Title of Invention	"A PROCESS FOR THE PEPARATION OF PURE 1-(4-FLUOROPHENYL)-1,3-DIHYDRO-5-ISOBENZOFURANCARBONITRILE"
Abstract	A process for the preparation of pure 1- (4-fluorophenyl)-1, 3- dihydro-5-isobenzofurancarbonitrile is disclosed by reacting 5-cyanophthalide with a 4-fluorophenylmagnesium halide, reducing the 3- hydroxymethyl-4- (4-fluorobenzoyl) benzonitrile with an agent reducing ketones to alcohols, submitting the thus obtained 3- hydroxymethyl-4- [ (4-fluorophenyl) hydroxymethyl] benzonitrile (C) to a cyclization reaction to give 1- (4-fluorophenyl)-1, 3- dihydro-5-isobenzofurancarbonitrile and recovering the pure 1- (4- fluorophenyl)-1, 3-dihydro-5-isobenzofurancarbonitrile (B), with a solvent isopropanol or methyl-t-butylether with less than 0.5% of 1,1-bis (4-fluorophenyl)-1, 3-dihydro-5-isobenzofurancarbonitrile.

Title of Invention

"A PROCESS FOR THE PEPARATION OF PURE 1-(4-FLUOROPHENYL)-1,3-DIHYDRO-5-ISOBENZOFURANCARBONITRILE"

Abstract

A process for the preparation of pure 1- (4-fluorophenyl)-1, 3- dihydro-5-isobenzofurancarbonitrile is disclosed by reacting 5-cyanophthalide with a 4-fluorophenylmagnesium halide, reducing the 3- hydroxymethyl-4- (4-fluorobenzoyl) benzonitrile with an agent reducing ketones to alcohols, submitting the thus obtained 3- hydroxymethyl-4- [ (4-fluorophenyl) hydroxymethyl] benzonitrile (C) to a cyclization reaction to give 1- (4-fluorophenyl)-1, 3- dihydro-5-isobenzofurancarbonitrile and recovering the pure 1- (4- fluorophenyl)-1, 3-dihydro-5-isobenzofurancarbonitrile (B), with a solvent isopropanol or methyl-t-butylether with less than 0.5% of 1,1-bis (4-fluorophenyl)-1, 3-dihydro-5-isobenzofurancarbonitrile.

