Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF ZAFIRLUKAST

Abstract

Title of the invention: "An improved process for the preparation of Zafirlukast". The present invention provides an improved process for the preparation of Zafirlukast of formula (I), which comprises esterification of 3-methoxy-4-methyl benzoic acid of formula (11) via formation of acid chloride, followed by bromination of the resulting ester to form bromo ester of formula (IV). 5-nitro indole of formula (V) is methylated with dimethyl sulphate in presence of sodium hydroxide to form l-methyl-5-nitro indole of formula (Va), which is then condensed with bromo ester of formula (IV) and further reduced with raney nickel to get an amine of formula (VIII). The resultant amine is sequentially condensed with cyclopentyl chloroformate of formula (IX) and ortho toluene sulfonamide of formula (lb) to afford the title compound in overall yield of 13 % starting fiism 3-methoxy-4-methyl benzoic acid of formula (II) and in overall yield of 21 % starting from 5- nitroindole of formula (V). The present process involves inexpensive raw materials and solvents, under safe operational conditions, by a commercially viable, industrially scaleable, environment friendly and cost effective process.

Full Text

The present invention relates to an improved process for the preparation of Zafirlukast, chemically known as [3-[[2-methoxy-4-[[[(2-methylphenyl)sulfonyl]amino]carbonyl]phenyl]methyl]-l-methyl-lH-indoIe-5-yl]carbamic Zafirlukast of formula (I) antagonize tiie pharmacological actions of one or more of the arachidonic acid metabolites known as leukotrienes. The compoimds are thus useful in the treatment of diseases in which leukotrienes are implicated and in which antagonism of their action is desired, such diseases include, for example, allergic pulmonary disorders such as asthma. BACKGROUND OF INVENTION: The synthetic procedure for preparation of Zafirlukast is described in US Patent 4,859,692. The patent discloses the preparation of Zafirlukast by condensing the 3-methoxy benzoic acid of formula (la) with ortho-toluenesulphonamide of formula (lb) in chloro solvents such as dichloromethane at 25-45°C for about 12-20 hours. The patent furthermore discloses the process for the prq>aration of compound of formula (la) The relevant synthetic scheme is represented as follows-. The process disclosed in US Patent 4,859,692 has some disadvantages, which renders the process unsuitable for commercialization. The disadvantages include, the usage of hazardous chemicals such as acetyl chloride, bromine, sodium hydride and relatively expensive palladium on carbon as catalyst for reduction process, not only escalates the cost of process, but also hi^-pressure apparatus is required for hydrogenation process. Moreover, solvent such as carbon tetrachloride (Class-I solvent as per ICH guidelines) is involved in prqiatation of intennediates, during the course of synthesis of Zafirlukast. Also the prior art process involves chromatographic column purifications in some stages, which is not preferable for commercial scale up. Thus rendering the process less cost effective and non-environmental friendly. Therefore, the main objective of the present invention is to provide an improved process for the preparation of Zafirlukast, using readily available, inexpensive raw materials and solvents, under safe operational conditions, by a commercially viable, industrially scaleable, environment friendly and cost effective process. SUMMARY OF THE INVENTION: The present invention provides an improved process for the preparation of Zafirlukast of formula (I), which comprises esterification of 3-methoxy-4-methyl benzoic acid of formula (II) via formation of acid chloride, followed by bromination of the resulting ester to form bromo ester of formula (TV). 5-nitro indole of formula (V) is methylated with dimethyl sulphate in presence of sodium hydroxide to form l-methyl-S-nitro indole of formula (Va), which is then condensed with bromo ester of formula (IV) and fiuther reduced with raney nickel to get an amine of formula (Vni). The resultant amine is sequentially condensed with cyclopentyl chlorofomiate of formula (DC) and ortho toluene sulfonamide of formula (lb) to afford the title compound in overall yield of 13 % starting from 3-methoxy-4-methyl benzoic acid of formula (II) and in overall yield of 21 % starting from 5- nitroindole of fomiula (V). The present process involves inexpensive raw materials and solvents, under safe operational conditions, by a commercially viable, industrially scaleable, environment friendly and cost effective process. DETAILED DESCRIPTION OF THE INVENTION: The present invention is directed to an improved process for synthesizing compound of formula (I) wherein 3-methoxy-4-methyl benzoic acid of formula (IT) is used as the starting material. The synthetic pathway can be depicted in the following Scheme. Accordingly an improved process for the preparation of Zafiriukast of formula (I), which comprises: a) reacting 3-methoxy-4-methyl benzoic acid of formula (II) with thionylchloride in methanol at a temperature ranging from 25-75°C, preferably at AO-SO^C till the reaction is substantially completes; b) decomposition of the reaction mass into chilled water and further work up to get an ester of formula (HI) in residual form ; c) reacting an ester of formula (HI) obtained from step (b) with 1,3-dibromo 5,5-dimethyl hydentoin in halogenated solvents using Azobis isobutyro nitrile catalj^t at a temperature ranging from 30°C to 110°C preferably 80-90°C till the reaction is substantially completes; d) decomposition of the reaction mass into chilled water and further work up to get bromo ester of fonnula (IV) in solid form; e) reacting 5-nitro indole of formula (V) with dimethyl sulfate in presence of inorganic base such as sodium hydroxide, sodium carbonate, sodium hi carbonate, potassium hydroxide, potassiiun carbonate or potassium bi carijonate, preferably sodium hydroxide Jo afford N-methyl-5-nitro indole of formula (Va); f) condensing bromo ester of formula (IV) with N-methyl 5-nitro indole of fonnula (Va) in a polar solvents such as dioxane in the presence of silver oxide as catalyst at temperature ranging from 40-70°C till the reaction is substantially completes followed by workup to get nitro indole derivative of formula (VII); g) reducing nitro indole derivative of formula (VII) obtained in step (f) using raney nickel in inert organic solvent at a hydrogen pressure of 2-5 kg/cm^ till the reaction substantially completes, followed by work up to yield the corresponding amine of fonnula (VIII); h) reaction of the amino compound of formula (Vm) obtained in step (g) with cyclopentyl chloroformate of formula (DC) in the presence of halogenated solvent using N-methylmorpholine as base and followed by reaction work up to get an ester of formula (X); i) hydrolyzing the ester obtained m step (h) in a mixture of methanol and tetrahydrofiiran using base such as lithium hydroxide till the reaction is substantially completes; j) acidifying the reaction mass with hydrochloric acid to get the solid compoimd which on further recrystallisation in a mixture of solvents toluene and hexane to get compound of fonnula (la); k) condensation of compound of formula (la) with ortho toluene sulfonamide of fonnula (lb) in halogenated solvent in presence of dimethylamino pyridine and dicyclohexyl carbodiimide at 30-35°C till the reaction substantially completes; k) fiulher reaction woric up and isolation from an alcoholic solvent, preferably methanol to get Zafirlukast of formula (I). The ester of formula (HI) is isolated by filtration in solid fonn after decomposing the reaction mass into chilled water, the preferred temperature is 0-5°C. The solid mass was further washed with water upto neutral pH and the wet cake is dissolved in water immiscible halogenated solvents comprising of dichloromethane, dichloroethane, chloroform or carbon tetrachloride, preferably dichloromethane. Water is separated from the resulting solution and solvent is distilled off to get the ester of formula (EQ) in residual form. The halogenated solvents mentioned in step (c) of the above process comprising of dichloromethane, dichloroethane, chloroform or carbon tetrachloride, preferably chloroform. The bromo ester of formula (TV) is isolated from ethereal solvents comprising of petroleum ether, diethyl ether, isopropyl ether and diisopropyl ether, preferably petroleum ether after reaction workup as mentioned in stq) (d) of the above process. The inert organic solvent may be used for reducmg the nitro compound of formula (Vin) is selected from methyl acetate, ethyl acetate, methanol, ethanol, iso propanol or n-butanol, preferably ethyl acetate. The halogenated solvent mentioned in steps (h) and (k) of the above process comprising of dichloromethane, dichloroethane, chloroform or carbon tetrachloride, preferably dichloromethane. The desired compoimd of Zafirlukast of formula (I) obtained in the above process is having enough purity, which enables to utilize in pharmaceutical formulations. The present invention does not involve usage of combination of sodium hydride and tetrahydrofiiran in preparation of nitro indole of fonnula (VII), which has an uncontrollable exothermic and can result in disaster as explosion during scale up. Also usage of relatively high expensive palladium on carbon as catalyst in tefra hydro fijran for reduction of nitroindole derivative of formula (VII) to convert amino indole derivative as in prior art is replaced in the present invention by using raney nickel which is che^ and safe catalyst. Moreover, the bromination of Methyl 3-methoxy-4-methyl benzoate of formula (HI) is carried out by using simple and safe reagent l,3-dibromo5, 5-dimethyl hydentoin (DBDMH) in chloroform solvent whereas in the prior art the process involves usage of hazardous reagent bromine and class-I solvent carbon tetrachloride. The prior art process for condensation of methyl 4-bromomethyl-3-methoxy benzoate of formula (IV) with nitro indole of foimula (V) yields unwanted isomer and resulted in low yield of required compound of fonnula (VI), whereas the present invention involves the condensation of 1-methyl-5-nitro indole of formula (Va) with compoimd of formula (IV), which minimizes the formation of isomer and resulted the compound of formula (VH) in high yield. The present mvention having further advantage that it involves usage of dicyclohexyl carbodiimide catalyst for the condensation of 4-[5-(cyclopentyloxy caibonyl) amJno-1-methylindole-3-yl-methyl]-3-methoxy benzoic acid of formula (la) with orthotoluene sulfonamide of formula (lb) to give Zafirlukast whereas the prior art procedure involves usage of costly raw material imide hydrochloride as a catalj^t for the condensation in which a tedious work-up involved to isolate the product and thus results in excess time for processing. Hence an improved process for the preparation of Zafirlukast of the present invention is safe, cost effective and ecofriendly process. Thus, the process of the present invention is provides a better method for the preparation Zafirlukast over prior art processes. The process of the present invention is also commercially viable for the preparation of Zafirlukast. Examples The present invention will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention. Example-1 Preparation of methyl 4- bromometbyl -3-methoxy benzoate (IV): (A) Preparation of methyl 3- methoxy-4-methyl benzoate (III): To a mixture of 3-methoxy-4-methyl benzoic acid (500 g, 3.01 moles) in methanol (1250ml), thionyl chloride (250ral) was added slowly in over a period of 2 hours at below 40°C. Then, the mass was heated slowly to 40-45°C and stirred for 2 hours. The reaction completion was confirmed by TLC. The reaction mass was cooled to 25-30°C and decomposed into chilled water (5 lit), further stirred for one hour and the solid was filtered under vacuum. The wet solid was washed with water (2x750ml), 10% soda ash solution (50g in 500ml) and followed by water (3xllit.). The wet solid was dissolved in dichlorometliane (1.5 lit.) and separated the aqueous layer fiom the resulting biphasic solution. The solvent was distilled off under vacuum and the residue was poured into glass tray for solidification ( 517 grams , 95.36 % ). and was taken for further step. (B) Preparation of methyl 4- bromomethyl-3-methoxy benzoate (TV): Methyl-3-methoxy-4-methyl benzoate (TS) (100 grams, obtained as per example-1 (A), AIBN (0.5g) and DBDMH (l,3-dibromo5, 5-dimethyl hydentoin) (90g) in chloroform (500 ml) were stirred under reflux for 6 hours. The reaction completion was confirmed by TLC and the mass was cooled to 25-30°C. Then the mass was decomposed into water under stirring and separated the organic layer fi-om the resulting bi-phasic solution. The organic layer was washed with 10% soda ash solution (500ml) followed by water (2x500m!). The solvent was distilled off under vacuum from the resulting organic layer and isolated the desired title compound from petroleum ether. Thus, obtained soUd compound was aerial dried to a constant weight (116g, 80.6 %). Example-2: Methyl-3-methoxy-4 [1-methyl-S-nitro indole-3-yl methyl] benzoate (VII) (A) Preparation of 1-methyl -5-nitro indole (Va): To the mixture of S-nitroindole (250 g), sodium hydroxide (80g) in tefrahydrofuran (Hit) was added dimethyl sulphate (I80ml) slowly under stirring in over a period of one hour at 30-40°C and further stirred the contents for about 3 hours. The organic solvent was distilled off form the reaction mass under vacuum; water (1 lit) was added to the residual mass and stirred to isolate the solid. The isolated solid was filtered and washed with water (1 lit). The compound was dried upto moisture content attains below 1% to afford 1-methyl -5-mtro indole (Va) (Weight-. 260 g. 96.29%) (B) Methyl ~3-methoxy-4 [l-methyl-S-nitro indole-3-yl methyl] benzoate (VII) Methyl 4-bromomethyl-3-methoxy benzoate (IV) [500 g, prepared as per example 1(B)], 1-methyl -5- nitro indole (Va) (250 g), silver oxide (200 g.) were suspended in dioxane (2.5 Ut), heated to reflux and stirred for 8 hours. The reaction mass was filtered on hyflow bed and washed with metiianol (500ml). The solvent was distilled off from the filtrate under vacuum to get the residue. Methanol (2.25 Ut) and ethyl acetate (250ml) were added to the residual mass and stirred at reflux for 15 minutes. Then, the mass was cooled to 25-35°C under stirring and filtered the solid, washed with methanol (500ml). Dried the compound at 55' 60°C to get the title compound (370 g, 73.8%). Example-3 Methyl -3-methoxy-4[l-methyl-5-amino indoIe-3-yI methyl] benzoate (VHI) Methyl -3-methoxy-4 [l-methyI-5-nitro indole-3-yl methyl] benzoate (VII) (250 g.), ethyl acetate (1 lit), Raney nickel (50 ml) and DM water (250 nil) were charged mto dry 2 liter SS hydrogenation vessel. Stured the contents under a hydrogen gas pressure of 3 kg/cm^ for about 4 hours. After reaction completion, the mass was filtered through hyflow bed and washed widi ethyl acetate (1.5 lit). DM water (750 ml) was added to the filtrate and pH of the mass was adjusted to 1.0 to 2.0 with aqueous hydrochloric acid solution (60 ml). Stirred the mass to isolate the solid and filtered the separated solid, washed with ethyl acetate (625 ml). The wet sohd was suspended in DM water (750 ml) and adjusted pH to 8.0 with soda ash solution (25 g in 250 ml of water), and then the compound was extracted into dichloromethane (500 x 2 ml). The Combined organic layer was washed with water (1250 ml) and distilled the solvent under vacuum to get the residue. Methanol (250 ml) was added to the residual mass and stirred at 0-5° C to separate the solid. The separated soUd was filtered, washed with methanol (50 ml) and dried at 50-55'C to afford the title compound (87.5 g, 38.2%). Example-4: Preparation of Methyl 4-[(5-cyclopentIoxy carbonyl) amino-l-methyl indole -3-yl methyl] - 3-methoxy benzoate (X): Methyl -3-methoxy-4 [l-methyl-5-amino mdole-3-yl methyl] benzoate(VIII) ( 75) grams, obtained as per Example -3) was condensed with cyclopentyl chloro formate (DC) as per the process disclosed in USP 4,859,692 (Example. 8 ) to afford the title compound (95.0 grams, 94.48 %). Exantple-S: Preparation of 4-[(5-cycIopenty»oi[y carbooyl) amino-1-methyl indole -3-yl methylI-3-methoxy benzoic acid (la): Methyl 4-[(5-cyclopentloxy carbonyl) amino-1-methyl indole -3-yl methyl] - 3-methoxy benzoate (X) ( 90 grams, obtained as per Example -4) was hydtolyzed with lithium hydroxide as per the process disclosed in USP 4,859,692 (Example.9 ) to afford the title compound (83 grams, 95.36 %). Example-6: [3U2-nietbosy-4-[l[(2-methylphenyI)$ulfoiiyllaniino]caTbonyl]phenyllmethyll-l-methyl-lH-indole-5-yl]carbamic acid cyclopentyl ester (I) (Zaflrluliast): 4-[(5-cyclopentyloxy carbonyl) amino-l-methylindole-3ylmethyl]-3-methGxy benzoic acid (la) (25 g., prepared as per example 5), dicyclohexyl carbodiimide (13.8 g.), dimethyl amino pyridine (2.5 g.) and Orthotoluene sulfonamide (lb) (25 g.) in a mixture of dichloromethane (250 ml) and dimethyl sulfoxide (25 ml) were stirred at 25-30'C for 12 hours. The reaction mass was filtered on hyflow and washed with dichloromethane (125 ml). Hydrochloric acid (7.5 ml) and water (250 ml) were added to filtrate and stirred for 10-15 minutes. The organic layer was separated and distilled the solvent under vacuum to get the residue. Methanol (250 ml) was added to the residue, cooled to 10-15°C and stirred for 45 minutes. The separated solid was filtered, washed with methanol (25 ml) and aerial dried to a constant weight to get the title compound (Zafirlukast)(31.5 g ,92.48 %) We claim: 1. An-improved process for the preparation afirlukast of formula (ft/ which comprises: hydroxide, potassium carbonate or potassium hi carbonate, preferably sodium hydroxide to afford N-methyl-5-nitro indole of formula (Va); f) condensing bromo ester of fonnula (IV) with N-methyl 5-nitro indole of formula g) reducing nitro indole derivative of formula (VII) obtained in step (f) using raney nickel in inert orgaruc solvent at a hydrogen pressure of 2-5 kg/cm^ till the reaction substantiaUv-^TTngaesTjijil lowed by work up to yield the corresponding amine of formula (VIH); h) reaction of the amino compound of formula (VDI) obtained m step (g) with cyclopentyl chloroformate of formula (IX) in the presence of halogenated solvent using N-methylmorpholine as base and followed by reaction work up to get an ester of formula (X); i) hydrolyzing the ester obtained in step (h) in a mixture of methanol and tetrahydrofiiran using base such as lithium hydroxide till the reaction is \\ acidifying the reaction mass with hydrochloric acid to get the solid compound ivhich on fiiti^^^resi^st^sation in a mixture of solvents toluene and hexane to get / compoimd of formi^fi^Ij^T^ k) ,cohdensatipa of compound of formula (la) with ortho toluene sulfonamide of formula (lb) in halogenated solvent in presence of dimethylamino pyridine and dicyclohexyl aminocarbodiimide at 30-35°C till the reaction st^Tantially completer ■ i) fiHjfi^^eaciion work up and isolation from an alcoholic solvent, preferably meJhMiol to get Zafirlukast of formula (I). 2. The process as claimed in claim (1) of step (c), (h) and (k), wherein the hogenated solvents comprising of dichloromethane, dichloroethane, chloroform aiid carbon tetrachloride. 3. The process as claimed in claim (1) of step (c) and claim (2), wherein the preferred halogenated solvent is chloroform. 4. The process as claimed in claim (1) of step (h), (k) and claim (2), wherein the preferred halogenated solvent is dichloromethane. 5. The process as claimed in claim (1) of step (g), wherein the catalyst for reduction is raney nickel. 6. The process as claimed in claim (1) of step (g), wherein the inert organic solvent for reduction comprismg of methyl acetate, ethyl acetate, methanol, ethanol, iso propanol or n-butanol. 7. The process as claimed in claim (1) and (6), wherein the inert organic solvent for reduction is ethyl acetate. 8. The process as claimed in claim (1) of step (g), wherein the pressure of hydrogen gas is in between 2-5 kg/cm^. 9. The process as claimed in claim (1) and (8), wherein the pressure of hydrogen gas is 3 kg/cml 10. The process as claimed in claim (1) of step (1), wherein the alcoholic solvents having C1-C4 straight or branched chain carbon atoms comprising of methanol, ethanol, propanol, iso propanol, n-butanol, secondary butanol and tertiary butanol. 11. The process as claimed in claim (1) and (10), wherein the alcoholic solvent is methanol. 12. The unproved process for the preparation of Zafirlukast is substantially as herein described and exemplified.

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