Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF FLUCONAZOLE

Abstract

This application discloses an improved process for the preparation of Fluconazole which comprises (i) acylating 1,3-difluorobenzene with chloroacetylchloride in presence of anhydrous aluminium chloride without using any solvent to obtain 2-chloro-2',4'-difluoroacetophenone and alkylating with 4-amino-4H-l,2,4-triazole in methanol as solvent to obtain 2-(4-amino-1,2,4-triazole-l-yl)-2\4'-difluoroacetophenone salt and deamination by conventional methods resulting 2-(lH-l,2,4-triazole-l-yl -2',4'-difluoroacetophenone reaction 2-(lH-2,4-triazole-l-yl)-2\4' difluoroacetophenone with trimetylsulphoxonium iodide, and lH-l,2,4-triazole in presence of aqueous base to give technical grade Fluconazole. Purifying the formed technical Fluconazole by using acid/base in the presence of organic solvent or solvents to give pure Fluconazole purity >99.0%.

Full Text

This invention relates to an improved process for the preparation of Fluconazole. Fluconazole which is 2-(2,4-difluorophenyl)-l,3-bis(lH-l,2,4-triazole-l-yl)-propan-2-ol and is an antifungal agent developed by Pfizer Inc. Fluconazole is therefore useful for treating various fungal infections such as mycohemis , mycosis ( both in the respiratory system and digestive system), and fungal meningitis, which are caused by, among others, various species of Candida coccidodes and trichophyton. Fluconazole inhibits the biosynthesis of ergosterol an important component of fungal cell membrane. The inhibition is highly specific to ergosterol biosynthesis in fungi. There are quite a number of processes known for the preparation of Fluconazole. For example process for the preparation of Fluconazole and its intermediates can be found in the following patents. CN1353108 (2002) discloses a process for the preparation of Fluconazole which involves the reaction of 2"Chloro-2',4'-difluoroacetophenone with 1,2,4-triazole produced insitu by thermal reaction of formamide , formic acid and hydrazine hydrate. The yields are lower because of the formation of an isomer due to the attack of 4-position of 1,2,4-triazole produced insitu with 2-chlorO"2',4'-difluoroacetophenone to give 2-(4H-.l,2,4-triazole-l-yl)-2',4'-difluoroacetophenone. WO02076955 (2002) The patent deals in the reaction of 2-(2,4-difluorophenyl)-2,3-epoxypropyl-lH-l,2,4-triazole with l-(trimethylsilyl)-l,2,4-triazole and 1,2,4-triazole-l-yl sodium to give 2-(2,4-difluorophenyl)-l,3-bis( 1,2,4-triazole-l-yl)-2-(trimethylsilyl-oxy)propane.Hydrolysing the silyl ether with aqueous methanol ,isopropylalcohol etc.) to give Fluconazole. This process mainly focuses on the modification of crystal structure of Fluconazole. The process is expensive because of the use of the expensive (l-trimethylsilyl)-l,2,4-triazole and 1,2,4-triazole-l-yl sodium. TW457239 (2001) discloses a process which involves the reaction of 2-chloro-2\4'-difluoroacetophenone with hydrazinehydrate to give hydrazone derivative. The hydrazone derivative is then cyclised with S-triazine to give 2 -(1H-1,2,4-triazole-1 -yl)-2' ,4' -difluoroacetophenone. This process is also expensive because of the use of the expensive S-triazine to cyclise the hydrazone derivative to 1,2,4-triazole derivative. In addition, the process is also hazardous because of the requirement of handling of the toxic hydrazinehydrate. US PATENT NO, 6063933(2000) deals with the preparation of 2-(2,4-difluoropheny)-l,3.bis-(lH-triazole-l-yl)-2,3-epoxypropane by the oxidation of the E-isomer of 1,3-bis-(lH-1,2,4-triazole-l-yl)-2-(2,4-difluorophenyl)-l-propene in methylene chloride, water and potassium carbonate with m-chloroperbenzoic acid. The epoxy derivative is further reacted in terahydrofurane with lithium aluminium hydride to give Fluconazole. m-Chlororperbenzoic acid, tetrahydrofurane, lithium aluminium hydride are expensive and hazardous chemicals . The process is therefore not commercially economical. US PATENT NO 5872258(1999) describes the formation of Fluconazole via the use of 3-(lH-1,2,4-triazole-1 -yl)-2-(2,4-difluorophenyl)-1 -propene. The preparation of starting material involves four steps from 1,3-difluorobenzene. The first step is the reaction of 1,3-difluorobenzene with isopropylalcohol and cone. Sulphuric acid to give 2-(2,4-difluorophenyl)-propane. The second step is bromination with N-bromosuccinamide to give l,2-dibromo-2-(difluorophenyl)-propane. The third step is reaction of second step product with 1,2,4-triazole to give the mixture of E and Z isomer of the starting material . The mixture of isomers are separated in the fourth step. The propene derivative is oxidized with potassium permangnate to give 2-(2,4-difluorophenyl)-2,3-dihydroxypropyl-1H-1,2,4-triazole in only 27% yield. This dihdroxy derivative is further reacted with sulphuryl chloride. Lot of effluents are generated in the oxidation step with potassium permangnate due to the formation of manganese dioxide .Sulfuryl chloride is expensive and hazardous. Therefore the process is not economical and not environment friendly. EP0967210(1999) deals with the manufacture of Fluconazole by the reaction of 2-(lH-l,2,4-triazole-l-yl)-2',4'-difluoroacetophenone with dihalomethane in the presence of samarium-(ll) iodide at -25 degree centigrade. The availability of samarium iodide commercially is difficult and quite expensive and also the reaction is carried out at very low temperature i.e. -25 degree centigrade, which makes the process expensive at commercial scale. CNl 126722(1996) discloses a process for the preparation of 2-(2,4-difluorophenyl)-2,3-epoxypropyl-lH-l,2,4-triazole and its purification as methanesulphonate salt. The process involves the conversion of 1,3 -difluorobenzene to 2-( 1H-1,2,4-difluorophenyl)-2' -4' -difluoroacetophenone in three steps using standard procedure. This product is reacted with trimethyl sulfoxonium iodide in aqueous base to give crude 2-(2,4-difluorophenyl)-2,3-epoxypropyl-lH-l,2,4-triazole. This is then purified by reacting with methanesulphonyl chloride in organic solvent. The epoxy derivative is converted to Fluconazole by standard procedure. The process is lengthy due to the isolation and purification of epoxy derivative and hence not economical. JP PATENT NO. 8217761(1996) deals with the preparation of 2-(lH-l,2,4-triazole-l-yl)-2\4'-difluoroacetophenone by the reaction of 2-chloro-2\4'-difluorophenyl acetophenone with 4-amino-l,2,4-triazole in solvent of straight or branched chain alcohol of 4 or more carbon atoms such as n-butanol. The product is extracted with water in combination with n-hexane. The aqueous phase is directly subjected to deamination treatment with sodium nitrite and hydrochloric acid. The solvent n-butanol is expensive and is lost at deamination step. The process is therefore expensive. Further the patent only deals in the preparation of 2-(lH-l,2,4-triazole4-yl) 2',4'-difluoroacetophenone which is an intermediate and also is not economical. 1112492211(1995) describes the reaction of 2"(2,4-difluorophenyl>l-bromo-3-(lH-l,2,4-l-yl)-2-propanol with 4-amino-l,2,4-triazole to give 2-(2,4-difluorophenyl)-l-(lH-l,2,4-triazole-l-yl)-3-(4H-4-amino-l,2,4-triazonium-l-yl)-2-propanol bromide. This salt is then deaminated using standard process to give crude Fluconazole, which is purified by recrystallising from isopropyl alcohol. The preparation of starting material is as per (i) the reported in literature (Synthesis 647,1983). The process involves the use of Grignard reaction of difluorobenzene magnesium bromide with 1,3-dichloroacetone or (ii) reaction of (lH-l,2,4-triazole-l) methyl magnesium chloride with 2-chloro-2',4'-difluoro-acetophenone. Both the processes are not safe because of handling of sensitive Grignard reactions. The product obtained by these processes are highly expensive due to use of expensive solvents such as tetrahydrofurane and also the alkyl halide used for making grignard reagents are either not available commercially or expensive . Hence the process is not economical. US PATENT NO 5710280(1998) describes a five step process starting from 1,3-difluorobenzene, The first step is formation of 2-chloro-2,4-difluoroacetophenone from 1,3-difluorobenzene ,chloroacetyl chloride via Friedel craft acylation in presence of methylene chloride as solvent. The second step is reaction of 2-chloro-2',4'-difluoroacetophenone with 4-aminO"l,2,4-triazole in acetonitrile ,and the product is filtered and dried . The third step is the deamination by standard procedure where the product is filtered and dried. Fourth step is the reaction of third step product with trimethyl sulphoxonium iodide, 1,2,4-triazole in aqueous base to give crude Fluconazole. The crude Fluconazole is recrystallised from ethylacetate/n-haxane. There is use of methylenechloride at first step and acetonitrile at second step. Methylenechloride is chlorinated solvent which is not preferred solvent, acetonitrile on decomposition emits highly toxic fumes of cyanide and nitriles. Therefore methylene chloride and acetonitrile are not most preferred solvents for handling and environmental safety. Moreover both these solvents are expensive and methylene chloride is low boiling solvent hence huge amount of losses at commercid level. The above process has the following drawbacks: (a) The use of methylene chloride at the acylation step of 1,3-difluorobenzene with chloroacetyl chloride in the presence of aluminium trichloride as the catalyst makes the process uneconomical .This is because methylene chloride is not only an expensive solvent but also has low boiling point, which results in huge amount of losses during work up. (b) Conversion of 2-chloro-2\4'-difluoroacetophenone(CAP) to 2-(4-amino-l,2,4-triazole-l-yl)- 2\4'-difluoroacetophenone salt (TAAP) by reaction of CAP with 4-amino-4H-1,2,4- triazole (4AT) using acetonitrile as the solvent. Acetonitrile is also expensive and there are heavy losses during filtration and drying. Moreover acetonitrile is not very good solvent handling wise. Therefore it would be advisable to avoid the use acetonitrile in the commercially applicable process Therefore the process is not only economical for commercial application but also not environmentally safe. OBJECTIVES OF THE INVENTION Consideringtheimportanceof the drug Fluconazole commercially it is felt that if an improved process which is not only economical but also enviroimientally friendly is developed it would be useful and beneficial to the society. Accordingly the main objective of the present invention is to provide an improved process for the preparation of Fluconazole which is economical by providing one pot reaction using only two steps including purification. Another objective of the present invention is to provide an improved process for the preparation of Fluconazole which is environmentally safe by avoiding use of solvents such as methylene chloride, acetonitrile etc. Still another objective of the present invention is to provide an improved process for the preparation of Fluconazole which is environmentally safe by the use of methanol as the solvent for condensation with 4H-amino-l,2,4-triazole instead of earlier reported solvents like acetonitrile, n-butanol & isopropanol. Yet another objective of the present invention is to provide an improved process for the preparation of Fluconazole in which the acylation of 1,3-difluorobenzene with chloro acetyl chloride is carried out without using any solvent thereby making the process economical, simple and safe The present invention has been developed based on our finding after a sustained research & development work that (i) by avoiding the use of methylenechloride in the step of preparing 2-chloro-2,4-difluoroacetophenone in step(i), and in step(ii) using methanol as the solvent in the reaction of 2-chloro-2',4'-difluoroacetophenone with 4-amino-l,2,4-triazole to give 2-(4-amino-l,2,4-triazole-l-yl)-2\4'-difluoroacetophenone. The separated salt is extracted in ethylacetate, or toluene or their mixture. The solvent is recovered under vacuum and the residue is reacted with trimethyl sulfoxonium iodide, l(H)-l,2,4-tria2ole in presence of base to give technical Fluconazole. The technical Fluconazole is purified by dissolving in dil. hydrochloric acid, treating with activated carbon. To the filtered solution, adding mixture of solvent, ethylacetate, acetone, and methanol and then adjusting pH to neutral with aqueous base. Pure Fluconazole separates which is filtered and dried, DETAILED DESCRIMTION OF IPJVENTION The present invention provides an improved process for the preparation of Fluconazole which comprises of acylating 1,3-difluorobenzene with chloroacetylchloride in the presence of anhydrous aluminium chloride with out using any solvent at a temperature in the range of 55 to 70°C, decomposing the resulting reaction mixture in water containg ethylacetate or toluene or their mixture to obtained 2-chloro-2',4'-difluoro acetatophenone after recovering ethylacetate or toluene or their mixture. The 2-chloro-2',4'-difluoroacetophene is alkylated with 4-amino-4H-1,2,4-triazole in the presence of methanol as solvent to obtain 2-(4-amino-l,2,4-triazole -1-yl)-2',4'-difluoroacetophenone salt in solution. The methanol is recovered by distillation under vacuum to give residue which is dissolved in hydrochloric acid and the solution is deaminated using sodium nitrite to obtain 2-(lH-l,2,4-triazole-l-yl)-2'4'-difluoroacetophenone which is extracted Avith ethylacetate or toluene or their mixture. The ethylacetate, toluene, or their mixture is recovered by distillation under vacuum, to give residue. The residue is reacted with trimethylsulfoxoniumiodide (TMSI) and lH-l,2,4-triazole in presence of an aqueous base. The ratio of trimethyl sulfoxoniumiodide(TMSI),l(H)-l,2,4-triazole,base to 1,3-difluorobenzene is 1:1.9:0.82 : 1.2 respectively. The pH of the reaction mixture is adjusted to neutral with dil. Hydrochloric acid The separated product is filtered and dried which is technical Fluconazole. The technical Fluconazole is purified by dissolving in dil. hydrochloric acid, treating the resulting solution with activated carbon, filtering over celite, adding a mixture of ethylacetate, acetone and methanol in the ratio ranging from 0.5 to 0.75 :0.5 to 0.75:0.05 to 0.2 respectively, adjusting the pH of the resulting solution to neutral with aqeous base to give pure Fluconazole (purity >99.0%) The process of the present invention is an one pot reaction, The details are given below: 1,3-Difluorobenzene is acylated according to Friedel-Crafts acylation using chloroacetylchloride in the presence of anhydrous aluminium chloride. This reaction is carried out without using any solvent . The completion of the reaction completion is monitored on Gas chromatograph and the absence of l,3-difluoroben2ene in the reaction mixture is checked. The reaction mixture is then quenched in toluene or ethylacetate or mixture. The recovery of solvent gives 2-chloro-2',4'-difluoroacetophenone ( CAP) in nearly quantitative yield The CAP so prepared is reacted with 4H-amino-l,2,4-triazole in methanol as the solvent. The quantity of methanol to be used may be preferably two to six times of the quantity of 1,3-difluorobenzene or more preferably two to four times or still more preferably about two times . The reaction may be conducted at a temperature in the range of 60-70 degree centigrade for about 3-24 hours, preferably 10-18 hours or ore preferably for about 12hours. The completion of the reaction is checked by thin layer chromatography. The unused methanol is recovered and the residue is dissolved in dilute . hydrochloric acid . The solution is subjected to deamination by conventional methods . The 2-(lH-l,2,4-triazole-l-yl )-2\4'-difluoroacetophenone formed is extracted in toluene or ethylacetate or their mixture . The organig layer is separated and the residue after the solvent recovery so obtained is reacted with trimethylsulfoxoniumiodide(TMSI), l,2,4-triazole(AT) and aqueous base as reported in US Pat.NO. 5710280 or mixture of solvent such methanol, isopropyl alcohoI,t-butanol,acetonitrile,dimethylformamide,dimethylsulphoxide as reported in W098/32744. The reaction is worked up by recovering the organic solvent, addition of water and adjusting pH to neutral with aqueous base. The separated technical Fluconazole is filtered and dried( purity more than 95% by HPLC). The technical Fluconazole so prepared is purified by dissolving in dil hydrochloric acid and mixed with solvents like ethylacetate , acetone ,and methanol or their mixtures in then ratio ranging from 0.5 to 0.75 : 0.5 to 0.75 : 0.05 to 0.2 based on the input of technical Fluconazole . The selection of the above said solvents are made based on the impurity profile of the technical Fluconazole produced. The impurities as determined on HPLC can be (a) the impurities after main peak of Fluconazole (b) the impurities before the main peak of Fluconazole. The impurities falling within the category (a) are removed / reduced by employing a mixture of ethyl acetate and acetone in the above said proportions and the impurities falling within the category (b) are removed / reduced by employing methanol in the above mentioned proportions . Accordingly the combination of the above said solvents in the above said proportions removes / reduces the impurities resulting in a product (Fluconazole) having purity in the range of 99 to 99.8% The pH of the clear solution is adjusted to neutral to give pure Fluconazole (purity more than 99to99.8%byHPLC It is believed that one skilled in the art can based on description given herein utilise the present invention to its fullest extent. Accordingly the example given below is only for the purpose of illustration only and therefore it should not be construed to limit the scope of the present invention. EXPERIMENTAL STEP -1 Preparation of technical grade Fluconazole Aluminium trichloride (anhydrous) 129.0 gms. was added to 1,3-difluorobenzene lOO.Ogms. Chloroacetylchloride (104.0 gms.) was added slowly to the resulting solution while stirring at about 20 degree centigrade. The reaction mixture was slowly heated to a temperature in the range of 55-60 degree centigrade during a period in the range of 3-5 hours. The completeion of the reaction was checked on gas chromatograph . When the reaction mixture was devoid of 1,3-difluorobenzene ,. the reaction mixture was cooled to below 10 degree centigrade and was added to cold water 500ml and ethylacetateSOOml. Organic layer is separated, and was washed with sodium bicarbonate solution and dried. . The organic layer was concentrated and proceeded further by addition of methanol 200mls and 4H-amino-l,2,4-triazole 80.0 gms. The reaction mixture was refluxed at about 70 degree centigrade. The reaction completion was checked on thin layer chromatography. After the completion of reaction the imused methanol was recovered under vacuum and to the residue dil. hydrochloric acid lOOOmls. was added To the above solution sodium nitrite 53.0 gms. in water 300mls. was added slowly at below 10 degree centigrade. Potassium carbonate was added to adjust the pH to neutral. Ethylacetate 500mls.was added and stirred for 30mins. The organic layer is separated and concentrated, the residue dissolved in water and potassium hydroxide 120.0 gms trimethylsulfoxonium iodide 190.0 gms and lH-l,2,4-triazole 82.0 gms. were added. The reaction mixture was stirred at below 35 degree centigrade. The reaction completion was checked on thin layer chromatography. The pH of the reaction mixture was adjusted to neutral with dil. hydrochloric acid to give technical Fluconazole. Yield 140.0 gms.( purity 95.0% by HPLC ). Step - 2 Purification of technical Fluconazole Technical Fluconazole 140.0 gms prepared according to the process described in step 1 above was dissolved in dil. hydrochloric acid. The solution was treated with activated carbon 10.0 gms and filtered over celite. To the clear colourless solution a mixture of ethylacetate, acetone and methanol in the ratio of 0.5: 0.5: 0.05 was added . The pH of solution was adjusted to neutral with aqueous ammonia give pure Fluconazole. Yield 100.0 gms. (purity 99.0 %by HPLC) • Advantages of the present invention 1. The process is an one pot reaction which eliminates the steps of isolation of intermediates, purification and drying thereby making the process economical 2. The process is far more effective than a process of step-by-step(stepped) preparation which enhances the capacity (Yield) )of manufacture. 3. The process does not employ any solvent in the step of acylation of 1,3-difluorobenzene with chloroacetylchloride 4. The product is extracted in toluene or ethylacetate or mixture. After recovery of solvent the residue is proceeded for condensation with 4H-amino-l,2,4-triazole.The condensation is carried out in methanol instead of earliar reported solvents like acetonitrile, n-butanol, isopropanol etc. which makes the process economical and safe 5. The benefits of methanol in comparision to other solvents being: (a) It is by far the cheapest solvents amongst all the other solvents used so far. (b) It is easy to recycle. (c) The TAAP salt is soluble in methanol as compared to other solvents where TAAP salt is insoluble. (d) The quantity of solvent required is nearly half than the other solvents. (e) The time taken to complete the reaction is also less. (f) The methanol is recovered and the residue is taken for deamination. 6. Purification process is simple and more economical We claim: 1) An improved process for the preparation of Fluconazole which comprises of acylating 1,3-difluorobenzene with chloroacetylchloride in the presence of anhydrous aluminium chloride with out using any solvent at a temperature in the range of 55 to 70°C, decomposing the resulting reaction mixture in water containg ethylacetate or toluene or their mixture to obtained 2-chloro-2',4'-difluoro acetatophenone after recovering ethylacetate or toluene or their mixture. The 2-chloro-2\4'-difluoroacetophene is alkylated with 4-amino-4H-1,2,4-triazole in the presence of methanol as solvent to obtain 2-(4-amino-l,2,4-triazole -1-yl)-2',4'-difluoroacetophenone salt in solution. The methanol is recovered by distillation under vacuum to give residue which is dissolved in hydrochloric acid and the solution is deaminated using sodium nitrite to obtain 2-(lH-l,2,4-tria2ole"l-yl)-2'4'-difluoroacetophenone which is extracted with ethylacetate or toluene or their mixture. The ethylacetate, toluene, or their mixture is recovered by distillation under vacuum, to give residue. The residue is reacted with trimethylsulfoxonixmiiodide (TMSI) and lH-l,2,4-triazole in presence of an aqueous base. The ratio of trimethyl sulfoxoniumiodide(TMSI),l(H)-l,2,4-triazole,base to 1,3-difluorobenzene is 1:1.9:0.82 : 1.2 respectively. The pH of the reaction mixture is adjusted to neutral with dil. Hydrochloric acid. The separated product is filtered and dried which is technical Fluconazole. The technical Fluconazole is purified by dissolving in dil hydrochloric acid, treating the resulting solution with activated carbon, filtering over celite, adding a mixture of ethylacetate, acetone and methanol in the ratio ranging from 0.5 to 0.75 :0.5 to 0.75:0.05 to 0.2 respectively, adjusting the pH of the resulting solution to neutral with aqeous base to give pure Fluconazole (purity >99.0%) 2. An improved process as claimed of claim 1 wherein the quantity of methanol to be used is two to six times of the quantity of 1,3-difluorobenzene , more preferably two to four times or still more preferably about two times . 3. An improved process as claimed in claim 1 wherein the alkylation reaction of 2-chloro-2',4'" difluoroacetophenone with 4-amino-4H-1,2,4 triazole is conducted at a temperature in the range of60-70 degree centigrade for about 3-24 hours, preferably 10-18 hours or more preferably for about 12hours. 4..An improved process as claimed of claims 1 to 3 is carried out without isolating the 2-(lH-l,2,4-triazole-l-yl)-2\4'-difluoroacetophenone salt formed. 5. An improved process for the preparation of Fluconazole substantially as herein described with reference to the Example

Documents:

705-che-2003-abstract.pdf

705-che-2003-claims duplicate.pdf

705-che-2003-claims original.pdf

705-che-2003-correspondnece-others.pdf

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705-che-2003-description(complete) duplicate.pdf

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705-che-2003-form 1.pdf

705-che-2003-form 19.pdf