CN110128412B - Preparation method of dextro-ilaprazole potassium salt mother liquor, dextro-ilaprazole and preparation method thereof - Google Patents
Preparation method of dextro-ilaprazole potassium salt mother liquor, dextro-ilaprazole and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a preparation method of a mother solution of dextro-ilaprazole potassium salt, dextro-ilaprazole and a preparation method thereof, and relates to a drug intermediate. The preparation method of the dextro-ilaprazole potassium salt mother liquor comprises the following steps: mixing and pulping the dextrorotatory ilaprazole potassium salt to be purified and a first organic solvent to enable dextrorotatory isomer of the ilaprazole potassium salt to enter mother liquor, and then carrying out solid-liquid separation to obtain the mother liquor enriched with the dextrorotatory ilaprazole potassium salt. The mother solution is used as a raw material and reacts with acid for reaction to generate the dexilaprazole, water and a second organic solvent are used for performing a dissolving assisting effect to avoid the precipitation of the dexilaprazole, and then the dexilaprazole is purified. The obtained dexilaprazole has a very high e.e value, is not influenced by the e.e value of the dexilaprazole potassium salt, and has stable e.e value and small batch-to-batch difference.
Description
Technical Field
The invention relates to the technical field of drug intermediates, and in particular relates to dexilaprazole and a preparation method thereof.
Background
Ilaprazole is a novel proton pump inhibitor and is used for treating duodenal ulcer, gastric ulcer and erosive esophagitis. Ilaprazole contains one chiral center and is a racemic mixture of two single enantiomers, the R and S enantiomers. CN101098867A discloses a method for preparing a single enantiomer of ilaprazole, and animal experiments show that the optical isomer of ilaprazole, i.e. dextrorotatory or levorotatory ilaprazole has more excellent therapeutic effect in treating diseases related to hyperacidity compared with its racemate.
Patent CN1098261C discloses several methods for purifying compounds with high enantiomeric content of prazole, in which racemic body is selectively crystallized with solvent, and then the solvent in the solution is removed by evaporation to obtain single enantiomer with improved optical purity. However, since ilaprazole is different from other prazoles in structure and property, the method is not suitable for an ilaprazole system, and the obtained product has a low e.e value and large batch-to-batch difference.
Patent CN108689995A discloses that 5- (1H-pyrrol-1-yl) -2- radical benzimidazole is used as the starting material to prepare the optically active ilaprazole through a series of chemical reactions, and the method has the disadvantages of complex reaction process, complicated steps and large organic solvent consumption. And the patent does not mention how to obtain dexilaprazole with a high e.e value from ilaprazole racemate or crude dexilaprazole.
Patent CN101098867B discloses a method for purifying crude dextro-ilaprazole, which comprises dissolving crude (+) -ilaprazole in organic solvent to obtain clear solution, decolorizing with activated carbon at room temperature, filtering, and evaporating. The residue was dissolved in a mixture of dichloromethane and butanone, stirred at room temperature for one or two days, left overnight in a refrigerator, and filtered to give (+) -ilaprazole as a white solid. The method has long time consumption and harsh experimental conditions, needs to be placed overnight at low temperature, and is not suitable for industrial production.
Disclosure of Invention
The invention aims to provide a preparation method of a dextrorotatory ilaprazole potassium salt mother liquor, which is characterized in that dextrorotatory ilaprazole potassium salt with a lower e.e value is added into a selected organic solvent for pulping through selection of the organic solvent, so that dextrorotatory body of the ilaprazole potassium salt selectively enters a liquid phase, the e.e value of the dextrorotatory ilaprazole potassium salt in the liquid phase is obviously improved, the result stability is high, and the quality stability of a dextrorotatory ilaprazole product is favorably improved.
The invention also aims to provide a preparation method of the dexilaprazole, which is not limited by the e.e value of the raw material, can obtain the dexilaprazole with high optical purity, has stable e.e value of the product and small batch difference, and is simple, convenient, feasible and suitable for industrial application.
The third purpose of the invention is to provide a dexilaprazole which has a high e.e value, a stable e.e value and a low production cost.
The method creatively uses the organic solvent to pulp the dextro-ilazole sylvite, so that the dextro-isomer of the ilaprazole sylvite is enriched in the liquid phase, the e.e value of the dextro-ilaprazole sylvite in the mother liquid can be obviously improved, the dextro-ilaprazole sylvite in the liquid phase is further purified, and the product with the e.e value higher than 98%, small batch-to-batch difference and high yield can be obtained.
The technical problem to be solved by the invention is realized by adopting the following technical scheme.
The invention provides a preparation method of a dexilaprazole potassium salt mother liquor, which comprises the following steps:
mixing and pulping the dextro-ilaprazole potassium salt to be purified and a first organic solvent, and then carrying out solid-liquid separation to obtain a dextro-ilaprazole potassium salt mother liquor enriched with dextro-isomer of ilaprazole potassium salt;
wherein the first organic solvent is selected from any one or more of acetonitrile, ethyl acetate, dichloromethane and tetrahydrofuran; preferably, the first organic solvent is dichloromethane and/or ethyl acetate;
preferably, the mixing of the dextro-ilazole potassium salt and the first organic solvent is performed by stirring for 1-17h at the temperature of 20-30 ℃, and the dextro-ilazole potassium salt and the first organic solvent form slurry; more preferably, the stirring time is 1-4 h.
The invention provides a preparation method of dexilaprazole, which comprises the following steps: taking the dextro-ilaprazole potassium salt mother liquor prepared by the preparation method as a raw material, mixing and reacting the dextro-ilaprazole potassium salt mother liquor, water, a second organic solvent and reaction acid, and purifying dextro-ilaprazole in a mixed liquor after reaction;
preferably, the purification process of the dexilaprazole comprises the following steps: and extracting the reacted mixed solution, and mixing the organic phase obtained by extraction with a third organic solvent to precipitate the dexilaprazole.
The invention also provides the dexilaprazole prepared by the preparation method of the dexilaprazole;
preferably, the e.e value of dexilaprazole is 98.0 to 99.5%.
The embodiment of the invention provides a preparation method of a dextro-ilaprazole potassium salt mother liquor, which has the beneficial effects that: according to the method, the dexilaprazole potassium salt dextroisomer is enriched in a liquid phase through the selection of an organic solvent, and a mother solution is separated through filtration, so that the e.e value of the dexilaprazole potassium salt in the mother solution is obviously improved, and the result stability is high.
The embodiment of the invention also provides a preparation method of the dexilaprazole, which comprises the steps of reacting the mother liquor serving as a raw material with a reaction acid to generate the dexilaprazole, performing a dissolving assisting effect by using water and a second organic solvent to avoid the precipitation of the dexilaprazole, and then purifying the dexilaprazole. The obtained dexilaprazole has a very high e.e value, is not influenced by the e.e value of the dexilaprazole potassium salt, and has a stable product e.e value and small batch difference; the process method is simple and easy to implement, is suitable for popularization and application, and does not need a large amount of organic solvents.
The invention also provides the dexilaprazole which is prepared by the preparation method of the dexilaprazole, has a very high e.e value and is low in production cost.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The dextro-ilaprazole and the preparation method thereof provided by the embodiments of the present invention are specifically described below.
The preparation method of the dexilaprazole provided by the embodiment of the invention comprises the following steps:
s1 preparation of D-ilaprazole potassium salt mother liquor
Mixing and pulping the dextro-ilaprazole potassium salt and a first organic solvent, and then carrying out solid-liquid separation to obtain a dextro-ilaprazole potassium salt mother liquor enriched with dextro-isomer of ilaprazole potassium salt. Through the selection of an organic solvent, the dextro-ilazole sylvite enters a liquid phase, and a mother solution is separated through filtration, so that the e.e value of the dextro-ilazole sylvite in the mother solution is obviously improved, and the result stability is high.
It should be added that the potassium salt of dexilaprazole cannot be replaced by other raw materials, such as dexilaprazole sodium salt, and the use of other salts cannot obtain dexilaprazole with a high e.e value, which is probably because sodium and potassium both belong to the same alkali metal elements, and the radius of potassium ions is larger than that of sodium ions, thereby better enhancing the discrimination between the two optical isomers.
