Field of the invention

The present invention relates to a novel crystalline form of hexamethylenediamine salt of Montelukast. It also relates to a process for the preparation of hexamethylenediamine salt of Montelukast and its use for the preparation of Montelukast Sodium.

Background of the invention

Montelukast is a selective cysteinyl leukotriene type 1 receptor antagonist. The chemical name of Montelukast Sodium is [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl]-3-[2-(1-hydroxy-1-methylethyl) phenyl] propyl] thio] methyl] cyclopropaneacetic acid, monosodium salt and molecular formula is C35H35ClNNaO3S and molecular weight is 608.17. Montelukast Sodium is represented by formula (I):

Formula (I)

Montelukast sodium is marketed by Merck under brand name Singulair® and is indicated for the treatment of asthma.

Montelukast sodium and related compounds were first disclosed in EP 480,717. The synthesis of montelukast sodium, as taught in patent EP 480,717, involves coupling methyl 1-(mercaptomethyl)cyclopropaneacetate with 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)ethenyl)phenyl)-(methanesulfonyloxypropyl) phenyl-2-propanol followed by hydrolysis of the resulting montelukast methyl ester so as to form a free acid, which is followed by conversion of this montelukast free acid to a corresponding sodium salt, isolated as an amorphous material by freeze-drying. The tedious chromatographic purifications of the methyl esters and final products required, makes the above process unsuitable for large scale production. Additionally, the yields obtained are poor. Sodium montelukast, obtained by this method, is an oily substance. The product in amorphous form is obtained only after lyophilisation, another process that is not economical in a large scale production.

U.S. Pat. No. 5,523,477 describes the formation of montelukast and its subsequent conversion into the dicyclohexyl ammonium salt, which is converted to montelukast sodium.

U.S. Pat. No. 5,614,632 teaches a method of preparing crystalline montelukast sodium, which involves the preparation of the dilithium dianion of 1-(mercaptomethyl) cyclopropaneacetic acid, using butyl lithium, followed by condensation thereof with the mesylate alcohol to yield montelukast acid as a viscous oil. The resulting montelukast acid is converted, via the corresponding dicyclohexyl ammonium salt, to crystalline montelukast sodium.

The extra purification step via the dicyclohexyl ammonium salt, which is disclosed in U.S. Pat. Nos. 5,523,477 and 5,614,632, is necessitated from the difficulties encountered in obtaining crystalline materials. Thus, the crude acid is purified via the dicyclohexylamine salt by reacting it with dicyclohexylamine in ethyl acetate, followed by addition of hexanes to effect crystallization of the dicyclohexylamine salt, or by the crystallization from toluene/heptane. It is mentioned by the inventors of patent 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.

WO 2005/105751 discloses a process for preparing Montelukast sodium comprising reacting 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)ethenyl(phenyl)-3-(hydroxypropyl) phenyl-2-propanol with methanesulfonyl chloride to obtain 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)ethenyl)phenyl)-(methanesulfonyloxypropyl)phenyl-2-propanol, which is subsequently reacted with 1-(mercaptomethyl)cyclopropaneacetic acid alkyl ester in a solvent and in the presence of a co-solvent and a base such as NaOH, followed by hydrolysis of the resulting product of the previous step to obtain Montelukast sodium.

WO 2007/069261 describes a method for the preparation of sodium Montelukast. Several intermediate Montelukast amine salts are cited, but only dicyclohexylamine salt is exemplified.

Apart from dicyclohexylamine, there have been disclosed several highly voluminous secondary amines useful in the purification step of preparing sodium Montelukast. For example, international patent application WO 2006/008751 discloses dipropylamine salt of Montelukast.

Additionally, there are disclosures which use primary amines of low molecular weight for the purification of Montelukast Sodium. However, the process to obtain these amines takes a large number of hours and/or the yields are low. For instance, WO 2006/043846 describes the preparation of pure sodium Montelukast by using the tert-butylamine salt of montelukast. As described therein, the tert-butylamine salt of Montelukast was obtained after several hours of stirring (32 h) at room temperature.

WO 2007/004237 describes the preparation of alpha-methylbenzylamine salt of montelukast through a process which takes about 24 hours at room temperature.

The present invention provides a process for preparing Montelukast Sodium comprising converting a novel crystalline form of hexamethylenediamine salt of Montelukast into Montelukast Sodium. Unexpectedly, the process for preparing this novel crystalline salt overcomes the above mentioned problems and allows obtaining highly pure Montelukast Sodium.

Object of the invention

Therefore, it is an object of the invention is to provide a novel crystalline form of hexamethylenediamine salt of Montelukast of the formula (VII).

Another object of the invention is to provide process for preparing crystalline form of hexamethylenediamine salt of Montelukast of the formula (VII).

Yet another object of the invention is to provide the use of said crystalline form of hexamethylenediamine salt of Montelukast of the formula (VII) for the preparation of Montelukast Sodium of the formula (I).

Summary of the invention

An aspect of the invention is related to the crystalline form of hexamethylenediamine salt of Montelukast of the formula (VII).

Another aspect of the invention is related to the process for preparing hexamethylenediamine salt of Montelukast of the formula (VII) in crystalline form.

Yet another aspect of the invention is directed to the use of said crystalline form of hexamethylenediamine salt of Montelukast of the formula (VII) for the preparation of Montelukast Sodium of the formula (I).

Further aspect of the invention is directed to a process for preparing Montelukast Sodium of the formula (I) comprising steps of,
a) treating hexamethylenediamine salt of Montelukast of the formula (VII) with an organic or inorganic acid in the presence of solvent,
b) treating the reaction mixture of step (a) with a source of sodium ion; and
c) isolating Montelukast Sodium of the formula (I), optionally crystallizing Montelukast Sodium of formula (I).
Yet another aspect of the invention is directed to a process for preparing crystalline form of hexamethylenediamine salt of Montelukast of the formula (VII) comprising steps of,
a) reacting mesylate alcohol of the formula (III) with 1-(mercaptomethyl)cyclopropaneacetic acid of the formula (V) in the presence of base and solvent to obtain a montelukast acid, optionally isolating montelukast acid of the formula (VI),
b) treating Montelukast acid of the formula (VI) with hexamethylenediamine in the presence of a solvent to obtain hexamethylenediamine salt of Montelukast of the formula (VII),
c) optionally, crystallizing hexamethylenediamine salt of Montelukast of the formula (VII)

Yet another aspect of the invention is directed to provide a process for the preparation of Montelukast Sodium of the formula (I), comprises steps of,
a) reacting ester alcohol of the formula (II) with Grignard reagent in the presence of solvent and reaction promoters to obtain compound 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)ethenyl(phenyl)-3-(hydroxypropyl)phenyl-2-propanol of the formula (III),
b) reacting the compound 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)ethenyl(phenyl)-3-(hydroxypropyl)phenyl-2-propanol of the formula (III) with methanesulfonyl chloride in the presence of solvent to obtain the mesylate alcohol of the formula (IV),
c) reacting mesylate alcohol of the formula (IV) with 1-(mercaptomethyl)cyclopropaneacetic acid of the formula (V) in the presence of base and solvent to obtain a montelukast acid of the formula (VI), optionally isolating montelukast acid of the formula (VI),
d) treating Montelukast acid of the formula (VI) with hexamethylenediamine in the presence of a solvent to obtain hexamethylenediamine salt of Montelukast of the formula (VII), optionally crystallizing hexamethylenediamine salt of Montelukast of the formula (VII),
e) treating hexamethylenediamine salt of Montelukast of the formula (VII) with an organic or inorganic acid in the presence of solvent,
f) treating the reaction mixture of step (e) with a source of sodium ion; and
g) isolating Montelukast Sodium of the formula (I), optionally crystallizing Montelukast Sodium of the formula (I)

Also subject-matter of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of hexamethylenediamine salt of Montelukast of the formula (VII) in crystalline form as herein defined, together with an appropriate amount of pharmaceutically acceptable excipients or carriers.

Yet another aspect of the invention relates to the use of the hexamethylenediamine salt of Montelukast of the formula (VII) in crystalline form as defined herein for the manufacture of a medicament.

Brief description of the figures

Figure-1 shows the X-ray powder diffraction pattern (XRPD) of hexamethylenediamine salt of Montelukast.

Figure-2 shows the Differential Scanning Calorimetry (DSC) thermogram of hexamethylenediamine salt of Montelukast.

Details description of the invention

Accordingly, the present invention provides a process for the preparation of Montelukast Sodium of the formula (I), comprises steps of,
a) reacting ester alcohol of the formula (II) with Grignard reagent in the presence of solvent and reaction promoters to obtain compound 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)ethenyl(phenyl)-3-(hydroxypropyl)phenyl-2-propanol of the formula (III),
b) reacting the compound 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)ethenyl(phenyl)-3-(hydroxypropyl)phenyl-2-propanol of the formula (III) with methanesulfonyl chloride in the presence of solvent to obtain the mesylate alcohol of the formula (IV),
c) reacting mesylate alcohol of the formula (IV) with 1-(mercaptomethyl)cyclopropaneacetic acid of the formula (V) in the presence of base and solvent to obtain a montelukast acid of the formula (VI), optionally isolating montelukast acid of the formula (VI),
d) treating Montelukast acid of the formula (VI) with hexamethylenediamine in the presence of a solvent to obtain hexamethylenediamine salt of Montelukast of the formula (VII), optionally crystallizing hexamethylenediamine salt of Montelukast of the formula (VII),
e) treating hexamethylenediamine salt of Montelukast of the formula (VII) with an organic or inorganic acid in the presence of solvent,
f) treating the reaction mixture of step (e) with a source of sodium ion; and
g) isolating Montelukast Sodium of the formula (I), optionally crystallizing Montelukast Sodium of the formula (I)

The process for the preparation of Montelukast Sodium for formula (I) depicts below in Scheme-I: