Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF 4-(4-FLUOROBENZOYL) BUTYRIC ACID

Abstract

ABSTRACT The present invention' provides an improved process for the preparation of 4-(4-fluorobenzoyl)butyric acid of formula-I, useful for the preparation of anti-hyperlipoproteinemetic drug ezetimibe with the desfluoro impurity at <0.1% level comprising (a) adding a solution of fluorobenzene, glutaric anhydride and halogenated solvent to a mixture of aluminum chloride, fluorobenzene and halogenated solvent at a temperature in the range of 10-25 °C (b) maintaining the reaction temperature in the range of 10-25 °C for a period of 2-4hr (c) pouring the reaction mixture into a 5-15% (w/w) hydrochloric acid below 10 °C (d) distilling the halogenated solvent at atmospheric pressure for its recovery (e) filtering and washing the residue with the same halogenated solvent used in step (a) above to obtain the compound of the formula-I (f) purifying the compound of the formula-I by dissolving it in aqueous base and precipitating the product by acidification after giving a carbon treatment to the basic solution (g) isolating the precipitated compound of formula-l by filtration, and (h) recrystallizing the purified acid from a single or mixture of solvents. The above process is commercially viable.

Full Text

INTRODUCTION The present invention relates to an improved process for the preparation of 4-(4-fluorobenzoyi)butyric acid. The 4-(4-fluorobenzoyl)butyric acid has the formula-l given be10w. The 4-(4-fluorobenzoyl)butyric acid has the formula-I is a key raw material for the synthesis of anti-hyperlipoproteinemetic drug ezetimibe (US 5767115, Schering). The main criticality in making the compound of formula-I lies in controlling the desfluoro ana10gue impurity (4-benzoylbutyric acid) at an acceptable level ( BACKGROUND OF THE INVENTION In the literature only two procedures are known for the preparation of compound of formula-I. In the first procedure reported by Compernolle (Tetrahedron, 49, 3193, 1993) fluorobenzene is reacted with glutaric anhydride under Friedel-Crafts conditions using aluminium ch10ride at 0°C to get the compound of formula-I in 78% yield. The reaction is done in methylene ch10ride medium. In this procedure reaction was done on a 15gr glutaric anhydride scale. The quality of final product with respect to impurities is not addressed in this reference. The main drawbacks in this procedure are: 1. Temperature of the reaction (0°C) is not suitable for scale up operations. At 0°C aluminum ch10ride-glutaric anhydrde complex is not soluble in the medium and a thick mass (difficult to stir by mechanical stirrer) will form. Because of improper mixing quality and yield of the product is 10w. 2. Quenching of Friedel-Crafts reaction by adding water or acid to the reaction mass is difficult on a larger scale. 3. Quality of fluorobenzene used in the process is not mentioned. This is very critical to get an acceptable quality of compound of formula-I with respect to desfluoro ana10gue impurity. In the second route (US patent, 6,207,822) for the synthesis of compound of formula-I, fluorobenzene is used as a solvent-cum-reagent in the Friedel-Crafts acylation with glutaric anhydride. The yield of compound of the formula-I reported in this procedure is 79%. The reaction is done at 5-12°C. The main disadvantages in this process are: 1. It requires high quality (benzene content in fluorobenzene should be less than 100ppm) fluorobenzene to get acceptable quality compound of formula-I. 2. Availability of high quality fluorobenzene is limited for emp10ying the process on a commercial scale. 3. Price of high quality fluorobenzene is almost 4 times higher than the normal quality (benzene content is 300-700ppm) fluorobenzene. Normal quality fluorobenzene is abundantly available in the market. Keeping in view of the above mentioned difficulties in implementing the above routes for making compound of formula-I on a commercial scale, we directed our research work to deve10p a simple, convenient, and economical process for the preparation of compound of formula-I which can also be utilized on a commercial scale The main objective of the present invention is, therefore, to provide an improved process for the preparation of compound of formula-I as defined above overcoming all the disadvantages present in the hitherto known processes. Another objective of the present invention is to provide an improved process for the preparation of compound of formula-I as defined above which is simple and economical. Another objective of the present invention is to provide an improved process for the preparation of compound of formula-I as defined above which does not have any mixing problem when the process is used on any scale of operation. Another objective of the present invention is to provide an improved process for the preparation of compound of formula-I as defined above which does not have reaction quenching problem when the process is used on any scale of operation. Still another objective of the present invention is to provide an improved process for the preparation of compound of formula-I as defined above which does not require high quality fluorobenzene. Another objective of the present invention is to provide an improved process for the preparation of compound of formula-I as defined above which does not require fluorobenzene as solvent medium to carry out the Friedel-Crafts reaction. SUMARY O INVENTION In our preliminary studies in the course of the R&D towards deve10pment of an improved process for the preparation of compound of formula-I as defined above we found that benzene is more reactive (about 5 times) than fluorobenzene in the above mentioned Friedel-Crafts acylation. This indicates that benzene present in fluorobenzene will react faster than fluorobenzene. Considering this observation we found that (i) by adjusting the ratio of fluorobenzene with regard to the glutaric anhydride used, (ii) dividing the amount of fluorobenzene used into two parts - one a10ng with glutaric anhydride and another part with the ha10genated solvent and (iii) fixing the quantity of the ha10genated solvent used, a process cab be deve10ped for the preparation of compound of the formula-I as defined above which overcomes the drawbacks of the hitherto known processes described above. Further the process deve10ped can also be useful for any commercial scale production of the said compound of the formula-I. The reaction can be conducted at a convenient temperature range of 10 to 25°C. Accordingly, the present invention provides an improved process for the preparation of compound (4-4(fluorobenzoyl)butyric acid) of the formula-I which comprises: (a) Preparing a solution of normal quality fluorobenzene, glutaric anhydride and ha10genated solvent, the amount of fluorobenzene used being in a molar ratio of 0.5 to 0.7 molar equivalent with regard to the amount of glutaric anhydride used. (b) Preparing a mixture of aluminum ch10ride, normal quality fluorobenzene and ha10genated solvent, the amount of fluorobenzene used being in a molar ratio of 0.5 to 0.6 molar equivalent with regard to the amount of glutaric anhydride used and the amount of ha10genated solvent used being at least 4-6 times (w/v) with regard to the amount of glutaric anhydride used. (c) Adding the solution obtained in step (a) to the mixture obtained in step (b) at a temperature in the range of 10 to 25°C. (d) Maintaining the resulting reaction mixture at a temperature in the range of 10 to 25°C for a period in the range of 2 to 4hrs. (e) Pouring the reaction mixture into cold dilute hydroch10ric acid. (f) Distilling the ha10genated solvent at atmospheric pressure for its recovery. (g) Filtering and washing the residue with the same ha10genated solved used in step (b) above to obtain the compound of the formula-I. (h) Purifying the compound of the formula-I by dissolving it in aqueous base and precipitating the product by acidification after giving a carbon treatment to the basic solution, (i) Isolating the precipitated compound of formula-I by filtration and if desired (j) Recrystallizing the purified acid from a single or mixture of solvents. The normal quality of fluorobenzene used in step (a) refers to the impurity level of benzene. The benzene content in fluorobenzene may be between 300-700ppm. The ha10genated solvent used in step (b) may be selected form methylene ch10ride, ethylene dich10ride, 1,1,2,2-tetrach10roethane. The base used in step (h) may be selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, and ammonia. The acid used in step (h) may be selected from hydroch10ric acid, hydrobromic acid, sulfuric acid, acetic acid, and propionic acid. The solvent used for recrystallization in step (j) may be selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, acetonitrile, methanol, ethanol, ethyl acetate, hexane or a mixture of these solvents. The details of the invention are described in Examples given be10w which are provided to illustrate the invention only and therefore should not be construed to limit the scope of the present invention. Example 1 Preparation of 4-(4-fluorobenzoy)lbutyric acid of formula-I using fluorobenzene (benzene content 300ppm) with methylene ch10ride as solvent: Into a 3L three-necked RB flask were charged 500ml of methylene ch10ride, 250gr of aluminum ch10ride and 45gr of fluorobenzene (benzene content 300ppm) under nitrogen atmosphere. The reaction mixture was cooled to 10°C and a solution of 100gr of glutaric anhydride, 45gr of fluorobenzene (benzene content 300ppm) and 500ml of methylene ch10ride was added s10wly over a period of 3hrs between 10-15°C. The reaction mixture was maintained for another one hour at the same temperature. The reaction mixture was s10wly poured onto a mixture of crushed ice (700gr) and cone. HCl (300ml) be10w 10°C. The reaction mass temperature was al10wed to reach 25°C and methylene ch10ride distilled off from the reaction mixture be10w 50°C. After cooling the reaction mixture to 20°C, solids were filtered off and washed with 500ml of water. The wet cake thus obtained was suspended in 250-300ml of methylene ch10ride and filtered. The solid compound was dissolved in 600ml of 4% sodium hydroxide, treated with 10gr of activated charcoal and fihered. The filtrate was acidified with cone. HCl and the precipitated acid was filtered. After washing the wet cake with 500ml of water, it was dissolved in 500ml of acetone. The acetone solution was s10wly cooled to 15-20°C and the solid filtered, washed with chilled acetone (50ml) and dried at 50-70°C to get 122gr of white crystalline soUd, m.p. 143°C. Purity by HPLC is 99.65%. Desfluoro impurity is less than 0.05%. Example 2 Preparation of 4-(4-fluorobenzoy)lbutyric acid of formula-I using fluorobenzene (benzene content 500ppm) with methylene ch10ride as solvent: Into a 3L three-necked RB flask were charged 500ml of methylene ch10ride, 250gr of aluminum ch10ride and 45gr of fluorobenzene (benzene content SOOppm) under nitrogen atmosphere. The reaction mixture was cooled to 10°C and a solution of 100gr of glutaric anhydride, 45gr of fluorobenzene (benzene content SOOppm) and SOOml of methylene ch10ride was added s10wly over a period of 3hrs between 10-1 S°C. The reaction mixture was maintained for another one hour at the same temperature. The reaction mixture was s10wly poured onto a mixture of crushed ice (700gr) and cone. HCl (300ml) be10w 10°C. The reaction mass temperature was al10wed to reach 25°C and methylene ch10ride distilled off from the reaction mixture be10w SO°C. After cooling the reaction mixture to 20°C, solids were filtered off and washed with SOOml of water. The wet cake thus obtained was suspended in 2S0-300ml of methylene ch10ride and filtered. The solid compound was dissolved in 600ml of 4% sodium hydroxide, treated with 10gr of activated charcoal and fihered. The filtrate pH was adjusted to 1.0-2.0 with cone. HCl and the precipitated acid of formula-l was filtered. After washing the wet cake with SOOml of water, it was dissolved in SOOml of acetone. The acetone solution was s10wly cooled to 15-20°C, maintained for 2h, and the solid filtered, washed with chilled acetone (50ml) and dried at 50-70°C to get 120gr of white crystalline solid of formula-I, m.p. 143-143.5°C. Purity by HPLC is 99.7%. Desfluoro impurity is less than 0.05%. Example 3 Preparation of 4-(4-fluorobenzoy)lbutyric acid of formula-I using fluorobenzene (benzene content 700ppm) with methylene ch10ride as solvent: Into a 3L three-necked RB flask were charged 500ml of methylene ch10ride, 250gr of aluminum ch10ride and 45gr of fluorobenzene (benzene content 700ppm) under nitrogen atmosphere. The reaction mixture was cooled to 10°C and a solution of 100gr of glutaric anhydride, 45gr of fluorobenzene (benzene content TOOppm) and 500ml of methylene ch10ride was added s10wly over a period of 3hrs between 10-15°C. The reaction mixture was maintained for another one hour at the same temperature. The reaction mixture was s10wly poured onto a mixture of crushed ice (700gr) and cone. HCl (300ml) be10w 10°C. The reaction mass temperature was al10wed to reach 25°C and methylene ch10ride distilled off from the reaction mixture be10w 50°C. After cooling the reaction mixture to 20°C, solids were filtered off and washed with 500ml of water. The wet cake thus obtained was suspended in 250-300ml of methylene ch10ride and filtered. The solid compound was dissolved in 600ml of 4% sodium hydroxide, treated with 10gr of activated charcoal and filtered. The filtrate pH was adjusted to 1.0-2.0 with cone. HCl and the precipitated acid of formula-I was filtered. After washing the wet cake with 500ml of water, it was dissolved in 500ml of acetone. The acetone solution was s10wly cooled to 15-20°C, maintained for 2h, and the solid filtered, washed with chilled acetone (50ml) and dried at 50-70°C to get 123gr of white crystalline solid of formula-I, m.p. I43°C. Purity by HPLC is 99.6%. Desfluoro impurity is less than 0.05%. Example 4 Preparation of 4-(4-fluorobenzoy)lbutyric acid of formula-I using fluorobenzene (benzene content 500ppm) with ethylene dich10ride as solvent: Into a 3L three-necked RB flask was charged ethylene dich10ride (500ml), aluminum ch10ride (250gr) and fluorobenzene (45gr) under nitrogen atmosphere. The reaction mixture was cooled to 10°C and a solution of glutaric anhydride (100gr), fluorobenzene (45gr) and ethylene dich10ride (500ml) was added s10wly over a period of 3hrs between 10-15°C. After maintaining for one hour at 15-18°C the reaction mixture was s10wly poured onto a mixture of crushed ice (700gr) and cone. HCl (300ml) be10w 10°C. The reaction mass temperature was raised to reach 25 °C and distilled off ethylene dich10ride from the reaction mixture be10w 100°C. After cooling the reaction mixture to 20°C, crude solid was filtered off and washed with 500ml of water. The wet cake thus obtained was suspended in 300ml of ethylene dich10ride and filtered. The solid compound was dissolved in 600ml of 4% sodium hydroxide, treated with 15gr of activated charcoal and filtered. The filtrate was acidified to pH 1.5-2.0 with cone. HCl and the precipitated acid was filtered. After washing the wet cake with 500ml of water, it was dried at 60-70°C to get 130gr of white solid, m.p. 140-142°C. This solid was dissolved in 500ml of acetone. The acetone solution was s10wly cooled to 15-20°C and the solid filtered, washed with chilled acetone (50ml) and dried at 50-70°C to get 120gr of white crystalline solid, m.p. 143°C. Purity by HPLC is 99.65%. Desfluoro impurity is less than 0.05%. Advantages of the present invention: 1. (a) By adjusting the ratio of fluorobenzene with regard to the glutaric anhydride used (b) divding the amount of fluorobenzene used into two parts - one a10ng with glutaric anhydride and another part with the ha10genated solvent and (c) conducting the Friedel-Crafts acylation at 10-20°C, the process can be made applicable to any scale of operation. 2. By using ha10genated solvent in the reaction, quality of required fluorobenzene could be relaxed to normal quality to make the process economical. 3. High quality compound of formula-I could be produced using normal quality fluorobenzene. We Claim: 1. An improved process for the preparation of 4-(4-fluorobenzoyl)butyric acid of formula-I, (a) adding a solution of fluorobenzene, glutaric anhydride and halogenated solvent, the amovmt of fluorobenzene used being in a molar ratio of 0.5 to 0.7 molar equivalent with regard to the amount of glutaric anhydride used to a mixture of aluminum chloride, fluorobenzene and halogenated solvent, the amount of fluorobenzene used being in a molar ratio of 0.5 to 0.6 molar equivalent with regard to the amount of glutaric anhydride used at a temperature in the range of 10-25 °C (b) maintaining the reaction temperature in the range of 10-25 °C for a period of 2-4hr (c) pouring the reaction mixture into a 5-15% (w/w) hydrochloric acid below 10 °C (d) distilling the halogenated solvent at atmospheric pressure for its recovery (e) uiltering and washing the residue with the same halogenated solvent used in step (a) above to obtain the compound of the formula-I (f) purifying the compound of the formula-I by dissolving it in aqueous base and precipitating the product by acidification after giving a carbon treatment to the basic solution (g) isolating the precipitated compound of formula-l by filtration, and (h) recrystallizing the purified acid from a single or mixture of solvents. 2. An improved process for the preparation of compound of formula-I as claimed in claim 1 wherein the benzene content in fluorobenzene used in step (a) is of 300- 700ppm, preferably between 300-500ppm. 3. An improved process for the preparation of compound of formuia-I as claimed in claims 1 & 2 wheirein the halogenated solvent used in step (a) is selected from methylene chloride, ethylene dichloride, 1,1,2,2-tetrachloroethylene, preferably methylene chloride or ethylene dichloride. 4. An improved process for the preparation of compound of formula-I as claimed in claims 1 to 3 wherein the quantity of halogenated solvent used in step (a) is 6 to 10 times (w/v) on glutaric anhydride, preferably 8 to 10 times. 5. An improved process for the preparation of compound of formula-I as claimed in claims 1 to 4 wherein the preferred temperature defined in step (a) and step (b) is between 10-20°C, more preferably between 12-18°C. 6. An improved process for the preparation of compound of formula-I as claimed in claims 1 to 5 wherein the base used in step (f) is selected from ammonia, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, preferably ammonia or sodium hydroxide. 7. An improved process for the preparation of compound of formula-I as claimed in claims 1 to 6 wherein the acid used in step (f) is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, propionic acid, preferably hydrochloric acid or sulfuric acid. 8. An improved process for the preparation of compound of formula-I as claimed in claims 1 to 7 wherein the solvent used in step (g) for recrystallizing the purified compound of formula-I is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, acetonitrile, methanol, ethanol, ethyl acetate, hexane or a mixture of these solvents, preferably acetone, toluene, hexane/ ethyl acetate. 9. An improved process for the preparation of compound 4-(4-fluorobenzoyl)butyric acid of formula-I as defined above substantially as herein described with reference to the Examples.

Documents:

0427-mas-2002 abstract duplicate.pdf

0427-mas-2002 abstract.pdf

0427-mas-2002 claims duplicate.pdf

0427-mas-2002 claims.pdf

0427-mas-2002 correspondence-others.pdf

0427-mas-2002 correspondence-po.pdf

0427-mas-2002 description (complete) duplicate.pdf

0427-mas-2002 description (complete).pdf

0427-mas-2002 form-1.pdf

0427-mas-2002 form-19.pdf

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