WO2009098271A1 - Procédé de purification du montélukast par préparation de sels d’addition acides et de sel de tert-amylamine - Google Patents

Procédé de purification du montélukast par préparation de sels d’addition acides et de sel de tert-amylamine Download PDF

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Publication number
WO2009098271A1
WO2009098271A1 PCT/EP2009/051345 EP2009051345W WO2009098271A1 WO 2009098271 A1 WO2009098271 A1 WO 2009098271A1 EP 2009051345 W EP2009051345 W EP 2009051345W WO 2009098271 A1 WO2009098271 A1 WO 2009098271A1
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Prior art keywords
montelukast
formula
compound
acid
salt
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PCT/EP2009/051345
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English (en)
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Jordi Bessa-Bellmunt
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Farmaprojects, S.A.
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Publication of WO2009098271A1 publication Critical patent/WO2009098271A1/fr

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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

  • the present invention relates to processes for the purification of montelukast by the preparation of acid addition salts and terf-amylamine salt.
  • Montelukast sodium is a leukotriene antagonist of formula:
  • Montelukast sodium is also known as sodium R-(E)-I -[[[1-[3-[2-[7-chloro-2-quinolinyl] ethenyl]phenyl]-3-[2-(1 -hydroxy-1 -methylethylJphenylJpropyOthioJ-methylJcyclopropa- neacetate.
  • This compound is useful in the treatment of asthma, inflammation, allergies, angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, uveitis and allograft rejection.
  • montelukast is purified by the preparation of an acid addition salt of a precursor.
  • This precursor does not contain the tertiary alcohol group of montelukast, but is a methyl ester precursor.
  • montelukast dicyclohexyl amine salt is converted into montelukast acid by treatment with a diluted solution of a weak acid: "This step is somewhat delicate because, during the acidification phase (referred to above) impurities may be formed, such as the unsaturated compound IX shown below, an impurity which is derived from the dehydration of the tertiary alcohol group and is then difficult to remove" (unsaturated compound IX corresponds to the styrene impurity according to our name convention).
  • the aim of this invention is to provide an efficient alternative process for preparing montelukast and salts thereof, especially its sodium salt, and for purifying such compounds.
  • the inventors have developed a simplified procedure for the purification of montelukast comprising the isolation of montelukast acid addition salts. Contrary to what is stated in EP1693368-A1 , the preparation of montelukast acid addition salts under controlled conditions, even in the presence of strong acids, does not lead to a significant formation of by-products from the dehydration of the tertiary alcohol, such as the styrene impurity, and, unexpectedly, acid addition salts of montelukast constitute a very efficient montelukast purification method.
  • the yield of the process is high and the reduction in the content of montelukast sulfoxide and Z impurity is surprisingly high.
  • the process involving such salts would avoid the use of more complex and expensive chromatographic techniques described in the prior art, which, according to US6320052, also provide low yield.
  • the invention relates to an acid addition salt of a compound of formula (I)
  • the invention in a second aspect, relates to a process for the preparation of compounds of formula (I) or base addition salts thereof, comprising the isolation of an acid addition salt according to the first aspect of the invention.
  • the invention relates to a compound of formula (II)
  • the compound of formula (II), montelukast ferf-amylamine salt, represents an atomic economy with regard to other amine salts such as dicyclohexylamine, amantadine and other ammonium salts.
  • the use of montelukast terf-amylamine is especially effective in reducing the content of styrene impurity and montelukast sulfoxide. Furthermore, it avoids the use of more complex and expensive chromatographic techniques described in the prior art.
  • montelukast terf-amylamine salt is stable, non hygroscopic and easy to handle in solid form, as the crystals obtained are easy to filter.
  • the product obtained by using this salt in purification steps is highly pure. Inventors have found conditions where the precipitation step of this ammonium salt is slow, which makes it easy to purify the product.
  • the invention relates to a process for the preparation of compounds of formula (I) or a base addition salt thereof, comprising the isolation of compounds of formula (II), and optionally the transformation of a compound of formula (I) into other base salts, such as the sodium salt.
  • the last two aspects of the invention are closely complementary to the first two aspects of the invention because the use of tert-amylamine enables an important reduction in the content of the styrene impurity and montelukast sulfoxide to be acheived, while the use of acid addition salts of montelukast enables the reduction of Z impurity and montelukast sulfoxide. Therefore, they are interrelated products with regard to montelukast purification processes.
  • the invention relates to pharmaceutical compositions comprising an acid addition salt of compound of formula (I) or solvates thereof including hydrates.
  • the invention relates to pharmaceutical compositions comprising a compound of formula (II) or solvates thereof including hydrates.
  • an “acid addition salt” is understood as being a salt prepared with an organic or inorganic acid.
  • Organic acids include acids such as alkyl/aryl sulfonates, for instance para-toluenesulfonic acid or methanesulfonic acid, tartaric acid, oxalic acid, citric acid, malic acid, formic acid.
  • Inorganic acids could include sulfuric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid.
  • Acid addition salts also include solvates thereof. Hydrates are also included as a specific type of solvate.
  • a "solid form" of a compound such as montelukast acid addition salts or montelukast tert-amylamine salts, is understood as being any state or form that is solid, and specifically includes crystalline forms, amorphous forms or mixtures thereof of these compounds or solvates thereof, including hydrates.
  • telukast sulfoxide is understood as being R-(E)-I -[[[1- [3-[2-[7-chloro-2-quinolinyl]ethenyl]phenyl]-3-[2-(1-hydroxy-1- methylethyl)phenyl]propyl]- sulfinyl]methyl] cyclopropaneacetic acid.
  • Z impurity is understood as being R-(Z)-I -[[[1-[3-[2-[7 - chloro-2-quinolinyl]ethenyl]phenyl]-3-[2-(1-hydroxy-1- methylethyl)phenyl]propyl]thio]methyl] cyclopropaneacetic acid.
  • styrene impurity is understood as being R-(E)-I -[[[1 -[3-[2-[7- chloro-2-quinolinyl]ethenyl]phenyl]-3-[2-(prop-1-en-2-yl)phenyl]propyl]thio]methyl] cyclopropaneacetic acid.
  • the compound of formula (M) "montelukast terf-amylamine”, “montelukast tert-amylamine salt”, “montelukast ferf-amylammonium (salt)” or “Montelukast 'AmNH 2 (salt)” are understood as being R-(E)-I -[[[1 -[3-[2-[7-ch loro-2- quinolinyl]ethenyl]phenyl]-3-[2-(1 -hydroxy-1 -methylethyl)phenyl]-propyl]thio]methyl] cyclopropaneacetic acid terf-amylamine salt.
  • “Montelukast terf-amylamine” and synonyms also include solvates thereof. Hydrates are also included as a specific type of solvate.
  • telukast or base addition salts thereof or “a compound of formula (I) or base addition salts thereof are understood as including, among others, the sodium salt, and solvates and hydrates of montelukast or base addition salts.
  • Figure 1 depicts the X-ray diffraction pattern of montelukast HCI salt.
  • Figure 2 depicts the X-ray diffraction pattern of montelukast terf-amylamine salt.
  • the first aspect of the invention relates to acid addition salts of montelukast.
  • Acid addition salts of montelukast, the compound of formula (I) can be prepared with either organic or inorganic acids.
  • a crude or a solution containing montelukast or a base addition salt thereof can be reacted with an organic or inorganic acid.
  • Organic acids include acids such as alkyl/aryl sulfonates, for instance para-toluenesulfonic acid or methanesulfonic acid, tartaric acid, oxalic acid, citric acid, malic acid and formic acid.
  • Inorganic acids could include sulfuric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid.
  • Acid addition salts also include solvates thereof. Hydrates are also included as a specific type of solvate.
  • the acid addition salts of montelukast are those prepared with acids selected from the group consisting of HCI, HBr and HI, preferably from HCI and HBr.
  • the invention relates to solid forms of acid addition salts of montelukast, preferably in crystalline form, which are especially useful in the purification process of montelukast and salts thereof.
  • the invention relates to a crystalline solid comprising montelukast HCI, characterized by powder X-ray diffraction pattern comprising the following peaks at degrees 2 ⁇ 3.9, 4.4, 5.7, 8.7, 12.7 and 17.6 ⁇ 0.2 degrees 2 ⁇ .
