Title of Invention	AN IMPROVED PROCESS FOR THE PREPARATION OF 5-BROMO-1-(4'-FLUOROPHENYL) -1, 3- DIHYDRO- ISO BENZOFURAN, AN INTERMEDIATE OF CITALOPRAM
Abstract	This invention discloses an improved process for the preparation of 5-bromo-I-(4- fluorophenyl)-1,3-dihydroisobenzofuran of formula-I, which is useful for the preparation of antidepressant drug citalopram. Process for the preparation of compound of formula- I 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 medium to get the dihydroxy compound (iii) Cyclization of the dihydroxy compound with an acid catalyst in a non-polar solvent system to get the compound offormula-I. The present method avoids the usage of earlier known lithium aluminum hydride reduction method and high vacuum distillation of compound of formula-I in making the antidepressant drug citalopram.

Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF 5-BROMO-1-(4'-FLUOROPHENYL) -1, 3- DIHYDRO- ISO BENZOFURAN, AN INTERMEDIATE OF CITALOPRAM

Abstract

This invention discloses an improved process for the preparation of 5-bromo-I-(4- fluorophenyl)-1,3-dihydroisobenzofuran of formula-I, which is useful for the preparation of antidepressant drug citalopram. Process for the preparation of compound of formula- I 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 medium to get the dihydroxy compound (iii) Cyclization of the dihydroxy compound with an acid catalyst in a non-polar solvent system to get the compound offormula-I. The present method avoids the usage of earlier known lithium aluminum hydride reduction method and high vacuum distillation of compound of formula-I in making the antidepressant drug citalopram.

Full Text	The present invention relates to an improved process for the preparation of 5-bromo-l-(4-flurophenyl)-l,3-dihydroisobenzofuran of formula-I and l-(4-flurophenyl)-l,3-dihydro-isobenzofuran-5-carbonitile of formula-II. The present invention particularly relates to an improved process for the preparation of the compound of the formula-I The compounds of the formulae-I & II are key intermediates used in the synthesis of known antidepressant drug l-(3-dimethylaminopropyl)-l-(41-fluorophenyl)-l,3-dihydro-isobenzofuran-5-carbonitrile (citalopram), of the formula-Ill) and its pharmaceutically acceptable acid addition salts thereof. BACKGROUND OF INVENTION The process for the preparation of antidepressant citalopram and its pharmaeeutical properties were 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 3 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-IV is reacted with p-fluorophenylmagnesium bromide to get a benzophenone derivative of the formula formula-V. This benzophenone derivative is reacted with 3-(N, N-dimethylamino) propylmagnesium chloride to get the dihydroxy intermediate of the formula-VI. Cyclization 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. Scheme-1 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. 9- r ,. This compound is reduced with lithium aluminum 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. Scheme-2 . i 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- 5 1 K 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 (CI 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-dimethyIamino) propyl side chain present in citalopram is introduced at an early stage, it is difficult 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 main objective of the present invention is to provide an improved process for the preparation of the intermediates of the formula I which is useful for the preparation of citalopram of the formula HI. Still another objective of the present invention is to provide an improved process for the preparation of the intermediate of the formula I useful for the preparation of citalopram of the formula III which is simple, economical and environmentally safe. Further objective of the present invention is to provide an improved process for the preparation of the formula I 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 compound of formula I, which is useful 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 compound of the formula-I 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 -I0°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 and cyclohexane and the like may be used in the step (ii). The acid catalyst such as p-tolunesulfonic acid, benzenesulfonic acid and sulphuric acid and the like may be used. This simplification has led to the synthesis of the crucial intermediate of the formula-II from the intermediate of the formula-IV in a very simple and easy to adopt manner suitable for any commercial scale. The advantage of the invention is that the compound of the formula-II can be prepared from the intermediate of the formula-I if desired with out isolation, which enhances the yield of the compound of the formula-II. Consequently when the process is employed for the preparation of citalopram further increases the yield of citalopram. In our co-pending application no 157/MAS/01 we have described an improved process for the preparation of citalopram of the formula-Ill based on the invention disclosed in this application. In our co-pending application no 947/MAS/01, which is divided out of our above said co- pending application no 157/MAS/Ol we have described and claimed an improved process for the preparation of compound of the formula II (l-(4"-fluorophenyI)-5-cyanophthalan) based on the present invention. The compound of the formula-II is a key intermediate used for the preparation of citalopram of the formula-HI described and claimed in application no 157/MAS/Ol. In our yet anther co-pending application no 948/MAS/01, which is also divided out of our above said co-pending application no 157/MAS/Ol we have described and claimed an improved process for the preparation of the intermediate of the formula-VIII (4-bromo-2- (hydroxymethyl)phenyl-(4"-fluorophenyl)methanol) based on the present invention. The invention is described in detail in the Example 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-bromophthaIan of the formula-I (a) Preparation of 4-bromo- (2-hydroxymethyl)-phenyl- (41-Huorophenyl) methanol of formula-VHI 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 (lOOgr) 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 HC1 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 p-(oluenesulfonic 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-toluene sulfuric 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. Example 2 Preparation of l-(4-fluorophenyl)-5-bromophthalan of the formula-I " (a) Preparation of 4-bromo- (2-hydroxymethyl)-phenyl- (4J-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 (lOOgr) in tetrahydronjran (600ml) at -10 to 0°C under nitrogen 12- 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 lhr at 10°C, reaction was quenched into dil hydrochloric acid (220ml cone HC1 in 1750ml water). After stirring the reaction mass for 30min, layers were separated. The aqueous r 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 benzenesulfonic 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. Example 3 Preparation of l-(4-fluorophenyl)-5-bromophthalan of the formula-I (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 tetrahydrofuran was added drop wise to a suspension of 5-bromophthalide (lOOgr) 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 200ml of ethanol keeping the temperature below 0°C. After maintaining for lhr at 10°C, reaction was quenched into dil hydrochloric acid (220ml cone HC1 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. "\ yuj JL i cp«i Hiiun ui i-^-nuoropnenyi)-3-DromophthaIan of formula-I using sulfuric acid as a catalyst The crude oily compound (200gr) obtained form Example 1 was dissolved in 1000ml of toluene and lOgr 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 oil. 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. The resulting compound of the formula II is produced in high yield (>90%) and of high purity (>99%) 3. The process is useful for any commercial scale and environmentally safe and economical. We claim, 1. An improved process for the preparation of 5-bromo-l-(4"-fluorophenyl)-l, 3-dihydro-isobenzofuran of formula-I, which is useful for the preparation of citalopram of formula-Ill, comprises: (i) Reduction of the benzophenone derivative of formula- V, with sodium borohydride in the presence of an alcoholic solvent at a temperature in the range of-25°C to 10°C to obtain the compound of formula- VIII, (ii) Reaction of the compound of formula-VIII obtained in step (i) with an acid catalyst in a non-polar solvent to obtain the compound of formula-I, 2 me process as claimed in claim 1 wherein the alcoholic solvent used in step (i) is selected from methanol, ethanol, isopropanol, n-butanol, preferably methanol or ethanol. 3. The process as claimed in claim 1 and 2 wherein the preferred temperature of the reaction in step (i) is between -15°C and 0°C. 4. The process as claimed in claim 1 to 3 wherein the non-polar solvent used in step (ii) is selected from benzene, toluene, xylene, cyclohexane, preferably, benzene, cyclohexane or toluene. 5. The process as claimed in claim 1 to 4 wherein the acid catalyst used in step (ii) is selected from benzenesulfonic acid, p-toluenesulfonic acid, sulfuric acid, preferably, p-toluenesulfonic acid. 6. An improved process for the preparation of 5-bromo-l-(4"-fluorophenyl)-l, 3- dihydro-isobenzofuran of formula-I, useful for the preparation of citalopram substantially as described herein with reference to the Examples 1 to 3, -

Full Text

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

The compounds of the formulae-I & II are key intermediates used in the synthesis of known antidepressant drug l-(3-dimethylaminopropyl)-l-(41-fluorophenyl)-l,3-dihydro-isobenzofuran-5-carbonitrile (citalopram), of the formula-Ill) and its pharmaceutically acceptable acid addition salts thereof.

BACKGROUND OF INVENTION
The process for the preparation of antidepressant citalopram and its pharmaeeutical properties were 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
3

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-IV is reacted with p-fluorophenylmagnesium bromide to get a benzophenone derivative of the formula formula-V. This benzophenone derivative is reacted with 3-(N, N-dimethylamino) propylmagnesium chloride to get the dihydroxy intermediate of the formula-VI. Cyclization 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.

Scheme-1
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.
9-

r ,. This compound is reduced with lithium aluminum 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.

Scheme-2 . i
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-
5

1 K 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 (CI 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-dimethyIamino) propyl side chain present in citalopram is introduced at an early stage, it is difficult 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 main objective of the present invention is to provide an improved process for the preparation of the intermediates of the formula I which is useful for the preparation of citalopram of the formula HI.
Still another objective of the present invention is to provide an improved process for the preparation of the intermediate of the formula I useful for the preparation of citalopram of the formula III which is simple, economical and environmentally safe.
Further objective of the present invention is to provide an improved process for the preparation of the formula I 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 compound of formula I, which is useful 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 compound of the formula-I

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 -I0°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 and cyclohexane and the like may be used in the step (ii). The acid catalyst such as p-tolunesulfonic acid, benzenesulfonic acid and sulphuric acid and the like may be used.
This simplification has led to the synthesis of the crucial intermediate of the formula-II from the intermediate of the formula-IV in a very simple and easy to adopt manner suitable for any commercial scale.
The advantage of the invention is that the compound of the formula-II can be prepared from the intermediate of the formula-I if desired with out isolation, which enhances the yield of the compound of the formula-II. Consequently when the process is employed for the preparation of citalopram further increases the yield of citalopram.
In our co-pending application no 157/MAS/01 we have described an improved process for the preparation of citalopram of the formula-Ill based on the invention disclosed in this application.
In our co-pending application no 947/MAS/01, which is divided out of our above said co-
pending application no 157/MAS/Ol we have described and claimed an improved process
for the preparation of compound of the formula II (l-(4"-fluorophenyI)-5-cyanophthalan)
based on the present invention. The compound of the formula-II is a key intermediate
used for the preparation of citalopram of the formula-HI described and claimed in
application no 157/MAS/Ol.
In our yet anther co-pending application no 948/MAS/01, which is also divided out of our
above said co-pending application no 157/MAS/Ol we have described and claimed an
improved process for the preparation of the intermediate of the formula-VIII (4-bromo-2-
(hydroxymethyl)phenyl-(4"-fluorophenyl)methanol) based on the present invention.

The invention is described in detail in the Example 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-bromophthaIan of the formula-I (a) Preparation of 4-bromo- (2-hydroxymethyl)-phenyl- (41-Huorophenyl) methanol of formula-VHI
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 (lOOgr) 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 HC1 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 p-(oluenesulfonic 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-toluene sulfuric 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.
Example 2
Preparation of l-(4-fluorophenyl)-5-bromophthalan of the formula-I "
(a) Preparation of 4-bromo- (2-hydroxymethyl)-phenyl- (4J-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 (lOOgr) in tetrahydronjran (600ml) at -10 to 0°C under nitrogen
12-

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 lhr at
10°C, reaction was quenched into dil hydrochloric acid (220ml cone HC1 in 1750ml
water). After stirring the reaction mass for 30min, layers were separated. The aqueous r
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 benzenesulfonic 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.
Example 3
Preparation of l-(4-fluorophenyl)-5-bromophthalan of the formula-I
(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 tetrahydrofuran was added drop wise to a suspension of 5-bromophthalide (lOOgr) 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 200ml of ethanol keeping the temperature below 0°C. After maintaining for lhr at 10°C, reaction was quenched into dil hydrochloric acid (220ml cone HC1 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.
"\
yuj JL i cp«i Hiiun ui i-^-nuoropnenyi)-3-DromophthaIan of formula-I using sulfuric acid as a catalyst
The crude oily compound (200gr) obtained form Example 1 was dissolved in 1000ml of toluene and lOgr 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 oil.
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. The resulting compound of the formula II is produced in high yield (>90%) and of high purity (>99%)
3. The process is useful for any commercial scale and environmentally safe and economical.

We claim,
1. An improved process for the preparation of 5-bromo-l-(4"-fluorophenyl)-l, 3-dihydro-isobenzofuran of formula-I,

which is useful for the preparation of citalopram of formula-Ill,
comprises:
(i) Reduction of the benzophenone derivative of formula- V,

with sodium borohydride in the presence of an alcoholic solvent at a temperature in the range of-25°C to 10°C to obtain the compound of formula- VIII,

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

2 me process as claimed in claim 1 wherein the alcoholic solvent used in step (i) is
selected from methanol, ethanol, isopropanol, n-butanol, preferably methanol or ethanol.
3. The process as claimed in claim 1 and 2 wherein the preferred temperature of the
reaction in step (i) is between -15°C and 0°C.
4. The process as claimed in claim 1 to 3 wherein the non-polar solvent used in step (ii)
is selected from benzene, toluene, xylene, cyclohexane, preferably, benzene,
cyclohexane or toluene.
5. The process as claimed in claim 1 to 4 wherein the acid catalyst used in step (ii) is
selected from benzenesulfonic acid, p-toluenesulfonic acid, sulfuric acid, preferably,
p-toluenesulfonic acid.
6. An improved process for the preparation of 5-bromo-l-(4"-fluorophenyl)-l, 3-
dihydro-isobenzofuran of formula-I, useful for the preparation of citalopram
substantially as described herein with reference to the Examples 1 to 3,

-

Documents:

946-mas-2001 abstract.pdf

946-mas-2001 claims.pdf

946-mas-2001 correspondence others.pdf

946-mas-2001 correspondence po.pdf

946-mas-2001 description (complete).pdf

946-mas-2001 form-1.pdf

946mas2001.jpg

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Patent Number

194560

Indian Patent Application Number

946/MAS/2001

PG Journal Number

20/2006

Publication Date

19-May-2006

Grant Date

05-Jan-2006

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

C 07 D 307/78

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA