WO2010064257A1 - Novel intermediates for producing [r-(e)]-1-[[[1-[3-[2-(7- chloro -quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy- methylethyl) phenyl]propyl]thio] methyl] cyclopropaneacetic acid, monosodium salt and process thereof - Google Patents

Novel intermediates for producing [r-(e)]-1-[[[1-[3-[2-(7- chloro -quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy- methylethyl) phenyl]propyl]thio] methyl] cyclopropaneacetic acid, monosodium salt and process thereof Download PDF

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WO2010064257A1
WO2010064257A1 PCT/IN2009/000354 IN2009000354W WO2010064257A1 WO 2010064257 A1 WO2010064257 A1 WO 2010064257A1 IN 2009000354 W IN2009000354 W IN 2009000354W WO 2010064257 A1 WO2010064257 A1 WO 2010064257A1
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phenyl
salt
montelukast
formula
homoveratrylamine
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PCT/IN2009/000354
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French (fr)
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WO2010064257A8 (en
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Puma Chandra Ray
Ghanta Mahesh Reddy
Ganji Tirmalaiah
Koudagani Rammohan
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Innogent Laboratories Private Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals

Definitions

  • This invention in general relates to a process for producing [R-(E)]-l-[[[l-[3- [2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(l-hydroxy- 1 - methylethyl)phenyl]propyl]thio] methyl] cyclopropaneacetic acid, monosodium salt (Montelukast sodium). More particularly the present invention provides novel intermediates, process for preparing the same and use thereof to produce the Montelukast sodium.
  • pulmonary disorders including asthma, chronic bronchitis and related obstructive airway diseases, (ii) allergies and allergic reactions such as allergic rhinitis, contact dermatitis, conjunctivitis and, (iii) arthritis inflammation or inflammatory bowel diseases, (iv) skin disorders, (v) cardiovascular disorders, (vi) ocular conditions like uveitis, cerebral disorder, (vii) glomerular nephritis, (viii) hepatitis and allograft rejections in mammals especially in human beings.
  • European patent No.480717 discloses a process for the preparation of montelukast and its salts, including reacting 2-(2-(2-(3(S)-(3-(2-(7-chloro-2- quinolinyl)-ethenyl) phenyl)-3-(methanesulfonyloxy) propyl) phenyl)-2-propoxy) tetrahydropyran with methyl l-(acetylthiomethyl) cyclopropane acetate in the presence of hydrazine, cesium carbonate in acetonitrile as a solvent to give methyl ester of montelukast in pyran protected form.
  • the protected compound was further treated with pyridinium p-toluene sulfonate and sodium hydroxide in a mixture of methanol and tetrahydrofuran as a solvent to obtain montelukast sodium.
  • the process used was as given in the scheme-I below. The process involves more number of steps, including protection and de-protection of diol intermediate. Furthermore, the process involves usage of hazardous and costly raw materials such as hydrazine, pyridinium p-toluene sulfonate in typical reaction conditions i.e., at very low temperatures, thereby making the process not suitable for commercial scale-up as depicted in Scheme-I.
  • United States Patent No. 5,614,632 discloses a process for the preparation of the sodium salt of montelukast and certain process intermediates. The process involves generating dilithium dianion of l-(mercaptomethyl) cyclopropaneacetic acid followed by condensation with 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-methanesulfonyloxypropyl) phenyl)-2-propanol (referred to as mesylated alcohol) to afford montelukast, further conversion to the corresponding sodium salt via dicyclohexylamine salt.
  • mesylated alcohol 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-methanesulfonyloxypropyl) phenyl)-2-propanol
  • the '632 patent also discloses a process for the preparation of crystalline montelukast sodium salt and mesylated alcohol.
  • the process involves reacting methyl 2-(3 (S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3- hydroxy propyl) benzoate with methyl magnesium chloride to give a diol followed by conversion to mesylated alcohol on reaction with methane sulfonyl chloride as given below in scheme- II.
  • WO 2008015703 discloses a primary amine salt of montelukast and process for preparing the same by treating montelukast with primary amine salts like isopropyl amine and cyclohexyl amine.
  • primary amine salts like isopropyl amine and cyclohexyl amine.
  • a process for producing the montelukast homoveratrylamine salt of formula II comprising reacting l-(mercaptomethyl) cyclopropyl) acetic acid with homoveratrylamine in presence of an organic solvent to obtain 1- (mercaptomethyl)cyclopropyl)acetic acid homoveratrylamine salt of formula III.
  • a process for producing the montelukast homoveratrylamine salt of formula II comprising condensing the compound of formula III with compound of formula IV ([S-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-[2-(l- hydroxy- 1-methylethyl) phenyl] propyl] methanesulfonate in presence of a base and suitable solvent to obtain the montelukast homoveratrylamine salt.
  • a novel intermediate l-(mercaptomethyl)cyclopropyl)acetic acid homoveratrylamine salt of formula III for producing montelukast sodium in accordance with still another embodiment of the present invention, there is provided a process for producing the novel intermediate 1- (mercaptomethyl)cyclopropyl)acetic acid homoveratrylamine salt of formula III comprising reacting l-(mercaptomethyl)cyclopropyl)acetic acid with homoveratrylamine in presence of an organic solvent.
  • a process for producing the montelukast sodium comprising treating 1- (mercaptomethyl) cyclopropyl) acetic acid with hornoveratryl amine in presence of an organic solvent to give the novel intermediate l-(mercaptomethyl)cyclopropyl)acetic acid homoveratrylamine salt of formula III, reacting the novel intermediate with compound of formula IV in presence of a base and suitable solvent to form montelukast homoveratrylamine salt of formula II and converting the montelukast homoveratrylamine salt to montelukast sodium.
  • a process for producing the montelukast sodium comprising reacting the novel intermediate 1 -(mercaptomethyl) cyclopropyl) acetic acid homoveratrylamine salt of formula III with compound of formula IV in presence of a base and suitable solvent to form montelukast homoveratrylamine salt of formula II and converting the montelukast homoveratrylamine salt to montelukast sodium.
  • Figure 1 illustrates characteristic X-ray powder diffraction pattern for the novel [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-[2-(l-hydroxy-l- methylethyl)phenyl]propyl] thio]methyl] cyclopropaneacetic acid (montelukast), homoveratrylamine salt of formula (II).
  • Figure 2 illustrates characteristic Differential Scanning Calorimetry (DSC) pattern for the novel [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3- [2-(l-hydroxy-l-methylethyl)phenyl]propyl] thio]methyl] cyclopropaneacetic acid (montelukast), homoveratrylamine salt of formula II.
  • Figure 3 illustrates characteristic X-ray powder diffraction pattern for the novel l-(mercaptomethyl)cyclopropyl)acetic acid homoveratrylamine salt of formula III.
