Title of Invention

PROCESS FOR PREPARATION OF 5-CYANOPHTHALIDE (INTERMEDIATE OF CITALOPRAM)

Abstract

A process for preparation of 5-cyano phthalide of formula I, wherein the said process comprises; a) condensing terphthalic acid (VI) and paraformaldehyde in sulfuric acid solvent, with gradual addition of sulfur trioxide as a condensing agent to form 5-carboxy phthalide (V) in the first stage; b) reacting the crude mass of said 5-carboxy phthalide (V) with sodium acetate and/or sodium propionate at 65-75°C, filtering to eliminate all the insoluble diphthalide and organic tars , whereby, sodium 5-carboxy phthalide (IV)goes into solution in water, precipitating the same on cooling the solution, and obtaining sodium 5-carboxy phthalide as a solid substantially free of terphthalic acid and diphthalide in the second stage; and c) suspending the sodium salt of carboxy phthalide (IV) in toluene as a solvent and adding dimethyl forma amide, treating the same with bis-trichloro methyl carbonate (triphosgene) to generate in-situ 5-chloro carbonyl phthalide, treating the same with gaseous ammonia or ammonium carbonate to yield 5-carbomoyl phthalide, retreating the same in the same pot with triphosgene to yield 5-cyano phthalide (I) in the third and final stage.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10; rule 13] "PROCESS FOR PREPARATION OF 5-CYANOPHTHALIDE (INTERMEDIATE OF CITALOPRAM)" (a) IPCA LABORATORIES LTD. (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: TECHNICAL FIELD This invention relates to an improved process for preparation of 5-cyanophthalide which is the key intermediate of citalopram. BACKGROUND AND PRIOR ART 5- cyanophthalide is an important drug intermediate used in the synthesis of citalopram which is a selective serotonin reuptake inhibitor possessing anti-depressant properties. US pat.no 4136193 (and DE2657013) was the first patent in which citalopram has been disclosed. Citalopram synthesis from 5-cyanophthalide is described in US pat.no 4650884. Preparation of 5-carboxy phthalide from terephthalic acid and conversion of 5-carboxy phthliude to 5-cyano phthalide are further described in this patent. US patent no 3607884 and J.Org.Chem.1970,35,1695-96 describes a process for preparation of 5-carboxy phthalide from terephthalic acid and liquid sulphur trioxide. There are many patents describing the process of preparation of citalopram. However, the prior art on 5-cyanophthalide is relatively few in number. Patent no. WO 00/391123 describes a method for the preparation of 5-cyanophthalide from 5-carboxyphthalide through the corresponding ester or acid chloride to the corresponding amide, (corresponding patent US no. 2002 019546). Patent no US 2002 028956 (WO 0044738) describes a method for the preparation of 5-cyano phthalide from 5-carboxyphthalide by reacting with a dehydrating agent such as thionyl chloride and sulphonamide. Patent no. WO 01/51477 discloses a method of preparation of 5-cyanophthalide. A method of preparation of 5-cyanophthalide from 5-carboxyphthalide is described in US pat.no. 6392060. Process for preparation of 5-carboxy phthalide from terephthalic acid is described in US patent no. 6403813. US patent no. 6441201 describes method of preparation of 5-cyanophthalide by reacting 5-carboxyphthalide with a dehydrogenating agent such as thionyl chloride and sulfonamide in particular sulfonamide. OBJECTIVE OF THE INVENTION It is an objective of the present invention to provide a process for preparation of 5-cyanophthalide a key intermediate of citalopram and further process of preparation of citalopram from 5-cyanophthalide in high yields with higher purity and better operator friendly operations at cheaper prices. DETAILED DESCRIPTION We distinguish our process from prior art while describing our invention In this invention disclosing the said process, sulfuric acid is used as a solvent for the reaction for terphthalic acid (Formula VI)and paraformaldehyde and sulfur trioxide as the condensing agent as against sulfur trioxide as solvent and reactant in the public domain patent (US 3607884) and J.Org. Chem. 1970,35,1695-96. The patents (WO0132642 AND WO 0132643) claim use of oleum 15-30 % and other condensing agents as zinc chloride as solvent and reactant .The virtue of our process pertaining to this part of the invention is reduced carbonisation and diphthalide (Formula VII)formation due to water scavenger liquid sulfur trioxide being added as the water is generated as against invention of process patent (W0132642 wherein sulfur trioxide is present from the very beginning leading to extensive carbonization and diphthalide formation). In this invention disclosing the said process, sodium salt of 5-carboxy phthalide (Formula IV, a new compound without CAS number) is manufactured isolated and characterized containing 0% terphthalic acid and 0% dipthallide by a unique process from the crude carboxy phthalide (V) in presence of impurities like sulphuric acid, diphthahde , terphthalic acid and organic tars which involves treatment of crude reaction mass with sodium acetate, sodium propionate at 65 to 75 deg C whereby all insoluble diphthahde and organic tars are eliminated by filtration and the sodium salt of 5-carboxy phthalide (Formula IV) goes in solution in water which precipitates on cooling and is obtained as a solid as against the uncharacterized sodium salt obtained by direct neutralization of the crude acid by bases like sodium bicarbonate and carbonate as used in (EP1321464) which cannot isolate the pure salt of 5-carboxy phthalide as even l,4,disodium -2-hydroxymethyl terphthalate can be precipitated by phthalide ring opening as used in the process as such cannot lead to absolute and selective isolation of sodium salt of 5-carboxy phthalide(Formula IV). In this invention disclosing the said process, the pure sodium salt of 5-carboxy phthalide (Formula IV) is suspended in toluene as solvent as chlorinated with bis trichloromethyl carbonate (triphosgene) to generate a in-situ 5-chloro carbonyl phthalide(Formula III) which on treatment with ammonium carbonate yields 5-carbamoyl phthalide (Formula II)which on retreatment in the same pot with bis trichloromethyl carbonate yields 5-cyano phthalide (Formula I) with no inorganic or organic sulfur and or phosphorus compounds which can lead to severe purification problems as against (US Pat 2002028956 and US Pat 2002019546) wherein conventional chlorinating agents like thionyl chloride, phosphorus oxychloride, phosphorus pentachloride are used as chlorinating agents and sulfamide, thionyl chloride combination used for dehydration leading to extensive purification problems as against the no residue chlorinating and dehydrating agent bis trichloromethyl carbonate which leaves no residue as the products of decomposition 4 being carbon dioxide and hydrogen chloride. The chemical structures of the compounds named herein before is incorporated below: EXPERIMENTAL STAGE-1: Crude Carboxy phthalide (V) The reactor is charged with 1400 ml sulphuric acid 100% followed by slow addition of terphthalic acid (200gms) at room temperature. Followed by the addition of para formaldehyde in a 1.5 molar excess. The masses is then heated to 100°C wherein 1 mole liquid sulfur trioxide is dropped over a period of 3 hours during the course of addition the temperature is maintain at 110-120°C for 2 hours followed by cooling the reaction mass to room temperature and quenching over ice water the mass is filtered to yield 5-carboxy phthalide STAGE-2: 5-Sodium carboxy phthalide (IV) The crude carboxyphthalide is slurred in water followed by addition of sodium acetate in a 1.2 molar excess of stage 1. The mass is then heated to 80°C and filtered through a sparkler filter. The filtrate so obtained is chilled to obtain pure 5-sodium carboxyphthalide with absence of di-carboxy salt as confirmed by HPLC The sodium salt is dried. STAGE-3: Cyano phthalide (I) In a reactor is charged toluene followed by the dried sodium salt of stage 2 to this mass is added 10 mole% of dimethyl formaamide and the reaction temperature is raised to 45°C. To this mass is now added dropwise a 40% solution of triphosgene in toluene (1.2 mole equivalent to sodium carboxy phthalide charged) at such a rate so as to maintain continuous evolution of CO2 gas. After addition the mass is heated to 60°C for 2 hours and then purged with nitrogen to free any acidic gases. The mass is now cooled to 10 °C followed by purging gaseous ammoma till distinctly alkaline pH is obtained. The reaction mass is now heated to reflux to free it from gaseous ammonia followed by addition of 5 mole percent dimethyl forma amide based on the sodium salt. Subsequently a 40 % solution of triphosgene in toluene is added continuously at reflux temperature maintain positive evolution of hydrochloric acid and CO2 gas. triphosgene so added is 1.2 mole based on sodium salt charged. The completion of reaction is tested by HPLC for conversion of total amide form to the nitrile. The reaction mass is now cooled and added to water. The diluted mass is stirred for 1 hour and filtered to provide very high purity 5-cyanopthalide. While the present invention is described above in connection with preferred or illustrative embodiments, these embodiments are not intended to be exhaustive or limiting of the invention. Rather, the invention is intended to cover all alternatives, modifications and equivalents included within its spirit and scope, as defined by the appended claims. We claim, 1. A process for preparation of 5-cyano phthalide of formula I, wherein the said process comprises; a) condensing terphthalic acid (VI) and paraformaldehyde in sulfuric acid solvent, with gradual addition of sulfur trioxide as a condensing agent to form 5-carboxy phthalide (V) in the first stage; b) reacting the crude mass of said 5-carboxy phthalide (V) with sodium acetate and/or sodium propionate at 65-75°C, filtering to eliminate all the insoluble diphthalide and organic tars , whereby, sodium 5-carboxy phthalide (IV)goes into solution in water, precipitating the same on cooling the solution, and obtaining sodium 5-carboxy phthalide as a solid substantially free of terphthalic acid and diphthalide in the second stage; and c) suspending the sodium salt of carboxy phthalide (IV) in toluene as a solvent and adding dimethyl forma amide, treating the same with bis-trichloro methyl carbonate (triphosgene) to generate in-situ 5-chloro carbonyl phthalide, treating the same with gaseous ammonia or ammonium carbonate to yield 5-carbomoyl phthalide, retreating the same in the same pot with triphosgene to yield 5-cyano phthalide (I) in the third and final stage. 2. A process as claimed in claim 1, wherein the formaldehyde used in the said condensation reaction is 1.5molar excess relative to terephthalic acid. 3. A process as claimed in claim 1, wherein the addition of terephthalic acid to sulfuric acid is carried out at room temperature. 4. A process as claimed in claim 1, wherein the liquid sulfur trioxide used is 1 mole relative to terephthalic acid used. 5. A process as claimed in claim 1, wherein the addition of the sulfur trioxide is carried out at a maintained temperature of 110-120°C. 6. A process as claimed in claim 1, wherein the reaction temperature of the condensation reaction is 125°C for 2 hours. 7. A process as claimed in claim 1, wherein the said sodium acetate used is 1.2 molar excess of stage 1 relative to crude carboxyphthalide obtained in stage I. 8. A process as claimed in claim 1, wherein the said reaction of sodium salt formation is carried out at 80°C. 9. A process as claimed in claim 1, wherein the said addition of chlorinating agent is carried out at 45°C.

Documents:

1074-mum-2003-claims.doc

1074-mum-2003-claims.pdf

1074-mum-2003-corespondence(ipo).pdf

1074-mum-2003-corespondence.pdf

1074-mum-2003-description(granted).doc

1074-mum-2003-description(granted).pdf

1074-mum-2003-form 1-24-nov-2003.pdf

1074-mum-2003-form 1.pdf

1074-mum-2003-form 18.pdf

1074-mum-2003-form 2(granted).doc

1074-mum-2003-form 2(granted).pdf

1074-mum-2003-form 2(provsional).pdf

1074-mum-2003-form 2(title page).pdf

1074-mum-2003-form 26.pdf

1074-mum-2003-form 3.pdf

1074-mum-2003-form 5.pdf