WO2005066185A1

WO2005066185A1 - Process for preparing 5-substituted -1-(4-fluorophenyl) -1,3-dihydroisobenzofurans

Info

Publication number: WO2005066185A1
Application number: PCT/IN2004/000007
Authority: WO
Inventors: Ambati Narahari Babu; Vuddamari Srinivas Goud; Santosh Laxman Gaonkar; Sulur G. Manjunatha; Ashok Krishna Kulkarni
Original assignee: Jubilant Organosys Limited
Priority date: 2004-01-12
Filing date: 2004-01-12
Publication date: 2005-07-21

Abstract

The present invention relates to a method for preparation and isolation of hitherto unknown solid boron complex of formula (v), which are obtained when 5-substituted phthalides are reacted with a solution of 4-fluorophenylmagnesiumbromide, followed by in situ reduction and complex formation in the presence of sodiumborohydride. Such boron complexes can be conveniently filtered to remove structurally similar impurities and subsequently subjected to cyclisation reaction in acidic medium to get high pure 5-substituted phthalens, which are key starting materials for manufacturing citalopram and pharmaceutically acceptable acid addition salts.

Description

PROCESS FOR PREPARING 5-SUBSTITUTED 1- (4-FLUOROPHENYL) -1 , 3 -DIHYDROISOBENZOFURANS

Field of the invention The present invention relates a method for preparation and isolation of hitherto unknown solid boron complex of formula (V) which are useful in the preparation of 5- substituted phthalens, which are key staring materials for manufacturing citalopram and pharmaceutically acceptable acid addition salts.

Formula (V) 10 Background to the Invention Citalopram and its pharmaceutically acceptable acid addition salts, such as the hydrogen bromide salt shown in Formula 1 below, described in US Patent No. 4,163,193, are valuable anti-depressant drugs with few side effects and have been commercially available for a number of years.

15 Formula 1 Many processes for the manufacture of citalopram and its acid addition salts are disclosed in the literature, from which it is apparent that 5-substituted phthalanes (5-substituted-1-(4-fluorophenyl)-1 ,3-dihydroisobenzofurans of Formulae (2A) and (2B) are very important key intermediates in the manufacture of citalopram.

20 Formula-2A Formula-2B Various processes for the preparation of

5-substituted-1-(4-fluorophenyl)-1 ,3-dihydroisobenzofurans have been described in the prior art, according to Scheme 1 shown below: Scheme 1

A: R = Br; B:R= CN

For example, the process described in US Patent No. 4,163,193 involves the reaction of 4-fluorophenyl magnesium bromide, generated in situ by the reaction of 4-fluorobromobenzene with magnesium in anhydrous diethyl ether solvent medium, with 5-bromophthalide of the Formula (3A) in tetrahydrofuran. After completion of the reaction, the reaction mass is quenched with aqueous ammonium chloride solution, followed by work-up to provide the intermediate 2-hydroxymethyl-4-broιmo-4- fluorobenzophenone hydroxymethyl-ketone of Formula (4A). The hydroxymethylketone of the Formula (4A) is then reduced with lithium aluminium hydride in ether medium to provide 4-bromo-2-hydroxymethylphenyl-(4- fluorophenyl)methanol (diol of Formula 5A). The diol of the Formula (5A) is then cyclized with aqueous phosphoric acid to produce crude 5-bromophthalane (5-bromo- 1-(4-fluorophenyl)-1 ,3-dihydroisobenzofuran of the Formula (2A) having an HPLC purity around 75-80%. The crude 5-bromophthalane is purified by high vacuum distillation at 170-175°C /1 mm Hg to get substantially pure 5-bromophthalane, which is then converted to 5-cyanophthalane (5-cyano-1-(4-fluorophenyl)-

