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CAS Name: 1-[[[(1R)-1-[3-[(1E)-2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid
Molecular Formula: C35H36ClNO3S
Molecular Weight: 586.18
Percent Composition: C 71.71%, H 6.19%, Cl 6.05%, N 2.39%, O 8.19%, S 5.47%
Montelukast is a leukotriene receptor antagonist (LTRA) used for the maintenance treatment of asthma and to relieve symptoms of seasonal allergies. It is usually administered orally. Montelukast blocks the action of leukotriene D4 on the cysteinyl leukotriene receptor CysLT1 in the lungs and bronchial tubes by binding to it. This reduces the bronchoconstriction otherwise caused by the leukotriene, and results in less inflammation. Because of its method of operation, it is not useful for the treatment of acute asthma attacks. Again because of its very specific locus of operation, it does not interact with other allergy medications such as theophylline. Montelukast is marketed in United States and many other countries by Merck & Co. with the brand name Singulair®. It is available as oral tablets, chewable tablets, and oral granules. In India and other countries, it is also marketed under the brand name Montair®, produced by Indian company Cipla.
MONTELUKAST (Singulair® Oral Granules) helps to reduce asthma symptoms (coughing, wheezing, shortness of breath, or chest tightness) and control your asthma. It does not provide instant relief and cannot be used to treat a sudden asthma attack. It works only when used on a regular basis to help reduce inflammation and prevent asthma attacks. This drug is also helpful in improving seasonal allergies, like hay fever.
Montelukast is effective in adults and children
Amongst the US approvals, tentative FDA approvals have been identified for generic Montelukast sodium, awarded to Endo, Glenmark, Mylan, Roxane, Sandoz, Teva and Torrent. The large number of generic authorisations awaiting launch in the UK is indicative of the likely competition the Singulair product will face across Europe upon SPC expiry
EP Pat. No. 480,717 discloses Montelukast sodium along with other related compounds and the methods for their preparation. The reported method of synthesis proceeds through corresponding methyl ester namely, Methyl 2-[(3S)-[3-[(2E)-(7-chloroquinolin – 2yl) ethenyl] phenyl] – 3 – hydroxypropyl] benzoate and involves coupling methyl 1- (mercaptomethyi) cyclopropaneacetate with a mesylate generated in-situ.
The methyl ester of Montelukast is hydrolyzed to free acids and the latter converted directly to Montelukast Sodium salt (Scheme -1). The process is not particularly suitable for large – scale production because it requires tedious chromatographic purification of the methyl ester intermediate and / or the final product and the product yield is low.
Scheme -1
U.S. Pat. No. 5,614632 disclosed a process for the preparation of crystalline Montelukast sodium, which comprises of the following steps (Scheme – 2):
■ Reaction of methyl 2-[3(S)-[3-[2-(7-chloroquinolin -2-yl) ethenyl] phenyl] -3- hydroxypropyl benzoate (I) with Grignard reagent, methyl magnesium chloride in presence of cerium chloride to give Diol (II) ■ Reaction of Diol (II) with methane sulfonyl chloride to afford 2-[2-[3 (s)-[3- (2-(7-chloro quinolin-2yl) ethenyl] phenyl]- 3 – methane sulfonyloxy propyl] phenyl] -2-propanol (III)
■ Condensation of 2-[2-[3(s)-[3-(2-(7-chloro quinolin – 2-yl) ethenyl] phenyl] –
3 – methane sulfonyloxypropyl] phenyl] – 2- propanol (III) with dilithium anion of 1-mercaptomethyl) cyclopropaneacetic acid, which has been generated by the reaction of l-(mercaptomethyl)cyclopropaneacetic acid (IV)with n-Butyl lithium
■ Isolation of the condensed product, Montelukast as solid Montelukast dicyclohexylamine salt
■ Purification and conversion of Montelukast dicyclohexylamine salt into Montelukast sodium
■ Crystallization of Montelukast sodium from a mixture of toluene and acetonitrile
The process disclosed in U.S Pat. No. 5,614,632 further involved the reaction of Diol (II) with methane sulfonyl chloride involves the reaction temperature of about – 25°C and the storage condition of the intermediate, 2-[2-[3(s)-[3-(2-(7-chloro quinolin – 2-yl) ethenyl] pheny] -3 -methane sulfonyloxy propyl] phenyl] -2-propanol (III) at temperature below – 150C for having the stability. The process further involves the reaction, formation of dilithium anion of l-(mercaptomethyl) cyclopropaneacetic acid which requires the usage of n-Butyl lithium, a highly flammable and hazardous reagent and the reaction is at temperature below -5°C further requires anhydrous conditions. Scheme – 2
Montelukast (trade names Singulair, Montelo-10, and Monteflo and Lukotas in India) is a leukotriene receptor antagonist(LTRA) used for the maintenance treatment of asthma and to relieve symptoms of seasonal allergies.[1][2] It is usually administered orally once a day. Montelukast is a CysLT1antagonist; it blocks the action of leukotriene D4 (and secondary ligands LTC4 and LTE4) on the cysteinyl leukotriene receptor CysLT1 in the lungs and bronchial tubes by binding to it. This reduces the bronchoconstriction otherwise caused by the leukotriene and results in less inflammation.
Because of its method of operation, it is not useful for the treatment of acute asthma attacks. Again because of its very specificmechanism of action, it does not interact with other asthma medications such as theophylline.
Another leukotriene receptor antagonist is zafirlukast (Accolate), taken twice daily. Zileuton (Zyflo), an asthma drug taken four times per day, blocks leukotriene synthesis by inhibiting 5-lipoxygenase, an enzyme of the eicosanoid synthesis pathway.