  • Figure 4 illustrates characteristic DSC pattern for the novel 1- (mercaptomethyl)cyclopropyl)acetic acid homoveratrylamine salt of formula III.
  • the amine salt is primary amine salt, more particularly homoveratrylamine salt.
  • l-(mercaptomethyl) cyclopropyl) acetic acid is a low melting solid and highly hygroscopic
  • the formation of 1- (mercaptomethyl)cyclopropyl)acetic acid homoveratrylamine salt of formula III which is highly stable and easy to handle, becomes the primary aspect of the present invention.
  • the intermediate of formula III can be prepared by reacting 1- (mercaptomethyl) cyclopropyl) acetic acid with primary amine in the presence of organic solvent or mixed organic solvents like dichloromethane, cyclohexane, ethyl acetate and heptane as illustrated in scheme-Ill.
  • This amine salt is subsequently condensed with the compound ([S-(E)]-1-[[[1- [3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-[2-(l-hydroxy-l-methylethyl) phenyl] propyl] methanesulfonate of formula FV in the presence of a base and suitable organic solvent to form Montelukast primary amine salt, more particularly
  • Montelukast homoveratrylamine salt an intermediate of formula II.
  • the base is taken from organolithium reagents, such as n-BuLi or alkali metal alkoxides, more preferably, sodium methoxide and the organic solvent is selected from Cj to C 4 alcohols, preferably methanol.
  • Montelukast homoveratrylamine salt of formula II can be prepared by reacting the novel intermediate compound (HI) with compound of formula IV, as described in the following scheme-IV
  • the formed Montelukast amine salt of formula II is directly converted into Montelukast sodium without isolating Montelukast free acid.
  • the Montelukast primary amine salt is converted into Montelukast sodium in the presence of polar organic solvent or non-polar organic solvent, organic acid or inorganic acid, sodium alkoxide and alcohols, and the organic solvent is selected from Ci to C 4 alcohols, preferably methanol. It is described in the following scheme- V: salt
  • novel intermediate [R-(E)]-l-[[[l-[3-[2-(7- chloro-2-quinolinyl) ethenyl] phenyl] -3-[2-(l-hydroxy-l-methylethyl)phenyl]propyl] thiojmethyl] cyclopropaneacetic acid (montelukast), homoveratrylamine salt of formula (II) can be prepared by treating montelukast free acid of formula IA with homoveratrylamine as depicted in following scheme-VII
  • novel intermediates produced according to the present invention are characterized by using different analytical tools such as X-ray powder diffraction patterns, and/or Differential Scanning Calorimetry (DSC). Powder X-ray Diffraction TPXRD)
  • the said intermediates of the present invention are characterized by their X- ray powder diffraction pattern.
  • the X-ray diffraction patterns of said intermediates of the invention were measured on P Analytical powder diffractometer equipped with goniometer of ⁇ / ⁇ configuration and X'Celerator detector.
  • the Cu-anode X-ray tube was operated at 4OkV and 30mA.
  • the experiments were conducted over the 2 ⁇ range of 2.0°-50.0°, 0.5 seconds step time.
  • the characteristic patterns are depicted in Figure l and 3.
  • Differential Scanning Calorimetry (DSC) The DSC measurements were carried out on Perkin Elmer.
  • novel intermediate l-(mercaptomethyl)cyclopropyl)acetic acid homoveratrylamine salt of formula III is characterized by powder X-ray diffraction pattern as shown in Figure 3 with peaks at 12.3, 14.9, 15.6, 16.6, 17.8, 18.5, 19.6, 21.5, 23.2, 24.7, 26.02 and 26.7 ⁇ 0.2 2 ⁇ values.
  • novel intermediate l-(mercaptomethyl)cyclopropyl)acetic acid homoveratrylamine salt of formula III is further characterized by DSC with two endothermic peaks; first at an extrapolated onset temperature ranging from 88.5 to 110°C attributed to desolvation, which is identified with peak at 91.4°C and a second at 102°C, as shown in Figure 4.
  • Example-4 Process for the preparation of Montelukast Homoveratryl amine using n-BuLi 125 ml of THF and 17.8 gm of the compound prepared in example- 1 was taken into round bottom (RB) flask and cooled to -5 to 0°C and then 19.6 ml of n- BuLi solution was slowly added to it and maintained for 30 minutes.
  • Part-1 The crude (60 gm) was dissolved in 1 vol toluene and distilled. The crude was again dissolved in 10 vol toluene and 21.7 gm of homoveratrylamine was added to it at room temperature and stirred for 12-14 hours. To this, 2 vol of heptane was added, stirred for 1 hour, filtered the solid and dried (56 gm). The dried compound was taken in 18 vol toluene and 12 vol heptane mixture and stirred for 1-2 hours. The solid was filtered and the compound was dried (54 gm, >98.1%)
  • Part 2 The crude (60 gm) was dissolved in 1 vol acetone and distilled. The crude was again dissolved in 10 vol acetone and 21.7 gm of homoveratrylamine was added to it at room temperature and stirred for 12-14 hours. To this, 2 vol of heptane was added, stirred for 1 hour, filtered the solid and dried at 60-65 0 C (46 gm). The dried compound was taken in 18 vol toluene and 12 vol heptane mixture and stirred for 1-2 hours. The solid was filtered and the compound was dried at 60-65 0 C (39 gm, Purity: >98.9%, mp: 131-133 0 C).
  • Example-6 Process for the preparation of Montelukast Homoveratryl amine using NaOMe and the purification process
  • the reaction mixture was quenched with 200 ml of water and extracted with 300 ml of DCM.
  • the pH of the aqueous layer was adjusted to 4- 4.5 by adding the 30 ml of 2N acetic acid solution and stirred for 30 minutes.
  • DCM and aqueous layers were separated and the DCM layer was dried over sodium sulfate.
  • the crude obtained (59.2 gm). The crude was divided in to two parts (part-1 and part- 2).
  • reaction mixture was extracted with DCM thrice (10 vol).
  • the organic phase was washed with sodium bicarbonate solution (10%).
  • the organic and aqueous phases were separated.
  • the solvent was distilled completely under reduced pressure at below 6O 0 C. Cooled the reaction mixture to 25-3O 0 C.
  • the crude was dissolved in toluene (1 Vol) and distilled the solvent completely under reduced pressure at below 6O 0 C. (Crude wt: 56 gm).
  • the reaction mixture was quenched with 400 ml of water and extracted with 600 ml of DCM.
  • the pH of the aqueous layer was adjusted to 4-4.5 by adding 60 ml of 2N acetic acid solution and stirred for 30 minutes.
  • the DCM and aqueous layers were separated and the DCM layer was dried over sodium sulfate.
  • the crude obtained 120 gm).
  • the crude (120 gm) was dissolved in 1 vol toluene and distilled.
  • the crude was again dissolved in 10 vol toluene and 43.5 gm of homoveratrylamine was added to it at room temperature and stirred for 12-14 hours.
  • 2 vol of heptane was added, stirred for 1 hour, filtered the solid and the wet material was taken in 18 vol toluene and 12 vol heptane mixture and stirred for 1-2 hours at room temperature.
  • the solid was filtered and dried (115 gm, >99%).
  • Methanolic NaOH solution was prepared by dissolving 0.52 gm of NaOH pellets in 10 ml of methanol. Methanolic NaOH solution was added to the reaction mixture and the reaction mixture was filtered to remove any extraneous matter. It was filtered through high- flow bed and washed with 10 ml of methanol and the solvent was completely distilled off under vacuum. 15 ml of toluene was added to it to get a clear solution and to this; 100 ml of heptane was added drop wise. The solid was filtered and washed with 20 ml of heptane and the compound was dried under high vacuum for 10-12 hours. (7.92 gm, Yield: 75%, Purity: >99.3%)

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Abstract

Disclosed herein are novel intermediates for producing [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 (montelukast sodium). Further the invention provides processes for preparing said intermediates.

Description

NOVEL INTERMEDIATES FOR PRODUCING [R-(E)]-l-[[[l-[3-[2-(7- CHLORO -QUINOLINYL)ETHENYL]PHENYL]-S-P-(I-HYDROXY-
METHYLETHYL) PHENYL]PROPYL]THIO] METHYL] CYCLOPROPANEACETIC ACID, MONOSODIUM SALT AND PROCESS THEREOF
Field of the Invention
This invention, in general relates to a process for producing [R-(E)]-l-[[[l-[3- [2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(l-hydroxy- 1 - methylethyl)phenyl]propyl]thio] methyl] cyclopropaneacetic acid, monosodium salt (Montelukast sodium). More particularly the present invention provides novel intermediates, process for preparing the same and use thereof to produce the Montelukast sodium.
Background of the Invention
Montelukast Sodium, described chemically as [R-(E)] -1-[[[1- [3- [2-(7-chloro-2- quinolinyl)ethenyl]phenyl]-3-[2-(l-hydroxy-l-methylethyl)phenyl]propyl]thio] methyl] cyclopropaneacetic acid, monosodium salt, and structurally by formula as given below, is a leukotriene antagonist. It is useful for the treatment, prevention or amelioration of: (i) pulmonary disorders including asthma, chronic bronchitis and related obstructive airway diseases, (ii) allergies and allergic reactions such as allergic rhinitis, contact dermatitis, conjunctivitis and, (iii) arthritis inflammation or inflammatory bowel diseases, (iv) skin disorders, (v) cardiovascular disorders, (vi) ocular conditions like uveitis, cerebral disorder, (vii) glomerular nephritis, (viii) hepatitis and allograft rejections in mammals especially in human beings.
Figure imgf000002_0001
Montelukast Sodium
Various processes for the preparation of montelukast and its salts are known in prior art. European patent No.480717 discloses a process for the preparation of montelukast and its salts, including reacting 2-(2-(2-(3(S)-(3-(2-(7-chloro-2- quinolinyl)-ethenyl) phenyl)-3-(methanesulfonyloxy) propyl) phenyl)-2-propoxy) tetrahydropyran with methyl l-(acetylthiomethyl) cyclopropane acetate in the presence of hydrazine, cesium carbonate in acetonitrile as a solvent to give methyl ester of montelukast in pyran protected form. The protected compound was further treated with pyridinium p-toluene sulfonate and sodium hydroxide in a mixture of methanol and tetrahydrofuran as a solvent to obtain montelukast sodium. The process used was as given in the scheme-I below. The process involves more number of steps, including protection and de-protection of diol intermediate. Furthermore, the process involves usage of hazardous and costly raw materials such as hydrazine, pyridinium p-toluene sulfonate in typical reaction conditions i.e., at very low temperatures, thereby making the process not suitable for commercial scale-up as depicted in Scheme-I.
Figure imgf000003_0001
Figure imgf000003_0003
Figure imgf000003_0002
Scheme-I
United States Patent No. 5,614,632 discloses a process for the preparation of the sodium salt of montelukast and certain process intermediates. The process involves generating dilithium dianion of l-(mercaptomethyl) cyclopropaneacetic acid followed by condensation with 2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3-methanesulfonyloxypropyl) phenyl)-2-propanol (referred to as mesylated alcohol) to afford montelukast, further conversion to the corresponding sodium salt via dicyclohexylamine salt. The '632 patent also discloses a process for the preparation of crystalline montelukast sodium salt and mesylated alcohol. The process involves reacting methyl 2-(3 (S)-(3-(2-(7-chloro-2-quinolinyl) ethenyl) phenyl)-3- hydroxy propyl) benzoate with methyl magnesium chloride to give a diol followed by conversion to mesylated alcohol on reaction with methane sulfonyl chloride as given below in scheme- II.
Figure imgf000004_0001
Scheme-II United States patent application No. US 20060004204 Al, discloses montelukast tertiary butylamine salt and a process for the preparation of montelukast and its acceptable salt employing the same. According to the process, the montelukast tertiary butylamine is converted into montelukast free acid followed by conversion to montelukast sodium salt. PCT application WO 2007072114 Al discloses quaternary ammonium salt of montelukast and process for preparing montelukast sodium employing the same.
WO 2008015703 discloses a primary amine salt of montelukast and process for preparing the same by treating montelukast with primary amine salts like isopropyl amine and cyclohexyl amine. In light of the foregoing processes there still exists a need to develop improved processes for large-scale production of montelukast and its pharmaceutically acceptable salts, without involving formation of unstable hazardous intermediates during the process.
Summary of the Invention It is principal object of the present invention to provide novel intermediates to produce [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(l-hydroxy- l-methylethyl)phenyl]propyl]thio] methyl] cyclopropaneacetic acid, monosodium salt (Montelukast sodium) at a large scale.
It is another object of the present invention to provide a commercially viable process for producing [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3- [2-(l-hydroxy-l-methylethyl)phenyl]propyl]thio] methyl] cyclopropaneacetic acid, monosodium salt (Montelukast sodium) employing stable intermediates.
The above and other objects of the present invention are further attained and supported by the following embodiments described herein. However, the scope of the invention is not restricted to the described embodiments herein after.
In accordance with a preferred embodiment of the present invention, there is provided a novel intermediate [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3 - [2-(l-hydroxy- 1 -methylethyl)phenyl]propyl] thio] methyl] cyclopropaneacetic acid (montelukast), homoveratrylamine salt of formula II for producing montelukast sodium.
In accordance with another preferred embodiment of the present invention there is provided a process for producing the montelukast homoveratrylamine salt of formula II comprising reacting l-(mercaptomethyl) cyclopropyl) acetic acid with homoveratrylamine in presence of an organic solvent to obtain 1- (mercaptomethyl)cyclopropyl)acetic acid homoveratrylamine salt of formula III.
In accordance with another preferred embodiment of the present invention there is provided a process for producing the montelukast homoveratrylamine salt of formula II comprising condensing the compound of formula III with compound of formula IV ([S-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-[2-(l- hydroxy- 1-methylethyl) phenyl] propyl] methanesulfonate in presence of a base and suitable solvent to obtain the montelukast homoveratrylamine salt.
In accordance with another preferred embodiment of the present invention there is provided a process for producing novel intermediate [R-(E)]-l-[[[l-[3-[2-(7- chloro-2-quinolinyl) ethenyl] phenyl] -3-[2-(l-hydroxy-l-methylethyl)phenyl] propyl] thio]methyl] cyclopropaneacetic acid (montelukast), homoveratrylamine salt of formula II comprising treating montelukast free acid with homoveratrylamine.
In accordance with yet another embodiment of the present invention, there is provided a novel intermediate l-(mercaptomethyl)cyclopropyl)acetic acid homoveratrylamine salt of formula III for producing montelukast sodium. In accordance with still another embodiment of the present invention, there is provided a process for producing the novel intermediate 1- (mercaptomethyl)cyclopropyl)acetic acid homoveratrylamine salt of formula III comprising reacting l-(mercaptomethyl)cyclopropyl)acetic acid with homoveratrylamine in presence of an organic solvent.
In accordance with yet another embodiment of the present invention, there is provided a process for producing the montelukast sodium comprising treating 1- (mercaptomethyl) cyclopropyl) acetic acid with hornoveratryl amine in presence of an organic solvent to give the novel intermediate l-(mercaptomethyl)cyclopropyl)acetic acid homoveratrylamine salt of formula III, reacting the novel intermediate with compound of formula IV in presence of a base and suitable solvent to form montelukast homoveratrylamine salt of formula II and converting the montelukast homoveratrylamine salt to montelukast sodium.
In accordance with yet another embodiment of the present invention, there is provided a process for producing the montelukast sodium comprising reacting the novel intermediate 1 -(mercaptomethyl) cyclopropyl) acetic acid homoveratrylamine salt of formula III with compound of formula IV in presence of a base and suitable solvent to form montelukast homoveratrylamine salt of formula II and converting the montelukast homoveratrylamine salt to montelukast sodium.
Brief Description of the Drawings
Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures wherein:
Figure 1: illustrates characteristic X-ray powder diffraction pattern for the novel [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-[2-(l-hydroxy-l- methylethyl)phenyl]propyl] thio]methyl] cyclopropaneacetic acid (montelukast), homoveratrylamine salt of formula (II).
Figure 2: illustrates characteristic Differential Scanning Calorimetry (DSC) pattern for the novel [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3- [2-(l-hydroxy-l-methylethyl)phenyl]propyl] thio]methyl] cyclopropaneacetic acid (montelukast), homoveratrylamine salt of formula II. Figure 3: illustrates characteristic X-ray powder diffraction pattern for the novel l-(mercaptomethyl)cyclopropyl)acetic acid homoveratrylamine salt of formula III. Figure 4: illustrates characteristic DSC pattern for the novel 1- (mercaptomethyl)cyclopropyl)acetic acid homoveratrylamine salt of formula III.
Detailed Description of the Invention
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
According to the present invention, there are provided novel intermediates R- (E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-[2-(l-hydroxy-l- methylethyl)phenyl]propyl] thio]methyl] cyclopropaneacetic acid (montelukast), homoveratrylamine salt of formula II and l-(mercaptomethyl)cyclopropyl)acetic acid homoveratrylamine salt of formula III to produce [R-(E)]-l-[[[l-[3-[2-(7-chloro-2- quinolinyl)ethenyl]phenyl]-3-[2-(l-hydroxy-l-methylethyl)phenyl]propyl]thio] methyl] cyclopropaneacetic acid, monosodium salt (Montelukast sodium) of formula I.
Figure imgf000007_0001
l-(mercaptomethyl)cyclopropyl)acetic acid homoveratrylaminesalt
Figure imgf000007_0002
(H)
(III) wherein the amine is represented as:
Figure imgf000007_0003
In the present invention, the amine salt is primary amine salt, more particularly homoveratrylamine salt. As l-(mercaptomethyl) cyclopropyl) acetic acid is a low melting solid and highly hygroscopic, the formation of 1- (mercaptomethyl)cyclopropyl)acetic acid homoveratrylamine salt of formula III, which is highly stable and easy to handle, becomes the primary aspect of the present invention. The intermediate of formula III can be prepared by reacting 1- (mercaptomethyl) cyclopropyl) acetic acid with primary amine in the presence of organic solvent or mixed organic solvents like dichloromethane, cyclohexane, ethyl acetate and heptane as illustrated in scheme-Ill.
Figure imgf000008_0001
Figure imgf000008_0002
(III) Scheme-Ill
This amine salt is subsequently condensed with the compound ([S-(E)]-1-[[[1- [3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-[2-(l-hydroxy-l-methylethyl) phenyl] propyl] methanesulfonate of formula FV in the presence of a base and suitable organic solvent to form Montelukast primary amine salt, more particularly
Montelukast homoveratrylamine salt an intermediate of formula II. The base is taken from organolithium reagents, such as n-BuLi or alkali metal alkoxides, more preferably, sodium methoxide and the organic solvent is selected from Cj to C4 alcohols, preferably methanol.
Figure imgf000009_0001
Montelukast homoveratrylamine salt of formula II can be prepared by reacting the novel intermediate compound (HI) with compound of formula IV, as described in the following scheme-IV
Figure imgf000009_0002
Figure imgf000009_0003
(II) Scheme IV
The formed Montelukast amine salt of formula II is directly converted into Montelukast sodium without isolating Montelukast free acid. According to one embodiment of the present invention the Montelukast primary amine salt is converted into Montelukast sodium in the presence of polar organic solvent or non-polar organic solvent, organic acid or inorganic acid, sodium alkoxide and alcohols, and the organic solvent is selected from Ci to C4 alcohols, preferably methanol. It is described in the following scheme- V: salt
Figure imgf000010_0001
Figure imgf000010_0002
Scheme-V
In the above conversion of Montelukast primary amine salt into Montelukast sodium, the Montelukast free acid is not isolated.
According to the present invention, the process for the preparation of Montelukast sodium can be described in the following scheme VI:
.amine salt
Figure imgf000011_0001
salt
Figure imgf000011_0002
Montelukast sodium (I) (II)
Scheme-VI
According to the present invention, novel intermediate [R-(E)]-l-[[[l-[3-[2-(7- chloro-2-quinolinyl) ethenyl] phenyl] -3-[2-(l-hydroxy-l-methylethyl)phenyl]propyl] thiojmethyl] cyclopropaneacetic acid (montelukast), homoveratrylamine salt of formula (II) can be prepared by treating montelukast free acid of formula IA with homoveratrylamine as depicted in following scheme-VII
Figure imgf000011_0003
Scheme -VII
Furthermore, the novel intermediates produced according to the present invention are characterized by using different analytical tools such as X-ray powder diffraction patterns, and/or Differential Scanning Calorimetry (DSC). Powder X-ray Diffraction TPXRD)
The said intermediates of the present invention are characterized by their X- ray powder diffraction pattern. The X-ray diffraction patterns of said intermediates of the invention were measured on P Analytical powder diffractometer equipped with goniometer of θ/θ configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 4OkV and 30mA. The experiments were conducted over the 2Θ range of 2.0°-50.0°, 0.5 seconds step time. The characteristic patterns are depicted in Figure l and 3. Differential Scanning Calorimetry (DSC) The DSC measurements were carried out on Perkin Elmer. The experiments were performed at a heating rate of 10.0°C/min over a temperature range of 35°C- 300°C purging with nitrogen at a flow rate of 50ml/min. Standard aluminum crucibles covered by lids with three pin holes were used. The characteristic measurements are depicted in Figure 2 and 4. The novel intermediate R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3 - [2-(l-hydroxy- 1 -methylethyl)phenyl]propyl] thio]methyl] cyclopropaneacetic acid (montelukast), homoveratrylamine salt of formula II is characterized by powder X-ray diffraction pattern as shown in Figure 1 with peaks at 7.4, 12.6, 13.3, 14.9, 16.2, 17.3, 19.36, 20.8, 22.0, 23.5, 24.1 and 24.9 ± 0.2 2Θ values.
The novel intermediate R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-[2-(l-hydroxy- 1 -methylethyl)phenyl]propyl] thio]methyl] cyclopropaneacetic acid (montelukast), homoveratrylamine salt of formula II is further characterized by DSC with two endothermic peaks; first at an extrapolated onset temperature ranging from 121.2 to 1400C attributed to desolvation, which is identified with peak at 131 °C (maxima), as shown in Figure 2.
The novel intermediate l-(mercaptomethyl)cyclopropyl)acetic acid homoveratrylamine salt of formula III is characterized by powder X-ray diffraction pattern as shown in Figure 3 with peaks at 12.3, 14.9, 15.6, 16.6, 17.8, 18.5, 19.6, 21.5, 23.2, 24.7, 26.02 and 26.7 ± 0.2 2Θ values.
The novel intermediate l-(mercaptomethyl)cyclopropyl)acetic acid homoveratrylamine salt of formula III is further characterized by DSC with two endothermic peaks; first at an extrapolated onset temperature ranging from 88.5 to 110°C attributed to desolvation, which is identified with peak at 91.4°C and a second at 102°C, as shown in Figure 4.
The following examples are provided to illustrate the process of the present invention. They, are however, not intended to limiting the scope of the present invention in any way and several variants of these examples would be evident to person ordinarily skilled in the art.
Example- 1
Process for the preparation of l-(mercaptomethvOcv~clopropyDacetic acid homoveratrylamine salt l-(mercaptomethyl)cyclopropyl)acetic acid (100 gm) was taken in a RB flask along with 500 ml of ethyl acetate and stirred for 30 minutes at 28-30 °C. To this, 148.7 gm of homoveratrylamine was slowly added and stirred for 4 hours at the same temperature. 300 ml of heptane was added to the reaction mixture and the solid was filtered, washed with heptane and dried. The compound was dried in oven at temperature below 60°C to get a constant weight. (210 gm, Purity: 96.5%)
Example-2
Process for the preparation of (S.Eyi-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenylV3- (2-(2-hvdroxypropan-2-vπphenyl)propyl methanesulfonate (Compound-IV)
Compound-V (25 gm) and 125 ml of toluene were taken in a RB flask at 25- 30°C and refluxed azeotropically for 30 minutes, distilled 3 vol of toluene azeotropically and cooled under nitrogen atmosphere to 50-60°C. To this, 237.5 ml of acetonitrile was added and cooled to 25-30°C. It was cooled to -15 to -100C and then
11.4 ml of N, N - diisopropylethylamine was added at the same temperature and stirred for 30-45 minutes. 4.65 ml of methanesulfonyl chloride was added slowly to it and seeded with compound-IV. The reaction mass was filtered, the solid was washed with 25 ml of chilled acetonitrile and 50 ml of chilled hexane. This wet compound was taken as such for the next step.
Example-3
Process for the preparation of Montelukast Homoveratryl amine using n-BuLi 125 ml of Tetra Hydrofuran (THF) and 17.8 gm of the compound prepared in example- 1 was taken into RB flask and cooled to -5 to 0°C and then 19.6 ml of n- BuLi solution was slowly added to it and maintained for 30 minutes. 39 gm of (S5E)- l-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2- yl)phenyl)propyl methanesulfonate (Compound-IV) (wet) was dissolved in 100 ml of THF in separate vessel and it was added to the reaction mass at -5 to 0°C under nitrogen atmosphere till the reaction was completed. After completion of the reaction, 100ml of water was added and 150 ml of Dichloro methane (DCM) was also added to it. The pH was adjusted to 4-5 by adding the 125 ml of 2N acetic acid solution and stirred for 20-30 minutes. DCM and aqueous layers were separated and the DCM layer was dried over sodium sulfate. The crude was dissolved in 100ml of ethyl acetate and the total ethyl acetate was distilled under vacuum and again the crude was dissolved in 125 ml of ethyl acetate and stirred for 20-30 minutes. To this, 10.8 gm of homoveratrylamine was added and seeded with Montelukast Homoveratrylamine salt and stirred for 14-16 hours. To this, 125ml of heptane was added, filtered the solid and the compound dried (35.7 gm, Yield: 59%).
Example-4 Process for the preparation of Montelukast Homoveratryl amine using n-BuLi 125 ml of THF and 17.8 gm of the compound prepared in example- 1 was taken into round bottom (RB) flask and cooled to -5 to 0°C and then 19.6 ml of n- BuLi solution was slowly added to it and maintained for 30 minutes. (S5E)- 1-(3-(2-(7- chloroquinolin-2-yl)vinyl)phenyl)-3r(2-(2-hydroxypropan-2-yl)phenyl)propyl methanesulfonate (Compound-IV) (wet) was dissolved in 100 ml of THF in separate vessel and it was added to the reaction mass at -5 to 0°C under nitrogen atmosphere till the reaction was completed. After completion of the reaction, the reaction mixture was quenched with aqueous sodium chloride solution at <15 °C. The reaction mixture was extracted with ethyl acetate. The pH was adjusted to 4-5 by adding the 125 ml of 2N acetic acid solution and stirred for 20-30 minutes. Ethyl acetate and aqueous layers were separated and the ethyl acetate layer was dried over sodium sulfate. The crude was dissolved in 100 ml of toluene and the total toluene was distilled under vacuum and again the crude was dissolved in 250 ml of toluene and stirred for 20-30 minutes. To this, 10.8 gm of homoveratrylamine was added and stirred for 12-14 hours. To this, 125 ml of heptane was added, filtered the solid and the compound dried (34.0 gm). Example-5
Process for the preparation of Montelukast Homoveratryl amine using NaOMe and the purification process
400 ml of Dimethyl formamide (DMF) and 71.5 gm of the compound prepared in example- 1 was taken into RB flask and cooled to -5 to 0°C and then 78.6 gm of NaOMe solution (30%) was slowly added to it and maintained for 30 minutes.
(S,E)-l-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2- yl)phenyl)propyl methanesulfonate (formula IV) was dissolved in 250 ml of DMF and it was added to the reaction mass at -5 to 0°C under nitrogen atmosphere and maintained for 10-12 hours. The reaction mixture was quenched with 400 ml of water and extracted with 600 ml of DCM. The pH of the aqueous layer was adjusted to 4-
4.5 by adding the 60 ml of 2N acetic acid solution and stirred for 30 minutes. DCM and aqueous layers were separated and the DCM layer was dried over sodium sulfate.
The crude obtained (120 gm). The crude was divided into two equal parts (Part-1 and Part-2).
Part-1: The crude (60 gm) was dissolved in 1 vol toluene and distilled. The crude was again dissolved in 10 vol toluene and 21.7 gm of homoveratrylamine was added to it at room temperature and stirred for 12-14 hours. To this, 2 vol of heptane was added, stirred for 1 hour, filtered the solid and dried (56 gm). The dried compound was taken in 18 vol toluene and 12 vol heptane mixture and stirred for 1-2 hours. The solid was filtered and the compound was dried (54 gm, >98.1%)
Part 2: The crude (60 gm) was dissolved in 1 vol acetone and distilled. The crude was again dissolved in 10 vol acetone and 21.7 gm of homoveratrylamine was added to it at room temperature and stirred for 12-14 hours. To this, 2 vol of heptane was added, stirred for 1 hour, filtered the solid and dried at 60-65 0C (46 gm). The dried compound was taken in 18 vol toluene and 12 vol heptane mixture and stirred for 1-2 hours. The solid was filtered and the compound was dried at 60-65 0C (39 gm, Purity: >98.9%, mp: 131-133 0C).
Example-6 Process for the preparation of Montelukast Homoveratryl amine using NaOMe and the purification process
200 ml of DMF and 36.3 gm of the compound prepared in example- 1 was taken into RB flask and cooled to -5 to O0C and then 39.3 gm of Sodium methoxide (NaOMe) solution (30%) was slowly added to it and maintained for 30 minutes. (S3E)- 1 -(3 -(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3 -(2-(2-hydroxypropan-2- yl)phenyl)propyl methanesulfonate (Compound-IV) was dissolved in 125 ml of DMF and it was added to the reaction at -5 to O0C under nitrogen atmosphere and maintained for 10-12 hours. The reaction mixture was quenched with 200 ml of water and extracted with 300 ml of DCM. The pH of the aqueous layer was adjusted to 4- 4.5 by adding the 30 ml of 2N acetic acid solution and stirred for 30 minutes. DCM and aqueous layers were separated and the DCM layer was dried over sodium sulfate. The crude obtained (59.2 gm). The crude was divided in to two parts (part-1 and part- 2).
Part-1:
The crude (29.5 gm) was dissolved in 1 vol toluene and distilled. The crude was again dissolved in 10 vol toluene and 11.0 gm of homoveratrylamine was added to it at room temperature and stirred for 12-14 hours. To this, 2 vol of heptane was added, stirred for 1 hour, filtered the solid and the wet material was taken 18 vol toluene and 12 vol heptane mixture and stirred for 1-2 hours at room temperature. The solid was filtered and dried (28.0 gm, >99 %). Part-2:
The crude (29.5 gm) was dissolved in 1 vol acetone and distilled. The crude was again dissolved in 10 vol acetone and 11.0 gm of homoveratrylamine was added to it at room temperature and stirred for 12-14 hours. To this, 2 vol of heptane was added, stirred for 1 hour, filtered the solid and the wet material was taken 18 vol toluene and 12 vol heptane mixture and stirred for 1-2 hours at room temperature. The solid was filtered and dried (20.4 gm, >99%). Example-7
Process for the preparation of Montelukast Homoveratryl amine using NaOMe and the purification process
200 ml of DMF and 36.3 gm of the compound prepared in example- 1 was taken into RB flask and cooled to -5 to O0C and then 39.3 gm of NaOMe solution (30%) was slowly added to it and maintained for 30 minutes. (S,E)-l-(3-(2-(7- chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propyl methanesulfonate (formula FV) was dissolved in 125 ml of DMF and it was added to the reaction at -5 to O0C under nitrogen atmosphere and maintained for 10-12 hours. To pre cooled 1500 ml of water at below 1O0C, was added the above reaction mixture. The reaction mixture was stirred for 30 minutes. Added 200 ml toluene to the above reaction mixture at 25-3O0C and adjusted the pH of the reaction mixture to 13-14 using with sodium hydroxide solution (39.3 gm in 1500 ml water). The reaction mixture was stirred for 30 minutes at 25-3O0C. The organic and aqueous phases were separated, washed the aqueous phase with toluene (3 x 2 vol). Then cooled the aqueous phase to 10-200C and adjusted the pH of the. reaction mixture to 6.5 with aqueous acetic acid solution (2N solution 400 ml). The reaction mixture was extracted with DCM thrice (10 vol). The organic phase was washed with sodium bicarbonate solution (10%). The organic and aqueous phases were separated. The solvent was distilled completely under reduced pressure at below 6O0C. Cooled the reaction mixture to 25-3O0C. The crude was dissolved in toluene (1 Vol) and distilled the solvent completely under reduced pressure at below 6O0C. (Crude wt: 56 gm).
The crude was again dissolved in toluene (10 vol) and the reaction mixture was cooled to 25-30 °C. Slowly addition of Homoveratryl amine (21.8 gm) at 25-3O0C was started and maintained for 12-14 hours. Then heptane (3.0 vol) was added and stirred for 2 hours.
Filtered the solid and washed with heptane (2.0 vol). The wet material was purified with acetone (10 vol). The wet material was dried at 60-650C (41 gm, Purity: >99.4%).
Example-8
Alternative process for the preparation of Montelukast Homoveratrylamine salt using 1 -(mercaptomethyDcvclopropyl)acetic acid
400 ml of DMF and 71.5 gm of l-(mercaptomethyl)cyclopropyl)acetic acid was taken into RB flask and cooled to -5 to O0C and then 78.6 gm of NaOMe solution (30%) was slowly added to it and maintained for 30 minutes. S5E)-I -(3-(2-(7- chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propyl methanesulfonate (Compound-IV) was dissolved in 250 ml of DMF and it was added to the reaction at -5 to 0 0C under nitrogen atmosphere and maintained for 10-12 hours. The reaction mixture was quenched with 400 ml of water and extracted with 600 ml of DCM. The pH of the aqueous layer was adjusted to 4-4.5 by adding 60 ml of 2N acetic acid solution and stirred for 30 minutes. The DCM and aqueous layers were separated and the DCM layer was dried over sodium sulfate. The crude obtained (120 gm).
The crude (120 gm) was dissolved in 1 vol toluene and distilled. The crude was again dissolved in 10 vol toluene and 43.5 gm of homoveratrylamine was added to it at room temperature and stirred for 12-14 hours. To this, 2 vol of heptane was added, stirred for 1 hour, filtered the solid and the wet material was taken in 18 vol toluene and 12 vol heptane mixture and stirred for 1-2 hours at room temperature. The solid was filtered and dried (115 gm, >99%).
Example-9 Process for the preparation of Montelukast sodium
10 gm of Montelukast Homoveratryl amine salt and 100 ml of DCM was taken in a RB flask at 25 - 350C and stirred for 10-15 minutes and cooled to 0 - 50C. Then 1.12 ml of acetic acid and 50 ml of water was added slowly to it. Both DCM and aqueous layers were separated and again aqueous layer was extracted with 20 ml of DCM. DCM layers were combined and washed with 200 ml of water and the organic layer was dried over sodium sulfate. 20 ml of methanol was added to the resulting residue and then total methanol was distilled off. To the resulting residue, 50 ml of methanol was added and reaction mass was cooled to 25-35°C. Methanolic NaOH solution was prepared by dissolving 0.52 gm of NaOH pellets in 10 ml of methanol. Methanolic NaOH solution was added to the reaction mixture and the reaction mixture was filtered to remove any extraneous matter. It was filtered through high- flow bed and washed with 10 ml of methanol and the solvent was completely distilled off under vacuum. 15 ml of toluene was added to it to get a clear solution and to this; 100 ml of heptane was added drop wise. The solid was filtered and washed with 20 ml of heptane and the compound was dried under high vacuum for 10-12 hours. (7.92 gm, Yield: 75%, Purity: >99.3%)
Example- 10 Process for the preparation of Montelukast sodium
5 gm of Montelukast Homoveratryl amine salt and 50 ml of DCM was taken in a RB flask at 25 - 350C and stirred for 10-15 minutes. 0.89 ml of methanolic HCl and water was slowly added to the reaction mixture at 25-30 0C and maintained for
30-45 minutes. The two layers were separated and the organic layer was washed the filtrate with 20 ml of water four times. The DCM layer was concentrated under vacuum. The crude was dissolved in 10 ml of methanol and distilled under vacuum. The crude was again dissolved in 25 ml of methanol and methanolic sodium hydroxide solution was added to it at 25-30 °C and stirred for 30 minutes. 0.3 gm of charcoal was added to it and stirred at 25-30 °C for 30 minutes. It was filtered through high-flow bed and washed with 5 ml of methanol and the solvent was completely distilled off under vacuum. The crude was dissolved in 10 ml of toluene and distilled under vacuum. The crude was again dissolved in 7.5 ml of toluene and it was added to 50 ml of heptane with stirring. It was maintained for 30-45 minutes. The solid was filtered and washed with dried at RT for 2 hours, at 60-65 0C for 6-8 hours and at 90- 95 °C for 10 hours (3.5 gm, Purity: >99.0%).
Example-11 Process for the preparation of Montelukast sodium
5 gm of Montelukast Homoveratryl amine salt and 19 vol of toluene were taken in a RB flask and slowly added acetic acid at 25 - 350C and maintained for 30- 45 minutes. The solid was filtered and washed the filtrate with 20 ml of water four times. The organic layer was separated and distilled under vacuum. The crude was dissolved in 2 vol of methanol and distilled under vacuum. The crude was again dissolved in 25 ml of methanol and methanolic sodium hydroxide solution was added to it at 25-30 °C and stirred for 30 minutes. 0.3 gm of charcoal was added to it and stirred at 25-30 °C for 30 minutes. It was filtered through high-flow bed and washed with 5 ml of methanol and the solvent was completely distilled off under vacuum. The crude was dissolved in 10 ml of toluene and distilled under vacuum. The crude was again dissolved in 7.5 ml of toluene and it was added to 50 ml of heptane with stirring. It was maintained for 30-45 minutes. The solid was filtered and washed with dried at RT for 2 hours, at 60-65 °C for 6-8 hours and at 90-95 °C for 10 hours (3.3 gm, Purity: >98.5%).
While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations would present themselves to those skilled in the art without departing from the scope and spirit of this invention.

Claims

We Claim:
1. A novel intermediate [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-[2-(l-hydroxy-l-methylethyl)phenyl]propyl] thiojmethyl] cyclopropaneacetic acid (montelukast), homoveratrylamine salt of formula (II) for the production of [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-[2-(l- hydroxy-l-methylethyl)phenyl]propyl] thio]methyl] cyclopropaneacetic acid sodium (Montelukast sodium),
Figure imgf000020_0001
wherein the amine is represented as:
Figure imgf000020_0002
2. The novel intermediate according to claim 1, wherein said intermediate is characterized in having an X-ray powder diffraction pattern as depicted in Figure 1.
3. The novel intermediate according to claim 1 , wherein said intermediate is characterized in having DSC pattern as depicted in Figure 2.
4. A process for producing a novel intermediate [R-(E)]-l-[[[l-[3-[2-(7- chloro-2-quinolinyl) ethenyl] phenyl] -3-[2-(l-hydroxy-l-methylethyl)phenyl]propyl] thio]methyl] cyclopropaneacetic acid, homoveratrylamine salt of formula II for the production of [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-[2-(l- hydroxy-l-methylethyl)phenyl]propyl] thiojmethyl] cyclopropaneacetic acid sodium (Montelukast sodium), salt
Figure imgf000021_0001
(II) wherein the amine is represented as:
Figure imgf000021_0002
comprising:
a) reacting l-(mercaptomethyl) cyclopropyl) acetic acid with homoveratrylamine in presence of an organic solvent to obtain 1- (mercaptomethyl)cyclopropyl)acetic acid homoveratrylamine salt of formula III; and
Figure imgf000021_0003
Figure imgf000021_0004
(III)
b) condensing the compound of formula III with compound ([S- (E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-[2-(l-hydroxy-l- methylethyl) phenyl] propyl] methanesulfonate of formula FV in presence of a base and suitable solvent to obtain the novel intermediate of formula II.
Figure imgf000022_0001
salt
Figure imgf000022_0002
(II)
5. The process according to claim 4, wherein the organic solvent is selected from dichloromethane, cyclohexane, ethyl acetate and heptane or mixtures thereof.
6. The process according to claim 4, wherein step (a) is carried out at a temperature between 28-300C.
7. The process according to claim 4, wherein the base used is selected from organolithium reagent or alkali metal alkoxide.
8. The process according to claim 7, wherein the organolithium reagent is n-BuLi.
9. The process according to claim 7, wherein the alkali metal alkoxide is sodium methoxide.
10. A process for producing a novel intermediate [R-(E)]-l-[[[l-[3-[2-(7- chloro-2-quinolinyl) ethenyl] phenyl] -3-[2-(l-hydroxy-l-methylethyl)phenyl]propyl] thio]methyl] cyclopropaneacetic acid, homoveratrylamine salt of formula II for the production of [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-[2-(l- hydroxy-l-methylethyl)phenyl]propyl] thiojmethyl] cyclopropaneacetic acid sodium (Montelukast sodium), comprising treating montelukast free acid with homoveratrylamine. 5
11. A novel intermediate, l-(mercaptomethyl)cyclopropyl)acetic acid homoveratrylamine salt of formula III for the production of [R-(E)]-l-[[[l-[3-[2-(7- chloro-2-quinolinyl) ethenyl] phenyl] -3-[2-(l-hydroxy-l-methylethyl)phenyl]propyl] thio]methyl] cyclopropaneacetic acid sodium:
Figure imgf000023_0001
l-(mercaptomethyl)cyclopropyl)acetic J Q acid homoveratrylaminesalt
(III)
12. The novel intermediate according to claim 11, wherein said intermediate is characterized in having an X-ray powder diffraction pattern as depicted in Figure 3.
15
13. The novel intermediate according to claim 11, wherein said intermediate is characterized in having DSC pattern as depicted in Figure 4.
14. The novel intermediate according to claim 11, for production of 0 montelukast sodium, wherein said montelukast sodium salt is prepared by a process comprising:
(a) reacting the novel intermediate 1-
(mercaptomethyl)cyclopropyl)acetic acid homoveratrylamine salt of formula III with compound ([S-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] 25 phenyl] -3-[2-(l-hydroxy-l-methylethyl) phenyl] propyl] methanesulfonate of formula IV, in presence of a base and a suitable solvent to form montelukast homoveratrylamine salt of formula II; and
Figure imgf000024_0001
salt
Figure imgf000024_0002
(ID
(b) converting the montelukast homoveratrylamine salt of formula II to montelukast sodium of formula I
Figure imgf000024_0003
Montelukast Sodium
(I)
15. A process for producing a novel intermediate 1- (mercaptomethyl)cyclopropyl)acetic acid homoveratrylamine salt of formula III for the production of [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-[2- (l-hydroxy-l-methylethyl)phenyl]propyl] thiojmethyl] cyclopropaneacetic acid sodium, comprising reacting l-(mercaptomethyl)cyclopropyl)acetic acid with homoveratrylamine in presence of an organic solvent.
Figure imgf000025_0001
Figure imgf000025_0002
(III)
16. The process according to claim 15, wherein the organic solvent is selected from dichloromethane, cyclohexane, ethyl acetate and heptane or mixtures thereof.
17. The process according to claim 15, wherein the reaction is carried out at a temperature between 28-30°C.
18. A process for producing montelukast sodium employing the novel intermediate l-(mercaptomethyl)cyclopropyl)acetic acid homoveratrylamine salt of formula III for the production of [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-[2-(l-hydroxy- 1 -methylethyl)phenyl]propyl] thio]methyl] cyclopropaneacetic acid sodium, comprising:
(a) treating l-(mercaptomethyl)cyclopropyl)acetic acid with homoveratryl amine in presence of an organic solvent to give the novel intermediate l-(mercaptomethyl)cyclopropyl)acetic acid homoveratrylamine salt of formula III;
Figure imgf000026_0001
Figure imgf000026_0002
(III)
(b) reacting the novel intermediate with compound ([S-(E)]-1-[[[1- [3-[2-(7-chloro-2-quinolinyl) ethenyl] phenyl] -3-[2-(l-hydroxy-l- methylethyl) phenyl] propyl] methanesulfonate of formula FV in presence of a base and suitable solvent to form montelukast homoveratrylamine salt of formula II; and
Figure imgf000026_0003
salt
Figure imgf000026_0004
(II)
(c) converting the montelukast homoveratrylamine salt of formula II to montelukast sodium of formula I
Figure imgf000027_0001
Montelukast Sodium
(I)
19. The process according to claim 18, wherein the base is selected from organolithium reagent or alkali metal alkoxide.
20. The process according to claim 19, wherein the organolithium reagent is n-BuLi.
21. The process according to claim 19, wherein the alkali metal alkoxide is sodium methoxide.
22. The process according to claim 18, wherein the montelukast primary amine salt is converted to montelukast sodium of formula I by a process comprising:
a) treating the montelukast homoveratrylamine salt of formula II with an acid and organic solvent to obtain a precipitate;
b) filtering and washing the solid formed; and
c) reacting with alkali metal hydroxide in presence of an alcohol.
23. The process according to claim 22, wherein the organic solvent is toluene.
24. The process according to claim 22, wherein the acid is organic or inorganic acid.
25. The process according to claim 24, wherein the organic acid is acetic acid.
26. The process according to claim 22, wherein the alcohol is a C1-C4 alcohol, preferably methanol.
27. A process for producing montelukast sodium of formula I employing novel intermediate montelukast homoveratryl amine salt of formula II,
Figure imgf000028_0001
Montelukast Sodium (I) comprising:
a) treating the montelukast homoveratrylamine.salt of formula II with an acid and organic solvent to obtain a precipitate;
b) filtering and washing the solid formed; and
c) reacting with alkali metal hydroxide in presence of an alcohol.
28. The process according to claim 27, wherein the organic solvent is toluene.
29. The process according to claim 27, wherein the acid is organic or inorganic acid.
30. The process according to claim 29, wherein the organic acid is acetic acid.
31. The process according to claim 27, wherein the alcohol is a Ci-C4 alcohol, preferably methanol.
PCT/IN2009/000354 2008-12-01 2009-06-18 Novel intermediates for producing [r-(e)]-1-[[[1-[3-[2-(7- chloro -quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy- methylethyl) phenyl]propyl]thio] methyl] cyclopropaneacetic acid, monosodium salt and process thereof WO2010064257A1 (en)

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