CN109912569B - Novel preparation method of esomeprazole magnesium trihydrate and intermediate thereof - Google Patents
Novel preparation method of esomeprazole magnesium trihydrate and intermediate thereof Download PDFInfo
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Abstract
The invention relates to a novel preparation method of esomeprazole magnesium trihydrate and an intermediate thereof, belonging to the pharmaceutical technology, wherein the preparation method comprises the steps of (1) carrying out condensation reaction to prepare omeprazole thioether, (2) carrying out chiral oxidation reaction to prepare esomeprazole; performing a potassium salt forming reaction to prepare esomeprazole potassium; ion exchange reaction to prepare the esomeprazole magnesium trihydrate. The method has the advantages of high product yield and purity, mild and safe reaction conditions, low energy consumption, easy control and suitability for industrial mass production.
Description
Technical Field
The invention relates to a chemical synthesis technology, in particular to a new preparation method of esomeprazole magnesium trihydrate and an intermediate thereof.
Background
Esomeprazole magnesium trihydrate, chemical name: bis-S-5-methoxy-2 { [ (4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl]Sulfinyl } -1H-benzimidazole magnesium trihydrate. Molecular formula C34H36MgN6O6S2·3H2O, molecular weight 767.1, the indication is gastroesophageal reflux disease, and helicobacter pylori can be eradicated by combining with proper antibiotics. Because of good performance of medicine property and convenient administration route, the Chinese medicinal composition is favored in clinical use.
The synthetic route generally comprises the ion exchange reaction of an intermediate esomeprazole sodium salt or potassium salt and a magnesium salt; the purity, yield and the like of the finished product depend on the reaction conditions adopted in the synthetic route, and whether the adopted reagents and the intermediates esomeprazole and esomeprazole sodium/potassium salt participating in the reaction are refined and the synthetic process thereof. In mass production, the synthetic route has feasibility by considering more factors, and the quality and the economic benefit are considered.
The preparation method of the intermediate esomeprazole is mainly divided into a biological enzyme catalytic oxidation method, a racemate omeprazole resolution method and an asymmetric catalytic oxidation method. The main drawback of the bio-enzyme catalytic oxidation method is that the operation is complicated and the cost is high, which is not suitable for mass production (as described in WO 9617076); however, the racemic omeprazole resolution method has the disadvantages that the yield is too low, and the resolution reagent used is generally toxic and expensive, so that the racemic omeprazole resolution method is not friendly to production personnel and environment (as described in CN 200980126581.0); the asymmetric catalytic oxidation method is generally considered to be more convenient and simpler than the two methods, has higher yield and is suitable for industrial production.
However, in view of the asymmetric catalytic oxidation synthesis methods reported at present (for example), the synthesis processes need to be improved in terms of economic efficiency, environmental friendliness, easier control and operation while considering the product quality. For example, CN104803978A discloses a method for preparing esomeprazole magnesium, wherein the temperature control range required by each step is from-20 ℃ to reflux temperature, and under the condition of mass production, the control of the reaction process is difficult, and the purity and yield as recorded in the data are difficult to obtain; CN104447699A also discloses a preparation method of esomeprazole magnesium trihydrate, the required highest reaction temperature needs to reach 70 ℃, the required temperature control range is between 0 and 70 ℃, and the control of the reaction process is difficult; and acetonitrile is added in the refining and purification of the intermediate potassium salt and is heated to 60-65 ℃ and stirred for 2.5 hours, but the acetonitrile is volatile, toxic and flammable and has potential safety hazard. According to the patent application publication, 4L acetonitrile is required for its preparation of 0.8 kg esomeprazole potassium; if the method is used for mass production according to the proportion, a large amount of acetonitrile is consumed in the production process; in addition, some steps of the method require temperatures as high as 70 ℃, which can anticipate that the potential safety hazard is easily escalated, and causes pollution to the environment and threats to the health of personnel in the production environment.
Disclosure of Invention
According to the improvement requirement of the preparation process of the esomeprazole magnesium trihydrate and the intermediate thereof in the field, the invention provides the synthesis method which is more mild in reaction conditions, simple and easily controlled in steps, environment-friendly and safe, thereby being suitable for large-scale industrial mass production under the condition of ensuring the yield and quality of the product.
The technical scheme of the invention is as follows:
in a first aspect, the invention provides a process for the preparation of esomeprazoleWhich is characterized by comprising
(1) Condensation reaction to prepare omeprazole thioether:
adding 95% ethanol into a reaction kettle, adding sodium hydroxide under the protection of nitrogen, controlling the temperature of the reaction solution to be 15-25 ℃, and sequentially adding 2-mercapto-5-methoxybenzimidazole, olmesartan chloride and potassium iodide; slowly heating to 50-55 ℃, keeping the temperature for reaction for 30 minutes to complete the condensation reaction, and purifying the product under the condition that the PH value is about 7 to obtain omeprazole thioether after purification;
the reaction equation is:
(2) chiral oxidation reaction, preparing esomeprazole:
omeprazole thioether is dissolved in toluene, a chiral reaction system is formed by adding diethyl D-tartrate and isopropyl titanate toluene solution, and the mixture is subjected to reaction at the temperature of 50 +/-3 ℃ for 30-60 minutes; cooling to 15-20 ℃, adding organic base, continuously cooling to 10-15 ℃, adding an oxidant, and completing chiral oxidation reaction at 25-30 ℃ to obtain an omeprazole reaction solution;
the reaction equation is as follows:
the organic base is selected from diisopropylethylamine, triethylamine, pyridine, 2, 6-dimethylpyridine or DBU.
The oxidant is selected from cumene hydroperoxide, toluene, tert-butyl hydroperoxide or hydrogen peroxide.
Preferably, in the condensation reaction, the following steps are included:
(1) adding 95% ethanol into a reaction kettle, adding sodium hydroxide under the protection of nitrogen, stirring and dissolving, controlling the temperature of the reaction solution to be 15-25 ℃, and sequentially adding 2-mercapto-5-methoxybenzimidazole, olmesartan chloride and potassium iodide; slowly heating to 50-55 ℃, and reacting for 30 minutes under the condition of heat preservation;
(2) sampling was monitored by TLC method with a developing solvent of 1:1, ethyl acetate and n-hexane are added until the 2-mercapto-5-methoxybenzimidazole spots disappear, the reaction is finished, and the next step of treatment is carried out;
(3) concentrating under reduced pressure at 45-50 ℃ to remove ethanol, adding ice water into the residue, and adjusting the pH value to be about 7 by using hydrochloric acid;
(4) adding dichloromethane, stirring for 15 minutes, standing for layering, and separating a dichloromethane layer; the aqueous layer was extracted three times with dichloromethane; combining dichloromethane phases, washing twice with purified water, washing twice with saturated saline, adding anhydrous sodium sulfate, and drying for 2 hours; filtration, and concentration of the filtrate under reduced pressure to a pale yellow dope, omeprazole thioether.
Preferably, the molar ratio between 2-mercapto-5-methoxybenzimidazole, olmesartan chloride, sodium hydroxide and potassium iodide in step (1) of the condensation reaction is 1:1.02:2.27: 0.027.
Preferably, the amount of 95% ethanol used in step (1) of the condensation reaction is 7 times by mass as much as that of the ormea chloride, or 8.8 times by mass as much as that of the 2-mercapto-5-methoxybenzimidazole.
Preferably, the amount of ice water added in step (3) of the condensation reaction is 5.55 times by mass as much as that of the ormea chloride.
Preferably, in the chiral oxidation reaction, the steps are as follows:
(1) adding toluene into the omeprazole thioether, heating to 45-50 ℃, stirring and dissolving completely, transferring into a 500L reaction kettle, and starting nitrogen protection;
(2) heating to 50 +/-3 ℃, adding purified water and diethyl D-tartrate, and reacting for 20min under the condition of heat preservation;
(3) slowly dripping the isopropyl titanate toluene solution, keeping the temperature of the reaction solution at 50 +/-3 ℃, and stirring for reaction for 50-60 min;
(4) cooling the reaction solution to 15-20 ℃, and adding an organic base (such as diisopropylethylamine, triethylamine, pyridine, 2, 6-dimethylpyridine or DBU); continuously cooling, and slowly dropwise adding a cumene hydroperoxide toluene solution at the temperature of 10-15 ℃; and after the dropwise adding, heating to 25-30 ℃ for reacting for 2 hours, sampling and detecting, and when the concentration of the omeprazole thioether spots in the reaction liquid is lower than that of the omeprazole thioether spots in the control liquid, indicating that the chiral oxidation reaction is completed, thus obtaining the esomeprazole reaction liquid.
Preferably, in the step (1) of the chiral oxidation reaction, toluene is added in an amount of 4 times the mass of omeprazole sulfide.
Preferably, in the step (2) of the chiral oxidation reaction, the molar ratio of the added water, diethyl D-tartrate and omeprazole thioether is 0.14: 0.3-0.6: 1; preferred molar ratios are 0.14:0.4: 1.
preferably, in step (3) of the chiral oxidation reaction, the isopropyl titanate toluene solution is a solution of isopropyl titanate dissolved in toluene at a mass ratio of 0.7-0.85:1, preferably, for example, 0.75-0.8: 1, in particular 0.78: 1; the amount of isopropyl titanate toluene added is such that the molar ratio of isopropyl titanate to omeprazole thioether is from 0.3 to 0.6: 1
Preferably, in the step (4) of the chiral oxidation reaction, the molar ratio of the organic base to the omeprazole thioether is 0.25-35: 1, preferably 0.3: 1.
preferably, in the step (4) of the chiral oxidation reaction, the cumene hydroperoxide toluene solution is a solution of cumene hydroperoxide dissolved in toluene, and the mass ratio of the cumene hydroperoxide toluene solution to the toluene is 0.30-0.45: 1, preferably, for example, 0.35 to 0.4: 1, in particular 0.385: 1; the molar ratio of the cumene hydroperoxide solution added in the step (2) to the omeprazole thioether is 0.95: 1, the mass ratio is 0.52: 1.
in another aspect, the present invention provides a method for preparing esomeprazole potassium salt, which is characterized by comprising the following steps
Step (ii) of
(1) Adding a potassium hydroxide methanol solution into a reaction kettle filled with omeprazole reaction liquid cooled to below 10 ℃; the reaction equation is
(2) Heating to 25-30 ℃ to separate out solids, stirring and reacting for 2 hours; filtration and cake mixing with toluene methanol 1:1 pulping the mixed solution for 20-40 minutes, and filtering;
(3) drying the filter cake under reduced pressure at 40-45 ℃ to obtain a crude product of esomeprazole potassium; sampling and inspecting the crude esomeprazole potassium, and entering the next step after the crude esomeprazole potassium which meets the quality control standard (the quality control standard of the intermediate 2).
Wherein the intermediate 2 comprises the following quality control standards: if an impurity peak exists in a chromatogram of a test solution, the area of an intermediate I (omeprazole thioether) is not larger than the area (0.5%) of a main peak of an impurity control solution, the impurity D with the retention time of about 0.95 relative to the main peak is not larger than 3.0% according to the area normalization method, other single impurity peaks are not larger than 1.5% according to the area normalization method, the total amount of impurities is not larger than 5.0%, and the ratio of the peak area of an optical isomer to the sum of the peak areas of the optical isomer and esomeprazole is not larger than 1.0%.
