FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"A PROCESS FOR SYNTHESIS OF MONTELUKAST SODIUM"
2. APPLICANT
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India
3.PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.


Technical field of the Invention:
The present invention relates to a process for synthesis of montelukast sodium through a novel intermediate.
Background and prior art:
Montelukast and its monosodium salt are well known leukotriene antagonists. They are used as an antiasthmatic agent. Leukotriene antagonists constitute a group of locally acting hormones produced in living system from arachidonic acid.
EP480717 disclosed certain substituted quinoline compounds including Montelukast sodium, methods of their synthesis and pharmaceutical compositions using theses compounds.The synthesis disclosed in this patent involves coupling of methyl-1-mercaptomethyl)cyaclopropaneacetate with 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)-ethenyl) phenyl)-methanesulfonyloxypropyl)phenyl-2-propanol followed by hydrolysis to form montelukast free acid which can be isolated as sodium salt.

Montelukast sodium
The alternate routes of synthesis are known in the art such as WO95/18107,US5614632, US20050107612,EP1783117,US5565473.
Montelukast sodium is a potent drug for treatment of asthma. Due to technical advancements there are constant efforts to develop newer routes of synthesis for montelukast sodium. The present invention describes a new route of synthesis of montelukast sodium.
Objectives of the invention:
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It is an object of the present invention to provide a process for synthesis of montelukast sodium through a novel intermediate.
It is a further object of the present invention to provide a simple and economic process for preparation of montelukast sodium.
Summary of the invention:
The present invention provides a new process for preparation of montelukast sodium which comprises conversion of 2-(2-(3-(S)-(3-2-(7-Chloro-quinolinyl)-ethenyl) phenyl-3-chloropropyl) phenyl-2-propanol (I) to a novel intermediate(II) through an intermediate step of protection of hydroxyl group of compound (I) using a suitable protecting agent, most preferably, 2, 4-dihydropyran in presence of triphenyl phosphonium bromide. The condensation of this novel intermediate compound with mercaptomethyl cyclopropane acetic acid or its acid derivative in presence of a base and a suitable solvent to get compound of formula (III) or (IIIA), respectively.
Further, deprotection of III using a deprotecting agent in form of acid or acid addition salt and followed by preparation of organic amine salt (IV). Alternatively, deprotection of IIIA, followed by hydrolysis and insitu conversion to compound IV. Finally, compound of formula IV is purified and treated with a suitable solvent and a solution of sodium methoxide in methanol to obtain the desired montelukast sodium.
Detailed description of the invention:
The present invention describes a new process for synthesis of Montelukast sodium with good yield and purity. The process is simple and involves less number of steps.
The reaction scheme 1 is collectively depicted as follows:
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(I)
(II)




COOH
(HI)

Where R = CN, CONH2, COOR' (R'=alkyl)

(IMA)

(1MB)


.organic amine salt
(IV)


Montelukast sodium

A preferred aspect of the process of the present invention comprises conversion of 2-(2-(3-(S)-(3-2-(7-Chloro-quinolinyl)-ethenyl) phenyl-3-chloropropyl) phenyl-2-propanol (I) to a compound of formula (III) or (IIIA) via compound (II). The conversion takes place through an intermediate step of protection of hydroxyl group of compound (I) using a suitable protecting agent, most preferably, 2, 4-dihydropyran in presence of triphenyl phosphonium bromide. The protection of hydroxyl group results in formation of a novel intermediate of formula (II). Compound of formula (I) can be prepared by any of the known methods of synthesis.
Compound of formula (II) is then further condensed with mercaptomethyl cyclopropane acetic acid in presence of a base and a suitable solvent to get compound of formula (III). The condensation takes place in presence of a base such as sodium hydride, cesium carbonate, n-butyl lithium or the like. The suitable solvent for the condensation can be selected from dimethylformamide, tetrahydrofuran, dioxane, preferably dimethylformamide.
Alternatively Compound of formula (II) is condensed with mercaptomethyl cyclopropane derivatives such as cyano, amido, alkyl ester in presence of a base and a suitable solvent to get compound of formula (IIIA).This is another aspect of the present invention. A suitable base and the solvent can be selected from hereinabove.
The condensation takes place by treating the compound of formula (II) with a base in presence of a suitable solvent as described above and heated at a temperature of 60°C. The reaction mass is then cooled to a temperature of 25-30 °C and further chilled to a temperature of 15-20 °C. A solution of mercaptomethyl cyclopropane acetic acid or its derivative in an inert solvent selected from tetrahydrofuran, dimethyl formamide or dioxane, preferably dimethylformamide is added to the reaction mixture. The reaction mass is heated to a temperature of 35-40 °C, cooled and filtered. To the clear filtrate water is added and pH of the aqueous layer is adjusted to 5-6 using aqueous acetic acid and extracted using a suitable solvent such as ethyl acetate, toluene, methylene chloride, preferably ethyl acetate. The solvent layer is then concentrated to get compound (III) or (IIIA).
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Compound of formula (III) or (IIIA) is then deprotected using a deprotecting agent in presence of a mixture of solvents selected from dimethylformamide: methanol or tetrahydrofuran: methanol. A suitable deprotecting agent in form of acid or acid addition salt is added thereto and heated the reaction mass to 40 °C. The preferred acid addition salts are selected from the group comprising pyridinium p-toluene sulphonate, pyridine hydrochloride, pyridine hydrobromide, most preferably pyridinium p-toluene sulphonate. A suitable organic solvent such as ethyl acetate is added and the reaction mass is cooled to 25-30 °C to obtain deprotected compounds of III or IIIA.
Tartaric acid solution and an organic amine salt such as isopropylamine, dicyclohexylamine, diisopropylethylamine, tert-octylamine are added thereto the deprotected compounds of III. The reaction mass is chilled to 0-5 °C, filtered the obtained solid and dried under vacuum at 35-40°C to yield Montelukast organic amine salt (IV).
Compound of formula (IIIB) obtained by the deprotection of IIIA is further hydrolyzed using a suitable base such as sodium hydroxide, potassium hydroxide and lithium hydroxide whereby the mercapto cyclopropane acetic acid derivative is hydrolysed and insitu converted to an organic amine salt (IV).
The organic amine salt of Montelukast (IV) obtained by any of the routes as described in Scheme 1 of the present invention. Compound of formula (IV) is further treated with a mixture of solvents such as mixture of methanol and ethyl acetate to isolate pure organic amine salt of Montelukast which has purity of more than 95%.
Montelukast sodium is prepared by treating pure organic amine salt of Montelukast with a suitable solvent such as toluene and a solution of sodium methoxide in methanol. The solvent is removed under vacuum at about 40-45°C. The residue is added to a solvent mixture of toluene and heptane at a temperature of 25-30°C. The resulting solid is stirred, filtered and dried under vacuum at a temperature of 85-90°C.
The use of 2,4-Dihydropyran as the protecting agent is the major aspect of the present invention. The protecting agent is stable in basic reaction conditions hence it assures that
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the hydroxyl group remains protected till the condensation of compound (II) and mercapto cyclopropane acetic acid or its derivative is complete. Protection of hydroxyl group using Dihydropyran has another advantage that it avoids formation of the styrene impurity thus enhancing purity of the product.
The invention will now be illustrated further in relation to the following examples without restricting the scope of the invention in any way.
Examples:
Example 1:
Preparation of (S-(E))-2-(3-(2-(7-Chloro-quinolinyl)-ethenyl)phenyl)-3-
chloropropyl)benzoic acid methyl ester.
(S)-(E)-2-(3-(2-(7-Chloro-quinolinyl)ethenyl)phenyl)-3 -hydroxy propyl)benzoic acid methyl ester (10 gms) was treated with methylene chloride (100 ml) at 25°C under nitrogen atmosphere. The reaction mass was cooled to 0-5°C and thionyl chloride (4.75 ml) was added. Methylene chloride was distilled out completely under vacuum at 35-40°C to get a residue. The residue was treated with 10% of methanol in acetonitrile (100 ml) at 40-45°C, followed by cooling to 25°C and filtered. The filtered solid was dried under vacuum at 40-45°C to yield the title compound (8 gms).
Example 2:
Preparation of 2-(2-(3-(S)-(3-2-(7-Chloro-quinolinyl)-ethenyl)phenyl-3-
chloropropyl)phenyl-2-propanol.
To 10 gms of the compound obtained from example 1, toluene (100 ml) was added. The reaction mass was chilled to 0-5°C and methyl magnesium chloride (72.8 ml) was added slowly at 0-5°C. The reaction mass was quenched slowly into ice-water mixture (100 ml) below 20°C and pH of the reaction mass was adjusted to 6.5 to 7.0 using 10% acetic acid. The organic layer was separated by extraction with toluene (50 ml x 2). The combined organic layer was concentrated under vacuum at 40-45°C to get residue. The title
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compound was isolated by treating the residue with heptane (50 ml), filtering and drying under vacuum at 40-45 °C to yield the title compound (8 gms)
Example 3:
Preparation of 2-(2-(3-(S)-(3-2-(7-Chloro-quinolinyl)ethenyl)phenyl)-3-
chloropropyl)phenyl-2-propoxy)-tetrahydropyran.
10 gms of 2-(2-(3-(S)-(3-2-(7-Chloro-quinolinyl)-ethenyl)phenyl-3-chloropropyl)phenyl-2-propanol was treated with methylene chloride (100 ml) under nitrogen atmosphere at 25°C. 2,4-dihydropyran (15.94 ml) and triphenyl phosphonium bromide (0.6 gm) were added thereto and heated to 40°C. The reaction mass was cooled to 25°C and concentrated under vacuum at 30-35°C to yield the title compound (10 gms).
Example 4:
Preparation of (R)-1 - [1 -(3 -(2-(7-Chloro-2-quinolinyl)-ethenyl)-phenyl)-3 -((2-(2-(2-
tetrahydropyranyloxy)-2-propyl)-phenyl)-propyl)thio]-cyclopropane acetic acid.
Dimethylformamide (50 ml) and cesium carbonate (28.3 gms) were mixed and slowly
heated to 60°C. Chilled to 15-20°C and a solution of mercaptomethyl cyclopropane acetic
acid in dimethylformamide (3.8 gms in 20 ml) was added thereto. The temperature of the
reaction mass was raised to 25-30°C, a solution of 2-(2-(3-(S)-(3-2-(7-Chloro-
quinolinyl)ethenyl)phenyl)-3-chloropropyl)phenyl-2-propoxy)-tetrahydropyran in
dimethylformamide (10 gms in 30 ml) was added slowly, further raised the temperature to 35-40°C. The reaction mass was cooled to 25 °C, inorganic salts were filtered and washed with dimethylformamide (10 ml). To the clear filtrate, water (120 ml) was added. The pH of the aqueous layer was adjusted to 5.0-6.0 using 10% acetic acid and extracted with ethyl acetate (100 m1x2) and concentrated under vacuum at 40-45 °C to yield the title compound (9 gms).
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Example 5:
Preparation of Montelukast isopropylamine salt
i) 10 gms of compound obtained from example 4, tetrahydrofuran (20 ml) and methanol (65 ml) were mixed under nitrogen atmosphere. To this mixture, pyridinium para-toluene sulfonate (0.856 gm) was added and heated to 40°C. Ethyl acetate (30 ml) was added to hot reaction mixture followed by cooling to 25°C. Further 0.5M tartaric acid solution (30 ml) and isopropylamine (1.6 ml) were added. The reaction mass was chilled to 0-5°C to get residue which was filtered and dried under vacuum at 35-40°C to obtain Montelukast isopropylamine salt (6.3 gms).
ii) Montelukast isopropylamine salt obtained from step i) was further purified by treating with 10% methanol in ethyl acetate (25 ml) at 25 °C. The reaction solution was heated to 45-50°C and chilled to 0-5°C to get a residue. The residue was filtered and dried under vacuum at 35-40°C to yield the title compound (5 gms, HPLC purity: 98.3%).
Example 6:
Preparation of Montelukast sodium
5 gms of Montelukast isopropylamine salt obtained from example 5 was treated with 50 ml of toluene at 25°C. A solution of sodium methoxide in methanol (0.4 gm in 10 ml) was added thereto. The solvent was removed under vacuum at 40°C. The residue was added to a solvent mixture of toluene (15 ml) and heptane (50 ml) at 25°C . The resulting solid was stirred, filtered and dried under vacuum at 85-90°C to isolate the title compound (4 gms).
Dated this 21st day of May 2008
Dr. P. Aruna Sree Agent for the Applicant
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