Full Text	PROCESS FOR THE PREPARATION OF A CYANOISGBEWZQFURAN The present invention concerns a process for the preparation, with a sole series of reactions, of pure 1-(4-fluorophenyl)-1,3-dihydro-5- isobenzofurancarbonitrile and for its conversion into the 1-[(3- (dimethylamino)propyl]-1-(4-fluoropheny!)-1,3-dihydro-5- isobenzofurancarbonitrile and its pharmaceutical acceptable salt. Said cyano-isobenzofuran, 1-[(3-(dimethylamino)propy!]-1-(4- fluorophenyl)-1,3-dihydro-5-isobenzo furancarbonitrile, represented by the formula A (Figure Removed) known with its International Non-proprietary Name "citalopram" is an active principle of drugs used, in form of its hydrobromide, for the preparation of pharmaceuticai compositions for the treatment of depression. Citalopram was described for the first time in the Belgian patent 850,401 (corresponding to US 4,136,193) and many methods for its preparation have been patented. Document US 4,136,193 discloses a family of compounds of formula A' N(CH3)2 (A1) wherein RI and R2 represent each a halogen, a trifluoromethyl group, a cyano group or a group R-CO- in which R is CrC4 alkyl. According to said document, the compounds of formula A' may be prepared by reaction of a compound of formula B' (Figure Removed) wherein R^ and R2 are as defined above, with a 3-(dimethylamino)propyl halide in the presence of a base. The same document does not say how the compounds of formula B' in which RI is cyano and RZ is fluoro are prepared, but in two examples it provides the preparation of a compound of formula B1, in which RI is bromo and Ra is fluoro, by reaction of 5- bromophthalide with 4-fluorophenyl magnesium bromide, reduction of 3- hydroxymethyl-4-(4-fluorobenzoyl)bromobenzene thus obtained with lithium aluminium hydride and cyclization of the diol thus obtained of formula C' (Figure Removed) wherein R-i is bromo and R2 is fluoro, with 60% phosphoric acid. From this document an ordinary expert infers that the method for the preparation of the compounds of formula A1 is of general character and that the reaction with 4-fluorophenyl magnesium bromide may be performed on the 5- cyanophthalide too. In fact, EP 171,943 discloses a method of synthesis which uses two Grignard reactions starting from 5-cyanophthalide, the first one being with 4-flourophenyl magnesium bromide and the second, on the magnesium derivative obtained, with 3-(dimethylamino)propyl magnesium chloride to obtain a diol, precursor of citalopram, of formula D (Figure Removed) which is cyclized to citalopram. Analogously, the document WO 98/19511 (corresponding to US 6,291,689) discloses a process wherein the 3-hydroxymethyl-4-(4- fluorobenzoyl)benzonitrile is reduced with sodium borohydride to obtain the diol of formula C1, wherein R-i is cyano and Ra is fluoro, which is cyclized to 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile in its turn converted to citalopram by reaction with 3-(dimethylamino)propyl chloride in the presence of a base. According to this document, the process may be carried out by isolating the intermediates or without isolating them, but said document does not give any information on how to carry out the process in a sole operation. Furthermore, the process described in WO 98/19511, which substantially overlaps that disclosed in the preceding documents BE 850,401 and US 4,136,193, provides 1 -(4-fluorophenyl)- 1,3-dihydro-5- isobenzofurancarbonitrile (compound of formula B' in which RI = CN and R2 = F) in a yield of 29% only. It has been hypothesized and experimentally demonstrated that the reaction of 4-fluorophenyl magnesium bromide with 5-cyanophthalide leads to a mixture in which, beside the desired 3-hydroxymethyl-4-(4~ fluorobenzoyl)benzonitrile, the 3-hydroxymethyl-4-[bis(4- fluorophenyl)hydrojcymethyl]benzonitrile is present in not negligible amounts. In the subsequent cycllzation this by-product, which remains unaltered during the reduction, for example with LiAIH4 or NaBH4l gives the 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile which, being difficulty separable from the intermediate 1-(4-fluorophenyl)-1,3- dihydro-5-isobenzofurancarbonitrile, involves noteworthy problems in the synthesis of the final citalopram. The confirmation of the formation of the above-mentioned by-products was possible by treatment of 5- cyanophthalide with an excess of 4-fluorophenyl magnesium bromide which, by favouring the formation of the 3-hydroxymethyl-4-[bis(4- fluorophenyl)hydroxymethyl] benzonitrile, allowed the isolation and the characterization of this by-product. The same principle has been applied to the preparation of 1,1-bis(4-fluorophenyl)-1,3-dihydro-5- isobenzofurancarbonitrile which has thus been isolated and characterized. Through the study of the solubility of 1,1-bis(4-fluorophenyl)-1,3-dihydro-5- isobenzofurancarbonitrile and of the 1-(4-fluorophenyl)-1,3-dihydro-5- isobenzofurancarbonitrile, it was possible to succeed in the separation of the two products in the course of the synthesis of citalopram starting from 5-cyanophthalide. In particular, thanks to the identification of the by-products, it has been found that, by operating according to Example 3 of BE 850,401 (US 4,036,193), starting from 5-cyanophthalide, after the reaction with 4- fiuorophenyl magnesium halide, the subsequent reduction to diol (C) and the cyclization to 1-(4-fluorophenyl)-1,3-dihydro-5- isobenzofurancsrbonitrile (B) it is possible to isolate the mixture containing the 1-(4-fluorophenyl)-1,3- dihydro-5-isobenzofurancarbonitrile and the 1,1-bis-(4-fluorophenyl)-1,3- dihydro-5-isobenzofuran carbonitrile and to treat said mixture with a solvent capable of dissolving the 1,1-bis-(4-fluorophenyl)-1,3-dihydro-5- isobenzofurancarbonitrile under condition in which 1-(4-fluorophenyl)-1,3- dihydro-5-isobenzofurancarbonitrile is practically insoluble, for example with isopropanol or with methyl-f-butylether. Under these conditions, the pure 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) is recovered in very high yields while the by-product 1,1-bis-(4-fluorophenyl)- 1,3-dihydro-5-isobenzofurancarbonitrile remains in solution and is thus eliminated. The reaction sequence takes place according to Scheme 1 below, wherein a preferred embodiment is illustrated. From 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile thus obtained, by reaction with a 3-(dimethylamin6)propyl halide in the presence of a condensing agent such as an alkaline metal, for example sodium amide or potassium amide, butyl lithium, phenyl lithium, sodium hydride and the like, as described in BE 850,401 (US 4,136,193), it is possible to obtain the citalopram in a high degree of purity in form of free base or of one of its non toxic acid addition salts. The expressions "pure citalopram" and "citalopram at high purity degree" indicate citalopram or a pharmaceutically acceptable salt thereof, in particular the hydrobromide, in which the 1,1-bis(4-fluorophenyl)-1,3- dihydro-5-isobenzofurancarbonitrile is not detectable in the NMR spectrum obtained with a Bruker AMX 400 MHz apparatus. The terms "soluble" and "insoluble" and the expression "capable of dissolving" indicate a solubility degree of the above compounds which allows an average skilled in the art to dissolve a product under normal conditions, namely at a reasonable concentration and temperature or to consider that, at said reasonable concentration and temperature said product does not dissolve, taking into account that in the case of 1-(4- fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile and of 1,1'-bis(4- fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile it is a matter of evaluating a difference of solubility between the two compounds. In an indicative but not limiting manner it may be considered that a solvent is suitable to the separation of the two compounds if, in said solvent, the 1,1 '-bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile is "very soluble", "soluble" or "fairly soluble" according to the criteria of the European Pharmacopea or of the United States Pharmacopea (DSP) while, in the same solvent, the 1-(4-fluorophenyl)-1,3-dihydro-5- isobenzofurancarbonitrile is "very slightly soluble" or "practically insoluble". Figure 1 illustrates the characteristics of the 3-hydroxymethyl-4- [bis(4-fluorophenyl)hydroxymethyl]benzonitrile in the 1H-NMR and 13CNMR spectra obtained with a Bruker AMX 400 MHz apparatus. Figure 2 illustrates the characteristics of the 1,1-bis(4-fluorophenyl)- 1,3-dihydro-5-isobenzofurancarbonitrile in the 1H-NMR and 13C-NMR spectra obtained with a Bruker AMX 400 MHz apparatus. (Figure Removed) Figure 3 illustrates the characteristics of the pure 1-(4-fluorophenyl)- 1,3-dihydro-5-isobenzofurancarbonitrile in the 1H-NMR and 13C-NMR spectra obtained with a Bruker AMX 400 MHz apparatus. Thus, it is an object of the present invention to provide a process for the preparation of 1-(4-fluoropheny!)-1,3-dihydro-5- isobenzofurancarbonitrile which comprises: (a) reacting 5-cyanophthalide with a 4-fluorophenyl magnesium halide; (b) treating the mixture thus obtained, containing the 3- hydroxymethyl-4-(4-fluoro- benzoyl)benzonitrile and the 3-hydroxymethyl- 4-[bis-(4-fluorophenyl)hydroxymethyl] benzonitrile; with an agent reducing ketones to alcohols; (c) submitting the mixture thus obtained, containing the 3- hydroxymethyl-4-[(4-fluorophenyl)hydroxymethyl]benzonitrile (C) and the 3-hydroxymethyl-4-[bis-(4-fluoro- phenyl)hydroxymethyl]benzonitrile, to a cyclization reaction and isolating a. mixture containing the 1-(4- fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile and the 1-(4- fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) and the 1,1- bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile; (d) treating the mixture thus obtained with a solvent capable of dissolving the 1,1-bis(4-fluorophenyl)-1,3-dihydro-5- isobenzofurancarbonitrile and in which the 1-(4-fluorophenyl)-1,3-dihydro- 5-isobenzofurancarbonitrile (B) is insoluble and recovering the pure 1-(4- fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B). Steps (a), (b) and (c) are carried out without isolating the intermediate compounds according to known literature methods, for example according to the method cited in US 4,136,193 and specifically described, starting from 5-bromophthalide, in examples 1 and 3 of said document. In particular, step (a), consisting of the treatment of 5-cyanophthalide with a 4-fluorophenyimagnesium halide, occurs according to a classical Grignard reaction procedure, for example under the conditions described in Example 1 of US 4,136,193 for the 5-bromophthalide, by treating 1,054-1,35 equivalents of a Grignard solution, titred at 15+20%, said solution being prepared from p-fiuorobromobenzene and magnesium turnings in an ether, for example in tetrahydrofuran, with 5-cyanophthalide and by adding said Grignard reagent in the amount capable of consuming practically the whole starting 5-cyanophthalide. In practice, the operator controls the course of the reaction by HPLC [column: Develosil C18 4.6 x 250 mm, 5^; DETECTOR: UV 240nm; FLOW: 1.5 ml/min; GRADIENT: A: aqueous NH4H2P04 + H3PO4 at pH = 2.85 / B: CH3CN/H2O = 9/1 (v/v)] and stops it when 2+3% of unreacted 5-cyanophthalide remains. The product thus obtained is directly submitted to the next step (b) consinsting of a reduction with an agent reducing ketones to alcohols for example with NaBH4l or with LiAIH4 as described in Example 3 of US 4,136,193, to obtain the corresponding 3-hydroxymethyl-4-[(4-fluorophenyl) hydroxymethyl]benzonitrile. According to a preferred embodiment, which allows the large scale preparation under conditions of safety, the reduction is carried out with an aqueous solution of NaBH4 and sodium hydroxide. Said aqueous solution is added at a temperature not higher than 15°C and the reaction is complete at the end of the addition. Thus, it is sufficient to eliminate the aqueous phase, to evaporate the organic solvent and to submit the residue to the subsequent step (c). Step (c), consisting of the diol cyclization, is conducted by treating the material obtained at the end of step (b) with 60% phosphoric acid as described in Example 1 of US 4,136,193 for the corresponding 3- hydroxymethyl-4-[(4-fluorophenyl)hydroxymethyl]-bromobenzene. According to a preferred embodiment, the method described in US 4,136,193 is rendered easier by dissolving the material obtained at the end of step (b) in an organic solvent, preferably ethyl acetate or tetrahydrofuran, and by carrying out the reaction with 60% phosphoric acid in a biphasic system, thus avoiding the formation of waxy residues which are difficult to treat. In practice, the residue obtained according to the preferred mode of conducting step (b) is dissolved in ethyl acetate and, after the addition of 60% phosphoric acid, the reaction is carried out in a biphasic, for example water/ethyl acetate, system. In step (d), the crude material thus obtained, containing the 1-(4- fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) and the 1,1- bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile is treated with a solvent capable of dissolving the 1,1-bis(4-fluorophenyl)-1,3-dihydro-5- isobenzofurancarbonitrile under conditions in which the 1-(4-fluorophenyl)- 1,3-dihydro-5-isobenzofurancarbonitrile (B) is practically insoluble, for example with isopropanol or with methyl-f-butylether. According to a preferred embodiment, the process of the present invention is carried out "one-pot", i.e. without isolating the intermediate products, until a 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile practically devoid of 1,1-bis(4-fluorophenyl)-1,3-dihydro-5- isobenzofurancarbonitrile is obtained, said 1-(4-fluorophenyl)-1,3-dihydro- 5-isobenzofurancarbonitrile being subsequently converted into citalopram. In practice, a Grignard solution is prepared by adding a solution of 4- fluorobromobenzene in tetrahydrofuran to magnesium turnings in the presence of traces of iodine at a temperature of about 70°C and, after about 30 minutes, at the same temperature, the solution is added portionwise to a suspension of 5-cyanophthalide in tetrahydrofuran at - 20-5-0°C, preferably at -10-5-0°C. At the end of the reaction, namely when less than 5% of the starting 5-cyanophthalide is present, the magnesium derivative is decomposed with water or, better, with an aqueous solution of ammonium chloride and the cold tetrahydrofuranic solution, containing the 3-hydroxymethyl-4-(4-fluorobenzoyl)benzonitrile and the 3-hydroxymethyl- 4[bis(4-fluorophenyl)hydroxymethyl]benzonitrile, is treated with an aqueous solution of NaBH4 and of NaOH. The obtained mixture, containing the 3-hydroxymethyl-4-[(4- fiuorophenyl)hydroxy methyljbenzonitrile (C) and the 3-hydroxymethyl-4- [bis(4-fluorophenyl)hydroxymethyl] benzonitrile, is extracted with ethyl acetate. The organic phase is concentrated, the residue is taken up with an organic solvent, preferably with ethyl acetate, and the solution is treated with 60% phosphoric acid and heated. At the end of the reaction, after separation of the phases, the organic phase, containing the 1-(4- fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile and the 1,1-bis-(4- fluorophenyl)-1,3-dihydro-5-iso benzofurancarbonitrile, is washed with water, decolorized with activated charcoal and concentrated under vacuum. The oily residue is treated with the selected solvent, preferably with isopropanol or with methyl-f-butylether, then the solvent is evaporated under vacuum. If needed, the operation of treatment with the solvent and of subsequent evaporation is repeated several times until, by taking up with the solvent, a crystalline suspension consisting of pure 1-(4- fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) is obtained. This compound is isolated in a 70+75% yield, calculated in respect of the starting 5-cyanophthalide, by simple filtration. In general, the product thus obtained, having a purity higher than 98%, contains the 1,1-bis(4- fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile in a percent lower than 0.5%, thus allowing the subsequent preparation of a citalopram with a high degree of purity, or of pharmaceutically acceptable salt thereof, by treatment with a 3-(dimethylamino)propyl halide in the presence of a basic condensing agent. This mode of operating is illustrated, in a preferred aspect thereof, in Scheme 2 below. The 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile containing the 1,1-bis(4-fluorophenyl)-1,3-dihydro-5- isobenzofurancarbonitrile in a percent lower than 0.5% is a new product which represents a further object of the present invention. The pure 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) obtained at the end of steps (a)-(d) above may be further made to react with a 3-(dimethylamino) propyl halide in the presence of a basic condensing agent to isolate citalopram at a high purity degree, or a pharmaceutically acceptable salt thereof, in yields which are higher than those obtained with any other known process using 5-cyanophthalide as starting material. Thus, it is another object of the present invention to provide a process for the preparation of citalopram or of a pharmaceuticaily acceptable salt thereof, which comprises: (a) reacting 5-cyanophthalide with a 4-fluorophenyl magnesium halide; (b) treating the mixture thus obtained, containing the 3- hydroxymethyl-4-(4-fluoro benzoyl)benzonitrile and the 3-hydroxymethyl-4- [bis-(4-fluorophenyl)hydroxymethyl] benzonitrile with a reducing agent of ketones to alcohols; (c) submitting the mixture thus obtained, containing the 3- hydroxymethyl-4-[(4-fluorophenyl)hydroxymethyl]benzonitriIe (C) and the 3-hydroxymethyl-4-[bis-(4-fluoro phenyl)hydroxymethyl]benzonitrile to a cyclization and isolating a mixture containing the 1-(4-fluorophenyl)-1,3- dihydro-5-isobenzofurancarbonitrile (B) and the 1,1-bis(4-fluoro phenyl)- 1,3-dihydro-5-isobenzofurancarbonitrile; (d) treating the mixture thus obtained with a solvent capable of dissolving the 1,1-bis(4-fluorophenyl)-1,3-dihydro-5- isobenzofurancarbonitrile and in which the 1-(4-fluorophenyl)-1,3-dihydro- 5-isobenzofurancarbonitrile (B) is insoluble and recovering the pure 1-(4- fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitriIe (B); (e) treating the pure 1-(4-fluorophenyl)-1,3-dihydro-5- isobenzofurancarbonitrile (B) with a 3-(dimetylamino)propyl halide in the. presence of a basic condensing agent and isolating citalopram as free base or as a pharmaceuticaily acceptable salt thereof. Steps (a)-(d) are carried out as described above and the pure 1-(4- fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) obtained at the end of step (d) is submitted to the subsequent step (e). In step (e), the chloride, the bromide or the iodide may indifferently be used as halide, the chloride being preferred. As a condensing basic agent, anyone of the bases commonly used in the alkylation reactions, such as sodium amide, potassium amide, butyl lithium, phenyl lithium or sodium hydride may be employed. (Figure Removed) The condensation is carried out in an inert solvent, preferably in dimethyl sulfoxide. Advantageously, the 1-(4-fluorophenyl)-1,3-dihydro-5- isobenzofurancarbonitrile (B) as obtained at the end of step (d) is dissolved in dimethyl sulfoxide, the solution thus obtained is added to a suspension of sodium hydride in dimethyl sulfoxide, the