  • the invention relates to a crystalline solid comprising montelukast HCI depicted in figure 1 , obtained from the process of Example 1.
  • This crystalline solid shows the following X-ray diffraction pattern (peaks with relative intensities of 10% or more included).
  • the invention relates to a process for the preparation of compounds of formula (I) or base addition salts thereof, comprising the isolation of an acid addition salt in solid form, preferably in crystalline form.
  • Acid addition salts of montelukast can be precipitated from solvents or solvent mixtures in following well-known methods to the person skilled in the art.
  • these salts are obtained by adding, to a crude or solution comprising montelukast or a montelukast salt, an acid in solution, for example aqueous, alcoholic or hydroalcoholic solutions, or in solid, liquid or gas form.
  • the preparation of acid additions salts is carried out preferably at temperatures lower than 10° C, preferably lower than 5 0 C, more preferably equal or lower than 0 0 C. This enables the acid addition salt of montelukast to be obtained using even strong acids without increasing the percentage of styrene impurity significantly.
  • the amount of acid used ranges from the stoichiometric amount needed to 3 moles per mole of montelukast, preferably from 1 mole to 2 moles of acid are used per mole of montelukast, more preferably from 1 mole to 1.7 moles of acid per mole of montelukast.
  • the invention relates to a process, wherein a compound of formula (I) is prepared from the corresponding acid addition salt by treatment with at least one base. More preferably, the process further comprises the isolation of an amine salt of a compound of formula (I) and the transformation of this amine salt into a compound of formula (I) or a salt thereof.
  • This amine salt (or ammonium salt) is preferably montelukast terf-amylamine salt.
  • the preparation of montelukast terf-amylamine comprises reacting montelukast acid and ferf-amylamine in an organic solvent system, optionally adding a solvent with lower polarity as antisolvent, such as cyclohexane or heptane; preferably the first organic solvent being an apolar aprotic solvent. More preferably, the organic solvent is toluene and cyclohexane is added as antisolvent. In a preferred embodiment, toluene and cyclohexane are used at a proportion of from 3:1 to 1 :3, more preferably at a proportion of from 2:1 to 1 :2, and even more preferably at a proportion of about 1 :1.
  • a third aspect of the invention relates to montelukast terf-amylamine salt.
  • the invention relates to solid forms of it, and more preferably, to crystalline forms.
  • the invention relates to a crystalline solid comprising montelukast ferf-amylamine, characterized by powder X-ray diffraction pattern comprising the following peaks at degrees 2 ⁇ 3.3, 8.5, 14.4, 16.2, 17.1 , 17.9, 19.0, 19.5, 20.2, 22.9, 23.6 and 25.6 ⁇ 0.2 degrees 2 ⁇ .
  • a fourth aspect of the invention is the preparation of montelukast or salts thereof comprising the isolation of montelukast ferf-amylamine salt in solid form, preferably in crystalline form, and optionally the transformation of montelukast into other base addition salts, such as the sodium salt.
  • the precipitation of montelukast terf-amylamine is carried out in suitable organic solvents, optionally adding a solvent with lower polarity as antisolvent, such as cyclohexane or heptane.
  • suitable organic solvents include the group of apolar aprotic solvents.
  • solvents examples include aromatic solvents (such as toluene, benzene, xylene), halogenated solvents (dichloromethane, carbon tetrachloride, chloroform), ethers (diethylether, diisopropylether, methyl-ferf- butylether).
  • the precipitation can be carried out in mixtures of alcoholic solvents, such as isopropyl alcohol, methanol or ethanol, acetone, ethylacetate or dichloromethane with less polar solvents such as cyclohexane or heptane, or by using alcoholic solvents, such as isopropyl alcohol, methanol or ethanol, acetone, ethylacetate or dichloromethane in supersaturated mixtures.
  • alcoholic solvents such as isopropyl alcohol, methanol or ethanol, acetone, ethylacetate or dichloromethane in supersaturated mixtures.
  • the precipitation of montelukast terf-amylamine can also be carried out using toluene and heptane or hexane as antisolvents, using para-xilene and cyclohexane, heptane or hexane as antisolvents, mixtures of ethers and alkanes, such as diethylether/heptane, methyl terf-butylether/heptane, mixtures of ketones and alkanes, such as acetone/heptane, acetone/hexane, acetone/cyclohexane or methyl isobutylketone and heptane, hexane or cyclohexane, mixtures of esters and alkanes, such as AcOEt/heptane, AcOEt/hexane, AcOEt/cyclohexane, AcOiPr/heptane, mixtures of water and water insoluble solvent
  • the preparation of montelukast terf-amylamine comprises reacting montelukast acid and ferf-amylamine in an organic solvent system, optionally adding a solvent with lower polarity as antisolvent, such as cyclohexane or heptane; preferably the first organic solvent being an apolar aprotic solvent.
  • apolar aprotic solvent is toluene and cyclohexane is added as antisolvent, preferably at a proportion of from 3:1 to 1 :3, more preferably at a proportion of from 2:1 to 1 :2, and even more preferably at a proportion of about 1 :1.
  • the invention relates to a process further comprising the isolation of an acid addition salt of a compound of formula (I).
  • the sodium salt of montelukast could be obtained either directly from its ferf-amylamine salt following procedures described in
  • WO2007005965 Example 7
  • previous recovery of montelukast free acid and applying procedures like those described in WO2007057228 (Example 16) and WO2007051828 (Example12).
  • the crystalline montelukast hydrochloride and montelukast ferf-amylamine salts were characterized by powder X-ray diffraction, thereby generating fingerprint powder X- ray diffraction patterns for each particular crystalline form. Measurements of 2 ⁇ values are accurate to within plus/minus 0.2 degrees 2 ⁇ . X-ray diffraction data were acquired using a Philips XPert x-ray diffracto meter. System description: Cu
  • K ⁇ 1 1.5419 A amstrongs, voltage 5OkV, current 40 mA, divergence and anti-scatter slits, 0.25° (0.5° in the first register), receiving slit, 0.10 mm, soller slits, 0.04 rad, scan, 2-40° 2 ⁇ (4-40° in the first register), step size, 0.03° 2 ⁇ , time per step, 2 s (1s in the first register).
  • Example 1 Preparation of 2-(1-((((R)-1-(3-((E)-2-(7-chloroquinolin-2-yl)vinyl) phenyO-S ⁇ -hydroxypropan ⁇ -yOphenyOpropyOsulfanyOmethyOcyclopropyl) acetic acid hydrochloride salt (montelukast-HCI).
  • Example 2 Preparation of 2-(1-((((K)-1-(3-((E)-2-(7-chloroquinolin-2-yl)vinyl) phenyO-S ⁇ -hydroxypropan ⁇ -yOphenyOpropyOsulfanyOmethyOcyclopropyl) acetic acid (montelukast acid)
  • Example 3 Preparation of 2-(1-((((K)-1-(3-((E)-2-(7-chloroquinolin-2-yl)vinyl) phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propyl)sulfanyl)methyl)cyclopropyl) acetic acid fe/t-amylammonium salt (montelukast- t AmNH 2 ).
  • the mixture was optionally seeded with pure crystals of Montelukast -'AmNH 2 and left stirring for 40 h at room temperature.
  • the white solid formed was filtered and washed with 20 mL of toluene/cyclohexane 1 :1 mixture to obtain 6.86 g (68%) of the title compound with the following impurity profile (HPLC, % area):
  • Example 4 Recrystallizations of 2-(1-((((f?)-1-(3-((E)-2-(7-chloroquinolin-2- yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propyl)sulfanyl)methyl) cyclopropyl) acetic acid fert-amylammonium salt (MOnIeIUkBSt 1 AmNH 2 ).
  • Example 4.2 1.95 g of the previously obtained solid were further purified by dissolving in 58 mL of toluene at 60 0 C and then left stirring at room temperature, optionally seeded with pure crystals of montelukast- t AmNH 2 , for 66 h. The solid formed was filtered and washed with 10 mL of toluene to obtain 1.15 g (59%) of the montelukast-'AmNH 2 with the impurity profile (HPLC, % area) shown in the table below:
  • Example 5 Preparation of 2-(1-((((f?)-1-(3-((E)-2-(7-chloroquinolin-2-yl)vinyl) phenyO-S ⁇ -hydroxypropan ⁇ -yOphenyOpropyOsulfanyOmethyOcyclopropyl) acetic acid hydrobromide salt (Montelukast-HBr).
  • Tablets are prepared by direct compression (Examples 6.1 and 6.2) and wet granulation (Example 6.3).
  • compositions prepared with montelukast sodium were prepared with montelukast sodium.
  • Compositions prepared with montelukast HCI showed good handling properties when compared with those prepared with montelukast sodium.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Quinoline Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne des procédés de purification de montélukast par préparation de sels d’addition acides et de sel de tert-amylamine. La préparation des sels d’addition acides est très efficace et ne conduit pas à l’augmentation des impuretés consécutives à la déshydratation de l’alcool tertiaire, par exemple les impuretés styrène, et l’utilisation du sel de tert-amylamine réduit considérablement la teneur en impureté styrène et le sulfoxyde de montélukast.
PCT/EP2009/051345 2008-02-06 2009-02-05 Procédé de purification du montélukast par préparation de sels d’addition acides et de sel de tert-amylamine WO2009098271A1 (fr)

