WO2011004298A1

WO2011004298A1 - Montelukast hexamethylenediamine salt and its use for the preparation of montelukast sodium

Info

Publication number: WO2011004298A1
Application number: PCT/IB2010/053041
Authority: WO
Inventors: Ravi Ponnaiah; Ashok Prasad; Sanjay Talukdar; Killol Patel; Hitarth Harshendu Acharya; Jitendra Parmar
Original assignee: Alembic Limited
Priority date: 2009-07-09
Filing date: 2010-07-02
Publication date: 2011-01-13

Abstract

The present invention relates to a montelukast hexamethylenediamine, Formule (I). It also relates to a process for the preparation of montelukast hexamethylenediamine and its use for the preparation of Montelukast Sodium.

Description

Title of Invention:

MONTELUKAST HEXAMETHYLENEDIAMINE SALT AND ITS USE FOR THE PREPARATION OF MONTELUKAST SODIUM

Field of the invention

[1]

[2] The present invention relates to Montelukast hexamethylenediamine. It also relates to a process for the preparation of montelukast hexamethylenediamine and its use for the preparation of Montelukast Sodium.

[3]

Background of the invention

[4] Montelukast is a selective cysteinyl leukotriene type 1 receptor antagonist. The

chemical name of Montelukast Sodium is [/?-(E)]-l-[[[l-[3-[2- (7-chloro-2-quinolinyl) ethenyl] phenyl]- 3-[2-(l-hydroxy-l-methylethyl) phenyl] propyl] thio] methyl] cyclo- propaneacetic acid, monosodium salt and molecular formula is C35H35ClNNaO3S and molecular weight is 608.17. Montelukast Sodium is represented by formula (I):

Formula (I)

[6]

[7] Montelukast sodium is marketed by Merck under brand name Singulair®and is

indicated for the treatment of asthma.

[8]

[9] 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 l-(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. [10]

[11] 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.

[12]

[13] U.S. Pat. No. 5,614,632 teaches a method of preparing crystalline montelukast

sodium, which involves the preparation of the dilithium dianion of l-(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.

[14]

[15] 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 di- cyclohexylamine 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.

[16]

[17] 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 l-(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.

[18]

[19] 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.

[20]

[21] 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.

[22]

[23] 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 hr) at room temperature.

[24]

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

[26]

[27] The present inventors have directed the research work towards preparation of a novel salt of montelukast which not only provides the desired purity but also devisal of all the disadvantages of the prior-art. Unexpectedly, when montelukast was converted to hexamethylenediamine salt and then it was further converted to montelukast sodium, the final compound was not only better in quality but also the yield and process efficacy was improved.

[28]

Summary of the invention

[29]

[30] The present invention provides a novel salt of montelukast, i.e hexamethylenediamine.

[31]

[32] Another aspect of the invention is the novel salt of montelukast as provided in the present invention is montelukast hexamethylenediamine.

[33]

[34] Yet another aspect of the invention is to provide process for the preparation of a

novel crystalline form of montelukast hexamethylenediamine of the formula (VII).

Formula (VII)

H₂N(CH₂)₆NH₂

[36]

[37] Yet another aspect of the invention is to provide the use of montelukast hexamethylenediamine of the formula (VII) for the preparation of Montelukast Sodium of the formula (I).

Formula (I)

[39]

[40] Yet another aspect of the present invention is to provide a process for the preparation of salt of montelukast in the form of hexamethylenediamine.

[41]

[42] Yet another aspect of the invention is to provide use of said crystalline form of montelukast hexamethylenediamine of the formula (VII) for the preparation of Montelukast Sodium of the formula (I).

Formula (I)

[44]

[45] Yet another aspect of the invention is to provide a process for the preparation of montelukast sodium of the formula (I) comprising:

[46] (a) treating montelukast hexamethylenediamine of the formula (VII) with an organic acid in the presence of water immiscible organic solvent;

[47] (b) treating the reaction mixture of step (a) with a source of sodium ion;

[48] (c) isolating Montelukast Sodium of the formula (I).

Formula (I)

[50]

[51] Yet another aspect of the invention to provide a process for the preparation of novel crystalline form of montelukast hexamethylenediamine , comprising :

[52] (a) providing a solution containing montelukast, hexamethylenediamine and solvent;

[53] (b) crystallizing a montelukast hexamethylenediamine from said solution. [55] Yet another aspect of the invention is to provide a process for the preparation of novel crystalline form of montelukast hexamethylenediamine of the formula (VII) comprising:

[56] a) reacting mesylate alcohol of the formula (IV)

[57]

Formula (IV)

[59] with l-(mercaptomethyl)cyclopropaneacetic acid of the formula (V)

[60]

Formula (V)

[62] in the presence of sodium methoxide or sodium ethoxide and aprotic dipolar solvent to obtain a montelukast acid, optionally isolating montelukast acid of the formula (VI);

Formula (VI)

[64]

[65] (b) treating montelukast acid of the formula (VI) with hexamethylenediamine in the presence of solvent to obtain montelukast hexamethylenediamine of the formula (VII);

Formula (VII)

H₂N(CH₂)₆NH₂

[67]

[68] Yet another aspect of the invention is to provide a process for the preparation of montelukast sodium of the formula (I) , comprising:

[69] (a) reacting ester alcohol of the formula (II)

Formula (II)

[71] [72] with Grignard reagent in the presence of tetrahydrofuran and reaction promoters to obtain compound

2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)ethenyl(phenyl)-3-(hydroxypropyl)phenyl-2-prop anol of the formula (III);

[73]

Formula (III)

[75]

[76] (b) reacting the compound

2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)ethenyl(phenyl)-3-(hydroxypropyl)phenyl-2-prop anol of the formula (III) with methanesulfonyl chloride in the presence of diisopropy- lethylamine to obtain the mesylate alcohol of the formula (IV);

Formula (IV)

[78] (c) reacting mesylate alcohol of the formula (IV) with

l-(mercaptomethyl)cyclopropaneacetic acid of the formula (V)

Formula (V)

[80] in the presence of sodium methoxide or sodium ethoxide in aprotic dipolar solvent to obtain a montelukast acid of the formula (VI);

Formula (VI)

[82] (d) treating montelukast acid of the formula (VI) with hexamethylenediamine in the presence of solvent to obtain montelukast hexamethylenediamine of the formula (VII);

Formula (VII)

H₂N(CH₂)₆NH₂

[84] [85] e) treating montelukast hexamethylenediamine of the formula (VII) with an organic acid in the presence of water immiscible organic solvent;

[86] f) treating the reaction mixture of step (e) with a source of sodium ion;

[87] g) isolating montelukast sodium of the formula (I).

Formula (I)

[89]

[90] Yet another aspect of the invention relates to a pharmaceutical composition

comprising an hexamethylenediamine salt of montelukast and at least one pharmaceutically acceptable excipients or carriers . The composition can be a therapeutically effective amount of montelukast hexamethylenediamine of the formula (VII) as herein defined, together with an appropriate amount of pharmaceutically acceptable excipients or carriers.

[91]

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

[93]

Brief description of the figures

[94]

[95] Figure-1 shows the X-ray powder diffraction pattern (XRPD) of montelukast hexamethylenediamine.

[96]

[97] Figure-2 shows the Differential Scanning Calorimetry (DSC) thermogram of montelukast hexamethylenediamine.

[98]

Details description of the invention

[99]

[100] As used herein, ' montelukast hexamethylenediamine ,' and variations thereof, mean any combination of hexamethylenediamine ions and montelukast ions, whether in solid state such as a crystalline substance or dissolved in a solvent. It also includes all polymorphic and pseudo- polymorphic salts, if any, including hydrates, etc. Generally a hexamethylenediamine montelukast salt can be represented by the formula (VII).

