CN106928193B - Preparation meets the method for the esomeprazole magnesium trihydrate of standards of pharmacopoeia - Google Patents
Preparation meets the method for the esomeprazole magnesium trihydrate of standards of pharmacopoeia Download PDFInfo
- Publication number
- CN106928193B CN106928193B CN201710137186.9A CN201710137186A CN106928193B CN 106928193 B CN106928193 B CN 106928193B CN 201710137186 A CN201710137186 A CN 201710137186A CN 106928193 B CN106928193 B CN 106928193B
- Authority
- CN
- China
- Prior art keywords
- room temperature
- stirring
- water
- weight
- esomeprazole
- 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.)
- Expired - Fee Related
Links
- KWORUUGOSLYAGD-YPPDDXJESA-N esomeprazole magnesium Chemical compound [Mg+2].C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C.C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C KWORUUGOSLYAGD-YPPDDXJESA-N 0.000 title claims abstract description 18
- 238000000034 method Methods 0.000 title claims abstract description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 29
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 27
- 238000003756 stirring Methods 0.000 claims abstract description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 26
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims abstract description 24
- FOFFPEFVSRGLOZ-JIDHJSLPSA-N potassium;5-methoxy-2-[(s)-(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]benzimidazol-1-ide Chemical compound [K+].C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C FOFFPEFVSRGLOZ-JIDHJSLPSA-N 0.000 claims abstract description 22
- 238000001035 drying Methods 0.000 claims abstract description 14
- 229910001629 magnesium chloride Inorganic materials 0.000 claims abstract description 12
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000000463 material Substances 0.000 claims abstract description 5
- 239000005909 Kieselgur Substances 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 3
- 238000007599 discharging Methods 0.000 abstract 2
- 229910052799 carbon Inorganic materials 0.000 abstract 1
- 238000009987 spinning Methods 0.000 abstract 1
- 229960000197 esomeprazole magnesium Drugs 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- YYINWHOQKIUBNL-UHFFFAOYSA-N magnesium;trihydrate Chemical compound O.O.O.[Mg] YYINWHOQKIUBNL-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000003749 cleanliness Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229960004770 esomeprazole Drugs 0.000 description 1
- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
技术领域technical field
本发明涉及药物合成工艺，尤其是涉及制备符合药典标准的埃索美拉唑镁三水合物的方法。The invention relates to a medicine synthesis process, in particular to a method for preparing esomeprazole magnesium trihydrate meeting the pharmacopoeia standard.
背景技术Background technique
专利WO9854171A2公开了由埃索美拉唑钾与硫酸镁反应制备埃索美拉唑镁，然后与水反应制备埃索美拉唑镁三水合物的方法。专利WO2004046134A2、WO2004089935A1、WO2007031845A2公开了由埃索美拉唑镁与水直接反应制备埃索美拉唑镁三水合物的方法。专利CN105111188A公开了将埃索美拉唑镁溶于C1-C3烷醇后经活性炭助滤，然后再与水反应制备埃索美拉唑镁三水合物的方法。Patent WO9854171A2 discloses a method for preparing esomeprazole magnesium by reacting esomeprazole potassium with magnesium sulfate, and then reacting with water to prepare esomeprazole magnesium trihydrate. Patents WO2004046134A2, WO2004089935A1, and WO2007031845A2 disclose methods for preparing esomeprazole magnesium trihydrate by directly reacting esomeprazole magnesium with water. Patent CN105111188A discloses a method for preparing esomeprazole magnesium trihydrate by dissolving esomeprazole magnesium in C1-C3 alkanol, using activated carbon as a filter aid, and then reacting with water.
按专利WO9854171A1、WO2004046134A2、WO2004089935A1和WO2007031845A2的描述制备埃索美拉唑镁三水合物，因采用的是在水中直接成盐，得到的三水合镁盐存在结晶度差，过滤困难，干燥时间长等问题，有的产品甚至要采用微波干燥等方法才能烘干，不利于商业生产。按专利CN105111188A的描述制备的埃索美拉唑镁三水合物颜色偏暗，终产品的溶解度不合格，不符合欧洲药典和美国药典的规定。Prepare esomeprazole magnesium trihydrate according to the descriptions of patents WO9854171A1, WO2004046134A2, WO2004089935A1 and WO2007031845A2. Because it uses direct salt formation in water, the obtained magnesium trihydrate salt has poor crystallinity, difficult filtration, long drying time, etc. The problem is that some products even need to be dried by microwave drying and other methods, which is not conducive to commercial production. The color of esomeprazole magnesium trihydrate prepared according to the description of patent CN105111188A is dark, the solubility of the final product is unqualified, and does not meet the requirements of the European Pharmacopoeia and the United States Pharmacopoeia.
发明内容Contents of the invention
本发明的目的就是为了解决上述问题，提供一种制备符合药典标准的埃索美拉唑镁三水合物的方法，旨在商业生产颜色和溶解度均符合欧洲药典和美国药典的埃索美拉唑镁三水合物。The purpose of the present invention is exactly in order to solve the above problems, provide a kind of method that prepares the esomeprazole magnesium trihydrate that meets Pharmacopoeia standard, aim at the esomeprazole that commercial production color and solubility all meet European Pharmacopoeia and American Pharmacopoeia Magnesium trihydrate.
为了实现上述目的，本发明采用如下技术方案：一种制备符合药典标准的埃索美拉唑镁三水合物的方法，包括如下步骤：In order to achieve the above object, the present invention adopts following technical scheme: a kind of method for preparing the esomeprazole magnesium trihydrate that meets Pharmacopoeia standard comprises the steps:
S101、室温下，将埃索美拉唑钾溶于水中，搅拌，然后投入活性炭，室温下搅拌后通过硅藻土滤床，用水洗涤；S101, at room temperature, dissolve esomeprazole potassium in water, stir, then drop into activated carbon, pass through a diatomite filter bed after stirring at room temperature, and wash with water;
S102、室温下，将步骤S101所得湿滤饼转移至另一反应器中，缓慢加入氯化镁溶液，然后投入EDTA溶液，搅拌后离心，用水洗涤，自旋干燥，卸料；S102. At room temperature, transfer the wet filter cake obtained in step S101 to another reactor, slowly add magnesium chloride solution, then put in EDTA solution, centrifuge after stirring, wash with water, spin dry, and discharge;
S103、将步骤S102所得物料转移至干燥设备中，加热至60-65℃并干燥3-4小时，冷却至室温后卸料。S103. Transfer the material obtained in step S102 to a drying device, heat to 60-65°C and dry for 3-4 hours, and then unload after cooling to room temperature.
优选地：步骤S101中，搅拌10-20分钟后投入活性炭。Preferably: in step S101, add activated carbon after stirring for 10-20 minutes.
优选地：步骤S101中，室温下搅拌25-35分钟后通过硅藻土滤床.Preferably: in step S101, after stirring at room temperature for 25-35 minutes, pass through a diatomaceous earth filter bed.
优选地：步骤S102中，搅拌25-35分钟后离心。Preferably: in step S102, centrifuge after stirring for 25-35 minutes.
优选地：步骤S102中，自旋干燥60分钟。Preferably: in step S102, spin drying for 60 minutes.
优选地：步骤S101中，埃索美拉唑钾与水的重量体积比为0.18-0.22KG/L。Preferably: in step S101, the weight-to-volume ratio of esomeprazole potassium to water is 0.18-0.22KG/L.
优选地：步骤S101中，按重量计，活性炭添加量为埃索美拉唑钾重量的0.018-0.023倍。Preferably: in step S101, by weight, the amount of activated carbon added is 0.018-0.023 times the weight of esomeprazole potassium.
优选地：步骤S102中，按照重量计，氯化镁溶液中氯化镁重量为埃索美拉唑钾重量的0.24-0.26倍。Preferably: in step S102, by weight, the weight of magnesium chloride in the magnesium chloride solution is 0.24-0.26 times the weight of esomeprazole potassium.
优选地：步骤S102中，按照重量计，EDTA溶液添加量与埃索美拉唑钾添加量之比为0.0068-0.0072。Preferably: in step S102, by weight, the ratio of the added amount of EDTA solution to the added amount of esomeprazole potassium is 0.0068-0.0072.
与现有技术相比，本发明具有如下有益效果：该方法操作方便，产品的颜色与溶解度均合格，利于商业化生产。Compared with the prior art, the invention has the following beneficial effects: the method is convenient to operate, and the color and solubility of the product are both qualified, which is beneficial to commercial production.
具体实施方式Detailed ways
一种制备符合药典标准的埃索美拉唑镁三水合物的方法，包括如下步骤：A method for preparing esomeprazole magnesium trihydrate meeting pharmacopoeia standards, comprising the steps:
S101、室温下，将埃索美拉唑钾溶于水中，搅拌，然后投入活性炭，室温下搅拌后通过硅藻土滤床，用水洗涤；S101, at room temperature, dissolve esomeprazole potassium in water, stir, then drop into activated carbon, pass through a diatomite filter bed after stirring at room temperature, and wash with water;
S102、室温下，将步骤S101所得湿滤饼转移至另一反应器(反应釜)中，缓慢加入氯化镁溶液，然后投入EDTA溶液，搅拌后离心，用水洗涤，自旋干燥，卸料；S102, at room temperature, transfer the wet filter cake obtained in step S101 to another reactor (reactor), slowly add magnesium chloride solution, then put into EDTA solution, centrifuge after stirring, wash with water, spin dry, and discharge;
S103、将步骤S102所得物料转移至干燥设备(厢式干燥箱)中，加热至60-65℃并干燥3-4小时，冷却至室温后卸料。S103. Transfer the material obtained in step S102 to drying equipment (box-type drying box), heat to 60-65°C and dry for 3-4 hours, and then unload after cooling to room temperature.
步骤S101中，搅拌10-20分钟后投入活性炭，优选为15分钟。In step S101, activated carbon is added after stirring for 10-20 minutes, preferably 15 minutes.
步骤S101中，室温下搅拌25-35分钟后通过硅藻土滤床，优选为30分钟。In step S101, after stirring at room temperature for 25-35 minutes, pass through a diatomaceous earth filter bed, preferably 30 minutes.
步骤S102中，搅拌25-35分钟后离心，优选为30分钟。In step S102, centrifuge after stirring for 25-35 minutes, preferably 30 minutes.
步骤S102中，自旋干燥55-65分钟，优选为60分钟。In step S102, spin drying for 55-65 minutes, preferably 60 minutes.
步骤S101中，埃索美拉唑钾与水的重量体积比为0.18-0.22KG/L，优选为0.2KG/L。In step S101, the weight-to-volume ratio of esomeprazole potassium to water is 0.18-0.22KG/L, preferably 0.2KG/L.
步骤S101中，按重量计，活性炭添加量为埃索美拉唑钾重量的0.018-0.023倍。In step S101, by weight, the amount of activated carbon added is 0.018-0.023 times the weight of esomeprazole potassium.
步骤S102中，按照重量计，氯化镁溶液中氯化镁重量为埃索美拉唑钾重量的0.24-0.26倍，优选为0.25倍。In step S102, by weight, the weight of magnesium chloride in the magnesium chloride solution is 0.24-0.26 times, preferably 0.25 times, the weight of esomeprazole potassium.
步骤S102中，按照重量计，EDTA溶液添加量与埃索美拉唑钾添加量之比为0.0068-0.0072。In step S102, by weight, the ratio of the added amount of EDTA solution to the added amount of esomeprazole potassium is 0.0068-0.0072.
本发明以埃索美拉唑钾为中间体制备埃索美拉唑镁三水合物。为了使埃索美拉唑镁三水合物的颜色合格，对埃索美拉唑钾进行了前处理，即将埃索美拉唑钾溶于水，然后投入活性炭室温搅拌30分钟后通过硅藻土滤床过滤；同时，为了使埃索美拉唑镁三水合物的溶解度符合规定，在与水的反应中加入(乙二胺四乙酸)EDTA溶液。The present invention uses esomeprazole potassium as an intermediate to prepare esomeprazole magnesium trihydrate. In order to make the color of esomeprazole magnesium trihydrate qualified, esomeprazole potassium was pretreated, that is, esomeprazole potassium was dissolved in water, then dropped into activated carbon and stirred at room temperature for 30 minutes and then passed diatomite Filter bed filtration; meanwhile, in order to make the solubility of esomeprazole magnesium trihydrate meet the requirements, add (ethylenediaminetetraacetic acid) EDTA solution in the reaction with water.
实施例：(1)检查反应釜的洁净度，Embodiment: (1) check the cleanliness of reactor,
(2)投入1300L-1480L水至反应釜，(2) Put 1300L-1480L water into the reactor,
(3)搅拌下投入260-296kg埃索美拉唑钾，(3) drop into 260-296kg esomeprazole potassium under stirring,
(4)室温下搅拌使完全溶解，(4) Stir at room temperature to dissolve completely,
(5)投入活性炭悬浮液(6kg活性炭+6L水)，(5) drop into activated carbon suspension (6kg activated carbon+6L water),
(6)搅拌10-15分钟，(6) Stir for 10-15 minutes,
(7)通过硅藻土滤床过滤，用260-296L水洗涤，收集滤液，(7) filter through a diatomaceous earth filter bed, wash with 260-296L water, collect the filtrate,
(8)将65-74kg氯化镁投入含水的桶中，搅拌使完全溶解，过滤，(8) 65-74kg magnesium chloride is dropped in the bucket containing water, stirs and makes dissolving completely, filters,
(9)室温下，于20分钟内将上述氯化镁溶液加入经活性炭处理的埃索美拉唑钾滤液中，(9) under room temperature, in 20 minutes, above-mentioned magnesium chloride solution is added in the esomeprazole potassium filtrate of gac-treated,
(10)投入EDTA溶液(2KG)至反应釜，(10) drop into EDTA solution (2KG) to reactor,
(11)搅拌约30分钟，(11) Stir for about 30 minutes,
(12)离心，用100L水洗涤，自旋干燥60分钟后卸料，(12) Centrifuge, wash with 100L water, unload after spin drying for 60 minutes,
(13)将上述步骤的物料转移至厢式干燥箱中，升温至60-65℃，干燥3-4小时。(13) Transfer the materials in the above steps to a box-type drying oven, raise the temperature to 60-65° C., and dry for 3-4 hours.
按照上述方法制得的产品颜色和溶解度如表一所示：The product color and solubility that make according to above-mentioned method are as shown in Table 1:
表一：Table I:
以上所述仅为本发明的优选实施方式，本发明的保护范围并不仅限于上述实施方式，凡是属于本发明原理的技术方案均属于本发明的保护范围。对于本领域的技术人员而言，在不脱离本发明的原理的前提下进行的若干改进，这些改进也应视为本发明的保护范围。The above descriptions are only preferred implementations of the present invention, and the scope of protection of the present invention is not limited to the above-mentioned implementations. All technical solutions belonging to the principle of the present invention belong to the scope of protection of the present invention. For those skilled in the art, some improvements made without departing from the principle of the present invention should also be regarded as the protection scope of the present invention.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710137186.9A CN106928193B (en) | 2017-03-09 | 2017-03-09 | Preparation meets the method for the esomeprazole magnesium trihydrate of standards of pharmacopoeia |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710137186.9A CN106928193B (en) | 2017-03-09 | 2017-03-09 | Preparation meets the method for the esomeprazole magnesium trihydrate of standards of pharmacopoeia |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106928193A CN106928193A (en) | 2017-07-07 |
| CN106928193B true CN106928193B (en) | 2018-12-11 |
Family
ID=59433049
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710137186.9A Expired - Fee Related CN106928193B (en) | 2017-03-09 | 2017-03-09 | Preparation meets the method for the esomeprazole magnesium trihydrate of standards of pharmacopoeia |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106928193B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108409714A (en) * | 2018-03-29 | 2018-08-17 | 成都通德药业有限公司 | The preparation method of esomeprazole, esomeprazole salt and esomeprazole magnesium |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004089935A1 (en) * | 2003-04-10 | 2004-10-21 | Hetero Drugs Limitd | Novel crystalline forms of s-omeprazole magnesium |
| CN102993184A (en) * | 2013-01-08 | 2013-03-27 | 湖南方盛制药股份有限公司 | Esomeprazole and preparation method of magnesium trihydrate of esomeprazole |
| CN104356114B (en) * | 2014-11-17 | 2017-02-22 | 江苏中邦制药有限公司 | Preparation method of esomeprazole magnesium trihydrate |
| CN104610227A (en) * | 2015-01-08 | 2015-05-13 | 浙江亚太药业股份有限公司 | High-pressure hydrothermal preparation method for esomeprazole magnesium polymorphic compound |
| CN105418588A (en) * | 2016-01-17 | 2016-03-23 | 青岛辰达生物科技有限公司 | Method for preparing high-purity esomeprazole magnesium trihydrate |
-
2017
- 2017-03-09 CN CN201710137186.9A patent/CN106928193B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN106928193A (en) | 2017-07-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108276504B (en) | A kind of technique for extracting high purity pectin from apple pomace | |
| CN106928193B (en) | Preparation meets the method for the esomeprazole magnesium trihydrate of standards of pharmacopoeia | |
| CN111560079A (en) | Preparation method of Iota carrageenan glue solution | |
| CN103833870B (en) | A kind of method extracting low-methoxy pectin from apple residue | |
| CN106387297A (en) | Preparation method of food grade casein | |
| JP2011527330A5 (en) | ||
| CN103804172B (en) | A kind of method improving organic acid production quality | |
| CN114874237B (en) | Refining method of cefotaxime sodium | |
| CN104610385B (en) | A kind of process for purification of aminoglucose hydrochloride | |
| CN112661767B (en) | A method for synchronously preparing sesame protein concentrate, sesame oil and sesamin from sesame meal | |
| CN104140475A (en) | Method for preparing quaternization chitosan | |
| CN102951626A (en) | Method for preparing high-purity stannous pyrophosphate | |
| CN106883202A (en) | A kind of preparation method of L ascorbyl palmitates | |
| CN106632734A (en) | Processing technology for extracting agar from Gelidium amansii | |
| CN102079749A (en) | Method for producing rifampicin raw material medicines with densities of less than or equal to 0.3g/ml and more than or equal to 0.8g/ml | |
| CN110669153A (en) | Method for extracting agar from gracilaria | |
| CN103043721B (en) | Method for preparing vanadyl sulfate | |
| CN105315300B (en) | A kind of cefoxitin sodium, preparation method and the usage | |
| CN101508849B (en) | A kind of preparation method of solvent red 135 | |
| CN104151279A (en) | Synthesis method of caronic anhydride | |
| CN104151324A (en) | Method for preparing ampicillin sodium by menstruum crystallization method | |
| KR101137894B1 (en) | Maunfacturing method of thiamine di-lauryl sulfate with high purity | |
| CN111675695A (en) | Topiroxostat refining method | |
| CN102786605B (en) | A kind of dilution crystallization method of separation and purification polysaccharide | |
| CN104072620B (en) | Utilize yellow sweet Compositions of Bamboo Shoot Shell to prepare the method for sodium carboxymethylcellulose |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20181211 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |