CN101914090B - Method for preparing levo-omeprazole - Google Patents
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Abstract
The invention relates to a method for preparing high-purity levo-omeprazole or metal salt thereof. A complex compound prepared by the reaction of (S)-binaphthol and titanium tetraisopropoxide under the reflux condition in the presence of an organic solvent is used as a catalyst, tert-butyl hydrogen peroxide decane solution is used as an oxidant, the levo-omeprazole with high chromatographic purity and high optical purity is obtained by asymmetrically oxidizing omeprazole thioether at room temperature without adding any organic alkali, and the levo-omeprazole and the alkali to prepare the levo-omeprazole metal salt. The purity and ee value of the purified levo-omeprazole and the salt thereof reach over 99 percent, the yield is over 62 percent, and the method is suitable for industrialized production.
Description
(1) technical field: the invention belongs to the chemical pharmaceutical technical field, relate to the method that a kind of asymmetry catalysis oxidation prepares levo-omeprazole.
(2) background technology: the chemical name of levo-omeprazole is ((S))-2-{[(3,5-dimethyl-4-methoxyl group-2-pyridyl) methyl] sulfoxide }-5-methoxyl group-1H-benzoglyoxaline, its structural formula is as follows:
Omeprazole is the proton pump inhibitor of first listing, is researched and developed successfully by Sweden Astra Pharma Inc. (predecessor of AstraZeneca drugmaker), at first goes on the market in Switzerland in 1988, and commodity are called " Antra ".Entered American market in 1989, and be used for the treatment of duodenal ulcer, stomach ulcer, reflux esophagitis and Zollinger-Ellison syndrome, commodity are called " Losec ".From then on, Losec is the fashionable whole world just, becomes one of medicine of U.S.'s recipe quantity maximum, between 1998～2000 years, first of continuous 3 years ranks whole world situation of selling well medicines.Losec global marketing volume was 62.60 hundred million dollars in 2000, can be rated as 20 end of the centurys " cookle ".
Levo-omeprazole has better security and curative effect with respect to omeprazole.No matter animal experiment or clinical trial prove that all side effect is much smaller than omeprazole.Therefore compare omeprazole, levo-omeprazole has higher market outlook.
At present, the existing ripe synthetic method of racemic omeprazole, and dropped into large-scale industrial production, and the industry of high optical purity levo-omeprazole preparation is still relatively more difficult.The preparation method of levo-omeprazole roughly has two classes: the asymmetric oxidation method of the Split Method of omeprazole and omeprazole thioether.
The structural formula of omeprazole thioether is as follows:
International Patent Application WO 02/098423 has been described the method for utilizing beta-cyclodextrin inclusion compound (S)-omeprazole.Chinese patent CN1087739, International Patent Application WO 2006/094904, WO2007/013743 etc. have described with (S)-binaphthol, di-phenanthrol or tartrate resolution of omeprazole obtain the interior inclusion complex of levo-omeprazole, and then obtain the method for levo-omeprazole from this inclusion complex with silicagel column or alkaline hydrolysis.Can waste the omeprazole of half with this type of Split Method resolution of omeprazole, cause environmental pollution and financial loss, and have optically active resolving agent price also expensive, therefore this Split Method is restricted in industrial extensive use.
International Patent Application WO 96/02535 discloses in the presence of chirality bitooth ligand diethyl tartrate and titanium metal network and thing and alkali, obtains the method for levo-omeprazole with hydrogen peroxide analog derivative oxidation omeprazole thioether.International Patent Application WO 03/089408 has been described under the complex catalysis of chiral monodentate (S)-(+)-mandelate and titanium or vanadium, and while oxidation omeprazole thioether in the presence of alkali obtains the method for levo-omeprazole.Chinese patent application CN1810803 has described at chirality bitooth ligand (R, R)-1, under 2-two (2-bromo-phenyl)-glycol and the titanium metal complex catalysis, do not add any organic bases, the omeprazole sulfide oxidation is become the method for levo-omeprazole with the hydroperoxide kind oxygenant.This class uses chiral catalyst asymmetric oxidation omeprazole thioether to obtain the relative and traditional Split Method of method of omeprazole, has the raw material availability height, and simple to operate, therefore the advantage that reactions steps is few has higher application prospect.It mainly is WO 96/02535 patent application of Aktiebolaget Astra that above-mentioned patent is used for industrialized, but there is following problem in this method: 1. the chiral ligand usage quantity is very large.2. organic bases has been used the diisopropyl ethyl amine that is of little use.These have all increased production cost and difficulty.
