WO2013058511A2 - 고순도 몬테루카스트 나트륨 염의 제조 방법 - Google Patents

고순도 몬테루카스트 나트륨 염의 제조 방법 Download PDF

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Publication number
WO2013058511A2
WO2013058511A2 PCT/KR2012/008411 KR2012008411W WO2013058511A2 WO 2013058511 A2 WO2013058511 A2 WO 2013058511A2 KR 2012008411 W KR2012008411 W KR 2012008411W WO 2013058511 A2 WO2013058511 A2 WO 2013058511A2
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WO
WIPO (PCT)
Prior art keywords
sodium salt
montelukast sodium
formula
light source
salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2012/008411
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English (en)
French (fr)
Korean (ko)
Other versions
WO2013058511A3 (ko
Inventor
이인상
이석주
신현익
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
LG Chem Ltd
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LG Life Sciences Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by LG Life Sciences Ltd filed Critical LG Life Sciences Ltd
Priority to IN2765CHN2014 priority Critical patent/IN2014CN02765A/en
Priority to CN201280050929.4A priority patent/CN103889957A/zh
Publication of WO2013058511A2 publication Critical patent/WO2013058511A2/ko
Publication of WO2013058511A3 publication Critical patent/WO2013058511A3/ko
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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 is a method for producing a high-purity montelukast sodium salt, and more particularly, after the medicament comprising the step of formulating the montelukast sodium salt and the step of formulating the synthesized montelukast sodium salt ( Iii) at least one of the processes is carried out in an atmosphere provided with a light source for irradiating a wavelength in a region of low photolysis of montelukast sodium salt.
  • Montelukast sodium salt is a material that exhibits an efficacy of TM SINGULAIR (TM Singulair, Korea MSD available), which is widely prescribed like asthma, allergic rhinitis, symptomatic treatment, pharmacologically is known as a leukotriene receptor antagonist.
  • the leukotriene produced by metabolic action of arachidonic acid in vivo includes LTB4, LTC4, LTD4, LTE4, among which LTC4, LTD4, LTE4 are cysteinyl leukotrienes (CysLTs), airway muscle and smooth muscle contraction, bronchial mucus secretion It is clinically important because it exhibits pharmacological effects such as palpation.
  • montelukast sodium salts are absorbent white and off-white powders that are soluble in ethanol, methanol and water, and hardly soluble in acetonitrile.
  • the absorbance was analyzed over a wavelength range of 200 ⁇ 800 nm using an ultraviolet-vis Spectrophotometer (manufactured by Shimadzu), as shown in Figure 1 , The spectrum shows the maximum of five peaks by transition at 211.0, 283.5, 327.5, 344.5, and 359.0 nm.
  • the montelukast sodium salt is an aromatic hydrocarbon with a conjugated conjugation structure, which is well matched to the structure with one quinoline and two phenyls.
  • the montelukast sodium salt in the solid phase is exposed to sunlight for about one week, the purity is reduced by about 20%, and in the case of chewing tablets containing unpacked montelukast sodium salt, when exposed to sunlight for about three weeks, the main photolysis by-product is represented as It is known that about 10% of the sulfoxide of 4 is produced to reduce the purity.
  • the present invention aims to solve the problems of the prior art as described above and the technical problems that have been requested from the past.
  • the inventors of the present application find that the montelukast sodium salt hardly absorbs light in a particular wavelength region, as described later, and work or illuminate in a dark room below 10 lux. Maintaining brightness above the illuminance of the working surface recommended by the Occupational Safety and Health Act without additional physical measures, such as covering the instrument with a filter, allows the operator to work in a safe environment and at the same time prevents the generation of photolysis byproducts as impurities as described above. It has been found that it is possible to establish a method of industrially producing the high purity montelukast sodium salt by suppressing it. The present invention has been completed based on this finding.
  • the method for preparing a medicament according to the present invention after the medicament comprising a step before the drug comprising the step of synthesizing the montelukast sodium salt of the formula (1) and the process of formulating the synthesized montelukast sodium salt And (iii) performing at least one of the steps in an atmosphere provided with a light source for irradiating a wavelength in a region where photodegradation of the montelukast sodium salt is low.
  • the present invention by performing the drug pre-process and / or drug post-process of the montelukast sodium salt in an atmosphere provided with a light source for irradiating the wavelength of the photodegradation region, the manufacturing process of the medicament under sufficient illumination to the operator safe environment In addition to making it possible to work in medicaments, it is possible to prepare medicaments containing montelukast sodium salts in high purity.
  • the post-pharmaceutical process including the process of formulating using the synthesized montelukast sodium salt, there is a lot of worker involvement and high possibility of exposure to light, so it is more preferable to perform the post-pharmaceutical process in the atmosphere as defined above. desirable.
  • the montelukast sodium salt in the previous pharmaceutical process can be prepared by various methods.
  • the montelukast sodium salt is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-oxide
  • the montelukast sodium salt of Formula 1 may be sulfonated with a compound of formula A, such as methanesulfonyl chloride, benzyl sulfonate, and mesylate, as shown in the following reaction scheme,
  • the compound may be prepared and prepared by performing a series of reactions, such as a coupling reaction and a hydrolysis reaction, using the methanesulfonyl compound and the compound represented by Chemical Formula 6.
  • the method for preparing the montelukast sodium salt can simplify the coupling reaction and the hydrolysis reaction using hexamethyldisilane alkali metal salt, and can increase the efficiency of the purification process using 4-tert-butylcyclohexylamine.
  • the drug post-process is, for example, by a known method of mixing, dissolving, granulating, sugar-making, powdering, emulsifying, encapsulating, trapping, lyophilizing and the like in a conventional manner. It can be done with
  • compositions may be prepared by conventional methods using one or more pharmaceutically acceptable carriers which comprise excipients or auxiliaries which facilitate the treatment of the active compounds into pharmaceutically usable formulations. have.
  • the pharmaceutical composition means a mixture of montelukast sodium salt and other chemical components such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound into the organism.
  • techniques for administering compounds including but not limited to oral, injection, aerosol, parenteral, and topical administration.
  • ERTAIN Thin Film For oral administration, it can be formulated readily by combining the active compounds with pharmacologically acceptable carriers known in the art. These carriers allow the montelukast sodium salt to be formulated into tablets, pills, sugars, capsules, liquids, gels, syrups, slurries, suspensions and the like. In particular, it is desirable to formulate into tablets, chewables, granules and OTF (Oral Thin Film).
  • compositions for oral use include mixing the montelukast sodium salt with one or more excipients, optionally grinding this mixture and, if necessary, treating the mixture of granules after permeation of appropriate adjuvants to obtain a tablet or sugar core.
  • excipients include fillers such as lactose, sucrose, mannitol, or sorbitol; Corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragakens, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl cellulose, and / or polyvinylpyrrolidone ( Cellulose-based materials such as PVP).
  • carriers such as disintergrating agents such as crosslinked polyvinyl pyrrolidone, urticaria, or salts thereof such as alginic acid or sodium alginate and lubricants such as magnesium stearate, binders and the like may be added.
  • compositions that can be used orally may include soft sealing capsules made of gelatin and plasticizers such as glycols or sorbitol, as well as pushable capsules made of gelatin.
  • the push-fix capsule may contain the active ingredients, as a mixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate.
  • the active compounds may be dissolved or dispersed in suitable solvents such as fatty acids, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be included. All preparations for oral administration should be in amounts suitable for such administration.
  • the OTF is based on a film composition for oral cavity, which contains a water-soluble polymer.
  • the water-soluble polymer is hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl polymer, polyethylene glycol, pullulan, gelatin, pectin, alginic acid, alginic acid Sodium, Carrageenan, Modified Starch, Casein, Whey Protein Isolate, Soy Protein Isolate, Jane, Levan, Elsinan, Gluten, Acacia Gum, Carrageenan, Arabian Gum, Guar Gum, Locust Gum, Xanthan Gum, Gellan Gum and Agar It may be at least one water-soluble polymer selected from the group consisting of.
  • Such a water-soluble polymer may be contained, for example, 50 to 90% by weight (w / w) based on the total weight of the OTF.
  • the present inventors dissolved the synthesized montelukast sodium salt in methanol solvent to measure the absorbance spectrum in the wavelength range of 200 ⁇ 800 nm, as a result, shows the maximum absorbance in the ultraviolet region, but almost no light in the 400 ⁇ 800 nm wavelength region The result was no absorption.
  • the light source for irradiating the wavelength in the region of low photolysis of the montelukast sodium salt may preferably be a light source having a wavelength of 400 to 800 nm.
  • Examples of the light source having such a wavelength range include sodium lamps, neon lamps, light emitting diodes (LEDs), and the like, but are not limited thereto.
  • each of the light sources was irradiated with montelukast sodium solution dissolved in methanol under the same conditions, and then high pressure liquid chromatography was used for the photolysis by-product of the Cis-isomer of Formula 2 and the sulfoxide of Formula 4.
  • the light stability of the montelukast sodium solution according to the light source type was confirmed.
  • the purity of montelukast sodium was high in the white LED.
  • a light emitting diode may be preferably used as the light source, more preferably a blue LED, a yellow LED, a white LED, or the like, and particularly preferably a white LED may be used.
  • one light source may be used in the atmosphere, or a combination of two or more light sources may be used.
  • the present invention also provides a medicament for treating asthma, which is prepared by the above method.
  • 1 is a graph of the absorbance spectrum of montelukast sodium salt.
  • the amount of Cis-isomers was analyzed using high pressure liquid chromatography over time while changing the light source as shown in Table 1 below, and the results are shown in Table 1 below.
  • the montelukast sodium used as a sample contained 0.25% of the Cis-isomer as a result of the analysis.
  • the cis -isomer is produced in a relatively small amount of sodium and the tungsten, in the order of sunlight.
  • Example 2 The same procedure as in Example 1 was carried out, except that a power source of 54 W and a voltage of 220 V were used as the LED, and the distance from the sample was 50 to 70 cm, and the illuminance was 250 to 300 lux. Table 3 shows.
  • the drug manufacturing process can be carried out under sufficient illumination to enable the worker to work in a safe environment, as well as to prepare a drug containing high purity of montelukast sodium salt.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Quinoline Compounds (AREA)
PCT/KR2012/008411 2011-10-17 2012-10-16 고순도 몬테루카스트 나트륨 염의 제조 방법 Ceased WO2013058511A2 (ko)

Priority Applications (2)

Application Number Priority Date Filing Date Title
IN2765CHN2014 IN2014CN02765A (https=) 2011-10-17 2012-10-16
CN201280050929.4A CN103889957A (zh) 2011-10-17 2012-10-16 制备高纯度孟鲁司特钠盐的方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020110106064A KR20130041664A (ko) 2011-10-17 2011-10-17 고순도 몬테루카스트 나트륨 염의 제조 방법
KR10-2011-0106064 2011-10-17

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WO2013058511A2 true WO2013058511A2 (ko) 2013-04-25
WO2013058511A3 WO2013058511A3 (ko) 2013-06-13

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JP (1) JP2014530234A (https=)
KR (1) KR20130041664A (https=)
CN (1) CN103889957A (https=)
IN (1) IN2014CN02765A (https=)
WO (1) WO2013058511A2 (https=)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016020321A (ja) * 2014-07-16 2016-02-04 大日本印刷株式会社 モンテルカストまたはその塩の製造方法
US12233055B2 (en) 2020-02-03 2025-02-25 Taro Pharmaceutical Industries Ltd. Topical Montelukast formulations

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3166799A1 (en) * 2020-02-03 2021-08-12 Vered Rosenberger Topical montelukast formulations

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7528254B2 (en) * 2006-02-27 2009-05-05 Chemagis Ltd. Process for preparing montelukast and salts thereof
US7700776B2 (en) * 2006-10-24 2010-04-20 Formosa Laboratories, Inc. Compounds and preparation for montelukast sodium
US8115004B2 (en) * 2006-11-20 2012-02-14 Msn Laboratories Limited Process for pure montelukast sodium through pure intermediates as well as amine salts
PL205444B1 (pl) * 2007-05-02 2010-04-30 Zak & Lstrok Ady Farmaceutyczn Sposób wytwarzania soli sodowej kwasu 1-(((1(R)-(3-(2-(7--chloro-2- chinolinylo)-etenylo)fenylo)-3-(2-(1-hydroksy-1- metyloetylo)fenylo)propylo)sulfanylo)metylo)-cyklopropanooctowego
CN101323589B (zh) * 2008-03-06 2010-10-06 台耀化学股份有限公司 化合物及孟鲁司特钠的制备方法
WO2009117381A2 (en) * 2008-03-17 2009-09-24 Dr. Reddy's Laboratories Ltd. Preparation of montelukast and its salts
KR101123292B1 (ko) * 2008-09-26 2012-03-19 주식회사 엘지생명과학 몬테루카스트 나트륨염의 제조방법
KR100990046B1 (ko) * 2010-07-30 2010-10-26 동국제약 주식회사 신규한 몬테루카스트 4-할로 벤질아민염 및 이를 이용한 몬테루카스트 나트륨염의 제조방법

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2016020321A (ja) * 2014-07-16 2016-02-04 大日本印刷株式会社 モンテルカストまたはその塩の製造方法
US12233055B2 (en) 2020-02-03 2025-02-25 Taro Pharmaceutical Industries Ltd. Topical Montelukast formulations

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Publication number Publication date
KR20130041664A (ko) 2013-04-25
JP2014530234A (ja) 2014-11-17
IN2014CN02765A (https=) 2015-07-03
WO2013058511A3 (ko) 2013-06-13
CN103889957A (zh) 2014-06-25

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