mixture is then treated with 3-(dimethylaminopropyl) chloride and the citalopram which forms is isolated according to the conventional methods, in form of free base or of a salt thereof. According to a preferred embodiment, at the end of the reaction water is added, citalopram is extracted with ethyl acetate and, after suitable washings with water, the organic phase containing citalopram is concentrated to an oil, essentially consisting of citalopram base, which, by treatment with HBr in acetone, affords a citalopram hydrobromide wherein the 1,1-bis(4-fluorophenyi)-1,3-dihydro-5-isobenzofurancarbonitrile is not detectable in the NMR spectrum obtained with a Bruker AMX 400MHz apparatus. The product thus obtained may be subsequently purified according to known methods, for example by repeated washings with cold water. Thus, the process of the present invention allows the preparation of citalopram hydrobromide in yields much higher than those obtained by all of the methods employing the 5-cyanophthalide as starting material. Furthermore, by avoiding the use of intermediates containing a prcursor of the CN group, the process of the invention is easier to be carried out and affords a citalopram with high purity in very satisfactory yields. In the preparations given hereinbelow the by-products that form in the synthesis starting from 5-cyanophthalide are isolated. They represent the reference standards for the control of the process of the invention. The following examples illustrate the invention. PREPARATION I 20% Solution of 4-fluorophenylmagnesium bromide in tetrahydrofuran In a 4-I flask, under nitrogen flow and at room temperature, 53.5 g of magnesium turnings and 0.3 g of iodine particles are charged, then the mixture is heated to 70°C and, in one hour, a solution of 369.5 g of 4- 15 fluorobromobenzene in 1960 ml of tetrahydrofuran is dropped thereinto. At the end of addition the mixture is heated at reflux at 68-70°C for 30 minutes, then the obtained solution is cooled to 25°C. There is obtained 2000 g of a 20% solution of 4-fluorophenylmagnesium bromide, to be stored in the dark and in nitrogen atmosphere. PREPARATION II 3-hydmxymethyl-4[bis(4-fluorophenyl)hydroxymethyl]benzonitrile (a) Synthesis To a suspension of 20 g of 5-cyanophthalide in 150 ml of tetrahydrofuran, under nitrogen flow, at 25°C, 422.6 g of the 20% solution of 4-fluorophenylmagnesium bromide obtained in PREPARATION I are added and a rise in temperature of the mixture to about 35°C is observed. The mixture is kept under stirring until, by a HPLC control [COLUMN: Develosil C18 4.6 x 250 mm, 5 ji; DETECTOR: UV 240 nm; FLOW: 1.5 ml/min; GRADIENT: A: aq. NH4H2PO4 + H3P04 - pH = 2.85 / B: CH3CN/H20 = 9/1 (v/v)], the disappearance of 5-cyanophthalide is observed. When the reaction is over, 200 ml of a 15% aqueous solution of ammonium chloride are added, maintaining the temperature not higher than 30°C, then the phases are separated and the organic one is concentrated under vacuum to obtain 52 g of a yellow oil, the raw 3-hydroxymethyl-4-[bis-(4- fluorophenyl)hydroxymethyl] benzonitrile, with a purity of 92.12%. (b) Purification In a 250-ml flask, 20 g of raw 3-hydroxymethyl-4-[bis(4- fluorophenyl) hydroxymethyljbenzonitrile obtained in the preceding synthesis and 100 ml of ethyl acetate are charged. The mixture is stirred until a solution is obtained, wherein 30 ml of silica gel 60 are added, then the solvent is evaporated under vacuum until a dry powder is obtained. Separately, a 5-cm diameter column is prepared with 300 ml of silica gel 60 (particles 0 0.063-0.200 mm) for gravimetric column, using a mixture hexane/ethyl acetate 9/1 (v/v) as eluent. The product previously adsorbed on silica gel 60 is charged into the column prepared as described and is eluted with the mixture itself. The fractions containing the product are collected and concentrated under vacuum at 50°C with Rotavapor® (the solution is getting foaming, so that during the concentration must be taken the due precautions). The oily residue obtained is treated with 100 ml dichloromethane and the solution is concentrated to give 11.6 g of 3- hydroxymethyl-4-[bis(4-fluorophenyl)hydro)cymethy!]benzonitrile as white crystals with m.p. = 66.4+72.3°C and purity (HPLC) = 97.35%. 1H-NMR and 13C-NMR product data are indicated in Figure 1. PREPARATION III 1,1-Bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (a) Synthesis In a 500-ml flask 22 g of raw 3-hydroxymethyl-4-[bis(4- fluorophenyl)hydroxy methyl]benzonitrile obtained in the preceeding step (a) of PREPARATION II and 100 ml of 60% H3P04 are charged and the mixture is heated to 100°C. After 31/2-hour stirring at the same temperature, the reaction is over: a control by HPLC [COLUMN: Develosil C18 4.6 x 250 mm, 5 (i; DETECTOR: UV 240 nm; FLOW: 1.5 ml/min; GRADIENT: A: aq. NH4H2P04 + H3P04 - pH = 2.85 / B: CH3CN/H20 = 9/1 (v/v)] detects the presence of 0.2% starting material. The mixture is treated, after cooling at 25°C, with 100 ml of ethyl acetate and 125 g of water + ice, then it is stirred at 25°C for 30 minutes. The phases are separated, the organic phase is collected and the aqueous one is extracted with 100 ml ethyl acetate. The aqueous phase is eliminated and the collected organic phases are washed with 150 ml of water. The separated organic phase is decolorized by treatment with 1 g activated charcoal. After 30-minute stirring at 25°C, the charcoal is eliminated by filtration through a Celite® layer and the filtrate is concentrated under vacuum at 50°C until a orange-yellow oil is obtained. Thus 23 g of raw 1,1-bis(4-fluorophenyl)-1,3-dihydro-5- isobenzofurancarbonitrile are obtained, with a purity (HPLC) = 88.6%. (b) Purification In a 1-1 flask 21 g of raw 1,1-bis(4-fluofophenyl)-1,3-dihydro-5- isobenzofuran carbonitrile obtained in (a) and 400 ml of hexane are charged. The mixture is heated at reflux for 30 minutes, is cooled at 0°C and is let under stirring for 2 hours at this temperature. The product is recovered as light yellow crystals by filtration and is washed with 20 ml of cold hexane. Thus 23 g of 1,1-bis(4-fluorophenyl)-1,3-dihydro-5- isobenzofurancarbonitrile are obtained, with m.p. = 104.7106.2°C and purity = 97.7%. 1H-NMR and 13C-NMR product data are indicated in Figure 2. EXAMPLE 1 . Pure 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile To a suspension of 95 g of 5-cyanophthalide in 710 ml of tetrahydrofuran, previously cooled at -10°C, 384 g of a 20% solution of 4- fluorophenylmagnesium bromide in tetrahydrofuran obtained in PREPARATION I ("Grignard solution") are dropped thereinto, in two hours at a temperature not higher than -5°G, then, in the same conditions, in three times, 230 g, 115 g and 49 g of Grignard solution are dropped thereinto. When the reaction is over, 675 ml of a 15% aqueous solution of ammonium chloride are added in about one hour, maintaining the temperature lower than 0°C. The phases are separated, the aqueous one is extracted with 285 ml of tetrahydrofuran and the organic phase is collected. The organic phase (950 ml), containing a theoretical quantity of 150 g of 3-hydroxymethyl-4-(4-fluorobenzoyl)benzonitrile, referred to the starting 5-cyanophthalide, and about 14+16% of 3-hydroxymethyl-4-[bis(4- fluorophenyl)hydroxymethyl]benzonitrile, is cooled at 05°C, under nitrogen atmosphere. A solution of 23.3 g of NaBhU, 230 ml of water and 1 ml of 30% NaOH is added to the mixture dropwise, in 30 minutes and at a temperature not higher than 15°C. At the end of the addition a control by HPLC [COLUMN: Develosil C18 4.6 x 250 mm, 5 n; DETECTOR: UV 240 nm; FLOW: 1.5 ml/min; GRADIENT: A: aq. NH4H2P04 + H3P04 - pH = 2.85 / B: ChbCN/hkO = 9/1 (v/v)] detects the disappearance of 3-hydroxymethyl-4- (4-fluorobenzoyl)benzonitrile. The temperature is kept to 25°C, the aqueous phase is eliminated and tetrahydrofuran is evaporated under vacuum at 50°C. 100 ml of ethyl acetate are added to the residue and the solvent is evaporated under vacuum at 50°C, then other 350 ml of ethyl acetate are added. The phases are separated, the organic phase is collected and the aqueous phase is extracted with 230 ml of ethyl acetate. The phases are separated, the aqueous phase is discarded and the organic phases are collected obtaining 720 ml of a solution in ethyl acetate containing 150 g of 3-hydroxymethyl-4-[(4- fluorophenyl)hydroxymethyl]benzonitrile and the same quantity of 3- hydroxymethyW-[bis(4-fluorophenyl)hydro)(ymethyl]benzonitrile contained into the starting solution. To this solution, 930 ml of 60% H3P04 are added at 25°C and the biphasic mixture water/ethyl acetate (81+82°C) is heated at reflux for 2 hours. A control by HPLC (see above) shows the disappearance of 3- hydroxyrnethyl-4-[(4-fluorophenyl) hydroxymethyl]benzonitrile and of 3- hydroxymethyl-4-[bis(4-fluorophenyi)hydroxymethyl] benzonitrile contained in the starting solution. In the mixture thus obtained, containing the 1-(4- fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile and about 1416% of 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitriie, 750 ml of water are dropped thereinto, then the phases are separated. The organic phase is collected and the aqueous one is extracted with 600 ml of ethyl acetate. After separation of the phases, the organic phases are collected and the aqueous one is extracted with additional 450 ml of ethyl acetate. The aqueous phase is discarded and the collected organic phases are washed with 750 ml of water containing NaCi. The organic phase is decolorized with 4.6 g of activated charcoal and, after 30 minutestirring at 25°C and subsequent filtration on Celite® layer, the filtrate is concentrated under vacuum at 50°C until an oily residue, that is treated with 150 ml of isopropanol. The solution is concentrate under vacuum at 50°C until a light yellow residue is obtained, which is treated with additional 150 ml of isopropanol. The suspension thus obtained is let under stirring for 30 minutes at 25°C, then for 15 hours at 0-5-5°C, and finally it is filtered. After washing on the filter with 2 x 30 ml of isopropanol, the product is dried under vacuum at 50°C to give 94 g of 1-(4- fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile with a 65.8% yield evaluated on the starting 5-cyanophthalide, with a purity (HPLC) = 98.298.5% and with a 1,1-bis(4-f!uorophenyl)-1,3-dihydro-5- isobenzofurancarbonitrile content lower than 0.5%. 1H-NMR and 13C-NMR product data are indicated in Figure 3. EXAMPLE 2 Pure -fluorophenyiyi.S'dihydro-S-isobenzofui-ancarbonitnle To a suspension of 95 g of 5-cyanophthalide in 710 ml of tetrahydrofuran, previously cooled at-10°C, 384 g of a 20% solution of 4- fluorophenylrnagnesium bromide in tetrahydrofuran obtained in PREPARATION I ("Grignard solution") are dropped thereinto, in two hours, at a temperature not higher than -5°C, then, in the same conditions, in three times, 230 g, 115 g and 49 g of the same Grignard solution are dropped thereinto. At the end of addition, 675 ml of a 15% aqueous solution of ammonium chloride are added in about one hour, maintaining the temperature not higher than 0°C. The phases are separated, the aqueous one is extracted with 285 ml of tetrahydrofuran. After separation of the phases, the aqueous one is discarded and the organic phases are collected (950 ml) containing the theoretical quantity of 150 g of 3- hydroxymethyl-4-(4-fIuorobenzoyl)benzonitrile, referred to the starting 5- cyanophthalide, and about 14+16% of 3-hydroxymethyl-4-[4-bis(4- fluorophenyl)hydroxymethyl] benzonitrile. The solution is cooled at 05°C under nitrogen atmosphere and a solution of 23.3 g of NaBH4, 230 ml of water and 1 ml of 30% NaOH is added to the mixture dropwise, in 30 minutes and at a temperature not higher than 15°C. At the end of the addition a control by HPLC (see Example 1) shows the disappearance of 3-hydroxymethyl-4-(4-fluorobenzoyl)benzonitrile. The mixture temperature is brought to 25°C and the phases are separated; the aqueous one is eliminated and tetrahydrofuran is evaporated under vacuum at 50°C. The residue obtained is taken up with 100 ml of ethyl acetate and the solvent is evaporated under vacuum at 50°C, then it is treated with additional 350 ml of ethyl acetate. The phases are separated, the organic one is collected and the aqueous one is extracted with 230 ml of ethyl acetate. After separation of the phases, the aqueous one is discarded and the organic ones are collected obtaining 720 ml of a solution containing a theoretical quantity of 150 g of 3-hydroxymethyl-4-[(4- fluorophenyl)hydroxymethyl]benzonitrile, referred to the starting 5- cyanophthalide, and the same quantity of the by-product 3-hydroxymethyl21 4-[bis(4-fluorophenyl)hydroxy_ methyljbenzonitrile contained in the starting solution. To the- solution thus obtained, 930 ml of 60% H3PO,4 are added at 25°C and the mixture is heated at reflux for 2 hours (81+82°C), after which a control by HPLC (see Example 1) shows the disappearance of 3- hydroxymethyl-4-[{4-fluorophenyl)hydroxy methyl]benzonitrile and of 3- hydroxymethyl-4-[bis(4-fluorophenyl)hydroxymethyl] benzonitrile contained in the starting solution. To the mixture obtained, containing 1-(4- fluorophenyi)-1,3-dihydro-5-isobenzofurancarbonitri!e and about 14+16% of 1l1-bis(4-f!uorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile, 750 ml of water are added, then the phases are separated. The organic phase is collected and the aqueous one is extracted with 600 ml of ethyl acetate, then the organic phases are collected and the aqueous one is extracted with additional 450 ml of ethyl acetate. After separation of the phases, the aqueous phase is discarded and the collected organic phases are washed with 750 ml of water containing NaCI. The separated organic phase is decolorized with 4.6 g of activated charcoal and, after 30-minute stirring at 25°C and subsequent filtration on Celite® layer, the filtrate is concentrated under vacuum at 50°C until an oily residue, that is treated with 50 ml of methyl-f-butylether. The mixture is concentrate under vacuum at 50°C until a light yellow residue is obtained, which is treated with additional 50 ml of methyl-f-butylether. The suspension is stirred for 30 minutes at 25°C, then for 15 hours at 0+5°C, and finally it is filtered. It is washed with 2 x 30 ml of cold methyl-f-butylether and dried under vacuum at 50°C. Thus 101 g of 1- (4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile with a purity (HPLC) = 98.298.5% and with a 1,1-bis(4-fluorophenyl)-1,3-dihydro-5- isobenzofurancarbonitrile content lower than 0.5% are obtained. The mother liquors are concentrated under vacuum at 50°C, the residue is treated with 100 ml of methyW-butylether and the suspension obtained is Set under stirring at 25°C for 30 minutes, then at Q+5°C for 15 hours. After filtration, the residue is washed with 2 x 15 ml of methyl-f-butylether and dried under vacuum at 50°C for 5 hours. Thus, additional 5.2 g of pure 1- (4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile are obtained. Total yield: 106.2 g 74.4% of the theoretical quantity, referred to the starting 5-cyanophthalide. EXAMPLE 3 Citalopram hydrobromide To a mixture 5.42 g sodium hydride in 120 ml of dimethylsulfoxide, previously heated at 60°C for 30 minutes, under nitrogen flow, a solution of 30 g of 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile obtained in Example 2 in 75 ml of dimethylsulfoxide is added, without exceeding 25°C. The solution is maintained under stirring for 30 minutes and, in 10 minutes, 33 g of 3-(dimethylamino)propylchloride are added without exceeding 25°C. After about 2-hour stirring at 25°C, the mixture is cooled at 10°C and 300 ml of water are added dropwise and then 120 ml of ethyl acetate. The mixture is stirred and diluted with 1650 ml of water and 120 ml of ethyl acetate. The mixture is let 1 hour under stirring, then the phases are separated; the organic one is collected and the aqueous one is washed with 3 x 150 ml of ethyl acetate. After separation of the phases, the aqueous one is discarded and the collected organic ones are washed with 900 ml of water. The organic phase is dehydrated with anhydrous Na2S04 and is concentrated under vacuum at 50°C until an oil is obtained, which is treated with 60 ml of acetone. The mixture is stirred in order to obtain a solution, that is cooled at 10°C and treated with about 10 ml of 48% HBr in order to adjust the pH value from 9.8+9.5 to 7.0. After 1 hour-stirring at pH - 7 constant, the solvent is evaporated under vacuum at 50°C and the residue is treated with 100 ml of acetone. The suspension is stirred at 25°C for 30 minutes, then it is cooled at Q+5°C and it is let at cold for 15 hours. The product is filtered, washed with cold acetone (0+5°C) and is dried under vacuum at 50°C. Thus 34.88 g of citalopram hydrobromide with a purity (HPLC) = 99.15% are obtained. We Claim: 1. A process for the preparation of pure 1- (4-fluorophenyl)-1, 3- dihydro-5-isobenzofurancarbonitrile (B) which comprises : (a) reacting 5-cyanophthalide with a 4-fluorophenylmagnesium halide to obtain a mixture of 3- hydroxymethyl-4- (4-fluorobenzoyl) benzonitrile and the 3- hydroxymethyl-4- [bis-(4-fluorophenyl) hydroxy methylbenzonitrile ; (b) reducing the 3- hydroxymethyl-4- (4-fluorobenzoyl) benzonitrile to 3- hydroxymethyl-4- [ (4-fluorophenyl) hydroxymethyl] benzonitrile (C), by treating the mixture obtained in step (a) with an agent reducing ketones to alcohols; (c) obtaining the mixture of step (b) containing the 3- hydroxymethyl-4- [ (4-fluorophenyl) hydroxymethyl] benzonitrile (C) and the 3-hydroxymethyl-4- [bis-(4-fluoro phenyl) hydroxymethyl] benzonitrile, submitting it to a cyclization reaction and isolating a mixture containing the 1- (4- fluorophenyl)-1, 3-dihydro-5-isobenzofurancarbonitrile (B) and the 1,1- bis (4-fluorophenyl)-1, 3-dihydro-5-isobenzofurancarbonitrile ; (d) treating the mixture thus obtained in step (c) with a solvent capable of dissolving the 1,1-bis (4-fluorophenyl)-1, 3-dihydro-5- isobenzofurancarbonitrile and in which the 1- (4-fluorophenyl)-1, 3-dihydro- 5-isobenzofurancarbonitrile (B) is insoluble and recovering the pure 1- (4- fluorophenyl)-1, 3-dihydro-5-isobenzofurancarbonitrile (B), wherein said solvent is isopropanol or methyl-t-butylether. 2. A process as claimed in claim 1, wherein, in step (b) the reduction is carried out with NaBH4 in water and sodium hydroxide. 3. A process as claimed in claim 1, wherein, in step (c), the cyclization is carried out with phosphoric acid in a biphasic water/organic solvent medium. 4. A process as claimed in claim 3, wherein said biphasic medium consists of water/ethyl acetate. 5. A process as claimed in claim 1, wherein the obtained pure 1- (4-fluorophenyl)-1, 3-dihydro-5-isobenzofurancarbonitrile (B) has a purity of more than 98% and yield of upto 75%. 6. 1- (4-Fluorophenyl)-1, 3-dihydro-5-isobenzofurancarbonitrile containing less than 0.5% of 1,1-bis (4-fluorophenyl)-1, 3-dihydro-5- isobenzofurancarbonitrile whenever prepared by the process of claims 1 to 5. 7. A process for the preparation of pure 1- (4- fluorophenyl)-1, 3-dihydro-5- isobenzofurancarbonitrile substantially as herein described with reference to the foregoing examples. 8. 1- (4-Fluorophenyl)-1, 3-dihydro-5-isobenzofurancarbonitrile whenever prepared by the process as herein described with reference to the foregoing examples.

Full Text

PROCESS FOR THE PREPARATION OF A CYANOISGBEWZQFURAN
The present invention concerns a process for the preparation, with
a sole series of reactions, of pure 1-(4-fluorophenyl)-1,3-dihydro-5-
isobenzofurancarbonitrile and for its conversion into the 1-[(3-
(dimethylamino)propyl]-1-(4-fluoropheny!)-1,3-dihydro-5-
isobenzofurancarbonitrile and its pharmaceutical acceptable salt.
Said cyano-isobenzofuran, 1-[(3-(dimethylamino)propy!]-1-(4-
fluorophenyl)-1,3-dihydro-5-isobenzo furancarbonitrile, represented by the
formula A
(Figure Removed) known with its International Non-proprietary Name "citalopram" is an active
principle of drugs used, in form of its hydrobromide, for the preparation of
pharmaceuticai compositions for the treatment of depression.
Citalopram was described for the first time in the Belgian patent
850,401 (corresponding to US 4,136,193) and many methods for its
preparation have been patented.
Document US 4,136,193 discloses a family of compounds of
formula A'
N(CH3)2
(A1)
wherein RI and R2 represent each a halogen, a trifluoromethyl group, a
cyano group or a group R-CO- in which R is CrC4 alkyl. According to said
document, the compounds of formula A' may be prepared by reaction of a
compound of formula B'
(Figure Removed) wherein R^ and R2 are as defined above, with a 3-(dimethylamino)propyl
halide in the presence of a base. The same document does not say how
the compounds of formula B' in which RI is cyano and RZ is fluoro are
prepared, but in two examples it provides the preparation of a compound
of formula B1, in which RI is bromo and Ra is fluoro, by reaction of 5-
bromophthalide with 4-fluorophenyl magnesium bromide, reduction of 3-
hydroxymethyl-4-(4-fluorobenzoyl)bromobenzene thus obtained with
lithium aluminium hydride and cyclization of the diol thus obtained of
formula C'
(Figure Removed) wherein R-i is bromo and R2 is fluoro, with 60% phosphoric acid. From this
document an ordinary expert infers that the method for the preparation of
the compounds of formula A1 is of general character and that the reaction
with 4-fluorophenyl magnesium bromide may be performed on the 5-
cyanophthalide too.
In fact, EP 171,943 discloses a method of synthesis which uses two
Grignard reactions starting from 5-cyanophthalide, the first one being with
4-flourophenyl magnesium bromide and the second, on the magnesium
derivative obtained, with 3-(dimethylamino)propyl magnesium chloride to
obtain a diol, precursor of citalopram, of formula D
(Figure Removed)

which is cyclized to citalopram.
Analogously, the document WO 98/19511 (corresponding to US
6,291,689) discloses a process wherein the 3-hydroxymethyl-4-(4-
fluorobenzoyl)benzonitrile is reduced with sodium borohydride to obtain
the diol of formula C1, wherein R-i is cyano and Ra is fluoro, which is
cyclized to 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile in
its turn converted to citalopram by reaction with 3-(dimethylamino)propyl
chloride in the presence of a base. According to this document, the
process may be carried out by isolating the intermediates or without
isolating them, but said document does not give any information on how to
carry out the process in a sole operation.
Furthermore, the process described in WO 98/19511, which
substantially overlaps that disclosed in the preceding documents BE
850,401 and US 4,136,193, provides 1 -(4-fluorophenyl)- 1,3-dihydro-5-
isobenzofurancarbonitrile (compound of formula B' in which RI = CN and
R2 = F) in a yield of 29% only.
It has been hypothesized and experimentally demonstrated that the
reaction of 4-fluorophenyl magnesium bromide with 5-cyanophthalide
leads to a mixture in which, beside the desired 3-hydroxymethyl-4-(4~
fluorobenzoyl)benzonitrile, the 3-hydroxymethyl-4-[bis(4-
fluorophenyl)hydrojcymethyl]benzonitrile is present in not negligible
amounts. In the subsequent cycllzation this by-product, which remains
unaltered during the reduction, for example with LiAIH4 or NaBH4l gives
the 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile which,
being difficulty separable from the intermediate 1-(4-fluorophenyl)-1,3-
dihydro-5-isobenzofurancarbonitrile, involves noteworthy problems in the
synthesis of the final citalopram. The confirmation of the formation of the
above-mentioned by-products was possible by treatment of 5-
cyanophthalide with an excess of 4-fluorophenyl magnesium bromide
which, by favouring the formation of the 3-hydroxymethyl-4-[bis(4-
fluorophenyl)hydroxymethyl] benzonitrile, allowed the isolation and the
characterization of this by-product. The same principle has been applied to
the preparation of 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-
isobenzofurancarbonitrile which has thus been isolated and characterized.
Through the study of the solubility of 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-
isobenzofurancarbonitrile and of the 1-(4-fluorophenyl)-1,3-dihydro-5-
isobenzofurancarbonitrile, it was possible to succeed in the separation of
the two products in the course of the synthesis of citalopram starting from
5-cyanophthalide.
In particular, thanks to the identification of the by-products, it has
been found that, by operating according to Example 3 of BE 850,401 (US
4,036,193), starting from 5-cyanophthalide, after the reaction with 4-
fiuorophenyl magnesium halide, the subsequent reduction to diol (C)
and the cyclization to 1-(4-fluorophenyl)-1,3-dihydro-5-
isobenzofurancsrbonitrile (B)
it is possible to isolate the mixture containing the 1-(4-fluorophenyl)-1,3-
dihydro-5-isobenzofurancarbonitrile and the 1,1-bis-(4-fluorophenyl)-1,3-
dihydro-5-isobenzofuran carbonitrile and to treat said mixture with a
solvent capable of dissolving the 1,1-bis-(4-fluorophenyl)-1,3-dihydro-5-
isobenzofurancarbonitrile under condition in which 1-(4-fluorophenyl)-1,3-
dihydro-5-isobenzofurancarbonitrile is practically insoluble, for example
with isopropanol or with methyl-f-butylether. Under these conditions, the
pure 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) is
recovered in very high yields while the by-product 1,1-bis-(4-fluorophenyl)-
1,3-dihydro-5-isobenzofurancarbonitrile remains in solution and is thus
eliminated.
The reaction sequence takes place according to Scheme 1 below,
wherein a preferred embodiment is illustrated.
From 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile
thus obtained, by reaction with a 3-(dimethylamin6)propyl halide in the
presence of a condensing agent such as an alkaline metal, for example
sodium amide or potassium amide, butyl lithium, phenyl lithium, sodium
hydride and the like, as described in BE 850,401 (US 4,136,193), it is
possible to obtain the citalopram in a high degree of purity in form of free
base or of one of its non toxic acid addition salts.
The expressions "pure citalopram" and "citalopram at high purity
degree" indicate citalopram or a pharmaceutically acceptable salt thereof,
in particular the hydrobromide, in which the 1,1-bis(4-fluorophenyl)-1,3-
dihydro-5-isobenzofurancarbonitrile is not detectable in the NMR spectrum
obtained with a Bruker AMX 400 MHz apparatus.
The terms "soluble" and "insoluble" and the expression "capable of
dissolving" indicate a solubility degree of the above compounds which
allows an average skilled in the art to dissolve a product under normal
conditions, namely at a reasonable concentration and temperature or to
consider that, at said reasonable concentration and temperature said
product does not dissolve, taking into account that in the case of 1-(4-
fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile and of 1,1'-bis(4-
fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile it is a matter of
evaluating a difference of solubility between the two compounds. In an
indicative but not limiting manner it may be considered that a solvent is
suitable to the separation of the two compounds if, in said solvent, the
1,1 '-bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile is "very
soluble", "soluble" or "fairly soluble" according to the criteria of the
European Pharmacopea or of the United States Pharmacopea (DSP)
while, in the same solvent, the 1-(4-fluorophenyl)-1,3-dihydro-5-
isobenzofurancarbonitrile is "very slightly soluble" or "practically insoluble".
Figure 1 illustrates the characteristics of the 3-hydroxymethyl-4-
[bis(4-fluorophenyl)hydroxymethyl]benzonitrile in the 1H-NMR and 13CNMR
spectra obtained with a Bruker AMX 400 MHz apparatus.
Figure 2 illustrates the characteristics of the 1,1-bis(4-fluorophenyl)-
1,3-dihydro-5-isobenzofurancarbonitrile in the 1H-NMR and 13C-NMR
spectra obtained with a Bruker AMX 400 MHz apparatus.
(Figure Removed) Figure 3 illustrates the characteristics of the pure 1-(4-fluorophenyl)-
1,3-dihydro-5-isobenzofurancarbonitrile in the 1H-NMR and 13C-NMR
spectra obtained with a Bruker AMX 400 MHz apparatus.
Thus, it is an object of the present invention to provide a process for
the preparation of 1-(4-fluoropheny!)-1,3-dihydro-5-
isobenzofurancarbonitrile which comprises:
(a) reacting 5-cyanophthalide with a 4-fluorophenyl magnesium
halide;
(b) treating the mixture thus obtained, containing the 3-
hydroxymethyl-4-(4-fluoro- benzoyl)benzonitrile and the 3-hydroxymethyl-
4-[bis-(4-fluorophenyl)hydroxymethyl] benzonitrile; with an agent reducing
ketones to alcohols;
(c) submitting the mixture thus obtained, containing the 3-
hydroxymethyl-4-[(4-fluorophenyl)hydroxymethyl]benzonitrile (C) and the
3-hydroxymethyl-4-[bis-(4-fluoro- phenyl)hydroxymethyl]benzonitrile, to a
cyclization reaction and isolating a. mixture containing the 1-(4-
fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile and the 1-(4-
fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) and the 1,1-
bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile;
(d) treating the mixture thus obtained with a solvent capable of
dissolving the 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-
isobenzofurancarbonitrile and in which the 1-(4-fluorophenyl)-1,3-dihydro-
5-isobenzofurancarbonitrile (B) is insoluble and recovering the pure 1-(4-
fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B).
Steps (a), (b) and (c) are carried out without isolating the intermediate
compounds according to known literature methods, for example according
to the method cited in US 4,136,193 and specifically described, starting
from 5-bromophthalide, in examples 1 and 3 of said document.
In particular, step (a), consisting of the treatment of 5-cyanophthalide
with a 4-fluorophenyimagnesium halide, occurs according to a classical
Grignard reaction procedure, for example under the conditions described
in Example 1 of US 4,136,193 for the 5-bromophthalide, by treating
1,054-1,35 equivalents of a Grignard solution, titred at 15+20%, said
solution being prepared from p-fiuorobromobenzene and magnesium
turnings in an ether, for example in tetrahydrofuran, with 5-cyanophthalide
and by adding said Grignard reagent in the amount capable of consuming
practically the whole starting 5-cyanophthalide. In practice, the operator
controls the course of the reaction by HPLC [column: Develosil C18 4.6 x
250 mm, 5^; DETECTOR: UV 240nm; FLOW: 1.5 ml/min; GRADIENT: A:
aqueous NH4H2P04 + H3PO4 at pH = 2.85 / B: CH3CN/H2O = 9/1 (v/v)]
and stops it when 2+3% of unreacted 5-cyanophthalide remains. The
product thus obtained is directly submitted to the next step (b) consinsting
of a reduction with an agent reducing ketones to alcohols for example with
NaBH4l or with LiAIH4 as described in Example 3 of US 4,136,193, to
obtain the corresponding 3-hydroxymethyl-4-[(4-fluorophenyl)
hydroxymethyl]benzonitrile.
According to a preferred embodiment, which allows the large scale
preparation under conditions of safety, the reduction is carried out with an
aqueous solution of NaBH4 and sodium hydroxide. Said aqueous solution
is added at a temperature not higher than 15°C and the reaction is
complete at the end of the addition. Thus, it is sufficient to eliminate the
aqueous phase, to evaporate the organic solvent and to submit the
residue to the subsequent step (c).
Step (c), consisting of the diol cyclization, is conducted by treating the
material obtained at the end of step (b) with 60% phosphoric acid as
described in Example 1 of US 4,136,193 for the corresponding 3-
hydroxymethyl-4-[(4-fluorophenyl)hydroxymethyl]-bromobenzene.
According to a preferred embodiment, the method described in US
4,136,193 is rendered easier by dissolving the material obtained at the
end of step (b) in an organic solvent, preferably ethyl acetate or
tetrahydrofuran, and by carrying out the reaction with 60% phosphoric acid
in a biphasic system, thus avoiding the formation of waxy residues which
are difficult to treat. In practice, the residue obtained according to the
preferred mode of conducting step (b) is dissolved in ethyl acetate and,
after the addition of 60% phosphoric acid, the reaction is carried out in a
biphasic, for example water/ethyl acetate, system.
In step (d), the crude material thus obtained, containing the 1-(4-
fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) and the 1,1-
bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile is treated with
a solvent capable of dissolving the 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-
isobenzofurancarbonitrile under conditions in which the 1-(4-fluorophenyl)-
1,3-dihydro-5-isobenzofurancarbonitrile (B) is practically insoluble, for
example with isopropanol or with methyl-f-butylether.
According to a preferred embodiment, the process of the present
invention is carried out "one-pot", i.e. without isolating the intermediate
products, until a 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile
practically devoid of 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-
isobenzofurancarbonitrile is obtained, said 1-(4-fluorophenyl)-1,3-dihydro-
5-isobenzofurancarbonitrile being subsequently converted into citalopram.
In practice, a Grignard solution is prepared by adding a solution of 4-
fluorobromobenzene in tetrahydrofuran to magnesium turnings in the
presence of traces of iodine at a temperature of about 70°C and, after
about 30 minutes, at the same temperature, the solution is added
portionwise to a suspension of 5-cyanophthalide in tetrahydrofuran at -
20-5-0°C, preferably at -10-5-0°C. At the end of the reaction, namely when
less than 5% of the starting 5-cyanophthalide is present, the magnesium
derivative is decomposed with water or, better, with an aqueous solution of
ammonium chloride and the cold tetrahydrofuranic solution, containing the
3-hydroxymethyl-4-(4-fluorobenzoyl)benzonitrile and the 3-hydroxymethyl-
4[bis(4-fluorophenyl)hydroxymethyl]benzonitrile, is treated with an
aqueous solution of NaBH4 and of NaOH.
The obtained mixture, containing the 3-hydroxymethyl-4-[(4-
fiuorophenyl)hydroxy methyljbenzonitrile (C) and the 3-hydroxymethyl-4-
[bis(4-fluorophenyl)hydroxymethyl] benzonitrile, is extracted with ethyl
acetate. The organic phase is concentrated, the residue is taken up with
an organic solvent, preferably with ethyl acetate, and the solution is
treated with 60% phosphoric acid and heated. At the end of the reaction,
after separation of the phases, the organic phase, containing the 1-(4-
fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile and the 1,1-bis-(4-
fluorophenyl)-1,3-dihydro-5-iso benzofurancarbonitrile, is washed with
water, decolorized with activated charcoal and concentrated under
vacuum. The oily residue is treated with the selected solvent, preferably
with isopropanol or with methyl-f-butylether, then the solvent is evaporated
under vacuum. If needed, the operation of treatment with the solvent and
of subsequent evaporation is repeated several times until, by taking up
with the solvent, a crystalline suspension consisting of pure 1-(4-
fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) is obtained. This
compound is isolated in a 70+75% yield, calculated in respect of the
starting 5-cyanophthalide, by simple filtration. In general, the product thus
obtained, having a purity higher than 98%, contains the 1,1-bis(4-
fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile in a percent lower
than 0.5%, thus allowing the subsequent preparation of a citalopram with a
high degree of purity, or of pharmaceutically acceptable salt thereof, by
treatment with a 3-(dimethylamino)propyl halide in the presence of a basic
condensing agent. This mode of operating is illustrated, in a preferred
aspect thereof, in Scheme 2 below.
The 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile
containing the 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-
isobenzofurancarbonitrile in a percent lower than 0.5% is a new product
which represents a further object of the present invention.
The pure 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile
(B) obtained at the end of steps (a)-(d) above may be further made to
react with a 3-(dimethylamino) propyl halide in the presence of a basic
condensing agent to isolate citalopram at a high purity degree, or a
pharmaceutically acceptable salt thereof, in yields which are higher than
those obtained with any other known process using 5-cyanophthalide as
starting material.
Thus, it is another object of the present invention to provide a
process for the preparation of citalopram or of a pharmaceuticaily
acceptable salt thereof, which comprises:
(a) reacting 5-cyanophthalide with a 4-fluorophenyl magnesium
halide;
(b) treating the mixture thus obtained, containing the 3-
hydroxymethyl-4-(4-fluoro benzoyl)benzonitrile and the 3-hydroxymethyl-4-
[bis-(4-fluorophenyl)hydroxymethyl] benzonitrile with a reducing agent of
ketones to alcohols;
(c) submitting the mixture thus obtained, containing the 3-
hydroxymethyl-4-[(4-fluorophenyl)hydroxymethyl]benzonitriIe (C) and the
3-hydroxymethyl-4-[bis-(4-fluoro phenyl)hydroxymethyl]benzonitrile to a
cyclization and isolating a mixture containing the 1-(4-fluorophenyl)-1,3-
dihydro-5-isobenzofurancarbonitrile (B) and the 1,1-bis(4-fluoro phenyl)-
1,3-dihydro-5-isobenzofurancarbonitrile;
(d) treating the mixture thus obtained with a solvent capable of
dissolving the 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-
isobenzofurancarbonitrile and in which the 1-(4-fluorophenyl)-1,3-dihydro-
5-isobenzofurancarbonitrile (B) is insoluble and recovering the pure 1-(4-
fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitriIe (B);
(e) treating the pure 1-(4-fluorophenyl)-1,3-dihydro-5-
isobenzofurancarbonitrile (B) with a 3-(dimetylamino)propyl halide in the.
presence of a basic condensing agent and isolating citalopram as free
base or as a pharmaceuticaily acceptable salt thereof.
Steps (a)-(d) are carried out as described above and the pure 1-(4-
fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile (B) obtained at the
end of step (d) is submitted to the subsequent step (e).
In step (e), the chloride, the bromide or the iodide may indifferently
be used as halide, the chloride being preferred.
As a condensing basic agent, anyone of the bases commonly used
in the alkylation reactions, such as sodium amide, potassium amide, butyl
lithium, phenyl lithium or sodium hydride may be employed.
(Figure Removed) The condensation is carried out in an inert solvent, preferably in
dimethyl sulfoxide.
Advantageously, the 1-(4-fluorophenyl)-1,3-dihydro-5-
isobenzofurancarbonitrile (B) as obtained at the end of step (d) is
dissolved in dimethyl sulfoxide, the solution thus obtained is added to a
