Citalopram and its pharmaceutically acceptable acid addition salts, such as its hydrogen bromide salt (Formula (I)) as described in U.S. Pat. No. 4,136,193, are anti-depressant drugs with few side effects.

Various processes for the preparation of citalopram have been described in the prior art. For example, U.S. Pat. No. 4,136,193 describes the alkylation of cyanophthalane with 3-dimethylaminopropylchloride, using sodium hydride as a base in a dimethylsulphoxide (DMSO) medium (Scheme-1). The reaction mixture is poured into ice water and extracted with ether. Then, after standard acid-base work-up, crude citalopram base is isolated as an oil. The isolated oil is purified by high vacuum distillation, (0.03 mm at 175-180° C.) and then converted to the hydrobromide salt.

Another process, as described in WO-A-98/19511, is the alkylation of cyanophthalane with 3-dimethylaminopropylchloride in the presence of a strong base (such as n-butyl lithium) and diisopropylamine in a dimethoxyethane medium at −50° C. (Scheme-2). After completion of the reaction, the reaction mixture is poured into ice water and extracted with toluene. After standard acid-base work-up using toluene as solvent, citalopram base is isolated as an oil. The oily base is then converted to acid addition salts such as citalopram hydrobromide and hydrochloride by conventional methods.

A drawback of the above two processes is that the citalopram base is isolated as an oil. Purification of citalopram oily base is carried out by high vacuum distillation (0.03 mm) at 175-181° C. Achieving such a very high vacuum at plant level is difficult and hence the process described is not easily transferable to the commercial scale. Apart from these constraints, citalopram base having a cyano group at the 5th position of the bicyclic ring system may decompose during high vacuum distillation at high temperature to form citalopram carboxamide as an impurity, resulting in poor quality and yield.
In yet another process, citalopram is made as described in U.S. Pat. No. 4,650,884. The process involves the successive Grignard reaction of 5-cyanophthalane with 4-fluorophenylmagnesiumbromide and N,N-dimethylaminopropylmagnesiumchloride and the cyclization of the resulting diol to obtain citalopram base as an oil (Scheme-3). The oily base is converted to the hydrobromide salt using anhydrous hydrogen bromide gas in acetone medium. Due to the poor quality of the oily base, repeated crystallization of the hydrobromide was necessary to obtain a pharmaceutically acceptable quality of citalopram hydrobromide.

Using the same strategy, citalopram base may be made as described in CA-A-1,339,452 [equivalent to U.S. Pat. No. 4,943,590, EP-A-347066 & GB-A-8,814,057 Scheme-3]. The racemic diol base, as described in the patent, is dissolved in dichloromethane. Triethylamine and methane sulphonyl chloride are added over a period of 1 hour. The reaction mixture is then washed twice with 0.1M sodium hydroxide solution, the organic phase is separated and dried over anhydrous magnesium sulphate followed by solvent concentration under reduced pressure, and the citalopram base is isolated as a crystalline solid. For the first time, citalopram base has been reported as a crystalline solid. However, no physical data are described here [EP-A-347066]. The solid base is converted to the hydrobromide salt using anhydrous hydrogen bromide gas in acetone medium.
DE-A-20 007 303 discloses yet another process for the isolation of citalopram base, as a solid, from citalopram hydrobromide. However, the process for making citalopram hydrobromide is not described. The isolated crystalline base is then converted into the desired salt. According to the process described here, pure citalopram hydrobromide is dissolved in 5 volumes of water and the pH is adjusted to about 10 with 6N sodium hydroxide. Citalopram base is then extracted into a non-polar organic solvent, such as toluene. The toluene is distilled off under reduced pressure and the resulting residue is triturated with n-heptane to precipitate citalopram base as a solid. The solid is then filtered to produce crystalline citalopram base.
The main disadvantage of this process is that citalopram hydrobromide has to be made first from the crude oily base isolated from the prior art process and then converted back to solid citalopram base. Then, the solid base is again converted to its corresponding hydrobromide salt. Thus, the process involves multiple operations which are tedious and time consuming. In addition, prolonged heating of citalopram base may increase the carboxamide impurity, resulting in poor quality citalopram.