CN112028824B - Preparation method of montelukast sodium - Google Patents
Preparation method of montelukast sodium Download PDFInfo
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- CN112028824B CN112028824B CN202011061702.2A CN202011061702A CN112028824B CN 112028824 B CN112028824 B CN 112028824B CN 202011061702 A CN202011061702 A CN 202011061702A CN 112028824 B CN112028824 B CN 112028824B
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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
- A61P11/06—Antiasthmatics
Abstract
The invention discloses a preparation method of montelukast sodium, which comprises the steps of reacting low-boiling-point organic amine salt of montelukast acid with alcohol as a solvent and an alcohol solution of sodium hydroxide as an alkali, concentrating under reduced pressure after the reaction is finished, adding water to dissolve the mixture to a specified concentration, and freeze-drying according to a corresponding freeze-drying procedure to obtain a finished product of montelukast sodium meeting requirements. The preparation method of montelukast sodium has the advantages of simple process, environmental protection, reduction in the use of a large amount of organic solvents, accordance with the characteristics of green chemistry and the like.
Description
Technical Field
The invention relates to a preparation method of montelukast sodium, and belongs to the technical field of medicines.
Background
Montelukast is an anti-asthma drug developed by Merck corporation, united states, and is approved by the Food and Drug Administration (FDA) to be marketed 2 months 1998 under the trade name "Singulair" in the form of film-coated tablets, chewable tablets, and granules, each in a size of 10mg, 5mg, and 4 mg. Subsequently, the product was marketed in 71 countries of Canada, Italy, Spain, Sweden, Switzerland, Germany, France and China.
Montelukast sodium, chemical name: 1- [ [ [ (R) -3- [ (E) -2- (7-chloro-2-quinolinyl) ethenyl ] - α - [2- (1-hydroxy-1-methylethyl) phenethyl ] benzyl ] thio ] methyl ] cyclopropaneacetic acid sodium salt; the structural formula is as follows:
in the prior art, regarding the synthesis of montelukast sodium, the montelukast sodium is prepared by solvent crystallization, for example, in the preparation method of montelukast sodium disclosed in patent CN1420113A, a large amount of toluene and n-heptane are used for crystallization, and the crystallization is carried out in vacuum to obtain white solid powder. The residues of n-heptane and toluene are not easy to reach the corresponding quality standard during the solvent crystallization process, and long-time drying (48 hours of drying in reference 1) is required to meet the requirement.
The vacuum freeze drying technology is a drying technology that freezes wet materials or solutions into solid state at a lower temperature, then directly sublimates the moisture in the solid state into gas state without passing through the liquid state under vacuum, and finally dehydrates the materials. The freeze drying has the advantages of stable material performance due to low-temperature oxygen isolation, looseness (no surface hardening) of products and the like, and has good application prospect. US5565473 simply mentions the preparation of montelukast sodium by freeze-drying a salt of montelukast acid, which is obtained as an oil by column chromatography, which is then dissolved in water and freeze-dried, using a procedure which makes column chromatography unsuitable for industrial production.
Disclosure of Invention
Aiming at the problems, the invention provides a preparation method of montelukast sodium, which comprises the steps of reacting low-boiling-point organic amine salt of montelukast acid with alcohol as a solvent and an alcoholic solution of sodium hydroxide as an alkali, after the reaction is finished, concentrating under reduced pressure, adding water to dissolve the mixture to a specified concentration, and freeze-drying according to a corresponding freeze-drying procedure to obtain a finished product of montelukast sodium meeting the requirements. The preparation method of montelukast sodium has the advantages of simple process, environmental protection, reduction in the use of a large amount of organic solvents, accordance with the characteristics of green chemistry and the like.
The technical scheme of the invention is as follows: a preparation method of montelukast sodium is characterized in that,
1) preparation of low boiling organic amine salts of montelukast acid
Under the protection of nitrogen, dissolving montelukast acid in a mixed solvent of toluene and methanol; controlling the temperature to be 20-30 ℃, adding low-boiling organic amine for reaction, and crystallizing after the reaction is finished; filtering, leaching and drying to obtain the low-boiling-point organic amine salt of the montelukast acid;
2) preparation of montelukast sodium
Adding the low-boiling-point organic amine salt of montelukast acid into an alcohol solvent under the protection of nitrogen, controlling the temperature to be 5-15 ℃, dropwise adding an alcoholic solution of sodium hydroxide, continuing stirring for reaction after dropwise adding is finished, and concentrating under reduced pressure;
3) freeze-drying
Dissolving the concentrated solution in purified water, filling into freeze-drying tray, and freeze-drying by freeze-drying process.
The freeze-drying process specifically comprises the following steps:
a refrigeration stage:
the first stage is as follows: the temperature of the separator plate of the freeze dryer is reduced to-5 ℃, the use time is 0.5-1.5 min, and the use time lasts for 0.5-1.5 min;
and a second stage: cooling to-15 ℃, taking 8-12 min, and keeping for 0.5-1.5 min;
and a third stage: cooling to-20 ℃, taking 40-60 min, and keeping for 0.5-1.5 min;
a fourth stage: cooling to-40 ℃, taking 0.5-1.5 min for 10-20 min;
drying stage:
vacuumizing to 0.20-0.40 mbar; sublimation drying is carried out in 4 stages:
stage 1: heating the separator plate of the freeze dryer to-5 ℃, taking 30-40 min for 220-260 min;
stage 2: cooling to-10 ℃, taking 8-12 min, and keeping for 600-700 min;
stage 3: heating to 0 ℃, and keeping the time for 100-150 min and 0.5-1.5 min;
and 4, stage: heating to 65 ℃, and keeping the time for 100-150 min and the time for 150-200 min;
analysis and drying:
vacuumizing to less than or equal to 0.05mbar, and keeping the temperature of a clapboard of a freeze dryer at 65 ℃ for 100-150 min.
The low-boiling organic amine refers to an amine which can be removed by concentration under reduced pressure and freeze-drying, and includes n-butylamine, diisopropylamine, isobutylamine, tert-butylamine and the like.
The alcohol solvent is methanol or ethanol. The alcoholic solution of sodium hydroxide is methanol or ethanol solution of sodium hydroxide.
Preferably, the volume ratio of the toluene to the methanol in the step 1) is 100: 1 to 2. The mole ratio of the montelukast acid to the low-boiling organic amine is 1: 1.01 to 1.05.
Preferably, the mole ratio of the low-boiling organic amine salt of montelukast acid in the step 2) to sodium hydroxide is 1: 1.01 to 1.05.
Preferably, the volume ratio of the concentrated solution in the step 3) to the purified water is 1: 20 to 40.
The reaction equation is as follows:
wherein R is1-NH-R2The low boiling point organic amine is mentioned above.
The invention has the beneficial effects that:
1. the method comprises the steps of firstly, adopting the low-boiling organic amine salt of montelukast acid, taking alcohol as a solvent, and taking an alcoholic solution of sodium hydroxide as a base to react to prepare montelukast sodium, wherein the low-boiling organic amine and the alcohol can be removed through reduced pressure concentration and freeze-drying, so that the problem of solvent residue of traditional solvent crystallization is solved, and the solvent residue is not detected in the production process by adopting the method;
2. according to the method, the reaction is carried out under the protection of nitrogen, the generation of oxidation impurities is avoided, the impurities in the montelukast acid are removed by utilizing the montelukast acid amine salt, the ammonium salt of the montelukast acid is further purified in a heat-preservation crystallization mode, the purity of the organic ammonium salt of the montelukast acid is more than or equal to 99.7%, the product is used as a raw material to prepare the montelukast sodium, the purity of the product is high, and the content of single impurities in the final product is lower than 0.1%;
3. the invention provides a matched freeze-drying process of montelukast sodium, which is used for freezing and sublimation drying in stages, so that impurities in the montelukast sodium are reduced to the minimum;
4. the method has the advantages of simple process, environmental protection, no solvent residue in the product and the like, and is suitable for industrial production.
Drawings
FIG. 1 is an HPLC chromatogram of the purity of the product of example 1 of the present invention.
Detailed Description
The invention will be further illustrated with reference to specific examples, without however restricting the scope of the invention thereto.
Montelukast acid 500g was prepared according to the method reported in patent CN 105541711A of the same company, with a purity of 99.5% by HPLC and a chiral purity of 99.9%.
Reaction equation of organic ammonium salt:
1. preparation of montelukast acid tert-butylamine salt
Under the protection of nitrogen, adding 580g of toluene, 10.5g of methanol and 66g of montelukast acid into a reaction tank, and stirring for 15 min; controlling the temperature to be 20-30 ℃, adding 8.5g of tert-butylamine, keeping the temperature to be 20-30 ℃, reacting for 8 hours, and crystallizing. Filtering, leaching with 24g of toluene, transferring into a forced air drying oven, carrying out forced air drying at 55 ℃ for 6-8 h, discharging, and obtaining a dry product 67.0g, wherein the yield is 90.0%, the purity is 99.8% by HPLC detection, and the chiral purity is 99.9%.
2. Preparation of n-butylamine salt of montelukast acid
Under the protection of nitrogen, 600g of toluene, 12g of methanol and 66g of montelukast acid are added into a reaction tank, and stirred for 15 min; controlling the temperature to be 20-30 ℃, adding 8.5g of n-butylamine, keeping the temperature to be 20-30 ℃, reacting for 10 hours, and crystallizing. Filtering, leaching with 30g of toluene, transferring into a forced air drying oven, carrying out forced air drying at 55 ℃ for 6-8 h, discharging, and obtaining 65.7g of a dry product, wherein the yield is 88.7%, the purity is 99.7% by HPLC detection, and the chiral purity is 99.9%.
3. Preparation of diisopropylamine montelukast acid:
under the protection of nitrogen, 600g of toluene, 12g of methanol and 66g of montelukast acid are added into a reaction tank, and stirred for 15 min; controlling the temperature to be 20-30 ℃, adding 11.6g of diisopropylamine, keeping the temperature to be 20-30 ℃, reacting for 10 hours, and crystallizing. Filtering, leaching with 28g of toluene, transferring into a forced air drying oven, carrying out forced air drying at 55 ℃ for 6-8 h, and discharging to obtain 66.7g of a dry product, wherein the yield is 85.4%, the purity is 99.8% by HPLC (high performance liquid chromatography) detection, and the chiral purity is 99.9%.
The montelukast sodium is prepared by adopting the raw materials.
Example 1:
1. salt formation
140g of methanol and 56g of montelukast acid tert-butylamine salt are added into a 1L three-necked bottle and stirred for 20min under the protection of nitrogen. Cooling the reaction liquid to 5-15 ℃, adding a sodium hydroxide methanol solution (3.5 g of sodium hydroxide is dissolved in 94g of methanol), and controlling the dripping time to be 10-30 min and the temperature to be 5-15 ℃. After the dropwise addition, stirring was continued for 20 min. The methanol is evaporated under reduced pressure, and the temperature of the heated water bath is controlled below 60 ℃. After distillation until the distillate flows out dropwise, 1680ml of purified water is added and dissolved for later use.
2. Filling
Filling the prepared liquid medicine into freeze-drying trays respectively, wherein the length of a freeze-drying plate frame is multiplied by the width of 29cm multiplied by 22cm, and the filling amount is 840ml per tray;
3. freeze-drying
The lyophilization recipe was set and run automatically, as follows:
1) and (3) refrigeration control:
| set temperature (. degree. C.) | Setting time (min) | Duration (min) | |
| First stage | -5 | 1 | 1 |
| Second stage | -15 | 10 | 1 |
| The third stage | -20 | 50 | 1 |
| Fourth stage | -40 | 1 | 15 |
2) Refrigeration control of the water catcher:
3) pre-vacuumizing:
| pre-evacuation (mbar) | Alarming vacuum (mbar) | Alarm vacuum duration(s) |
| 0.4000 | 0.60 | 15 |
4) Primary drying:
| set temperature (. degree. C.) | Setting time (min) | Duration (min) | Setting vacuum (mbar) | |
| Stage 1 | -5 | 35 | 240 | 0.28 |
| Stage 2 | -10 | 10 | 660 | 0.28 |
| |
0 | 120 | 1 | 0.28 |
| Stage 4 | 65 | 130 | 180 | 0.28 |
5) And (3) resolving and drying:
| set temperature (. degree. C.) | Setting time (min) | Duration (min) | Setting vacuum (mbar) | |
| |
65 | 1 | 120 | 0.0000 |
6) Analysis and drying pressure test:
| pressure rise value (Pa) | Test time (min) | Number of tests | Interval time (min) |
| ≤5 | 2 | 3 | 30 |
4. Charging nitrogen, discharging, packaging, and detecting purity of 99.86% (shown in figure 1) according to pharmacopeia method. The water content was 0.6%, methanol was not detected as a gas phase residual solvent, and tert-butylamine was not detected.
Example 2:
1. salt formation
140g of methanol and 56g of n-butylamine montelukast acid salt are added into a 1L three-necked flask and stirred for 20min under the protection of nitrogen. Cooling the reaction liquid to 5-15 ℃, adding a sodium hydroxide methanol solution (3.5 g of sodium hydroxide is dissolved in 94g of methanol), and controlling the dripping time to be 10-30 min and the temperature to be 5-15 ℃. After the dropwise addition, stirring was continued for 20 min. The methanol is evaporated under reduced pressure, and the temperature of the heated water bath is controlled below 60 ℃. After distillation until the distillate flows out dropwise, 1680ml of purified water is added and dissolved for later use.
2. Filling and freeze-drying were carried out according to the procedure of example 1, and the purity was checked to be 99.7%. The water content was 0.5%, methanol was not detected as a gas phase residual solvent, and n-butylamine was not detected.
Example 3:
1. salt formation
140g of methanol and 58g of diisopropylamine montelukast acid are added into a 1L three-necked flask and stirred for 20min under the protection of nitrogen. Cooling the reaction liquid to 5-15 ℃, adding a sodium hydroxide methanol solution (3.5 g of sodium hydroxide is dissolved in 94g of methanol), and controlling the dripping time to be 10-30 min and the temperature to be 5-15 ℃. After the dropwise addition, stirring was continued for 20 min. The methanol is evaporated under reduced pressure, and the temperature of the heated water bath is controlled below 60 ℃. After distillation until the distillate flows out dropwise, 1680ml of purified water is added and dissolved for later use.
2. Filling and freeze-drying were carried out according to the procedure of example 1, and the purity was measured to be 99.82%. The water content was 0.7%, methanol was not detected as a gas-phase residual solvent, and diisopropylamine was 5 ppm.
Example 4:
1. salt formation
150g of ethanol and 56g of montelukast acid tert-butylamine salt are added into a 1L three-necked bottle and stirred for 20min under the protection of nitrogen. Cooling the reaction liquid to 5-15 ℃, adding a sodium hydroxide ethanol solution (3.5 g of sodium hydroxide is dissolved in 100g of ethanol), and controlling the dropping time to be 10-30 min and the temperature to be 5-15 ℃. After the dropwise addition, stirring was continued for 20 min. Distilling under reduced pressure to remove ethanol, and heating water bath at 60 deg.C or below. After distillation until the distillate flows out dropwise, 1680ml of purified water is added and dissolved for later use.
2. Filling and freeze-drying were carried out according to the procedure of example 1, and the purity was checked to be 99.85%. The water content was 0.5%, and the gas phase residual solvent ethanol was not detected.
Control experiment 1: crystallization method using n-butylamine salt of montelukast acid with reference to CN201310463503 example 1 solvent
1. 20g of n-butylamine salt of montelukast acid (0.034 mol) was slurried with 200ml of methanol and replaced with nitrogen 3 times. A methanolic sodium hydroxide solution (40ml methanol +1.36g sodium hydroxide +1.36ml water) was added and stirred for 30 minutes. The solvent was evaporated under reduced pressure. Adding 100ml of toluene, dissolving and cleaning, dripping 1000ml of n-heptane for separating, filtering, vacuum drying the materials at 55 ℃ for 12h, sampling and detecting, and detecting the residual solvent in a gas phase: toluene 8662ppm and n-heptane 56234ppm, with the limits toluene < 890ppm and n-heptane < 5000 ppm.
2. Continuously heating to 70 ℃, vacuum drying for 12h, sampling and detecting, and detecting residual solvent in a gas phase: 3062ppm of toluene and 21686ppm of n-heptane;
3. grinding, continuously vacuum drying at 70 ℃ for 16h, sampling and detecting, and detecting residual solvent in a gas phase: toluene 620ppm, n-heptane 8670 ppm;
4. grinding, continuously vacuum drying at 70 ℃ for 10h, sampling and detecting, and detecting residual solvent in a gas phase: toluene 180ppm, n-heptane 3300 ppm.
Control experiment 2: the montelukast di-n-butylamine salt prepared from di-n-butylamine is prepared according to the process.
1. Salt formation
140g of methanol and 63g of di-n-butylamine montelukast acid salt are added into a 1L three-necked flask and stirred for 20min under the protection of nitrogen. Cooling the reaction liquid to 5-15 ℃, adding a sodium hydroxide methanol solution (3.5 g of sodium hydroxide is dissolved in 94g of methanol), and controlling the dripping time to be 10-30 min and the temperature to be 5-15 ℃. After the dropwise addition, stirring was continued for 20 min. The methanol is evaporated under reduced pressure, and the temperature of the heated water bath is controlled below 60 ℃. After distillation until the distillate flows out dropwise, 1680ml of purified water is added and dissolved for later use.
2. Filling and freeze-drying were carried out according to the procedure of example 1, and the purity was checked to be 99.7%. The water content was 1.0%, methanol was not detected as a gas-phase residual solvent, and 85000ppm of di-n-butylamine was not met with the quality standard.
As can be seen from control experiment 1: the n-butylamine salt of montelukast acid is used for preparing montelukast sodium by a solvent crystallization method, and long-time drying is needed to ensure that the residual solvent reaches the standard required by pharmacopeia. As can be seen from control experiment 2: di-n-butylamine salt of montelukast cannot be used for the freeze-drying of the present invention.
Claims (5)
1. The preparation method of montelukast sodium is characterized by comprising the following steps:
1) preparation of low boiling organic amine salts of montelukast acid
Under the protection of nitrogen, dissolving montelukast acid in a mixed solvent of toluene and methanol; controlling the temperature to be 20-30 ℃, adding low-boiling organic amine for reaction, and crystallizing after the reaction is finished; filtering, leaching and drying to obtain the low-boiling-point organic amine salt of the montelukast acid; the low-boiling organic amine is n-butylamine, diisopropylamine, isobutylamine or tert-butylamine;
2) preparation of montelukast sodium
Adding the low-boiling-point organic amine salt of montelukast acid into an alcohol solvent under the protection of nitrogen, controlling the temperature to be 5-15 ℃, dropwise adding an alcoholic solution of sodium hydroxide, continuing stirring for reaction after dropwise adding is finished, and concentrating under reduced pressure; the alcohol solvent is methanol or ethanol; the alcoholic solution of sodium hydroxide is a methanol or ethanol solution of sodium hydroxide;
3) freeze-drying
Dissolving the concentrated solution in purified water, filling into a freeze-drying tray, and freeze-drying by freeze-drying process;
the freeze-drying process specifically comprises the following steps:
a refrigeration stage:
the first stage is as follows: the temperature of the separator plate of the freeze dryer is reduced to-5 ℃, the use time is 0.5-1.5 min, and the use time lasts for 0.5-1.5 min;
and a second stage: cooling to-15 ℃, taking 8-12 min, and keeping for 0.5-1.5 min;
and a third stage: cooling to-20 ℃, taking 40-60 min, and keeping for 0.5-1.5 min;
a fourth stage: cooling to-40 ℃, taking 0.5-1.5 min for 10-20 min;
drying stage:
vacuumizing to 0.20-0.40 mbar; sublimation drying is carried out in 4 stages:
stage 1: heating the separator plate of the freeze dryer to-5 ℃, taking 30-40 min for 220-260 min;
stage 2: cooling to-10 ℃, taking 8-12 min, and keeping for 600-700 min;
stage 3: heating to 0 ℃, and keeping the time for 100-150 min and 0.5-1.5 min;
and 4, stage: heating to 65 ℃, and keeping the time for 100-150 min and the time for 150-200 min;
analysis and drying:
vacuumizing to less than or equal to 0.05mbar, and keeping the temperature of a clapboard of a freeze dryer at 65 ℃ for 100-150 min.
2. The method for preparing montelukast sodium according to claim 1, wherein the volume ratio of toluene to methanol in step 1) is 100: 1 to 2.
3. The method for preparing montelukast sodium according to claim 1, wherein the mole ratio of the montelukast acid to the low-boiling organic amine in the step 1) is 1: 1.01 to 1.05.
4. The method for preparing montelukast sodium according to claim 1, wherein the mole ratio of the low-boiling organic amine salt of montelukast acid to sodium hydroxide in the step 2) is 1: 1.01 to 1.05.
5. The preparation method of montelukast sodium according to any of claims 1 to 4, wherein the ratio of the concentrated solution to the purified water in step 3) is 1: 20 to 40.
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Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5565473A (en) * | 1990-10-12 | 1996-10-15 | Merck Frosst Canada, Inc. | Unsaturated hydroxyalkylquinoline acids as leukotriene antagonists |
| US7189853B2 (en) * | 2004-04-15 | 2007-03-13 | Dr. Reddy's Laboratories Limited | Process for the preparation of [R-(E)-1-[[[1-[3-[2-[7-chloro-2-quinolinyl]ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid (Montelukast) and its pharmaceutically acceptable salts |
| WO2007069261A1 (en) * | 2005-12-13 | 2007-06-21 | Msn Laboratories Limited | An improved process for the preparation of montelukast and its pharmaceutically acceptable salts |
| WO2008062478A2 (en) * | 2006-11-20 | 2008-05-29 | Manne Satyanarayana Reddy | Improved process for pure montelukast sodium through pure intermediates as well as novel amine salts |
| CZ302518B6 (en) * | 2007-07-09 | 2011-06-29 | Zentiva, A. S. | Method of isolation and purification of montelukast |
| EP2265586A4 (en) * | 2008-03-17 | 2012-10-03 | Reddys Lab Ltd Dr | Preparation of montelukast and its salts |
| JP2015007000A (en) * | 2013-06-24 | 2015-01-15 | 株式会社トクヤマ | Method for producing crystal of montelukast free acid |
| CN111170939A (en) * | 2019-12-20 | 2020-05-19 | 牡丹江恒远药业股份有限公司 | Preparation method of high-purity montelukast sodium and intermediate thereof |
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