FIELD OF THE INVENTION

The invention relates to an improved process for the manufacture of Methyl-2-(3-(2-(7- chloro-2-quinolinyl)-ethenyl)phenyl)-3-oxopropyl)benzoate II, which is an intermediate in the manufacture of Montelukast sodium of formula I.

I (H=Na)

BACKGROUND OF THE INVENTION: The compound of the formula I is well known as a Leukotriene antagonist and an inhibitor of leukotriene biosynthesis. These compounds are effective in the treatment of asthmatic disorders, etc. Several processes for the manufacture of the same are reported. An important intermediate in the synthesis of the compound of the formula I is the compound of the formula II. This intermediate is synthesized by subjecting intermediate of formula III to conditions of Heck reaction as known to those well versed in the art. This transformation involves coupling of the olefin III with the aryl halide of formula IV, followed by prototropic shifts to give the title compound II.

The European Patent No. 480717 relates to the manufacture of unsaturated hydroxyalkylquinoline acids having activity as leukotriene antagonists and to methods for their preparation. Also reported are the compounds of the formula II, which is as stated above an important intermediate in the synthesis of compounds of the formula I. This intermediate is manufactured from a compound of the formula III by utilizing Lithium salts, Palladium acetate and methyl-2-bromoacetate.

III

This process utilizes costly chemicals especially the noble metal salts and other raw materials in large quantities which makes the process commercially unviable. Further the procedures for isolation and purification are difficult and inconvenient to carry out. Besides these processes give the compound in low purities and are hence not economical and commercially attractive.

European Patent No. 500360 relates to quinoline-containing ketoacids as leukotriene antagonists and to methods for their preparation. Also, reported are the compounds of the formula II, which is as stated above an important intermediate in the synthesis of compounds of the formula I. This intermediate is manufactured by utilizing Lithium salts, Palladium acetate and methyl 2-bromoacetate. This process again suffers from low yields and is hence not economical. Therefore it is very difficult and inconvenient to carry out the process.

European Patent No. 399818 relates to diarylstyrylquinoline diacids as leukotriene antagonists and to methods for their preparation. Also reported are the compounds of the formula II, which is as stated above an important intermediate in the synthesis of compounds of the formula I. This intermediate is manufactured by utilizing Lithium salts, Palladium acetate and methyl 2-bromoacetate. This process gives the compound of the formula II in low purity and yields (c.a 65-75%) and is not commercially viable.

Thus, there is a need in the art to provide a process for the manufacture of compound of formula II in high yield and purity.

OBJECTS OF THE INVENTION:

An object of the present invention is to provide a process for the transformation from a compound of the formula III to a compound of the formula II in high yields and purity.

DETAILED DESCRIPTION-

The present invention relates to a process for the preparation of methyl 2-(3-(2-(7-chloro-2- quinolinyl)-ethenyl)phenyl)-3-oxopropyl)benzoate of the formula II,

II III

IV X = Cl, Br, I

comprising the steps of reacting l-(3-(2-(7-chloro-2-quinolinyl)ethenylphenyl)-2-propen-l-ol of the formula III with methyl 2-halobenzoate of the formula IV at 50 ⁰ C to 150 ⁰ C in an ionic liquid of the formula MR _a X ^" wherein M, R, R ₁ , R ₂ are as defined below in presence of a base and a metal catalyst, followed by extraction and crystallization using an organic solvent to obtain a compound of formula II.

In the ionic liquid described, it may be possible to utilize the quaternary ammonium salts of the formula NR1R2R3R4X ^" (M=N as indicated above) where R ₁ , R ₂ , R3 and R ₄ connote alkyl such as methyl, ethyl, n- or iso-propyl, n-, iso- or tert- butyl etc; aralkyl such as benzyl, phenethyl, substituted phenethyl, phenylpropyl etc; aryl such as phenyl, substituted phenyl etc and X could be halo, alkyl sulfonate etc. The ionic liquid used in the synthesis may be selected from the group comprising tetrabutyl ammonium bromide, tetrabutyl ammonium chloride, tetrabutyl ammonium hydrogen sulfate, or imidazolium salts such as l-bromo-3- methylimidazolium hexaphosphate or l-bromo3-methylimidazolium tetrafluoroborate, 1- cyclohexyl-3 -methyl tris(perfluoroethyl)trifluorophosphate or quaternary phoshphonium salts such as tetraphenylphosphonium bromide or methyltriphenylphosphonium bromide, preferably tetrabutyl ammonium bromide. A favorable ratio of the ionic liquid with respect to the substrate of formula III may be 10-50% but preferably 25-30%. The ionic liquid along with the catalyst may be recycled a number of times but preferably for up to 5 cycles.

One advantage of the invention is that it does not require use of any additional conventional solvent like dimethylformamide (DMF) or N-methylpyrrolidone (NMP). Further the final product may be isolated by extraction and distillation and the catalyst residue recycled several times. This also results in reduced environmental burden since there is practically no discharge. Since, the present invention utilizes ionic liquids for conversion of a compound of formula III to a compound of formula II, the efficiency of the process is better, the product quality is also better and ecologically beneficial.

The metal catalyst may be selected from the group comprising palladium acetate, palladium chloride, palladium bromide or palladium complex with triaryl phosphine. The preferred catalyst is palladium acetate. The amount of catalyst may be in a weight ratio of 0.1 to 1.0 % with respect to compound III.

The base employed is selected from group comprising of triethyl amine, triisopropyl amine or tributyl amine, preferably triethyl amine. The base is preferably used in the range of 1.0 to 5.0 moles with respect to the input substrate of formula III. The organic solvent comprises of a hydrocarbon such as benzene, toluene, preferably toluene or a chlorinated hydrocarbon such as methylene chloride, ethylene chloride, alkyl nitriles such as acetonitriles.

The following examples are illustrative of the invention but not limitative to the scope thereof.

EXAMPLES

Example 1

100 gm of l-(3-(2-(7-chloro-2-quinolinyl)ethenylphenyl)-2-propen-l-ol and 93.4 gm of methyl-2-iodobenzoate are suspended in 100 ml toluene. To this 25 gm of tetrabutylammonium bromide is added followed by 41.2 gm of triethylamine and 0.5 gm of Palladium acetate. The reaction mass is heated to 80 ⁰ C for 6 hrs. The reaction mass is cooled and extracted with toluene (1200 ml) and the residue is again extracted with 500 ml x 2 of toluene. The toluene layer is concentrated and the residue after crystallization is filtered, washed and dried at 55 ⁰ C under vacuum to get 120 gm of methyl-2-(3-(2-(7-chloro-2- quinolinyl)-ethenyl)phenyl)-3-oxopropyl)benzoate. Water content (by Karl Fisher) = 0.15%; Chemical assay (by HPLC) = 98.5%; Yield = 85% (by theory).

Example 2 (Recycling procedure)

100 gm of l-(3-(2-(7-chloro-2-quinolinyl)ethenylphenyl)-2-propen-l-ol and 93.4 gm of methyl-2-iodobenzoate are suspended in the above residue. To this 41.2 gm of triethylamine is added. The reaction mass is heated to 80 ⁰ C for 6 hrs. The reaction mass is cooled and extracted with toluene (1200 ml) and the residue is again extracted with 500 ml x 2 of toluene. The toluene layer is concentrated and the residue after crystallization is filtered, washed and dried at 55°C under vacuum to get 121 gm of methyl-2-(3-(2-(7-chloro-2- quinolinyl)-ethenyl)phenyl)-3-oxopropyl)benzoate. Water content (by Karl Fisher) = 0.13%; Chemical assay (by HPLC) = 98.6%; Yield = 86% (by theory)

The above example can be repeated up to a maximum of 5 batches without affecting the yield and quality parameters.

Example 3

100 gm of l-(3-(2-(7-chloro-2-quinolinyl)ethenylphenyl)-2-propen-l-ol and 93.4 gm of methyl-2-iodobenzoate are suspended in 100 ml toluene. To this 35 gm of tetraphenyl phosphonium bromide is added followed by 41.2 gm of triethylamine and 0.5 gm of

Palladium acetate. The reaction mass is heated to 8O ⁰ C for 22 hrs. The reaction mass is cooled and extracted with toluene (1200 ml) and the residue is again extracted with 500 ml x 2 of toluene. The toluene layer is concentrated and the residue after crystallization is filtered, washed and dried at 55 ⁰ C under vacuum to get 115 gm of methyl-2-(3-(2-(7-chloro-2- quinolinyl)-ethenyl)phenyl)-3-oxopropyl)benzoate. Water content (by Karl Fisher) = 0.14%; Chemical assay (by HPLC) = 98.1%; Yield = 81.5% (by theory)

Example 4

100 gm of l-(3-(2-(7-chloro-2-quinolinyl)ethenylphenyl)-2-propen-l-ol and 93.4 gm of methyl-2-iodobenzoate are suspended in 100 ml toluene. To this 35 gm of methyl triphenyl phosphonium bromide is added followed by 41.2 gm of triethylamine and 0.5 gm of

Palladium acetate. The reaction mass is heated to 80 ⁰ C for 22 hrs. The reaction mass is cooled and extracted with toluene (1200 ml) and the residue is again extracted with 500 ml x

2 of toluene. The toluene layer is concentrated and the residue after crystallization is filtered, washed and dried at 55 ⁰ C under vacuum to get 117 gm of methyl-2-(3-(2-(7-chloro-2- quinolinyl)-ethenyl)phenyl)-3-oxopropyl)benzoate. Water content (by Karl Fisher) = 0.19%;

Chemical assay (by HPLC) = 98.24%; Yield = 83% (by theory)