The present invention relates to the method that a kind of novel omeprazole thioether asymmetric oxidation prepares levo-omeprazole and metal-salt thereof.
(3) summary of the invention: task of the present invention is that the complex compound that forms take chiral ligand (S)-binaphthol and tetraisopropoxy titanium is as catalyzer, take tertbutyl peroxide decane solution as oxygenant, the omeprazole thioether is carried out asymmetric oxidation obtain levo-omeprazole.
Do not need to add any organic bases in the asymmetric oxidation process of the present invention.
Preparation method's processing condition of the present invention are gentle, and good reproducibility is easy to industrialized production, and the levo-omeprazole optical purity of using the inventive method to prepare is high, and purified rear ee value (enantio-selectivity) can reach more than 99%, and good stability.
The invention provides a kind of levo-omeprazole directly and the alkali salify prepare the method for levo-omeprazole metal-salt.
The technical solution used in the present invention: the present invention is in organic solvent, do not add any organic bases, under the complex catalysis that is formed by (S)-binaphthol and tetraisopropoxy titanium, make oxygenant with tertbutyl peroxide decane solution, omeprazole thioether asymmetric oxidation is become levo-omeprazole, obtain the high purity levo-omeprazole through separation and purification; The levo-omeprazole that obtains by with the alkali salify, can obtain the metal-salt of levo-omeprazole.
The omeprazole thioether that the present invention describes prepares the method for levo-omeprazole through asymmetric oxidation, in organic solvent, and the complex compound catalyst of first preparation (S)-binaphthol and tetraisopropoxy titanium formation, its step is as described below:
1) (S)-and the preparation of the complex compound that binaphthol and tetraisopropoxy titanium form: (S)-binaphthol is joined in the reaction vessel, add organic solvent, slowly drip again tetraisopropoxy titanium, after drip finishing, this mixture or solution are heated to backflow, and under reflux temperature, react 1～3 hour;
2) asymmetric oxidation: take by weighing an amount of omeprazole thioether, join step 1) in the complex compound of preparation, add tertbutyl peroxide decane solution, reaction solution is stirring reaction 8 hours at room temperature, obtains levo-omeprazole again;
3) separating-purifying levo-omeprazole: reaction solution is concentrated, add ethyl acetate and 10% aqueous sodium hydroxide solution, extraction, the water intaking phase, water adds 10% acetum to pH=8～9 with ethyl acetate washing 3 times.Use ethyl acetate extraction, get organic phase, concentrated, obtain the higher levo-omeprazole of ee value; With the higher levo-omeprazole of acetone solution ee value, be heated to 45 ℃, add soda-lye, insulation is 2 hours under the vigorous stirring, is cooled to-8～10 ℃, drips toluene in order to crystallization, obtains the levo-omeprazole sodium salt; The levo-omeprazole sodium salt is dissolved in the mixed solvent of water and acetone, and adds a small amount of ammoniacal liquor, be cooled to-10 ℃, slowly drip 10% acetum, to pH=8～9, keep low temperature to stir 4 hours, filter, oven dry obtains highly purified levo-omeprazole.
(S)-binaphthol of the present invention is 1～2: 1 with the molar equivalent ratio of tetraisopropoxy titanium, is preferably 2: 1.
The present invention is in step 1) described in organic solvent be not only the reaction solvent of Kaolinite Preparation of Catalyst complex compound, it also is asymmetric oxidation reaction solvent of lower step, select suitable organic solvent very important to the inventive method, because organic solvent can not only affect the activity of catalyzer, and can affect enantioselectivity in oxidising process.This organic solvent comprises tetrahydrofuran (THF), methylene dichloride, tetracol phenixin, ethyl acetate, toluene etc.Compare these organic solvents through experiment, the inventor finds that tetrahydrofuran (THF) is best to the solvability of (S)-binaphthol, and the gained reaction result is that reacting coarse product ee value is also high than other solvent.Therefore the optimum solvent of this reaction is tetrahydrofuran (THF).
Reflux time can not be too short in preparation complex compound process, otherwise the formation of impact (S)-binaphthol and tetraisopropoxide titanium complex, reflux time can be 1～3 hour, best reflux time is 2 hours.
The selection of the solution form of oxygenant tertbutyl peroxide is most important to this reaction.To this type of reaction, tertbutyl peroxide occurs mainly with the form of the aqueous solution in the existing document.The inventor finds that in reaction system of the present invention if replace tertbutyl peroxide decane solution with the tertbutyl peroxide aqueous solution, the reacting coarse product ee value that obtains is very low, and as described in Example 10, reacting coarse product ee value only has 6.58%.Through many experiments, the inventor finds can access best reaction result with tertbutyl peroxide decane solution as oxygenant.Tertbutyl peroxide decane solution is buied from ALDRICH company.
The tertbutyl peroxide consumption can be 0.9～1.1 molar equivalent (with respect to the omeprazole thioether), preferred 1.0 molar equivalents.
In step 3) in " levo-omeprazole that the ee value is higher " that obtain can react salify with alkali reagent, through further purifying, can obtain the levo-omeprazole metal-salt of higher ee value.
Described metal-salt can be sodium salt or magnesium salts.
After purified, HPLC purity and the ee value of levo-omeprazole and metal-salt thereof all reach more than 99%, and ultimate yield is between 62.7%～74.2%.
Measure through nuclear magnetic resonance map analysis, polarimeter with the product that the inventive method prepares, the affirmation structure is levo-omeprazole.
Advantage of the present invention is: with respect to the industrialized preparing process of levo-omeprazole, the present invention is take (S)-binaphthol as part, take tertbutyl peroxide decane solution as oxygenant, so that reaction conditions is gentle, HPLC purity and ee value reach more than 99%, and yield is more than 62%, and preparation technology is simple, low in the pollution of the environment, be suitable for suitability for industrialized production.
(4) specific embodiments:
Embodiment by the embodiment form further specifies the present invention, but can not limit content of the present invention, the organic solvent that the present invention selects, proportional range, reaction conditions etc. are not limited in embodiment and describe, the technology that foregoing of the present invention is realized all belongs to scope of the present invention, the embodiment of the invention adopts laboratory test data, but is suitable for equally suitability for industrialized production.
HPLC purity given in the embodiment of the invention is by high effective liquid chromatography for measuring, and design parameter is as follows:
Chromatographic column: Waters symmetry C8,150 * 3.9mm, 5 μ m
Moving phase: ACN: Na
2HPO
4Damping fluid (0.01mol/l)=1: 3
Flow velocity: 0.8ml/min
UV detects wavelength: 280nm
Retention time: 12.6min
Ee value given in the embodiment of the invention is measured by chiral hplc, and design parameter is as follows:
Chromatographic column: CHIRALPAK AD 250 * 4.6mm, 10 μ m
Moving phase: normal hexane: ethanol: methyl alcohol=34: 3: 3
Flow velocity: 1.5ml/min
UV detects wavelength: 280nm
Retention time: levo-omeprazole 14.5min
Dextrorotation omeprazole 40min
The preparation of embodiment 1 levo-omeprazole
In the there-necked flask of 150ml, drop into (S)-binaphthol (6.3g, 22.0mmol), with the dissolving of 60ml tetrahydrofuran (THF), add tetraisopropoxy titanium (3.1g, 11.0mmol), be heated to backflow, and under reflux temperature, reacted 2 hours; Reaction solution is cooled to room temperature, add omeprazole thioether (18.1g, 55.0mmol) and tertbutyl peroxide decane solution (8.3g, 55.0mmol 5.5mol/l annotates: tertbutyl peroxide decane total solution weight 8.3g, contain the 55.0mmol tertbutyl peroxide, this strength of solution is 5.5mol/l, and is as follows), stirring at room 8 hours.Through the chirality stratographic analysis, reacting coarse product ee value is 82.26%.
The reactant rotary evaporation is concentrated, uses the 100ml acetic acid ethyl dissolution, drips 10% sodium hydroxide solution 36ml, stirs 2 hours.Separatory, the water intaking phase, water washs (30ml * 3) with ethyl acetate.Add 10% acetum to pH=8～9, with ethyl acetate extraction (30ml * 3).The combined ethyl acetate phase, rotary evaporation is concentrated.Enriched material 36ml acetone solution, simultaneously with the 1.9g dissolution of sodium hydroxide in 3.8g water, join in the acetone soln after the dissolving fully, 45 ℃ of lower vigorous stirring 2 hours, the reaction solution rotary evaporation is concentrated into 6.6ml, adds 66ml water and 4.4ml ammoniacal liquor, is cooled to-10 ℃, slowly drip 10% acetum to pH=8～9, keep-10 ℃ and stirred 10 hours.Filter, wash (30ml * 3) with water.45 ℃ of lower vacuum-drying 6 hours obtains white levo-omeprazole solid 11.9g.Yield: 62.7%, HPLC purity 99.85%, ee value: 99.32%.
The preparation of embodiment 2 levo-omeprazole sodium
In the there-necked flask of 150ml, drop into (S)-binaphthol (6.3g, 22.0mmol), with the dissolving of 60ml tetrahydrofuran (THF), add tetraisopropoxy titanium (3.1g, 11.0mmol), be heated to backflow, and under reflux temperature, reacted 2 hours.Reaction solution is cooled to room temperature, adds omeprazole thioether (18.1g, 55.0mmol) and tertbutyl peroxide decane solution (8.3g, 55.0mmol, 5.5mol/l), stirring at room 8 hours.Through the chirality stratographic analysis, reacting coarse product ee value is 82.12%.
The reactant rotary evaporation is concentrated, uses the 100ml acetic acid ethyl dissolution, drips 10% sodium hydroxide solution 36ml, stirs 2 hours.Separatory, the water intaking phase, water washs (30ml * 3) with ethyl acetate.Add 10% acetum to pH=8～9, with ethyl acetate extraction (30ml * 3).The combined ethyl acetate phase, rotary evaporation is concentrated.Enriched material 36ml acetone solution, simultaneously with the 1.9g dissolution of sodium hydroxide in 3.8g water, join in the acetone soln 45 ℃ of lower vigorous stirring 2 hours fully after the dissolving.Be cooled to room temperature, slowly drip 108ml toluene in order to crystallization.Filter, use the 18ml washing with acetone, obtain white levo-omeprazole sodium solid 14.1g.Yield: 69.8%, HPLC purity: 99.97%, ee value: 99.72%.
The preparation of embodiment 3 levo-omeprazole magnesium
In the there-necked flask of 150ml, drop into (S)-binaphthol (6.3g, 22.0mmol), with the dissolving of 60ml tetrahydrofuran (THF), add tetraisopropoxy titanium (3.1g, 11.0mmol), be heated to backflow, and under reflux temperature, reacted 2 hours.Reaction solution is cooled to room temperature, adds omeprazole thioether (18.1g, 55.0mmol) and tertbutyl peroxide decane solution (8.3g, 55.0mmol, 5.5mol/l), stirring at room 8 hours.Through the chirality stratographic analysis, reacting coarse product ee value is 82.15%.
The reactant rotary evaporation is concentrated, uses the 100ml acetic acid ethyl dissolution, drips 10% sodium hydroxide solution 36ml, stirs 2 hours.Separatory, the water intaking phase, water washs (30ml * 3) with ethyl acetate.Add 10% acetum to pH=8～9, with ethyl acetate extraction (30ml * 3).The combined ethyl acetate phase, rotary evaporation is concentrated.Enriched material 36ml acetone solution, the magnesium methylate methanol solution with 26.0g 8% joins in the acetone soln simultaneously, 45 ℃ of lower vigorous stirring 2 hours.Be cooled to room temperature, slowly drip 108ml toluene in order to crystallization.Filter, use the 18ml washing with acetone, obtain white levo-omeprazole magnesium solid 14.6g.Yield: 74.2%, HPLC purity: 99.69%, ee value: 99.02%.
The preparation of embodiment 4 levo-omeprazoles
In the there-necked flask of 150ml, drop into (S)-binaphthol (6.3g, 22.0mmol), with the dissolving of 60ml tetrahydrofuran (THF), add tetraisopropoxy titanium (3.1g, 11.0mmol), be heated to backflow, and under reflux temperature, reacted 1 hour.Reaction solution is cooled to room temperature, adds omeprazole thioether (18.1g, 55.0mmol) and tertbutyl peroxide decane solution (8.3g, 55.0mmol, 5.5mol/l), stirring at room 8 hours.Through the chirality stratographic analysis, reacting coarse product ee value is 46.02%.
The preparation of embodiment 5 levo-omeprazoles
In the there-necked flask of 150ml, drop into (S)-binaphthol (6.3g, 22.0mmol), with the dissolving of 60ml tetrahydrofuran (THF), add tetraisopropoxy titanium (3.1g, 11.0mmol), be heated to backflow, and under reflux temperature, reacted 3 hours.Reaction solution is cooled to room temperature, adds omeprazole thioether (18.1g, 55.0mmol) and tertbutyl peroxide decane solution (8.3g, 55.0mmol, 5.5mol/l), stirring at room 8 hours.Through the chirality stratographic analysis, reacting coarse product ee value is 79.8%.
The preparation of embodiment 6 levo-omeprazoles
In the there-necked flask of 150ml, drop into (S)-binaphthol (3.1g, 11.0mmol), with the dissolving of 60ml tetrahydrofuran (THF), add tetraisopropoxy titanium (3.1g, 11.0mmol), be heated to backflow, and under reflux temperature, reacted 2 hours.Reaction solution is cooled to room temperature, adds omeprazole thioether (18.1g, 55.0mmol) and tertbutyl peroxide decane solution (8.3g, 55.0mmol, 5.5mol/l), stirring at room 8 hours.Through the chirality stratographic analysis, reacting coarse product ee value is 46.02%.
The preparation of embodiment 7 levo-omeprazoles
In the there-necked flask of 150ml, drop into (S)-binaphthol (4.7g, 16.5mmol), with the dissolving of 60ml tetrahydrofuran (THF), add tetraisopropoxy titanium (3.1g, 11.0mmol), be heated to backflow, and under reflux temperature, reacted 2 hours.Reaction solution is cooled to room temperature, adds omeprazole thioether (18.1g, 55.0mmol) and tertbutyl peroxide decane solution (8.3g, 55.0mmol, 5.5mol/l), stirring at room 8 hours.Through the chirality stratographic analysis, reacting coarse product ee value is 54.98%.
The preparation of embodiment 8 levo-omeprazoles
In the there-necked flask of 150ml, drop into (S)-binaphthol (6.3g, 22.0mmol), with the dissolving of 60ml tetrahydrofuran (THF), add tetraisopropoxy titanium (3.1g, 11.0mmol), be heated to backflow, and under reflux temperature, reacted 2 hours.Reaction solution is cooled to room temperature, adds omeprazole thioether (18.1g, 55.0mmol) and tertbutyl peroxide decane solution (7.5g, 49.5mmol, 5.5mol/l), stirring at room 8 hours.Through the chirality stratographic analysis, reacting coarse product ee value is 78.71%.
The preparation of embodiment 9 levo-omeprazoles
In the there-necked flask of 150ml, drop into (S)-binaphthol (6.3g, 22.0mmol), with the dissolving of 60ml tetrahydrofuran (THF), add tetraisopropoxy titanium (3.1g, 11.0mmol), be heated to backflow, and under reflux temperature, reacted 2 hours.Reaction solution is cooled to room temperature, adds omeprazole thioether (18.1g, 55.0mmol) and tertbutyl peroxide decane solution (9.1g, 60.5mmol, 5.5mol/l), stirring at room 8 hours.Through the chirality stratographic analysis, reacting coarse product ee value is 80.51%.
The preparation of embodiment 10 levo-omeprazoles
In the there-necked flask of 150ml, drop into (S)-binaphthol (6.3g, 22.0mmol), with the dissolving of 60ml tetrahydrofuran (THF), add tetraisopropoxy titanium (3.1g, 11.0mmol), be heated to backflow, and under reflux temperature, reacted 2 hours.Reaction solution is cooled to room temperature, adds omeprazole thioether (18.1g, 55.0mmol) and the tertbutyl peroxide aqueous solution (16.5g, 55.0mmol, 70% aqueous solution), stirring at room 8 hours.Through the chirality stratographic analysis, reacting coarse product ee value is 6.58%.
The preparation of embodiment 11 levo-omeprazoles
In the there-necked flask of 150ml, drop into (S)-binaphthol (6.3g, 22.0mmol), add the 60ml methylene dichloride, add again tetraisopropoxy titanium (3.1g, 11.0mmol), be heated to backflow, and under reflux temperature, reacted 2 hours.Reaction solution is cooled to room temperature, adds omeprazole thioether (18.1g, 55.0mmol) and tertbutyl peroxide decane solution (8.3g, 55.0mmol, 5.5mol/l), stirring at room 8 hours.Through the chirality stratographic analysis, reacting coarse product ee value is 31.20%.
The preparation of embodiment 12 levo-omeprazoles
In the there-necked flask of 150ml, drop into (S)-binaphthol (6.3g, 22.0mmol), add the 60ml tetrachloromethane, add again tetraisopropoxy titanium (3.1g, 11.0mmol), be heated to backflow, and under reflux temperature, reacted 2 hours.Reaction solution is cooled to room temperature, adds omeprazole thioether (18.1g, 55.0mmol) and tertbutyl peroxide decane solution (8.3g, 55.0mmol, 5.5mol/l), stirring at room 8 hours.Through the chirality stratographic analysis, reacting coarse product ee value is 16.1%.
The preparation of embodiment 13 levo-omeprazoles
In the there-necked flask of 150ml, drop into (S)-binaphthol (6.3g, 22.0mmol), add the 60ml ethyl acetate, add again tetraisopropoxy titanium (3.1g, 11.0mmol), be heated to backflow, and under reflux temperature, reacted 2 hours.Reaction solution is cooled to room temperature, adds omeprazole thioether (18.1g, 55.0mmol) and tertbutyl peroxide decane solution (8.3g, 55.0mmol, 5.5mol/l), stirring at room 8 hours.Through the chirality stratographic analysis, reacting coarse product ee value is 18.28%.
The preparation of embodiment 14 levo-omeprazoles
In the there-necked flask of 150ml, drop into (S)-binaphthol (6.3g, 22.0mmol), add 60ml toluene, add again tetraisopropoxy titanium (3.1g, 11.0mmol), be heated to backflow, and under reflux temperature, reacted 2 hours.Reaction solution is cooled to room temperature, adds omeprazole thioether (18.1g, 55.0mmol) and tertbutyl peroxide decane solution (8.3g, 55.0mmol, 5.5mol/l), stirring at room 8 hours.Through the chirality stratographic analysis, reacting coarse product ee value is 14.44%.
Claims (8)
1. the preparation method of a levo-omeprazole, it is characterized in that described method is: in tetrahydrofuran solvent, do not add any organic bases, under the complex catalysis that is formed by (S)-binaphthol and tetraisopropoxy titanium, make oxygenant with tertbutyl peroxide decane solution, omeprazole thioether asymmetric oxidation is become levo-omeprazole.
2. preparation method according to claim 1, it is characterized in that complex compound that described (S)-binaphthol and tetraisopropoxy titanium form in tetrahydrofuran solvent under the reflux temperature reaction obtain, (S)-binaphthol is 1～2: 1 with the molar equivalent ratio of tetraisopropoxy titanium.
3. preparation method according to claim 2 is characterized in that described (S)-binaphthol and the molar equivalent ratio of tetraisopropoxy titanium are 2: 1.
4. according to claim 1 and 2 or 3 described preparation methods, the preparation method who it is characterized in that described (S)-binaphthol and tetraisopropoxide titanium complex: (S)-binaphthol is joined in the reaction vessel, add organic solvent tetrahydrofuran, drip again tetraisopropoxy titanium, after dropwising, this mixture solution is heated to backflow, and under reflux temperature, reacted 1-3 hour.
5. preparation method according to claim 4 is characterized in that complex compound that (S)-binaphthol and tetraisopropoxy titanium form reacts to obtain back flow reaction 2 hours under reflux temperature.
6. preparation method according to claim 1 is characterized in that tertbutyl peroxide and the molar equivalent ratio of omeprazole thioether are 1: 0.9～1.1.
7. preparation method according to claim 6 is characterized in that tertbutyl peroxide and the molar equivalent ratio of omeprazole thioether are 1.0.
8. preparation method according to claim 1 is characterized in that asymmetric oxidation finishes under the stirring at room condition.
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| CN102816149B (en) * | 2011-06-10 | 2015-05-13 | 上海汇伦生命科技有限公司 | Preparation method for high-enantioselectivity synthesized (S)-omeprazole and salt thereof |
| CN104892575A (en) * | 2015-04-13 | 2015-09-09 | 江苏中邦制药有限公司 | Novel synthesis method of chiral imidazole sulfoxide 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 |
| CN110746428A (en) * | 2019-10-29 | 2020-02-04 | 株洲千金药业股份有限公司 | Preparation method of R-type chiral sulfoxide compound |
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