suspension of sodium hydride in dimethyl sulfoxide, the mixture is then
treated with 3-(dimethylaminopropyl) chloride and the citalopram which
forms is isolated according to the conventional methods, in form of free
base or of a salt thereof.
According to a preferred embodiment, at the end of the reaction
water is added, citalopram is extracted with ethyl acetate and, after
suitable washings with water, the organic phase containing citalopram is
concentrated to an oil, essentially consisting of citalopram base, which, by
treatment with HBr in acetone, affords a citalopram hydrobromide wherein
the 1,1-bis(4-fluorophenyi)-1,3-dihydro-5-isobenzofurancarbonitrile is not
detectable in the NMR spectrum obtained with a Bruker AMX 400MHz
apparatus. The product thus obtained may be subsequently purified
according to known methods, for example by repeated washings with cold
water.
Thus, the process of the present invention allows the preparation of
citalopram hydrobromide in yields much higher than those obtained by all
of the methods employing the 5-cyanophthalide as starting material.
Furthermore, by avoiding the use of intermediates containing a prcursor of
the CN group, the process of the invention is easier to be carried out and
affords a citalopram with high purity in very satisfactory yields.
In the preparations given hereinbelow the by-products that form in
the synthesis starting from 5-cyanophthalide are isolated. They represent
the reference standards for the control of the process of the invention.
The following examples illustrate the invention.
PREPARATION I
20% Solution of 4-fluorophenylmagnesium bromide in tetrahydrofuran
In a 4-I flask, under nitrogen flow and at room temperature, 53.5 g
of magnesium turnings and 0.3 g of iodine particles are charged, then the
mixture is heated to 70°C and, in one hour, a solution of 369.5 g of 4-
15
fluorobromobenzene in 1960 ml of tetrahydrofuran is dropped thereinto. At
the end of addition the mixture is heated at reflux at 68-*70°C for 30
minutes, then the obtained solution is cooled to 25°C. There is obtained
2000 g of a 20% solution of 4-fluorophenylmagnesium bromide, to be
stored in the dark and in nitrogen atmosphere.
PREPARATION II
3-hydmxymethyl-4[bis(4-fluorophenyl)hydroxymethyl]benzonitrile
(a) Synthesis
To a suspension of 20 g of 5-cyanophthalide in 150 ml of
tetrahydrofuran, under nitrogen flow, at 25°C, 422.6 g of the 20% solution
of 4-fluorophenylmagnesium bromide obtained in PREPARATION I are
added and a rise in temperature of the mixture to about 35°C is observed.
The mixture is kept under stirring until, by a HPLC control [COLUMN:
Develosil C18 4.6 x 250 mm, 5 ji; DETECTOR: UV 240 nm; FLOW: 1.5
ml/min; GRADIENT: A: aq. NH4H2PO4 + H3P04 - pH = 2.85 / B: CH3CN/H20
= 9/1 (v/v)], the disappearance of 5-cyanophthalide is observed. When the
reaction is over, 200 ml of a 15% aqueous solution of ammonium chloride
are added, maintaining the temperature not higher than 30°C, then the
phases are separated and the organic one is concentrated under vacuum
to obtain 52 g of a yellow oil, the raw 3-hydroxymethyl-4-[bis-(4-
fluorophenyl)hydroxymethyl] benzonitrile, with a purity of 92.12%.
(b) Purification
In a 250-ml flask, 20 g of raw 3-hydroxymethyl-4-[bis(4-
fluorophenyl) hydroxymethyljbenzonitrile obtained in the preceding
synthesis and 100 ml of ethyl acetate are charged. The mixture is stirred
until a solution is obtained, wherein 30 ml of silica gel 60 are added, then
the solvent is evaporated under vacuum until a dry powder is obtained.
Separately, a 5-cm diameter column is prepared with 300 ml of silica gel
60 (particles 0 0.063-0.200 mm) for gravimetric column, using a mixture
hexane/ethyl acetate 9/1 (v/v) as eluent. The product previously adsorbed
on silica gel 60 is charged into the column prepared as described and is
eluted with the mixture itself. The fractions containing the product are
collected and concentrated under vacuum at 50°C with Rotavapor® (the
solution is getting foaming, so that during the concentration must be taken
the due precautions). The oily residue obtained is treated with 100 ml
dichloromethane and the solution is concentrated to give 11.6 g of 3-
hydroxymethyl-4-[bis(4-fluorophenyl)hydro)cymethy!]benzonitrile as white
crystals with m.p. = 66.4+72.3°C and purity (HPLC) = 97.35%.
1H-NMR and 13C-NMR product data are indicated in Figure 1.
PREPARATION III
1,1-Bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile
(a) Synthesis
In a 500-ml flask 22 g of raw 3-hydroxymethyl-4-[bis(4-
fluorophenyl)hydroxy
methyl]benzonitrile obtained in the preceeding step (a) of PREPARATION
II and 100 ml of 60% H3P04 are charged and the mixture is heated to
100°C. After 31/2-hour stirring at the same temperature, the reaction is
over: a control by HPLC [COLUMN: Develosil C18 4.6 x 250 mm, 5 (i;
DETECTOR: UV 240 nm; FLOW: 1.5 ml/min; GRADIENT: A: aq. NH4H2P04 +
H3P04 - pH = 2.85 / B: CH3CN/H20 = 9/1 (v/v)] detects the presence of
0.2% starting material. The mixture is treated, after cooling at 25°C, with
100 ml of ethyl acetate and 125 g of water + ice, then it is stirred at 25°C
for 30 minutes. The phases are separated, the organic phase is collected
and the aqueous one is extracted with 100 ml ethyl acetate. The aqueous
phase is eliminated and the collected organic phases are washed with 150
ml of water. The separated organic phase is decolorized by treatment with
1 g activated charcoal. After 30-minute stirring at 25°C, the charcoal is
eliminated by filtration through a Celite® layer and the filtrate is
concentrated under vacuum at 50°C until a orange-yellow oil is obtained.
Thus 23 g of raw 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-
isobenzofurancarbonitrile are obtained, with a purity (HPLC) = 88.6%.
(b) Purification
In a 1-1 flask 21 g of raw 1,1-bis(4-fluofophenyl)-1,3-dihydro-5-
isobenzofuran carbonitrile obtained in (a) and 400 ml of hexane are
charged. The mixture is heated at reflux for 30 minutes, is cooled at 0°C
and is let under stirring for 2 hours at this temperature. The product is
recovered as light yellow crystals by filtration and is washed with 20 ml of
cold hexane. Thus 23 g of 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-
isobenzofurancarbonitrile are obtained, with m.p. = 104.7*106.2°C and
purity = 97.7%.
1H-NMR and 13C-NMR product data are indicated in Figure 2.
EXAMPLE 1 .
Pure 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile
To a suspension of 95 g of 5-cyanophthalide in 710 ml of
tetrahydrofuran, previously cooled at -10°C, 384 g of a 20% solution of 4-
fluorophenylmagnesium bromide in tetrahydrofuran obtained in
PREPARATION I ("Grignard solution") are dropped thereinto, in two hours
at a temperature not higher than -5°G, then, in the same conditions, in
three times, 230 g, 115 g and 49 g of Grignard solution are dropped
thereinto. When the reaction is over, 675 ml of a 15% aqueous solution of
ammonium chloride are added in about one hour, maintaining the
temperature lower than 0°C. The phases are separated, the aqueous one
is extracted with 285 ml of tetrahydrofuran and the organic phase is
collected.
The organic phase (950 ml), containing a theoretical quantity of 150
g of 3-hydroxymethyl-4-(4-fluorobenzoyl)benzonitrile, referred to the
starting 5-cyanophthalide, and about 14+16% of 3-hydroxymethyl-4-[bis(4-
fluorophenyl)hydroxymethyl]benzonitrile, is cooled at 0*5°C, under
nitrogen atmosphere. A solution of 23.3 g of NaBhU, 230 ml of water and 1
ml of 30% NaOH is added to the mixture dropwise, in 30 minutes and at a
temperature not higher than 15°C. At the end of the addition a control by
HPLC [COLUMN: Develosil C18 4.6 x 250 mm, 5 n; DETECTOR: UV 240 nm;
FLOW: 1.5 ml/min; GRADIENT: A: aq. NH4H2P04 + H3P04 - pH = 2.85 / B:
ChbCN/hkO = 9/1 (v/v)] detects the disappearance of 3-hydroxymethyl-4-
(4-fluorobenzoyl)benzonitrile. The temperature is kept to 25°C, the
aqueous phase is eliminated and tetrahydrofuran is evaporated under
vacuum at 50°C. 100 ml of ethyl acetate are added to the residue and the
solvent is evaporated under vacuum at 50°C, then other 350 ml of ethyl
acetate are added. The phases are separated, the organic phase is
collected and the aqueous phase is extracted with 230 ml of ethyl acetate.
The phases are separated, the aqueous phase is discarded and the
organic phases are collected obtaining 720 ml of a solution in ethyl acetate
containing 150 g of 3-hydroxymethyl-4-[(4-
fluorophenyl)hydroxymethyl]benzonitrile and the same quantity of 3-
hydroxymethyW-[bis(4-fluorophenyl)hydro)(ymethyl]benzonitrile contained
into the starting solution.
To this solution, 930 ml of 60% H3P04 are added at 25°C and the
biphasic mixture water/ethyl acetate (81+82°C) is heated at reflux for 2
hours. A control by HPLC (see above) shows the disappearance of 3-
hydroxyrnethyl-4-[(4-fluorophenyl) hydroxymethyl]benzonitrile and of 3-
hydroxymethyl-4-[bis(4-fluorophenyi)hydroxymethyl] benzonitrile contained
in the starting solution. In the mixture thus obtained, containing the 1-(4-
fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile and about 14*16%
of 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitriie, 750 ml
of water are dropped thereinto, then the phases are separated. The
organic phase is collected and the aqueous one is extracted with 600 ml of
ethyl acetate. After separation of the phases, the organic phases are
collected and the aqueous one is extracted with additional 450 ml of ethyl
acetate. The aqueous phase is discarded and the collected organic
phases are washed with 750 ml of water containing NaCi. The organic
phase is decolorized with 4.6 g of activated charcoal and, after 30 minutestirring
at 25°C and subsequent filtration on Celite® layer, the filtrate is
concentrated under vacuum at 50°C until an oily residue, that is treated
with 150 ml of isopropanol. The solution is concentrate under vacuum at
50°C until a light yellow residue is obtained, which is treated with
additional 150 ml of isopropanol. The suspension thus obtained is let
under stirring for 30 minutes at 25°C, then for 15 hours at 0-5-5°C, and
finally it is filtered. After washing on the filter with 2 x 30 ml of isopropanol,
the product is dried under vacuum at 50°C to give 94 g of 1-(4-
fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile with a 65.8% yield
evaluated on the starting 5-cyanophthalide, with a purity (HPLC) =
98.2*98.5% and with a 1,1-bis(4-f!uorophenyl)-1,3-dihydro-5-
isobenzofurancarbonitrile content lower than 0.5%.
1H-NMR and 13C-NMR product data are indicated in Figure 3.
EXAMPLE 2
Pure -fluorophenyiyi.S'dihydro-S-isobenzofui-ancarbonitnle
To a suspension of 95 g of 5-cyanophthalide in 710 ml of
tetrahydrofuran, previously cooled at-10°C, 384 g of a 20% solution of 4-
fluorophenylrnagnesium bromide in tetrahydrofuran obtained in
PREPARATION I ("Grignard solution") are dropped thereinto, in two hours,
at a temperature not higher than -5°C, then, in the same conditions, in
three times, 230 g, 115 g and 49 g of the same Grignard solution are
dropped thereinto. At the end of addition, 675 ml of a 15% aqueous
solution of ammonium chloride are added in about one hour, maintaining
the temperature not higher than 0°C. The phases are separated, the
aqueous one is extracted with 285 ml of tetrahydrofuran. After separation
of the phases, the aqueous one is discarded and the organic phases are
collected (950 ml) containing the theoretical quantity of 150 g of 3-
hydroxymethyl-4-(4-fIuorobenzoyl)benzonitrile, referred to the starting 5-
cyanophthalide, and about 14+16% of 3-hydroxymethyl-4-[4-bis(4-
fluorophenyl)hydroxymethyl] benzonitrile. The solution is cooled at 0*5°C
under nitrogen atmosphere and a solution of 23.3 g of NaBH4, 230 ml of
water and 1 ml of 30% NaOH is added to the mixture dropwise, in 30
minutes and at a temperature not higher than 15°C. At the end of the
addition a control by HPLC (see Example 1) shows the disappearance of
3-hydroxymethyl-4-(4-fluorobenzoyl)benzonitrile. The mixture temperature
is brought to 25°C and the phases are separated; the aqueous one is
eliminated and tetrahydrofuran is evaporated under vacuum at 50°C. The
residue obtained is taken up with 100 ml of ethyl acetate and the solvent is
evaporated under vacuum at 50°C, then it is treated with additional 350 ml
of ethyl acetate. The phases are separated, the organic one is collected
and the aqueous one is extracted with 230 ml of ethyl acetate. After
separation of the phases, the aqueous one is discarded and the organic
ones are collected obtaining 720 ml of a solution containing a theoretical
quantity of 150 g of 3-hydroxymethyl-4-[(4-
fluorophenyl)hydroxymethyl]benzonitrile, referred to the starting 5-
cyanophthalide, and the same quantity of the by-product 3-hydroxymethyl21
4-[bis(4-fluorophenyl)hydroxy_ methyljbenzonitrile contained in the starting
solution.
To the- solution thus obtained, 930 ml of 60% H3PO,4 are added at
25°C and the mixture is heated at reflux for 2 hours (81+82°C), after which
a control by HPLC (see Example 1) shows the disappearance of 3-
hydroxymethyl-4-[{4-fluorophenyl)hydroxy methyl]benzonitrile and of 3-
hydroxymethyl-4-[bis(4-fluorophenyl)hydroxymethyl] benzonitrile contained
in the starting solution. To the mixture obtained, containing 1-(4-
fluorophenyi)-1,3-dihydro-5-isobenzofurancarbonitri!e and about 14+16%
of 1l1-bis(4-f!uorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile, 750 ml
of water are added, then the phases are separated. The organic phase is
collected and the aqueous one is extracted with 600 ml of ethyl acetate,
then the organic phases are collected and the aqueous one is extracted
with additional 450 ml of ethyl acetate. After separation of the phases, the
aqueous phase is discarded and the collected organic phases are washed
with 750 ml of water containing NaCI. The separated organic phase is
decolorized with 4.6 g of activated charcoal and, after 30-minute stirring at
25°C and subsequent filtration on Celite® layer, the filtrate is concentrated
under vacuum at 50°C until an oily residue, that is treated with 50 ml of
methyl-f-butylether. The mixture is concentrate under vacuum at 50°C until
a light yellow residue is obtained, which is treated with additional 50 ml of
methyl-f-butylether. The suspension is stirred for 30 minutes at 25°C, then
for 15 hours at 0+5°C, and finally it is filtered. It is washed with 2 x 30 ml of
cold methyl-f-butylether and dried under vacuum at 50°C. Thus 101 g of 1-
(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile with a purity
(HPLC) = 98.2*98.5% and with a 1,1-bis(4-fluorophenyl)-1,3-dihydro-5-
isobenzofurancarbonitrile content lower than 0.5% are obtained. The
mother liquors are concentrated under vacuum at 50°C, the residue is
treated with 100 ml of methyW-butylether and the suspension obtained is
Set under stirring at 25°C for 30 minutes, then at Q+5°C for 15 hours. After
filtration, the residue is washed with 2 x 15 ml of methyl-f-butylether and
dried under vacuum at 50°C for 5 hours. Thus, additional 5.2 g of pure 1-
(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile are obtained.
Total yield: 106.2 g * 74.4% of the theoretical quantity, referred to the
starting 5-cyanophthalide.
EXAMPLE 3
Citalopram hydrobromide
To a mixture 5.42 g sodium hydride in 120 ml of dimethylsulfoxide,
previously heated at 60°C for 30 minutes, under nitrogen flow, a solution
of 30 g of 1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile
obtained in Example 2 in 75 ml of dimethylsulfoxide is added, without
exceeding 25°C. The solution is maintained under stirring for 30 minutes
and, in 10 minutes, 33 g of 3-(dimethylamino)propylchloride are added
without exceeding 25°C. After about 2-hour stirring at 25°C, the mixture is
cooled at 10°C and 300 ml of water are added dropwise and then 120 ml
of ethyl acetate. The mixture is stirred and diluted with 1650 ml of water
and 120 ml of ethyl acetate. The mixture is let 1 hour under stirring, then
the phases are separated; the organic one is collected and the aqueous
one is washed with 3 x 150 ml of ethyl acetate. After separation of the
phases, the aqueous one is discarded and the collected organic ones are
washed with 900 ml of water. The organic phase is dehydrated with
anhydrous Na2S04 and is concentrated under vacuum at 50°C until an oil
is obtained, which is treated with 60 ml of acetone. The mixture is stirred in
order to obtain a solution, that is cooled at 10°C and treated with about 10
ml of 48% HBr in order to adjust the pH value from 9.8+9.5 to 7.0. After 1
hour-stirring at pH - 7 constant, the solvent is evaporated under vacuum
at 50°C and the residue is treated with 100 ml of acetone. The suspension
is stirred at 25°C for 30 minutes, then it is cooled at Q+5°C and it is let at
cold for 15 hours. The product is filtered, washed with cold acetone
(0+5°C) and is dried under vacuum at 50°C. Thus 34.88 g of citalopram
hydrobromide with a purity (HPLC) = 99.15% are obtained.

We Claim:
1. A process for the preparation of pure 1- (4-fluorophenyl)-1, 3- dihydro-5-isobenzofurancarbonitrile (B) which comprises :
(a) reacting 5-cyanophthalide with a 4-fluorophenylmagnesium halide to obtain
a mixture of 3- hydroxymethyl-4- (4-fluorobenzoyl) benzonitrile and the 3-
hydroxymethyl-4- [bis-(4-fluorophenyl) hydroxy methylbenzonitrile ;
(b) reducing the 3- hydroxymethyl-4- (4-fluorobenzoyl) benzonitrile to 3-
hydroxymethyl-4- [ (4-fluorophenyl) hydroxymethyl] benzonitrile (C), by treating
the mixture obtained in step (a) with an agent reducing ketones to alcohols;
(c) obtaining the mixture of step (b) containing the 3- hydroxymethyl-4- [ (4-fluorophenyl) hydroxymethyl] benzonitrile (C) and the 3-hydroxymethyl-4- [bis-(4-fluoro phenyl) hydroxymethyl] benzonitrile, submitting it to a cyclization reaction and isolating a mixture containing the 1- (4- fluorophenyl)-1, 3-dihydro-5-isobenzofurancarbonitrile (B) and the 1,1- bis (4-fluorophenyl)-1, 3-dihydro-5-isobenzofurancarbonitrile ;
(d) treating the mixture thus obtained in step (c) with a solvent capable of dissolving the 1,1-bis (4-fluorophenyl)-1, 3-dihydro-5- isobenzofurancarbonitrile and in which the 1- (4-fluorophenyl)-1, 3-dihydro- 5-isobenzofurancarbonitrile (B) is insoluble and recovering the pure 1- (4- fluorophenyl)-1, 3-dihydro-5-isobenzofurancarbonitrile (B), wherein said solvent is isopropanol or methyl-t-butylether.

2. A process as claimed in claim 1, wherein, in step (b) the reduction is carried out with NaBH4 in water and sodium hydroxide.
3. A process as claimed in claim 1, wherein, in step (c), the cyclization is carried out with phosphoric acid in a biphasic water/organic solvent medium.
4. A process as claimed in claim 3, wherein said biphasic medium consists of water/ethyl acetate.

5. A process as claimed in claim 1, wherein the obtained pure 1- (4-fluorophenyl)-1, 3-dihydro-5-isobenzofurancarbonitrile (B) has a purity of more than 98% and yield of upto 75%.
6. 1- (4-Fluorophenyl)-1, 3-dihydro-5-isobenzofurancarbonitrile containing less than 0.5% of 1,1-bis (4-fluorophenyl)-1, 3-dihydro-5- isobenzofurancarbonitrile whenever prepared by the process of claims 1 to 5.

7. A process for the preparation of pure 1- (4- fluorophenyl)-1, 3-dihydro-5-
isobenzofurancarbonitrile substantially as herein described with reference to the
foregoing examples.
8. 1- (4-Fluorophenyl)-1, 3-dihydro-5-isobenzofurancarbonitrile whenever
prepared by the process as herein described with reference to the foregoing
examples.

Documents:

4040-DELNP-2005-Abstract-(24-07-2008).pdf

4040-delnp-2005-abstract.pdf

4040-DELNP-2005-Claims-(24-07-2008).pdf

4040-delnp-2005-claims.pdf

4040-DELNP-2005-Correspondence-Others-(21-07-2008).pdf

4040-DELNP-2005-Correspondence-Others-(24-07-2008).pdf

4040-DELNP-2005-Correspondence-Others-12-03-2008.pdf

4040-delnp-2005-correspondence-others.pdf

4040-delnp-2005-description (complete)-24-07-2008.pdf

4040-delnp-2005-description (complete).pdf

4040-DELNP-2005-Drawings-12-03-2008.pdf

4040-delnp-2005-drawings.pdf

4040-DELNP-2005-Form-1-(24-07-2008).pdf

4040-delnp-2005-form-1.pdf

4040-delnp-2005-form-18.pdf

4040-DELNP-2005-Form-2-(24-07-2008).pdf

4040-delnp-2005-form-2.pdf

4040-DELNP-2005-Form-3-12-03-2008.pdf

4040-delnp-2005-form-3.pdf

4040-delnp-2005-form-5.pdf

4040-DELNP-2005-GPA-12-03-2008.pdf

4040-delnp-2005-pct-101.pdf

4040-delnp-2005-pct-210.pdf

4040-delnp-2005-pct-304.pdf

4040-delnp-2005-pct-401.pdf

4040-delnp-2005-pct-409.pdf

4040-DELNP-2005-Petition-137-(22-07-2008).pdf

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Patent Number

225288

Indian Patent Application Number

4040/DELNP/2005

PG Journal Number

48/2008

Publication Date

28-Nov-2008

Grant Date

06-Nov-2008

Date of Filing

08-Sep-2005

Name of Patentee

ADORKEM TECHNOLOGY SPA

Applicant Address

VIA L. DA VINCI, 28, 1-24062 COSTA VOLPINO, ITALY.

Inventors:

#	Inventor's Name	Inventor's Address
1	COTTICELLI, GIOVANNI	VIA PENATI, 8, I-20063 CERNUSCO SUL NAVIGLO, ITALY.
2	DALL'ASTA, LEONE	VIA FRIULI, 11, I-20135 MILANO, ITALY.
3	DI LERNIA, GIANLUCA	VIA MANZONI, 29/C4, I-20090 BUCCINASCO, ITLY.

PCT International Classification Number

C07D 307/87

PCT International Application Number

PCT/EP2004/002522

PCT International Filing date

2004-03-09

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	MI2003 A000479	2003-03-13	Italy