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EP08101340.1 2008-02-06

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012020271A1 (fr) 2010-08-11 2012-02-16 Richter Gedeon Nyrt. Procédé pour la préparation de montélukast sodique
CN105646344A (zh) * 2016-02-29 2016-06-08 山东新时代药业有限公司 一种孟鲁司特的纯化方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005040123A1 (fr) * 2003-10-10 2005-05-06 Synhton B. V. Montelukast a l'etat solide
EP1693368A1 (fr) * 2005-02-18 2006-08-23 CHEMI S.p.A. Procédé pour la préparation de Montelukast
WO2007012075A2 (fr) * 2005-07-20 2007-01-25 Dr. Reddy's Laboratories Ltd. Preparation de montelukast

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005040123A1 (fr) * 2003-10-10 2005-05-06 Synhton B. V. Montelukast a l'etat solide
EP1693368A1 (fr) * 2005-02-18 2006-08-23 CHEMI S.p.A. Procédé pour la préparation de Montelukast
WO2007012075A2 (fr) * 2005-07-20 2007-01-25 Dr. Reddy's Laboratories Ltd. Preparation de montelukast

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012020271A1 (fr) 2010-08-11 2012-02-16 Richter Gedeon Nyrt. Procédé pour la préparation de montélukast sodique
CN105646344A (zh) * 2016-02-29 2016-06-08 山东新时代药业有限公司 一种孟鲁司特的纯化方法
CN105646344B (zh) * 2016-02-29 2018-08-14 山东新时代药业有限公司 一种孟鲁司特的纯化方法

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