The Mont in Montelukast stands for Montreal, the place where Merck developed the drug.[3]
Singulair was covered by U.S. Patent No. 5,565,473[9] which expired on August 3, 2012.[10] The same day, the FDA approved several generic versions of montelukast.[11]
On May 28, 2009, the United States Patent and Trademark Office announced their decision to launch a reexamination of the patent covering Singulair. The decision to reexamine was driven by the discovery of references that were not included in the original patent application process. The references were submitted through Article One Partners, an online research community focused on finding literature relating to existing patents. The references included a scientific article produced by a Merck employee around the key ingredient of Singulair, and a previously filed patent in the same technology area.[12]
On December 17, 2009, the U.S. Patent and Trademark Office determined that the patent in question was valid based on the initial reexamination and new information provided.[13]
Montelukast is currently available in film coated tablet and orodispersible tablet formulations for once-daily administration, and also available as an oral granule formulation which is specifically designed for administration to paediatric patients.
Patent family US17493193A claims crystalline Montelukast sodium and processes for its preparation . Patents within this family are not considered to be a constraint to generic competition because the protected technology may possibly be circumvented by the synthesis and use of different molecular forms and/or salts. Patent family US33954901P relates to the specific marketed oral granule formulation of Montelukast.
The chemical name of montelukast sodium is: Sodium 1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid and its structure is represented as follows:
Montelukast is apparently a selective, orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT1 receptor.
The chemical name for montelukast sodium is [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl] cyclopropaneacetic acid, monosodium salt. Montelukast sodium salt is understood to be represented by the following structural formula:
U.S. patent No. 5,565,473 (“’473 patent”) is listed in the FDA’s Orange Book for montelukast sodium. The ’473 patent recites a broad class of leulcotriene antagonists as “anti-asthmatic, anti-allergic, anti-inflammatory, and cycloprotective agents” represented by a generic chemical formula. ’473 patent, col. 2,1. 3 to col. 4,1. 4. Montelukast is among the many compounds represented by that formula. The ’473 patent also refers to pharmaceutical compositions of the class of leukotriene antagonists of that formula with pharmaceutically acceptable carriers. Id. at col. 10,11. 42-46.
Montelukast sodium is currently marketed by Merck in the form of film coated tablets and chewable tablets under the trade name Singular®. The film coated tablets reportedly contain montelukast sodium and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, hydroxypropylcellulose, magnesium stearate, titanium dioxide, red ferric oxide, yellow ferric oxide, and carnauba wax. The chewable tablets reportedly containmontelukast sodium and the following inactive ingredients: mannitol, microcrystalline cellulose, hydroxypropylcellulose, red ferric oxide, croscarmellose sodium, cherry flavor, aspartame, and magnesium stearate. Physicians’ Desk Reference, 59th ed. (2005), p. 2141.
However, there is a need in the art to improve the stability of compositions of montelukast and particularly those of the sodium salt.
Montelukast sodium is a leukotriene antagonist and inhibits the leukotriene biosynthesis. It is a white to off-white powder that is freely soluble in methanol, ethanol, and water and practically insoluble in acetonitrile.
A montelukast sodium salt is a substance which exhibits efficacy of Singulair (available from Korean MSD) generally used for the treatment of asthma as well as for the symptoms associated with allergic rhinitis, which is pharmaceutically known as a leukotriene receptor antagonist. Leukotrienes produced in vivo by metabolic action of arachidonic acid include LTB4, LTC4, LTD4 and LTE4. Of these, LTC4, LTD4 and LTE4 are cysteinyl leukotrienes (CysLTs), which are clinically essential in that they exhibit pharmaceutical effects such as contraction of airway muscles and smooth muscles and promotion of secretion of bronchial mucus.
Montelukast sodium salt is a white and off-white powder which has physical and chemical properties that it is well soluble in ethanol, methanol and water and is practically insoluble in acetonitrile.
A conventionally known method for preparing a montelukast sodium salt is disclosed in EP Patent No. 480,717. However, the method in accordance with the EP Patent requires processes for introducing and then removing a tetrahydropyranyl (THP) protecting group and purification by chromatography, thus being disadvantageously unsuitable for mass-production. In addition, the method disadvantageously requires investment in high-cost equipment, for example, to obtain amorphous final compounds by lyophilization.
Meanwhile, U.S. Pat. No. 5,614,632 discloses an improved method for preparing a montelukast sodium salt by directly reacting a methanesulfonyl compound (2) with 1-(lithium mercaptomethyl)cyclopropaneacetic acid lithium salt, without using the tetrahydropyranyl protecting group used in EP Patent No. 480,717, purifying in the form of a dicyclohexylamine salt by adding dicyclohexylamine to the reaction solution, and converting the salt into a montelukast sodium salt (1).
However, the method in accordance with the US patent should use n-butyl lithium as a base in the process of preparing the 1-(lithium mercaptomethyl)cyclopropaneacetic acid lithium salt and thus requires an improved process due to drawbacks that n-butyl lithium is dangerous upon handling and is an expensive reagent.
PCT International Patent Laid-open No. WO 2005/105751 discloses a method for preparing a montelukast sodium salt, comprising coupling methyl 1-(mercaptomethyl)cyclopropane acetate (3) used in step 10 shown in Example 146 of EP Patent 480,717 with a methanesulfonyl compound (2) in the presence of a solvent/cosolvent/base, performing hydrolysis, recrystallizing the resultingmontelukast acid (4) in the presence of a variety of solvents to obtain highly puremontelukast acid (4), and converting the same into a montelukast sodium salt (1).
