Title of Invention	A PROCESS FOR PREPARATION OF PHTHALANES
Abstract	A PROCESS FOR PREPARATION OF PHTHALANES

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FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION (See section 10}rules13) A Pieces FOR" [PREPARATION OF PHTHALANES Cipia Limited of 289 Bellasis Road, Mumbai Central, Mumbai - 400 008 The following specification (particularly) describes the nature of the invention and the manner in which it is to be performed» Fujtd of the Invention: The present invention relates to a process for the preparation of phthalanes of general formula III as shown below, particularly but not exclusively citalopram. Background and Prior Art Description: GB 1526331 describes citalopram and other closely similar phthalanes of formula II: The antidepressant drug citalopram, l-[3- (dimethylamino)propyl]-l- (4- fluorophenyl)-l, 3-dihydro-5-isobenzofurancarbonitrile, has the formula I: wherein R1 and R2 each represents halogen, a trifluoromethyl group, a cyano group or R-CO-wherein R is an a\ky\ Tadicai with from 1 to 4 carloon atoms, and acid addition salts thereof with pharmaceutical^ acceptable acids. 2 GB1526331 describes a number of processes for making citalopram, among which is a process in which a compound of formula II in which R1 is bromine and R2 is fluorine, is reacted with cuprous cyanide in an inert organic solvent to obtain a compound of formula II in which Rl is a cyano group, i. e. to obtain citalopram. This process is particularly described in Example 3 of GB 1526331 where the yellow oil l-(4"-fluorophenyl)-5-bromophthalane (free base) and cuprous cyanide are refluxed in dimethyl formamide. Dimethyl formamide dissolves the bromophthalane. The citalopram so formed is crystallized out by pouring the reaction mixture into an aqueous solution of sodium cyanide. The Inventors have investigated this process and have found that it is; difficult to carry out and generally gives only a low yield. The Inventors have tried the same process but without any solvent, and whilst the reaction conversion is good, it is very difficult to isolate pure white citalopram product. The Inventors have now found a way in which these difficulties can be reduced or overcome. Statement of the Invention Accordingly, the present invention provides a process for the preparation of a phthalane of formula III: whereinR2 is halogen, trifluoromethyl, cyano or R-CO- wherein R is an alkyl radical having from 1 to 4 carbon atoms, and acid addition salts thereof, which comprises reacting a salt of a compound of formula II in which R1 is halogen and R2 is as defined above, with cuprous cyanide, with heat in the presence of an organic liquid such as herein described, at a temperature up to the boiling point of the organic liquid. Detailed Description of the Invention: According to one aspect of the present invention, there is provided a process for the preparation of a phthalane of formula II in which R1 is cyano and R2 is as defined for formula II above, wherein a salt of a compound of formula II in which R1 is halogen, is reacted with cuprous cyanide. The process is especially useful for making citalopram in which case R1 in the compound of formula II is initially bromine, chlorine or iodine, and R2 is fluorine. Other phthalanes can also be made. . . In the process of the invention, we prefer to use the oxalate salt, but other salts can equally be used. For example, the fumarate, acetate, maleate, mesylate, citrate, lactate, tartrate, besylate, tosylate, mandelate, benzoate, salicylate and other organic acid salts. According to a further preferred feature of the invention, the salt is reacted with the cuprous cyanide as a suspension in an organic liquid. There are many possible such liquids, as will be clear to those skilled in the art. We prefer to use diglyme but other possible organic liquids include sulfolane, dimethylsulfoxide, Nmethyl pyrrolidone, tetraglyme, ethylene glycol. The reaction is effected under heat over a period of time. The exact conditions will depend on the organic liquid and, to a lesser extent, the salt used. The reaction is preferably conducted under an inert atmosphere, e. g. nitrogen. By way of example, we have found that in the case of the oxalate salt and using diglyme as the organic liquid, the suspension is preferably heated at 150-155 C for about three hours. More generally, the time of heating will be from 1 to 5 hours at or below the reflux temperature of the organic liquid. At the end of the reaction, citalopram is recovered from the reaction mixture by any suitable means. We have found that washing the organic liquid with an aqueous base and then extracting the citalopram into an aqueous acid solution is satisfactory. Upon neutralisation of the acid solution, the citalopram precipitates out and can be recrystallised as desired. Since citalopram is normally used in the form of its hydrobromide salt, conversion thereto is preferably effected in the usual way. 4 In the above recovery procedure, we prefer to use an aqueous solution of ethylene diamine as the base, but other bases can be used such as ammonia, monomethylamine, dimethylamine, other amines, and alkali metal hydroxides. The preferred aqueous acid solution is an organic acid solution. We prefer to use acetic acid but other acids can be used such as hydrochloric acid, sulphuric acid, phosphoric acid, formic acid and other organic and mineral acids. In order that the invention may be more fully understood, the following Example is given by way of illustration only. Example Bromophthalane oxalate lOOg and cuprous cyanide 35g are suspended in diglyme500ml and heated under a blanket of nitrogen to a temperature of 150-155° C and maintained for 3 hours. The reaction mass is then cooled to 50° C andlOOml of a 50% aqueous solution of ethylene diamine is added. The lower aqueous layer is drained off. The organic layer is diluted with toluene500ml and further washed with ethylene diamine solution followed_by 5%JEDTA solution. The product is extracted into 10% solution of acetic acidl50ml. Under vigorous stirring, 25% aqueous ammonia solution is then introduced into the acetic acid extract to ensure complete neutralization of the acid. The product which precipitates out is filtered. The crude product is then crystallized from n-hexane. The purified citalopram base is then taken in ethyl acetate or isopropyl alcohol, water and aqueous hydrobromic acid is added. The product is filtered and dried in a vacuum oven to obtain 35g of citalopram hydrobromide. WE CLAIM. A process for the preparation of a phthatane of formula EI: wherein R2 is halogen, trifluoromethyl, cyano or R-CO- wherein R is an alkyl radical having from 1 to .4 carbon atoms, and acid addition salts thereof, which comprises reacting a salt of a compound of formula II in which R1 is halogen and R2 is as defined above, with cuprous cyanide, with heat in the presence of an organic liquid such as herein described, at a temperature up to the boiling point of the organic liquid. 1. A process as claimed in claim 1, whereinR2 is fluorine. 3. A process as claimed in claim 1 or 2, wherein said salt is an organic acid salt. 4. A process as claimed in claim 3, wherein the salt of formula II is the oxalate. 5. A process as claimed in claim 3, wherein the salt of formula II is the fumarate, acetate, maleate, mesylate, citrate, lactate, tartrate, besylate, tosylate, madelate, benzoate or salicylate. 6. A process as claimed in any of claims 1 to 5, wherein the salt of formula II is reacted wi th the cuprous cyanide in an organic liquid. 7. A process as claimed in claim 6, wherein the organic liquid is diglyme. 6 8. A process as claimed in claim 6, wherein the organic liquid is sulfolane, dimethyl sulfoxide, N-methyl pyrrolidone, tetraglyme or ethylene glycol. 9. A process as claimed in any of claims 1 to 8, wherein the reaction is conducted under heating in an inert atmosphere. 10. A process as claimed in any of claims 1 to 9, wherein at the end of the reaction, the reaction mixture is washed with an aqueous base, and the phthalane is extracted from the wash liquid into an aqueous acid solution. 11. A process as claimed in claim 10, wherein the base is ammonia, an amine, or an alkali metal hydroxide, and the acid is an organic acid. 12. A process as claimed in claim 9 or 10, wherein the aqueous acid solution extract isneutralised to precipitate the phthalane. 13. A process as claimed in any of claims 1 to 12, wherein the phthalane of formula III is citalopram. 14. A process as claimed in any of claims 1 to 13, wherein the phthalane of formula III is converted to a salt thereof. 15. A process for the preparation of a phthalane of formula III substantially as herein described with reference to the example. Dated this 4th day of September, 2003 7

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844-mumnp-2003-abstract(18-11-2004).doc

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844-mumnp-2003-cancelled pages(18-11-2004).pdf

844-mumnp-2003-claims(granted)-(18-11-2004).doc

844-mumnp-2003-claims(granted)-(18-11-2004).pdf

844-mumnp-2003-corresponednce(18-08-2006).pdf

844-mumnp-2003-corresponednce(ipo)-(28-09-2004).pdf

844-mumnp-2003-form 19(08-09-2003).pdf

844-mumnp-2003-form 1a(07-01-2004).pdf

844-mumnp-2003-form 1a(30-01-2004).pdf

844-mumnp-2003-form 2(granted)-(18-11-2004).doc

844-mumnp-2003-form 2(granted)-(18-11-2004).pdf

844-mumnp-2003-form 26(07-01-2004).pdf

844-mumnp-2003-form 3(04-02-2004).pdf

844-mumnp-2003-form 3(07-01-2004).pdf

844-mumnp-2003-form 5(07-01-2004).pdf

844-mumnp-2003-pct-ipea-409(03-10-2003).pdf

844-mumnp-2003-pct-isa-210(03-10-2003).pdf

844-mumnp-2003-petition under rule 138(18-11-2004).pdf