WO2010036048A2 - 몬테루카스트 나트륨염의 제조방법 - Google Patents
몬테루카스트 나트륨염의 제조방법 Download PDFInfo
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- WO2010036048A2 WO2010036048A2 PCT/KR2009/005472 KR2009005472W WO2010036048A2 WO 2010036048 A2 WO2010036048 A2 WO 2010036048A2 KR 2009005472 W KR2009005472 W KR 2009005472W WO 2010036048 A2 WO2010036048 A2 WO 2010036048A2
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- bistrimethylsilylamide
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- 0 CC(C)(c1c(CC[C@](c2cccc(C=Cc(cc3)nc4c3ccc(Cl)c4)c2)SCC2(CC(*)=O)CC2)cccc1)O Chemical compound CC(C)(c1c(CC[C@](c2cccc(C=Cc(cc3)nc4c3ccc(Cl)c4)c2)SCC2(CC(*)=O)CC2)cccc1)O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic System
- C07F1/04—Sodium compounds
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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
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- 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
- A61P11/02—Nasal agents, e.g. decongestants
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Definitions
- the present invention relates to a method for preparing montelukast sodium salt, and more particularly, an alkali metal base is further added after coupling a methanesulfonyl compound of formula 2 with a compound of formula 3 in the presence of a bistrimethylsilylamide alkali metal salt.
- an alkali metal base is further added after coupling a methanesulfonyl compound of formula 2 with a compound of formula 3 in the presence of a bistrimethylsilylamide alkali metal salt.
- To prepare a compound of formula 4 by heating and hydrolyzing it, reacting with 4-tert-butylcyclohexylamine and purifying to prepare an amine salt of formula 5, and then converting the amine salt into a sodium salt. It relates to a manufacturing method comprising.
- Montelukast sodium salt is a substance that shows the efficacy of Singulair ® (SMS), which is widely prescribed for the treatment of asthma and allergic rhinitis symptoms, and is known pharmacologically as a leukotriene receptor antagonist.
- SMS Singulair ®
- 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 Pharmacological effects such as palpation are clinically important.
- montelukast sodium salts are absorbent white and off-white powders that are soluble in ethanol, methanol and water, and hardly soluble in acetonitrile.
- the known method for preparing montelukast sodium salt is disclosed in European Patent No. 480,717.
- the manufacturing method of the European patent has a problem in that it is necessary to remove the tetrahydropyranyl (THP) protecting group and then remove it, and it is not suitable for mass production.
- THP tetrahydropyranyl
- US Patent No. 5,614,632 does not use the tetrahydropyranyl protecting group used in European Patent No. 480,717, without the methanesulfonyl compound (2) and 1- (lithium mercaptomethyl) cyclopropane acetate lithium salt
- dicyclohexane is added to the obtained reaction to purify it into dicyclohexane salt form, which is then converted back to montelukast sodium salt (1).
- PCT WO 2005/105751 discloses a methyl 1- (mercaptomethyl) cyclopropane acetate (3) in the coupling reaction step, as in step 10 of Example 146 shown in EP 480,717.
- the obtained montelukast acid (4) is recrystallized in a variety of solvents to obtain a high purity montelukast acid ( 4) is obtained, which is then converted into montelukast sodium salt (1) to prepare.
- one of tetrahydrofuran and dimethyl carbonate is selected as a solvent during a coupling reaction, and a polar solvent such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone is selected as a cosolvent.
- a polar solvent such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone is selected as a cosolvent.
- One is selected from, and the base is defined in the claims to select one of sodium hydroxide, lithium hydroxide, hydrogen chloride, sodium methoxide, tert-butoxide potassium diisopropylamine lithium, quaternary ammonium salt.
- a mixed solvent must be used in the coupling reaction, and the mixed solvent is different from the solvent used in the hydrolysis reaction, so that the co-solvent used is distilled under reduced pressure or extracted before proceeding with the hydrolysis reaction. It is additionally necessary to remove by a method.
- an object of the present invention is to solve the problems of the prior art as described above and the technical problem that has been requested from the past.
- the inventors of the present application after extensive research and various experiments, used a bistrimethylsilylamide alkali metal salt and 4-tert-butylcyclohexylamine in the process of preparing the montelukast sodium salt.
- the present inventors have found that a montelukast sodium salt that can be simplified, suitable for mass production, and high in yield and purity can be prepared, and has completed the present invention.
- the manufacturing method according to the present invention is a method for preparing the montelukast sodium salt of the formula (1),
- the montelukast sodium salt of Chemical Formula 1 is prepared by sulfonating a compound of Chemical Formula A with a compound such as methanesulfonyl chloride, benzyl sulfonate, as shown in the following scheme, to prepare a methanesulfonyl compound of Chemical Formula 2
- a series of reactions such as coupling reaction and hydrolysis reaction.
- the method for preparing montelukast sodium salt according to the present invention can simplify the coupling reaction and the hydrolysis reaction using bistrimethylsilylamide alkali metal salt, and can increase the efficiency of the purification process using 4-tert-butylcyclohexylamine. Therefore, the montelukast sodium salt suitable for mass production and high in yield and purity can be produced.
- the coupling reaction of step (i) may be carried out in a solvent in which the coupling reaction can be carried out without affecting the chemical properties of the compounds of Formulas 2 and 3, preferably tetrahydrofuran , 2-methyltetrahydrofuran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone and toluene can be carried out in a solvent selected from the group consisting of.
- bistrimethylsilylamide alkali metal salt used in step (i) one or two or more preferably selected from the group consisting of bistrimethylsilylamidelithium, bistrimethylsilylamide sodium and bistrimethylsilylamide potassium can be used.
- the hydrolysis reaction of step (i) may be carried out continuously in the same reactor after completion of the coupling reaction, without undergoing any other processing.
- step (i) is carried out in the presence of a bistrimethylsilylamide alkali metal salt, so as demonstrated in the experimental results of the following examples, to remove the solvent of the coupling process prior to the progress of the hydrolysis reaction. It is possible to obtain a high yield of montelukast acid (compound of formula 4) without additionally performing a process such as distillation under reduced pressure or extraction.
- step (i) can omit other processes such as distillation or extraction under reduced pressure, thereby simplifying the overall manufacturing process of montelukast sodium salt while maintaining a high yield of montelukast acid.
- the alkali metal base of step (i) is not particularly limited as long as it is an alkali metal base capable of preparing the compound of Formula 4 by removing the methyl group of the compound of Formula 3 in the hydrolysis process, preferably sodium hydroxide.
- One, two or more selected from the group consisting of lithium hydroxide and potassium hydroxide may be used.
- step (i) the compound of Formula 3 is reacted with the methanesulfonyl compound of Formula 2, so that the amount of the compound to be prepared may be adjusted to produce a high yield of the compound of Formula 4, wherein the compound of Formula 3 is It is preferable to use 1.0 equivalent-2.0 equivalent with respect to a methanesulfonyl compound, and it is more preferable to use 1.1-1.5 equivalent.
- step (i) is preferably carried out at a relatively low temperature so that the methanesulfonyl compound of formula 2 and the compound of formula 3 can be easily coupled, for example, -20 °C to 0 °C In about 1 to 10 hours.
- step (i) should be carried out at an appropriate temperature so that the compound of formula 4 can be prepared without decomposing the methanesulfonyl compound of formula 2 and the compound of formula 3, for example, 40 It may be performed for about 5 to 20 hours at °C to 60 °C.
- the 4-tert-butylcyclohexylamine of step (ii) may be used in the form of a single or mixed isomeric compound, for example a trans single isomer or a cis / trans isomer mixture.
- reaction conditions of step (ii) is not particularly limited as long as the reaction conditions of the compound of Formula 4 and the compound of 4-tert-butylcyclohexylamine can be produced by reacting them without changing the chemical properties.
- 4-tert-butylcyclohexylamine reacts with the compound of Formula 4 and the amount to be adjusted to be prepared in a high yield of the compound of Formula 5 bar
- 4-tert-butylcyclohexylamine is represented by Preference is given to using 1.0 to 3.0 equivalents relative to the compound.
- step (ii) is preferably carried out at 0 ° C to 90 ° C so that the compound of formula (4) is smoothly crystallized to be produced as a solid to be produced as an amine salt of the formula (5).
- reaction conditions of step (iii) are not particularly limited as long as they are reaction conditions capable of converting the amine salt compound of formula 5 to the montelukast sodium salt of formula 1, preferably acetone, acetonitrile, ethyl acetate, butyl acetate, methanol , Ethanol, isopropanol, toluene, hexane, cyclohexane, heptane, diisopropylether, tetrahydrofuran and methyl ethyl ketone, and may be performed in one or more solvents, more preferably, toluene and heptane It can be carried out in a mixed solvent.
- a montelukast sodium salt solid can be obtained by obtaining a solution converted to and slowly adding this solution to a heptane solvent.
- the present invention also provides the amine salt compound of Formula 5 obtained as an intermediate in the preparation of the montelukast sodium salt.
- These amine salt compounds of formula 5 are themselves novel compounds.
- the amine salt compound of formula 5 may be prepared as a high purity montelukast sodium salt showing high yield by converting it into sodium salt using an organic solvent as mentioned above and methanol and sodium hydroxide.
- the 4-tert-butylcyclohexylamine used in the preparation process may be a trans single isomer or a cis / trans isomer mixture, but the amine salt compound of Formula 5 obtained therefrom is confirmed in Example 15 below. trans single isomeric compound.
- Figure 4 is a graph of the X-ray diffraction spectrum of the amine salt compound of formula 5 according to Example 12 of the present invention.
- the temperature inside the reactor was raised to 50 ° C. and reacted at the same temperature for 10 hours. After the reaction was completed, the mixture was cooled to room temperature, 30 ml of acetic acid was slowly added to pH 5, 50 ml of ethyl acetate and 30 ml of 10% aqueous sodium chloride solution were added, the organic layer was separated, and the organic layer was washed with 20 ml of water. After drying over sodium sulfate, the solvent was removed by distillation under reduced pressure to obtain 4.17 g (purity 92.4%) of the title compound as a yellow solid.
- Example 2 The compound prepared in Example 2 (4.17 g, purity 92.4%) was dissolved in 60 ml of ethyl acetate, and 2.0 g of 4-tert-butylcyclohexylamine was added at room temperature. The reaction temperature was raised to 80 ° C and stirred for 1 hour, and then slowly cooled to room temperature. At this time, as the crystallization progressed, a solid was produced, and when the solid production was completed, 80 ml of hexane was slowly added dropwise and stirred.
- reaction was stirred at room temperature for about 3 hours, filtered using a filter, washed with hexane and dried to give 4.3 g of the title compound as a pale white solid with a purity of 98.7% and an optical activity of 99.8% e.e.
- Example 2 The compound prepared in Example 2 (4.17 g, purity 92.4%) was dissolved in 60 ml of toluene and 2.0 g of 4-tert-butylcyclohexylamine was added at room temperature. The reaction temperature was raised to 80 ° C and stirred for 1 hour, and then slowly cooled to room temperature. At this time, as the crystallization progressed, a solid was produced, and when the solid production was completed, 80 ml of hexane was slowly added dropwise and stirred.
- reaction was stirred at room temperature for about 3 hours, filtered through a filter, washed with hexane and dried to give 4.8 g of the title compound as a white white solid with a purity of 98.9% and an optical activity of 99.8% e.e.
- Example 2 The compound prepared in Example 2 (4.17 g, purity 92.4%) was dissolved in 60 ml of toluene and 2.0 g of 4-tert-butylcyclohexylamine was added at room temperature. The reaction temperature was raised to 80 ° C and stirred for 1 hour, and then slowly cooled to room temperature. At this time, as the crystallization progressed, a solid was produced, and when the solid production was completed, 80 ml of acetonitrile was slowly added dropwise and stirred slowly.
- reaction was stirred at room temperature for about 3 hours, filtered through a filter, washed with acetonitrile and dried to give 4.4 g of the title compound as an off-white solid with a purity of 98.8% and an optical activity of 99.8% e.e.
- Example 2 The compound prepared in Example 2 (4.17 g, purity 92.4%) was dissolved in 60 ml of toluene and 2.0 g of 4-tert-butylcyclohexylamine was added at room temperature. The reaction temperature was raised to 80 ° C and stirred for 1 hour, and then slowly cooled to room temperature. At this time, as the crystallization progressed, a solid was produced, and when the solid production was completed, 80 ml of heptane was slowly added dropwise and stirred slowly.
- reaction was stirred at room temperature for about 3 hours, filtered through a filter, washed with haptan and dried to give 4.7 g of the title compound as an off-white solid with a purity of 98.9% and an optical activity of 99.8% e.e.
- the reaction mixture thus obtained was concentrated and 40 ml of toluene was added thereto, and the solution was slowly added dropwise to 80 ml of heptane contained in a separate reactor. At this time, as the crystallization proceeded, a solid was produced, and after the solid formation was completed, the reaction was stirred at room temperature for about 1 hour. After filtration using a filter, washing with heptane and drying gave 3.35 g of the title compound as an off-white solid, with a purity of 99.7% and an optical activity of 99.8% e.e.
- Example 9 40 ml of ethyl acetate and 30 ml of water were added dropwise to the compound prepared in Example 9 (1.0 g, purity> 99%), followed by slowly adding 7.5% tartaric acid to adjust the pH to 4-5. Thereafter, the mixture was stirred at room temperature for about 30 minutes. The reaction mixture was separated into an organic layer and a water layer, and then the obtained water layer was concentrated completely under reduced pressure to obtain crystalline 4-tert-butylcyclohexylamine tartaric acid salt (0.39 g), which was then completely dissolved in 15 ml of water, followed by 4N sodium hydroxide was slowly added dropwise to the resulting solid, which was filtered and dried under nitrogen to give a white solid.
- the method for preparing montelukast sodium salt of the present invention can simplify the coupling reaction and the hydrolysis reaction and increase the efficiency of the purification process. Therefore, the montelukast sodium salt is suitable for mass production and has high yield and purity. There is an effect that can be produced.
Abstract
Description
Claims (15)
- 하기 화학식 1의 몬테루카스트 나트륨염을 제조하는 방법으로서,(i) 하기 화학식 2의 메탄술포닐 화합물과 하기 화학식 3의 화합물을 비스트리메틸실릴아미드알칼리금속염 존재 하에 커플링 반응시킨 후, 알칼리 금속 염기를 추가로 투입하고 가열하여 가수분해시킴으로써 하기 화학식 4의 화합물을 제조하는 단계;(ii) 상기 화학식 4의 화합물을 4-tert-부틸시클로헥실아민과 반응시킨 후 정제하여 하기 화학식 5의 아민염을 제조하는 단계;(iii) 상기 화학식 5의 아민염을 나트륨염으로 변환시키는 단계;를 포함하는 것을 특징으로 하는 제조방법.
- 제 1 항에 있어서, 상기 단계(i)의 커플링 반응은 테트라히드로퓨란, 2-메틸테트라히드로퓨란, 디메틸포름아미드, 디메틸아세트아미드, N-메틸피롤리돈 및 톨루엔으로 이루어진 군에서 선택되는 단일 용매에서 수행하는 것을 특징으로 하는 제조방법.
- 제 1 항에 있어서, 상기 단계(i)의 비스트리메틸실릴아미드알칼리금속염은 비스트리메틸실릴아미드리튬, 비스트리메틸실릴아미드나트륨 및 비스트리메틸실릴아미드칼륨으로 이루어진 군에서 선택된 하나 또는 둘 이상인 것을 특징으로 하는 제조방법.
- 제 1 항에 있어서, 상기 단계(i)의 가수분해 반응은 상기 커플링 반응의 완료 후 다른 처리과정을 거치지 않고 같은 반응기에서 연속하여 수행하는 것을 특징으로 하는 제조방법.
- 제 1 항에 있어서, 상기 단계(i)의 알칼리 금속 염기는 수산화나트륨, 수산화리튬 및 수산화칼륨으로 이루어진 군에서 선택된 하나 또는 둘 이상인 것을 특징으로 하는 제조방법.
- 제 1 항에 있어서, 상기 단계(i)에서 화학식 3의 화합물은 화학식 2의 메탄설포닐 화합물에 대해 1.0 당량 내지 2.0 당량으로 사용하는 것을 특징으로 하는 제조방법.
- 제 1 항에 있어서, 상기 단계(i)의 커플링 반응은 -20℃ 내지 0℃의 온도에서 수행하는 것을 특징으로 하는 제조방법.
- 제 1 항에 있어서, 상기 단계(i)의 가수분해 반응은 40℃ 내지 60℃의 온도에서 수행하는 것을 특징으로 하는 제조방법.
- 제 1 항에 있어서, 상기 단계(ii)의 4-tert-부틸시클로헥실아민은 trans 단일 이성질체, 또는 cis/trans 이성질체 혼합물인 것을 특징으로 하는 제조방법.
- 제 1 항에 있어서, 상기 단계(ii)의 반응은 아세톤, 아세토니트릴, 에틸 아세테이트, 테트라히드로퓨란, 메틸렌클로라이드, 클로로포름, 톨루엔, 크실렌, 헥산, 시클로헥산 및 헵탄으로 이루어진 군에서 선택된 하나 또는 둘 이상의 용매에서 수행하는 것을 특징으로 하는 제조방법.
- 제 1 항에 있어서, 상기 단계(ii)의 4-tert-부틸시클로헥실아민은 화학식 4의 화합물에 대해 1.0 내지 3.0 당량으로 사용하는 것을 특징으로 하는 제조방법.
- 제 1 항에 있어서, 상기 단계(ii)의 반응은 0℃ 내지 90℃의 온도에서 수행하는 것을 특징으로 하는 제조방법.
- 제 1 항에 있어서, 상기 단계(iii)의 반응은 아세톤, 아세토니트릴, 에틸 아세테이트, 부틸 아세테이트, 메탄올, 에탄올, 이소프로판올, 톨루엔, 헥산, 시클로헥산, 헵탄, 디이소프로필에테르, 테트라히드로퓨란 및 메틸에틸케톤으로 이루어진 군에서 선택된 하나 또는 둘 이상의 용매에서 수행하는 것을 특징으로 하는 제조방법.
- 제 14 항에 있어서, 상기 아민염 화합물은 trans 단일 이성질체인 것을 특징으로 하는 아민염 화합물.
Priority Applications (4)
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BRPI0914185-5A BRPI0914185A2 (pt) | 2008-09-26 | 2009-09-25 | Método para preparar sais de montelucaste de sódio |
CN200980138227XA CN102164897B (zh) | 2008-09-26 | 2009-09-25 | 制备孟鲁司特钠盐的方法 |
JP2011528936A JP5531018B2 (ja) | 2008-09-26 | 2009-09-25 | モンテルカストナトリウム塩の製造方法 |
US13/062,353 US8426600B2 (en) | 2008-09-26 | 2009-09-25 | Method for preparing montelukast sodium salts |
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KR20080094731 | 2008-09-26 |
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KR (1) | KR101123292B1 (ko) |
CN (1) | CN102164897B (ko) |
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CN104055741A (zh) * | 2013-03-18 | 2014-09-24 | 青岛大学 | 一种孟鲁司特钠片剂及其制备方法 |
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KR100990046B1 (ko) * | 2010-07-30 | 2010-10-26 | 동국제약 주식회사 | 신규한 몬테루카스트 4-할로 벤질아민염 및 이를 이용한 몬테루카스트 나트륨염의 제조방법 |
KR20130041664A (ko) * | 2011-10-17 | 2013-04-25 | 주식회사 엘지생명과학 | 고순도 몬테루카스트 나트륨 염의 제조 방법 |
CN103570618A (zh) * | 2013-09-30 | 2014-02-12 | 浙江车头制药股份有限公司 | 一种孟鲁司特钠盐的制备方法 |
CN105622500B (zh) * | 2016-02-29 | 2018-03-02 | 山东新时代药业有限公司 | 孟鲁司特钠中间体的制备方法 |
JP2021536467A (ja) | 2018-09-06 | 2021-12-27 | インノファーマスクリーン インコーポレイテッド | 喘息またはパーキンソン病の処置のための方法および組成物 |
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- 2009-09-23 KR KR1020090089931A patent/KR101123292B1/ko not_active IP Right Cessation
- 2009-09-25 US US13/062,353 patent/US8426600B2/en not_active Expired - Fee Related
- 2009-09-25 CN CN200980138227XA patent/CN102164897B/zh not_active Expired - Fee Related
- 2009-09-25 JP JP2011528936A patent/JP5531018B2/ja not_active Expired - Fee Related
- 2009-09-25 BR BRPI0914185-5A patent/BRPI0914185A2/pt not_active IP Right Cessation
- 2009-09-25 WO PCT/KR2009/005472 patent/WO2010036048A2/ko active Application Filing
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CN104055741A (zh) * | 2013-03-18 | 2014-09-24 | 青岛大学 | 一种孟鲁司特钠片剂及其制备方法 |
CN104055741B (zh) * | 2013-03-18 | 2017-02-15 | 青岛大学 | 一种孟鲁司特钠片剂及其制备方法 |
Also Published As
Publication number | Publication date |
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CN102164897B (zh) | 2013-04-17 |
US20110166356A1 (en) | 2011-07-07 |
JP2012503648A (ja) | 2012-02-09 |
JP5531018B2 (ja) | 2014-06-25 |
US8426600B2 (en) | 2013-04-23 |
BRPI0914185A2 (pt) | 2015-08-04 |
CN102164897A (zh) | 2011-08-24 |
KR20100035597A (ko) | 2010-04-05 |
WO2010036048A3 (ko) | 2010-08-19 |
KR101123292B1 (ko) | 2012-03-19 |
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