Title of Invention	AN IMPROVED PROCESS FOR PREPARING MONTELUKAST AND SALTS THEREOF
Abstract	A method for the preparation of montelukast and salts thereof has been described. The method comprises of following steps: (a) (S)-l-(3-((E)-2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-isopropenylphenyllpropyl methane sulphonate (styrene mesylate salt) (b) coupling with 1-(mercapto methyl) cyclopropane acetic acid followed by saltification with an amine gives styrene amine salt (c) Converting styrene amine salt to Montelukast amine salt (d) Converting Montelukast amine salt to Montelukast free acid and or its required alkali/alkaline salt

Title of Invention

AN IMPROVED PROCESS FOR PREPARING MONTELUKAST AND SALTS THEREOF

Abstract

A method for the preparation of montelukast and salts thereof has been described. The method comprises of following steps: (a) (S)-l-(3-((E)-2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-isopropenylphenyllpropyl methane sulphonate (styrene mesylate salt) (b) coupling with 1-(mercapto methyl) cyclopropane acetic acid followed by saltification with an amine gives styrene amine salt (c) Converting styrene amine salt to Montelukast amine salt (d) Converting Montelukast amine salt to Montelukast free acid and or its required alkali/alkaline salt

Full Text	Field of the invention: The present invention relates to improved processes for the preparation of Montelukast and its salts thereof. Background of the invention: Montelukast sodium namely Sodium 1-[[[(lR)-1-[3-[(lE)-2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(1-hydroxy-1 -methylethyl) phenyl] propyl] thio] methyl] cyclo propane acetic acid has the formula Montelukast sodium is a leukotriene antagonist and inhibits the synthesis of leukotriene biosynthesis. It is useflul as anti-asthmatic, anti-allergic, anti-inflammatory, cytoprotective agent and hence useful in the treatment of angina, cerebral spasm, glomerular nephritis, hepatic, end toxemia, uveitis and allograft rejection. EF 0 480 717 discloses Montelukast sodium along with other related compounds and the methods for their preparation. The reported method of synthesis proceeds though corresponding methyl ester namely, and involves coupling methyl 1 -(mercaptomethyl) cyclopropane acetate with a mesylate generated in-situ. The methyl ester is hydrolyzed to free acids and the latter converted directly to Montelukast sodium salt. The process is not suitable for large-scale production because it requires tedious chromatographic purification of the methyl ester intermediate and br the final product with low yield. U.S. Pat. No.5,614,632 discloses a process for the preparation of the sodium salt of montelukast and certain process intermediates. The process involves generation of dilithium dianion of 1- (mercaptomethyl) cyclopropaneacetic acid followed by condensation with 2-(2-(3 (S)-(3-(2-(7- chloro-2-quinolinyl) ethenyl) phenyl)-3-methanesulfonyloxypropyl) phenyl)-2-propanol (referred as mesylated alcohol) to afford montelukast, which is further converted to the corresponding sodium salt via dicyclohexyl amine salt. The ‘362 patent also discloses a process for the preparation of crystalline montelukast sodium salt and mesylated alcohol. The process involves reacting methyl 2(3 (S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-hydroxy propyl) benzoate with methyl magnesium chloride to give a diol, which is further converted to mesylated alcohol on reaction with methane suffonyl chloride. While certain processes of its preparation are known, there is a continuing need for new processes of preparation of montelukast and its salts. It is mentioned by the inventors of patent U.S. Pat. No. 5,614,632, that the crystalline montelukast dicyclohexylantine salt offers an efficient method for the purification of montelukast, which circumvents the need to use chromatographic purification. Processes for preparation of montelukast and its intermediates have also been described in U.S. Patent No’s. 5,523,477, and U.S. Patent Application Publication Nos. 2005/0234241, 2005/0256156, 2005/0107612, and International Application PublicationNos. WO 2005/105749,WO 2005/000807, WO 2004/108679, and WO 2006/021974. WO 2006/08751 discloses a process for preparation of Montelukast sodium by neutralizing Montelukast organic amine salts such as [alpha}-Methyl benzyl amine salt, diisopropyl amine salt, dibenzyl amine salt followed by treatment with ethanolic sodium hydroxide. Although many processes have been described in the prior art for the preparation of montelukast and its intermediates, there still remains a need for a process for the preparation of montelukast which is industrially viable. Summary of the invention: The main object of the present invention is to provide an improved process for the preparation of Montelukast and its salts thereof. Another object of the present invention is to provide novel amine salts of Montelukast. Another object of the invention is to provide a process for the preparation of novel amine salts of Montelukast. Another object of the present invention is to provide a process for the preparation of Montelukast alkali/alkaline salts using nine salts of Montelukast. Another object of the present invention is to provide a process for the preparation of Montelukast alkalilalkaline salts without isolating Montelukast free acid. Another object of the present invention is to provide a process for the preparation of Montelukast and its salts which is scalable and economical. The present invention is best described with the following synthetic scheme-1; Detailed description of the invention: In accordance with the present invention the main object is to prepare montelukast and salts thereof comprising the steps of: a. Treating 2-[2-[3(S)-[3-[2-(7-Chloro-2-quniolinyl)ethenyl]phenyl]-3-hydroxypropyl] phenyl]-2-propanol with acetic anhydride yields (S)-l-(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3-(2-isopropenyl phenyl] propyl acetate b. Converting (S)-l-(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3-(2-isopropenyl phenyl] propyl acetate to (S)-l-(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3-(2-isopropenyl phenyl] propan-1-ol (hydroxy styrene) c. Treating (S)-l -(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3-(2-isopropenyl phenyl] propan-1-ol with methane sulfonyl chloride yields (S)-l-(3-((E)-2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-isopropenylphenyl]propyl methane sulphonate (styrene mesylate salt) d. Condensing (S)-l-(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3-(2-iso propenyl phenyl] propyl methane sulphonate with l-(mercapto methyl) cyclopropane acetic acid followed by saltification with an amine gives (l-[(R)-l-(3-[(E)-2-(7-chloroquinolin-2-yl)vinyl]-phenyl)-3-(2-isopropenylphenyl)propylsulfanylmethyl] cyclopropyl] acetic acid amine salt (styrene amine salt) e. Converting (l-[(R)-l-(3-[(E)-2-(7-chloroquinolin-2-yl)vinyl]-phenyl)-3-(2-isopropenyl phenyl) propylsulfanylmethyl] cyclopropyl] acetic acid amine salt to montelukast amine salt f. Converting Montelukast amine salt to Montelukast free acid and or its required alkali/alkaline salt In a preferred embodiment, 2-[2-[3(S)-[3 -{2-(7-Chloro-2-quniofinyl)ethenyl]phenyl]-3- hydroxypropyl] phenyl]-2-propanol is treated with acetic anhydride followed by dehydration with PTSA yields (S)- I -(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3 -(2-isopropenyl phenyl] propylacetate of Formula (III). The compound of formula (III) is converted to (S)- 1 -(3-((E)-2-(7-chloroquinolin-2.yl) vinyl) phenyl)-3-(2-isopropenyl phenyl] propan- 1-01 (hydroxy styrene) of Formula (IV) The compound of formula (IV) is mesylated with methane sulfonyl chloride or tosylated with toluene sulfonyl chloride to form (S)-1 -(3-((E)-2-(7-chloroquinolin-2.yl) vinyl) phenyl)-3-(2- isopropenylphenyl]propyl methane suiphonate (mesylated styrene) of formula (V) or a corresponding tosylate. Also, use of other leaving group-containing compounds instead of the mesylale or tosylate intermediate is also contemplated. The reaction may process in poiar solvent or non-polar solvent, or in a mixture of polar and non-polar organic solvents. The resulting leaving group containing intermediate (e.g., mesylate or tosylate, preferably, mesylate is then condensed with 1 -mercapto methyl cyclopropane acetic acid of formula in the presence of a base. The use of a mixture of polar organic solvents is preferred. The product of this reaction is preferably isolated in the form of an organic amine salt, preferably, dicyclohexyl amine salt of formula (VI). The resultant amine salt is reacted with sulphuric acid to get Montelukast free acid and is again converted to its organic amine salt of formula (VII) to get more pure compound. The amine salt of Montelukast of formula (VII) is conveniently converted into alkalilallcaline salts, preferably sodium salt using sodium methoxide or sodium hydroxide. In a specific embodiment, the invention provides a process for the preparation of Montelukast and its pharmaceutically acceptable salts, preferably, its sodium salt, which involves: a) reacting the hydroxy styrene compound with methane sulfonyl chloride in the presence of a tertiary amine, for example, diisopropyl ethyl amine or triethyl amine, in a polar and non-polar or mixture of organic solvents at a temperature of -25 to5O°C.; b) stirring the reaction mass obtained in step (a) till the reaction substantially completes and subsequently working up the mixture to obtain the mesylated compound of formula (V); c) reacting the mesylated compound of formula (V) with I -mercapto methyl cyclopropane acetic acid in polar organic solvents or mixture of polar solvents in the presence of a base, for example, sodium methoxide, sodium ethoxide, sothm hydride, n-butyl lithium, or cesium carbonate preferably 25% sodium methoxide in methanol at a temperature of -15 to6O°C.; d) stirring the reaction mass obtained in step (c) till the reaction complies and subsequently working it up to obtain a styrene compound, which is then reacted with dicyclohexyl amine salt to afford the amine salt of formula (VI); e) treating the dicyclohexyl amine salt of formula (VI) with sulphuric acid wherein the sulphuric acid is either aqueous or concentrated at a temperature of-20 to +50°C.; f) stirring the reaction mass obtained in step (e) till the reaction complies and subsequently working it up to isolate Montelukast acid and further reacting the resultant montelukast free acid with primary, secondary or tertiary amities, preferably l-methyl-3-phenylpropylamine, 1,2- cyclohexyl diamine to afford the amine salt of formula (VII); g) converting the amine salt into its pharmaceutically acceptable salts by generating the montelukast free acid from montelukast amine salt in halogenated solvents, for example, chloroform, dichloromethane or dichloroethane, preferably, dichloromethane, or an aromatic hydrocarbon, for example toluene in the presence of an organic acid, preferably acetic acid; h) converting the obtained solution in step (g) to sodium salt of Montelukast using sodium hydroxide, sodium methoxide or sodium ethoxide in alcohols such as from methanol, ethanol, propanol, butanol, 2-propanol or tert.butanol, preferably, by using ethanolic sodium hydroxide; i) distilling the solvent from the reaction solution of step (g) under reduced pressure and; j) dissolving the above residue in methanol and treating with activated carbon k) distilling methanol completely and isolating the desired product by adding cyclohexane, npentane, n-heptane or hexanes; and l) drying the isolated solid at 50-95°C. under vacuum. The Montelukast sodium obtained in the present novel process is having >99.0% enantiomeric excess purity and resulted in amorphous form. The Montelukast sodium obtained in the present process is also free flowing and non-solvated solid; hence it is well suited for pharmaceutical applications. Unless stated to the contrary, any use of the words such as ‘including,’‘containing,”“comprising,’“having’ and the like, means “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Except where the context indicates to the contrary, all exemplary values are intended to be fictitious, unrelated to actual entities and are used for purposes of illustration only. Most of the foregoing alternative embodiments are not mutually exclusive, but may be implemented in various combinations. As these and other variations and combinations of the features discussed above can be utilized without departing from the invention as defined by the claims, the foregoing description of the embodiments should be taken by way of illustration rather than by way of limitation of the invention as defined by the appended claims. Examples: The present invention will now be further explained in the following examples. However, the present invention should not be construed as limited thereby. One of ordinary skill in the art will understand how to vary the exemplified preparations to obtain the desired results. Example - I: Preparation of (S)-l.(3-((E)-2-(7-chloroquinolin-2-yI)vinyl) phenyl)-3-(2-(1-bydroxy-1-metbylethyl) phenyl] propyl acetate. To a stirred solution of 2-[2-[3(S)-[3-[2-(l-Cffloro-2-quniolinyl)ethenyl]phenyl]-3-hydroxy propyl]phenyl]-2-propanol (100gm) in dichioromethane (500m1) at 25-30°C 4-di(methyl amino) pyridine (5.32gm) was added and cooled to 0°C. To the reaction mixture Triethylamine (26.4gm) was added at 0°C. Acetic anhydride (26.7gm) was added slowly at temp.0-5°C over 30-60 mm and maintained the reaction at temp. 0-5°C over 30 mm. Reaction completion was monitored by TLC. After reaction completion the reaction mass was quenched into 7% NaI-1C03(500m1) and stirred for lsniln.Temperature was raised to 25-30°C and maintained for 30 mm. Reaction mass was settled for 15 mm and separated the organic layer. Aq.layer was extracted with dichioromethane (250m1). The combined organic layer was washed with 25% NH4C1 solution (500mi). Organic layer was distilled below 40°C to get the desired product as residue. Output: 108.0gm Example — II: Preparation of (S)-1-(3-((E)-2-(7-cbloroquinolin-2-yI) vinyl) phenyl)-3-(2-isopropenyl phenyl] propyl acetate PTSA (62.4gm) was suspended in toluene (300m1) at 25-30°C and moisture was removed by azeotropic distillation. After removal of moisture reaction mass was cooled to 70°C and distilled toluene completely under reduced pressure to get residue. The obtained residue was cooled to room temperature and charged dichloromethane (300m1) and stage-I (108gm of stage-I dissolved in 200m1 dichioromethane). The reaction mass temp was raised to reflux and maintained for 2 hrs. Reaction completion was monitored by TLC. After reaction completion the reaction mass was quenched into 7% NaHCO3 (300m1) and stirred for 15mm. Reaction mass temp was raised to 25-30°C and maintained for 30 ruin. Reaction mass was settled for 15 mm and the organic layer was separated. Aq.layer was extracted with dichioromethane (200ml) at 25-30°C. The combined organic layer was washed with of DM Water (2x300m1). Organic layer was concentrated below 40°C to get the desired product as residue. Output: 101.2 gin Example - III: Preparation of (S)-1-(3-((E)-2-(7-cbloroquinolin-2-yl) vinyl) pbenyl)-3-(2-lsopropenyl phenyl] propan-1-ol HCL To a stirred solution of Stage-H (101gm) in methanol (500m1) NaO}I solution (35gm of NaOH dissolved in 52ml DM Water) was added at 25-30°C over 30 mm. Reaction completion was checked by TLC. After reaction completion methanol and water were completely distilled under reduced pressure below 50°C. The residue was dissolved in ethy’ acetate (600m1). To the obtained solution UM water (500m1) was added pH was adjusted to 6.5-7.0 slowly with 1:1 dilHC1 at 25-30°C. Aq layer was separated and again extracted with ethyl acetate (200m1). The combined organic layer was washed with OM Water (500m1). The separated organic layer was dried over sodium sulphate and concentrated completely under reduced pressure at temp below 45°C. The obtained residue was dissolved in methanol (300m1) and methanolic HCI (80m1 of 8%) was added over 30-60 mm at room temperature. Reaction mixture was maintained for 2 hrs at room temperature one hour at 10-1 5°C. The precipitated product was filtered and washed the wet cake with chilled methanol (SOmI). Output: 88.0 gin Example - IV: Preparation of (S)-1-(3-ffE)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3-(2-iso propenyl phenylj propyl methane suiphonate To a stirred solution of compound obtained in Example-lIT (100gm) in dichioromethane (600m1), DM water (300m1) was charged and pH was adjusted to 7.5 to 8.0 with ammonia solution at 25- 30°C. Reaction mass was stirred for 30 mm at 25-30°C and settled for 10 miii. Organic layer was separated and the aq.layer was extracted with dichloromethane(200m1). The combined organic layer was washed with UM Water (2x300m1). Dichioromethane was distilled completely below 40°C to get residue. The obtained residue was dissolved in dichioromethane (600rnl) and cooled to 0°C. Di isopropyl ethyl amine (DIPEA) (40.6gm) was added under N2 atmosphere and again cooled to -30°C. Methane suiphonyl chloride (31.33gm) was added at -30 to -25°C slowly over 60 mm and maintained the reaction at -30° to -25°C for 2 hrs under N2 atmosphere. Reaction completion was checked by TLC. After reaction completion. the reaction mass was quenched in to 7% NaHCO3 (l000ml) below 5°C. The reaction mass was maintained for 10 mm at 0-5°C and 30 mm at 25-30°C. Organic layer was separated and aq.layer was extracted with dichioromethane (200m1).The combined organic layer was washed with DM water (2x500m1). Dichloromethane was distilled out completely below 40°C to get desired product as residue. Output: 105.0 gin Example –V: Preparation of (S)-1-(3-((E)-2-(7-chloroquinolln-2-yl) vinyl) phenyl)-3-(2-iso propenyl phenyl] propyl methane suiphonate To a stirred solution of Stage-ITT (100gm) in dichloromethane (300ml) Diisopropylethylamine (27.1 gm) was charged and Reaction mass was stirred for 30 mm at 40-45°C. Dichloromethane was distilled completely below 40°C to get residue. The obtained residue was dissolved in dichloromethane (l000mI) and cooled to 0°C. Di isopropyl ethyl aniine (DIPEA) (40.6gm) was added under N2 atmosphere and again cooled to 0°C. Methane sulphonyl chloride (31.33gm) was added at 0 to 5°C slowly over 60 mm and maintained the reaction at 0° to 5°C for 2 hrs under N2 atmosphere. Reaction completion was checked by TLC. After reaction completion, the reaction mass was quenched in to 7% NaHCO3 (I000mI) below 5°C. The reaction mass was maintained for 10 mm at 0-5°C and 30 mm at 25-30°C. Organic layer was separated and aq.Iayer was extracted with dichloromethane (200ml).The combined organic layer was washed with DM water (2x500m1). Dichloromethane was distilled out completely below 40°C to get desired product as residue. Output: 105.0 gin Example - VI: Preparation of DCHA salt of (l-I(R)-l-(3-[(E)-2-(7-cliloroquinolin-2-yl) vinylj-phenyl)-3-(2- isopropenyiphenyl) propylsulfanylmethyl] cyclopropylj acetic acid (Styrene DCHA salt) To a stirred solution of 1 -(mercapto methyl) cyclopropane acetic acid (46gm) in DMF (300m1), NaH (25gm) was added in four equal lots over 60 mlii at -5 - 0°C. The reaction mixture was maintained for 2 hrs at -5 - 0°C. Stage-1V (100gm dissolves in 300m1 of DMF) was added at -5- 0°C over 1 hr. The reaction mixture was maintained at 0-5°C for 15 hrs. The reaction completion was checked by The. After reaction completion reaction mixture was quenched in to mixture of 10% NaC1 (l000ml), and ethyl acetate (I000ml) below 10°C. Reaction mixture was stirred for 10 mm at 0-10°C and 30 mm at room temperature. Organic layer was separated and the aq.layer was extracted with ethyl acetate (500 ml). The combined organic layer was washed with 5% tartaric acid solution (500m1) followed by of DM Water (2x500m1). Separated organic layer was dried over 25 g of Sodium sulphate. Ethyl acetate was distilled completely under reduced pressure below 45°C. The obtained residue was dissolved in ethyl acetate (600m1) at room temperature. To the above solution dicyclohexyl amine (50n1l) was added at room temperature over 30 min under nitrogen atmosphere. Reaction mixture was maintained for 1 hr at room temperature and seeded with pure dicyclohexyl amine salt. Reaction mixture was maintained for 12-24 Irs at room temperature. n-Hexane (1 200ml) was added slowly at room temperature over 60 mm and maintained for 12 Irs. The precipitated product is filtered and washed with of nHexane (200m1). Output: 100.0 gm Example - VII: Preparation of DCHA salt of (1-ftR)-t-(3-[(E)-2-(7-chloroquinoin-2-yl) vinylj-phenyl)-3-(2- isopropenylphenyl) propylsulfanylmethyll cyclopropyl] acetic acid (Styrene DCHA salt) To a stirred solution of 1-(mercapto methyl) cyclopropane acetic acid (36.7 gm) in UM? (300m1), sodium methoxide (108.6 gin 25% methanolic soth) was added over 60 min at 0-5°C. The reaction mixture was maintained for 2 hrs at 0-5°C. mesylated Styrene (100gm dissolves in 300m1 of DMF) was added at 0-5°C over 1 hr. The reaction mixture was maintained at 0-5°C for 15 hrs. The reaction completion was checked by TLC. After reaction completion reactionmixture was quenched in to mixture of 10% NaCI (1000m1), and ethyl acetate (l000ml) below 10°C. Reaction mixture was stirred for 10 mm at 0-10°C and 30 mm at room temperature. Organic layer was separated and the aq.layer was extracted with ethyl acetate (500 ml). The combined organic layer was washed with 5% tartaric acid solution (500m1) followed by of DM Water (2x500m1). Separated organic layer was dried over 25 g of Sodium sulphate. Ethyl acetate was distilled completely under reduced pressure below 45°C. The obtained residue was dissolved in ethyl acetate (600m1) at room temperature. To the above solution dicyclohexyl amine (50m1) was added at room temperature over 30 mm under nitrogen atmosphere. Reaction mixture was naintained for 1 hr at room temperature and seeded with pure dicyclohexyl amine salt. Reaction mixture was maintained for 12-24 hrs at room temperature. n-Hexane (l200ml) was added slowly at room temperature over 60 niln and maintained for 12 hrs. The precipitated product is riltered and washed with of n-Hexane (200m1). Dutput: 101.0gm Example — VIII: Preparation of Montelukast amine salt To a stirred solution of Styrene DCHA salt (100gm) in dichioromethane (SOOml) to OM Water :300m0 was charged and pH was adjusted 4.0 to 4.5 with 1:1 dil Acetic acid at 25-30°C. The eaction mixture was stirred for stirred for 30 mm at room temperature. Organic layer was eparated and aq.layer was extracted with dichioromethane (300m1). The combined organic layer was washed with DM water (2x300m1). Organic layer was concentrated under below 40°C to get emi solid material. n-Hexane (500m1) was added and stirred for 30 mill at room temperature. [‘he precipitate was filtered and washed the wet cake with n-Hexane (100ml).The wet product was dried at 40-45°C to get styrene free acid (73gm). Syrene free acid (73gm) was added to sulfuric acid (365m1 of 80%) in equal lots at 5°-l0°C. teaction mass was maintained for 1 hr at 5-10°C. Reaction completion was monitored by TLC. \fter the reaction completion (product is —65%, styrene is —30%) the reaction mass was 1uenched into a mixture of DM water (730m1),ethyl acetate (l30ml) and t-butanol (730m1) ,elow 10°C. After quenching the reaction mass pH was adjusted to 3.5-4.0 with 20% NaOH ,elowl0°C. Again the temperature was raised to 25-30°C and maintained for 30 min. Organic ayer was separated and aq. layer was extracted with ethyl acetate (2x730m1) at room emperature. The combined organic layer was washed with 1DM water (2x730m1). The organic ayer was over sodium sulphate and concentrated under reduced pressure below 45°C to get the [esired product as residue. The obtained residue was subjected to column chromatography Mobile phase is dichloromethane: methanol, 99.5: 0.5). The separated montelukast free acid was lissolved in ethyl acetate (I 8Oml) at 40°C and cooled to room temperature under N2 atmosphere. To the obtained solution 1-methyl-3-phenylpropylamine (9.7m1) was added slowly at 25-30°C over 30 min. Reaction mass was maintained for 60 mm, seeded and maintain for 12-16 hrs at 25-30°C under N2 atmosphere. After the product was precipitated, n-Hexane (360mJ) was added slowly over 1 hr at 25-30°C. The reaction mass was maintained at 25-30°C for 12 hrs. The precipitated product was filtered and washed the wet cake with n-Hexane (60m1). The wet product was dried at 45-50°C. The dried product was purified by recrystallization in toluene. Output: 70.0gm Example — IX: Preparation of Montelukast amine salt To sulfuric acid (500 ml of 80%) styrene DCHA salt (100 gm) was added in equal lots at 5°- 10°C. Reaction mass was maintained for 1 hr at 5-10°C. Reaction completion was monitored by HPLC. After the reaction completion the reaction mass was quenched into a mixture of DM water (l000ml),ethyl acetate (l000ml) and t-butanol (l000nil) below 10°C. After quenching the reaction mass pH was adjusted to 3.5-4.0 with 20% NaOH belowl 0°C. Again the temperature was raised to 25-30°C and maintained for 30 mm. Organic layer was separated and aq. layer was extracted with ethyl acetate (2x500m1) at room temperature. The combined organic layer was washed with 5% brine (2xl000ml). The organic layer was over sodium sulphate and concentrated under reduced pressure below 45°C to get the desired product as residue. The obtained residue was subjected to colunm chromatography (Mobile phase is dichioromethane: methanol, 99.5: 0.5). The separated montelukast free acid was dissolved in ethyl acetate (300m1) at 40°C and cooled to room temperature under N2 atmosphere. To the obtained solution 1-methyl-3-phenylpropylamine (16.2m1) was added slowly at 25-30°C over 30 mm. Reaction mass was maintained for 60 mm, seeded and maintain for 12-16 hrs at 25- 30°C under N2 atmosphere. After the product was precipitated, n-Hexane (600m1) was added slowly over 1 hr at 25-30°C. The reaction mass was maintained at 25-30°C for 12 his. The precipitated product was filtered and washed the wet cake with n-Hexane (lOOmi). The wet product was dried at 45-50°C. The dried product was purified by recrystallization in toluene. Output: 50.0gm Purity by HPLC: 98.2% Example - X: Preparation of Montelukast sodium salt To a suspension of Montelukast 1 -methyl-3-phenylpropylamine salt (100gm) in dichioromethane (2000ml) DM water (l000ml) was charged p1-1 was adjusted to 4.0 to 4.5 with acetic acid (1:1) at 25-30°C. Reaction mass was maintained at 25-30°C for 30 mm and settle for 20 mm. Organic layer was separated and aq.layer was extracted with dichloromethane (1 000ml). The combined organic layer was washed with DM Water (1000 ml). To the organic layer ethanolic NaOH solution (235 ml of ethanol, 2.1 ml of DM Water and 5.17 g of NaOH) was slowly added over 30 mm and maintained at 25-30°C for 30 mm. Dichioromethane was distilled completely below40°C to get semi solid material. Then methanol (800 ml) was charged at 40-45°C under N, atmosphere and stirred for 10 mm. The obtained clear solution was treated with activated carbon and filtered the mass over hyflo bed and washed with methanol (200m1). The clear filtrate was distilled out completely under reduced pressure below 45CC. Pentane (lOOmi) was charged to the above residi.ie and distilled out methanol traces completely below 45°C. Again Pentane (2000m1) was and maintained for 4 hrs at 25-30°C under N, atmosphere. The precipitated product was filtered under N2 atmosphere and washed the wet cake with Pentane (1 OOml). The obtained wet cake was dried under vacuum for 2 hrs at 50°C, 2 hr at 70-75°C finally at 85-95°C for 24 brs. Output: 70.0 gm HPLC Purity: 99.5% We claim; 1. A process for preparation of Montelukast or a salt thereof, said process comprising the steps of a. Reacting (S)-l -(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3-(2-isopropenyl phenyl] propan- 1-01 with methane sulfonyl chloride or toluene sulfonyl chloride to obtain a mesylated or tosylated derivative (hydroxy styrene mesylate or tosylate salt) b. Condensing hydroxy styrene mesylate salt or tosylate with 1 -(mercapto methyl) cyclopropane acetic acid followed by saltification with an amine gives (1-[(R)-1-(3- [(E)-2-(7-chloroquinolin-2-yl)vinyl]-phenyl)-3-(2-isopropenylphenyl)propylsuJfanyl methylj cyclopropyl] acetic acid amine salt (styrene amine salt) c. Converting styrene amine salt to Montelukast amine salt; and d. Converting Montelukast amine salt to Montelulcast free acid and/or its required alkali/alkaline salt 2. The process as claimed in claim Ta, wherein the reaction is carried out in presence of an organic solvent selected from the group comprising of chlorinated hydrocarbons, aromatic hydrocarbons, Tetrahydrofliran and mixtures thereof. 3. The process as claimed in claim lb. wherein the reaction is carried out in a polar solvent in a presence of a base 4. The process as claimed in claim 3, wherein said polar solvent is selected from the group comprising of N,N-dimethylformamide, dimethylsulphoxide, N,N-dimethylacetamide, Nmethylpyrrolidine, methanol, THE and mixtures thereof. 5. The process as claimed in claim 3, wherein said base is selected from metal alkoxides, metal hydrides, metal carbonates, alkyl lithium salts and mixtures thereof 6. The process as claimed in claim Ib, wherein the preferable amine salt is dicyclohexylamine salt. 7. The process as claimed in claim Ic, wherein the reaction includes treating said styrene amine salt with sulphuric acid and isolating the obtained Montelukast as amine salt. 8. The process as claimed in claim 1 c, wherein the reaction optionally includes converting said styrene nine salt to its free acid and treating with sulphuric acid and isolating the obtained Montelukast as amine salt. 9. The process as claimed in claim ic, wherein said Montelukast amine salt is selected from I -methyl-3-phenylpropylamine, 1 ,2-cyclohexyl diamine salt and mixtures thereof. 10. The process as claimed in claim Id, wherein the reaction includes converting said Montelukast amine salt to its free acid and treating alkali/alkaline base and isolating Montelukast as its alkalilalkaline salts. 11. The process as claimed in claim 10, wherein the reaction further includes (i) providing a solution of Montelukast free acid in a halogenated solvent, aromatic solvent, alkanols and mixtures thereof; (ii) treating said solution with an alcoholic base to convert said Montelukast free acid into a alkatilalkaline salt of Montelukast; (iii) concentrating the reaction mass to dryness; (iv) adding a cyclic or acyclic hydrocarbon solvent to said solution thereby precipitating said alkalilalkaline salt of Montelukast. 12. The process as claimed in claim Id, wherein the reaction optionally includes treating Montelukast amine salt with alkali/alkaline base and isolating Montelukast as its alkalilalkaline salts. 13. The process as claimed in claim 12, wherein the reaction includes (i) providing a solution of Montelukast amine salt in a halogenated solvent, aromatic solvent, or mixtures thereof; (ii) treating said solution with an alkali/ailcaline base to convert said Montelukast amine salt into a salt of Montelukast; (iii) concentrating the reaction mass to dryness; (iv) adding a cyclic or acyclic hydrocarbon solvent to said solution thereby precipitating said alkalilalkaline salt of Montelukast. 14. The process as claimed in claim 13, wherein alkali/alkaline base is selected from the group consisting of sodium hydroxide, sodium methoxide or sodium ethoxide in methanol, ethanol, propanol, butanol, 2-propanol or tert-butanol 15. The process as claimed in claims 11 & 13, wherein said hydrocarbon solvent is selected from the group consisting of cyclohexane, pentane, hexane, heptane and mixtures thereof.

Full Text

Field of the invention:

The present invention relates to improved processes for the preparation of Montelukast and its salts thereof.

Background of the invention:

Montelukast sodium namely Sodium 1-[[[(lR)-1-[3-[(lE)-2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(1-hydroxy-1 -methylethyl) phenyl] propyl] thio] methyl] cyclo propane acetic acid has the formula

Montelukast sodium is a leukotriene antagonist and inhibits the synthesis of leukotriene biosynthesis. It is useflul as anti-asthmatic, anti-allergic, anti-inflammatory, cytoprotective agent and hence useful in the treatment of angina, cerebral spasm, glomerular nephritis, hepatic, end toxemia, uveitis and allograft rejection.

EF 0 480 717 discloses Montelukast sodium along with other related compounds and the methods for their preparation. The reported method of synthesis proceeds though corresponding methyl ester namely, and involves coupling methyl 1 -(mercaptomethyl) cyclopropane acetate with a mesylate generated in-situ. The methyl ester is hydrolyzed to free acids and the latter converted directly to Montelukast sodium salt. The process is not suitable for large-scale production because it requires tedious chromatographic purification of the methyl ester intermediate and br the final product with low yield.

U.S. Pat. No.5,614,632 discloses a process for the preparation of the sodium salt of montelukast and certain process intermediates. The process involves generation of dilithium dianion of 1- (mercaptomethyl) cyclopropaneacetic acid followed by condensation with 2-(2-(3 (S)-(3-(2-(7- chloro-2-quinolinyl) ethenyl) phenyl)-3-methanesulfonyloxypropyl) phenyl)-2-propanol (referred as mesylated alcohol) to afford montelukast, which is further converted to the corresponding sodium salt via dicyclohexyl amine salt. The ‘362 patent also discloses a process for the preparation of crystalline montelukast sodium salt and mesylated alcohol. The process involves reacting methyl 2(3 (S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-hydroxy propyl) benzoate with methyl magnesium chloride to give a diol, which is further converted to mesylated alcohol on reaction with methane suffonyl chloride. While certain processes of its preparation are known, there is a continuing need for new processes of preparation of montelukast and its salts. It is mentioned by the inventors of patent U.S. Pat. No. 5,614,632, that the crystalline montelukast dicyclohexylantine salt offers an efficient method for the purification of montelukast, which circumvents the need to use chromatographic purification.

Processes for preparation of montelukast and its intermediates have also been described in U.S. Patent No’s. 5,523,477, and U.S. Patent Application Publication Nos. 2005/0234241,
2005/0256156, 2005/0107612, and International Application PublicationNos. WO 2005/105749,WO 2005/000807, WO 2004/108679, and WO 2006/021974.

WO 2006/08751 discloses a process for preparation of Montelukast sodium by neutralizing Montelukast organic amine salts such as [alpha}-Methyl benzyl amine salt, diisopropyl amine salt, dibenzyl amine salt followed by treatment with ethanolic sodium hydroxide.

Although many processes have been described in the prior art for the preparation of montelukast and its intermediates, there still remains a need for a process for the preparation of montelukast which is industrially viable.

Summary of the invention:

The main object of the present invention is to provide an improved process for the preparation of Montelukast and its salts thereof.

Another object of the present invention is to provide novel amine salts of Montelukast.

Another object of the invention is to provide a process for the preparation of novel amine salts of Montelukast.

Another object of the present invention is to provide a process for the preparation of Montelukast alkali/alkaline salts using nine salts of Montelukast.

Another object of the present invention is to provide a process for the preparation of Montelukast alkalilalkaline salts without isolating Montelukast free acid.

Another object of the present invention is to provide a process for the preparation of Montelukast and its salts which is scalable and economical.

The present invention is best described with the following synthetic scheme-1;

Detailed description of the invention:

In accordance with the present invention the main object is to prepare montelukast and salts thereof comprising the steps of:

a. Treating 2-[2-[3(S)-[3-[2-(7-Chloro-2-quniolinyl)ethenyl]phenyl]-3-hydroxypropyl] phenyl]-2-propanol with acetic anhydride yields (S)-l-(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3-(2-isopropenyl phenyl] propyl acetate

b. Converting (S)-l-(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3-(2-isopropenyl phenyl] propyl acetate to (S)-l-(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3-(2-isopropenyl phenyl] propan-1-ol (hydroxy styrene)

c. Treating (S)-l -(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3-(2-isopropenyl phenyl] propan-1-ol with methane sulfonyl chloride yields (S)-l-(3-((E)-2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-isopropenylphenyl]propyl methane sulphonate (styrene mesylate salt)

d. Condensing (S)-l-(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3-(2-iso propenyl phenyl] propyl methane sulphonate with l-(mercapto methyl) cyclopropane acetic acid followed by saltification with an amine gives (l-[(R)-l-(3-[(E)-2-(7-chloroquinolin-2-yl)vinyl]-phenyl)-3-(2-isopropenylphenyl)propylsulfanylmethyl] cyclopropyl] acetic acid amine salt (styrene amine salt)

e. Converting (l-[(R)-l-(3-[(E)-2-(7-chloroquinolin-2-yl)vinyl]-phenyl)-3-(2-isopropenyl phenyl) propylsulfanylmethyl] cyclopropyl] acetic acid amine salt to montelukast amine salt

f. Converting Montelukast amine salt to Montelukast free acid and or its required alkali/alkaline salt

In a preferred embodiment, 2-[2-[3(S)-[3 -{2-(7-Chloro-2-quniofinyl)ethenyl]phenyl]-3- hydroxypropyl] phenyl]-2-propanol is treated with acetic anhydride followed by dehydration with PTSA yields (S)- I -(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3 -(2-isopropenyl phenyl] propylacetate of Formula (III). The compound of formula (III) is converted to (S)- 1 -(3-((E)-2-(7-chloroquinolin-2.yl) vinyl) phenyl)-3-(2-isopropenyl phenyl] propan- 1-01 (hydroxy styrene) of Formula (IV)

The compound of formula (IV) is mesylated with methane sulfonyl chloride or tosylated with toluene sulfonyl chloride to form (S)-1 -(3-((E)-2-(7-chloroquinolin-2.yl) vinyl) phenyl)-3-(2- isopropenylphenyl]propyl methane suiphonate (mesylated styrene) of formula (V) or a corresponding tosylate. Also, use of other leaving group-containing compounds instead of the mesylale or tosylate intermediate is also contemplated. The reaction may process in poiar solvent or non-polar solvent, or in a mixture of polar and non-polar organic solvents. The resulting leaving group containing intermediate (e.g., mesylate or tosylate, preferably, mesylate is then condensed with 1 -mercapto methyl cyclopropane acetic acid of formula in the presence of a base. The use of a mixture of polar organic solvents is preferred. The product of this reaction is preferably isolated in the form of an organic amine salt, preferably, dicyclohexyl amine salt of formula (VI).

The resultant amine salt is reacted with sulphuric acid to get Montelukast free acid and is again converted to its organic amine salt of formula (VII) to get more pure compound. The amine salt of Montelukast of formula (VII) is conveniently converted into alkalilallcaline salts, preferably sodium salt using sodium methoxide or sodium hydroxide.

In a specific embodiment, the invention provides a process for the preparation of Montelukast and its pharmaceutically acceptable salts, preferably, its sodium salt, which involves:

a) reacting the hydroxy styrene compound with methane sulfonyl chloride in the presence of a tertiary amine, for example, diisopropyl ethyl amine or triethyl amine, in a polar and non-polar or mixture of organic solvents at a temperature of -25 to5O°C.;

b) stirring the reaction mass obtained in step (a) till the reaction substantially completes and subsequently working up the mixture to obtain the mesylated compound of formula (V);

c) reacting the mesylated compound of formula (V) with I -mercapto methyl cyclopropane acetic acid in polar organic solvents or mixture of polar solvents in the presence of a base, for example, sodium methoxide, sodium ethoxide, sothm hydride, n-butyl lithium, or cesium carbonate preferably 25% sodium methoxide in methanol at a temperature of -15 to6O°C.;

d) stirring the reaction mass obtained in step (c) till the reaction complies and subsequently working it up to obtain a styrene compound, which is then reacted with dicyclohexyl amine salt to afford the amine salt of formula (VI);

e) treating the dicyclohexyl amine salt of formula (VI) with sulphuric acid wherein the sulphuric acid is either aqueous or concentrated at a temperature of-20 to +50°C.;

f) stirring the reaction mass obtained in step (e) till the reaction complies and subsequently working it up to isolate Montelukast acid and further reacting the resultant montelukast free acid with primary, secondary or tertiary amities, preferably l-methyl-3-phenylpropylamine, 1,2- cyclohexyl diamine to afford the amine salt of formula (VII);

g) converting the amine salt into its pharmaceutically acceptable salts by generating the montelukast free acid from montelukast amine salt in halogenated solvents, for example, chloroform, dichloromethane or dichloroethane, preferably, dichloromethane, or an aromatic hydrocarbon, for example toluene in the presence of an organic acid, preferably acetic acid;

h) converting the obtained solution in step (g) to sodium salt of Montelukast using sodium hydroxide, sodium methoxide or sodium ethoxide in alcohols such as from methanol, ethanol, propanol, butanol, 2-propanol or tert.butanol, preferably, by using ethanolic sodium hydroxide;

i) distilling the solvent from the reaction solution of step (g) under reduced pressure and;

j) dissolving the above residue in methanol and treating with activated carbon

k) distilling methanol completely and isolating the desired product by adding cyclohexane, npentane, n-heptane or hexanes; and

l) drying the isolated solid at 50-95°C. under vacuum.

The Montelukast sodium obtained in the present novel process is having >99.0% enantiomeric excess purity and resulted in amorphous form. The Montelukast sodium obtained in the present process is also free flowing and non-solvated solid; hence it is well suited for pharmaceutical applications.

Unless stated to the contrary, any use of the words such as ‘including,’‘containing,”“comprising,’“having’ and the like, means “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Except where the context indicates to the contrary, all exemplary values are intended to be fictitious, unrelated to actual entities and are used for purposes of illustration only. Most of the foregoing alternative embodiments are not mutually exclusive, but may be implemented in various combinations. As these and other variations and combinations of the features discussed above can be utilized without departing from the invention as defined by the claims, the foregoing description of the embodiments should be taken by way of illustration rather than by way of limitation of the invention as defined by the appended claims.

Examples:
The present invention will now be further explained in the following examples. However, the present invention should not be construed as limited thereby. One of ordinary skill in the art will understand how to vary the exemplified preparations to obtain the desired results.

Example - I:
Preparation of (S)-l.(3-((E)-2-(7-chloroquinolin-2-yI)vinyl) phenyl)-3-(2-(1-bydroxy-1-metbylethyl) phenyl] propyl acetate.
To a stirred solution of 2-[2-[3(S)-[3-[2-(l-Cffloro-2-quniolinyl)ethenyl]phenyl]-3-hydroxy propyl]phenyl]-2-propanol (100gm) in dichioromethane (500m1) at 25-30°C 4-di(methyl amino) pyridine (5.32gm) was added and cooled to 0°C. To the reaction mixture Triethylamine (26.4gm) was added at 0°C. Acetic anhydride (26.7gm) was added slowly at temp.0-5°C over 30-60 mm and maintained the reaction at temp. 0-5°C over 30 mm. Reaction completion was monitored by TLC. After reaction completion the reaction mass was quenched into 7% NaI-1C03(500m1) and stirred for lsniln.Temperature was raised to 25-30°C and maintained for 30 mm. Reaction mass was settled for 15 mm and separated the organic layer. Aq.layer was extracted with dichioromethane (250m1). The combined organic layer was washed with 25% NH4C1 solution (500mi). Organic layer was distilled below 40°C to get the desired product as residue.
Output: 108.0gm

Example — II:
Preparation of (S)-1-(3-((E)-2-(7-cbloroquinolin-2-yI) vinyl) phenyl)-3-(2-isopropenyl phenyl] propyl acetate
PTSA (62.4gm) was suspended in toluene (300m1) at 25-30°C and moisture was removed by azeotropic distillation. After removal of moisture reaction mass was cooled to 70°C and distilled toluene completely under reduced pressure to get residue. The obtained residue was cooled to room temperature and charged dichloromethane (300m1) and stage-I (108gm of stage-I dissolved in 200m1 dichioromethane). The reaction mass temp was raised to reflux and maintained for 2 hrs. Reaction completion was monitored by TLC. After reaction completion the reaction mass was quenched into 7% NaHCO3 (300m1) and stirred for 15mm. Reaction mass temp was raised to 25-30°C and maintained for 30 ruin. Reaction mass was settled for 15 mm and the organic layer was separated. Aq.layer was extracted with dichioromethane (200ml) at 25-30°C. The combined organic layer was washed with of DM Water (2x300m1). Organic layer was concentrated below 40°C to get the desired product as residue.
Output: 101.2 gin

Example - III:
Preparation of (S)-1-(3-((E)-2-(7-cbloroquinolin-2-yl) vinyl) pbenyl)-3-(2-lsopropenyl phenyl] propan-1-ol HCL
To a stirred solution of Stage-H (101gm) in methanol (500m1) NaO}I solution (35gm of NaOH dissolved in 52ml DM Water) was added at 25-30°C over 30 mm. Reaction completion was checked by TLC. After reaction completion methanol and water were completely distilled under reduced pressure below 50°C. The residue was dissolved in ethy’ acetate (600m1). To the obtained solution UM water (500m1) was added pH was adjusted to 6.5-7.0 slowly with 1:1 dilHC1 at 25-30°C. Aq layer was separated and again extracted with ethyl acetate (200m1). The combined organic layer was washed with OM Water (500m1). The separated organic layer was dried over sodium sulphate and concentrated completely under reduced pressure at temp below 45°C. The obtained residue was dissolved in methanol (300m1) and methanolic HCI (80m1 of 8%) was added over 30-60 mm at room temperature. Reaction mixture was maintained for 2 hrs at room temperature one hour at 10-1 5°C. The precipitated product was filtered and washed the wet cake with chilled methanol (SOmI).
Output: 88.0 gin

Example - IV:
Preparation of (S)-1-(3-ffE)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3-(2-iso propenyl phenylj propyl methane suiphonate
To a stirred solution of compound obtained in Example-lIT (100gm) in dichioromethane (600m1), DM water (300m1) was charged and pH was adjusted to 7.5 to 8.0 with ammonia solution at 25- 30°C. Reaction mass was stirred for 30 mm at 25-30°C and settled for 10 miii. Organic layer was separated and the aq.layer was extracted with dichloromethane(200m1). The combined organic layer was washed with UM Water (2x300m1). Dichioromethane was distilled completely below 40°C to get residue. The obtained residue was dissolved in dichioromethane (600rnl) and cooled to 0°C. Di isopropyl ethyl amine (DIPEA) (40.6gm) was added under N2 atmosphere and again cooled to -30°C. Methane suiphonyl chloride (31.33gm) was added at -30 to -25°C slowly over 60 mm and maintained the reaction at -30° to -25°C for 2 hrs under N2 atmosphere. Reaction completion was checked by TLC. After reaction completion. the reaction mass was quenched in to 7% NaHCO3 (l000ml) below 5°C. The reaction mass was maintained for 10 mm at 0-5°C and 30 mm at 25-30°C. Organic layer was separated and aq.layer was extracted with dichioromethane (200m1).The combined organic layer was washed with DM water (2x500m1). Dichloromethane was distilled out completely below 40°C to get desired product as residue.
Output: 105.0 gin

Example –V:
Preparation of (S)-1-(3-((E)-2-(7-chloroquinolln-2-yl) vinyl) phenyl)-3-(2-iso propenyl phenyl] propyl methane suiphonate
To a stirred solution of Stage-ITT (100gm) in dichloromethane (300ml) Diisopropylethylamine (27.1 gm) was charged and Reaction mass was stirred for 30 mm at 40-45°C. Dichloromethane was distilled completely below 40°C to get residue. The obtained residue was dissolved in dichloromethane (l000mI) and cooled to 0°C. Di isopropyl ethyl aniine (DIPEA) (40.6gm) was added under N2 atmosphere and again cooled to 0°C. Methane sulphonyl chloride (31.33gm) was added at 0 to 5°C slowly over 60 mm and maintained the reaction at 0° to 5°C for 2 hrs under N2 atmosphere. Reaction completion was checked by TLC. After reaction completion, the reaction mass was quenched in to 7% NaHCO3 (I000mI) below 5°C. The reaction mass was maintained for 10 mm at 0-5°C and 30 mm at 25-30°C. Organic layer was separated and aq.Iayer was extracted with dichloromethane (200ml).The combined organic layer was washed with DM water (2x500m1). Dichloromethane was distilled out completely below 40°C to get desired product as residue.
Output: 105.0 gin

Example - VI:
Preparation of DCHA salt of (l-I(R)-l-(3-[(E)-2-(7-cliloroquinolin-2-yl) vinylj-phenyl)-3-(2- isopropenyiphenyl) propylsulfanylmethyl] cyclopropylj acetic acid (Styrene DCHA salt)
To a stirred solution of 1 -(mercapto methyl) cyclopropane acetic acid (46gm) in DMF (300m1), NaH (25gm) was added in four equal lots over 60 mlii at -5 - 0°C. The reaction mixture was maintained for 2 hrs at -5 - 0°C. Stage-1V (100gm dissolves in 300m1 of DMF) was added at -5- 0°C over 1 hr. The reaction mixture was maintained at 0-5°C for 15 hrs. The reaction completion was checked by The. After reaction completion reaction mixture was quenched in to mixture of 10% NaC1 (l000ml), and ethyl acetate (I000ml) below 10°C. Reaction mixture was stirred for 10 mm at 0-10°C and 30 mm at room temperature. Organic layer was separated and the aq.layer was extracted with ethyl acetate (500 ml). The combined organic layer was washed with 5% tartaric acid solution (500m1) followed by of DM Water (2x500m1). Separated organic layer was dried over 25 g of Sodium sulphate. Ethyl acetate was distilled completely under reduced pressure below 45°C. The obtained residue was dissolved in ethyl acetate (600m1) at room temperature. To the above solution dicyclohexyl amine (50n1l) was added at room temperature over 30 min under nitrogen atmosphere. Reaction mixture was maintained for 1 hr at room temperature and seeded with pure dicyclohexyl amine salt. Reaction mixture was maintained for 12-24 Irs at room temperature. n-Hexane (1 200ml) was added slowly at room temperature over
60 mm and maintained for 12 Irs. The precipitated product is filtered and washed with of nHexane (200m1).
Output: 100.0 gm

Example - VII:
Preparation of DCHA salt of (1-ftR)-t-(3-[(E)-2-(7-chloroquinoin-2-yl) vinylj-phenyl)-3-(2- isopropenylphenyl) propylsulfanylmethyll cyclopropyl] acetic acid (Styrene DCHA salt)
To a stirred solution of 1-(mercapto methyl) cyclopropane acetic acid (36.7 gm) in UM?
(300m1), sodium methoxide (108.6 gin 25% methanolic soth) was added over 60 min at 0-5°C. The reaction mixture was maintained for 2 hrs at 0-5°C. mesylated Styrene (100gm dissolves in 300m1 of DMF) was added at 0-5°C over 1 hr. The reaction mixture was maintained at 0-5°C for 15 hrs. The reaction completion was checked by TLC. After reaction completion reactionmixture was quenched in to mixture of 10% NaCI (1000m1), and ethyl acetate (l000ml) below 10°C. Reaction mixture was stirred for 10 mm at 0-10°C and 30 mm at room temperature. Organic layer was separated and the aq.layer was extracted with ethyl acetate (500 ml). The combined organic layer was washed with 5% tartaric acid solution (500m1) followed by of DM Water (2x500m1). Separated organic layer was dried over 25 g of Sodium sulphate. Ethyl acetate was distilled completely under reduced pressure below 45°C. The obtained residue was dissolved in ethyl acetate (600m1) at room temperature. To the above solution dicyclohexyl amine (50m1) was added at room temperature over 30 mm under nitrogen atmosphere. Reaction mixture was naintained for 1 hr at room temperature and seeded with pure dicyclohexyl amine salt. Reaction mixture was maintained for 12-24 hrs at room temperature. n-Hexane (l200ml) was added slowly at room temperature over 60 niln and maintained for 12 hrs. The precipitated product is riltered and washed with of n-Hexane (200m1).
Dutput: 101.0gm

Example — VIII: Preparation of Montelukast amine salt
To a stirred solution of Styrene DCHA salt (100gm) in dichioromethane (SOOml) to OM Water :300m0 was charged and pH was adjusted 4.0 to 4.5 with 1:1 dil Acetic acid at 25-30°C. The eaction mixture was stirred for stirred for 30 mm at room temperature. Organic layer was eparated and aq.layer was extracted with dichioromethane (300m1). The combined organic layer was washed with DM water (2x300m1). Organic layer was concentrated under below 40°C to get emi solid material. n-Hexane (500m1) was added and stirred for 30 mill at room temperature. [‘he precipitate was filtered and washed the wet cake with n-Hexane (100ml).The wet product was dried at 40-45°C to get styrene free acid (73gm).

Syrene free acid (73gm) was added to sulfuric acid (365m1 of 80%) in equal lots at 5°-l0°C. teaction mass was maintained for 1 hr at 5-10°C. Reaction completion was monitored by TLC. \fter the reaction completion (product is —65%, styrene is —30%) the reaction mass was 1uenched into a mixture of DM water (730m1),ethyl acetate (l30ml) and t-butanol (730m1) ,elow 10°C. After quenching the reaction mass pH was adjusted to 3.5-4.0 with 20% NaOH ,elowl0°C. Again the temperature was raised to 25-30°C and maintained for 30 min. Organic ayer was separated and aq. layer was extracted with ethyl acetate (2x730m1) at room emperature. The combined organic layer was washed with 1DM water (2x730m1). The organic ayer was over sodium sulphate and concentrated under reduced pressure below 45°C to get the [esired product as residue. The obtained residue was subjected to column chromatography Mobile phase is dichloromethane: methanol, 99.5: 0.5). The separated montelukast free acid was lissolved in ethyl acetate (I 8Oml) at 40°C and cooled to room temperature under N2 atmosphere.

To the obtained solution 1-methyl-3-phenylpropylamine (9.7m1) was added slowly at 25-30°C over 30 min. Reaction mass was maintained for 60 mm, seeded and maintain for 12-16 hrs at 25-30°C under N2 atmosphere. After the product was precipitated, n-Hexane (360mJ) was added slowly over 1 hr at 25-30°C. The reaction mass was maintained at 25-30°C for 12 hrs. The precipitated product was filtered and washed the wet cake with n-Hexane (60m1). The wet product was dried at 45-50°C. The dried product was purified by recrystallization in toluene. Output: 70.0gm

Example — IX: Preparation of Montelukast amine salt
To sulfuric acid (500 ml of 80%) styrene DCHA salt (100 gm) was added in equal lots at 5°- 10°C. Reaction mass was maintained for 1 hr at 5-10°C. Reaction completion was monitored by HPLC. After the reaction completion the reaction mass was quenched into a mixture of DM water (l000ml),ethyl acetate (l000ml) and t-butanol (l000nil) below 10°C. After quenching the reaction mass pH was adjusted to 3.5-4.0 with 20% NaOH belowl 0°C. Again the temperature was raised to 25-30°C and maintained for 30 mm. Organic layer was separated and aq. layer was extracted with ethyl acetate (2x500m1) at room temperature. The combined organic layer was washed with 5% brine (2xl000ml). The organic layer was over sodium sulphate and concentrated under reduced pressure below 45°C to get the desired product as residue. The obtained residue was subjected to colunm chromatography (Mobile phase is dichioromethane: methanol, 99.5: 0.5). The separated montelukast free acid was dissolved in ethyl acetate (300m1) at 40°C and cooled to room temperature under N2 atmosphere.

To the obtained solution 1-methyl-3-phenylpropylamine (16.2m1) was added slowly at 25-30°C over 30 mm. Reaction mass was maintained for 60 mm, seeded and maintain for 12-16 hrs at 25- 30°C under N2 atmosphere. After the product was precipitated, n-Hexane (600m1) was added slowly over 1 hr at 25-30°C. The reaction mass was maintained at 25-30°C for 12 his. The precipitated product was filtered and washed the wet cake with n-Hexane (lOOmi). The wet product was dried at 45-50°C. The dried product was purified by recrystallization in toluene. Output: 50.0gm
Purity by HPLC: 98.2%

Example - X: Preparation of Montelukast sodium salt
To a suspension of Montelukast 1 -methyl-3-phenylpropylamine salt (100gm) in dichioromethane (2000ml) DM water (l000ml) was charged p1-1 was adjusted to 4.0 to 4.5 with acetic acid (1:1) at 25-30°C. Reaction mass was maintained at 25-30°C for 30 mm and settle for 20 mm. Organic layer was separated and aq.layer was extracted with dichloromethane (1 000ml). The combined organic layer was washed with DM Water (1000 ml). To the organic layer ethanolic NaOH solution (235 ml of ethanol, 2.1 ml of DM Water and 5.17 g of NaOH) was slowly added over 30 mm and maintained at 25-30°C for 30 mm. Dichioromethane was distilled completely below40°C to get semi solid material. Then methanol (800 ml) was charged at 40-45°C under N, atmosphere and stirred for 10 mm. The obtained clear solution was treated with activated carbon and filtered the mass over hyflo bed and washed with methanol (200m1). The clear filtrate was distilled out completely under reduced pressure below 45CC. Pentane (lOOmi) was charged to the above residi.ie and distilled out methanol traces completely below 45°C. Again Pentane (2000m1) was and maintained for 4 hrs at 25-30°C under N, atmosphere. The precipitated product was filtered under N2 atmosphere and washed the wet cake with Pentane (1 OOml). The obtained wet cake was dried under vacuum for 2 hrs at 50°C, 2 hr at 70-75°C finally at 85-95°C for 24 brs.
Output: 70.0 gm
HPLC Purity: 99.5%

We claim;

1. A process for preparation of Montelukast or a salt thereof, said process comprising the steps of

a. Reacting (S)-l -(3-((E)-2-(7-chloroquinolin-2-yl) vinyl) phenyl)-3-(2-isopropenyl phenyl] propan- 1-01 with methane sulfonyl chloride or toluene sulfonyl chloride to obtain a mesylated or tosylated derivative (hydroxy styrene mesylate or tosylate salt)
b. Condensing hydroxy styrene mesylate salt or tosylate with 1 -(mercapto methyl) cyclopropane acetic acid followed by saltification with an amine gives (1-[(R)-1-(3- [(E)-2-(7-chloroquinolin-2-yl)vinyl]-phenyl)-3-(2-isopropenylphenyl)propylsuJfanyl
methylj cyclopropyl] acetic acid amine salt (styrene amine salt)

c. Converting styrene amine salt to Montelukast amine salt; and

d. Converting Montelukast amine salt to Montelulcast free acid and/or its required alkali/alkaline salt

2. The process as claimed in claim Ta, wherein the reaction is carried out in presence of an organic solvent selected from the group comprising of chlorinated hydrocarbons, aromatic hydrocarbons, Tetrahydrofliran and mixtures thereof.

3. The process as claimed in claim lb. wherein the reaction is carried out in a polar solvent in a presence of a base

4. The process as claimed in claim 3, wherein said polar solvent is selected from the group comprising of N,N-dimethylformamide, dimethylsulphoxide, N,N-dimethylacetamide, Nmethylpyrrolidine, methanol, THE and mixtures thereof.

5. The process as claimed in claim 3, wherein said base is selected from metal alkoxides, metal hydrides, metal carbonates, alkyl lithium salts and mixtures thereof

6. The process as claimed in claim Ib, wherein the preferable amine salt is dicyclohexylamine salt.

7. The process as claimed in claim Ic, wherein the reaction includes treating said styrene amine salt with sulphuric acid and isolating the obtained Montelukast as amine salt.

8. The process as claimed in claim 1 c, wherein the reaction optionally includes converting said styrene nine salt to its free acid and treating with sulphuric acid and isolating the obtained Montelukast as amine salt.

9. The process as claimed in claim ic, wherein said Montelukast amine salt is selected from I -methyl-3-phenylpropylamine, 1 ,2-cyclohexyl diamine salt and mixtures thereof.

10. The process as claimed in claim Id, wherein the reaction includes converting said Montelukast amine salt to its free acid and treating alkali/alkaline base and isolating Montelukast as its alkalilalkaline salts.

11. The process as claimed in claim 10, wherein the reaction further includes (i) providing a solution of Montelukast free acid in a halogenated solvent, aromatic solvent, alkanols and mixtures thereof; (ii) treating said solution with an alcoholic base to convert said Montelukast free acid into a alkatilalkaline salt of Montelukast; (iii) concentrating the reaction mass to dryness; (iv) adding a cyclic or acyclic hydrocarbon solvent to said solution thereby precipitating said alkalilalkaline salt of Montelukast.

12. The process as claimed in claim Id, wherein the reaction optionally includes treating Montelukast amine salt with alkali/alkaline base and isolating Montelukast as its alkalilalkaline salts.

13. The process as claimed in claim 12, wherein the reaction includes (i) providing a solution of Montelukast amine salt in a halogenated solvent, aromatic solvent, or mixtures thereof; (ii) treating said solution with an alkali/ailcaline base to convert said Montelukast amine salt into a salt of Montelukast; (iii) concentrating the reaction mass to dryness; (iv) adding a cyclic or acyclic hydrocarbon solvent to said solution thereby precipitating said alkalilalkaline salt of Montelukast.

14. The process as claimed in claim 13, wherein alkali/alkaline base is selected from the group consisting of sodium hydroxide, sodium methoxide or sodium ethoxide in methanol, ethanol, propanol, butanol, 2-propanol or tert-butanol

15. The process as claimed in claims 11 & 13, wherein said hydrocarbon solvent is selected from the group consisting of cyclohexane, pentane, hexane, heptane and mixtures thereof.

Documents:

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Patent Number

269501

Indian Patent Application Number

1284/CHE/2008

PG Journal Number

44/2015

Publication Date

30-Oct-2015

Grant Date

26-Oct-2015

Date of Filing

26-May-2008

Name of Patentee

LAURUS LABS PVT LTD

Applicant Address

2ND FLOOR SERENE CHAMBERS ROAD #7 BANJARA HILLS HYDERABAD 500034

Inventors:

#	Inventor's Name	Inventor's Address
1	INDUKURI VENKATA SUNIL KUMAR	3RD FLOOR, UMA HYDERABAD HOUSE, RAJBHAVAN ROAD, SOMAJIGUDA, HYDERABAD-500082
2	MR. SIMHADRI SRINIVAS	3RD FLOOR, UMA HYDERABAD HOUSE, RAJBHAVAN ROAD, SOMAJIGUDA, HYDERABAD-500082
3	DR. CHAVA SATYANARAYANA	3RD FLOOR, UMA HYDERABAD HOUSE, RAJBHAVAN ROAD, SOMAJIGUDA, HYDERABAD-500082

PCT International Classification Number

A61K31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA