Title of Invention

A PROCESS FOR THE MANUFACTURE OF 3-(3' -SULFAMYL-4'-CHLOROPHENYL) PHTHALIMIDINE

Abstract

A process for manufacture of 3-(3’-silfamyl-4’-chlorophenyl) phthalimidine comprising; heating a mixture of chlorosulphonic aicd, thionyl chloride and 3-(4’-chlorophenyl) phthalimidine of Formula I to a temperature of about 75 to 100ºC for a period of 4 to 6 hours and then isolating Formula II by quenching the reaction mass on ice and water mixture to precipitate the product; filtering said precipitate containing 3-(3’-chlorosulfonyl-4’-chlorophenyl) phthalimidine; suspending the above product in an organic solvent and cooling to 0-5ºC; purging ammonia gas slowly at 0-5ºC for 4-5 hrs to adjust the pH between 10-11; raising the temperature of said reaction mixture to 25 to 30ºC and maintaining for 2-3 hrs; adding demineralized water; cooling the reaction mixture to 0-5ºC; adjusting the pH of the reaction mixture to 7-8 with hydrochloric acid solution and maintaining the temp at 0-5ºC to precipitate the 3-(3’-sulfomyl-4’-chlorophenyl) phthalimidine of formula III.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10; Rule 13] "A PROCESS FOR THE MANUFACTURE OF 3(3-SULFAMYL-4"-CHLOROPHENYL) PHTHALIMIDINE" (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: Field of invention: A process for the manufacture of 3-(3" -sulfamyl-4" -chlorophenyl) phthalimidine which is a key intermediate used in the synthesis of 3-hydroxy-3- (3" -sulfamyl-4" -chlorophenyl) phthalimidine (Chlorthalidone) which is used as an antihypertensive, diuretic and also for the treatment of renal and cardiovascular disorder. Background and Prior art: Chlorthaliodne is used in the treatment of high blood pressure and fluid retention caused by various conditions including heart diseases. It is particularly known as "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. 3-(3"-sulfamyl-4"chlorophenyl) phthalimidine is a key intermediate of chlorthalidone. Chlorthalidone and related compounds (intermediates) and methods of preparations were first disclosed in US patent no 3055904. US patent no 3055904 discloses isoindoline derivatives such as substituted 3-(4-halo-3"-sulfonylphenyl)phthalides, related derivatives and methods of preparations. US patent 4331600 and EP51215 report the preparation of new intermediates for the preparation of certain phthalimidines and phthalazinones such as 3-aryl-3-hydroxy phthalimidines. Chlorthalidone derivatives and its intermediates and method of preparation are disclosed in US 4188330. Reported synthetic processes in the prior art for the title compound of Formula (III), wherein, the addition of chlorosulfonic acid was in parts to the 3-(4"-chlorophenyl) phthalimidine of formula (I) in dry chloroform. Reaction was carried out at reflux temperature for 3.5 hrs. After completion of reaction the reaction mixture was poured over crushed ice and pH was adjusted to 10 by passing ammonia gas in the aqueous suspension followed by distillation of chloroform under vacuum. The pH of the reaction mass was adjusted to 7 with glacial acetic acid to precipitate the product, which was filtered to get the crude product. The crude product was crystallized from aqueous dimethylformamide to give 3-(3" -sulfamyl-4"chlorophenyl) phthalimidine of formula (III).The compound of formula (I) i.e. 3- (4"chlorophenyl) phthalimidine is used for the synthesis of said intermediate is very well reported in literature. The synthesis of 3-(4"-chlorophenyl) phthalimidine followed by 2-(4"chlorobenzyl) benzoic acid is very well documented in the literature. (References - EP51215, EP51217, US 4500636, US 4379092 and US 53764664). The major drawback of the prior art process is incomplete reaction, low yield and high impurity level due to hydrolysis of sulphonylchloride moiety of Formula II to sulphonic acid group ( formula IV) and complex work up procedures. Another drawback is the use of chloroform as a solvent in chlorosulfonation. Use of solvents like carbon tetra chloride and chloroform in high temperature reactions are considered to non-echo friendly, under Montreal convention and other international chemical treaties. Use of multi halogenic organic solvents in reactions are being discouraged and discontinued. Chloroform is also known to be carcinogenic and unfriendly for human health and safety. The process described in this invention does not involve the use of chloroform in the chlorosulphonation. OBJECTIVES The main objective of the present invention is to provide a simple, economical & plant friendly process for the manufacturing of 3-(3" -sulfamyl-4" -chlorophenyl) phthalimidine of high quality in high yield. Another objective of the present invention is to avoid the use of solvent such as chloroform in chlorosulfonation. The further objective of the present invention is to reduce the impurity level (i.e., due to the hydrolysis of 3-(3" -chlorosulfonyl- 4" -chlorophenyl) phthalimidine), which is formed during amidation in aqueous ammoniacal solution. Summary of the invention: This invention relates to a manufacture of 3-(3" -sulfamyl-4" -chlorophenyl) phthalimidine which is a key intermediate for the synthesis of 3-hydroxy-3- (3"-sulfamyl-4"-chlorophenyl) phthalimidine (Chlorthalidone) widely used as an antihypertensive, diuretic and for treatment of renal and cardiovascular disorder. Detailed Description: In accordance with the above basic objective of the present invention, there is provided a process for preparation of 3-(3" -sulfamyl-4" -chlorophenyl) phthalimidine involving the reaction between 3-(4"-chlorophenyl) phthalimidine of formula (I), chlorosulphonic acid and thionyl chloride at a temperature range of 75-100°C, preferably 75-85°C for a period of 4-6 hrs. After completion of the reaction, the reaction mixture is cooled to 30-35°C and quenched on an ice-water mixture. The precipitated slurry is filtered to get the 3-(3"-chlorosulfonyl-4"-chlorophenyl) phthalimidine of Formula (II). The latter is then suspended in solvents like acetone, dichloromethane, dichloroethane, isopropanol, butanol. This solution is purged with ammonia gas at a temperature of 0-5°C till to get pH of 10-11. Then the temperature of the reaction mixture is raised up to 25-30°C, and maintained for 4-5 hrs. The pH is adjusted to neutral with an acid to get the precipitate of 3-(3"-sulfamyl-4"-chlorophenyl) phthalimidine of Formula (III), which is isolated after filtration. The molar ratio of 3-(4" - chlorophenyl) phthalimidine with chlorosulfonic acid is in the range of 1.1 to 20, preferably 1.1:10- 12 moles. The molar ratio of 3-(4" - chlorophenyl) phthalimidine to thionyl chloride is in the range of 1.1 to 5, preferably 1.1: 2 to2.5moles. Example-1 3-(3" -chlorosulfonyl- 4" -chlorophenyl) phthalimidine A mixture of chlorosulfonic acid (490 gm), thionyl chloride (99.2gm) and 3-(4"- chlorophenyl) phthalimidine (100 gm) is heated with stirring for 3-4 hrs at a temperature range of 75-80°C. Then, the reaction mixture is cooled to 30-35°C and quenched on a mixture of ice and water (2.0 kg) at 0-5°C temperature. The precipitated product is isolated by filtration. Yield of the wet cake = 420-450 gm Example-2 3-(3" -sulfamyl-4" -chlorophenyl) phthalimidine The above wet cake 3-(3"-chlorosulfonyl- 4"-chlorophenyl) phthalimidine is suspended in 1 L acetone and cooled to 0-5°C. Ammonia gas is purged slowly at 0 to5°C to adjust the pH between 10 to 11 and then the temperature is raised to 25-30°C and maintained for 2-3 hrs. 700ml D.M water is added and cooled the reaction mixture to 0-5°C. The pH of the reaction mixture is adjusted to 7.0 to 8.0 with hydrochloric acid solution, maintaining the temperature at 0-5°C to get the precipitate. The precipitate is filtered to obtain 3-(3"-sulfamyl-4 "-chlorophenyl) phthalimidine of formula (III). Yield of the product =110-120 gms Purity = 99.0 to 99.5 by HPLC assay We claim 1. A process for manufacture of 3-(3"-sulfamyl-4"-chlorophenyl) phthalimidine (Formula III), comprising; heating a mixture of chlorosulphonic acid, thionyl chloride and 3-(4"- chlorophenyl) phthalimidine of Formula I to a temperature of about 75 to 100°C for a period of 4 to 6 hours and then isolating Formula II by quenching the reaction mass on ice and water mixture to precipitate the product; filtering said precipitate containing 3-(3"-chlorosulfonyl-4"-chlorophenyl) phthalimidine (Formula II); suspending the above product in an organic solvent and cooling to 0-5°C; purging ammonia gas slowly at 0-5 °C for 4-5 hrs to adjust the pH between 10-11; raising the temperature of said reaction mixture to 25 to 30°C and maintaining for 2-3hrs; adding demineralized water; cooling the reaction mixture to 0-5°C; adjusting the pH of the reaction mixture to 7-8 with hydrochloric acid solution and maintaining the temp at 0-5°C to precipitate the 3-(3"-sulfomyl-4"-chlorophenyl) phthalimidine of Formula III. 2. The process as claimed in claim 1, wherein the preferred temperature of the said reaction is 75-80°C. 3. The process as claimed in claim 1, wherein the said reaction mixture is stirred preferably for 3-4 hrs. 4. The process as claimed in claim 1, wherein the said molar ratio of 3-(4"-chlorophenyl) phthalimidine and chlorosulphoic acid is in the range of 1.1:20 and preferably 1.1:10-12moles. 5. The process as claimed in claim 1, wherein the said molar ratio of phthalimidine and thionyl chloride is in a molar ratio of 1.1:5 and preferably 1.1:2 to2.5 moles. 6. The process as claimed in claim 1, wherein, the said solvent to suspend the reaction mixture is selected from acetone, dichloromethane; diehloro ethane, isopropanol and butanol. 7. The process as claimed in claim 1, wherein the said solvent is acetone. 8. A process for manufacture of 3-(3"-sulfamyl-4"-chlorophenyl) phthalimidine, as substantially described herein with reference to the foregoing examples 1 and 2. Dated this the 26th day of March 2004 Dr. Gopakumar G. Nair Agent for the Applicant

Documents:

374-mum-2004-cancelled pages(15-02-2005).pdf

374-mum-2004-claims(granted)-(15-02-2005).doc

374-mum-2004-claims(granted)-(15-02-2005).pdf

374-mum-2004-correspondence(13-10-2005).pdf

374-mum-2004-correspondence(ipo)-(22-11-2004).pdf

374-mum-2004-drawing(15-02-2005).pdf

374-mum-2004-form 1(15-02-2005).pdf

374-mum-2004-form 1(26-03-2004).pdf

374-mum-2004-form 19(10-09-2004).pdf

374-mum-2004-form 2(granted)-(15-02-2005).doc

374-mum-2004-form 2(granted)-(15-02-2005).pdf

374-mum-2004-form 26(26-03-2004).pdf

374-mum-2004-form 3(26-03-2004).pdf

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

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