Patent Application
20110112300
The present invention relates to improved processes for the preparation of Montelukast and its salts thereof.
Montelukast sodium namely Sodium 1-[[[(1R)-1-[3-[(1E)-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 useful 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.
EP 0 480 717 discloses Montelukast sodium along with other related compounds and the methods for their preparation. The reported method of synthesis proceeds through 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 for 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 sulfonyl 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 U.S. Pat. No. 5,614,632, that the crystalline montelukast dicyclohexylamine 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. Pat. No. 5,523,477, and U.S. Patent Application Publication Nos. 2005/0234241, 2005/0256156, 2005/0107612, and International Application Publication Nos. 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.
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 amine salts of Montelukast.
Another object of the present invention is to provide a process for the preparation of Montelukast alkali/alkaline 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;
In accordance with the present invention the main object is to prepare montelukast and salts thereof comprising the steps of;
In a preferred embodiment, 2-[2-[3(S)-[3-[2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-3-hydroxypropyl]phenyl]-2-propanol is treated with acetic anhydride followed by dehydration with PTSA yields (S)-1-(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-ol (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)phenyl)-3-(2-isopropenylphenyl]propyl methane sulphonate (mesylated styrene) of formula (V) or a corresponding tosylate. Also, use of other leaving group-containing compounds instead of the mesylate or tosylate intermediate is also contemplated. The reaction may process in polar 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 alkali/alkaline 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 to 50° 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 1-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, sodium hydride, n-butyl lithium, or cesium carbonate preferably 25% sodium methoxide in methanol at a temperature of −15 to 60° 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 amines, preferably 1-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, n-pentane, 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.
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.
To a stirred solution of 2-[2-[3(S)-[3-[2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-3-hydroxy propyl]phenyl]-2-propanol (100 gm) in dichloromethane (500 ml) at 25-30° C. 4-di(methyl amino)pyridine (5.32 gm) was added and cooled to 0° C. To the reaction mixture Triethylamine (26.4 gm) was added at 0° C. Acetic anhydride (26.7 gm) was added slowly at temp. 0-5° C. over 30-60 min and maintained the reaction at temp. 0-5° C. over 30 min. Reaction completion was monitored by TLC. After reaction completion the reaction mass was quenched into 7% NaHCO3(500 ml) and stirred for 15 min. Temperature was raised to 25-30° C. and maintained for 30 min. Reaction mass was settled for 15 min and separated the organic layer. Aq.layer was extracted with dichloromethane (250 ml). The combined organic layer was washed with 25% NH4Cl solution (500 ml). Organic layer was distilled below 40° C. to get the desired product as residue.
Output: 108.0 gm
PTSA (62.4 gm) was suspended in toluene (300 ml) 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 (300 ml) and stage-I (108 gm of stage-I dissolved in 200 ml dichloromethane). 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 (300 ml) and stirred for 15 min. Reaction mass temp was raised to 25-30° C. and maintained for 30 min. Reaction mass was settled for 15 min and the organic layer was separated. Aq.layer was extracted with dichloromethane (200 ml) at 25-30° C. The combined organic layer was washed with of DM Water (2×300 ml). Organic layer was concentrated below 40° C. to get the desired product as residue.
Output: 101.2 gm
To a stirred solution of Stage-II (101 gm) in methanol (500 ml) NaOH solution (35 gm of NaOH dissolved in 52 ml DM Water) was added at 25-30° C. over 30 min. 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 ethyl acetate (600 ml). To the obtained solution DM water (500 ml) was added pH was adjusted to 6.5-7.0 slowly with 1:1 dil HCl at 25-30° C. Aq layer was separated and again extracted with ethyl acetate (200 ml). The combined organic layer was washed with DM Water (500 ml). 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 (300 ml) and methanolic HCl (80 ml of 8%) was added over 30-60 min at room temperature. Reaction mixture was maintained for 2 hrs at room temperature one hour at 10-15° C. The precipitated product was filtered and washed the wet cake with chilled methanol (50 ml).
Output: 88.0 gm
To a stirred solution of compound obtained in Example-III (100 gm) in dichloromethane (600 ml), DM water (300 ml) 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 min at 25-30° C. and settled for 10 min. Organic layer was separated and the aq.layer was extracted with dichloromethane (200 ml). The combined organic layer was washed with DM Water (2×300 ml). Dichloromethane was distilled completely below 40° C. to get residue. The obtained residue was dissolved in dichloromethane (600 ml) and cooled to 0° C. Diisopropyl ethyl amine (DIPEA) (40.6 gm) was added under N2 atmosphere and again cooled to −30° C. Methane sulphonyl chloride (31.33 gm) was added at −30 to −25° C. slowly over 60 min 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 (1000 ml) below 5° C. The reaction mass was maintained for 10 min at 0-5° C. and 30 min at 25-30° C. Organic layer was separated and aq.layer was extracted with dichloromethane (200 ml). The combined organic layer was washed with DM Water (2×500 ml). Dichloromethane was distilled out completely below 40° C. to get desired product as residue.
Output: 105.0 gm
To a stirred solution of Stage-III (100 gm) in dichloromethane (300 ml) Diisopropylethylamine (27.1 gm) was charged and Reaction mass was stirred for 30 min at 40-45° C. Dichloromethane was distilled completely below 40° C. to get residue. The obtained residue was dissolved in dichloromethane (1000 ml) and cooled to 0° C. Diisopropyl ethyl amine (DIPEA) (40.6 gm) was added under N2 atmosphere and again cooled to 0° C. Methane sulphonyl chloride (31.33 gm) was added at 0 to 5° C. slowly over 60 min 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 (1000 ml) below 5° C. The reaction mass was maintained for 10 min at 0-5° C. and 30 min at 25-30° C. Organic layer was separated and aq.layer was extracted with dichloromethane (200 ml). The combined organic layer was washed with DM water (2×500 ml). Dichloromethane was distilled out completely below 40° C. to get desired product as residue.
Output: 105.0 gm
To a stirred solution of 1-(mercapto methyl)cyclopropane acetic acid (46 gm) in DMF (300 ml), NaH (25 gm) was added in four equal lots over 60 min at −5-0° C. The reaction mixture was maintained for 2 hrs at −5-0° C. Stage-IV (100 gm dissolves in 300 ml 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 TLC. After reaction completion reaction mixture was quenched in to mixture of 10% NaCl (1000 ml), and ethyl acetate (1000 ml) below 10° C. Reaction mixture was stirred for 10 min at 0-10° C. and 30 min 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 (500 ml) followed by of DM Water (2×500 ml). 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 (600 ml) at room temperature. To the above solution dicyclohexyl amine (50 ml) 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 hrs at room temperature. n-Hexane (1200 ml) was added slowly at room temperature over 60 min and maintained for 12 hrs. The precipitated product is filtered and washed with of n-Hexane (200 ml).
Output: 100.0 gm
To a stirred solution of 1-(mercapto methyl)cyclopropane acetic acid (36.7 gm) in DMF (300 ml), sodium methoxide (108.6 gm 25% methanolic soln) was added over 60 min at 0-5° C. The reaction mixture was maintained for 2 hrs at 0-5° C. mesylated Styrene (100 gm dissolves in 300 ml 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 reaction mixture was quenched in to mixture of 10% NaCl (1000 ml), and ethyl acetate (1000 ml) below 10° C. Reaction mixture was stirred for 10 min at 0-10° C. and 30 min 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 (500 ml) followed by of DM Water (2×500 ml). 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 (600 ml) at room temperature. To the above solution dicyclohexyl amine (50 ml) 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 hrs at room temperature. n-Hexane (1200 ml) was added slowly at room temperature over 60 min and maintained for 12 hrs. The precipitated product is filtered and washed with of n-Hexane (200 ml).
Output: 101.0 gm
To a stirred solution of Styrene DCHA salt (100 gm) in dichloromethane (500 ml) to DM Water (300 ml) was charged and pH was adjusted 4.0 to 4.5 with 1:1 dil Acetic acid at 25-30° C. The reaction mixture was stirred for stirred for 30 min at room temperature. Organic layer was separated and aq.layer was extracted with dichloromethane (300 ml). The combined organic layer was washed with DM water (2×300 ml). Organic layer was concentrated under below 40° C. to get semi solid material. n-Hexane (500 ml) was added and stirred for 30 min at room temperature. The precipitate was filtered and washed the wet cake with n-Hexane (100 ml). The wet product was dried at 40-45° C. to get styrene free acid (73 gm).
Styrene free acid (73 gm) was added to sulfuric acid (365 ml of 80%) in equal lots at 5°-10° C. Reaction mass was maintained for 1 hr. at 5-10° C. Reaction completion was monitored by TLC. After the reaction completion (product is ˜65%; styrene is ˜30%) the reaction mass was quenched into a mixture of DM water (730 ml), ethyl acetate (730 ml) and t-butanol (730 ml) below 10° C. After quenching the reaction mass pH was adjusted to 3.5-4.0 with 20% NaOH below 10° C. Again the temperature was raised to 25-30° C. and maintained for 30 min. Organic layer was separated and aq. layer was extracted with ethyl acetate (2×730 ml) at room temperature. The combined organic layer was washed with DM water (2×730 ml). 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 column chromatography (Mobile phase is dichloromethane:methanol, 99.5:0.5). The separated montelukast free acid was dissolved in ethyl acetate (180 ml) at 40° C. and cooled to room temperature under N2 atmosphere:
To the obtained solution 1-methyl-3-phenylpropylamine (9.7 ml) was added slowly at 25-30° C. over 30 min. Reaction mass was maintained for 60 min, seeded and maintain for 12-16 hrs at 25-30° C. under N2 atmosphere. After the product was precipitated, n-Hexane (360 ml) 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 (60 ml). The wet product was dried at 45-50° C. The dried product was purified by recrystallization in toluene.
Output: 70.0 gm
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 (1000 ml), ethyl acetate (1000 ml) and t-butanol (1000 ml) below 10° C. After quenching the reaction mass pH was adjusted to 3.5-4.0 with 20% NaOH below 10° C. Again the temperature was raised to 25-30° C. and maintained for 30 min. Organic layer was separated and aq. layer was extracted with ethyl acetate (2×500 ml) at room temperature. The combined organic layer was washed with 5% brine (2×1000 ml). 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 column chromatography (Mobile phase is dichloromethane:methanol, 99.5:0.5). The separated montelukast free acid was dissolved in ethyl acetate (300 ml) at 40° C. and cooled to room temperature under N2 atmosphere.
To the obtained solution 1-methyl-3-phenylpropylamine (16.2 ml) was added slowly at 25-30° C. over 30 min. Reaction mass was maintained for 60 min, seeded and maintain for 12-16 hrs at 25-30° C. under N2 atmosphere. After the product was precipitated, n-Hexane (600 ml) 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 (100 ml). The wet product was dried at 45-50° C. The dried product was purified by recrystallization in toluene.
Output: 50.0 gm
Purity by HPLC: 98.2%
To a suspension of Montelukast 1-methyl-3-phenylpropylamine salt (100 gm) in dichloromethane so (2000 ml) DM water (1000 ml) was charged pH 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 min and settle for 20 min. Organic layer was separated and aq.layer was extracted with dichloromethane (1000 ml). 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 min and maintained at 25-30° C. for 30 min. Dichloromethane was distilled completely below 40° C. to get semi solid material. Then methanol (800 ml) was charged at 40-45° C. under N2 atmosphere and stirred for 10 min. The obtained clear solution was treated with activated carbon and filtered the mass over hyflo bed and washed with methanol (200 ml). The clear filtrate was distilled out completely under reduced pressure below 45° C. Pentane (100 ml) was charged to the above residue and distilled out methanol traces completely below 45° C. Again Pentane (2000 ml) was and maintained for 4 hrs at 25-30° C. under N2 atmosphere. The precipitated product was filtered under N2 atmosphere and washed the wet cake with Pentane (100 ml). 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 hrs.
Output: 70.0 gm
HPLC Purity: 99.5%
| Number | Date | Country | Kind |
|---|---|---|---|
| 1284/CHE/2008 | May 2008 | IN | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/IN09/00299 | 5/25/2009 | WO | 00 | 2/17/2010 |