[101] Formula (VII)

H₂N(CH₂)₆NH₂

[103]

[104] It has been found that a montelukast hexamethylenediamine salt can be readily

isolated in solid, particularly crystalline form. A montelukast hexamethylenediamine can be formed by combining hexamethylenediamine and montelukast in a solution. Typically the free base and the free acid, respectively, are used although it may be possible to use salt forms of either compound. The novel montelukast hexamethylenediamine can be easily isolated from the reaction mixture in the crystalline form, and then, if necessary, purified by recrystallization / purification from typical organic solvents to reduce impurities down to a pharmaceutically-acceptable level. The montelukast hexamethylenediamine can be easily converted to the free montelukast acid that, if necessary, is further converted into another pharmaceutically acceptable salt, for example, into the sodium salt.

[105]

[106] In one embodiment, the present invention is related to the crystalline form of montelukast hexamethylenediamine of the formula (VII).

[107]

[108] The montelukast hexamethylenediamine is characterized by an X-ray powder

diffraction pattern substantially presented in Table 1 and in FIG. 1.

[109]

[HO] XRPD data of the montelukast hexamethylenediamine

[Table 1]

[Table ]

[111]

[112] DSC diagram of the montelukast hexamethylenediamine shows the melting point, determined as 'the onset peak', equal to 160.20° C.

[113]

[114] In another embodiment, the present invention, the use of hexamethylenediamine in making crystalline montelukast salt provides for an alternative method for isolating and/or purifying crude montelukast acid before its conversion to montelukast sodium. The known organic amines that have been used for this same purpose, i.e. the dicyclo- hexylamine or t-butyl amine, are flammable, toxic and irritant liquids which are unstable in open air and of unpleasant smell. For instance the t-butyl amine boils already at about 45⁰C and its toxicity, expressed as LD50 value in rats after oral administration is 44 mg/kg. Dicyclohexylamine is a high boiling flammable liquid with the LD50 toxicity of 373 mg/kg. Thus, in using them during chemical synthesis, special precautions may be necessary to protect the worker and the environment. To the contrary, hexamethylenediamine is a stable solid compound of low toxicity (LD50 is 792-1127 mg/kg) and it can be handled with less difficulty.

[115]

[116] In another embodiment, the present invention is to provide a process for the

preparation of novel crystalline form of montelukast hexamethylenediamine of the formula (VII) comprising:

[117] a) reacting mesylate alcohol of the formula (IV) with

l-(mercaptomethyl)cyclopropaneacetic acid of the formula (V) in the presence of sodium methoxide or sodium ethoxide in aprotic dipolar solvent to obtain a montelukast acid, optionally isolating montelukast acid of the formula (VI);

[118] b) treating montelukast acid of the formula (VI) with hexamethylenediamine in the presence of a solvent to obtain montelukast hexamethylenediamine of the formula (VII);

[119] c) if required, converting the free acid from step (f) to a pharmaceutically- acceptable salt of montelukast.

[120]

[121] In the preferred embodiment of the invention, the dianion of

l-(mercaptomethyl)cyclopropaneacetic acid of the formula (V) is generated from disodium salt of l-(mercaptomethyl)cyclopropaneacetic acid , which salt is much easier to obtain then the dilithium one, provided that appropriate reaction parameters are maintained.

[122]

[123] The disodium salt of l-(mercaptomethyl)cyclopropaneacetic acid is prepared in the reaction of the acid with sodium alkoxide, e.g., sodium tert-butoxide or sodium methoxide, in a solution of aprotic dipolar solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA) or 1-methylpyrrolidone (NMP) at a temperature not exceeding 25° C.

[124]

[125] The mesylate alcohol of the formula (IV) is added to a solution of

l-(mercaptomethyl)cyclopropaneacetic acid disodium salt in the same solvent. The reaction mixture is stirred at the temperature of the range from -2O⁰C to 3O⁰C, preferably at about -5° C. After complete conversion of the reagents, the reaction mixture is diluted with an inert organic solvent and neutralized with aqueous solution of sodium chloride.

[126]

[127] The montelukast acid may be in an isolated form or it may be as part of a reaction mixture after the synthesis. Montelukast acid in an isolated form in such a case it is dissolved in the solvent prior to the treatment with hexamethylenediamine. Montelukast acid as part of a reaction mixture after the synthesis, the reaction mixture is treated with hexamethylenediamine.

[128]

[129] Generally the montelukast as part of a reaction mixture dissolved in the solvent and the solution treated with hexamethylenediamine . Hexamethylenediamine may be combined with the montelukast acid solution in a solid state, or, in a dissolved form. The solvent may be the same or different than that used for dissolution of the montelukast acid.

[130]

[131] The reaction temperature at which the montelukast acid solution and hexamethylenediamine are combined is about 1O⁰C to 8O⁰C. The preferred temperature is about 30-35⁰C of the reaction.

[132]

[133] The useful solvents for both salt formation and crystallization of a montelukast hexamethylenediamine salt selected form the group comprising Ci-C₄ aliphatic alcohols (methanol, ethanol, isopropanol), C₂-C₆ aliphatic ketones ( acetone, methyl isopropyl ketone), C₄-C₈ aliphatic ethers (diethyl ether, di tert. butyl ether), C₄-C₆ cyclic ethers ( tetrahydrofurane, dioxane), C₃-C₈ aliphatic esters (ethyl acetate), C₅-C₈ hydrocarbons (toluene, heptane), Ci-C₄ chlorinated hydrocarbons (chloroform, dichloromethane), aliphatic C₂-C₄ nitriles (acetonitrile), and like and mixtures thereof. The preferred solvent is ethyl acetate.

[134]

[135] A montelukast hexamethylenediamine salt precipitates preferably from the reaction mixture spontaneously, but the precipitation may be also induced by cooling, concentrating the solution or adding an antisolvent. Seeds of montelukast hexamethylenediamine salt may be added to induce or enhance precipitation as well.

[136]

[137] The precipitated product is isolated from the reaction mixture by conventional

separation techniques, e.g. by filtration or centrifugation and is optionally washed and dried. As the filter cake is often quite voluminous, so that the washing would be less effective, it is recommended to suspend it in a suitable amount of the solvent and filter again. [138]

[139] The improvement of the purity may be performed by one or more recrystallizations / purification of the montelukast hexamethylenediamine from a suitable solvent and/or by converting the formed (and preferably isolated) hexamethylenediamine salt into montelukast acid and repeating the process of salt formation. Preferably, a montelukast hexamethylenediamine salt product having a purity of higher than 95% is obtained, which may be used as an intermediate in making montelukast sodium of pharmaceutical grade. For pharmaceutical product it is desirable to have isolated montelukast hexamethylenediamine salt greater than 99% purity.

[140]

[141] The thus obtained montelukast hexamethylenediamine salt of chromatographic purity of higher than 95% could be further purified by a single or multiple purification steps either from the same solvent or from another solvent. In the preferred embodiment of the invention, the salt is purified from an organic solvent such as methanol, ethanol, isopropyl alcohol, toluene, ethyl acetate, acetone, methyl isobutyl ketone or from the mixtures thereof with other solvents such as, e.g., hexane, heptane, acetonitrile, diethyl ether or t-butyl-methyl ether. More preferably, the salt is purified from a solvent selected from the group comprising toluene/methanol, toluene/hexane, toluene/ heptane, toluene/diethylether, ethylacetate/hexane or acetone/hexane mixtures.

[142]

[143] In another embodiment, of the invention is related to the amorphous form of montelukast hexamethylenediamine.

[144]

[145] The montelukast hexamethylenediamine may be provided in an amorphous form. A suitable process for making amorphous montelukast hexamethylenediamine is freeze drying or sprays drying of an aqueous solution of montelukast hexamethylenediamine.

[146]

[147] In another embodiment, of the invention is directed to the use of said montelukast hexamethylenediamine of the formula (VII) for the preparation of Montelukast Sodium of the formula (I).

[148]

[149] The invention also provides a process for the preparation montelukast Sodium of the formula (I) comprising:

[150] a) treating montelukast hexamethylenediamine of the formula (VII) with an organic acid in the presence of water immiscible organic solvent;

[151] b) treating the reaction mixture of step (a) with a source of sodium ion;

[152] c) isolating Montelukast Sodium of the formula (I).

[153] [154] In making montelukast sodium, the isolated montelukast hexamethylenediamine may be either converted to the montelukast acid, which is isolated and then converted into montelukast sodium, or it may be converted into the sodium salt directly, via the montelukast acid in the non-isolated state. The montelukast acid in the non-isolated state is generally more convenient. To do this, the montelukast hexamethylenediamine salt is combined with a water immiscible organic solvent. To this suspension, organic acid dissolved in water is added. The organic layer comprising the montelukast acid is then separated optionally the montelukast acid is isolated from this solution, by removal of the solvent by evaporation or by other known means. Preferably, solution of montelukast acid is treated with a source of sodium ion for instance sodium hydroxide or sodium Ci-C₄ alkoxide, in an approximately equimolar amount in respect to the montelukast acid. The solution of montelukast sodium is then concentrated and converted into crystalline or amorphous montelukast sodium, as known in the art.

[155]

[156] The preferred water immiscible organic solvent in the present invention are aromatic hydrocarbon such as benzene or toluene, aliphatic hydrocarbon such as hexane or heptane, an aliphatic ester such as ethyl acetate, chlorinated hydrocarbon such as dichloromethane. The most preferred water immiscible organic solvent is

dichloromethane.

[157]

[158] The preferred organic acids are tartaric acid, acetic acid, formic acid, oxalic acid and like and mixtures thereof. The most preferred organic acid is tartaric acid.

[159]

[160] The obtained montelukast sodium salt could be further purified by a single or

multiple purification steps either from the same solvent or from another solvent. In the preferred embodiment of the invention, the salt is purified from an organic solvent such as methanol, ethanol, isopropyl alcohol, toluene, ethyl acetate, acetone, methyl isobutyl ketone or from the mixtures thereof with other solvents such as, e.g., hexane, heptane, acetonitrile, diethyl ether or tert-butyl-methyl ether. More preferably, the salt is purified from a solvent selected from the group comprising toluene/methanol, toluene/hexane, toluene/heptane, toluene/diethylether, ethylacetate/hexane or acetone/ hexane mixtures.

[161]

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

[163]

1 ormuld ( VI) Mesylate alochol

Formula (IV)

1) Hexamethylenediamme, solvent

2) Crystallization

Hexamethylenediamme salt of Montelukast Montelukast Sodium

Formula (VHj loπnula (I )

[164] Scheme-I

[165]

[166] The known prior art solid state amine salts of montelukast suffer from the disadvantage that the corresponding amine moieties are not pharmaceutically acceptable due to their relatively high toxicity. To the contrary, montelukast hexam- ethylenediamine is pharmaceutically acceptable. It may either replace montelukast sodium in it's therapeutically regimens, or it may also enhance the therapeutic potential of montelukast per se.

[167]

[168] The present invention provides a pharmaceutical composition comprising the montelukast hexamethylenediamine and at least one pharmaceutically acceptable carrier and/or excipients. The composition may be adapted for various types of administration. It may be administered orally via a solid dosage form, by inhalation through mucosa, or in an injectable form, for instance. The selection of excipients is dependent on the administration route.

[169]

[170] Yet another aspect of the invention relates to the use of the montelukast hexamethylenediamine of the formula (VII) in crystalline form as defined herein for the man- ufacture of a medicament.

[171]

[172] The following examples illustrate the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual examples but rather to the scope of the appended claims.

[173]

[174] Example 1

[175] Preparation of montelukast hexamethy lenediamine salt

[176] 700 ml of acetonitrile, 100 g of 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)

phenyl)-3-hydroxypropyl)phenyl)-2-propanol and 200 ml of toluene were charged into a round bottom flask followed by 35.2g of diisopropylethylamine was added to the reaction mixture and was heated to 4O⁰C to get clear solution and further cooling to -27° C. Solution of methanesulfonyl chloride (27.5g in 100ml toluene) was added drop wise to the reaction mass in 90-120 minutes at -27° C, followed by stirring for about 1 hours. Separated wet solid was filtered under N ₂ atmosphere and the solid was washed with 100 ml of acetonitrile cooled at temperature of -25° C.

[177]

[178] 28.72 g of (l-mercaptomethyl)cyclopropaneacetonitrile and 500 ml of

N,N-dimethylformamide were charged in another round bottom flask followed by cooling to about -10° C. 30% methanolic solution of sodium methoxide was added drop wise to the above reaction mass in about 30 minutes under N ₂ atmosphere. The reaction mass was maintained at -10° C. and stirred for 60 minutes, followed by charging of the mesylated compound under N ₂ atmosphere to the reaction mass.

Resultant reaction mixture was stirred for 15 hours at -5⁰C. Reaction mass was quenched using sodium chloride solution (75g sodium chloride in 500 ml water) in 30-45 minutes followed by allowing the temperature of the reaction to raise to 15° C. The reaction mass was extracted with 600 ml of ethyl acetate at 25⁰C under N ₂ atmosphere followed by separation of the organic layer.

[179]

[180] The organic layer was separated was treated with solution of tartaric acid (25g

tartaric acid in 200ml water) followed by stirring for 10-15min. The organic layer containing the product was separated and charged with 10%sodium chloride solution. The organic layer containing the product was separated and charged with ethyl acetate and solution of hexamethy lenediamine (15.22g hexamethy lenediamine in 100ml ethyl acetate). The precipitate was formed after intensive stirring. The reaction mixture was stirred for 5.0 hours at room temperature. The wet cake was separated and was washed with 100 ml of cold ethyl acetate. Wet cake was dried at about 55° C to obtain purified montelukast hexamethylenediamine salt (crude). [181] Yield (w/w) 0.90, % Yield (64%), Purity by HPLC greater than 95%

[182]

[183] Example 2

[ 184] Purification of montelukast hexamethylenediamine salt

[185] The montelukast hexamethylenediamine salt (crude) was transferred to a round

bottom flask containing solution 1000 ml of toluene and 100ml methanol at 3O⁰C and gradually the temperature was raised to 65⁰C followed by stirring reaction mass for 60min. The reaction mass was cooled to 4O⁰C in 60min followed by stirring reaction mass for 15 min. the solid was filtered and washed with 100ml toluene and 10ml methanol. The slurry was filtered and dried under vacuum at 5O⁰C to obtain purified montelukast hexamethylenediamine salt.

[ 186] Yield (w/w) 0.68, % Yield (68%), Purity by HPLC greater than 99%

[187] X-ray powder diffraction pattern: as shown in FIG. 1

[188]

[189] Example 3

[190] Preparation of montelukast sodium

[191] 400ml of dichlorome thane was taken into a reactor and lOOg of montelukast hexamethylenediamine salt was added to it. A solution of 13.96 g of tartaric acid in 200ml water was prepared. The tartaric acid solution was added to the reaction mass and stirred for 15-20 minutes. The organic layer was separated and the aqueous layer was extracted into 18.4 liters of dichloromethane. The combined dichloromethane layer was washed with 3x300ml water. In a separate reactor a solution of 8.0g of sodium hydroxide in 80ml of methanol was prepared. The sodium hydroxide solution was added to the above reaction mass and stirred for 5-10 minutes. The reaction mass was given a carbon treatment and filtered. The carbon bed was washed with 100ml of dichloromethane. The filtrate was subjected to vacuum at temperature of 30-35° C.

[192]

[193] The obtained oily residue was dissolved in 100ml toluene and the solvent is

completely distilled off under vacuum at 45⁰C to obtain oily residue. The residue thus obtained is further dissolved in 100ml toluene and the solvent is completely distilled off under vacuum at 45⁰C to obtain oily residue. The oily residual mass is dissolved in 300ml toluene followed by stirring the reaction mass at 35-45⁰C to get clear solution to this clear solution charge 900ml n-heptane under N ₂ atmosphere for 20-30 minutes. The desired isolated compound is filtered under Nitrogen atmosphere and washed with 100ml n-heptane; further the compound is filtered under vacuum and dried under vacuum at 70-80° C to yield amorphous form of Montelukast sodium.

[194] Yield (w/w) 0.94, % Yield (90%), Purity by HPLC greater than 99%

[195]

Claims

[Claim 1] 1. A montelukast hexamethylenediamine.

[Claim 2] 2. A novel crystalline form of Montelukast hexamethylenediamine.

[Claim 3] 3. A novel crystalline form of montelukast hexamethylenediamine having X-ray diffraction pattern substantially as shown in FIG. 1.

[Claim 4] 4. A novel crystalline form of montelukast hexamethylenediamine characterized by an XRD pattern with peaks at 8.8, 16.3, 17.3, 17.9, 19.3, 19.8, 20.9 and 22.3 degrees two-theta +0.2 degrees two-theta.

[Claim 5] 5. A process for the preparation of novel crystalline form of montelukast hexamethylenediamine comprising:

a. providing a solution containing montelukast, hexamethylenediamine , and solvent;

b. crystallizing a montelukast hexamethylenediamine from said solution.

[Claim 6] 6. A process for the preparation of montelukast sodium of the formula

(I) comprising:

a. treating montelukast hexamethylenediamine of the formula (VII) with an organic acid in the presence of water immiscible organic solvent;

b. treating the reaction mixture of step (a) with a source of sodium ion;

c. isolating montelukast sodium of the formula (I).

[Claim 7] 7. A process for the preparation of novel crystalline form of montelukast hexamethylenediamine of the formula (VII) comprising:

a. reacting mesylate alcohol of the formula (IV) with

l-(mercaptomethyl)cyclopropaneacetic acid of the formula (V) in the presence of sodium methoxide or sodium ethoxide and aprotic dipolar 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 solvent to obtain montelukast hexamethylenediamine of the formula (VII).

[Claim 8] 8. A process for the preparation of Montelukast Sodium of the formula

(I), comprising:

a. reacting ester alcohol of the formula (II) with Grignard reagent in the presence of tetrahydrofuran and reaction promoters to obtain compound 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)ethenyl(phenyl)-3-(hydroxy propyl)phenyl-2-propanol of the formula (III);

b. reacting the compound

2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)ethenyl(phenyl)-3-(hydroxy propyl)phenyl-2-propanol of the formula (III) with methane- sulfonyl chloride in the presence of diisopropylethylamine to obtain the mesylate alcohol of the formula (IV);

c. reacting mesylate alcohol of the formula (IV) with

l-(mercaptomethyl)cyclopropaneacetic acid of the formula (V) in the presence of sodium methoxide or sodium ethoxide in aprotic dipolar 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 hexam- ethylenediamine in the presence of a solvent to obtain montelukast hexamethylenediamine of the formula (VII);

e. treating montelukast hexamethylenediamine of the formula (VII) with an organic acid in the presence of water immiscible organic solvent;

f. treating the reaction mixture of step (e) with a source of sodium ion;

g. isolating Montelukast Sodium of the formula (I).

[Claim 9] 9. The process according to claim 5, 7 and 8, wherein said solvent selected from the group comprising of methanol, ethanol, isopropanol, acetone, methyl isopropyl ketone, diethyl ether, di-tert. butyl ether, tetrahydrofuran, dioxane, ethyl acetate, toluene, heptane, chloroform, dichloromethane, acetonitrile, and mixtures thereof.

[Claim 10] 10. The process according to claim 9, wherein said solvent is ethyl acetate.

[Claim 11] 11. The process according to claim 7 and 8, wherein said aprotic

dipolar solvent is selected from the group comprising of dimethyl- formamide (DMF), dimethylsulf oxide (DMSO), dimethylacetamide (DMA), 1-methylpyrrolidone (NMP) and mixtures thereof.

[Claim 12] 12. The process according to claim 11, wherein said aprotic dipolar solvent is dimethylformamide.

[Claim 13] 13. The process according to claim 7, 6 and 8, wherein said water immiscible organic solvent is selected from the group comprising of benzene, toluene, hexane, heptane, ethyl acetate, dichloromethane.

[Claim 14] 14. The process according to claim 13, wherein said aprotic dipolar solvent is dimethylformamide.

[Claim 15] 15. The process according to claim 6 and 8, wherein said organic acids acid is selected from the group comprising of tartaric acid, acetic acid, formic acid, oxalic acid and mixture thereof.

[Claim 16] 16. The process according to claim 15, wherein said organic acids is tartaric acid