Title of Invention	AN IMPROVED PROCESS FOR THE PREPARATION OF 1-(4'-FLUORO-PHENYL) -1, 3- DIHYDRO- ISOBENZOFURAN-5-CARBONITRILE, AN INTERMEDIATE OF CITALOPRAM
Abstract	This invention discloses an improved process for the preparation of 1-( 41-fluorophenyl)- 1,3-dihydro-isobenzofuran-5-carbonitrile of formula-II, which is useful for the preparation of citalopram, a well-known antidepressant drug available in the market. Process for the preparation of compound of formula-II comprises: (i) A Grignard reaction on 5-bromophthalide with 4-fluorophenylmagnesium bromide to get a benzophenone derivative (ii) Reduction of the benzophenone derivative with sodium borohydride in alcoholic solvent medium to get a dihydroxy compound. (iii) Cyclization of the dihydroxy compound with an acid catalyst in non-polar solvent system to get a phthalane derivative. - (iv) Reaction of the phthalane derivative with cuprous cyanide in dimethylformamide medium to get the cyano derivative of formula-II after crystallization from alcoholic solvent with or without dimethylformamide. Compound of formula-II obtained by this method is of high purity and upon further conversion to citalopram product formed in high yield (80%) and high purity (99%).

Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF 1-(4'-FLUORO-PHENYL) -1, 3- DIHYDRO- ISOBENZOFURAN-5-CARBONITRILE, AN INTERMEDIATE OF CITALOPRAM

Abstract

This invention discloses an improved process for the preparation of 1-( 41-fluorophenyl)- 1,3-dihydro-isobenzofuran-5-carbonitrile of formula-II, which is useful for the preparation of citalopram, a well-known antidepressant drug available in the market. Process for the preparation of compound of formula-II comprises: (i) A Grignard reaction on 5-bromophthalide with 4-fluorophenylmagnesium bromide to get a benzophenone derivative (ii) Reduction of the benzophenone derivative with sodium borohydride in alcoholic solvent medium to get a dihydroxy compound. (iii) Cyclization of the dihydroxy compound with an acid catalyst in non-polar solvent system to get a phthalane derivative. - (iv) Reaction of the phthalane derivative with cuprous cyanide in dimethylformamide medium to get the cyano derivative of formula-II after crystallization from alcoholic solvent with or without dimethylformamide. Compound of formula-II obtained by this method is of high purity and upon further conversion to citalopram product formed in high yield (80%) and high purity (99%).

Full Text	INTRODUCTION The present invention relates to an improved process for the preparation of 5-bromo-l-(4"-flurophenyl)-l,3-dihydro-isobenzofuran of formula-I and l-(4"-fluorophenyl)-l,3-dihydro-isobenzofuran-5-carbonitrile of formula-II. The present invention particularly relates to an improved process for the preparation of the compound of formula-1. The compounds of the formulae-I & II are key intermediates used in the synthesis of known antidepressant drug l-(3-dimethylaminopropyl)-l-(4"-fluorophenyl)-l,3-dihydro-isobenzofuran-5-carbonitrile (citalopram), of the formula-Ill) and its pharmaceutically acceptable acid addition salts thereof The process for the preparation of antidepressant citalopram and its pharmaceutical properties was first disclosed in DE Patent no. 2,657,013 (1977) corresponding to US Patent no, 4,136,193 (1979). Subsequently it was also disclosed in GB patent no.l,526,331 (1978). The basic process for the preparation of citalopram described in the above-referred patents involves two major routes illustrated in Scheme-1 and Scheme-2. Major difference in these two routes is introduction of dimethylaminopropyl side chain at an early stage (Scheme-1) or at a later stage (Scheme-2). In the first route, 5-bromophthalide of the formula-lV is reacted with p-fluorophenyl-magnesium bromide to get a benzophenone derivative of the formula-V. This benzophenone derivative is reacted with 3-N,N-dimethylaminopropylmagnesium chloride to get the dihydroxy intermediate of the Formula-VI. Cyclization of this with an acid catalyst resulted in the formation of phthalane derivative of the Formula-VII. This bromophthalane derivative is reacted with copper cyanide to get the citalopram base of the Formula-Ill. In the second route, 5-bromophthalide of the formula-IV is reacted with p-fluorophenyl-magnesium bromide to get the corresponding benzophenone derivative of the Formula-V. This compound is reduced with lithium aluminium hydride to get the dihydroxy compound of the formula-VIII, which is cyclized with an acid catalyst to get the phthalane derivative of the formula-I. The bromo group is replaced with a cyano group and alkylated with the required side chain to get the citalopram base. Bogeso (EP patent no.171,943, corresponding to US patent no.4,650,884) has indicated that the methods described in the above patents for the preparation of citalopram possess some problems in the scale-up to commercial production. In an attempt to develop a shorter route for the preparation of citalopram and to avoid the risk involved in the metalation step used previously, Bogeso started with 5-cyanophthalide of the Formula-IX and surprisingly found that cyano group survived the cyclization step where 70% sulfuric acid was used at 80°C temperature (Scheme-3). Further processes have been disclosed in international patent application nos. WO 98/019511, WO 98/019512, WO 98/019513, WO 99/030548, WO 00/011926, WO 00/013648, and WO 00/023431. International patent application no. WO 98/019511 discloses a process for the manufacture of citalopram wherein a compound of the Formula-X was reduced with sodium borohydride to get a compound of the Formula-XII. However, yield is only 40% and large quantity (-50 times) of alcohol was used. This compound of the Formula-XII is subjected to ring closure and the resulting 5-substituted dihydroisobenzofuran derivative is converted to the corresponding 5-cyano derivative and alkylated with (3-dimethylamino) propyl halogenide to obtain citalopram. wo 98/019512 and WO 98/019513 relate to methods wherein a 5-amino-, 5-carboxy- or 5-(sec-aminocarbonyl) phthalide is subjected to two successive Grignard reactions, ring closure and conversion of the resulting 1,3-dihydroisobenzofuran derivative to the corresponding 5-cyano compound, i.e. citalopram. International patent application no. 99/030548 discloses a process for the preparation of citalopram wherein cyano group was introduced from the corresponding 5-aldehyde analogue of citalopram. International patent application nos. WO 00/011926 and WO 00/013648 disclose an improved process for the preparation of citalopram wherein 5-halogen (C1 or Br) analogue of citalopram is activated by using palladium or nickel complex catalyst to introduce the corresponding cyano group present in citalopram. International patent application no. WO 00/023431 discloses a process for introduction of cyano group present in citalopram via the corresponding 5-oxazolyl analogue of citalopram. A major drawback in the scale up to commercial production of citalopram by following the original patent process (disclosed in US patent no.4,136,193) is removal of impurities present in citalopram to an acceptable level of pharmaceutical quality. Methods followed to improve the quality of citalopram are either by chemical purification (via acid addition salt where ever applicable) or by high vacuum distillation. Chemical method does not seem to remove the impurities up to the acceptable level because some of the impurities like compound of Formula-VI, Formula-VII or Formula-XIII have similar salt formation properties with an acid. All the intermediates involved in the original patent for the preparation of citalopram have very high boiling point (~200°C at Second route of the original patent for the preparation of citalopram involves purification of intermediate compounds of the Formula I and II by high vacuum distillation (180-200°C at Third and simplified route (disclosed in EP Patent no. 171,943) for the preparation of citalopram involves the introduction of 5-cyano group present in citalopram at the beginning itself This route also has major drawback of removal of impurities present in citalopram. Repeated recrystallization technique was described in making pharmaceutically acceptable quality citalopram. Also, there is a considerable loss if required product (citalopram) in this technique. All other international patents published between 1998 and 2000 are involving with various methods to introduce 5-cyano group from different functional groups. All these methods are focusing on new chemistry and are not adaptable for commercial production. Citalopram has become a well-known antidepressant drug that has now been on the market and has shown great promise as a valuable antidepressant drug with few side effects. Keeping in view of the difficulties in commercialization of the above-mentioned processes for the preparation of citalopram, we aimed to develop a simple and economical process for commercial production of citalopram. We observed that a promising approach for such a process is to (a) improve the quality of one or more of the isolable intermediates by simple techniques (b) avoid costly and risky reagents like lithium aluminum hydride and (c) minimize the effluents like large quantity of phosphoric acid. The present invention has been developed based on our finding that if the (3-dimethylamino) propyl side chain present in citalopram is introduced at an early stage, it is difficuh to remove the related impurities by conventional methods. Further if a simple crystallization technique for the formation of one or more of the isolable intermediates, it becomes easy to get citalopram with acceptable pharmaceutical quality. Accordingly the present invention relates to an improved process for the preparation of the intermediate of the formula-II, which is useful for the preparation of citalopram of the formula-Ill. Another objective of the present invention is to provide an improved process for the preparation of the intermediate of the formula-II useful for the preparation of citalopram of the formula-Ill avoiding the formation of impurities. Yet another objective of the present invention is to provide an improved process for the preparation of the intermediate of the formula-II useful for the preparation of citalopram with high yield (>90%) and high purity (>99%) Still another objective of the present invention is to provide an improved process for the preparation of the intermediate of the formula-II useful for the citalopram of the formula-Ill, which is simple, economical and environmentally safe. Still another objective of the present invention is to provide an improved process for the preparation of the intermediate of the formula-II, which is useful for the preparation of citalopram employing a simple crystallization technique. Further objective of the present invention is to provide an improved process for the preparation of the formula-II, which is useful for the preparation of citalopram by replacing the costly and hazardous lithium aluminum hydride with simple sodium borohydride and with no involvement of additional steps. Another objective of the present invention is to provide an improved process for the preparation of the formula-II which is usefial for the preparation of citalopram by replacing or reducing the acid catalyst used in the cyclization step of the synthesis. Accordingly the present invention provides an improved process for the preparation of intermediate of formula-II, which is useful for the preparation of citalopram which comprises: (i) reducing the magnesium salt of a benzophenone derivative of the formula-V (iii) reacting the compound of the formula-I obtained in step (ii) with copper (I) cyanide in dimethylformamide solvent medium and isolating the resulting cyano compound, by re-crystallization by using polar and or alcoholic solvents to obtain the compound of the formula-II The intermediate compound of the formula-II so formed may be converted into citalopram of the formula-Ill by any conventional methods. The process for the preparation of citalopram based on the present invention has been made the subject matter of our co-pending application no 157/MAS/01. Similarly, the process of preparing another key intermediate of the formula-I useful for the preparation of the intermediate of the formula-II which is also a key intermediate for the preparation of citalopram has been made the subject matter of our above said co¬pending application no 946/MAS/01, which is divided out of our application no 157/MAS/Ol. In another co-pending application no 948/MAS/01, which is divided out of our application no 157/MAS/Ol we have described and claimed a process for preparing another intermediate of the formula-VIII useful for the preparation of the intermediate of the formulae-I & II which is also a key intermediate for the preparation of citalopram. The reduction in step (i) may be effected at a temperature in the range of -25°C to 25°C preferably at a temperature in the range of -10°C to 0°C. The protic solvent used in step (i) may be selected from methanol, ethanol, isopropanol, n-butanol, t-butanol and the like. In another preferred embodiment of the invention the non-polar solvent such as benzene, toluene, xylene, cyclohexane and the like may be used in the step (ii). The acid catalyst such as p-toluenesulphonic acid, benzenesulphonic acid and sulphuric acid and the like may be used. The crystallization method employed for the isolation of the compound of formula-II consists of dissolving the crude compound of the formula-II formed in single solvent like methanol, ethanol or isopropanol, or mixed solvent like isopropyl alcohol/methanol, isopropyl alcohol/dimethylformamide, methanol/dimethylformamide, etc. The ratio of the combination may be 4-5:1-3, preferably 3-4:1-2. The isolated intermediate of formula-II by the process of the present invention is found to be of very high purity (>99% by HPLC) with a melting point of 96-97°C. Further confirmation of the quality was checked by converting this intermediate to the required citalopram hydrobromide salt by known method (US patent no.4,136,193) without requiring any re-crystallization process. It is interesting to note that the intermediate of formula-II has got good crystallization property leaving all the impurities in the solvent medium of crystallization. This simplification has led to the synthesis of this crucial intermediate of the formula II in a very simple and easy to adopt manner suitable for any commercial scale. Also, without any repeated re-crystallization techniques, citalopram hydrobromide could be prepared. The advantage of the invention is that the compound of the formula-II can be prepared without isolating the intermediate of the formula-I, which enhances the yield of the compound of the formula-II, Consequently when the process is employed for the preparation of citalopram flirther increases the yield of citalopram. The invention is described in detail in the Examples given below which are provided only by way of illustration and therefore should not be construed to limit the scope of the invention further illustrated by the following example. Example 1 Preparation of l-(4-fluorophenyl)-5-cyanophthalan of formula-II (a) Preparation of 4-bromo-(2-hydroxymethyi)-phenyl-(4"-fIuorophenyI)methanol of formula-VIII The Grignard solution prepared from 90gr of 4-fluorobromobenzene and 13gr magnesium turnings in 450ml of tetrahydrofuran was added drop wise to a suspension of 5-bromophthalide (100gr) in tetrahydrofuran (600ml) at -10 to 0°C under nitrogen atmosphere. After the addition was over the reaction mixture was stirred at same temperature for another 3hrs and treated with a slurry of sodium borohydride (25gr) in 300ml of isopropyl alcohol keeping the temperature below 10°C. After maintaining for Ihr at 10°C, reaction was quenched into dil hydrochloric acid (220ml cone HCl in 1750ml water). After stirring the reaction mass for 30min, layers were separated. The aqueous layer was extracted with 3 x 100ml of toluene. Combined organic layer was washed with saturated sodium chloride (300ml) and dried over sodium sulfate. Solvents were removed under vacuum below 60°C to get the crude compound of the formula-VIII (200gr). This compound is suitable for use in next stage of the process. (b) Preparation of l-(4-fluorophenyi)-5-bromophthalan of formula-I using p- toluenesulfonic acid as catalyst The crude oily compound of the formula-VIII (200gr) obtained from step (a) above was dissolved in 1000ml of toluene. To this solution was added lOgr of p-toluenesulfonic acid and heated to reflux. Water formed in the reaction was removed using Dean-stark apparatus. When the water formation was over, reaction mass was cooled to room temperature and 1000ml of water added. After stirring for 30min organic layer was separated and the aqueous layer extracted with 3 x 100ml of toluene. The combined organic layer was washed with 2 x 250ml of 5% sodium carbonate solution. Finally the organic layer was washed with saturated sodium chloride. Toluene was removed under vacuum below 60°C to get the crude compound of the formula-1 (150gr) as an oil. (c) Preparation of l-(4-fluorophenyl)-5-cyanophthalan of formula-II To a solution of the compound of the formula I (150gr) obtained in step (b) above in dimethylformamide (360) was added freshly prepared copper (I) cyanide (76gr). The resulting suspension was slowly heated to reflux temperature and maintained at reflux for 4 - 5hrs. After cooling the reaction mass to 40 - 50°C, aqueous ammonia (200ml, 10% w/v) was added and stirred for 30min. After filtering off the insoluble salts, layers were separated. The organic layer was washed with 200ml of dil. ammonia (10% solution). Combined aq. layers were extracted with 100ml of toluene. Toluene layers were combined and the solvent distilled off under vacuum at 50 - 60°C to give the crude cyano compound of the formula-II (120gr) as a semi-solid. (d) Purification of l-(4-fluorophenyl)-5-cyanophthalan by re-crystallization technique Re-crystallization from isopropyl alcohol The crude compound of the formula-II (50gr) obtained in step(c) above was dissolved in 200ml of isopropyl alcohol by heating to 60-70°C and treated with 5gr of charcoal. After filtration, cooling to 20-25°C, it was kept at this temperature for 8-12hrs. Filtration of the solids and washing with 20 - 25ml of isopropyl alcohol gave light yellow crystalline solid (35gr) M. P. is 96-97°C. Purity by HPLC is 98%. Example 2 Preparation of l-(4-fluorophenyl)-5-cyanophthalan of formula-II (a) Preparation of 4-bromo-(2-hydroxymethyl)-phenyl-(4^-fluorophenyl)methanol of formula-VIII The Grignard solution prepared from 90gr of 4-fluorobromobenzene and 13gr magnesium turnings in 450ml of tetrahydrofuran was added drop wise to a suspension of 5-bromophthalide (100gr) in tetrahydrofliran (600ml) at -10 to 0°C under nitrogen atmosphere. After the addition was over the reaction mixture was stirred at same temperature for another 3hrs and treated with a slurry of sodium borohydride (25gr) in 100ml of methanol keeping the temperature below 0°C. After maintaining for Ihr at 10°C, reaction was quenched into dil hydrochloric acid (220ml cone. HCl in 1750ml water). After stirring the reaction mass for 30min, layers were separated. The aqueous layer was extracted with 3 x 100ml of toluene. Combined organic layer was washed with saturated sodium chloride (300ml) and dried over sodium sulfate. Solvents were removed under vacuum below 60°C to get the crude compound of the formula-VIII (200gr), This compound is suitable for use in next stage of the process. (b) Preparation of l-(4-fIuorophenyl)-5-bromophthalan of formula-I using benzene- sulfonic acid as catalyst The crude oily compound of the formula VIII (200gr) obtained from step (a) above was dissolved in 1000ml of toluene. To this solution was added lOgr of benzenesulfonic acid and heated to reflux. Water formed in the reaction was removed using Dean-stark apparatus. When the water formation was over, reaction mass was cooled to room temperature and 1000ml of water added. After stirring for 30min organic layer was separated and the aqueous layer extracted with 3 x 100ml of toluene. The combined organic layer was washed with 2 x 250ml of 5% sodium carbonate solution. Finally the organic layer was washed with saturated sodium chloride. Toluene was removed under vacuum below 60°C to get the crude compound of the formula-I (150gr) as an oil. (c) Preparation of l-(4-fluorophenyl)-5-cyanophthalan of formula-II To a solution of the compound of the formula I (150gr) obtained in step (b) above in dimethylacetamide (300ml) was added freshly prepared copper (I) cyanide (76gr). The resulting suspension was slowly heated to 150-160°C and maintained at that temperature for 4-5hrs. After cooling the reaction mass to 40-50°C, aqueous ammonia (200ml, 10% w/v) was added and stirred for 30min. After filtering off the insoluble salts, layers were separated. The organic layer was washed with 200ml of dil. ammonia (10% solution). Combined aq. layers were extracted with 100ml of toluene. Toluene layers were combined and the solvent distilled off under vacuum at 50-60°C to give the crude cyano compound of the formula-II (120gr) as a semi-solid. (d) Purification of l-(4-fluorophenyl)-5-cyanophthaIan of the formula-II by re- crystallization technique Purification by re-crystallization from methanol The crude compound of the formula-II (50gr) obtained in step (c) above was dissolved in 150ml of refluxing methanol and treated with 5gr of charcoal. After filtration of carbon, filtrate was cooled to 20-25°C and maintained for 8-12hrs. Filtration of the solid and washing the wet cake with 25ml of methanol gave 25gr of white crystalline solid. M.P. is 97-98°C. Purity by HPLC is 99%. Example 3 Preparation of l-(4-fluorophenyl)-5-cyanophthalan of formula-II (a) Preparation of 4-bromo-(2-hydroxymethyl)-phenyl-(41-fluorophenyl)methanol of formula-VIII The Grignard solution prepared from 90gr of 4-fluorobromobenzene and 13gr magnesium turnings in 450ml of THF was added drop wise to a suspension of 5-bromophthalide (100gr) in THF (600ml) at -10 to 0°C under nitrogen atmosphere. After the addition was over the reaction mixture was stirred at same temperature for another 3hrs and treated with a slurry of sodium borohydride (25gr) in 200ml of ethanol keeping the temperature below 0°C. After maintaining for 1hr at 10°C, reaction was quenched into dil hydrochloric acid (220ml cone HCl in 1750ml water). After stirring the reaction mass for 30min, layers were separated. The aqueous layer was extracted with 3 x 100ml of toluene. Combined organic layer was washed with saturated sodium chloride (300ml) and dried over sodium sulfate. Solvents were removed under vacuum below 60°C to get the crude compound of the formula-VIII (200gr). This compound is suitable for use in next stage of the process. (b) Preparation of l-(4-fluorophenyl)-5-bromophthalan of formula-I using sulfuric acid as a catalyst The crude oily compound (200gr) obtained form Example 3 (a) was dissolved in 1000ml of toluene and 10gr of cone, sulfuric acid was added to this solution. The reaction mixture was heated to reflux and water formed in the reaction was removed azeotropically. After completion of the reaction usual work up gave 150gr of the compound of the formula-II as an oil. (c) Preparation of l-(4-fluorophenyI)-5-cyanophthalan of formula-II To a solution of the compound of the formula-I (150gr) obtained in step (b) above in pyridine (150ml) was added freshly prepared copper (I) cyanide (76gr). The resulting suspension was slowly heated to reflux temperature and maintained at reflux for 4-5hrs. After cooling the reaction mass to 40-50°C, aqueous ammonia (200ml, 10% w/v) was added and stirred for 30min. After filtering off the insoluble salts, layers were separated. The organic layer was washed with 200ml of dil. ammonia (10% solution). Combined aq. layers were extracted with 100ml of toluene. Toluene layers were combined and the solvent distilled off under vacuum at 50-60°C to give the crude cyano compound of the formula-II (120gr) as a semi-solid. d) Purification of l-(4-fluorophenyl)-5-cyanophthalan of the formula-II by re-crystallization technique Re-crystallization from isopropyl alcohol/dimethylformamide The crude compound of the formula-II (150gr) obtained in step(c) above was dissolved in 100ml of isopropyl alcohol/dimethylformamide (80:20) at 50-60°C and treated with 5gr of active charcoal. After filtration of the charcoal, filtrate was cooled to 10-15°C and maintained for 3-4 hrs at this temperature. The solids formed were filtered and the wet cake washed with 20ml of isopropyl alcohol to get white crystalline solid. M.P. is 97-98°C. Purity by HPLC is 98.5%. ADVANTAGES OF THE PRESENT INVENTION: 1. Replacing lithium aluminum hydride with sodium borohydride is very much cost effective and free of any hazardous nature. 2. Simple crystallization method for the cyano compound of the formula-II has avoided the high vacuum distillation of the corresponding bromo derivative of the formula-I. 3. The resulting compound of the formula-II is produced in high yield (>90%) and of high purity (>98%). 4. The process is useful for any commercial scale and environmentally safe and economical. We Claim: 1. An improved process for the preparation of l-(41-fluorophenyl)-l,3-dihydroisobenzofuran-5-carbonitrile of formula-II useful for the preparation of citalopram of formula-Ill, Which comprises: (i) reducing the magnisium salt of the benzophenone derivative of formula-V, using sodium borohydride in the presence of a protic solvent to obtain a compound of formula-VIII, (ii) reacting the compound of formula-VIIl obtained in step (i) with an acid catalyst in a non-polar solvent to obtain a compound of formula-I, (iii) reacting the compound of the formula-I obtained in step (ii) with copper (I) cyanide in dimethylformamide solvent medium and isolating the resulting cyano compound, by re-crystallization by using polar and or alcoholic solvents to obtain the compound of the formula-II 2. A process as claimed in claim 1 wherein the protic solvent used in step (i) may be methanol, ethanol, isopropyl alcohol, n-butanol, preferably methanol or ethanol. 3. A process as claimed in claim 1 and 2 wherein the temperature of reaction may be in the range of-25°C to 10°C, preferably in the range of-15°C to 0°C. 4. A process as claimed in claims 1 to 3 wherein the non-polar solvent used in step (ii) may be benzene, toluene, xylene, cyclohexane, preferably benzene or toluene. 5. A process as claimed in claim 1 to 4 wherein the catalyst used in step (ii) may be benzenesulfonic acid, p-toluenesulfonic acid, sulfuric acid, and preferably p-toluenesulfonic acid. 6. A process as claimed in claims 1 to 5 wherein the solvent used for recrystallization in step (iii) is selected from methanol, isopropanol, ethanol, with or without dimethylformamide, or a combination thereof. 7. A process as claimed in claim 6 wherein the solvent used for recrystallization is a combination of isopropanol with dimethylformamide. 8. A process as claimed in claim 7 wherein the ratio of isopropanol & dimethylformamide used ranges from 5-6; 1-3, preferably in the range 3-4.1-2. 9. An improved process for the preparation of compound of formula-II, which is useful for the preparation of citalopram of formula-Ill substantially as herein described with reference to Examples 1 to 3.

Full Text

INTRODUCTION
The present invention relates to an improved process for the preparation of 5-bromo-l-(4"-flurophenyl)-l,3-dihydro-isobenzofuran of formula-I and l-(4"-fluorophenyl)-l,3-dihydro-isobenzofuran-5-carbonitrile of formula-II. The present invention particularly relates to an improved process for the preparation of the compound of formula-1.

The compounds of the formulae-I & II are key intermediates used in the synthesis of known antidepressant drug l-(3-dimethylaminopropyl)-l-(4"-fluorophenyl)-l,3-dihydro-isobenzofuran-5-carbonitrile (citalopram), of the formula-Ill) and its pharmaceutically acceptable acid addition salts thereof

The process for the preparation of antidepressant citalopram and its pharmaceutical properties was first disclosed in DE Patent no. 2,657,013 (1977) corresponding to US Patent no, 4,136,193 (1979). Subsequently it was also disclosed in GB patent no.l,526,331 (1978).
The basic process for the preparation of citalopram described in the above-referred patents involves two major routes illustrated in Scheme-1 and Scheme-2. Major difference in these two routes is introduction of dimethylaminopropyl side chain at an early stage (Scheme-1) or at a later stage (Scheme-2).

In the first route, 5-bromophthalide of the formula-lV is reacted with p-fluorophenyl-magnesium bromide to get a benzophenone derivative of the formula-V. This benzophenone derivative is reacted with 3-N,N-dimethylaminopropylmagnesium chloride to get the dihydroxy intermediate of the Formula-VI. Cyclization of this with an acid catalyst resulted in the formation of phthalane derivative of the Formula-VII. This bromophthalane derivative is reacted with copper cyanide to get the citalopram base of the Formula-Ill.

In the second route, 5-bromophthalide of the formula-IV is reacted with p-fluorophenyl-magnesium bromide to get the corresponding benzophenone derivative of the Formula-V. This compound is reduced with lithium aluminium hydride to get the dihydroxy compound of the formula-VIII, which is cyclized with an acid catalyst to get the

phthalane derivative of the formula-I. The bromo group is replaced with a cyano group and alkylated with the required side chain to get the citalopram base.
Bogeso (EP patent no.171,943, corresponding to US patent no.4,650,884) has indicated that the methods described in the above patents for the preparation of citalopram possess some problems in the scale-up to commercial production.
In an attempt to develop a shorter route for the preparation of citalopram and to avoid the risk involved in the metalation step used previously, Bogeso started with 5-cyanophthalide of the Formula-IX and surprisingly found that cyano group survived the cyclization step where 70% sulfuric acid was used at 80°C temperature (Scheme-3).

Further processes have been disclosed in international patent application nos. WO 98/019511, WO 98/019512, WO 98/019513, WO 99/030548, WO 00/011926, WO 00/013648, and WO 00/023431. International patent application no. WO 98/019511 discloses a process for the manufacture of citalopram wherein a compound of the Formula-X was reduced with sodium borohydride to get a compound of the Formula-XII. However, yield is only 40% and large quantity (-50 times) of alcohol was used. This compound of the Formula-XII is subjected to ring closure and the resulting 5-substituted dihydroisobenzofuran derivative is converted to the corresponding 5-cyano derivative and alkylated with (3-dimethylamino) propyl halogenide to obtain citalopram.

wo 98/019512 and WO 98/019513 relate to methods wherein a 5-amino-, 5-carboxy- or 5-(sec-aminocarbonyl) phthalide is subjected to two successive Grignard reactions, ring closure and conversion of the resulting 1,3-dihydroisobenzofuran derivative to the corresponding 5-cyano compound, i.e. citalopram.
International patent application no. 99/030548 discloses a process for the preparation of citalopram wherein cyano group was introduced from the corresponding 5-aldehyde analogue of citalopram.
International patent application nos. WO 00/011926 and WO 00/013648 disclose an improved process for the preparation of citalopram wherein 5-halogen (C1 or Br) analogue of citalopram is activated by using palladium or nickel complex catalyst to introduce the corresponding cyano group present in citalopram.
International patent application no. WO 00/023431 discloses a process for introduction of cyano group present in citalopram via the corresponding 5-oxazolyl analogue of citalopram.
A major drawback in the scale up to commercial production of citalopram by following the original patent process (disclosed in US patent no.4,136,193) is removal of impurities present in citalopram to an acceptable level of pharmaceutical quality. Methods followed to improve the quality of citalopram are either by chemical purification (via acid addition salt where ever applicable) or by high vacuum distillation. Chemical method does not

seem to remove the impurities up to the acceptable level because some of the impurities like compound of Formula-VI, Formula-VII or Formula-XIII have similar salt formation properties with an acid.
All the intermediates involved in the original patent for the preparation of citalopram have very high boiling point (~200°C at Second route of the original patent for the preparation of citalopram involves purification of intermediate compounds of the Formula I and II by high vacuum distillation (180-200°C at Third and simplified route (disclosed in EP Patent no. 171,943) for the preparation of citalopram involves the introduction of 5-cyano group present in citalopram at the beginning itself This route also has major drawback of removal of impurities present in citalopram. Repeated recrystallization technique was described in making pharmaceutically acceptable quality citalopram. Also, there is a considerable loss if required product (citalopram) in this technique.
All other international patents published between 1998 and 2000 are involving with various methods to introduce 5-cyano group from different functional groups. All these methods are focusing on new chemistry and are not adaptable for commercial production.
Citalopram has become a well-known antidepressant drug that has now been on the market and has shown great promise as a valuable antidepressant drug with few side effects. Keeping in view of the difficulties in commercialization of the above-mentioned processes for the preparation of citalopram, we aimed to develop a simple and economical process for commercial production of citalopram.
We observed that a promising approach for such a process is to (a) improve the quality of one or more of the isolable intermediates by simple techniques (b) avoid costly and risky reagents like lithium aluminum hydride and (c) minimize the effluents like large quantity of phosphoric acid.
The present invention has been developed based on our finding that if the (3-dimethylamino) propyl side chain present in citalopram is introduced at an early stage, it is difficuh to remove the related impurities by conventional methods. Further if a simple crystallization technique for the formation of one or more of the isolable intermediates, it becomes easy to get citalopram with acceptable pharmaceutical quality.
Accordingly the present invention relates to an improved process for the preparation of the intermediate of the formula-II, which is useful for the preparation of citalopram of the formula-Ill.

