FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2006
PROVISIONAL SPECIFICATION [See section 10, Rule 13]
A PROCESS FOR THE PREPARATION OF MONTELUKAST ACID AND ITS SODIUM SALT
MACLEODS PHARMACEUTICALS LTD, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, WHOSE ADDRESS IS 304-ATLANTA ARCADE, OPP. HOTEL LEELA, MAROL CHURCH ROAD, ANDHERI (E) MUMBAI - 400 059, MAHARASHTRA, INDIA
THE FOLLOWING SPECIFICATION DESCRIBES THE INVENTION.
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FIELD OF INVENTION
This invention relates to an improved industrially suitable process for preparation of Montelukast sodium and more particularly relates to a method for the preparation of montelukast sodium salt using di-phenylchloro phosphate as an activating agent for 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-hydroxypropyl) phenyl-2-propanol, a key intermediate for montelukast sodium.
BACKGROUND & PRIOR ART OF INVENTION
The chemical name for the montelukast sodium is: [R-(E)}[[1-[3-2-(7-chloro-2-quinoliyl) ethenyl] phenyl]-3-[2-(1-hydroxy-1-methylethyl) phenyl[propyl] thio] methyl] cyclopropane acetic acid, monosodium salt, and it is generally represented by formula:

The title compound (Formula I) is a leukotriene antagonist and useful in the anti-asthmatic, anti-alergic, anti-inflammatory, and cytoprotective agent. Various methods for the synthesis of the title compound and its related compounds were reported in the prior art. EP Patent No. 480717
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discloses the process for the preparation of sodium salt of montelukast, which involves, reaction of 2-(2-(2-(3 (S)-(3-(2-(7-chloro-2-quinolenyl)-ethenyl) phenyl)-3-(methanesulfonyloxy) propyl) phenyl)-2-propoxy) tetra hydro pyran with methyl 1-(acetylthiomethyl) cyclopropane acetate in presence of hydrazine and cesium carbonate to yield methyl ester of montelukast. Further treatment of montelukast ester with pyridinium p-toluene sulfonate and sodium hydroxide in methanol resulted formation of montelukast sodium.
A detailed synthesis of title compound is reported in US patent No. 5, 565,473. The report involves reaction of 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-hydroxypropyl)phenyl-2-propanol with methane sufonyl chloride, further coupled with 1-(mercaptomethyl) cyclopropane acetic acid methyl ester in presence of sodium hydride or cesium carbonate in tetrahydrofuran which was further hydrolysed to montelukast acid and finally converted to its sodium salt. These processes are difficult on large scale due to some tedious reaction conditions, low yields and freeze drying of compound.
US Patents No. 5,614,632 reported synthesis of montelukast sodium in crystalline form by reaction of 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-hydroxypropyl) phenyl-2-propanol with methane sulfonyl chloride, in the presence of base to yield 2-(2-3(S)-(3-(7-chloro-2-quiniolinyl)-ethenyl)phenyl)-3-methanesulfonyloxypropyl)phenyl-2-propanol followed by chiral substitution of mesyl group by 1-(mercaptomethyl) cyclopropane acetic
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acid through dilitihium dianion formation of 1-(mercaptomethyl) cyclopropane acetic acid or its methyl ester. There are several more reports such as EP 1631550, US 2005/0256156 A1, WO 95/18107, WO 2004/108679, WO 2005/105751, US 2006/0194839 containing the preparation of montelukast sodium through dilitihim dianion formation of 1-(mercaptomethyl) cyclopropane acetic acid or its methyl ester followed by coupling with 2-(2-3(S)-(3-(7-chloro-2-quiniolinyl)-ethenyl) phenyl)-3-methanesulfonyloxypropyl) phenyl-2-propanol to form methyl ester of montelukast, which was further converted to sodium salt through acid. US 2005/023424 disclosed a process for preparation of montelukast sodium by isolating t-butyl amine salt of montelukast, followed by purification of t-butyl amine salt and further converted to montelukast sodium. Similarly WO/2006/064269 reported route through magnesium salt of montelukast.
Several bases reported for coupling of 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-hydroxypropyl) phenyl-2-propanol with 1-(mercaptomethyl) cyclopropane acetic acid or its ester such as lithium hydroxide, sodium hydroxide, sodium methoxide, n-butyl lithium, lithium methoxide, di-isopropylethylamine, potassium tertiary butoxide, and quarternary ammonium bases etc.
There are several another routes reported for the synthesis of montelukast sodium in US 2005/0245569, WO 2006/008751 but these involves the number of stages like protection, deprotection, use of costly raw materials,
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some unsafe chemicals which makes the process not suitable for large scale-production.
In all prior art most of the processes explains activation of 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-hydroxypropyl)phenyl-2-propanol with methane sulfonyl chloride to form mesylate, which is very sensitive, stable at -15 °C, has to prepare just before thiolation step, this problem is even more compounded in thiolation with with 1-(mercaptomethyl) cyclopropane acetic acid or ester due to use of costly, unsafe chemicals and raw materials. Moreover, chiral neucleophilic substitution of mesylate group by 1-(mercaptomethyl) cyclopropane acetic acid or ester is carried out at low temperatures for longer periods.
Because of these limitations in prior art processes, there is a scientific and industrial need to develop a better, cheap, and safe process for the preparation of montelukast sodium salt, having more stable intermediates, use of safe chemicals and easy operations.
This invention is, therefore, made with the following objects so that most of the drawbacks or limitations of the prior art processes for the preparation of montelukast sodium salt could be overcome.
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OBJECT OF INVENTION
It is an object of the present invention to provide a process for the preparation of montelukast acid, its salt, using a novel intermediate, which is easy to handle, storage, and economically feasible. It is another object of the present invention to provide an improved safe, and easy process for the production of montelukast sodium salt.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of sodium salt of montelukast comprising the following steps;
a) activating the 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-hydroxypropyl)phenyl-2-propanol with di-phenylphosphoryl group in the presence of a base and co-solvent;
b) reacting the product of step a with 1-(mercaptomethyl) cyclopropane acetic acid alkyl ester in the presence of base and solvent;
c) hydrolyzing the product of step b to obtain the alkali salt of montelukast;
In the other embodiment, co-solvent is removed prior to step-b, preferably it is removed by distillation after the aqueous work-up. In another embodiment, base used is dimethylaminopyridine, mole ratio of base is between 1.0 and 6.0, preferably 4.0.
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In another embodiment, solvent is non-polar, preferably dichloromethane.
In another embodiment, reaction temperature is between -70 to -10 °C,
preferably at -70 °C.
In another embodiment, reaction period is between 0.5 h to 12.0 h.
In another embodiment, the process further comprises the coupling between
product of step a and 1-(mercaptomethyl) cyclopropane acetic acid alkyl
ester to obtain ester of montelukast.
In another embodiment, base used for coupling is sodium hydroxide.
In another embodiment, solvent used in coupling (step b) is water and
tetrahydrofuran.
In another embodiment, the process comprises the hydrolyzing of product of
step b and its salt formation to give montelukast sodium.
In another embodiment, alkali used for salt preparation is sodium hydroxide.
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8
Synthetic Scheme for Amorphous Montelukast Sodium



DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides a process for the preparation of sodium salt of montelukast comprising the following steps;
a) activating the 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-hydroxypropyl)phenyl-2-propanol with di-phenylphosphoryl group in the presence of a base and co-solvent.
b) reacting the product of step a with 1-(mercaptomethyl) cyclopropane acetic acid alkyl ester in the presence of base and solvent.
c) hydrolysing the product of step b to obtain the alkali salt of montelukast. A preferable pharmaceutical^ salt is sodium salt.
Step a, is the activation of 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-hydroxypropyl)phenyl-2-propanol by phosphoryl group, preferably performing the reaction using diphenylchlorophosphate, which preserves the desired chirality of the molecule.
Activation of 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-hydroxypropyl) phenyl-2-propanol by diphenylchlorophosphate group is carried in non-polar solvent in the presence of a base, preferably dichloromethane. The reaction temperature kept between -70 and -10 °C, most preferably at -70 °C, for 1.0 to 3.0 h. Isolation of product of step a
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involves, aqueous work-up, distillation and crystallization in ethyl acetate-hexane.
The present invention provides a novel intermediate for the preparation of
montelukast sodium salt. All the prior art processes advocating the activation
of 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-
hydroxypropyl)phenyl-2-propanol by sulfonyl group viz mesylate or benzylsulfonate, till to date there is no report for activation of 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3-hydroxypropyl)phenyl-2-propanol by phosphoryl group, moreover, this novel intermediate for the preparation for the sodium salt is more stable and could be easily isolated as solid powder, unlike other salts reported in the prior art. It can be store at moderate temperatures.
Step b is thiolation of product of step a, the solvent used is dimethylformamide, water and tetrahydrofuran, most preferably tetrahydrofuran. The solvent is removed prior to step c. Base used for the thiolation of product of step a, is alkaline earth hydroxides, more preferably sodium hydroxide, which is inexpensive, cheap and easy to handle.
The thiolation of product of step a; is performed in the excess mole ratio of base, between 1.0 to 7.0 mole, per mole of product of step a more preferably 2.4 to 2.5 moles per mole of substrate. The reaction temperature is -10 to 30 °C, preferably 5 °C.