1 ,3-dihydroisobenzofuran of the Formula (2B) by reaction with cuprous cyanide followed by purification. The main drawback of this process is in the handling of diethyl ether at plant level. Diethyl ether is a highly volatile, inflammable solvent having a very low flash point. Hence, efficient recovery and recycling of the solvent at the commercial level is not possible. Furthermore, the handling of lithium aluminium hydride, a highly pyrophoric, moisture-sensitive material is also very difficult at plant level. Therefore, the process is not commercially attractive. Crude 5-bromophthalane is purified through high vacuum distillation at high temperature. However, achieving such a high vacuum in the plant level is difficult. Repeated crystallisation steps are required to get desired quality of 5-cyanophthalane. US Patent No. 6,291 ,689 discloses a process for preparing 5-cyanophthalane

(5-cyano-1-(4-fluorophenyl)-1 ,3-dihydroisobenzofuran of the Formula (2B) in which a solution of 4-fluorophenyl magnesium bromide prepared from 4-bromofluorobenzene and magnesium turnings in dry tetrahydrofuran is added drop-wise to a suspension of 5-cyanophthalide (3B) in dry tetrahydrofuran below 5°C. After 4-fluorophenyl magnesium bromide addition is completed, ethanol is added to the reaction mixture and a large excess of sodium borohydride (2.0 molar equivalents) is added lot-wise to the reaction mixture. The reaction mixture is stirred overnight at room temperature and then about 2/3 of the solvent is removed under vacuum. Water is added to the reaction mixture and the resulting solution is extracted with ethyl acetate. The ethyl acetate is then distilled off under vacuum to provide the crude diol 4-cyano-2- hydroxymethylphenyl-(4-fluorophenyl)methanol of the formula (5B) as an oil. The oil is purified by column chromatography to produce the pure diol of Formula (5B) as a solid. However, the oil as such is cyclised in the presence of 60% phosphoric acid solution at 80°C for 3 hours. The acid solution is then extracted twice with toluene and the organic layer is separated. The combined toluene layer is distilled under vacuum to get the oily residue having HPLC 85-90%. The oily residue is then crystallized in ethanol to produce the pure 5-cyanophthalane of the Formula (2B). The overall yield is

29% from 5-cyanophthalide. The major drawbacks of this process are that: i) an expensive solvent, anhydrous tetrahydrofuran, is used which, under the reaction work-up conditions, is difficult to recover and recycle, thus rendering the process uneconomical; ii) different solvents (e.g. ethyl acetate and toluene) are used at different stages and hence the process becomes commercially unattractive; iii) a large excess of sodium borohydride is used during the reduction stage, making the process potentially dangerous; and iv) repeated crystallisations are required to get desired quality of 5- cyanophthalane PCT publication WO 02/066453 discloses a process for preparing 5- cyanophthalne (5-cyano-1(4-fluorophenyl)-1,3 dihydoisobenzofuran of the Formula 2B, wherein 5-bromophthalide (3A) is reacted with a solution of 4-fluoro phenyl magnesium bromide, prepared from 4-bromo fluorobenzene and magnesium turnings in dry tetrahydrofuran at 0-5°C. 4-fluoro phenyl magnesium bromide addition is completed then reaction mass is diluted with alcoholic solvents like methanol, ethanol and isopropyl alcohol followed by addition of sodium borohydride at 10°C. After completion of the reduction, reaction mass is diluting with aq. hydrochloric acid. The resulting solution is extracted into toluene. The toluene layer is removed under reduced pressure to get oily crude diol compound (5A). The diol compound is subjected to cyclization in the presence of para-toluene sulphonic acid in toluene medium to get 5-bromo-1-(4-fluorophenyl)-1,3 -dihydroisobenzofuran (2A) . The crude5-bromo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran (2A) is subjected to cyanation reaction with copper (I) cyanide in dimethylformamide at 150- 160°C, followed by work up to get crude 5-cyano-1-(4-fluorophenyl)-1 ,3- dihydroisobenzofuran (2B) with HPLC purity of around 80-85%, which is purified in different solvents and mixture of solvents to get pure 5-cyanophthalane (2B). The major drawbacks of this process are that: i) repeated purification steps are required to get desired quality of 5-cyano-1-( 4- fluorophenyl)-1,3-dihydroisobenzofuran from crude 5-cyano-1-(4-fluorophenyl)-1 ,3 dihydroisobenzofuran thus rendering the process uneconomical. The present invention provides a simple procedure for the preparation and isolation of free flowing solid of boron complex of Formula (V) which as it is subjected to cyclization reaction with aqueous hydrochloric acid to produce corresponding 5- substituted phthalanes of Formula (2) with high purity. Summary of the Invention According to the present invention it has now been surprisingly found that solid boran complex of Formula (V)

Formula (V) wherein R is selected from Br; CN; CI; I; NH2 and CO2; can be prepared in good yields, by a process comprising: a) subjecting 5-substitued phthalide of Formula (3) in a solvent to Grignard reaction with a solution containing a 4-fluorophenylmagnesium halides followed by quenching to obtain hydroxymethylketone a compound of Formula (4) in a solvent medium. b) diluting the solvent medium containing said compound of Formula (4) with alcoholic solvents, adding sodiumborohydride to get boron complex of formula (V) c) subjecting said boron complex to cyclization reaction in the presence of an acid to produce 5-substituted phthalnes, which are key starting material for the preparation of citalopram,

wherein R is selected from Br; CN; CI; I; NH2 and CO2 In a preferred embodiment, where the 5-bromo 1-(4-fluorophenyl)-1 ,3-dihydro- isobenzofuran is 5-bromophthalane(2A), the corresponding 5-substituted phthalide is 5-bromophthalide(3A). Similarly, where the 5-cyano 1-(4-fluorophenyl)-1 ,3-dihydro-isobenzofuran is 5-cyanophthalane(2B), the corresponding 5-substituted phthalide is 5- cyanophthalide(3B). Detailed Description of the Invention According to the method of the present invention, it has been surprisingly found that the boron complex of Formula (V) can be prepared in good yields by a Grignard reaction with substituted phthalides (3) in which the molar ratio of 4-fluorophenyl magnesium halide to the 5-substituted phthalide is preferably is 1:1 to 1.4 :1.The solvent is selected from the group of 1 ,4-dioxane, diethylether or dimethoxyethane. and tetrahydrofuran (THF) for generating 4-fluorophenyl magnesiumhalides. The most preferred ether solvent is tetrahydrofuran ( THF). 5-substituted phthalides of the Formula (3) is taken in a solvent selected from the group consisting of aliphatic or aromatic chlorinated solvents or aromatic hydrocarbons. Where the solvent is an aliphatic or aromatic chlorinated solvent, it is selected from the group consisting of methylene dichloride, ethylene dichloride, carbon tetrachloride, chloroform, chlorobenzene, dichlorobenzene, and mixtures thereof. Methylene dichloride and especially chloroform are particularly preferred. As aromatic hydrocarbon co-solvents, toluene, benzene or xylene, or mixtures thereof, are preferred. Toluene is particularly preferred. Particularly preferably, the ether solvent and a solvent medium for 5-substituted phthlides are both dry and suitably, the volumetric ratio of ether solvent to a solvent medium for 5-substituted phthlides is between 3 : 10 and 6 : 7. The lowest proportion of the ether solvent to the solvent medium for 5-substituted phthlides is restricted by the tendency of the Grignard reagent to precipitate out of solution. The Grignard reaction is suitably carried out at a temperature below 10°C, preferably at a temperature from -6°C to +6°C, and most preferably, at a temperature from -6°C to - 2°C. The process comprises boron complex formation, a ketone reduction and step following the Grignard reaction. The reducing agent for the reduction and complex formation is sodium borohydride. Preferably, about 0.25 to about 1.0 molar equivalents of sodium borohydride are used. Particularly, preferably, only about 0.5 molar equivalents of sodium borohydride are used. In this reaction, sodium borohydride is used for reducing ketone and also formation of boron complex of formula (V). The two reactions (reduction, complex formation) are carried out in situ in a single stage. The structurally similar impurities and the starting materials of formula (3) can be removed by filtration to get pure boron complex of Formula (V) which is characterised by NMR spectrum and elemental analysis. The NMR spectrum shows the following peaks at (δ ppm). Solvent is CD3OD; 4.48 -4.73 dd 2H ; 6.07 s 1 H ; 7.04-7.87 m 7H aromatic, and the same compound analysed by elemental analysis shows 3-4% of boron content. Structurally similar impurities are formed during the Grignard reaction of 5- substituted phthalides with 4-fluorophenylmagnesium halide in a solvent medium followed by reduction in the presence of sodiumborohydride. These impurities have high boiling points. The process further comprises carrying out a cyclisation reaction of the boron complex. The cyclization reaction is carried out in presence of an inorganic acid or organic acid. Inorganic acids that may be used include aqueous phosphoric acid and aqueous sulphuric acid, but preferably, aqueous hydrochloric acid, more preferably concentrated hydrochloric acid, is used. Organic acids that may be used include methanesulfonic acid, benzenesulfonic acid and para-toluene sulfonic acid (PTSA). A particularly, preferred organic acid is PTSA. The amount of acid used is suitably a limited amount and preferably is a catalytic amount. In a preferred embodiment of the invention, starting from 5-bromophthalide of Formula (3A), a solution of 4-fluorophenyl magnesium bromide is prepared from 4-bromofluorobenzene, magnesium turnings and catalytic amount of iodine in dry tetrahydrofuran (THF), and is added drop-wise to a suspension of 5-bromophthalide of Formula (3A) in a dry dichloromethane under nitrogen atmosphere at a temperature below 10°C, preferably -6°C to +δ°C, and most preferably -6°C to -2°C, over a period of 4-6 hours. After the addition is completed, the reaction mixture is quenched with 20% aqueous ammonium chloride solution, and the organic layer is separated and diluted with methanol. Then, sodium borohydride (0.5-1.0 molar equivalents, preferably 0.5 molar equivalents) is added lot-wise to the reaction mixture at a temperature of below 25°C and the reaction mixture is further stirred for an additional 2 hours at the same temperature. After the completion of the reaction, the solvent is distilled off completely under reduced pressure to obtain a residue, which is treated with non polar solvents like n-hexane, n-heptane and pentane, (the most preferred non polar solvent being n-hexane) and stirred for 2-3 hours at 0-5°C. The precipitated solid is filtered and washed with n-hexane to obtain pure boron complex of Formula (VA). The above isolated boron complex of formula (VA) is then as such subjected to cyclization reaction in the presence of an inorganic acid or organic acid. A particularly preferred organic acid is para-toluene sulfonic acid (PTSA), and this is suitably used in catalytic amounts. For example, solid boron complex and aqueous hydrochloric acid mixture is heated to 60-70°C for 2-3 hours. After the completion of the reaction, the reaction mass is cooled to room temperature and extracted with an aliphatic or aromatic hydrocarbon, such as n-hexane, cyclohexane, benzene and toluene. The organic layer is washed with dilute sodium hydroxide solution and water. The organic layer is treated with activated charcoal, and concentrated under reduced pressure to provide 5- bromophthalane of the Formula (2A) having a purity of greater than 98% Alternatively and preferably, solid boron complex is suspended in an organic solvent, for example, in toluene, and a catalytic amount of p-toluene sulfonic acid (5- 10% w/w) is added. The resulting mixture is heated to 85-90°C. After the completion of the reaction, the reaction mixture is washed with dilute sodium hydroxide solution, water and finally the solvent is removed under reduced pressure to produce 5-bromophthalane of the Formula (IIA). 5-Bromophthalane of the Formua (2A) can be converted to 5-cyanophthalane (2 B) using known procedures, without any further purification to get pure 5-cyanophthale HPLC having a purity of more than 98%. In a second embodiment, starting from 5-cyanophthalide of Formula (3B), a solution of 4-fluorophenyl magnesium bromide in tetrahydrofuran is added drop-wise over a period of 4-6 hours to a suspension of 5-cyanophthalide of Formula (3B) in a dry dichloromethane under nitrogen atmosphere below 10°C (preferably, -6°C to +6°C, and most preferably, -6°C to -2°C). After the addition of 4-fluorophenyl magnesium bromide is completed, the reaction mixture is quenched with 20% aqueous ammonium chloride solution. The organic layer is separated and diluted with methanol. Then sodiumborohydride (0.5 molar equivalents) is added lot-wise to the reaction mixture below 25°C (suitably 15°C to 20°C) and the reaction mixture is stirred for additional 4-6 hours. The reaction mixture is cooled to below 10°C and the precipitated solid is filtered to produce pure crystalline boron complex with more than 98% purity by HPLC. The crystalline boron complex of Formula (VB) is taken in an organic solvent such as toluene or methanol, preferably toluene, followed by cyclisation in 30% aqueous hydrochloric acid at 65-70°C. After the completion of the reaction, the reaction mass is cooled to 25-30°C and extracted into water immiscible organic solvents such as benzene, toluene, dichloromethane, dichloroethane and ethylacetate. The preferred organic solvent is dichloromethane. The organic layer is treated with activated carbon and concentrated under reduced pressure to get residue. Isopropanol is added to the residue to provide white crystalline 5-cyanophthalane of the Formula (2B) having a purity of more than 99% by HPLC. The cyclisation may also be carried out in toluene using a catalytic amount of p-toluenesulfonic acid (5- 10% w/w with respect to 5-cyanophthalide) to produce 5-cyanophthalane of the Formula (2B). In summary, there are several major advantages of the present invention over the prior art procedures. First, the process allows isolation of hitherto unknown boron complex of Formula-V. Such solid boron complex can be filtered to remove structurally similar impurities, which are formed during the Grignard reaction of 5- substituted phthalides with a solution of 4-fluorophenyl magnesium halides followed by reduction, In other words, these structurally similar impurities are removed by simple filtration, without applying any high vacuum distillation at higher temperature and repeated crystallizations of intermediate stages. Furthermore, using the method of the present invention, 0.50 molar equivalents of sodium borohydride is sufficient to reduce the hydroxyketone of the Formula (4) into boron complex of Formula (V), The present invention will now be described in greater detail with reference to the following examples, which are merely intended to further illustrate the present invention and not to limit the scope thereof:

Example 1 : Process for preparation of 5-cyano phthalane (2B). a) Isolation of Boron complex (VB) from 5-cyanophthalide (2B) A solution of 4-fluorophenyl magnesium bromide prepared from 153.33g 4- fluoro¹ bromobenzene (0.876 moles), 25.33g magnesium turnings (1.055 moles) and 0.05g iodine in dry 300ml tetrahydrofuran, was added to a suspension of 100g 5-cyanophthalide (0.628 moles) in 1000ml methylene dichloride at -6 to -2°C. After the reaction was completed, the reaction mass was quenched with 100ml 20% aqueous ammonium chloride solution. The organic layer was separated and diluted with 100ml of methanol. Slowly, 12g of sodium borohydride (0.324moles) was added over a period of one hour at below 25°C, and the same temperature was maintained for 4-6 hours. The mixture was then cooled to 5-10°C, maintained for 2 hours and then the precipitated boron complex VB solid was filtered. The solid was washed with chilled dichloromethane and dried under vacuum below 40°C to provide pure boron complex. Weight: 115-120g HPLC purity: 98-99% b) Cyclization of the boron complex (VB) Above isolated boron complex of Formula (VB) 100gm was subjected to cyclization in aqueous hydrochloric acid (250ml) at 65-70°C and maintained for 4-5 hours. After completion of the reaction, reaction mass was diluted with 250ml water and then 5-cyanophthalane was extracted into the toluene 2x200ml. The toluene layer is washed with water 100ml and concentrated completely under reduced pressure to get residue, which is diluted with isopropyl alcohol to get 5-cyanophthale as a solid. The solid is filtered and washed with chilled isopropyl alcohol. Weight: 90-95gm HPLC purity: 98-99% Example 2: Process for Preparation of 5-bromophthalane (2A) a) Isolation of boran complex (VA) from 5-bromo phthalide (2A) A solution of 4-fluorophenyl magnesium bromides prepared from 116g 4-fluoro bromobenzene (0.662 moles), 18.81g magnesium turnings (0.78 moles) and 0.05g iodine in dry 300ml tetrahydrofuran was added to a suspension of 100g 5-bromophthalide (0.469 moles) in 1000ml of dichloromethane at -6 to -2°C. After the reaction was completed, the reaction mass was quenched with 100ml 20% aqueous ammonium chloride solution. The organic layer was separated and diluted with 100ml of methanol. Slowly, 12g of sodium borohydride (0.324moles) was added in lots over a period of one hour at below 25°C and the temperature was maintained for additional one hour. The solvent was removed under reduced pressure to get residue. The residue was treated with n-Hexane 500 ml to precipitate boron complex of Formula -

VA as a solid , which was separated by filtration. Weight: 80-85g

Purity by HPLC: 98% b) Cyclization of the boron complex (VA) Above isolated boron complex of Formula (VA) 100gm was subjected to cyclisation in aqueous hydrochloric acid (250ml) at 65-70°C and maintained for 4-5 hours. After completion of the reaction, the reaction mass is diluted with 250ml water

Then 5-cyanophthalane was extracted into the toluene 2x200ml. The toluene layer is washed with water 100ml and concentrated completely under reduced pressure to get oil residue.

Oil weight: 80-85g Purity by HPLC: 98%

Claims

Claims:

1. A compound of the Formula (V) .

Formula (V) wherein R is selected from Br; CN; CI; I; NH2 and CO2.

2. A process for the preparation and isolation of a compound of the Formula (V), which are useful in the preparation of 5 substituted phthalanes (2A)

Formula (V)

wherein R is selected from Br; CN; CI; I; NH2 and CO2, which comprises: a) suspending 5-substituted phthalide of the Formula (3) in a solvent and subjecting it to Grignard reaction with a solution of 4-fluorophenylmagnesiumhalides, followed by quenching with an aqueous acid solution to produce a compound of Formula (4) in a solvent medium; and

Formula-4 b) diluting said compound of Formula (4) with an alcoholic solvent, and adding sodiumborohydride to reduce the ketone and produce solid boron complex of the Formula (V ).

3. A process as claimed in claim 1 wherein said solid boron complex of the Formula (V) is subjected to cyclization reaction in the presence of an acid to produce corresponding 5-substituted phthalanes of the Formula (2) wherein R is selected from Br; CN; CI; I; NH2 and CO2.

4. A process as claimed in claim 2 wherein in step a) said 5-substitued phthalides are taken in a solvent selected from the group consisting of dichloromethane, dichloroethane, chloroform, carbontetrachloride, benzene, toluene, chlorobenzene and xylene, most preferred solvent is dichloromethane.

5. A process as claimed in claim 2 or 3 wherein in step a), said solution of 4- fluorophenylmagnesium bromide said solution of 4-fluorophenylmagnesium halide is selected from 4-brom-1-fluorobenzene and, 4-bromo-1- chloro benzene.

6. A process as claimed in any one of claims 2 to 5, wherein in step b), said alcoholic solvent groups are selected from methanol, ethanol and isopropyl alcohol.

7. A process as claimed in any one of claims 2 to 6 wherein in step c), said a solid boron complex is filtered.

8. A process for the preparation of 5-substituted phthalanes, which comprises cyclizing a boron complex of the Formula (V ) having the following structure

wherein R is selected from Br and CN, in the presence of acidic medium to get corresponding 5-substituted phthalanes.

9. A process for the preparation _vof 5 substituted phthalanes of the Formula (2A)

wherein R is selected from Br; CN; CI; I; NH2 and CO2, which comprises: a) suspending 5-substituted phthalide of the Formula (3) in a solvent and subjecting it to Grignard reaction with a solution of 4-fluorophenylmagnesiumhalides, followed by quenching with an aqueous acid solution to produce a compound of Formula (4) in a solvent medium;

Formula-4 b) diluting said compound of Formula (4) with an alcoholic solvent, and adding sodiumborohydride to reduce the ketone and produce solid boron complex of the Formula (V ); and c) subjecting said solid boron complex of the Formula (V ) to cyclization reaction in the presence of an acid to produce corresponding 5-substituted phthalanes of the Formula (2). wherein R is selected from Br; CN; CI; I; NH2 and CO2.