Another objective of the present invention is to provide an improved process for the preparation of the intermediate of the formula-II useful for the preparation of citalopram of the formula-Ill avoiding the formation of impurities.
Yet another objective of the present invention is to provide an improved process for the preparation of the intermediate of the formula-II useful for the preparation of citalopram with high yield (>90%) and high purity (>99%)
Still another objective of the present invention is to provide an improved process for the preparation of the intermediate of the formula-II useful for the citalopram of the formula-Ill, which is simple, economical and environmentally safe.
Still another objective of the present invention is to provide an improved process for the preparation of the intermediate of the formula-II, which is useful for the preparation of citalopram employing a simple crystallization technique.
Further objective of the present invention is to provide an improved process for the preparation of the formula-II, which is useful for the preparation of citalopram by replacing the costly and hazardous lithium aluminum hydride with simple sodium borohydride and with no involvement of additional steps.
Another objective of the present invention is to provide an improved process for the preparation of the formula-II which is usefial for the preparation of citalopram by replacing or reducing the acid catalyst used in the cyclization step of the synthesis.
Accordingly the present invention provides an improved process for the preparation of intermediate of formula-II,

which is useful for the preparation of citalopram which comprises:
(i) reducing the magnesium salt of a benzophenone derivative of the formula-V

(iii) reacting the compound of the formula-I obtained in step (ii) with copper (I) cyanide in dimethylformamide solvent medium and isolating the resulting cyano compound, by re-crystallization by using polar and or alcoholic solvents to obtain the compound of the formula-II

The intermediate compound of the formula-II so formed may be converted into citalopram of the formula-Ill by any conventional methods. The process for the preparation of citalopram based on the present invention has been made the subject matter of our co-pending application no 157/MAS/01.
Similarly, the process of preparing another key intermediate of the formula-I useful for the preparation of the intermediate of the formula-II which is also a key intermediate for the preparation of citalopram has been made the subject matter of our above said co¬pending application no 946/MAS/01, which is divided out of our application no 157/MAS/Ol.
In another co-pending application no 948/MAS/01, which is divided out of our application no 157/MAS/Ol we have described and claimed a process for preparing another intermediate of the formula-VIII useful for the preparation of the intermediate of the formulae-I & II which is also a key intermediate for the preparation of citalopram.
The reduction in step (i) may be effected at a temperature in the range of -25°C to 25°C preferably at a temperature in the range of -10°C to 0°C. The protic solvent used in step (i) may be selected from methanol, ethanol, isopropanol, n-butanol, t-butanol and the like.
In another preferred embodiment of the invention the non-polar solvent such as benzene, toluene, xylene, cyclohexane and the like may be used in the step (ii). The acid catalyst such as p-toluenesulphonic acid, benzenesulphonic acid and sulphuric acid and the like may be used.
The crystallization method employed for the isolation of the compound of formula-II consists of dissolving the crude compound of the formula-II formed in single solvent like methanol, ethanol or isopropanol, or mixed solvent like isopropyl alcohol/methanol, isopropyl alcohol/dimethylformamide, methanol/dimethylformamide, etc. The ratio of the combination may be 4-5:1-3, preferably 3-4:1-2.
The isolated intermediate of formula-II by the process of the present invention is found to be of very high purity (>99% by HPLC) with a melting point of 96-97°C. Further confirmation of the quality was checked by converting this intermediate to the required

citalopram hydrobromide salt by known method (US patent no.4,136,193) without requiring any re-crystallization process. It is interesting to note that the intermediate of formula-II has got good crystallization property leaving all the impurities in the solvent medium of crystallization.
This simplification has led to the synthesis of this crucial intermediate of the formula II in a very simple and easy to adopt manner suitable for any commercial scale. Also, without any repeated re-crystallization techniques, citalopram hydrobromide could be prepared.
The advantage of the invention is that the compound of the formula-II can be prepared without isolating the intermediate of the formula-I, which enhances the yield of the compound of the formula-II, Consequently when the process is employed for the preparation of citalopram flirther increases the yield of citalopram.
The invention is described in detail in the Examples given below which are provided only by way of illustration and therefore should not be construed to limit the scope of the invention further illustrated by the following example.
Example 1
Preparation of l-(4-fluorophenyl)-5-cyanophthalan of formula-II
(a) Preparation of 4-bromo-(2-hydroxymethyi)-phenyl-(4"-fIuorophenyI)methanol of
formula-VIII
The Grignard solution prepared from 90gr of 4-fluorobromobenzene and 13gr magnesium turnings in 450ml of tetrahydrofuran was added drop wise to a suspension of 5-bromophthalide (100gr) in tetrahydrofuran (600ml) at -10 to 0°C under nitrogen atmosphere. After the addition was over the reaction mixture was stirred at same temperature for another 3hrs and treated with a slurry of sodium borohydride (25gr) in 300ml of isopropyl alcohol keeping the temperature below 10°C. After maintaining for Ihr at 10°C, reaction was quenched into dil hydrochloric acid (220ml cone HCl in 1750ml water). After stirring the reaction mass for 30min, layers were separated. The aqueous layer was extracted with 3 x 100ml of toluene. Combined organic layer was washed with saturated sodium chloride (300ml) and dried over sodium sulfate. Solvents were removed under vacuum below 60°C to get the crude compound of the formula-VIII (200gr). This compound is suitable for use in next stage of the process.
(b) Preparation of l-(4-fluorophenyi)-5-bromophthalan of formula-I using p-
toluenesulfonic acid as catalyst
The crude oily compound of the formula-VIII (200gr) obtained from step (a) above was dissolved in 1000ml of toluene. To this solution was added lOgr of p-toluenesulfonic acid and heated to reflux. Water formed in the reaction was removed using Dean-stark apparatus. When the water formation was over, reaction mass was cooled to room temperature and 1000ml of water added. After stirring for 30min organic layer was

separated and the aqueous layer extracted with 3 x 100ml of toluene. The combined organic layer was washed with 2 x 250ml of 5% sodium carbonate solution. Finally the organic layer was washed with saturated sodium chloride. Toluene was removed under vacuum below 60°C to get the crude compound of the formula-1 (150gr) as an oil.
(c) Preparation of l-(4-fluorophenyl)-5-cyanophthalan of formula-II
To a solution of the compound of the formula I (150gr) obtained in step (b) above in dimethylformamide (360) was added freshly prepared copper (I) cyanide (76gr). The resulting suspension was slowly heated to reflux temperature and maintained at reflux for 4 - 5hrs. After cooling the reaction mass to 40 - 50°C, aqueous ammonia (200ml, 10% w/v) was added and stirred for 30min. After filtering off the insoluble salts, layers were separated. The organic layer was washed with 200ml of dil. ammonia (10% solution). Combined aq. layers were extracted with 100ml of toluene. Toluene layers were combined and the solvent distilled off under vacuum at 50 - 60°C to give the crude cyano compound of the formula-II (120gr) as a semi-solid.
(d) Purification of l-(4-fluorophenyl)-5-cyanophthalan by re-crystallization
technique
Re-crystallization from isopropyl alcohol
The crude compound of the formula-II (50gr) obtained in step(c) above was dissolved in 200ml of isopropyl alcohol by heating to 60-70°C and treated with 5gr of charcoal. After filtration, cooling to 20-25°C, it was kept at this temperature for 8-12hrs. Filtration of the solids and washing with 20 - 25ml of isopropyl alcohol gave light yellow crystalline solid (35gr) M. P. is 96-97°C. Purity by HPLC is 98%.
Example 2
Preparation of l-(4-fluorophenyl)-5-cyanophthalan of formula-II
(a) Preparation of 4-bromo-(2-hydroxymethyl)-phenyl-(4^-fluorophenyl)methanol of formula-VIII
The Grignard solution prepared from 90gr of 4-fluorobromobenzene and 13gr magnesium turnings in 450ml of tetrahydrofuran was added drop wise to a suspension of 5-bromophthalide (100gr) in tetrahydrofliran (600ml) at -10 to 0°C under nitrogen atmosphere. After the addition was over the reaction mixture was stirred at same temperature for another 3hrs and treated with a slurry of sodium borohydride (25gr) in 100ml of methanol keeping the temperature below 0°C. After maintaining for Ihr at 10°C, reaction was quenched into dil hydrochloric acid (220ml cone. HCl in 1750ml water). After stirring the reaction mass for 30min, layers were separated. The aqueous layer was extracted with 3 x 100ml of toluene. Combined organic layer was washed with saturated sodium chloride (300ml) and dried over sodium sulfate. Solvents were removed

under vacuum below 60°C to get the crude compound of the formula-VIII (200gr), This compound is suitable for use in next stage of the process.
(b) Preparation of l-(4-fIuorophenyl)-5-bromophthalan of formula-I using benzene-
sulfonic acid as catalyst
The crude oily compound of the formula VIII (200gr) obtained from step (a) above was dissolved in 1000ml of toluene. To this solution was added lOgr of benzenesulfonic acid and heated to reflux. Water formed in the reaction was removed using Dean-stark apparatus. When the water formation was over, reaction mass was cooled to room temperature and 1000ml of water added. After stirring for 30min organic layer was separated and the aqueous layer extracted with 3 x 100ml of toluene. The combined organic layer was washed with 2 x 250ml of 5% sodium carbonate solution. Finally the organic layer was washed with saturated sodium chloride. Toluene was removed under vacuum below 60°C to get the crude compound of the formula-I (150gr) as an oil.
(c) Preparation of l-(4-fluorophenyl)-5-cyanophthalan of formula-II
To a solution of the compound of the formula I (150gr) obtained in step (b) above in dimethylacetamide (300ml) was added freshly prepared copper (I) cyanide (76gr). The resulting suspension was slowly heated to 150-160°C and maintained at that temperature for 4-5hrs. After cooling the reaction mass to 40-50°C, aqueous ammonia (200ml, 10% w/v) was added and stirred for 30min. After filtering off the insoluble salts, layers were separated. The organic layer was washed with 200ml of dil. ammonia (10% solution). Combined aq. layers were extracted with 100ml of toluene. Toluene layers were combined and the solvent distilled off under vacuum at 50-60°C to give the crude cyano compound of the formula-II (120gr) as a semi-solid.
(d) Purification of l-(4-fluorophenyl)-5-cyanophthaIan of the formula-II by re-
crystallization technique
Purification by re-crystallization from methanol
The crude compound of the formula-II (50gr) obtained in step (c) above was dissolved in 150ml of refluxing methanol and treated with 5gr of charcoal. After filtration of carbon, filtrate was cooled to 20-25°C and maintained for 8-12hrs. Filtration of the solid and washing the wet cake with 25ml of methanol gave 25gr of white crystalline solid. M.P. is 97-98°C. Purity by HPLC is 99%.
Example 3
Preparation of l-(4-fluorophenyl)-5-cyanophthalan of formula-II
(a) Preparation of 4-bromo-(2-hydroxymethyl)-phenyl-(41-fluorophenyl)methanol of formula-VIII

The Grignard solution prepared from 90gr of 4-fluorobromobenzene and 13gr magnesium turnings in 450ml of THF was added drop wise to a suspension of 5-bromophthalide (100gr) in THF (600ml) at -10 to 0°C under nitrogen atmosphere. After the addition was over the reaction mixture was stirred at same temperature for another 3hrs and treated with a slurry of sodium borohydride (25gr) in 200ml of ethanol keeping the temperature below 0°C. After maintaining for 1hr at 10°C, reaction was quenched into dil hydrochloric acid (220ml cone HCl in 1750ml water). After stirring the reaction mass for 30min, layers were separated. The aqueous layer was extracted with 3 x 100ml of toluene. Combined organic layer was washed with saturated sodium chloride (300ml) and dried over sodium sulfate. Solvents were removed under vacuum below 60°C to get the crude compound of the formula-VIII (200gr). This compound is suitable for use in next stage of the process.
(b) Preparation of l-(4-fluorophenyl)-5-bromophthalan of formula-I using sulfuric
acid as a catalyst
The crude oily compound (200gr) obtained form Example 3 (a) was dissolved in 1000ml of toluene and 10gr of cone, sulfuric acid was added to this solution. The reaction mixture was heated to reflux and water formed in the reaction was removed azeotropically. After completion of the reaction usual work up gave 150gr of the compound of the formula-II as an oil.
(c) Preparation of l-(4-fluorophenyI)-5-cyanophthalan of formula-II
To a solution of the compound of the formula-I (150gr) obtained in step (b) above in pyridine (150ml) was added freshly prepared copper (I) cyanide (76gr). The resulting suspension was slowly heated to reflux temperature and maintained at reflux for 4-5hrs. After cooling the reaction mass to 40-50°C, aqueous ammonia (200ml, 10% w/v) was added and stirred for 30min. After filtering off the insoluble salts, layers were separated. The organic layer was washed with 200ml of dil. ammonia (10% solution). Combined aq. layers were extracted with 100ml of toluene. Toluene layers were combined and the solvent distilled off under vacuum at 50-60°C to give the crude cyano compound of the formula-II (120gr) as a semi-solid.
d) Purification of l-(4-fluorophenyl)-5-cyanophthalan of the formula-II by re-crystallization technique
Re-crystallization from isopropyl alcohol/dimethylformamide
The crude compound of the formula-II (150gr) obtained in step(c) above was dissolved in 100ml of isopropyl alcohol/dimethylformamide (80:20) at 50-60°C and treated with 5gr of active charcoal. After filtration of the charcoal, filtrate was cooled to 10-15°C and maintained for 3-4 hrs at this temperature. The solids formed were filtered and the wet cake washed with 20ml of isopropyl alcohol to get white crystalline solid. M.P. is 97-98°C. Purity by HPLC is 98.5%.

ADVANTAGES OF THE PRESENT INVENTION:
1. Replacing lithium aluminum hydride with sodium borohydride is very much cost effective and free of any hazardous nature.
2. Simple crystallization method for the cyano compound of the formula-II has avoided the high vacuum distillation of the corresponding bromo derivative of the formula-I.
3. The resulting compound of the formula-II is produced in high yield (>90%) and of high purity (>98%).
4. The process is useful for any commercial scale and environmentally safe and economical.

We Claim:
1. An improved process for the preparation of l-(41-fluorophenyl)-l,3-dihydroisobenzofuran-5-carbonitrile of formula-II useful for the preparation of citalopram of formula-Ill,

Which comprises:
(i) reducing the magnisium salt of the benzophenone derivative of formula-V,

using sodium borohydride in the presence of a protic solvent to obtain a compound of formula-VIII,

(ii) reacting the compound of formula-VIIl obtained in step (i) with an acid catalyst in a non-polar solvent to obtain a compound of formula-I,

(iii) reacting the compound of the formula-I obtained in step (ii) with copper (I) cyanide in dimethylformamide solvent medium and isolating the resulting cyano compound, by re-crystallization by using polar and or alcoholic solvents to obtain the compound of the formula-II

2. A process as claimed in claim 1 wherein the protic solvent used in step (i) may be methanol, ethanol, isopropyl alcohol, n-butanol, preferably methanol or ethanol.
3. A process as claimed in claim 1 and 2 wherein the temperature of reaction may be in the range of-25°C to 10°C, preferably in the range of-15°C to 0°C.
4. A process as claimed in claims 1 to 3 wherein the non-polar solvent used in step (ii) may be benzene, toluene, xylene, cyclohexane, preferably benzene or toluene.
5. A process as claimed in claim 1 to 4 wherein the catalyst used in step (ii) may be benzenesulfonic acid, p-toluenesulfonic acid, sulfuric acid, and preferably p-toluenesulfonic acid.
6. A process as claimed in claims 1 to 5 wherein the solvent used for recrystallization in step (iii) is selected from methanol, isopropanol, ethanol, with or without dimethylformamide, or a combination thereof.

7. A process as claimed in claim 6 wherein the solvent used for recrystallization is a
combination of isopropanol with dimethylformamide.
8. A process as claimed in claim 7 wherein the ratio of isopropanol &
dimethylformamide used ranges from 5-6; 1-3, preferably in the range 3-4.1-2.
9. An improved process for the preparation of compound of formula-II, which is useful
for the preparation of citalopram of formula-Ill substantially as herein described with
reference to Examples 1 to 3.

Documents:

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0947-mas-2001 correespondence-po.pdf

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Patent Number

194532

Indian Patent Application Number

947/MAS/2001

PG Journal Number

08/2007

Publication Date

23-Feb-2007

Grant Date

19-Dec-2005

Date of Filing

22-Nov-2001

Name of Patentee

NATCO PHARMA LTD

Applicant Address

NATCO HOUSE, ROAD NO.2, BANJARA HILLS, HYDERABAD 500 033

Inventors:

#	Inventor's Name	Inventor's Address
1	PULLA REDDY MUDDASANI	NATCO PHARMA LTD., NATCO HOUSE, ROAD NO.2, BANJARA HILLS, HYDERABAD 500 033
2	VENKAIAH CHOWDARY NANNAPANENI	NATCO PHARMA LTD NATCO HOUSE, ROAD NO 2, BANJARA HILLS, HYDERABAD 500 033,

PCT International Classification Number

C07D307/87

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA