Title of Invention	AN IMPROVED PROCESS FOR THE PREPARATION OF 4-BROMO-2-(HYDROXYMETHLY) PHENYL-(4'-FLUOROPHENLY) METHANOL, AN INTERMEDIATE OF CITALOPRAM
Abstract	This invention discloses an improved process for the preparation of 4-bromo- (2- hydroxymethyl)-phenyl-(4'-fluorophenyl) methanol of formula-VIII, which is useful for the preparation of citalopram. Process for the .preparation of compound of formula- vrn comprises: (i) Reaction of 5-bromophthalide with p-fluorophenylmagnesiuln bromide in tetrahydrofuran medium at -25°C to +l00C to get a benzophenone derivative (ii) Reduction of the benzophenone derivative (without isolation) "With sodium borohydride in alcoholic solvent medium at -20°C to soC to get the dihydroxy compound offormula~ VIII. This simplification of process led to the avoidance of isolation of benzophenone derivative and use of lithium aluminum hydride in the process.

Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF 4-BROMO-2-(HYDROXYMETHLY) PHENYL-(4'-FLUOROPHENLY) METHANOL, AN INTERMEDIATE OF CITALOPRAM

Abstract

This invention discloses an improved process for the preparation of 4-bromo- (2- hydroxymethyl)-phenyl-(4'-fluorophenyl) methanol of formula-VIII, which is useful for the preparation of citalopram. Process for the .preparation of compound of formula- vrn comprises: (i) Reaction of 5-bromophthalide with p-fluorophenylmagnesiuln bromide in tetrahydrofuran medium at -25°C to +l00C to get a benzophenone derivative (ii) Reduction of the benzophenone derivative (without isolation) "With sodium borohydride in alcoholic solvent medium at -20°C to soC to get the dihydroxy compound offormula~ VIII. This simplification of process led to the avoidance of isolation of benzophenone derivative and use of lithium aluminum hydride in the process.

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 procesgfor the preparation of 4-bromo-(2-hydroxymethyl) phenyl-(4"-fluorophenyl)methanol of formula-VIII. The process for the preparation of antidepressant citalopram and its pharmaceutical 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 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-fluorophenyl-magnesium bromide to get a benzophenone derivative of the formula-V. This benzophenone derivative is reacted with 3-N,N-dimethyiaminopropylmagnesium chloride to get the dihydroxy intermediate of the formula-VI. Cyclization 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 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-1. The bromo group is replaced with a cyano group and alkylated with the required side chain to get the citalopram base. Bogeso (EP 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 appUcation 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, i 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 resuhing 5-substituted dihydroisobenzofliran 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 resuhing 1,3-dihydroisobenzofuran derivative to the corresponding 5-cyano compound, i.e. citalopram. « International patent application no WO 99/030548 discloses a process for the preparation of citalopram wherein cyano group was introduced from the corresponding 5-aldehyde analogue of citalopram. t 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 formulae-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 re-crystallization 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. STATEMENT OF INVENTION 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 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-VIII, which is useful for the preparation of citalopram of the formula-Ill. Still another objective of the present invention is to provide an improved process for the preparation of the intermediate of the formula-I usefiil for the preparation of citalopram of the formula-Ill, which is simple, economical and environmentally safe. Yet another objective of the present invention is to provide an improved process for the preparation of intermediates of the formula-I, which is useful for the preparation of citalopram avoiding the introduction of 3-(dimethylamino) propyl side chain present in citalopram at an early stage. Further objective of the present invention is to provide an improved process for the preparation of intermediate 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. (ii) Reducing the benzophenone derivative of formula-V with sodium borohydride in the presence of a protic solvent to get the compound of formula-VIII. The temperature of the Grignard reaction may be in the range of-25°C to 0°C and the solvent may be tetrahydrofliran. The reduction 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, isopropyl alcohol, n-butanol, t-butanol, and the like. This simplification has led to the synthesis of the crucial intermediates of the formulae-I&II from the compound of the formula-IV in a very simple and easy to adopt manner suitable for any commercial scale. In our co-pending and main application no 157/MAS/Ol we have described and claimed an improved process for the preparation of compound of formula III, l-(3-dimethylaminopropyl)-1-(4"-fluorophenyl)-1,3-dihydro-isobenzofuran-5-carbonitrile (citalopram) based on the present invention. In our co-pending application no 946/MAS/Ol, 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 the compound 5-bromo-l-(4"-fluorophenyl)-l, 3-dihydro-isobenzofuran of the formula-I based on the present invention. The compound of formula-I is a key intermediate used for the preparation of citalopram of the formula-Ill described and claimed in our co-pending application no 157/MAS/Ol. In our yet another co-pending application no 947/MAS/Ol, 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 compound, l-(4"-fluorophenyl)-l,3-dihydro-isobenzofuran-5-carbonitrile of formula-II based on the present invention. The compound of the formula-II is a key intermediate used for the preparation of citalopram of the formula-III described and claimed in our co-pending application no 157/MAS/Ol. 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 4-bromo- (2-hydroxymethyl)phenyI-(4"-fluorophenyl) methanol of formula-VIII The Grignard solution prepared from 90gr of 4-fluorobromobenzene and 13gr magnesium turnings in 450ml of tetrahydrofliran was added drop wise to a suspension of 5-bromophthalide (lOOgr) 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 300ml of isopropyl alcohol keeping the temperature below 10°C. After maintaining for Ihr at 10°C, reaction was quenched into dilute hydrochloric acid (220ml cone, hydrochloric acid 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. Example 2 Preparation of 4-bromo-(2-hydroxymethyl) phenyi-(4"-fluorophenyl)methanol of formula-VIII The Grignard solution prepared from 90gr of 4-fluorobromobenzene and 13gr magnesium turnings in 450ml of tetrahydrofliran was added drop wise to a suspension of 5-bromophthalide (lOOgr) 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 dilute hydrochloric acid (220ml cone, hydrochloric acid 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. Example 3 Preparation of 4-bromo- (2-hydroxymethyl)phenyl- (4"-fluorophenyI)methanol of formula-VIII The Grignard solution prepared from 90gr of 4-fluorobromobenzene and 13gr magnesium turnings in 450ml of tetrahydrofiaran was added drop wise to a suspension of 5-bromophthalide (lOOgr) in tetrahydrofiaran (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 Ihr at 10°C, reaction was quenched into dilute hydrochloric acid (220ml cone, hydrochloric acid 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. ADVANTAGES OF THE PRESENT INVENTION: 1. Replacing lithium aluminium hydride with sodium borohydride is very much cost effective and free of any hazardous nature. 2. The resulting compound of the formula-VIII is produced in high yield (>90 %). 3. The process is usefiil for any commercial scale and environmentally safe and economical. We Claim: 1. An improved process for the preparation of 4-bromo-(2-hydroxymethyl)phenyl-(4"-fluorphenyl)methanol of the formula-VIII, (ii) Reducing the benzophenone derivative of formula-V with sodium borohydride in the presence of an alcoholic solvent at -25°C to +10°C to get the dihydroxy compound of formula-VIII, (iii) Isolating the compound of formula-VIII by extracting into toluene and distilling off the solvent below 60°C. 2. A process as claimed in claim 1 wherein the temperature of the Grignard reaction is between -25°C to -10°C, preferably, between -20°C to -15°C. 3. A process as claimed in claim 1 and 2 wherein the temperature of the reduction step is-" between -20°C to 5°C, preferably, -15°C to 0°C 4) A process as claimed in claim 1 to 3 wherein the alcoholic solvent used in reduction itep is selected from methanol, ethanol, isopropyl alcohol, n-butanol, t-butanol, )referably, methanol or ethanol, most preferably methanol. 5). An improved process for the preparation of 4-bromo-(2-hydroxymethyl)phenyl-(4"-luorphenyl)methanol of the formula-VIII useful for the preparation of citalopram ;ubstantially as described herein with reference to the 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 procesgfor the preparation of 4-bromo-(2-hydroxymethyl) phenyl-(4"-fluorophenyl)methanol of formula-VIII.

The process for the preparation of antidepressant citalopram and its pharmaceutical 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 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-fluorophenyl-magnesium bromide to get a benzophenone derivative of the formula-V. This benzophenone derivative is reacted with 3-N,N-dimethyiaminopropylmagnesium chloride to get the dihydroxy intermediate of the formula-VI. Cyclization 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 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-1. The bromo group is replaced with a cyano group and alkylated with the required side chain to get the citalopram base.

Bogeso (EP 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 appUcation 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, i
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 resuhing 5-substituted
dihydroisobenzofliran 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 resuhing 1,3-dihydroisobenzofuran derivative to the corresponding 5-cyano compound, i.e. citalopram.

«
International patent application no WO 99/030548 discloses a process for the preparation
of citalopram wherein cyano group was introduced from the corresponding 5-aldehyde
analogue of citalopram. t
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 formulae-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 re-crystallization 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.
STATEMENT OF INVENTION
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 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-VIII, which is useful for the preparation of citalopram of the formula-Ill.
Still another objective of the present invention is to provide an improved process for the preparation of the intermediate of the formula-I usefiil for the preparation of citalopram of the formula-Ill, which is simple, economical and environmentally safe.
Yet another objective of the present invention is to provide an improved process for the preparation of intermediates of the formula-I, which is useful for the preparation of

citalopram avoiding the introduction of 3-(dimethylamino) propyl side chain present in citalopram at an early stage.
Further objective of the present invention is to provide an improved process for the preparation of intermediate 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.

(ii) Reducing the benzophenone derivative of formula-V with sodium borohydride in the presence of a protic solvent to get the compound of formula-VIII.
The temperature of the Grignard reaction may be in the range of-25°C to 0°C and the solvent may be tetrahydrofliran.
The reduction 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, isopropyl alcohol, n-butanol, t-butanol, and the like.
This simplification has led to the synthesis of the crucial intermediates of the formulae-I&II from the compound of the formula-IV in a very simple and easy to adopt manner suitable for any commercial scale.
In our co-pending and main application no 157/MAS/Ol we have described and claimed an improved process for the preparation of compound of formula III, l-(3-dimethylaminopropyl)-1-(4"-fluorophenyl)-1,3-dihydro-isobenzofuran-5-carbonitrile (citalopram) based on the present invention.
In our co-pending application no 946/MAS/Ol, 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 the compound 5-bromo-l-(4"-fluorophenyl)-l, 3-dihydro-isobenzofuran of the formula-I based on the present invention. The compound of formula-I is a key intermediate used for the preparation of citalopram of the formula-Ill described and claimed in our co-pending application no 157/MAS/Ol.
In our yet another co-pending application no 947/MAS/Ol, 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 compound, l-(4"-fluorophenyl)-l,3-dihydro-isobenzofuran-5-carbonitrile of formula-II based on the present invention. The

compound of the formula-II is a key intermediate used for the preparation of citalopram of the formula-III described and claimed in our co-pending application no 157/MAS/Ol.
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 4-bromo- (2-hydroxymethyl)phenyI-(4"-fluorophenyl) methanol of formula-VIII
The Grignard solution prepared from 90gr of 4-fluorobromobenzene and 13gr magnesium turnings in 450ml of tetrahydrofliran was added drop wise to a suspension of 5-bromophthalide (lOOgr) 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 300ml of isopropyl alcohol keeping the temperature below 10°C. After maintaining for Ihr at 10°C, reaction was quenched into dilute hydrochloric acid (220ml cone, hydrochloric acid 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.
Example 2
Preparation of 4-bromo-(2-hydroxymethyl) phenyi-(4"-fluorophenyl)methanol of formula-VIII
The Grignard solution prepared from 90gr of 4-fluorobromobenzene and 13gr magnesium turnings in 450ml of tetrahydrofliran was added drop wise to a suspension of 5-bromophthalide (lOOgr) 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 dilute hydrochloric acid (220ml cone, hydrochloric acid 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.

Example 3
Preparation of 4-bromo- (2-hydroxymethyl)phenyl- (4"-fluorophenyI)methanol of formula-VIII
The Grignard solution prepared from 90gr of 4-fluorobromobenzene and 13gr magnesium turnings in 450ml of tetrahydrofiaran was added drop wise to a suspension of 5-bromophthalide (lOOgr) in tetrahydrofiaran (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 Ihr at 10°C, reaction was quenched into dilute hydrochloric acid (220ml cone, hydrochloric acid 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.
ADVANTAGES OF THE PRESENT INVENTION:
1. Replacing lithium aluminium hydride with sodium borohydride is very much cost effective and free of any hazardous nature.
2. The resulting compound of the formula-VIII is produced in high yield (>90 %).
3. The process is usefiil for any commercial scale and environmentally safe and economical.

We Claim:
1. An improved process for the preparation of 4-bromo-(2-hydroxymethyl)phenyl-(4"-fluorphenyl)methanol of the formula-VIII,

(ii) Reducing the benzophenone derivative of formula-V with sodium borohydride in the presence of an alcoholic solvent at -25°C to +10°C to get the dihydroxy compound of formula-VIII,

(iii) Isolating the compound of formula-VIII by extracting into toluene and distilling off the solvent below 60°C.
2. A process as claimed in claim 1 wherein the temperature of the Grignard reaction is between -25°C to -10°C, preferably, between -20°C to -15°C.
3. A process as claimed in claim 1 and 2 wherein the temperature of the reduction step is-" between -20°C to 5°C, preferably, -15°C to 0°C
4) A process as claimed in claim 1 to 3 wherein the alcoholic solvent used in reduction itep is selected from methanol, ethanol, isopropyl alcohol, n-butanol, t-butanol, )referably, methanol or ethanol, most preferably methanol.
5). An improved process for the preparation of 4-bromo-(2-hydroxymethyl)phenyl-(4"-luorphenyl)methanol of the formula-VIII useful for the preparation of citalopram ;ubstantially as described herein with reference to the Examples 1 to 3.

Documents:

0948-mas-2001 abstract.jpg

0948-mas-2001 abstract.pdf

0948-mas-2001 claims.pdf

0948-mas-2001 correspondence-others.pdf

0948-mas-2001 correspondence-po.pdf

0948-mas-2001 description (complete).pdf

0948-mas-2001 form-1.pdf

948.jpg

« Previous Patent

Next Patent »

Patent Number

194950

Indian Patent Application Number

948/MAS/2001

PG Journal Number

08/2007

Publication Date

23-Feb-2007

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

PCT International Classification Number

N/A

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA