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
PROCESS FOR THE PREPARATION OF CHLOROTHIAZIDE OR SALT THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: D-4, M.I.D.C. Area, Chikalthana, Aurangabad - 431210
(M.S.) India
3. PREAMBLE TO THE DESCRIPTION
The invention provides process for the preparation of chlorothiazide or salt thereof which is very simple and easily scalable at commercial scale. The process of invention is provides enhanced yield and purity of chlorothiazide and salts thereof.
The following specification particularly describes the invention and the manner in which it is to be performed.


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4. DESCRIPTION
The invention provides process for the preparation of chlorothiazide or salt thereof which is very simple and easily scalable at commercial scale. The process of invention is provides enhanced yield and purity of chlorothiazide and salts thereof.
Chlorothiazide of Formula I is chemically known as 6-chloro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. It is commercially available under the trade name DIURIL®.
DIURIL® is indicated for the adjunctive therapy in edema associated with congestive heart failure, renal dysfunction such as nephrotic syndrome, acute glomerulonephritis, and chronic renal failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. It is also indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs.

FORMULA I
U.S. Patent No. 2,809,194 discloses synthesis of chlorothiazide.
U.S. Patent No. 3,160,629 discloses the synthesis of chlorothiazide by oxidation of 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide with potassium permanganate.
Several other processes are known in the art for preparation of chlorothiazide from 5-chloro-2,4-sulfamylaniline such as U.S. Patent No. 2,965,675 and U.S.
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Patent No. 2,937,169; British patent No. 0,826,923 and French Patent No. 1,271,021.
The inventors have developed the process of preparation of chlorothiazide or salt thereof which involves the preparation of 5-chloro-2-4-disulfamyl aniline and its conversion to chlorothiazide. The chlorothiazide is further crystallize with polar protic solvent and or mixture of polar aprotic solvent to get chlorothiazide having purity 99% or more.
In one of the aspect of the process of preparation of chlorothiazide or its salt thereof involves following steps;
a) contacting meta chioroaniline in presence of phosphorous trichloride with chloro sulphonic acid to get compound of formula II,

Formula II b) compound of formula II is converted to compound of formula III in presence of ester solvent and base,

c) compound of formula III is cyclize with formic acid to get crude chlorothiazide,
d) isolating pure chlorothiazide or salt from the suitable solvent from the reaction mixture thereof.
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The process involves the use of phosphorous trichloride while converting meta chioro aniline to 5-chloro-aniline-2,4-disulfonyl chloride of formula II in presence of chlorosulphonic acid. The use of phosphorous trichloride subsides the frothing during the reaction, which is difficult to control at commercial scale production. The uses of ester solvent in presence of base gives enhance yield of and purity of compound of formula IN. The compound of Formula III is cyclized when it was reflux with formic acid. After completion of reaction formic acid is partially removed and the crude chlorothiazide is isolated by addition of water in the reaction mixture. The crude chlorothiazide is crystallized in suitable organic solvent and subsequently converted into salts thereof.
Embodiments of the invention include one or more of the following features. For example, the process of preparation of chlorothiazide salts is carried out in alkanol solvents in presence of a base. The base in the process can be ammonium hydroxide or ammonia gas. In case when the base is ammonia gas, it is bubbled through the solvent used in the process. The chlorothiazide salt formed by the process has purity of 99.5 % or more when measured by HPLC.
The crude chlorothiazide is defined herein as the chlorothiazide having purity between 90 to 98 % when measured by HPLC.
The term ester solvent includes the solvent methyl acetate, ethyl acetate, butyl acetate or mixture thereof.
The bases include the example of ammonium hydroxide, sodium hydroxide, potassium hydroxide and the like.
The term isolation includes the isolation of the compound by removal of the solvent from the reaction mixture or addition of antisolvent, filtration, decantation and centrifugation.
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The term used herein the suitable solvents it includes the use of polar aprotic solvent, polar protic solvent or mixture thereof.
The examples of polar protic and polar aprotic solvent solvents includes solvents such as water, acetic acid, methanol, ethanol, n-propano!, n-butanol, dimethyl formamide, dimethyl sulphoxide, acetonitrile, dioxane, acetone, THF or mixture thereof.
The invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Example Stage-I: A) 5-Chloro-2,4disulfonvl chloride.
To the solution of chlorosulfonic acid (582.0 gm) meta-chloro aniline (75 gm) was added at temperature 30 to 60°c in a period of 2 hours. Temperature of reaction mixture was then raised gradually to 115-120°C and maintained for an hour. Reaction mass was then cooled to 75-80°c and Phosphorus trichloride (100 ml) Temperature of reaction mass was then gradually increased to 90-95°C and after completion reaction mixture is cooled to room temperature and quenched with chilled water (1.20L). The product was filtered and wet cake is submitted for next step. Yield: 256 gm (Wet)
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B) 5-Chloro-2, 4disulfamvl Aniline:
Wet 5-Chloro-2, 4-disulfonyl chloride (250 gm) was dissolved in ethyl acetate (450 ml). The reaction mass was cooled (0-5°C) and ammonia solution (350 ml) was added. After completion of reaction water (750 ml) was added. The ethyl acetate was distilled out. After removal of ethyl acetate the reaction mixture is cooled to room temperature and product is filtered, washed and dried. Yield: 140.0 gm Assay: 98% (HPLC) MP= 258°C
Stage-ll: Chlorothiazide Crude:
5-Chloro-2, 4disu!famyl Aniline (100 gm) was charged to formic acid (1.25 ml) and reaction mixture refluxed for 4 hours. After completion of reaction formic acid was distilled out under vacuum and then residue was treated with water (1 L). The reaction mixture was further stirred for an hour. The product is filtered, washed and dried to yield title compound.
Yield = 98 gm
Purity = 97.25% (By HPLC)
Stage-Ill: Purificatiion
Chlorothiazide obtained from stage II 2 (92 gm ) was dissolved in N, N Dimethyl
Form amide (185 ml ) to obtained clear solution. The methanol (552 ml) was
added to precipitate the compound, which was filtered, washed, isolated and
dried.
Yield : 84 gm
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Purity = 99.86% (By HPLC) MP = 358°C
Staqe-IV: Preparation of chlorothiazide sodium
To the solution of chlorothiazide (100 gm) in methanol (250 ml) was added methanolic sodium hydroxide solution (14 gm sodium hydroxide; in 400 ml of methanol) to obtain clear solution. The solution concentrated at atmospheric pressure and product is completely precipitated by addition of ethyl acetate (400 ml). The precipitated product was filtered, washeq, isolated and dried to yield chlorothiazide sodium
Yield: 100 gm
Purity = 99.89% (by HPLC)
Moisture content = 1.14 %
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We claim:
1. A process of preparation of chlorothiazide or salts thereof, the process comprises of;
a) contacting meta chloroaniline in presence of
phosphorous trichloride with chloro sulphonic acid to
get compound of formula ||,

Formula II
b) compound of formula II is converted to compound of
formula III in presence of ester solvent and base,

c) compound of formula III is cyclize with formic acid to get crude chlorothiazide,
d) isolating pure chlorothiazide or salt from the suitable solvent from the reaction mixture thereof.

2. The process of claim 1, wherein ester solvents includes methyl acetate, ethyl acetate, butyl acetate or mixture thereof.
3. The process of claim 2, wherein solvent is ethyl acetate.

The process of claim 1, wherein base ammonium hydroxide or ammonia gas.
The process of claim 4, wherein base is ammonium hydroxide.
The process of claim 1, wherein the suitable solvents are polar protic solvent, polar aprotic solvent and mixture thereof.
The process of claim 6, wherein suitable solvent is mixture of dimethyl formamide and methanol.
The process of claim 6, wherein suitable solvent is mixture of dimethyl sulphoxide and methanol.
The process of claim 1, wherein the chlorothiazide or it salt having purity 99.5% or more when measured by HPLC.
this TH day of July, 2008 For Wockhardt Limited

(Mandar kodgule) Authorized signatory
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