Specifically, the potassium salt of dexilaprazole can be synthesized by an existing method or a commercially available product. The method for synthesizing the D-ilaprazole potassium Salt can be obtained by referring to the method for synthesizing a prazole drug (Rajendra D.Mahale et al Davis Oxaziridine-media assay Synthesis of Proton Pump inhibition Using DBU Salt of Process Sulfide organic Process Research & Development2010,14, 1264-1268). The specific method comprises the following steps: 10g of thioether, 6.53g of DBU, 50mL of isopropanol and 50mL of toluene were sequentially added to a 100mL three-necked flask at room temperature. Then adding 7.22g of (S-) camphorsulfodumene, reacting for 2 hours at 10 ℃, stopping the reaction, filtering to obtain a mother liquor (the e.e value is 70-80%), spin-drying the solvent, adding 50ml of water, stirring, dropwise adding 25% glacial acetic acid aqueous solution by mass fraction into the mixed phase system, adjusting the pH to be approximately equal to 8.0, adding 50 ml/time of dichloromethane, and extracting twice. And (3) separating an organic layer, carrying out spin drying, adding 1.2mL of KOH and 2mL of methanol relative to the mass of the ilaprazole per gram into the oily matter, stirring for a certain time, then beginning to separate out potassium salt, slowly adding 10mL of isopropyl ether relative to the mass of the ilaprazole per gram, promoting the separation of potassium salt, and filtering to obtain a dextrorotatory ilaprazole potassium salt solid, wherein the e.e value is 70-80%. In the specific embodiment of the invention, the preparation method of the dextro-ilaprazole potassium salt is prepared by adopting the method.
It should be added that the e.e value mentioned in the present invention is a conventionally understood meaning, and can be calculated by multiplying (R-S)/(R + S) by 100%, and will not be described in detail herein.
Specifically, the first organic solvent is selected from any one or more of acetonitrile, ethyl acetate, dichloromethane and tetrahydrofuran; preferably, the first organic solvent is dichloromethane and/or ethyl acetate; the mixing of the dextro-ilaprazole potassium salt to be purified and the first organic solvent is carried out by stirring for 1-4h at the temperature of 20-30 ℃, and the obtained mixture is slurry. The first organic solvents can form slurry with the dexilaprazole potassium salt, the dexilaprazole potassium salt dextroisomer enters a liquid phase after stirring for a certain time, and the liquid phase is separated by filtering.
In a preferred embodiment, the first organic solvent is dichloromethane; preferably, the dosage of dichloromethane corresponding to each gram of the dexilaprazole potassium salt to be purified is 4-12 mL; more preferably 4-8 mL. In a preferred embodiment, the first organic solvent is ethyl acetate; preferably, the dosage of the ethyl acetate corresponding to the dexilaprazole potassium salt to be purified per gram is 6-16 mL; more preferably 12-16 mL. The e.e value of the product can be influenced to a certain extent by the dosage of the first organic solvent, if the dosage of the first organic solvent is too large or too small, the e.e value of the product can be influenced, and the e.e value of the product can be further promoted by the dichloromethane and the ethyl acetate.
S2 reaction step
Mixing the dextro-ilaprazole potassium salt mother liquor, water, a second organic solvent and reaction acid for reaction. The method is characterized in that the dexilaprazole potassium salt is used as a reaction raw material, the reaction raw material is dissolved and then reacts with reaction acid to generate the dexilaprazole, and water and a second organic solvent are used for playing a role in dissolving assistance to avoid the precipitation of the dexilaprazole. The inventors have found that the potassium salt can be converted to the hydrogen salt and precipitation can be prevented by the reaction method of the present invention.
In the step of mixing and reacting the right-handed ilaprazole potassium salt mother liquor and the acid for reaction, the pH of the reaction mixed solution is 8-9, and the pH can be controlled by regulating and controlling the dosage of the acid for reaction. Preferably, the reacting acid is a weak acid; more preferably, the acid for reaction is any one selected from dilute acetic acid, phosphoric acid, potassium dihydrogen phosphate and ammonium chloride; more preferably dilute acetic acid. In general, weak acid can achieve the reaction purpose, and the dilute acetic acid is easy to obtain, so that the e.e value of the obtained product is also ideal. Specifically, the step of mixing and reacting the dextrorotatory ilaprazole potassium salt mother liquor with the reaction acid is quickly completed without long time.
Further, the second organic solvent is selected from any one or more of methanol, ethanol and isopropanol; methanol is preferred. The second organic solvent and water play a role in assisting dissolution, so that the generated dexilaprazole is positioned in a liquid phase, and the purpose can be achieved by adopting the raw materials.
S3, purification step
And extracting the reacted mixed solution, and mixing the organic phase obtained by extraction with a third organic solvent to precipitate the dexilaprazole. And (3) extracting by adopting a solvent capable of dissolving the dexilaprazole, and mixing the extracted organic phase with a third organic solvent incapable of dissolving the dexilaprazole to separate out the dexilaprazole so as to obtain a product with higher purity.
Specifically, the organic solvent used in the extraction process is dichloromethane, and the inventors found that the yield of the product can be significantly improved by using dichloromethane, but other organic solvents have an influence on the yield, which is probably because the dichloromethane can well dissolve dexilaprazole, so that the product is separated out and located in an organic phase.
Preferably, a drying agent is added to the organic phase obtained by the extraction before the organic phase is mixed with the third organic solvent, and then the organic phase is filtered, and the filtrate is dried by spinning. Residual moisture in the organic phase can be removed through the drying agent, the drying agent is removed through filtration, and finally the solvent is completely removed through rotary evaporation by using a rotary evaporator.
Further, the third organic solvent is selected from isopropanol and/or acetonitrile, preferably isopropanol. The solubility of the dexilaprazole in isopropanol or acetonitrile is weak, so that the dexilaprazole can be precipitated and further purified. Preferably, the amount of the third organic solvent used per gram of the dexilaprazole potassium salt to be purified is 8-10mL, and the mixing of the organic phase and the third organic solvent is performed under stirring at a temperature of 20-30 ℃. The excessive use amount of the third organic solvent causes raw material waste, and the excessive use amount cannot completely separate out the dexilaprazole, thereby affecting the product yield.
The embodiment of the invention also provides the dexilaprazole prepared by applying the preparation method of the dexilaprazole. The dexilaprazole prepared by the method has a very high e.e value which is approximately 98.0-99.5%; the preparation method is simple and easy to implement, and the amount of the required organic solvent is less, so that the production cost can be obviously reduced.
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1
The embodiment provides a preparation method of dexilaprazole, which comprises the following steps:
2.00g of (+) -ilaprazole potassium salt (e.e 79.4%) was taken, 24ml of dichloromethane was added, and beating was performed at 20 ℃ for 4 hours. And filtering out a filtrate, adding 10mL of water and 8mL of methanol after the filtrate is dried in a rotary manner, uniformly stirring, adding dilute acetic acid to adjust the pH value to 8.0, adding dichloromethane to extract twice, adding 10mL of dichloromethane each time, combining organic phases, adding anhydrous magnesium sulfate and triethylamine, drying for 30mins, filtering, adding 16mL of isopropanol after the filtrate is dried in a rotary manner, stirring for 1.5h at the temperature of 20-30 ℃, filtering to obtain (+) -ilaprazole solid, weighing 0.79g after vacuum drying, measuring the e.e value to be 99.3%, measuring the product yield in the (+) -ilaprazole potassium salt mother liquor to be 49%, and measuring the yield of the (+) -ilaprazole solid in the final product to be 79.8%.
In the present invention, the yield of the (+) -ilaprazole potassium salt mother liquor and the yield of (+) -ilaprazole solid in the final product are calculated as follows:
the method for calculating the product yield in the (+) -ilaprazole potassium salt mother liquor comprises the following steps: filtering out ilaprazole potassium salt mother liquor after pulping, drying the obtained solid in vacuum for 16h, and weighing the solid to M, wherein the weight of the ilaprazole potassium salt as a raw material is M, and the yield is as follows:
the calculation method of the yield of (+) -ilaprazole solid in the final product is as follows: (final weight of (+) -ilaprazole solid/weight ilaprazole in mother liquor) x 100%.
Example 2
The embodiment provides a preparation method of dexilaprazole, which comprises the following steps: 2.00g of (+) -ilaprazole potassium salt (e.e 79.4%) was taken, 24ml of dichloromethane was added, and beating was performed at 30 ℃ for 1 hour. And then filtering out a filtrate, adding 10mL of water and 8mL of methanol after the filtrate is dried in a rotary manner, uniformly stirring, adding diluted acetic acid to adjust the pH value to 8.0, adding dichloromethane to extract twice, adding 10mL of dichloromethane each time, combining organic phases, adding anhydrous magnesium sulfate and triethylamine, drying for 30mins, filtering, adding 16mL of acetonitrile after the filtrate is dried in a rotary manner, stirring for 1.5h at the temperature of 20-30 ℃, filtering to obtain (+) -ilaprazole solid, weighing 0.75g after vacuum drying, and measuring the e.e value to be 99.0%, wherein the product yield in the (+) -ilaprazole potassium salt mother liquor is 51% and the yield of the (+) -ilaprazole solid is 81.3%.
Examples 3 to 6
The embodiment provides a preparation method of dexilaprazole, which has the same specific steps as those of embodiment 2 except that: the solvent, the volume of the solvent and the pulping time used for pulping in the preparation of the dexilaprazole potassium salt mother liquor are shown in table 1.
TABLE 1 details of the beating procedure in examples 3-6
Examples 7 to 11
The embodiment provides a preparation method of dexilaprazole, which comprises the following steps:
0.9g of (+) -ilaprazole potassium salt (e.e 77%) is taken, a volume of dichloromethane is added, and the mixture is pulped for about 16h at 30 ℃. Subsequent procedures referring to example 2, the volumes of methylene chloride corresponding to examples 7 to 11 were 3.6mL, 7.2mL, 9.0mL, 10.8mL and 16.2mL in this order; the beating times in examples 7-11 were 16.4h, 16.45h, 16.5h, 16.55h and 16.6h, respectively.
Examples 12 to 16
The embodiment provides a preparation method of dexilaprazole, which comprises the following steps:
0.9g of (+) -ilaprazole potassium salt (e.e 77%) is taken, a volume of ethyl acetate is added, and the mixture is pulped for about 16h at 30 ℃. Subsequent procedures referring to example 2, the volumes of ethyl acetate corresponding to examples 12 to 16 were 7.2mL, 9.0mL, 12.6mL, 14.4mL and 18mL in this order; the beating times in examples 12-16 were 16.0h, 16.05h, 16.10h, 16.15h and 16.20h, respectively.
Examples 17 to 20
This example provides a method for preparing dexilaprazole, which comprises the steps substantially the same as those of example 2, except that the e.e value of the dexilaprazole potassium salt as the raw material, and the e.e values in examples 17 to 20 are 70.6, 75.8, 78.7 and 80.5, respectively.
Comparative example 1
The comparative example provides a preparation method of high optical purity ilaprazole potassium salt, comprising the following steps:
taking (+) -ilaprazole potassium salt (e.e 73.1%, oily matter), spin-drying the solvent, adding 1.2 equivalents of KOH and 8mL of methanol relative to the mass of each gram of ilaprazole into the oily matter, stirring for a certain time to precipitate racemic potassium salt (e.e value is 0-10%), and filtering. The filtrate detected an e.e value of 92.0%.
Comparative example 2
The comparative example provides a preparation method of high optical purity ilaprazole potassium salt, comprising the following steps:
taking (+) -ilaprazole potassium salt (e.e 75.4%, oily matter), spin-drying the solvent, adding 1.2 equivalents of KOH and 8mL of methanol relative to the mass of each gram of ilaprazole into the oily matter, stirring for a certain time to precipitate racemic potassium salt (e.e value is 0-10%), and filtering. The filtrate detected an e.e value of 86.2%.
Comparative example 3
The comparative example provides a preparation method of high optical purity ilaprazole potassium salt, comprising the following steps:
taking (+) -ilaprazole potassium salt (e.e 76.6%, oily matter), spin-drying the solvent, adding 1.2 equivalents of KOH and 8mL of methanol relative to the mass of each gram of ilaprazole into the oily matter, stirring for a certain time to precipitate racemic potassium salt (e.e value is 0-10%), and filtering. The filtrate tested an e.e value of 88.6%.
Comparative example 4
The comparative example provides a preparation method of dexilaprazole, which comprises the following specific steps of: the solvent, the volume of the solvent and the pulping time are used for pulping in the preparation of the dextro-ilaprazole potassium salt mother liquor, the pulping solvent is methanol, and the pulping time is 16.15 h.
Comparative example 5
The comparative example provides a preparation method of dexilaprazole, which comprises the following specific steps of: solvent, solvent volume and pulping time used in pulping in the preparation of the dextro-ilaprazole potassium salt mother liquor, wherein the pulping solvent is methyl tert-butyl ether, and the pulping time is 16.2 h.
Test example 1
The filtrates of comparative examples 1-3 were tested for e.e values. The e.e values of the filtrates of comparative examples 1-3 were 92.0%, 86.2% and 88.6% in that order. The experimental results in the group show that the e.e value of the (+) -ilaprazole potassium salt in the mother liquor cannot be effectively improved by adding the solvent methanol and stirring for crystallization, the e.e value of the (+) -ilaprazole potassium salt in the mother liquor is still low, the difference among the experiments in each group is large, and the result is unstable. Therefore, the solvent disclosed in the prior art is used to selectively promote the crystallization of the raceme so as to increase the content of a single enantiomer in the mother solution, and is not suitable for the ilaprazole system.
Test example 2
The e.e values of the filtrates obtained after the beating filtration in test examples 3 to 6 and comparative examples 4 to 5 were as shown in Table 2.
Table 2 e values of the dexilaprazole potassium salt in the mother liquor when slurrying with different solvents
As can be seen from table 2, when the solvent is methanol, the e.e value of the dexilaprazole potassium salt in the mother liquor cannot be increased, and when the solvent is acetonitrile, ethyl acetate, dichloromethane, and tetrahydrofuran, the e.e value of the mother liquor can be increased to a certain extent, wherein the e.e value of the dexilaprazole potassium salt can be increased to more than 98% by ethyl acetate and dichloromethane.
Test example 3
The e.e values of the filtrates obtained after beating and filtering in test examples 7-20, the e.e values of the dexilaprazole obtained in the final preparation, and the product yield results are shown in table 3.
Table 3 d-ilaprazole potassium salt mother liquor and d-ilaprazole e.e value test results
The test results of examples 7-16 show that when the amount of dichloromethane added is 4-12mL, especially 4-8mL, relative to the mass (g) of (+) -ilaprazole potassium salt, the e.e value of the mother liquor can be increased to more than 98.5%, the yield of the product in the mother liquor reaches more than 50%, and the yield of the purified product in the mother liquor reaches more than 80%; when the addition amount of ethyl acetate is 8-20mL, particularly 12-20mL, relative to the mass (g) of (+) -ilaprazole potassium salt, the e.e value of the mother liquor is increased to more than 98.0%.
The test results of examples 17-20 show that the e.e value of the raw material (+) -ilaprazole potassium salt is 70.6%, 75.8%, 78.7% and 80.5%, the e.e value can be increased to about 99.0% by adopting the method of the invention, and the e.e value of the product is not limited by the e.e value of the raw material.
In conclusion, according to the preparation method of the mother liquor of the dexilaprazole potassium salt, provided by the invention, the dexilaprazole potassium salt is left in the liquid phase through the selection of the organic solvent, and impurities are removed through filtration, so that the e.e value of the dexilaprazole potassium salt in the mother liquor is obviously improved.
The embodiment of the invention also provides a preparation method of the dexilaprazole, which comprises the steps of reacting the mother liquor serving as a raw material with a reaction acid to generate the dexilaprazole, performing a dissolving assisting effect by using water and a second organic solvent to avoid the precipitation of the dexilaprazole, and then purifying the dexilaprazole. The obtained dexilaprazole has a very high e.e value, is not influenced by the e.e value of the dexilaprazole potassium salt, and has a stable product e.e value and small batch difference; the method is simple and easy to implement in synthesis process, is suitable for popularization and application, and does not need a large amount of organic solvents. The invention also provides the dexilaprazole which is prepared by the preparation method of the dexilaprazole and has a very high e.e value.
The embodiments described above are some, but not all embodiments of the invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the invention as claimed, but is merely representative of selected embodiments of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Claims (24)
1. A preparation method of a dextro-ilaprazole potassium salt mother liquor is characterized by comprising the following steps:
mixing and pulping the dextro-ilaprazole potassium salt to be purified and a first organic solvent, and performing solid-liquid separation to obtain a dextro-ilaprazole potassium salt mother liquor enriched with the dextro-ilaprazole potassium salt;
wherein the first organic solvent is selected from any one or more of acetonitrile, ethyl acetate, dichloromethane and tetrahydrofuran.
2. The method according to claim 1, wherein the first organic solvent is dichloromethane and/or ethyl acetate.
3. The method for preparing dexilaprazole according to claim 1, wherein the mixing of the potassium salt of dexilaprazole and the first organic solvent is performed by stirring at a temperature of 20 to 30 ℃ for 1 to 17 hours, and the potassium salt of dexilaprazole forms a slurry with the first organic solvent.
4. The process according to claim 3, wherein the stirring time is 1 to 4 hours.
5. The method of claim 1, wherein the first organic solvent is methylene chloride.
6. The method according to claim 5, wherein the amount of dichloromethane per gram of the dexilaprazole potassium salt to be purified is 4 to 12 mL.
7. The method according to claim 5, wherein the amount of dichloromethane per gram of the dexilaprazole potassium salt to be purified is 4-8 mL.
8. The method of claim 1, wherein the first organic solvent is ethyl acetate.
9. The method according to claim 8, wherein the amount of ethyl acetate per gram of the dexilaprazole potassium salt to be purified is 6-16 mL.
10. The method according to claim 8, wherein the amount of ethyl acetate per gram of the dexilaprazole potassium salt to be purified is 12-16 mL.
11. A preparation method of dexilaprazole is characterized by comprising the following steps:
the method of any one of claims 1 to 10, wherein the method comprises the steps of preparing a mother solution of the D-ilaprazole potassium salt, mixing and reacting the mother solution of the D-ilaprazole potassium salt, water, a second organic solvent and a reaction acid, and purifying the D-ilaprazole in the mixed solution after the reaction.
12. The method of preparing dexilaprazole of claim 11, wherein the purification of dexilaprazole comprises: and extracting the reacted mixed solution, and mixing the organic phase obtained by extraction with a third organic solvent to precipitate the dexilaprazole.
13. The process for preparing dexilaprazole of claim 11, wherein in the step of mixing the mother solution of a potassium salt of dexilaprazole with the reaction acid, the pH of the reaction mixture solution is 8 to 9.
14. The method of preparing dexilaprazole of claim 13, wherein the acid used in the reaction is a weak acid.
15. The method for preparing dexilaprazole of claim 13, wherein the acid for reaction is any one selected from the group consisting of dilute acetic acid, phosphoric acid, monopotassium phosphate, and ammonium chloride.
16. The method of preparing dexilaprazole of claim 15, wherein the acid used in the reaction is dilute acetic acid.
17. The method for preparing dexilaprazole of claim 11, wherein the second organic solvent is selected from any one or more of methanol, ethanol, and isopropanol.
18. The method of preparing dexilaprazole of claim 17, wherein the second organic solvent is methanol.
19. The process for preparing dexilaprazole of claim 12, wherein the organic solvent used in the extraction is dichloromethane.
20. The process for preparing dexilaprazole of claim 12, wherein the third organic solvent is selected from isopropanol and/or acetonitrile.
21. The method of preparing dexilaprazole of claim 20, wherein the third organic solvent is isopropanol.
22. The method of preparing dexilaprazole of claim 20 wherein the amount of said third organic solvent per gram of dexilaprazole potassium salt to be purified is 8-10 mL.
23. The process for preparing dexilaprazole as claimed in claim 12, wherein a drying agent is added to the organic phase obtained by extraction before the organic phase is mixed with the third organic solvent, followed by filtration and spin drying of the filtrate.
24. The process for preparing dexilaprazole of claim 23, wherein the mixing of the organic phase with the third organic solvent is performed under stirring at a temperature of 20 to 30 ℃.
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| CN106045975A (en) * | 2016-05-05 | 2016-10-26 | 丽珠医药集团股份有限公司 | A preparing method for high-purity ilaprazole sodium |
| CN108794451A (en) * | 2017-04-26 | 2018-11-13 | 深圳市华先医药科技有限公司 | A kind of synthesis of chiral Iprazole method |
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| CN105566294A (en) * | 2014-10-08 | 2016-05-11 | 江苏奥赛康药业股份有限公司 | D-ilaprazole sodium compound and pharmaceutical composition thereof |
| CN106045975A (en) * | 2016-05-05 | 2016-10-26 | 丽珠医药集团股份有限公司 | A preparing method for high-purity ilaprazole sodium |
| CN108794451A (en) * | 2017-04-26 | 2018-11-13 | 深圳市华先医药科技有限公司 | A kind of synthesis of chiral Iprazole method |
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