In addition, WO 2005/105751 claims that, in the coupling reaction, one is selected from tetrahydrofurane and dimethylcarbonate as a solvent, a highly polar solvent is selected from dimethylformamide, dimethylacetamide and N-methylpyrrolidone as a cosolvent, and one is selected from sodium hydroxide, lithium hydroxide, sodium hydride, sodium methoxide, potassium tert-butoxide, lithium diisopropylamine and quaternary ammonium salts, as a base.
However, WO 2005/105751 discloses that, since the coupling reaction requires use of a mixed solvent and the mixed solvent is different from the solvent used for hydrolysis, a process for removing the cosolvent through distillation under reduced pressure or extraction is further required prior to hydrolysis.
Further, in accordance with the method of WO 2005/105751, recrystallization is performed in the presence of a variety of solvents in order to obtain a highly puremontelukast acid (4) and the resulting recrystallization yield is varied in a range of 30 to 80%, depending on the solvent. In the case where desired purity is not obtained, recrystallization is repeated until montelukast acid (4) with a desired purity can be obtained. Disadvantageously, the method causes deterioration in overall yield.
European Patent No. 480,717 discloses montelukast sodium and its preparation starting with the hydrolysis of its ester derivative to the crude sodium salt, acidification of the crude to montelukast acid, and purification of the crude acid by column chromatography to give montelukast acid as an oil. The resulting crude oil in ethanol was converted to montelukast sodiumby the treatment with an equal molar aqueous sodium hydroxide solution. After removal of the ethanol, the montelukastsodium was dissolved in water and then freeze dried. The montelukast sodium thus obtained is of a hydrated amorphous form as depicted in FIG. 2.
The reported syntheses of montelukast sodium, as pointed out by the inventor in EP 737,186, are not suitable for large-scale production, and the product yields are low. Furthermore, the final products, as the sodium salts, were obtained as amorphous solid which are often not ideal for pharmaceutical formulation. Therefore, they discloses an efficient synthesis of montelukastsodium by the use of 2-(2-(3-(S)-(3-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-methanesulfonyloxypropyl)phenyl)-2-propanol to couple with the dilithium salt of 1-(mercaptomethyl)cyclopropaneacetic acid. The montelukast acid thus obtained is converted to the corresponding dicyclohexylamine salt and recrystallized from a mixture of toluene and acetonitrile to obtain crystallinemontelukast sodium. This process provides improved overall product yield, ease of scale-up, and the product sodium salt in crystalline form.
According to the process described in EP 737,186, the chemical as well as optical purities of montelukast sodium depends very much on the reaction conditions for the mesylation of the quinolinyl diol with methanesulfonyl chloride. For instance, the reaction temperature determinates the chemical purity of the resulting coupling product montelukast lithium, due to the fact that an increase in the reaction temperature resulted in decreased selectivity of mesylation toward the secondary alcohol. Mesylation of the tertiary alcohol occurred at higher temperature will produce, especially under acidic condition, the undesired elimination product, the styrene derivative. This styrene impurity is difficult to remove by the purification procedure using DCHA salt formation; while excess base, butyl lithium in this case, present in the reaction mixture causes the formation of a cyclization by-product, which will eventually reduce the product yield.
PCT WO 2005/105751 discloses an alternative process for preparing montelukast sodium by the coupling of the same mesylate as disclosed in ’186 patent with 1-(mercaptomethyl)cyclopropane alkyl ester in the presence of a base. In this patent, the base butyl lithium, a dangerous and expensive reagent, is replaced with other milder organic or inorganic base. However, the problem concerning the formation of the styrene impurity is still not resolved.
Process for the manufacture of 1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropane acetic acid, sodium salt [montelukast sodium (I)] consisting of: i. Converting methyl 1-(mercaptomethyl)-cyclopropaneacetate to a metal salt (X) using a metal hydroxide, ii. Subjecting the metal salt (X) to monometallation to provide a dimetallide (XI). iii. Converting a diol of formula (II) to a mesylate of formula (III) and reacting (III) in situ with (XI) affordin the metal salt of 1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropane acetic acid. iv. Reacting the metal salt in-situ with a base and purifying to afford an amine salt (XII). v. Treating (XII) with a sodium base and precipitating out montelukast sodium (I).
more info
European Patent No. 480,717 disclose the montelukast and its preparation method first be hydrolyzed to the crude ester derivatives sodium, then this crude product was acidified to montelukast acid (montelukastacid), Finally, column chromatography purification of this crude acid into oily montelukast acid. This oilMontelukast acid in ethanol, by equimolar amounts of sodium hydroxide solution and converted to montelukast sodium.
The ethanol was removed aftermontelukast sodium dissolved in water, followed by freeze-drying. Finally obtainedmontelukast shown in Figure 2 is amorphous hydrated.
The invention, in European Patent No. 737,186 points out, thismontelukast synthesis method is not suitable for mass production, and the low yield.
Moreover, the resulting amorphous solid salt, are generally not used in pharmaceutical formulations.
Therefore, they disclose the synthesis of an effective method of montelukast sodium, which uses 2 – (2 – (3 – (S) – (3 – (7 – chloro-2 – quinolinyl) ethenyl) phenyl) -3 – methylsulfonyl) phenyl) -2 – propanol and 1 – (methylthio alcohol) cyclopropane coupling the lithium salt of acetic acid, the resulting Montelukast acid is converted into a corresponding bicyclic hexyl amine salt, and from a mixture of toluene and acetonitrile recrystallization to prepare crystalline montelukast. This method greatly improves the productivity, ease of mass production, and the product is crystalline sodium salt.
According to European Patent No. 737,186 described method for preparingmontelukast chemical purity and optical purity depends largely quinoline diol with methanesulfonyl chloride in the reaction between the mesylated condition.
For example, the reaction temperature resulted in an increase of the secondary alcohols methanesulfonyl selective reduction, the reaction temperature determines the coupling product (montelukast lithium) chemical purity. Occurs at a higher temperature mesylation tertiary alcohols, in particular under acidic conditions, will produce impurities, such as styrene derivatives.
This impurity is difficult styrene generated by using the DCHA salt (DCHA salt formation) in the purification process to remove; present in the reaction mixture and excess base, butyl lithium cyclized by-products resulting in the formation will eventually reduce the yield of the product.
W02005/105751 disclose another preparation method of montelukast sodium, which is the methanesulfonic acid (European Patent No. 737,186 is the same) in an alkaline state where 1_ (methyl mercaptan yl) cyclopropyl alkyl ester and coupling thereof. In this patent, the dangerous and expensive alkaline-butyl lithium reagent, is replaced by other more moderate organic or inorganic base. However, the formation of styrene impurity problem is still not resolved
LitReferences: Selective cysteinyl leukotriene type 1 receptor antagonist. Prepn: M. L. Belley et al.,EP480717; eidem,US5565473 (1992, 1996 both to Merck Frosst); M. Labelle et al.,Bioorg. Med. Chem. Lett.5, 283 (1995).
Pharmacological profile: T. R. Jones et al.,Can. J. Physiol. Pharmacol.73, 191 (1995).
LC determn in human plasma: R. D. Amin et al.,J. Pharm. Biomed. Anal.13, 155 (1995).
Review of pharmacology and clinical efficacy in asthma: A. Markham, D. Faulds, Drugs56, 251-256 (1998).
Clinical trial in pediatric asthma: B. Knorr et al.,J. Am. Med. Assoc.279, 1181 (1998); with loratadine, q.v., in allergic rhinitis: E. O. Meltzer et al., J. Allergy Clin. Immunol.105, 917 (2000).
Comparison with cetirizine, q.v., in urticaria: M. L. Pacor et al., Clin. Exp. Allergy31, 1607 (2001).
Review of pharmacology and clinical experience: Z. Diamant, A. P. Sampson, J. Drug Eval. Respir. Med.1, 53-88 (2002).
Lipkowitz, Myron A. and Navarra, Tova (2001) The Encyclopedia of Allergies (2nd ed.) Facts on File, New York, p. 178, ISBN 0-8160-4404-X
HPLC (isocratic mode) chromatograms were measured with the EliteLachrom device made by the Hitachi Company. Stationary phase: RP-18e was used for the analyses; column temperature was 20 °C. Mobile phase: Acetonitrile (80%) and a 0.1 M aqueous solution of ammonium formate adjusted to pH 3.6 with formic acid (20%) were used. The flow rate of the mobile phase was 1.5 mL/min. Detection at the wavelength of 234 nm was used. Methanol was used as the solvent for preparation of samples; 10−20 μL of the solution was used for the injection. The isocratic HPLC method was used for checking the compositions of the reaction mixtures.
HPLC (gradient mode) chromatograms were measured with the Alliance HPLC device with PDA detector. Stationary phase: STAR RP-8e, 250 mm × 4 mm, 5 μm was used for the analyses; column temperature was 15 °C. Mobile phase: Acetonitrile (A) and 0.01 M aqueous solution of KH2PO4 adjusted to pH 2.2 with phosphoric acid (B) were used. Gradient mode with the flow rate of mobile phase 0.8 mL/min was used. Composition on the start was 60% of A and 40% of B, then changed to 15% of A and 85% of B over 20 min; this composition was held for 5 min, then changed to 60% of A and 40% of B over 5 min, and this composition was held to the end (overall time 35 min.). Detection at the wavelength of 234 nm was used. Methanol was used as the solvent for the preparation of the samples; 10−20 μL of the solution was used for the injection. The gradient HPLC method was used for checking the quality of the target substance including its salts with amines and of isolated standards of impurities.
HPLC (determination of (S)-enantiomer by HPLC) chromatograms were measured with the Alliance HPLC device with PDA detector. Stationary phase: Chiralpak IA (5 μm), size 0.25 m, internal diameter 4.6 mm (manufactured by Daicel) was used for the analyses, column temperature 10 °C. Mobile phase: hexane/ethanol/1,4-dioxan/trifluoroacetic acid (77:3:20:0,1 v/v/v) was used. The flow rate of the mobile phase was 1.0 mL/min. Detection at the wavelength of 285 nm was used. Methanol was used as the solvent for preparation of samples; 10 μL of the solution was used for the injection. The isocratic elution was used for checking the optical purity of target montelukast. Typical retention times: montelukast: 9.3 min, (S)-montelukast: 12.9 min.
KEY REFERENCES
(a) Ray, U. K.;Boju, S.; Pathuri, S. R.; Meenakshisunderam, S. (Aurobindo Pharma Limited, India). PCT Patent Application WO/2008/001213, 2008.
(b) Wang, Y.; Wang, Y.; Brand, M.; Kaspi, J. (Chemagis Ltd., Israel). PCT Patent Application WO/2007/088545, 2007.
(c) Turchetta, S.;Tuozzi, A.; Ullucci, E.; de Ferra, L. (Chemi S.P.A.; Italy). European Patent Application EA 1,693,368, 2008.
(d) Srinivas, P. L.; Rao, D. R.; Kankan, R. N.; Relekar, J. P. (Cipla Limited, India). PCT Patent Application WO/2006/064269, 2006.
