GB2376945A

GB2376945A - Citalopram preparation

Info

Publication number: GB2376945A
Application number: GB0115708A
Authority: GB
Inventors: Yusuf Khwaja Hamied; Rajendra Narayanrao Kankan; Dharmaraj Ramachandra Rao
Original assignee: Cipla Ltd
Current assignee: Cipla Ltd
Priority date: 2001-06-27
Filing date: 2001-06-27
Publication date: 2002-12-31
Also published as: GB0115708D0

Abstract

Citalopram or a pharmaceutically acceptable salt of optical isomer thereof is prepared in high yield by reacting a salt of compound of formula: <EMI ID=1.1 HE=51 WI=97 LX=711 LY=830 TI=CF> <PC>where X represents a substituent such as halo which can be replaced by cyano, with cuprous cyanide in an organic solvent, and optionally converting the citalopram so formed into a pharmaceutically acceptable salt thereof.

Description

CITALOPRAM PROCESS The present invention relates to an improved process for preparing citalopram and pharmaceutically acceptable salts thereof.

Citalopram is a well known antidepressant compound and its preparation is described in GB 1526331. Its chemical name is 1-[3-

(dimethylamino) propyl]-l- (4-fluorophenyl)-5-phthalancarbonitrile (or, alternatively, 1-[3- (dimethyl amino) propyl]-1- ( 4-tluorophenyl) -1, 3-dihydro-5isobenzofurancarbonitrile). GB 1526331 describes various ways of preparing the compound, including its preparation by reacting 1-(4-fluorophenyl)-1-(3dimethylaminopropyl) -5-bromophthalane (shown below)

with cuprous cyanide in dimethylfonnamide. In GB 1526331, the 5-bromophthalane intermediate is used in the form of the free base which is normally a liquid at room

temperature. We have found certain disadvantages with this process, particularly in respect of the use of the free base. The process is not workable on a commercial scale, because the yield of product is poor. Being normally a liquid (an oil), the bromophthalane intermediate is difficult to provide easily at the required level of purity (i. e. without the use of time consuming purification), and this can thus lead to impurities in the end product which then need to be removed. It is possible to operate the process without the use of a solvent, but it is then very difficult to isolate the product in pure form from the reaction mixture.

We have now found a way of improving the above process which, surprisingly, substantially eliminates the problems associated with the prior method of operation.

According to the present invention, there is provided a process for the preparation of citalopram of formula (I) :

or a pharmaceutically acceptable salt or optical isomer thereof, which process comprises reacting a salt of an intermediate compound of formula:

where X represents a substituent such as halo which can be replaced by cyano, with cuprous cyanide in an organic solvent, and optionally converting the citalopram so formed into a pharmaceutically acceptable salt thereof.

The use of a salt of a compound of formula (II) confers certain advantages. The salt is a solid material and thus can be easily handled and stored, and has better stability than the liquid base. Being a solid, the starting material can be easily purified to the desired level of purity and this thus reduces the level of impurities in the citalopram end product. Unlike the prior art process (where the phthalane intermediate is in the form of a liquid oil), in the present process both the starting material and the cuprous cyanide are in suspension in the organic solvent. In the present process, the use of a solvent helps to reduce the number of by-products formed during the reaction and thus eliminates the need to distil citalopram base. The process is simple to operate, provides a good yield of product, and can be easily scaled up for commercial production.

As starting material, we prefer to use 5-halo substituted phthalanes such as the 5-bromophthalane intermediate, 1-(4-fluorophenyl)-1-(3- dimethylaminopropyl)-5-bromophthalane, although other 5-substituted intermediates can be used if desired. The important requirement is that the 5-substitiuent can be replaced by a cyano group. These intermediate compounds can be prepared, for example, by the methods described in GB 1526331 or by other known methods, as will be clear to those skilled in the art.

We prefer to use the oxalate salt of the phthalane intermediate, but other salts of organic acids such as the fumarate, maleate, citrate, acetate or formate salts can also be used. It is also possible to use inorganic salts, such as the hydrochloride, hydrobromide or sulphate salts. The oxalate salt is advantageous because it is easier to isolate when compared to other salts.

The organic solvent can be any suitable solvent, but we prefer to use diglyme. Other suitable solvents include N, N-dimethylacetamide, Nmethylpyrrolidone, ethyleneglycol, diethyleneglycol, monoglyme, sulpholane, hexamethylphosphoramide (HMPA), and dimethylsulfoxide (DMSO). Generally, from about 1.5 to 8 volumes of solvent with respect to the weight of the phthalane

intermediate are required. A preferred range is from about 3 to about 5 volumes of solvent with respect to the weight of the intermediate.

The reaction is generally carried out at a temperature of between 110

and 180 C but the maximum temperature will depend upon the boiling point of the solvent. A preferred reaction temperature is between 130 and 160 C. For diglyme, we prefer to use a temperature of between about 150 and 155 C.

Typically, the molar ratio of phthalane intermediate to cuprous cyanide will be from about 1: 1.2 to about 1: 4. We prefer to use a ratio of from 1: 1.2 to 1: 2, with a ratio of 1: 1.7 being particularly preferred.

The reaction mixture is maintained at the selected temperature for a period of between 1 and 10 hours. The exact time required will generally depend upon the solvent used. The reaction is usually complete within about 3 hours, and this will be a typical period when the solvent is diglyme. Once the reaction is complete, the product is separated from the reaction mixture and purified by crystallising from an organic solvent. Crystallisation can be from any suitable solvent and suitable solvents include n-hexane, n-heptane, aqueous isopropanol, aqueous methanol, and mixtures of C6-C7 hydrocarbons and lower alcohols.

The purified citalopram is then optionally converted into a pharmaceutically acceptable salt, and we prefer to use the hydrobromide salt although other salts can be used as will be clear to those skilled in the art. The hydrobromide salt is, for example, obtained by treating citalopram dissolved in an organic solvent with aqueous hydrobromic acid. The precipitated salt is then filtered in order to obtain solid crystals of citalopram hydrobromide.

The present process can be employed in circumstances where it is desired to obtain the R or S optical isomers of citalopram in isolation, as well as in the production of racemic citalopram.

The following examples illustrate the invention.

Example 1 100g of 5-Bromo-l- [3 (dimethylamino) propyl]-1- (4-fluorophenyl)-1, 3-dihydro-5isobenzofurane oxalate (bromophthalane oxalate) and 35g of cuprous cyanide are suspended in diglyme (500ml) 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 about 50 C and 100ml of a 50% aqueous ethylene diamine is added and stirred. The lower aqueous layer is drained off. The organic layer is diluted with toluene (500ml) and further washed with EDTA solution. The product is extracted in 10% aqueous acetic acid (150ml). Under vigorous stirring, aqueous ammonia is introduced into the acetic acid extract to ensure complete neutralisation of the acid. The product is filtered, dried and crystallised from n-hexane. The purified citalopram is dissolved in ethyl acetate and aqueous hydrobromic acid is added to precipitate the hydrobromide salt.

The product is filtered and dried under vacuum to obtain citalopram HBr (55g).

Example 2 1 OOg of 5-Bromo-1- [3 (dimethylamino) propyl]-l- ( 4-fluorophenyl) -1, 3-dihydro-5isobenzofurane hydrobromide (bromophthalane HBr) and 35g of cuprous cyanide are suspended in dimethylacetamide (400ml) and heated under a blanket of nitrogen to a

temperature of 140-145 C and maintained for 4 hours. The reaction mass is then cooled to about 60 C and 100ml of a 50% aqueous ethylene diamine is added and stirred. The lower aqueous layer is drained off. The solvent is then distilled off under vacuum and the residue is dissolved in toluene (500ml) and further washed with EDTA solution. The product is extracted in 10% aqueous acetic acid (150ml). Under vigorous stirring, aqueous ammonia is introduced into the acetic acid extract to ensure complete neutralisation of the acid. The product is filtered, dried and crystallised from n-heptane. The purified citalopram is dissolved in isopropanol and aqueous hydrobromic acid is added to precipitate the hydrobromide salt. The product is filtered and dried under vacuum to obtain citalopram HBr (50g).

Claims

CLAIMS: 1. A process for the preparation of citalopram of formula (I) :

or a pharmaceutically acceptable salt or optical isomer thereof, which process comprises reacting a salt of an intermediate compound of formula :

where X represents a substituent such as halo which can be replaced by cyano, with cuprous cyanide in an organic solvent, and optionally converting the citalopram so formed into a pharmaceutically acceptable salt thereof.
2. A process according to claim I wherein the salt of the said intermediate is the oxalate, fumarate, maleate, citrate, acetate, formate, hydrochloride, hydrobromide or the sulphate salt.

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3. A process according to claim 1 or 2 wherein the salt of the said intermediate is the oxalate salt.
4. A process according to any preceding claim wherein X is bromo.
5. A process according to any preceding claim wherein the organic solvent is diglyme.
6. A process according to any preceding claim wherein the ratio of solvent to the said intermediate compound (volume by weight) is from 1.5 : 1 to 8: 1.
7. A process according to any preceding claim wherein said ratio is from 3: 1 to 5: 1.
8. A process according to any preceding claim wherein the molar ratio of the said intermediate compound to cuprous cyanide is from 1: 1.2 to 1: 4.
9. A process according to any preceding claim wherein the reaction is carried out at a temperature of from 110 to 180 C, preferably between 130 to 160 C.
10. A process according to any preceding claim wherein citalopram is converted into its hydrobromide salt, its hydrochloride salt or its oxalate salt.