Title of Invention

AN IMPROVED PROCESS FOR THE SYNTHESIS OF 2-(2,4-DIFLUOROPHENYL)-1,3-BIS(1H-1,2,4-TRIAZOL-1-YL)PROPAN-2-OL

Abstract

An improved for the synthesis of fluconazole comprising reacting the compound of formula II(X=F)with trimethyl sulphoxonium iodide in presence of alkali metal hydroxide and phase transfer catalyst in a solvent combination of toluence and water;isolating the resulting oxirane compound of Formula III and reacting the oxirance compound with 1,2,4 triazole of Formula IV with alkali metal hydroxide in presence of polar aprotic solvent used in molar amounts ranges from about 1.00 to2.0,thereby limiting the formation of impurities to obtain fluconazole in good yield.

Full Text

FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule!3) 1. TITLE OF THE INVENTION: An improved process for the synthesis of 2- (2,4-difluorophenyl)-l,3-bis (1H-1, 2,4-triazol-l-yl) propan-2-ol 2. APPLICANT (S) (a) NAME: IPCA LABORATORIES LTD. (b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: 48, Kandivli Industrial Estate, MumbaMOO 067 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed. Field of invention This invention relates to an improved process for the synthesis of 2-(2,4-difluorophenyl)-1,3-bis (lH=-l,2,4-triazol-l-yl) propan-2-ol in higher yield by limiting the formation of impurities. Background of the Invention Fluconazole has been widely used as effective anti-fungal agent in the clinical field. The chemical name of fluconazole is 2-(2,4-difluorophenyl)-l,3-bis (lH-l,2,4-triazol-l-yl) propan-2-ol and is expressed by Formula I. Formula I The GB2078719 describes ("719 patent) very effective fungicide compounds having substantial plant growth regulating effect, illustrated by Formula IA. Formula IA According to a subsequent United States patent No. 4404216 ("216 patent) the compound 2-(2,4-diflourophenyl)-l,3-bis (l,2,4-triazol-l-yl)-propan-2-ol (Fluconazole - Formula I) belonging to the above group can be used as human fungicide too. Fluconazole is one among other very effective human fungicide drug in the market. The "719 patent disclosed two routes for the synthesis of compound of Formula IA. The first process (scheme 1) involves reacting an oxirane (where X illustrates chlorine atoms only). 2 compound of Formula III with 1,2,4-triazole of Formula IV or its sodium salt in presence of a base like potassium carbonate or sodium hydride at a temperature of 20 to 100°C under anhydrous conditions. Scheme 1 Formula II Formula III Formula IA A second alternative process (Scheme 2) was provided by reacting a compound of Formula V (where X illustrates Chlorine atoms only) with 1, 2, 4-triazole (or sodium triazolate) in presence of a base. Formula V Formula IV The process for the synthesis of active substance, fluconazole, described in the United States patent ("216 patent) uses the compound of Formula III or Formula V (where X is Fluorine) and 1,2,4-triazole as the starting materials, but same bases (potassium carbonate or sodium 3 hydride) were used in the reaction at a temperature ranging from 50° to 100° C in anhydrous conditions. In both cases as above, according to "216 patent, two isomers were observed namely Formula I and Formula VI (also referred as isofluconazole) in the product mixture. In "216 patent it was stated that, "the product will generally be contaminated with the isomer in which one of the triazole rings is attached to the adjacent CH2 via the 4-position". The product is contaminated with a large amount of fluconazole isomer (Formula VI), which necessitates exhaustive purification procedures such as column chromatography to isolate the desired product from the side product isofluconazole. Formula VI The reason for this behavior of reaction is that the reactant 1,2,4 - triazole exists in two tautomeric forms namely, 1 - H isomer and A-H isomer. This isomeric problem resulted in lack of regio - specificity in the fluconazole synthesis, as described in "216 patent, and leads to the following disadvantages: i) Incomplete reaction with potassium carbonate; ii) Low overall yield; (42 %) iii) Requirement for tedious work up and purification procedures; iv) Use of sodium hydride, which is not plant friendly base. Subsequently, Bauer et al. reported an improved one-pot synthesis of Fluconazole in Journal of Heterocyclic Chemistry 1993 starting from Formula II as shown in the Scheme 3. 4 Scheme 3: (CH3)3SOI KOH, Triazole X Formula II (X = F) According to this method, the mixture of two compounds of Formula II (X = F) and IV were refluxed for 24 hours in the presence of trimethylsulfoxonium iodide (shown in Scheme 3) and potassium hydroxide in tertiary butanol to give Fluconazole.Unlike the conventional prior arts, the above manufacturing process comprises one-step reaction starting from the intermediate of Formula II that is performed under a mild condition. Accordingly a production yield of 38% was observed in this reaction but was contaminated with many impurities namely, compound of Formula VI (isofluconazole), Formula VIII (one of the fluorine atom is replaced by triazole) and the diol of Formula VII. Higher amount of isofluconazole still remains a major problem. Here again, not only this process requires additional purification to get a product of desired purity, the reaction also takes minimum 24 hours for completion. Formula VII Formula VIII 5 In an improved version of the above prior art, United States patent No. 5710281 talks about carrying out an alternative one pot reaction, in reaction media like water or polar aprotic solvent such as dimethyformamide or dimethylsulphoxide. In this process the production yields are slightly higher (44%1238-MUM-2004-FORM 2 [TITLE PAGE]) and the formation of impurity of Formula VIII was reduced to about 2-3%. On the contrary the isomer formation due to the lack of regio-selectivity was increased to about 19 to 20% (HPLC area % based on Fluconazole formed in the reaction) and the reaction took even longer time for completion (40 hours). The impurity formation (impurities of Formula VI, VII, and VIII) still remained a major problem in the Fluconazole synthesis. Apart from the above discussed prior art, various other synthetic routes were also reported. (United States patent No. 5710280, CA2150884, W09832744, EP0618198, RU2163804, WO9620181, US6063933, WO9744330, WO9507895, US5707976, CA2051281, ES2049663, ES8605753, ES8604939, ES8604940, ES8604934, CN1353108). Although the chemistry involved in these reported synthetic routes are not too difficult but involves new reactants or intermediates or adds the number of stages to make them industrially not viable. These synthetic processes also use 1,2,4-triazole as the reactant in the final fluconazole preparation resulting in the formation of isofluconazole. The "216 and "719 patents direct the use of potassium carbonate or sodium hydride as base in the reaction of oxirane (Formula III) and triazole (Formula IV) in anhydrous conditions. It is observed that those reactions using a weaker base like potassium carbonate does not go to completion as per the teaching from the said patents. Also isomeric impurity (Formula VI) is about 15% (HPLC area %). When a base like sodium hydride is used in the reaction in N, N-dimethylformamide, we found higher amount of other impurities are formed in the reaction in an amount of 12% to 44%, variable depending on the temperature of reaction. Moreover the number of impurities and the amount at which these are formed in fluconazole synthesis makes it very difficult to get satisfactory yields of product of pharmaceutical quality. 6 Sodium hydride handling on plant scale requires special arrangement making it costly and unfriendly on plant scale. This led the present inventors to find suitable conditions for improving the yield of fluconazole by limiting the formation of impurities in the reaction. The present inventors surprisingly found that Fluconazole can be obtained in significantly higher yield and better purity, which is the subject of the present invention, wherein very common and economical base is used and the product is free of impurity of Formula VIII. Objective of the present invention It is an objective of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art or to provide a useful alternative. It is an object of the present invention in its preferred form to provide an improved industrial process for preparation of fluconazole in high yield and pharmaceutically acceptable purity by reducing the formation of impurities normally associated in the prior processes. Other objectives include 1) Development of a process wherein the generation of impurities of Formula VIII and the diol of Formula VII are substantially free or considerably low. 2) Development of a high throughput conditions for production of Fluconazole by methods and reagents safer on an industrial scale-up point of view. 3) Reduction of time cycle of reaction, thereby reducing overheads of production expenses. Summary of the invention Accordingly, an improved process for the synthesis of Fluconazole is provided by reacting oxirane of Formula III (X =F) with 1, 2,4-triazole of Formula IV, in presence of an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide in conditions effective to give the following advantages such as better regio-selectivity; reducing the formation of diol of Formula VII, 7 free from compound of Formula VIII and increased yields. In the preferred embodiment of the present invention, the reaction is effected at a temperature of 60 to 65°C in presence of sodium hydroxide in presence of polar aprotic solvents especially dimethylforrnamide wherein oxirane of Formula III (X = F), 1,2,4-triazole and sodium hydroxide are in a molar amounts ranging from about 1.0 : 1.5 : 1.5 to 1.0 : 2.0 : 2.0 respectively, thereby limiting the formation of isofluconazole in the reaction to a level of 11 to 12% (based on HPLC area percentage of Fluconazole produced in the reaction). In another aspect of the present invention there is provided a high throughput process for the formation of oxirane of Formula III (X = F). In a preferred embodiment, the said process involves reaction of compound of Formula II (X = F) with trimethylsulphoxonium iodide in presence of sodium hydroxide and a phase-transfer catalyst in a solvent combination of toluene and water wherein the compound of Formula II (X - F) and trimethylsulphoxonium iodide are at a molar ratio of about 1.25 to about 1.50. The isolated compound of Formula V has a purity of at least 94% (By HPLC) with an isolated yield of 85%. The present process provides high reaction rates with minimal impurity generation, easy isolation of intermediate and product in high purity. Detailed description of the invention The production of Fluconazole by conventional methods reported in the prior art resulted in poor yields. The main reasons being, the formation of isomeric impurity resulting from 1,2,4-triazole that existed in two tautomeric forms namely \-H tautomer and 4-H tautomer as shown below and various other impurities. The reported reaction conditions resulted into higher proportions of a regioisomer of Fluconazole namely isofluconazole (Formula VI) in large amounts except in European 8 patent No.0618198 where the 4-position of triazole was blocked by an amino group. Now both the regio-isomers namely fluconazole and isofluconazole have almost identical properties, and resulted into problems in isolation of Fluconazole from its isomer. Also, the reaction reported in the one-pot reaction according to scheme 3 (United States patent No. 5710280) in water as a solvent resulted into: 1) opening of the epoxide ring to give an impurity of Formula VII (diol), and 2) knockout of one of the Fluorine atom from the 4-position of the starting material of Formula II(X = F) resulting into major impurity of Formula VIII by substitution of triazole ring at 4-position. This results when the starting material of Formula II(X = F) and triazole are present together in presence of base in the reaction. Attempts to remove the impurity of Formula VIII to get a pharmaceutically acceptable purity resulted in very poor yield of Fluconazole. This necessitates the isolation of oxirane (Formula III) and then reacting with triazole. According to the present invention, there is provided an efficient process for the isolation of higher purity oxirane of Formula III (X = F) in high throughput reaction conditions without forming a methanesulfonate salt. Accordingly compound of Formula II (X = F) was reacted with trimethylsulphoxonium iodide in presence of alkali metal hydroxide and a phase-transfer catalyst in a solvent combination of toluene-water system wherein the trimethylsulphoxonium iodide and alkali metal hydroxide are in molar excess relative to the starting material. The molar ratio of compound II (X = F) and trimethylsulphoxonium iodide is in the range of about 1: 1.25 to 1:1.50 resulting in oxirane of purity, at least 94% in the reaction, sufficient to proceed to the next stage. The phase-transfer catalyst advantageously used in the process is cetrimide (cetyltrimetylammonium bromide) or TBAB (tetrabutylammomium bromide) The reaction is performed at a temperature of about 60 to 80°C and preferably at a temperature of about 60 to 65°C. The resulting oxirane was isolated as oil by layer separation, washing the organic layer with water and removing toluene by distillation. The oil solidifies upon standing. Attempts to purify the oxirane III by forming the methane 9 sulphonate salt resulted in very poor yields of oxirane methanesulphonate salt and further needed to be hydrolyzed in the subsequent fluconazole formation. According to the present invention, the epoxide III obtained in the above process step is reacted with triazole in presence of alkali metal hydroxides in polar aprotic organic solvents for fluconazole formation. It was observed that using bases like potassium carbonate resulted in higher isomeric impurity formation. The use of alkali metal hydroxides especially sodium hydroxide in a molar ratio of 1.5 to 2.0 relative to compound III resulted in lowering of the regioisomer - isofluconazole, as well as impurity resulted from fluorine substitution and completes the reaction faster (2-3 hrs). Accordingly, compound III, 1,2,4-triazole and sodium hydroxide in a molar ratio of from about 1:1.5:1.5 to about 1: 2.0 : 2.0 are reacted in a solvent like N, N - dimethylformamide. The preferable temperature for reducing the impurity formation is about 60 to 65°C. The reaction is rapid and finishes in 2 to 3 hours under the improved conditions as against the reported longer reaction time. Fluconazole formed in the reaction, according to the present invention, is isolated by the following steps of: concentrating the reaction mass by distilling N,N-dimethylformamide on completion of reaction; dissolving the residue in water and extrating fluconazole with dichloromethane; concentrating dichloromethane solution ; reslurrying the mass in toluene at about 70 to 90°C; filtering precipitated fluconazole ; and crystallizing crude fluconazole from water. The following non-limiting specific examples are presented to illustrate the best mode of carrying out the process of the present invention. Examples: Example 1: Charged compound of Formula II (X = F) 100 gm (0.448 m), trimethyl sulphoxonium iodide 133.2 gm (0.605 m), sodium hydroxide 24.21 gm (0.605 m), TBAB 4 gm, water (720 ml), 10 and toluene 720 ml in a round bottom flask and stirred. Heated the reaction mass to 60°C and maintained for 3.5 hrs. Cooled the reaction mass to 30°C and separated the organic phase. Extracted the aqueous phase with toluene (450 ml).Combined the toluene layers and washed with water. Distilled the toluene under vacuum to isolate the epoxide. The weight of isolated epoxide was 91.8 gm (86.44%), having 95% purity by HPLC. Example 2: Charged epoxide (Formula III, X = F) 91.8 gm (0.387 m), sodium hydroxide 23.2 gm (0.58m), 1,2,4 - triazole 40.12 gm (0.58 m) and N,N- dimethylformamide (826 ml) in a round bottomed flask and stirred. Heated the reaction mass to 60°C and maintained for 2.0 hrs. Cooled the reaction mass to 30°C and distilled the solvent under vacuum to get the concentrated mass. Added water to the reaction mass and extracted the aqueous solution with dichloromethane (3000 ml). Dichloromethane layer was washed with water and distilled dichloromethane to get the residual mass. Charged toluene (500 ml) to the residual mass and heated to 80 - 85°C. Maintained the reaction mass for 1.5 hrs, cooled to 25°C and maintained for 1.0 hr. filtered the solid mass to isolate crude fluconazole. Dried the product at 50°C.The yield of crude fluconazole was 83.30 gm (70.16%). Crystallized the product from water yielded 66.50 gm (56.04%) of pure fluconazole. Example 3: Charged epoxide (Formula III, X = F) 44.5 gm (0.187m), sodium hydroxide 15.02 gm (0.375m), 1,2,4 - triazole 25.9 gm (0. 375 m) and N, N- dimethylformamide (410 ml) in a round bottomed flask and stirred. Heated the reaction mass to 60°C and maintained for 2.0 hrs. The reaction mass was cooled to RT and distilled the solvent under vacuum to get the concentrated mass. Added water to the reaction mass and extracted the aqueous solution with dichloromethane (1500 ml). Dichloromethane layer was washed with water and distilled dichloromethane to get the residual mass. Charged toluene (220 ml) to the residual mass and heated to 80 - 85°C. Maintained the reaction mass for 1.5 hrs, cooled to 25°C and 11 We claim, 1. An improved process for the synthesis of fluconazole of Formula I, wherein said process comprising the steps of; Formula I Formula III Formula IV heating a mixture of oxirane compound of Formula III, 1,2,4 triazole of Formula IV and alkali metal hydroxide in presence of N,N-dimethylformamide, wherein, the compound III and 1,2,4-triazole are at a molar ratio in the range of about 1.0 : 1.5 to about 1.0 : 2.0 respectively, to form fluconazole in said mixture; and isolating the fluconazole of Formula I from the reaction mass. 2. The process as claimed in claim 1, wherein said alkali metal hydroxide is selected from lithium hydroxide, sodium hydroxide and potassium hydroxide. 3. The process as claimed in claim lor 2, wherein said alkali metal hydroxide is sodium hydroxide. 4. The process as claimed in any one of the preceding claim, wherein the molar ratio of oxirane compound III, 1,2,4 triazole (Formula IV) and sodium hydroxide is 1.0 : 1.5 : 1.5 to 1.0 : 2.0 : 2.0 respectively. 5. The process as claimed in any one of the preceding claim, wherein molar ratio of said sodium hydroxide is 1.5 to 2.0 relative to oxirane compound III. 13 6. The process as claimed in any of the preceding claim, wherein said reaction is carried out at a temperature of 60-65°C. 7. The process as claimed claim 1, wherein the process for isolation of said fluconazole comprising the steps of: concentrating the reaction mass by distilling N,N-dimethyformarnide to obtain a residue; dissolving said residue in water; extracting fluconazole with dichloromethane from said solution; separating the dichloromethane layer from aqueous layer; concentrating said dichloromethane solution to obtain a residue; reslurrying said residue in toluene at a temperature of about 70 to 90°C; filtering the precipitate from toluene; and dissolving said precipitate in water and crystallizing pure fluconazole from water solution. 8. An improved process for synthesis of fluconazole and its isolation as substantially described herein with reference to the foregoing examples 1 to 3. Dated this 5th day of January 2005 Dr. Gopakumar G. Nair Agent for the Applicant

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