(4) Adding acetone into another reaction kettle, adding a crude esomeprazole potassium product under the protection of nitrogen, stirring, heating to 45-50 ℃, adding activated carbon, and keeping the temperature and decoloring for half an hour;
(5) filtering to remove active carbon, and concentrating under reduced pressure at 45-50 ℃ to remove acetone; adding methanol into the residue, stirring and heating to 45-50 ℃, and keeping the temperature for 1 hour;
(6) naturally cooling to 20-30 ℃, and filtering to obtain a white solid; and (3) pulping the solid for 30 minutes by using methanol, filtering, drying at 45-50 ℃ under reduced pressure for 5 hours, sampling and checking the obtained product to obtain esomeprazole potassium suitable for the ion exchange reaction, wherein the sampling and checking of the product meet the quality standard (namely the quality control standard of the intermediate 3), and repeating the steps (4) - (6) on the product which does not meet the quality standard.
And (3) intermediate 3 quality standard: if an impurity peak exists in a chromatogram of the test solution, the content of the impurity D (about 0.95 relative to the retention time of a main peak) is not more than 0.2 percent calculated by an area normalization method, other single impurity peaks are not more than 0.1 percent calculated by the area normalization method, and the total content of the impurity is not more than 0.5 percent; the ratio of the peak area of the optical isomer to the sum of the peak areas of the optical isomer and esomeprazole is not more than 0.2%.
Preferably, in the step (1) of the potassium salt-forming reaction, the methanolic potassium hydroxide solution is a solution of potassium hydroxide dissolved in methanol at a mass ratio of 1:5-8, preferably 1: 6-7, in particular 1: 6.76; the molar ratio of potassium hydroxide methanol to omeprazole sulfide added in step (1) is 1.45: 1, the mass ratio is 0.27: 1.
preferably, in the step (2) of the potassium salt forming reaction, the amount of the toluene-methanol mixed solution added is such that the mass ratio of omeprazole sulfide to the methanol/toluene mixed solvent is 1:1.4, i.e., 1:0.7 to methanol and 1:0.7 to toluene.
Preferably, the amount of acetone added in step (4) of the potassium salt forming reaction is such that the mass ratio of acetone to crude esomeprazole potassium salt is 12: 1.
Preferably, the amount of methanol added in step (5) of the potassium salt forming reaction is such that the mass ratio of methanol to crude esomeprazole potassium salt is 3.5: 1.
Preferably, the mass ratio of the amount of methanol added in the step (6) of the potassium salt-forming reaction to the crude potassium salt is 1:1.
In another aspect of the present invention, there is provided a process for preparing esomeprazole magnesium trihydrate,
comprises the following steps:
(1) adding pure water into a reaction kettle containing esomeprazole potassium, stirring and dissolving, carrying out filter pressing to the reaction kettle in a clean area, and carrying out nitrogen protection;
(2) heating to 35-40 ℃, dropwise adding the magnesium chloride hexahydrate aqueous solution, keeping the temperature and stirring for 3-4 hours after the dropwise adding is finished, filtering,
(3) and pulping and washing the filter cake by using purified water, and drying for 10-15 hours in a fluidized bed dryer at 45-50 ℃ to obtain the finished product of the esomeprazole magnesium.
In the chromatogram of the esomeprazole potassium, if an impurity peak is contained, the impurity D (the retention time of the relative main peak is about 0.95) is not more than 0.2% calculated according to an area normalization method, other single impurity peaks are not more than 0.1% calculated according to the area normalization method, and the total amount of impurities is not more than 0.5%; the ratio of the peak area of the optical isomer to the sum of the peak areas of the optical isomer and esomeprazole is calculated, and is not more than 0.2%.
Preferably, in the step (1), the weight ratio of esomeprazole potassium to pure water is 1: 5-10.
A process for the preparation of esomeprazole magnesium trihydrate, comprising
(1) Preparing esomeprazole: a process for preparing esomeprazole using any of the foregoing;
(2) preparation of esomeprazole potassium: adopting any one of the preparation methods of the esomeprazole potassium;
(3) ion exchange reaction to prepare esomeprazole magnesium trihydrate: the preparation method of any of the aforementioned esomeprazole magnesium trihydrate is adopted.
In the invention, 95% ethanol is adopted in the condensation reaction, all raw materials can be dissolved in the ethanol, so that the whole system is subjected to homogeneous reaction, the reaction time is shortened, the reaction yield is improved, and the yield reaches over 95%. The reaction temperature only needs to reach 50-55 ℃, which is 5-10 ℃ lower than the temperature needed by the prior similar technologies, thus reducing the energy consumption; the PH value of the reaction is 7, the reaction system is mild, the PH value does not need to be adjusted repeatedly, the pH value can be adjusted in place by adding hydrochloric acid, and the operation is simple and convenient.
In the chiral oxidation reaction, the reaction temperature is about 50 ℃, the temperature is 5-10 ℃ lower than the temperature required by the prior similar technology, the energy consumption is reduced, the reaction temperature required when the organic base is added and the temperature in the process of adding the oxidant and the temperature for finishing the chiral oxidation reaction are respectively 15-20 ℃, 10-15 and 25-30 ℃, and the precise screening and design on the reaction temperature can be realized
In the ion exchange reaction, except two chemical reagents of esomeprazole potassium and soluble magnesium salt which participate in the reaction, other solvents are not needed, the reaction temperature is about 35-40 ℃, and in the prior art, the magnesium salt is usually formed in methanol and then reacts in water to form trihydrate; the invention directly carries out ion exchange reaction in water to form the esomeprazole magnesium salt trihydrate in one step. The quality and purity of the obtained potassium salt are ensured in the previous reaction step, so that the purity of the product can be effectively ensured, the obtained magnesium salt is only slightly soluble in water and can be effectively separated out, and the yield can be effectively ensured. In the purification step, other chemical reagents are not needed, and the purified product is obtained by adopting the methods of purification, pulping, washing and drying, and the purity of the product is not influenced.
The invention improves the reactions in each stage in the synthesis route of the esomeprazole magnesium trihydrate, ensures the yield and the product quality, simultaneously ensures that the conditions of the whole synthesis process are milder, simpler, easy to control, safe, low in energy consumption and less in impurities in the synthesis process. Experimental data show that in the condensation reaction, ethanol is used as a reaction solvent, and each reaction material is dissolved in the ethanol, so that the whole reaction system is in a homogeneous reaction, the reaction time is greatly shortened, and the yield of the omeprazole thioether is improved to 100%. In the reaction of potassium salt formation, salifying and crystallizing, filtering and refining the potassium salt to simplify the purification operation, so as to obtain the potassium salt with high purity (the purity is more than or equal to 99.5 percent, and isomers are hardly detected); the esomeprazole magnesium trihydrate is obtained by directly ion exchanging the magnesium salt in water, the operation steps are simplified, the energy consumption and the environmental pollution are reduced, and the quality is high. The method reduces energy consumption and environmental pollution while ensuring yield and quality, and is suitable for mass production.
Drawings
FIG. 1 shows the detection results of the high performance liquid chromatography of omeprazole thioethers prepared by the invention;
FIG. 2 shows the detection results of high performance liquid chromatography for related substances in crude esomeprazole potassium salt prepared by the present invention;
FIG. 3 shows the detection results of the high performance liquid chromatography method for crude esomeprazole potassium salt isomer prepared by the present invention;
FIG. 4 shows the detection results of high performance liquid chromatography for the related substances of esomeprazole potassium salt refined by the present invention;
FIG. 5 shows the detection results of high performance liquid chromatography for related substances of esomeprazole magnesium salt refined by the present invention;
FIG. 6 shows the detection results of high performance liquid chromatography of esomeprazole potassium salt isomer refined by the present invention.
Detailed Description
EXAMPLE 1 preparation of omeprazole thioethers (intermediate 1) by condensation reaction
The reaction equation is as follows:
(1) 102.0kg of 95% ethanol is added into a 200L reaction kettle, 6.2kg of medicinal sodium hydroxide is added under the protection of nitrogen, and the mixture is stirred and dissolved. Controlling the temperature of the reaction solution to be 15-25 ℃, sequentially adding 11.9kg of 2-mercapto-5-methoxybenzimidazole, 15.0kg of olmesartan chloride (67.87 mol) and 0.3kg of potassium iodide, slowly heating to 50-55 ℃, and carrying out heat preservation reaction for 30 minutes;
(wherein the molar ratio of the 2-mercapto-5-methoxybenzimidazole to the olmesartan chloride to the sodium hydroxide to the potassium iodide is 1:1.02:2.27: 0.027; the amount of 95% ethanol is 7 times the mass of the olmesartan chloride, or 8.8 times the mass of the 2-mercapto-5-methoxybenzimidazole).
(2) Sampling and monitoring by a TLC method (a developing agent ethyl acetate: n-hexane ═ 1:1) to remove spots of 2-mercapto-5-methoxybenzimidazole, finishing the reaction and carrying out post-treatment; if the 2-mercapto-5-methoxybenzimidazole spots are still visible, the reaction is continued and samples are taken every 15 minutes for monitoring until the spots disappear.
(3) Concentrating under reduced pressure at 45-50 ℃ to remove ethanol. To the residue, 83.3kg of ice water was added in an amount of 5.55 times by mass as much as that of the ormea chloride, and the pH value was adjusted to about 7 with hydrochloric acid.
(4) Adding 30kg of dichloromethane, stirring for 15 minutes, standing for layering, and separating a dichloromethane layer; the aqueous layer was extracted three times with dichloromethane (16.7 kg x 3 each time). The dichloromethane phases were combined, washed twice with purified water (33.3kg x 2), twice with saturated brine (32.5kg x 2), and dried over 10kg anhydrous sodium sulfate for 2 hours. Filtration and concentration of the filtrate under reduced pressure gave 21.62kg of intermediate 1 (i.e. omeprazole sulfide 64.54mol in the form of a pale yellow dope) with a purity of 98.383% (see FIG. 1). The yield was 64.54/67.87 ═ 95.1%.
Example 2 preparation of Esciprazole by chiral Oxidation
The reaction equation is as follows:
(1) 87.7kg of toluene (the amount of toluene is 4 times of the mass of omeprazole sulfide) is added into 21.62kg of the intermediate I (containing 64.54mol omeprazole sulfide) obtained in example 1, the temperature is raised to 50 ℃, the mixture is stirred and dissolved completely, and then the mixture is transferred into a 500L reaction kettle, and nitrogen protection is started.
(2) Heating to 50 +/-3 ℃, adding 169g of purified water and 5.47kg of diethyl D-tartrate, keeping the temperature for reaction for 20min, slowly dropwise adding a toluene solution of isopropyl titanate (5.79kg of isopropyl titanate is dissolved in 7.4kg of toluene), and stirring and reacting for 50-60 min at the temperature of 50 +/-3 ℃ while maintaining the temperature of the reaction solution. Wherein the molar ratio of the water, the diethyl D-tartrate, the isopropyl titanate and the omeprazole thioether is 0.14:0.4: 0.3: 1.
(3) cooling to 15-20 ℃, and adding 2.66kg of triethylamine. And (3) continuously cooling, slowly dropwise adding a cumene hydroperoxide toluene solution (11.28kg of cumene hydroperoxide is dissolved in 29.3kg of toluene) at the temperature of 10-15 ℃, and heating to 25-30 ℃ after dropwise adding to obtain the esomeprazole. Wherein the molar ratio of the added triethylamine to the omeprazole thioether is 0.3: 1.
sampling after 2 hours, monitoring by a TLC method (developing agent ethyl acetate), wherein the concentration of the intermediate I spot in the reaction liquid is lower than that of the intermediate I spot in the control liquid, and obtaining esomeprazole after the chiral oxidation reaction is finished for entering into a potassium salt forming reaction. If the concentration of the intermediate I spot is higher than that of the intermediate I spot in the control solution, the reaction is continued. Samples were taken every 30 minutes until the control spot concentration was below.
EXAMPLE 3 Potassium salt formation reaction
The reaction equation is as follows:
(1) cooling the esomeprazole reaction solution obtained in example 2 to below 10 ℃, slowly adding a potassium hydroxide methanol solution (5.92kg of potassium hydroxide is dissolved in 40kg of methanol), and precipitating a solid;
(2) heating to 25-30 ℃, stirring and reacting for 2 hours. Filtering, pulping the filter cake for 30 minutes by using a mixed solution of 14.6kg of toluene and 14.6kg of methanol, and filtering;
(3) and drying the filter cake at 40-45 ℃ under reduced pressure to obtain 21.5kg of crude esomeprazole potassium product (intermediate 2, containing 20.90g of esomeprazole potassium and having a molecular weight of 384, namely 54.427mol) with the purity of 97.216% (shown in figure 2), sampling, inspecting, and entering a refining process when the quality control standard of the intermediate 2 is met. If not, performing rework treatment until meeting the quality control standard of the intermediate 2
(wherein, the quality control standard of the intermediate 2 is that if an impurity peak exists in a chromatogram of a test solution, the area of the intermediate I (omeprazole thioether) is not more than the area of a main peak of an impurity control solution (0.5%), the retention time of the impurity D relative to the main peak is about 0.95 is not more than 3.0% calculated by an area normalization method, other single impurity peaks are not more than 1.5% calculated by the area normalization method, the total amount of the impurity is not more than 5.0%, and the ratio of the peak area of the optical isomer to the peak area (the sum of the peak areas of the optical isomer and the esomeprazole) is not more than 1.0% calculated by the area.
The rework processing method comprises the following steps: adding the obtained intermediate 2 into a toluene/methanol mixed solution with the mass volume of 2 times, pulping for 1 hour, and filtering. And drying the filter cake at 40-45 ℃ under reduced pressure.
The crude (intermediate 2) yield was 84.33% ((54.427/64.54) × 100%).
The reaction equation is as follows:
(5) Filtering to remove active carbon, concentrating under reduced pressure at 45-50 deg.C to remove acetone, adding 75.5kg methanol into the residue, stirring, heating to 45-50 deg.C, and maintaining for 1 hr.
(6) Naturally cooling to 20-30 ℃, and filtering to obtain white solid. The solid was slurried with 21.0Kg of methanol for 30 minutes, filtered and dried at 45-50 ℃ under reduced pressure for 5 hours to give 15.0Kg of intermediate 3 with a yield of 69.8% (15/21.5 × 100% ═ 69.8%)
Sampling and inspecting, and entering the next reaction when the quality of the intermediate 3 is met. If not, repeating (steps (4) - (6)) to continue the secondary refining until the quality standard is met.
The intermediate 3 reaches the quality standard: if an impurity peak exists in a chromatogram of the test solution, the content of the impurity D (about 0.95 relative to the retention time of a main peak) is not more than 0.2 percent calculated by an area normalization method, other single impurity peaks are not more than 0.1 percent calculated by the area normalization method, and the total content of the impurity is not more than 0.5 percent; the ratio of the peak area of optical isomer to the sum of the peak areas of optical isomer and esomeprazole is not more than 0.2%
After secondary purification (steps (4) - (6)), 11.5kg of intermediate 3 meeting the quality standard was obtained with a yield of 76.7% (11.5/15 × 100% ═ 76.7%); the total yield of the two purification steps was 53.5% (11.5/21.5 × 100% ═ 53.5%).
Liquid chromatography detection showed 99.78% purity, see figure 4.
Example 4 preparation of Esomeprazole magnesium trihydrate
The reaction equation is as follows:
(1) 102.7kg of purified water and 11.5kg of intermediate 3 prepared in example 3 are added into a 500L reaction kettle, stirred and dissolved, and then pressure-filtered into the 500L reaction kettle in a clean area under the protection of nitrogen.
(2) Heating to 35-40 ℃, dropwise adding magnesium chloride hexahydrate aqueous solution (3.6kg of magnesium chloride hexahydrate is dissolved in 34kg of purified water), keeping the temperature and stirring for 3-4 hours after the dropwise adding is finished, filtering,
(3) and pulping and washing the filter cake by using 34kg of purified water, and drying in a fluidized bed dryer at 45-50 ℃ for 10-15 hours to obtain about 9.0kg of esomeprazole magnesium finished product with the yield of 78.5%. (two molecules of potassium salt gave one molecule of magnesium salt trihydrate with equivalent molecular weight. 9.0/11.52 × 100%: 78.5%)
Quality detection of the product obtained by the method of the invention
1. Detection of omeprazole sulfide obtained by the invention
Detection conditions are as follows: high performance liquid chromatography (China pharmacopoeia 2015 edition fourth department general rule 0512) with octadecylsilane chemically bonded silica (Boston pHlex C18150 mm X4.6 mm 5 μm) as filler; acetonitrile-phosphate buffer solution (pH7.6, 5.2ml of 1mol/L sodium dihydrogen phosphate solution and 63ml of 0.5mol/L disodium hydrogen phosphate solution are taken, and solution diluted to 1000ml by adding water-water (10: 10: 80) is taken as mobile phase A, and acetonitrile-phosphate buffer solution (pH7.6) -water (80: 1: 19) is taken as mobile phase B. Performing gradient elution; the flow rate was 1.0ml per minute and the detection wavelength was 302 nm. Respectively taking 20 μ l of the test solution and the impurity control solution, injecting into a liquid chromatograph, recording chromatogram,
the results are shown in fig. 1, bee table is shown below,
2. detection of esomeprazole potassium salt crude product
(1) And (3) detection of related substances: performing high performance liquid chromatography (0512, the fourth part of the pharmacopoeia 2015 edition) with octadecylsilane chemically bonded silica (Boston pHlex C)18150mm × 4.6mm 5 μm) as a filler; acetonitrile-phosphate buffer solution (pH7.6, 5.2ml of 1mol/L sodium dihydrogen phosphate solution and 63ml of 0.5mol/L disodium hydrogen phosphate solution are taken, and solution diluted to 1000ml by adding water-water (10: 10: 80) is taken as mobile phase A, and acetonitrile-phosphate buffer solution (pH7.6) -water (80: 1: 19) is taken as mobile phase B. Performing gradient elution; the flow rate was 1.0ml per minute and the detection wavelength was 302 nm. And (3) respectively taking 20 mu l of the test solution and the impurity control solution, injecting into a liquid chromatograph, and recording a chromatogram, wherein as shown in figure 2, peaks are shown as follows, the retention time of the esomeprazole potassium salt crude product is 19.603 minutes, and the purity reaches 97.216%.
(2) Detection of isomers: according to the measurement of high performance liquid chromatography (0512 of the fourth portion of the pharmacopoeia 2015 edition), alpha 1-acid glycoprotein bonded silica gel is used as a filling agent, acetonitrile-phosphate buffer solution (pH6.0) (156.0 g/L sodium dihydrogen phosphate solution 70ml and 179.1g/L disodium hydrogen phosphate solution 20ml are mixed, then the mixture is diluted to 1000ml with water, 250ml of the solution is diluted to 1000.0ml with water (65: 435) is used as a mobile phase, the detection wavelength is 302nm, and the flow rate is 0.6ml per minute. As shown in fig. 3, the peaks are shown below, and the crude esomeprazole potassium salt isomer retention time is 4.330 minutes:
3. the detection method of esomeprazole potassium salt and magnesium salt comprises the following steps:
the products to be tested are the intermediate 3 obtained by the invention and the esomeprazole magnesium trihydrate.
(1) Related substances are as follows: performing high performance liquid chromatography (0512, the fourth part of the pharmacopoeia 2015 edition) with octadecylsilane chemically bonded silica (Boston pHlex C)18150mm × 4.6mm 5 μm) as a filler; acetonitrile-phosphate buffer solution (pH7.6, 5.2ml of 1mol/L sodium dihydrogen phosphate solution and 63ml of 0.5mol/L disodium hydrogen phosphate solution are taken, and solution diluted to 1000ml by adding water-water (10: 10: 80) is taken as mobile phase A, and acetonitrile-phosphate buffer solution (pH7.6) -water (80: 1: 19) is taken as mobile phase B. Gradient elution was performed according to the following table; the flow rate was 1.0ml per minute and the detection wavelength was 280 nm. Injecting 20 μ l of the sample solution into a liquid chromatograph, recording chromatogram,
exemplary results for esomeprazole potassium salt are shown in figure 4, with the peaks tabulated below:
the potassium salt used for ion exchange reaction has retention time of 19.562min and purity of 99.781%
Exemplary results for esomeprazole magnesium salt are shown in fig. 5, with the peaks tabulated below:
the retention time of the esomeprazole magnesium trihydrate obtained by the method is 20.282 minutes, and the purity of the esomeprazole magnesium trihydrate reaches 99.977%.
(2) Isomers: according to the measurement of high performance liquid chromatography (0512 of the fourth portion of the pharmacopoeia of China 2015), alpha 1-acid glycoprotein bonded silica gel is used as a filling agent, acetonitrile-phosphate buffer solution (pH6.0) (156.0 g/L sodium dihydrogen phosphate solution 70ml and 179.1g/L disodium hydrogen phosphate solution 20ml are mixed, then the mixture is diluted to 1000ml with water, 250ml of the solution is diluted to 1000.0ml with water (65: 435) is used as a mobile phase, the detection wavelength is 302nm, the flow rate is 0.6ml per minute, as shown in figure 6, and the isomer retention time is 4.709 minutes.
The above detection results show that the product obtained by the method of the invention achieves ideal conditions in terms of quality and purity.
Claims (14)
1. A preparation method for preparing esomeprazole is characterized by comprising the following steps:
(1) condensation reaction to prepare omeprazole thioether:
adding 95% ethanol into a reaction kettle, adding sodium hydroxide under the protection of nitrogen, controlling the temperature of the reaction solution to be 15-25 ℃, and sequentially adding 2-mercapto-5-methoxybenzimidazole, olmesartan chloride and potassium iodide; slowly heating to 50-55 ℃, keeping the temperature for reaction for 30 minutes to complete the condensation reaction, and purifying the product under the condition that the PH value is 7 to obtain omeprazole thioether after purification;
(2) chiral oxidation reaction, preparing esomeprazole:
omeprazole thioether is dissolved in toluene, a chiral reaction system is formed by adding diethyl D-tartrate and isopropyl titanate toluene solution, and the mixture is subjected to reaction at the temperature of 50 +/-3 ℃ for 30-60 minutes; and (3) cooling to 15-20 ℃, adding an organic base, continuously cooling to 10-15 ℃, adding an oxidant, and completing the chiral oxidation reaction at 25-30 ℃ to obtain the esomeprazole reaction solution.
2. The process according to claim 1, wherein the organic base is selected from diisopropylethylamine, triethylamine, pyridine, 2, 6-dimethylpyridine or DBU; the oxidant is selected from cumene hydroperoxide, toluene, tert-butyl hydroperoxide or hydrogen peroxide.
3. The method according to claim 1, wherein the condensation reaction comprises the steps of:
(1) adding 95% ethanol into a reaction kettle, adding sodium hydroxide under the protection of nitrogen, stirring and dissolving, controlling the temperature of the reaction solution to be 15-25 ℃, and sequentially adding 2-mercapto-5-methoxybenzimidazole, olmesartan chloride and potassium iodide; slowly heating to 50-55 ℃, and reacting for 30 minutes under the condition of heat preservation;
(2) sampling was monitored by TLC method with a developing solvent of 1:1, ethyl acetate and n-hexane are added until the 2-mercapto-5-methoxybenzimidazole spot disappears, the reaction is finished, and the next step of treatment is carried out;
(3) concentrating under reduced pressure at 45-50 ℃ to remove ethanol, adding ice water into the residue, and adjusting the pH value to be about 7 by using hydrochloric acid;
(4) adding dichloromethane, stirring for 15 minutes, standing for layering, and separating a dichloromethane layer; the aqueous layer was extracted three times with dichloromethane; combining dichloromethane phases, washing twice with purified water, washing twice with saturated saline, adding anhydrous sodium sulfate, and drying for 2 hours; filtration and concentration of the filtrate under reduced pressure gave a pale yellow viscous mass, i.e. omeprazole thioether.
4. The method according to claim 3, wherein the molar ratio of 2-mercapto-5-methoxybenzimidazole, olmechloride, sodium hydroxide and potassium iodide in the condensation reaction in step (1) is 1:0.95 to 1.1:2.1 to 2.4:0.02 to 0.035.
5. The production method according to claim 3, characterized in that, in the step (1) of the condensation reaction, the molar ratio between 2-mercapto-5-methoxybenzimidazole, olmesartan chloride, sodium hydroxide and potassium iodide is 1:1.02:2.27: 0.027;
the amount of 95% ethanol used in step (1) of the condensation reaction is 6 to 8 times by mass, preferably 7 times by mass, of the amount of the olmesartan chloride; or 8.5 to 9.5 times by mass, preferably 8.8 times by mass, of 2-mercapto-5-methoxybenzimidazole;
the amount of ice water added in the condensation reaction step (3) is 5 to 6 times by mass, preferably 5.55 times by mass, of the amount of the ormea chloride.
6. The method according to claim 1, wherein the chiral oxidation reaction comprises the following steps:
(1) adding toluene into the omeprazole thioether, heating to 45-50 ℃, stirring and dissolving completely, transferring into a 500L reaction kettle, and starting nitrogen protection;
(2) heating to 50 +/-3 ℃, adding purified water and diethyl D-tartrate, and reacting for 20min under the condition of heat preservation;
(3) slowly dripping the isopropyl titanate toluene solution, keeping the temperature of the reaction solution at 50 +/-3 ℃, and stirring for reaction for 50-60 min;
(4) cooling the reaction liquid to 15-20 ℃, and adding organic base; continuously cooling, and slowly dropwise adding a cumene hydroperoxide toluene solution at the temperature of 10-15 ℃; and after the dropwise adding, heating to 25-30 ℃ for reacting for 2 hours, sampling and detecting, and when the concentration of the omeprazole thioether spots in the reaction liquid is lower than that of the omeprazole thioether spots in the control liquid, indicating that the chiral oxidation reaction is completed, thus obtaining the esomeprazole reaction liquid.
7. The production method according to claim 6,
in the step (1), the amount of the added toluene is 3.5-4.5 times of the mass of the omeprazole thioether;
in the step (2), the molar ratio of the added water to the diethyl D-tartrate to the omeprazole thioether is 0.14: 0.3-0.6: 1; preferred molar ratios are 0.14:0.4: 1;
in the step (3) of the chiral oxidation reaction, the isopropyl titanate toluene solution is a solution obtained by dissolving isopropyl titanate in toluene, and the mass ratio of the isopropyl titanate to the toluene is 0.7-0.85: 1; (ii) a The amount of the isopropyl titanate toluene added in the step (3) enables the molar ratio of the isopropyl titanate to the omeprazole thioether to be 0.3-0.6: 1; (ii) a
In the step (4) of the chiral oxidation reaction, the molar ratio of the organic base to the omeprazole thioether is 0.25-35: 1; in the step (4) of the chiral oxidation reaction, the cumene hydroperoxide toluene solution is a solution obtained by dissolving cumene hydroperoxide in toluene, and the mass ratio of the cumene hydroperoxide toluene solution to the toluene is 0.30-0.45: 1; the molar ratio of the cumene hydroperoxide solution added in the step (4) to the omeprazole thioether is 0.95: 1, the mass ratio is 0.52: 1.
8. the production method according to claim 7,
in the step (1), the amount of the added toluene is 4 times of the mass of the omeprazole thioether;
in the step (3) of the chiral oxidation reaction, the isopropyl titanate toluene solution is a solution obtained by dissolving isopropyl titanate in toluene, and the mass ratio of the isopropyl titanate to the toluene is 0.78: 1; the amount of the isopropyl titanate toluene added in the step (3) enables the molar ratio of the isopropyl titanate to the omeprazole thioether to be 0.3: 1;
in the step (4) of the chiral oxidation reaction, the molar ratio of the organic base to the omeprazole thioether is 0.3:1
In the step (4) of the chiral oxidation reaction, the cumene hydroperoxide toluene solution is a solution obtained by dissolving cumene hydroperoxide in toluene, and the mass ratio of the cumene hydroperoxide toluene solution to the toluene is 0.385: 1.
9. the method of claim 6, wherein the organic base is diisopropylethylamine, triethylamine, pyridine, 2, 6-lutidine, or DBU.
10. The preparation method of the esomeprazole potassium salt is characterized by comprising the following steps:
(1) preparing an esomeprazole reaction solution by the preparation method of any one of claims 1-9; (2) adding a potassium hydroxide methanol solution into a reaction kettle filled with an esomeprazole reaction solution cooled to below 10 ℃;
(3) heating to 25-30 ℃ to separate out solids, stirring and reacting for 2 hours; filtration and cake mixing with toluene methanol 1:1 pulping the mixed solution for 20-40 minutes, and filtering;
(4) drying the filter cake under reduced pressure at 40-45 ℃ to obtain a crude product of esomeprazole potassium; sampling and inspecting the esomeprazole potassium crude product, entering the next step,
wherein if an impurity peak exists in the chromatogram of the esomeprazole potassium solution meeting the quality control standard, the omeprazole thioether contained in the esomeprazole potassium solution is not more than 0.5 percent of the area of the main peak of the impurity control solution, the impurity D with the retention time of about 0.95 relative to the main peak is not more than 3.0 percent calculated according to an area normalization method, other single impurity peaks are not more than 1.5 percent calculated according to the area normalization method, the total amount of impurities is not more than 5.0 percent, and the ratio of the peak area of the optical isomer to the sum of the peak areas of the optical isomer and the esomeprazole is not more than;
(5) adding acetone into another reaction kettle, adding a crude esomeprazole potassium product under the protection of nitrogen, stirring, heating to 45-50 ℃, adding activated carbon, and keeping the temperature and decoloring for half an hour;
(6) filtering to remove active carbon, and concentrating under reduced pressure at 45-50 ℃ to remove acetone; adding methanol into the residue, stirring and heating to 45-50 ℃, and keeping the temperature for 1 hour;
(7) naturally cooling to 20-30 ℃, and filtering to obtain a white solid; pulping the solid for 30 minutes by using methanol, filtering, drying for 5 hours at 45-50 ℃ under reduced pressure, sampling and checking the obtained product to obtain esomeprazole potassium meeting the quality standard, and repeating the steps (5) - (7) on the product not meeting the quality standard; the quality standard is as follows: if an impurity peak exists in the chromatogram, the retention time of the impurity D relative to the main peak is about 0.95 and cannot exceed 0.2 percent according to the area normalization method, other single impurity peaks are not more than 0.1 percent according to the area normalization method, and the total amount of impurities is not more than 0.5 percent; the ratio of the peak area of the optical isomer to the sum of the peak areas of the optical isomer and esomeprazole is not more than 0.2%.
11. The method according to claim 10, wherein in the step (2) of the potassium salt-forming reaction, the methanolic potassium hydroxide solution is a solution of potassium hydroxide dissolved in methanol at a mass ratio of 1:5 to 8, or 1: 6.76; the molar ratio of potassium hydroxide methanol to omeprazole sulfide added in step (2) is 1.45: 1;
in the step (3) of the potassium salt forming reaction, the added toluene-methanol mixed solution is added in an amount such that the mass ratio of omeprazole thioether to the methanol/toluene mixed solvent is 1:1.4, namely the mass ratio of omeprazole thioether to methanol is 1:0.7, and the mass ratio of omeprazole thioether to toluene is 1: 0.7;
the amount of acetone added in the step (5) of the potassium salt forming reaction is such that the mass ratio of acetone to the crude esomeprazole potassium salt is 10-14: 1;
the amount of methanol added in the step (6) of the potassium salt forming reaction is such that the mass ratio of methanol to crude esomeprazole potassium salt is 3-4: 1;
the mass ratio of the amount of methanol added in the step (7) of the potassium salt forming reaction to the crude esomeprazole potassium salt is 1:1.
12. The preparation method of esomeprazole magnesium trihydrate is characterized by comprising the following steps:
(1) obtaining esomeprazole potassium by the preparation method of claim 10 or 11;
(2) adding pure water into a reaction kettle containing esomeprazole potassium, stirring and dissolving, carrying out filter pressing to the reaction kettle in a clean area, and carrying out nitrogen protection;
(2) heating to 35-40 ℃, dropwise adding the magnesium chloride hexahydrate aqueous solution, keeping the temperature and stirring for 3-4 hours after the dropwise adding is finished, filtering,
(3) pulping and washing the filter cake with purified water, and then drying in a fluidized bed dryer at 45-50 ℃ for 10-15 hours to obtain a finished product of esomeprazole magnesium;
in the chromatogram of the esomeprazole potassium, if an impurity peak is contained, the retention time of the impurity D relative to the main peak is about 0.95 and is not more than 0.2% calculated by an area normalization method, other single impurity peaks are not more than 0.1% calculated by the area normalization method, and the total amount of impurities is not more than 0.5%; the ratio of the peak area of the optical isomer to the sum of the peak areas of the optical isomer and esomeprazole is calculated, and is not more than 0.2%.
13. The preparation method according to claim 12, wherein in the step (1), the weight ratio of the esomeprazole potassium to the pure water is 1: 5-10.
14. A process for the preparation of esomeprazole magnesium trihydrate, comprising
(1) Preparing esomeprazole: preparing esomeprazole by the preparation method of any one of claims 1-9;
(2) preparation of esomeprazole potassium: a process for the preparation of esomeprazole potassium by the process of claim 10 or 11;
(3) ion exchange reaction: the process according to claim 12 or 13 for the preparation of esomeprazole magnesium trihydrate.
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