction from solvent.
The inorganic base catalyzed transformation of formula I to II is carried out preferably at a temperature of 75°C to 100°C. The most preferable temperature range is 80°C to 85°C.
In process, according to present invention, inorganic base such as sodium or potassium hydroxides are preferably used in a molar ratio of 1.1 to 3 moles per mole of starting material of formula I and most preferably in the ratio of 1.5 to 2 moles.
The reaction of 2-(4'-chlorobenzoyl) benzoic acid (formula I) is carried out with 1.1 to 5.0 molar equivalents of hydroxylamine hydrochloride and preferably in the molar ratio of 2.5 to 3.0 mole and the reaction was completed in 4 to 7 hours at a temperature range of 80° C to 85° C in presence of 2 moles of sodium hydroxide.
On completion of reaction the product precipitates from these solvents, used in the present invention, and is filtered under suction to give a compound of formula II in substantially pure form.
The improved process of the invention is advantageous as it substantially reduces the impurity formation in the reaction thereby making the isolation of the product from a single solvent and eliminates further crystallization, recovery and recyclability of pyridines, and handling as well as effluent problem associated with pyridine.
The following actual examples are provided to illustrate the invention and are not limiting the scope of the complete disclosure.
5

Examples:
Example 1:
(4-(4'-chlorophenyl)-5,6-benz-2,3-oxazoline-l-one)
In a reaction vessel, a mixture of 2-(4'-chlorobenzoyl) benzoic acid (100 gm), hydroxylamine hydrochloride (100 gm), sodium hydroxide (24 gm) and isopropanol (600 ml) was heated to a temperature of 80° to 85°C and maintained for a period of 6 hours. The reaction mixture was cooled to room temperature (nearly 25°C and the precipitated crystals were filtered under suction and dried. The dry weight of compound of Formula II obtained was 95 gm. The yield is 96%
Example 2:
(4-(4'-chlorophenyl)-5, 6-benz-2,3-oxazoline-l-one)
In a reaction vessel, a mixture of 2-(4'-chlorobenzoyl) benzoic acid (100 gm), hydroxylamine hydrochloride (125 gm), sodium hydroxide (25 gm) and demeneralized water (1000 ml) was heated to a temperature of 80° to 85° C and maintained for a period of 6 hours. The reaction mixture was cooled to room temperature (nearly 25° C) and the precipitated crystals were filtered under suction and dried. The dry weight of compound of Formula II obtained was 95 gm. The yield is 96%
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We claim,
1. An improved process for manufacture of benzoxazine-1 -one derivative corresponding to the Formula II, where X denotes Chlorine or Bromine; preferably 4-(4' -chlorophenyl)-5,6-benz-2,3 -oxazine-1 -one

x^
i 1 „


y,
X » CI, Br
Formula

A.
1
r. ->!
I! v
X «= Ct. Br
Formula II

wherein, the said process comprises of reacting a compound of Formula I with hydroxylamine hydrochloride in presence of an inorganic base and a solvent at a temperature of 75° to 100° C and isolating the said compound of Formula II from the said solvent.
2. The process as claimed in claim 1 wherein, molar ratio of 2-(4'-chlorobenzoyl) benzoic acid of Formula (I) to hydroxylamine hydrochloride is 1.1 to 5.0.
3. The process as claimed in claim 1 wherein, molar ratio of 2-(4'-chlorobenzoyl) benzoic acid of Formula (I) to hydroxylamine hydrochloride is 2.5 to 3.0.
4. The process as claimed in claim 1 wherein, inorganic base used is selected from sodium hydroxide, potassium hydroxide or mixtures thereof.
5. The process as claimed in claim 1 wherein, inorganic base is used in molar ratio of 1.1 to 3.0 with respect to 2-(4'-chlorobenzoyl) benzoic acid.
6. The process as claimed in claim 1 wherein, inorganic base is used in molar ratio of 1.5-2.0 with respect to 2-(4'-chlorobenzoyl) benzoic acid.
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7. The process as claimed in claim 1 wherein, solvent used for carrying out the reaction is selected from isopropyl alcohol, ethanol, water or their mixture thereof in the range of 1 to 99.
8. The process as claimed in claim 1 wherein, the said process is carried out preferably at a temperature of 80° to 90° C.
9. An improved process for manufacture of benzoxazine-1-one derivative corresponding to the Formula II, preferably 4-(4'-chlorophenyl)-5,6-benz-2,3-oxazine-1-one as substantially described herein with reference to the foregoing examples 1 to 2.
Dated this 2nd Day of Jan 2004
8

Abstract
This invention describes an improved process for preparation of 4-(4'-chlorophenyl)-5,6-benz-2,3-oxazine-l-one (benzoxazine-1-one), a key intermediate of 3-hydroxy-3-(3'-sulfamyl-4'-chlorophenyl)phthalimidine {chlorthalidone) which is widely used as an antihypertensive, diuretic and for treatment of renal and cardiovascular disorder.
9

Documents:

7-mum-2004-abstract(10-02-2005).doc

7-mum-2004-abstract(10-02-2005).pdf

7-mum-2004-abstract.doc

7-mum-2004-abstract.pdf

7-mum-2004-cancelled pages(10-02-2005).pdf

7-mum-2004-claims(granted)-(10-02-2005).doc

7-mum-2004-claims(granted)-(10-02-2005).pdf

7-mum-2004-claims.doc

7-mum-2004-claims.pdf

7-mum-2004-correspondence(10-02-2005).pdf

7-mum-2004-correspondence(ipo)-(03-01-2005).pdf

7-mum-2004-correspondence-received-010205.pdf

7-mum-2004-correspondence-received-010904.pdf

7-mum-2004-correspondence-received-100205.pdf

7-mum-2004-correspondence-received-140104.pdf

7-mum-2004-correspondence-received-230604.pdf

7-mum-2004-correspondence-received-250604.pdf

7-mum-2004-correspondence-received-281204.pdf

7-mum-2004-correspondence-received.pdf

7-mum-2004-descripiton (complete).pdf

7-mum-2004-form 1(02-01-2004).pdf

7-mum-2004-form 1(10-02-2004).pdf

7-mum-2004-form 1(14-01-2004).pdf

7-mum-2004-form 19(14-01-2004).pdf

7-mum-2004-form 2(granted)-(10-02-2005).doc

7-mum-2004-form 2(granted)-(10-02-2005).pdf

7-mum-2004-form 26(02-01-2004).pdf

7-mum-2004-form 3(02-01-2004).pdf

7-mum-2004-form 3(28-12-2004).pdf

7-mum-2004-form-1.pdf

7-mum-2004-form-19.pdf

7-mum-2004-form-2.pdf

7-mum-2004-form-26.pdf

7-mum-2004-form-3-020104.pdf

7-mum-2004-form-3.pdf

7-mum-2004-granted.pdf


Patent Number 213624
Indian Patent Application Number 7/MUM/2004
PG Journal Number 13/2008
Publication Date 31-Mar-2008
Grant Date 09-Jan-2008
Date of Filing 02-Jan-2004
Name of Patentee M/S. IPCA LABORATORIES LIMITED
Applicant Address 48 KANDIVLI INDUSTRIAL ESTATE MUMBAI 400 067
Inventors:
# Inventor's Name Inventor's Address
1 KUMAR ASHOK B/203 STERLING CO.HSG SOC. A2-A3 SUNDARBAN COMPLEX ANDHERI (WEST) MUMBAI 400 053
2 SINGH DHARMENDRA BUILDING NO D/3 A WING ROOM NO 8 SAHYADRI NAGAR CHARKOP KANDIVLI (WEST) MUMBAI 400 067
3 GUPTA NITIN A-502 SHANTIDOOT CO-OP SOCIETY PLOT NO 47 SECTOR 2 CHARKOP KANDIVLI (WEST) MUMBAI 400 067
4 JADHAV ATUL 8 J.M.PEREIRA CHAWL ST.FRANCIS ROAD VILE PARLE (WEST) MUMBAI 400 056
5 PANDYA DARPAN A-502 SHANTIDOOT CO-OP SOCIETY PLOT NO 47 SECTOR 2 CHARKOP KANDIVLI (WEST) MUMBAI 400 067
PCT International Classification Number A61K31/245
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA