CN102603716A - Method for preparing (S)-pantoprazole in high-enantioselectivity way - Google Patents
Method for preparing (S)-pantoprazole in high-enantioselectivity way Download PDFInfo
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Abstract
The invention relates to the field of medicinal chemistry, in particular to a method for preparing (S)-pantoprazole in a high-enantioselectivity way. The method is characterized in that any organic alkali is not added under the condition of chiral reagent existence, and oxidants are used for directly oxidizing 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)-methyl]-sulfenyl]-1H-benzimidazole. The ee value of the (S)-pantoprazole obtained by using the method provided by the invention can reach 100 percent.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to a kind of method of high antimer selectivity preparation (S)-pantoprazole.
Background technology
Compound (S)-pantoprazole, (S)-5-difluoro-methoxy-2-[[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl]-1H-benzoglyoxaline and pharmaceutical salts thereof be described in CN1822835A.Pantoprazole is a proton pump inhibitor, and through the final step that gastric acid inhibitory produces with two site covalent attachment of the H+-K+-ATP enzyme system of parietal cell, this effect is dose-dependently and the gastric acid secretion under basis and the stimulation state is all suppressed.The S-Pantoprazole Sodium can be used for treatment and the disorderly diseases associated of gastric acid secretion like acute hemorrhage of upper gastrointestinal tract and assistant-Emhorn syndromess such as gastroesophageal reflux, gastritis, AGML, stomach ulcer, plyability stomach ulcer, duodenitis, duodenal ulcers as proton pump inhibitor research as the Esso omeprazole.Describing the S-Pantoprazole Sodium in the U.S. Pat 5888535 has than racemic modification Pantoprazole Sodium and the stronger gastric acid inhibitory excretory effect of R type isomer.Saying in general sense, the S-Pantoprazole Sodium can Mammals particularly philtrum be used for prevention and treatment and hydrochloric acid in gastric juice diseases associated.
International Patent Application WO 94/24867 and WO94/25028 advocate compound (-)-be used to treat the purposes of human stomach trouble with (+)-pantoprazole.Described each steric isomer is compared with other steric isomer separately has the pharmacy advantage.Also describe the possible salt of many different steric isomers, particularly preferably be sodium salt.
WO96/17076 and WO96/17077 have described the use mikrobe and have carried out selectively oxidizing sulfur ether or selective reduction sulfone compound, obtain the method for the sulfoxide compound of single enantiomer.
Have been found that in International Patent Application WO 94/24867 especially preferred (-)-or (S)-the pantoprazole sodium salt, it can not form the form of stably stored.In for the trial that obtains stable (-)-pantoprazole oral dosage form; Have been found that the alkali reaction magnesium salts of (S)-pantoprazole; Particularly, have very surprising stability property, make them in the purposes of solid or oral dosage form, become particularly suitable candidate with the form of hydrate.Draw sodium salt to compare with (-)-dissolve holder, they have the stability property of sizable improvement.
International Patent Application WO 04/013126 has been described (S)-pantoprazole-magnesium and hydrate thereof.
International Patent Application WO 2005/070426, WO2005/074929, US 2006/0216346 etc. disclose the preparation method of (S)-pantoprazole sodium salt and magnesium salts thereof, and said hydration (S)-Pantoprazole Sodium all is a crystalline form in the patent.
Chinese patent CN1312150 disclose (S)-pantoprazole-magnesium duohydrate with (S)-pantoprazole sodium hydrate synthetic, the hydration of its preparation (S)-Pantoprazole Sodium enhydrous amount is between 2%～12%.Disclosing its hydration (S)-Pantoprazole Sodium crystallization in the patent is not a stable form, and it is deposited all colors and becomes brown under 70 ℃, and forms a large amount of degradation productions.
International monopoly WO2005070426, WO2005074929, US20060216346 etc. disclose the preparation method of S-pantoprazole sodium salt and magnesium salts thereof.The preparation method of pantorazole salt all adopts pantoprazole under different condition, to react with basic salt in above-mentioned disclosed patent.
Chinese patent CN1717402 (WO2004/052881) has described and has used chirality zirconium complex or chirality hafnium complex to prepare the method for S-pantoprazole.This method be (+)-or (-)-tartaric acid derivatives and zirconium alkoxide (IV) or alkoxyl group hafnium (IV) in the presence of, selectively oxidizing sulfur ether synthesizes the S-pantoprazole.
Chinese patent CN1810803A has described a kind of use metal titanium and chiral diol part produced in situ titanium-containing catalyst, preparation S-pantoprazole.
The preparation method of pantoprazole single enantiomer describes in patents such as WO92/08716, WO96/27989, WO91/12221, WO94/27988, CN1070489, CN1717402 to some extent; Wherein WO91/12221, WO94/27988 and WO92/08716 have described the method that directly sulfoxide compound of racemic modification is split into single corresponding body; What WO96/27989 and CN1070489 adopted is the method for chiral oxidization, and what CN1717402 adopted is the selective oxidation method.
In the publication of above-mentioned preparation pantoprazole single enantiomer; Mainly contain following three kinds of methods: the one, adopt the method for chiral selectors that the raceme pantoprazole is split; Lock out operation in the split process is quite loaded down with trivial details, raw material availability low (like WO91/12221, WO94/27988 and WO92/08716); The 2nd, adopt biochemical method; Using enzyme to come that the pantoprazole thioether is carried out oxidation perhaps reduces to the pantoprazole sulfone; Obtain the single enantiomer of pantoprazole; But this method needs special experimental installation and experimental technique, relatively too loaded down with trivial details and trouble (like WO96/17076 and WO96/17077); The 3rd, adopt the asymmetric oxidation method, use the prothetic group of chirality or the single enantiomer of Preparation of Catalyst pantoprazole, this method convenient and easy with respect to the above two (like CN1157614A and CN1717402).But present this method also has obvious defects: 1) need a large amount of special organic basess; This has increased the complicacy of cost and operation.2) (the S)-pantoprazole chiral purity purity that obtains is not high enough.
Summary of the invention
The invention discloses the method that a kind of enantio-selectivity catalysed oxidation processes prepares optical purity enantiomorph (S)-pantoprazole.
The invention provides a kind of simple method and prepare optical purity enantiomorph (S)-5-difluoro-methoxy-2-[[(3; 4-dimethoxy-2-pyridyl) methyl] sulfinyl]-method of 1H-benzoglyoxaline (be called for short (S)-pantoprazole); Promptly under the situation that chiral reagent exists; Do not add any organic bases, use oxygenant direct oxidation 5-difluoro-methoxy-2-[[(3,4-dimethoxy-2-pyridyl) methyl]-sulfenyl]-1H-benzoglyoxaline.(S)-pantoprazole ee value that the inventive method obtains can reach 100%.
Reaction formula is following:
Preparing method of the present invention comprises: chiral ligand, titanium tetraisopropylate, pantoprazole thioether and hydrogen phosphide cumene reaction are promptly got, wherein chiral ligand be (1R, 2S)-1-amino-2-indanol or (1S, 2R)-1-amino-2-indanol.Be about to chiral ligand, titanium tetraisopropylate, pantoprazole thioether and hydrogen phosphide cumene in reaction.The reaction back adds alkaline aqueous solution cancellation reaction and promptly gets, and wherein oxygenant is a hydrogen phosphide cumene in the hand reaction.Chiral ligand preferably (1R, 2S)-1-amino-2-indanol.
The mol ratio of pantoprazole thioether, chiral ligand, titanium tetraisopropylate, hydrogen phosphide cumene is preferably: 1: 0.5～1: 0.1～0.5: 1～3.More preferably 1: 1: 0.5: 2.32.
The reaction solvent of above-mentioned reaction is preferred: one or more of hexane, methylene dichloride, chloroform, tetracol phenixin, benzene,toluene,xylene, chlorobenzene, oil of mirbane, ether, tertbutyl ether, N, N-Methyl pyrrolidone, acetonitrile.More preferably acetonitrile.
Preferred on the operation: comprising: add chiral ligand and titanium tetraisopropylate reaction 10 to 60 minutes earlier, add the reaction of pantoprazole thioether and hydrogen phosphide cumene again.Chiral ligand and titanium tetraisopropylate reaction are in order to prepare bitooth ligand titanium complex catalyzer.Preferred 0 ℃ to 30 ℃ of this temperature of reaction, more preferably 10 ℃ to 20 ℃.More preferably 10 to 15 minutes complexing time.
The oxidizing reaction temperature room temperature gets final product, preferably 10 ℃ to 20 ℃.Preferred 1 to 24 hour of oxidization time, more preferably the time is 2 to 4 hours.
The purifying of (S)-pantoprazole that the present invention describes can be used organic solvent extraction after alkaline aqueous solution is adjusted to alkalescence through adding in the reaction soln; Add acidic aqueous solution or organic acid adjustment of acidity in the extraction liquid; And SX, recrystallization in organic solvent.
Purification process is preferred: tell water through adding in the reaction soln after alkaline aqueous solution is adjusted to alkalescence, add acidic aqueous solution then or organic acid is adjusted to neutrality, use organic solvent extraction, recrystallization.Preferred method is: add toluene in the reaction system earlier, add ammoniacal liquor then and stir, isolate water, merge the ammoniacal liquor layer; In ice-water bath, transfer pH to 7.5～8, use ethyl acetate extraction again, merge organic layer with glacial acetic acid; Revolve then and steam ETHYLE ACETATE, (the S)-pantoprazole episome that obtains is used acetic acid ethyl dissolution, drip sherwood oil again; Stir, filter, vacuum-drying gets (S)-pantoprazole episome.
The present invention also comprises the method for a kind of preparation (S)-Pantoprazole Sodium, comprising: (S)-pantoprazole episome of above-mentioned preparation is dissolved in the acetonitrile, adds the NaOH solution stirring then, then acetonitrile is steamed, add ether and stir, filter, be drying to obtain.
Among this preparation method, forbidding in this system has water, and water plays disadvantageous effect in this reaction, and with reference to embodiment 1 method, ingredient proportion is following: the pantoprazole thioether: 1-amino-2-indanol: Ti (OiPr)
4: the mol ratio of hydrogen phosphide cumene is: 1: 1: 0.5: 2.32.Under the situation that dropping 2 is dripped, productive rate is 35%, and the ee value is 54%.
Description of drawings
Fig. 1 is the HPLC figure of pantoprazole enantiomer chiral purity;
Fig. 2 is the HPLC figure of the optical purity test of (S)-pantoprazole;
Fig. 3 is DTA (TG) figure that (S)-pantoprazole draws the azoles sodium hydrate;
Fig. 4 is (S)-Pantoprazole Sodium
1H-NMR figure;
Fig. 5 is (S)-Pantoprazole Sodium mass spectrum;
Embodiment
(1R, 2S)-1-amino-2-indanol 0.01mol is dissolved in the 20ml acetonitrile, and whipped state adds Ti (OiPr) down
4(0.005mol), be cooled to 15 ℃, stirred 15 minutes, add pantoprazole thioether (0.01mol) then; Slowly drip hydrogen phosphide cumene 0.0232mol then, continue reaction 3 hours, in reaction system, add 20ml toluene, stir 10min; Add 12.5% ammoniacal liquor (50ml * 3) then and respectively stir 20min, separatory merges the ammoniacal liquor layer; In ice-water bath, transfer pH to 7.5～8 then, use ETHYLE ACETATE (50ml * 3) extraction again, merge organic layer with glacial acetic acid; Steam ETHYLE ACETATE then,, drip the 3ml petroleum ether and stirring then the acetic acid ethyl dissolution of (the S)-pantoprazole episome that obtains with 3ml; Filter, vacuum-drying below 40 ℃ obtains 2.40 gram (S)-pantoprazoles behind the purifying.Yield: 62.66%; Ee (%): 100%; Relevant collection of illustrative plates is seen Fig. 1～Fig. 5.
Chirality HPLC condition is: the chiral analysis post, with ethanol: diethylamine=1000: 1 is a moving phase, and flow velocity is 0.3mL/min, and ultraviolet detection is at 220nm.RT is t
S=14.58.
Embodiment 2
(1R, 2S)-1-amino-2-indanol 0.005mol is dissolved in the 20ml methylene dichloride, and whipped state adds Ti (OiPr) down
4(0.005mol), be cooled to-12 ℃, stirred 15 minutes, add pantoprazole thioether (0.01mol) then; Slowly drip hydrogen phosphide cumene 0.01mol then, continue reaction 20 hours, in reaction system, add 20ml toluene, stir 10min; Add 12.5% ammoniacal liquor (50ml * 3) then and respectively stir 20min, separatory merges the ammoniacal liquor layer; In ice-water bath, transfer pH to 7.5～8 then, use ETHYLE ACETATE (50ml * 3) extraction again, merge organic layer with glacial acetic acid; Steam ETHYLE ACETATE then,, drip the 3ml petroleum ether and stirring then the acetic acid ethyl dissolution of (the S)-pantoprazole episome that obtains with 3ml; Filter, vacuum-drying below 40 ℃ obtains 1.43 gram (S)-pantoprazoles behind the purifying.Yield: 37.33%; Ee (%): 45.86%.
Embodiment 3
(1R, 2S)-1-amino-2-indanol 0.0067mol is dissolved in the 20ml methylene dichloride, and whipped state adds Ti (OiPr) down
4(0.005mol), be cooled to 0 ℃, stirred 15 minutes, add pantoprazole thioether (0.01mol) then; Slowly drip hydrogen phosphide cumene 0.015mol then, continue reaction 11 hours, in reaction system, add 20ml toluene, stir 10min; Add 12.5% ammoniacal liquor (50ml * 3) then and respectively stir 20min, separatory merges the ammoniacal liquor layer; In ice-water bath, transfer pH to 7.5～8 then, use ETHYLE ACETATE (50ml * 3) extraction again, merge organic layer with glacial acetic acid; Steam ETHYLE ACETATE then,, drip the 3ml petroleum ether and stirring then the acetic acid ethyl dissolution of (the S)-pantoprazole episome that obtains with 3ml; Filter, vacuum-drying below 40 ℃ obtains 1.54 gram (S)-pantoprazoles behind the purifying.Yield: 40.21%; Ee (%): 53.27%.
Embodiment 4
(1R, 2S)-1-amino-2-indanol 0.01mol is dissolved in the 20ml methylene dichloride, and whipped state adds Ti (OiPr) down
4(0.005mol), be cooled to 15 ℃, stirred 15 minutes, add pantoprazole thioether (0.01mol) then; Slowly drip hydrogen phosphide cumene 0.0232mol then, continue reaction 3 hours, in reaction system, add 20ml toluene, stir 10min; Add 12.5% ammoniacal liquor (50ml * 3) then and respectively stir 20min, separatory merges the ammoniacal liquor layer; In ice-water bath, transfer pH to 7.5～8 then, use ETHYLE ACETATE (50ml * 3) extraction again, merge organic layer with glacial acetic acid; Steam ETHYLE ACETATE then,, drip the 3ml petroleum ether and stirring then the acetic acid ethyl dissolution of (the S)-pantoprazole episome that obtains with 3ml; Filter, vacuum-drying below 40 ℃ obtains restraining 2.01 (S)-pantoprazoles behind the purifying.Yield: 52.48%; Ee (%): 72.91%.
(1R, 2S)-1-amino-2-indanol 0.005mol is dissolved in the 20ml toluene, and whipped state adds Ti (OiPr) down
4(0.005mol), be cooled to-12 ℃, stirred 15 minutes, add pantoprazole thioether (0.01mol) then; Slowly drip hydrogen phosphide cumene 0.01mol then, continue reaction and in system, add 12.5% ammoniacal liquor (50ml * 3) after 10.5 hours and respectively stir 20min, separatory merges the ammoniacal liquor layer; In ice-water bath, transfer pH to 7.5～8 then, use ETHYLE ACETATE (50ml * 3) extraction again, merge organic layer with glacial acetic acid; Steam ETHYLE ACETATE then,, drip the 3ml petroleum ether and stirring then the acetic acid ethyl dissolution of (the S)-pantoprazole episome that obtains with 3ml; Filter, vacuum-drying below 40 ℃ obtains 1.47 gram (S)-pantoprazoles behind the purifying.Yield: 38.38%; Ee (%): 78.95%.
Embodiment 6
(1R, 2S)-1-amino-2-indanol 0.01mol is dissolved in the 20ml toluene, and whipped state adds Ti (OiPr) down
4(0.005mol), be cooled to 0 ℃, stirred 15 minutes, add pantoprazole thioether (0.01mol) then; Slowly drip hydrogen phosphide cumene 0.0232mol then, continue reaction and in reaction system, add 12.5% ammoniacal liquor (50ml * 3) after 6 hours and respectively stir 20min, separatory merges the ammoniacal liquor layer; In ice-water bath, transfer pH to 7.5～8 then, use ETHYLE ACETATE (50ml * 3) extraction again, merge organic layer with glacial acetic acid; Steam ETHYLE ACETATE then,, drip the 3ml petroleum ether and stirring then the acetic acid ethyl dissolution of (the S)-pantoprazole episome that obtains with 3ml; Filter, vacuum-drying below 40 ℃ obtains 1.92 gram (S)-pantoprazoles behind the purifying.Yield: 50.13%; Ee (%): 81.94%.
Embodiment 7
(1R, 2S)-1-amino-2-indanol 0.0067mol is dissolved in the 20ml N-Methyl pyrrolidone, and whipped state adds Ti (OiPr) down
4(0.005mol), be cooled to 0 ℃, stirred 15 minutes, add pantoprazole thioether (0.01mol) then; Slowly drip hydrogen phosphide cumene 0.0232mol then, continue reaction 7 hours, in reaction system, add 20ml toluene, stir 10min; Add 12.5% ammoniacal liquor (50ml * 3) then and respectively stir 20min, separatory merges the ammoniacal liquor layer; In ice-water bath, transfer pH to 7.5～8 then, use ETHYLE ACETATE (50ml * 3) extraction again, merge organic layer with glacial acetic acid; Steam ETHYLE ACETATE then,, drip the 3ml petroleum ether and stirring then the acetic acid ethyl dissolution of (the S)-pantoprazole episome that obtains with 3ml; Filter, vacuum-drying below 40 ℃ obtains 1.51 gram (S)-pantoprazoles behind the purifying.Yield: 39.4%; Ee (%): 98.84%.
(1R, 2S)-1-amino-2-indanol 0.005mol is dissolved in the 20ml acetonitrile, and whipped state adds Ti (OiPr) down
4(0.005mol), be cooled to-20 ℃, stirred 15 minutes, add pantoprazole thioether (0.01mol) then; Slowly drip hydrogen phosphide cumene 0.01mol then, continue reaction 20 hours, in reaction system, add 20ml toluene, stir 10min; Add 12.5% ammoniacal liquor (50ml * 3) then and respectively stir 20min, separatory merges the ammoniacal liquor layer; In ice-water bath, transfer pH to 7.5～8 then, use ETHYLE ACETATE (50ml * 3) extraction again, merge organic layer with glacial acetic acid; Steam ETHYLE ACETATE then,, drip the 3ml petroleum ether and stirring then the acetic acid ethyl dissolution of (the S)-pantoprazole episome that obtains with 3ml; Filter, vacuum-drying below 40 ℃ obtains 1.63 gram (S)-pantoprazoles behind the purifying.Yield: 42.56%; Ee (%): 98.36%.
(1R, 2S)-1-amino-2-indanol 0.007mol is dissolved in the 20ml acetonitrile, and whipped state adds Ti (OiPr) down
4(0.005mol), be cooled to-10 ℃, stirred 15 minutes, add pantoprazole thioether (0.01mol) then; Slowly drip hydrogen phosphide cumene 0.02mol then, continue reaction 8 hours, in reaction system, add 20ml toluene, stir 10min; Add 12.5% ammoniacal liquor (50ml * 3) then and respectively stir 20min, separatory merges the ammoniacal liquor layer; In ice-water bath, transfer pH to 7.5～8 then, use ETHYLE ACETATE (50ml * 3) extraction again, merge organic layer with glacial acetic acid; Steam ETHYLE ACETATE then,, drip the 3ml petroleum ether and stirring then the acetic acid ethyl dissolution of (the S)-pantoprazole episome that obtains with 3ml; Filter, vacuum-drying below 40 ℃ obtains 1.70 gram (S)-pantoprazoles behind the purifying.Yield: 44.39%; Ee (%): 98.90%.
(1R, 2S)-1-amino-2-indanol 0.009mol is dissolved in the 20ml acetonitrile, and whipped state adds Ti (OiPr) down
4(0.005mol), be cooled to 0 ℃, stirred 15 minutes, add pantoprazole thioether (0.01mol) then; Slowly drip hydrogen phosphide cumene 0.03mol then, continue reaction 5 hours, in reaction system, add 20ml toluene, stir 10min; Add 12.5% ammoniacal liquor (50ml * 3) then and respectively stir 20min, separatory merges the ammoniacal liquor layer; In ice-water bath, transfer pH to 7.5～8 then, use ETHYLE ACETATE (50ml * 3) extraction again, merge organic layer with glacial acetic acid; Steam ETHYLE ACETATE then,, drip the 3ml petroleum ether and stirring then the acetic acid ethyl dissolution of (the S)-pantoprazole episome that obtains with 3ml; Filter, vacuum-drying below 40 ℃ obtains restraining 2.11 (S)-pantoprazoles behind the purifying.Yield: 55.09%; Ee (%): 98.96%.
Embodiment 11
(S)-pantoprazole episome 2.64g that embodiment 1 method is made is dissolved in the 23ml acetonitrile, adds the NaOH solution stirring of 0.55g 50% then, steams acetonitrile then, and the ether that adds 15ml again stirs, and filters, and drying can obtain (S)-Pantoprazole Sodium.Recrystallization promptly obtains highly purified (S)-Pantoprazole Sodium in 9ml acetone and 18ml water then, and suction filtration vacuum-drying below 40 ℃ obtains 2.71g (S)-Pantoprazole Sodium, and yield is 97.0%.
Claims (9)
1. method for preparing (S)-pantoprazole; It is characterized in that comprising: chiral ligand, titanium tetraisopropylate, pantoprazole thioether and hydrogen phosphide cumene reaction are promptly got; Wherein chiral ligand be (1R, 2S)-1-amino-2-indanol or (1S, 2R)-1-amino-2-indanol.
2. the process of claim 1 wherein that the mol ratio of pantoprazole thioether, chiral ligand, titanium tetraisopropylate, hydrogen phosphide cumene is: 1: 0.5～1: 0.1～0.5: 1～3.
3. the preparation method of claim 2, wherein the mol ratio of pantoprazole thioether, chiral ligand, titanium tetraisopropylate, hydrogen phosphide cumene is: 1: 1: 0.5: 2.32.
4. the process of claim 1 wherein that reaction solvent is selected from: one or more of hexane, methylene dichloride, chloroform, tetracol phenixin, benzene,toluene,xylene, chlorobenzene, oil of mirbane, ether, tertbutyl ether, N, N-Methyl pyrrolidone, acetonitrile.
5. the method for claim 4, wherein reaction solvent is an acetonitrile.
6. the process of claim 1 wherein and comprise: add chiral ligand and titanium tetraisopropylate reaction 10 to 60 minutes earlier, add the reaction of pantoprazole thioether and hydrogen phosphide cumene again.
7. the method for claim 1 also comprises purifying, and purification process is: add toluene in the reaction system earlier, add ammoniacal liquor then; Merge the ammoniacal liquor layer, in ice-water bath, transfer pH to 7.5～8, use ethyl acetate extraction again, merge organic layer with glacial acetic acid; Revolve and steam ETHYLE ACETATE, in the pantoprazole episome that obtains, add ETHYLE ACETATE and stir and make it dissolving, drip sherwood oil then; Stirring is separated out solid for a moment and is added the ETHYLE ACETATE stirring again, filters, and vacuum-drying gets (S)-pantoprazole.
8. method for preparing (S)-Pantoprazole Sodium is characterized in that comprising: (the S)-pantoprazole of claim 1 preparation is dissolved in the acetonitrile, adds the NaOH solution stirring then, steam acetonitrile, and stirrings that add diethyl ether again, filtration, drying promptly gets.
9. the process of claim 1 wherein that temperature of reaction is 10 ℃ to 20 ℃.
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Cited By (7)
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| CN102863426A (en) * | 2012-09-21 | 2013-01-09 | 湖南赛隆药业有限公司 | Improved method for preparing (-)-pantoprazole sodium through Sharpless asymmetric epoxidation reaction |
| CN103242294A (en) * | 2013-03-23 | 2013-08-14 | 广东华南药业集团有限公司 | (S)-pantoprazole sodium dihydrate and preparation method thereof |
| CN103570682A (en) * | 2012-07-31 | 2014-02-12 | 江苏柯菲平医药有限公司 | Preparation method of S-pantoprazole sodium |
| CN105693694A (en) * | 2016-04-22 | 2016-06-22 | 广东华南药业集团有限公司 | Method for refining (S)-pantoprazole |
| CN105968097A (en) * | 2016-05-17 | 2016-09-28 | 杭州华东医药集团新药研究院有限公司 | Industrial production method of S-pantoprazole sodium |
| CN106632249A (en) * | 2016-09-30 | 2017-05-10 | 青岛云天生物技术有限公司 | Method for preparing (S)-pantoprazole sodium |
| CN108503622A (en) * | 2018-04-28 | 2018-09-07 | 福州闽海药业有限公司 | A kind of process for purification of Pantoprazole Sodium |
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| CN103570682A (en) * | 2012-07-31 | 2014-02-12 | 江苏柯菲平医药有限公司 | Preparation method of S-pantoprazole sodium |
| CN102863426A (en) * | 2012-09-21 | 2013-01-09 | 湖南赛隆药业有限公司 | Improved method for preparing (-)-pantoprazole sodium through Sharpless asymmetric epoxidation reaction |
| CN103242294A (en) * | 2013-03-23 | 2013-08-14 | 广东华南药业集团有限公司 | (S)-pantoprazole sodium dihydrate and preparation method thereof |
| CN105693694A (en) * | 2016-04-22 | 2016-06-22 | 广东华南药业集团有限公司 | Method for refining (S)-pantoprazole |
| CN105693694B (en) * | 2016-04-22 | 2019-01-25 | 广东华南药业集团有限公司 | A kind of refining methd of (S)-Pantoprazole |
| CN105968097A (en) * | 2016-05-17 | 2016-09-28 | 杭州华东医药集团新药研究院有限公司 | Industrial production method of S-pantoprazole sodium |
| CN106632249A (en) * | 2016-09-30 | 2017-05-10 | 青岛云天生物技术有限公司 | Method for preparing (S)-pantoprazole sodium |
| CN108503622A (en) * | 2018-04-28 | 2018-09-07 | 福州闽海药业有限公司 | A kind of process for purification of Pantoprazole Sodium |
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