(e) Reguri, B. R.; Bollikonda, S.;Bulusu, V. V. N. C. S.; Kasturi, R. K.; Aavula, S. K. (Dr. Reddy’s Laboratory, India). U.S. Patent Application U.S.2005/0107612, 2005.
(f) Coppi, L.; Bartra Sanmarti, M.; Gasanz Guillen, Y.; Monsalvatje Llagostera, M.; Talavera Escasany, P. (Esteve Quimica, S.A., Spain). PCT Patent Application WO/2007/051828, 2007.
(g) Hung, J. T.; Wei, C. P. (Formosa Laboratories, Inc., Taiwan). U.S. Patent Application U.S.2008/0097104, 2008.
EXAMPLE 8Sodium 1-(((1(R)-(3 -(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane-acetateToluene (1000 mL) and water ((950 mL) were placed in a 12 liter extractor equipped with an overhead stirrer, a thermocouple, a nitrogen inlet and an addition funnel. With good mixing of the solvents, solid dicyclohexylamine salt of Example 7 (64.3 g, 82.16 mmol) was added via a powder funnel and toluene (260 mL) was used to rinse in the remaining solid. To the well stirred suspension, acetic acid (2 M, 62 mL, 124 mmol) was added at room temperature. After approximately 10 minutes stirring was stopped. Two clear phases (yellow organic layer and colorless aqueous layer) resulted, and the aqueous waste layer was drained off. Water (950 mL) was charged to the extractor and the layers were mixed thoroughly for approx. 10 minutes.
The agitation was stopped and the aqueous waste layer was drained off.To the organic layer (1270 mL) containing the free acid a titrated solution of sodium hydroxide in 1 % aqueous ethanol (aqueous without ethanol (0.486 M, 169 mL, 82.13 mmol) was added in a steady stream over 10 minutes at room temperature under a nitrogen atmosphere. After 10 minutes age, the clear solution of the desired sodium salt was filtered through a pad of solkafloc using toluene (100 ml) for transfer and cake wash.
The clear filtrate was transferred under nitrogen to a 3 liter, 3-necked flask equipped with an overhead stirrer, a thermocouple, a nitrogen inlet and a distillation head. The solution was concentrated under vacuum to about 400 ml (ca. 40 mm Hg, ≤40°C). The distillation head was replaced with a reflux condenser and an addition funnel. The concentrate was maintained at 40 ± 2°C and acetonitrile (400 mL) was added over 20 minutes. The clear solution was seeded with 0.5 g of the crystalline sodium salt, and the resulting mixture was maintained at 40 ± 2°C for 1.5 hours, by which time a good seed bed was established.Acetonitrile (400 ml) was slowly added over 20 minutes, maintaining the batch temperature at 40 ± 2°C. The white suspension was stirred at 40 ± 2°C for 1 hour and acetonitrile (400 mL) was slowly added over 20 minutes. The slurry was aged at 40 ± 2°C for 12 hours.
A sample of the suspension was examined by cross-polarized micro-scopy to confirm crystallinity of the solid. The suspension was cooled to room temperature and aged at room temperature for 1 hour. The crystalline sodium salt was suction filtered through a sintered funnel under nitrogen. The cake was washed with acetonitrile (400 ml). The crystalline sodium salt cake was broken up in a nitrogen glove bag and dried under vacuum with nitrogen bleed at 40-45°C. The product (49 g, 80.59 mmol, 98% yield) was packaged in a well sealed brown bottle under nitrogen. The reaction mixture and the isolated product were protected from light at all times.
HPLC assay of the sodium salt: >99.5 A%. Chiral purity: 99.8% ee. 1H NMR (CD3OD) δ 8.23 (d, 1H), 7.95 (d, 1H), 7.83 (d, 1H), 7.82 (d, 1H), 7.75 (d, H), 7.70 (bs, 1H), 7.54 (dt, 1H), 7.46 (dd, 1H), 7.42-7.35 (m, 3H), 7.37 (d, 1H), 7.14-7.00 (m, 3H), 4.86 (s, active H), 4.03 (dd, 1H), 3.09 (m, 1H), 2.82 (m, 1H), 2.66 (d, 1H), 2.52 (d, 1H), 2.40 (d, 1H), 2.30 (d, 1H), 2.24-2.14 (m, 2H), 1.51 (two s, 6H), 0.52-0.32 (m, 4H). DSC melting endotherm with a peak temperature of 133°C and an associated heat of 25 J/g.
X-ray powder diffraction pattern: as shown in FIGURE 3.
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Paper
J. Liang*, J. Lalonde, B. Borup, V. Mitchell, E. Mundorff, N. Trinh, D. A. Kochrekar, R. N. Cherat, G. G. Pai
Codexis, Inc., Redwood City, USA and Arch PharmaLabs Limited, Mumbai, India
Development of a Biocatalytic Process as an Alternative to the (-)-DIP-Cl-Mediated Asymmetric Reduction of a Key Intermediate of Montelukast
Org. Process Res. Dev. 2010, 14: 193-198
Montelukast sodium (Singulair®) is a leukotriene receptor antagonist prescribed for the treatment of asthma and allergies. Workers at Codexis used directed evolution and high-throughput screening to engineer a robust and efficient ketoreductase enzyme (CDX-026) that accomplished the asymmetric reduction of ketone A, which is essentially water insoluble, at a loading of 100 g/L in the presence of ca. 70% organic solvents at 45 ˚C. The (S)-alcohol B was obtained in >95% yield in >99.9% ee and in >98.5% purity on a >500 mol scale.
The enzymatic reduction entails the reversible transfer of a hydride from isopropanol to the ketone A with concomitant formation of acetone. The reaction is driven to completion by the fortuitous crystallization of the monohydrate B. The four-step conversion of B into montelukast sodium is described in the Merck process patent (M. Bhupathy, D. R. Sidler, J. M. McNamara, R. P. Volante, J. J. Bergan US 6320052, 2001). This biocatalytic reduction is superior to the reduction of A with (-)-DIPCl previously used in the manufacture of montelukast
Impurities
Montelukast sodium (I) is an active ingredient of products used for the treatment of respiration diseases, mainly asthma and nasal allergy. Montelukast sodium, chemically the sodium salt of [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(l-hydroxy-l- methylethyl)phenyl]propyl]thio]-methyl]cyclopropane acetic acid is described by the chemical formula (I).
(I)
The first solution of chemical synthesis of montelukast (I) was described in the patent no. EP 0480717 Bl and subsequently in specialized literature as well (M.Labele, Bioorg.Med.Chem.Lett. 5 (3), 283-288 (1995)). More possibilities of chemical synthesis of montelukast (I) are described in the following patents: EP 0480717 Bl, EP 0737186 Bl, US 2005/0234241 Al, WO 2005/105751 Al, US 2005/0107612 Al, WO 2005/105749 A2, WO 2005/105750 Al, US 2007/208178 Al.
(H) R alkyl
R-ι> R2 alkyl or hydrogen
For the process of isolation and purification of crude montelukast salts of montelukast with some amines (II) or montelukast acid (III) in the solid state have been used so far. Among montelukast salts with amines salts with dicyclohexylamine (EP 0737186 Bl, WO 04108679A1), tert-butylamine (US 2005/0107612 Al, WO 06043846A1), ethylphenylamine (US 2005/0107612 Al), isopropylamine (WO 2007/005965 Al), di-n-propylamine (WO 2007/005965 Al) and with cycloalkylamines (C5-C9, US 2007/213365 Al) have been described. Solid forms of montelukast acid, both crystalline and amorphous, have been described in a number of patent applications: WO 2005/040123, WO 2005/073194 A2, WO 2005/074893 Al, WO 2005/074893 Al, WO 2004/108679 Al, WO 2005/074935 Al. The most common method used in practice consists in purifying crude montelukast (I) via its salts with secondary amines, mainly with dicyclohexylamine (EP 0737186 Bl).
The sodium salt of montelukast, its preparation and various forms, amorphous or crystalline, , are described in a number of patents or patent applications, e.g. amorphous montelukast sodium is dealt with by EP 0737186 Bl, WO 03/066598 Al, WO 2004/108679 Al, WO 2005/074893 Al, WO 2006/054317A1 a WO 2007/005965. Crystalline polymorphs of montelukast sodium are described by WO 2004/091618 Al and WO 2005/075427 A2.
Processes of isolation and purification of montelukast are of crucial economic significance as they make it possible to obtain a substance that can be used for pharmaceutical purposes. These processes are used to remove impurities that result from the chemical instability of montelukast as well as the instability of the raw materials used for its chemical synthesis or non-selectivity of chemical reactions, or they may be represented by residues of the raw materials used, especially solvents. There is a general rule that chemical purity of the active pharmaceutical ingredient (API) produced in the industrial scale is one of the critical parameters for its commercialization. The American Food and Drug Administration (FDA) as well as European medicament control offices require, according to the Q7A ICH (International Conference on Harmonization) instruction, that API is freed from impurities to the maximum possible extent. The reason is achieving maximum safety of using the drug in the clinical practice. National inspection and control offices usually require that the content of an individual impurity in an API should not exceed the limit of 0.1%. All the substances (generally referred to as impurities) contained in an API over the limit of 0.1% should be isolated and characterized in accordance with the ICH recommendations. It is also recommended to isolate and characterize degradation products that are generated during the storage or usability period of API (ICH Guideline, 2006). In order to obtain information about the stability of a substance and to describe degradation products so-called “stress tests” are performed. Within these tests the API is subjected to a series of critical conditions the selection of which depends on the structure of the tested API. Usually, the influence of an increased temperature, air humidity, light, oxygen and stability in a wide pH range is assessed.
In the montelukast molecule there are a number of functional groups that impair the chemical stability of this substance. Montelukast is known to be prone to several types of degradation; it is mainly the case of three kinds of chemical transformation: (a) Oxidation of the mercapto group to the sulphoxide according to equation (1),
(b) Isomerisation at the location of the double bond from geometry (E) to (Z), or trans to cis by the effect of light according to equation (2),
(c) Dehydration at the location of tert. alcohol, producing the corresponding olefin according to equation (3).
Literature (E.D.Nelson, J.Pharm.Sci. 95, 1527-1539 (2006), C.Dufresne, J.Org.Chem. 1996, 61(24), 8518-8525, WO 2007005965A1) describes increased sensitivity of montelukast (or rather the mercapto group, which montelukast contains) to oxygen, see equation (I)). As the main product of oxidation of montelukast (I) (E)-montelukast-sulfoxide, chemically the sodium salt of [R-(E)]]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(l-hydroxy- l-methylethyl)-phenyl]propyl]sulfmyl]methyl]cyclopropane acetic acid, described with chemical formula (IV), is mentioned. Contamination of the product with this impurity is undesirable. For this reason the processes leading to the target substance are carried out with the exclusion of oxygen, i.e. under the protective atmosphere of an inert gas (e.g. nitrogen according to EP 0737186 Bl). (E)-Montelukast-sulfoxide (IV) has also been described as a product of the oxidative metabolism of montelukast (Balani S. K. et al: Drug Metabolism and Disposition (1997) 25 (11), 1282-87, Dufrense C: J.Org.Chem. (1996) 61(24), 8518-25).
Exposure of montelukast to light causes its isomerization while a montelukast derivative with geometry (Z) is generated in the location of the double bond (Smith Glen A. et al: Pharm.Res. 2004, 21(9), 1539-44). The impurity resulting from photo-instability is (Z)-montelukast, chemically the sodium salt of l-[[[(lR)-l-[3-[(lZ)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]- 3-[2-(l-hydroxy-l-methylethyl)phenyl]propyl]thio]methyl]cyclopropane acetic acid, which is described by chemical formula (V), see equation (2).
Another degradation impurity described in literature (WO 2007005965A1) is montelukast dehydrated, chemically the sodium salt of l-[[[(lR)-l-[3-[(lE)-2-(7-chloro-2- quinolinyl)ethenyl]-phenyl]-3-[2-(l-methylethenyl)phenyl]propyl]thio]methyl]cyclopropane acetic acid, described by chemical formula (VI), see equation (3).
Recently, montelukast or its pharmaceutically acceptable salt is known to function as an antagonist and also as a biosynthesis inhibitor against leukotrienes. The sodium salt of montelukast is commercially available from Merck under the trademark of Singulair® for treating asthma.
EP 480,717 discloses a method of preparing said montelukast sodium salt: As shown in Reaction Scheme 1, methyl 1-(mercaptomethyl)cyclopropylacetate of formula (B) is coupled with the compound of formula (A) to produce the compound of formula (C) as an intermediate, and the compound of formula (C) is then hydrolyzed to obtain the free acid form thereof, followed by treating the free acid with NaOH. However, this method gives a low yield or the manufacturing cost is high.
THP: tetrahydropyranyl
PPTS: Pyridinium p-toluenesulfonateIn order to solve the above-mentioned problems, EP 737,186 suggests a method as shown in Reaction Scheme 2. This method uses a methanesulfonyl compound of formula (A′) having an unprotected hydroxyl group instead of the THP-protected compound of formula (A). Further, this method uses 1-(mercaptomethyl)cyclopropylacetate dilithium salt of formula (B′) instead of methyl 1-(mercaptoethyl)cyclopropylacetate of formula (B), thereby making the subsequent deprotection step unnecessary. Subsequently, dicyclohexylamine is added to the compound of formula (C″) to produce the compound of formula (D), which is converted to the desired sodium salt.
However, the methanesulfonyl compound of formula (A′) used in the above process as a starting material is very unstable, which makes the whole process very complicated. Namely, the reaction to produce the compound of formula (A′) must be performed at a low temperature of about −30° C. and the product is required to be kept at about −15° C. The compound of formula (A′) thus produced is unstable toward moisture and air, and therefore, the reaction thereof has to be conducted quickly under carefully controlled conditions. Also, the synthesis of the compound of formula (B′) requires the use of n-butyllithium which is very explosive and unstable toward moisture and air. Thus, the method described in Reaction Scheme is not suitable for large-scale production.
Example 1Preparation of 2-(2-(3-(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)-phenyl)-3-diphenylphosphate oxypropyl)phenyl)-2-propanol20 g of 2-(2-(3-(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-hydroxypropyl)phenyl)-2-propanol was dissolved in 240 ml of a mixture of methylene chloride and toluene (2:1), and 7.31 ml (1.2 eq.) of triethylamine was slowly added thereto. To the resulting mixture, 13.6 ml of diphenylchlorophosphate and 1.06 g of 4-dimethylaminopyridine were sequentially added dropwise. After about 1 hr, the completion of the reaction was confirmed by thin layer chromatography (TLC). The reaction mixture was treated with 100 ml of methylene chloride and 200 ml of distilled water. With shaking, the organic layer was separated and dried over sodium sulfate, followed by removing the solvent under reduced pressure. The residue thus obtained was dissolved in 60 ml of a mixture of ethyl acetate and n-hexane (1:3), and the product was recrystallized therefrom. The crystallized product was filtered, washed with 40 ml of distilled water and dried to obtain 29.5 g (97.8%) of the title compound as a yellow solid.m.p.: 127° C.1H-NMR (300 MHz, CDCl3): δ 8.4 (1H, d), 7.94 (1H, d), 7.75 (3H, m), 6.97-7.35 (20H, m), 5.70-5.72 (1H, m), 3.02-3.09 (2H, m), 2.29-2.34 (2H, m), 1.65 (3H, s), 1.59 (3H, s).
Example 2Preparation of 1-(((1-(R)-(3-(2-(7-chloro-2-quinolidyl)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methyl-ethyl)phenyl)propyl)thio)methyl)-cyclopropylacetic acid12.7 g of 1-(mercaptomethyl)cyclopropylacetic acid dissolved in 90 ml of dimethylformamide was slowly added to a solution of 6.26 g of 60% sodium hydride dissolved in 90 ml of dimethylformamide at 0 to 5° C. To the resulting mixture, 30 g of 2-(2-(3-(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-diphenylphosphate oxypropyl)phenyl)-2-propanol obtained in Example 1 dissolved in 120 ml of dimethylformamide was slowly added dropwise. After the temperature was slowly increased to room temperature, the reaction was run for 18 to 20 hrs. Then, the reaction mixture was neutralized with a saturated ammonium chloride aqueous solution, and treated with ethyl acetate and distilled water. With shaking, the organic layer was separated and dried over sodium sulfate, followed by removing the solvent under reduced pressure. The residue thus obtained was dissolved in 270 ml of cyclohexane, and the product was recrystallized therefrom. The crystallized product was filtered, washed and dried to obtain 22.2 g (87.1%) of the title compound as a yellow solid.
1H-NMR (300 MHz, CD3OD): δ 8.27 (1H, d), 7.98 (1H, s), 7.78 (2H, d), 7.73 (2H, d), 7.38-7.56 (6H, m), 7.07-7.14 (3H, m), 4.84 (1H, t), 3.30-3.33 (1H, m), 2.84-2.87 (1H, m), 2.52 (2H, s), 2.41 (2H, s), 2.18-2.23 (2H, m), 1.55 (6H, s), 0.37-0.52 (4H, m).
Example 3Preparation of 1-(((1-(R)-(3-(2-(7-chloro-2-quinolidyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methyl-ethyl)phenyl)propyl)-thio)methyl)cyclopropylacetate sodium saltStep 1: Preparation of methyl 1-(((1-(R)-(3-(2-(7-chloro-2-quinolidyl)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methyl-ethyl)phenyl)propyl)thio)methyl)-cyclopropylacetate
2.1 g of methyl 1-(acetylthiomethyl)cyclopropylacetate dissolved in 35 ml of dimethylformamide was slowly added to a solution of 0.71 g of 60% sodium hydride dissolved in 35 ml of dimethylformamide at a temperature ranging from 0 to 5° C. To the resulting mixture, 7.73 g of 2-(2-(3-(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-diphenylphosphate oxypropyl)phenyl)-2-propanol obtained in Example 1 dissolved in 35 ml of dimethylformamide was slowly added dropwise at a temperature ranging from 0 to 5° C. After about 1 hr, the reaction mixture was treated with ethyl acetate and distilled water. With shaking, the organic layer was separated and dried over sodium sulfate, followed by removing the solvent under reduced pressure to obtain 5.68 g (84.5%) of the title compound as a yellow liquid.
1H-NMR (300 MHz, CDCl3): δ 8.12 (2H, d), 7.66-7.74 (4H, m), 7.37-7.48 (6H, m), 7.12-7.20 (3H, m), 3.96 (1H, t), 3.14-3.16 (1H, m), 2.88 (1H, m), 2.53 (2H, s), 2.43 (2H, s), 1.62 (6H, d), 0.41-0.54 (4H, m).
Step 2: Preparation of 1-(((1-(R)-(3-(2-(7-chloro-2-quinolidyl)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methyl-ethyl)phenyl)propyl)thio)methyl)-cyclopropyl acetic acid
12 g of methyl 1-(((1-(R)-(3-(2-(7-chloro-2-quinolidyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methyl-ethyl)phenyl)propyl)thio)methyl)cyclopropylacetate obtained in step 1 was dissolved in a mixture of 60 ml of tetrahydrofuran and 30 ml of methyl alcohol. After adjusting the temperature to 10 to 15° C., 24 g of 10% NaOH solution was slowly added to the resulting mixture. Then, the temperature was slowly increased to room temperature (24 to 27° C.), and the reaction mixture was stirred for 20 hrs. After reaction was completed, the organic layer was separated and dried, followed by removing the solvent under reduced pressure. The residue thus obtained was mixed with water layer again, and 120 ml of toluene was added thereto. Subsequently, the pH of the reaction product was adjusted to 4 by adding 300 ml of acetic acid. The organic layer was separated again and dried over sodium sulfate, followed by removing the solvent under reduced pressure. The residue thus obtained was dissolved in 96 ml of a mixture of isopropanol and distilled water (2:1), and the product was recrystallized therefrom. The crystallized product was filtered to obtain 9.82 g (83%) of the title compound as a yellow solid.
Montelukast acid
1H-NMR (300 MHz, CD3OD): δ 8.27 (1H, d), 7.98 (1H, s), 7.78 (2H, d), 7.73 (2H, d), 7.38-7.56 (6H, m), 7.07-7.14 (3H, m), 4.84 (1H, t), 3.30-3.33 (1H, m), 2.84-2.87 (1H, m), 2.52 (2H, s), 2.41 (2H, s), 2.18-2.23 (2H, m), 1.55 (6H, s), 0.37-0.52 (4H, m).
m.p.: 154° C., purity>99%
Step 3: Preparation of 1-(((1-(R)-(3-(2-(7-chloro-2-quinolidyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methyl-ethyl)phenyl)propyl)thio)-methyl)cyclopropylacetate sodium salt
5 g of 1-(((1-(R)-(3-(2-(7-chloro-2-quinolidyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methyl-ethyl)phenyl)propyl)thio)methyl)cyclopropylacetic acid obtained in step 2 was mixed with 10 ml of toluene, followed by removing the solvent under reduced pressure to remove the solvent. To the residue thus obtained, 14.5 ml of toluene and 13 ml of 0.5N NaOH/MeOH solution were sequentially added. The resulting mixture was stirred for 30 min, followed by removing the solvent under reduced pressure. The residue was dissolved in 10 ml of toluene and 50 ml of n-hexane, and the product was recrystallized therefrom. The crystallized product was filtered to obtain 5.1 g (98%) of the title compound as a pale yellow solid.
Montelukast sodium
1H-NMR (300 MHz, CD3OD): δ 8.29 (1H, d), 7.99 (1H, s), 7.83-7.91 (3H, m), 7.72 (1H, s), 7.49-7.52 (2H, m), 7.38-7.44 (4H, m), 7.10-7.15 (3H, m), 4.04 (1H, t), 3.08 (1H, m), 2.82 (1H, m), 2.66 (1H, d), 2.52 (1H, d), 2.43 (1H, d), 2.29 (1H, d), 2.16-2.24 (2H, m), 1.52 (6H, s), 0.33-0.52 (4H, m)
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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MONTELUKAST
New Drug Approvals 