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Step c is the hydrolysis of the product of step b to form montelukast acid and the subsequent formation of montelukast alkali salt, can be performed by any method reported in prior art. See for example WO 2005/105751. Solvent used in the reaction is methanol, water and tetrahydrofuran. Base used for the salt preparation is selected from alkali metal hydroxides, preferably sodium hydroxide.
Montelukast sodium prepared in this invention may be used for the pharmaceutical formulations and the use in the treatment of respiratory diseases.
The present invention is described with reference to the following examples illustrating the process for the preparation of montelukast sodium. However, these examples are provided for illustrative purposes only and or not to be construed as limitations on scope of the process of this invention.
EXAMPLES
Example 1: Preparation of methyl ester of 1-(mercaptomethyl) cyclopropane acetic acid
To a 250.0 ml round bottom flask, solution of 1-(mercaptomethyl) cyclopropane acetic acid (10.0 g) in methanol (100.0 ml) was charged. The reaction mixture then cooled to 0 to 5 °C, followed by slow addition of thionyl chloride (7.4 ml), maintaining the temperature of the reaction mixture 0 to 5
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°C. Reaction mixture then heated to reflux for 2.0 h. After completion of the reaction, methanol is distilled of under reduced pressure to yield methyl ester of 1-(mercaptomethyl) cyclopopane acetic acid as oil. (9.0 g)
Example 2: Preparation of 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-phosphoryloxypropyl) phenyl-2-propanol
To a 250.0 ml round bottom flask, solution of 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-3-hydroxypropyl) phenyl-2-propanol (5.0 g) in 50.0 ml dichloromethane under nitrogen. To the reaction mixture dimethylaminopyridine (5.3 g) was added and stirred for 30.0 min at 25 °C. Reaction mixture then cooled to -70 °C and added di-phenyl chlorophosphate (7.5 ml) slowly. After complete addition, reaction mixture maintained for 2.0 h. Water to the reaction mixture (25.0 ml) after completion of reaction. Aqueous layer separated and extracted with dichloromethane (20.0 ml), collected organic layer washed by aqueous hydrochloride (0.5 M, 20.0 ml), followed by washing with 5% sodium bicarbonate solution (20.0 ml), and finally washed by saturated sodium chloride solution. (20.0 ml) Organic layer dried over sodium sulphate and distilled off under reduced pressure to get oily residue which was dissolved in 25.0 ml of ethyl acetate and added 200.0 ml of hexane. Allowed to stir at 25 °C for overnight and solid obtained filtered off to yield yellow coloured compound (7.3 g) which was dried at 30 °C for 1.0 h.
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Example 3: Preparation of [R-(E)-1[[[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-1 (hydroxyl-1 -methylethyl)phenyl]propyl]thio]methyl] cyclopropaneacetic acid methyl ester.
To a 100.0 ml of round bottom flask, solution of methyl ester of 1-
(mercaptomethyl) cyclopropane acetic acid (2.97 g) from Example 1, in
dimethylformamide (25.0 ml) was charged. 47% of sodium hydroxide
solution (1.56 g) was added to the reaction mixture, under nitrogen. The
reaction mixture stirred for 30.0 min at 25 °C and 22.0 ml of 25% of 2-(2-
(3(S)-(3-(7-chloro-2-quinolinyl)-ethenyl)phenyl)-3- phosphoryloxypropyl)
phenyl-2-propanol from Example 2, in tetrahydrofuran was added to reaction mixture. Viscous solution stirred overnight about 20 °C and added 100 ml of 5% sodium chloride solution and 100 ml ethyl acetate. Organic layer separated, washed with water (2 x 50.0 ml), followed by drying with sodium sulphate, and disilled off under reduced pressure to obtain 3.0 g of reaction product.
Example 4: Preparation of [R-(E)-1[[[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-1 (hydroxyl-1 -methylethyl)phenyl]propyl]thio]methyl] cyclopropaneacetic acid sodium salt
[R-(E)- 1 [[[3 -[2 -(7- chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-1 (hydroxyl-1 -methylethyl)phenyl] propyl] thio] methyl] cyclopropaneacetic acid methyl
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ester from Example 3 (2.9 g) was diluted with methanol (7.6 ml), followed by addition of 10% sodium hydroxide solution (2.5 g). Turbid solution obtained clarified by adding 0.5 ml of tetrahydrofuran. The clear solution was then stirred for 50.0 h at room temperature and evaporated to get oily residue, which further partitioned between ethyl acetate (20.0 ml) and water (10.0 ml). Organic phase washed by 5% sodium chloride solution (5.0 ml) to remove excess of sodium hydroxide and diluted with heptane (20.0 ml) to afford separable heavy liquid, which on separation stripped thoroughly with ethanol and evaporated to dryness to obtain the reaction product.
Dated this 29th day of September, 2006
FOR MACLEODS PHARMACEUTICALS LIMITED
By their Agent
KAJAL MANIK
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