CN103951675A - Preparation method for clopidogrel hydrogen sulphate - Google Patents
Preparation method for clopidogrel hydrogen sulphate Download PDFInfo
- Publication number
- CN103951675A CN103951675A CN201410185431.XA CN201410185431A CN103951675A CN 103951675 A CN103951675 A CN 103951675A CN 201410185431 A CN201410185431 A CN 201410185431A CN 103951675 A CN103951675 A CN 103951675A
- Authority
- CN
- China
- Prior art keywords
- preparation
- clopidogrel
- organic solvent
- free alkali
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Abstract
The invention provides a preparation method for clopidogrel hydrogen sulphate. The preparation method for clopidogrel hydrogen sulphate comprises the following steps: dissolving clopidogrel free alkali in an organic solvent to obtain a solvent system mixture, adding the solvent system mixture in a concentrated sulphuric acid organic solvent at a temperature of minus 20 to 20 DEG C, stirring to separate out solids, then heating to 15-50 DEG C and continuing to stir for 3-20 hours, and filtering and drying to obtain the clopidogrel hydrogen sulphate. The preparation method provided by the invention is convenient to operate, simple in aftertreatment and especially has a remarkable effect of reducing the residual solvent of clopidogrel hydrogen sulphate; the obtained product is high in yield, good in purity, stable in quality, and suitable for large-scale industrialized production.
Description
Technical field
The present invention relates to low and high-purity sulfuric acid clopidogrel hydrogen compound of a kind of solvent residual amount and preparation method thereof.
Technical background
Cardiovascular and cerebrovascular thrombotic diseases is a kind of major disease that has a strong impact on human health, but anticoagulant is the effective way of this disease for the treatment of.Bisulfate clopidogrel (Clopidogrel Hydrogen Sulfate, suc as formula I) be anticoagulant of new generation, chemistry (S)-α-(2-chloro-phenyl-)-6 by name, 7-dihydro-thiophene also [3,2-c] pyridine-5 (4H)-methyl acetate hydrosulfate, commodity are called Plavix (Plavix).This product is researched and developed by French Sai Nuofei, takes the lead in March, 1998, in U.S.'s listing, entering Chinese market August calendar year 2001.Effective in cure strong, safe, the advantage such as side effect is little, expense is low of this medical instrument, has become the first-line drug for the treatment of thrombotic diseases at present.
Prepare at present the solvent that bisulfate clopidogrel is conventional and have methyl iso-butyl ketone (MIBK), ethyl acetate and methyl tertiary butyl ether etc.The method of preparation is first clopidogrel free alkali to be dissolved, and then adds the vitriol oil of dilution, separates out bisulfate clopidogrel.But the bisulfate clopidogrel product that uses the method to prepare often has the shortcomings such as salify is insufficient, residual solvent is high.The insufficient meeting of salify causes finished product to have being clamminess the phenomenon of reuniting, and the too high meeting of residual solvent causes product unstable.In addition,, in the process of later stage placement, too high residual solvent also can impel impurity A and impurity C to raise at the content of finished product.WO2010046852 patent report uses ethyl acetate to pull an oar to bisulfate clopidogrel, reduced to a certain extent the content of residual solvent, but it is not remarkable to fall the effect of residual solvent, and can introduces another kind of solvent, the making beating of use ethyl acetate, has also increased the risk that turns brilliant.
The preparation method that traditional sulfuric acid joins in free alkali often contains a large amount of residual solvents.And feeding manner, as dropping order, material concentration and churning time have larger impact to residual solvent.Therefore, need to carry out to these processing parameters the optimization of system, exploitation is a kind of obtains low and highly purified clopidogrel hydrogen sulfate compound of solvent residual amount and preparation method thereof.
Summary of the invention
The object of the invention is to develop low and highly purified clopidogrel hydrogen sulfate compound of a kind of solvent residual amount and preparation method thereof, make the bisulfate clopidogrel product making have low residual solvent, the good and method of high purity, quality is applicable to industrialized production.
The preparation method of a kind of bisulfate clopidogrel provided by the invention, adopts following technical scheme:
First clopidogrel free alkali is dissolved in to organic solvent, then by above-mentioned solvent system mixture, at-20～20 DEG C of temperature, drop in vitriol oil organic solvent, stirring is separated out after solid, then be warming up to 15～50 DEG C continue to stir after 3～20 hours, filter, the dry bisulfate clopidogrel that to obtain.
Organic solvent described in the method is ketone, ester or ethers; Wherein, ketone is selected from methyl iso-butyl ketone (MIBK), 2-butanone, 2 pentanone, tertiary butyl methyl ketone or cyclopentanone, preferable methyl isobutyl ketone; Ester class is selected from methyl acetate, ethyl acetate or n-butyl acetate, ethyl acetate, and ethers is selected from methyl tertiary butyl ether or isopropyl ether, preferable methyl tertbutyl ether.
The mass percent concentration of the vitriol oil organic solvent described in the method is 1～30%, and preferred concentration is 3～15%.
Clopidogrel free alkali liquid is added in vitriol oil organic solvent at-20～20 DEG C described in the method, preferably temperature is-15～10 DEG C.
It is 5～50% that clopidogrel free alkali liquid described in the method is dissolved in its mass percent concentration in organic solvent, and preferred concentration is 5～25%.
Clopidogrel free alkali described in the method is 1: 1～1: 2 with the ratio of sulfuric acid amount of substance, and the amount ratio of preferred substance is 1: 1～1: 1.5.
The dropping clopidogrel free alkali liquid time described in the method is preferably 0.5～5 hour, and further preferably the time is 1～3 hour.
Described in the method, be warming up to 15～50 DEG C, preferably temperature is 20～40 DEG C.
Continuation churning time described in the method is 3～20 hours, and preferably the time is 5～15 hours.
Clopidogrel free alkali is dissolved in organic solvent by optimal technical scheme of the present invention, then by above-mentioned solvent system mixture, at-20～20 DEG C of temperature, drop in vitriol oil organic solvent, stirring is separated out after solid, be warming up to again 15～50 DEG C continue to stir after 3～20 hours, filter, the dry bisulfate clopidogrel that to obtain, wherein organic solvent is methyl iso-butyl ketone (MIBK) or ethyl acetate or methyl tertiary butyl ether.
The present invention is by above preferred technical scheme, provide a kind of solvent residual amount low and highly purified clopidogrel hydrogen sulfate compound I, this Compound I comprise methyl iso-butyl ketone (MIBK)≤500ppm or more low energy reach 380ppm, ethyl acetate≤420ppm or more low energy reach 330ppm, and methyl tertiary butyl ether≤240ppm or more low energy reach 120ppm;
The preparation method's tool that adopts the present invention to reduce bisulfate clopidogrel residual solvent has the following advantages:
1, easy to operate, aftertreatment simple, be applicable to industrial amplification production;
2, acquisition the finished product solvent residual amount is low, constant product quality, the high residual solvent successful that reduces of purity;
3, crystallization salify is abundant, avoids the double team of clopidogrel free alkali.
Embodiment
The present invention is further described in conjunction with the embodiments.Following examples just illustrate the present invention, and not limit by any way the present invention.
The quality examination of bisulfate clopidogrel and analysis are respectively with reference to the bisulfate clopidogrel determination method specifying in American Pharmacopeia and European Pharmacopoeia.
Embodiment 1: by 10g concentrated sulfuric acid dissolution in 990g methyl isobutyl ketone solution, cooling solution to 20 DEG C until completely dissolved, then slowly adding mass concentration is 50% clopidogrel free alkali methyl isobutyl ketone solution 63g, feed time is 0.5h, limit edged stirs, separate out white solid, after feeding in raw material, reaction solution is warming up to 15 DEG C, at this temperature, continue to stir 3h, filter, dry, obtain bisulfate clopidogrel, detect as bisulfate clopidogrel crystal formation I through XRD, yield 88%, purity is 99.8%, mp:184～186 DEG C, [α]
d=55.0 °, residual solvent (GC): 450ppm.
Embodiment 2: by 10g concentrated sulfuric acid dissolution in 323g methyl isobutyl ketone solution, cooling solution to 20 DEG C until completely dissolved, then slowly adding mass concentration is 40% clopidogrel free alkali methyl isobutyl ketone solution 75g, time for adding is 1h, limit edged stirs, separate out white solid, after feeding in raw material, reaction solution is warming up to 20 DEG C, at this temperature, continue to stir 5h, filter, dry, obtain bisulfate clopidogrel, detect as bisulfate clopidogrel crystal formation I through XRD, yield 90%, purity is 99.6%, mp:184～186 DEG C, [α]
d=55.0 °, residual solvent (GC): 500ppm.
Embodiment 3: by 10g concentrated sulfuric acid dissolution in 24g methyl isobutyl ketone solution, cooling solution to 20 DEG C until completely dissolved, then slowly adding mass concentration is 30% clopidogrel free alkali methyl isobutyl ketone solution 73g, time for adding is 2h, limit edged stirs, separate out white solid, after feeding in raw material, reaction solution is warming up to 30 DEG C, at this temperature, continue to stir 10h, filter, dry, obtain bisulfate clopidogrel, detect as bisulfate clopidogrel crystal formation I through XRD, yield 85%, purity is 99.8%, mp:184～186 DEG C, [α]
d=55.0 °, residual solvent (GC): 460ppm.
Embodiment 4: by 10g concentrated sulfuric acid dissolution in 57g methyl isobutyl ketone solution, cooling solution to 20 DEG C until completely dissolved, then slowly adding mass concentration is 25% clopidogrel free alkali methyl isobutyl ketone solution 66g, time for adding is 3h, limit edged stirs, separate out white solid, after feeding in raw material, reaction solution is warming up to 40 DEG C, at this temperature, continue to stir 15h, filter, dry, obtain bisulfate clopidogrel, detect as bisulfate clopidogrel crystal formation I through XRD, yield 83%, purity is 99.5%, mp:184～186 DEG C, [α]
d=55.0 °, residual solvent (GC): 380ppm.
Embodiment 5: by 10g concentrated sulfuric acid dissolution in 90g ethyl acetate solution, cooling solution to 20 DEG C until completely dissolved, then slowly adding mass concentration is 15% clopidogrel free alkali ethyl acetate solution 210g, time for adding is 5h, limit edged stirs, separate out white solid, after feeding in raw material, reaction solution is warming up to 50 DEG C, at this temperature, continue to stir 20h, filter, dry, obtain bisulfate clopidogrel, detect as bisulfate clopidogrel crystal formation I through XRD, yield 91%, purity is 99.7%, mp:184～186 DEG C, [α]
d=55.0 °, residual solvent (GC): 330ppm.
Embodiment 6: by 10g concentrated sulfuric acid dissolution in 323g ethyl acetate solution, cooling solution to 20 DEG C until completely dissolved, then slowly adding mass concentration is 5% clopidogrel free alkali ethyl acetate solution 596g, time for adding is 1h, limit edged stirs, separate out white solid, after feeding in raw material, reaction solution is warming up to 20 DEG C, at this temperature, continue to stir 3h, filter, dry, obtain bisulfate clopidogrel, detect as bisulfate clopidogrel crystal formation I through XRD, yield 92%, purity is 99.6%, mp:184～186 DEG C, [α]
d=55.0 °, residual solvent (GC): 350ppm.
Embodiment 7: by 10g concentrated sulfuric acid dissolution in 24g ethyl acetate solution, cooling solution to 20 DEG C until completely dissolved, then slowly adding mass concentration is 40% clopidogrel free alkali ethyl acetate solution 55g, time for adding is 2h, limit edged stirs, separate out white solid, after feeding in raw material, reaction solution is warming up to 25 DEG C, at this temperature, continue to stir 5h, filter, dry, obtain bisulfate clopidogrel, detect as bisulfate clopidogrel crystal formation I through XRD, yield 84%, purity is 99.8%, mp:184～186 DEG C, [α]
d=55.0 °, residual solvent (GC): 420ppm.
Embodiment 8: by 10g concentrated sulfuric acid dissolution in 990g ethyl acetate solution, cooling solution to 20 DEG C until completely dissolved, then slowly adding mass concentration is 50% clopidogrel free alkali ethyl acetate solution 33g, time for adding is 3h, limit edged stirs, separate out white solid, after feeding in raw material, reaction solution is warming up to 35 DEG C, at this temperature, continue to stir 10h, filter, dry, obtain bisulfate clopidogrel, detect as bisulfate clopidogrel crystal formation I through XRD, yield 83%, purity is 99.5%, mp:184～186 DEG C, [α]
d=55.0 °, residual solvent (GC): 410ppm.
Embodiment 9: by 10g concentrated sulfuric acid dissolution in 90g methyl tertbutyl ethereal solution, cooling solution to 20 DEG C until completely dissolved, then slowly adding mass concentration is 30% clopidogrel free alkali methyl tertbutyl ethereal solution 106g, time for adding is 0.5h, limit edged stirs, separate out white solid, after feeding in raw material, reaction solution is warming up to 30 DEG C, at this temperature, continue to stir 15h, filter, dry, obtain bisulfate clopidogrel, detect as bisulfate clopidogrel crystal formation I through XRD, yield 90%, purity is 99.6%, mp:184～186 DEG C, [α]
d=55.0 °, residual solvent (GC): 210ppm.
Embodiment 10: by 10g concentrated sulfuric acid dissolution in 57g methyl tertbutyl ethereal solution, cooling solution to 20 DEG C until completely dissolved, then slowly adding mass concentration is 15% clopidogrel free alkali methyl tertbutyl ethereal solution 199g, time for adding is 1h, limit edged stirs, separate out white solid, after feeding in raw material, reaction solution is warming up to 40 DEG C, at this temperature, continue to stir 20h, filter, dry, obtain bisulfate clopidogrel, detect as bisulfate clopidogrel crystal formation I through XRD, yield 87%, purity is 99.5%, mp:184～186 DEG C, [α]
d=55.0 °, residual solvent (GC): 120ppm.
Embodiment 11: by 10g concentrated sulfuric acid dissolution in 323g methyl tertbutyl ethereal solution, cooling solution to 20 DEG C until completely dissolved, then slowly adding mass concentration is 25% clopidogrel free alkali methyl tertbutyl ethereal solution 88g, time for adding is 2h, limit edged stirs, separate out white solid, after feeding in raw material, reaction solution is warming up to 45 DEG C, at this temperature, continue to stir 10h, filter, dry, obtain bisulfate clopidogrel, detect as bisulfate clopidogrel crystal formation I through XRD, yield 86%, purity is 99.7%, mp:184～186 DEG C, [α]
d=55.0 °, residual solvent (GC): 240ppm.
Embodiment 12: by 10g concentrated sulfuric acid dissolution in 90g methyl tertbutyl ethereal solution, cooling solution to 20 DEG C until completely dissolved, then slowly adding mass concentration is 5% clopidogrel free alkali methyl tertbutyl ethereal solution 328g, time for adding is 3h, limit edged stirs, separate out white solid, after feeding in raw material, reaction solution is warming up to 50 DEG C, at this temperature, continue to stir 12h, filter, dry, obtain bisulfate clopidogrel, detect as bisulfate clopidogrel crystal formation I through XRD, yield 89%, purity is 99.6%, mp:184～186 DEG C, [α]
d=55.0 °, residual solvent (GC): 200ppm.
Table 1. residual solvent analytical results
Low and high-purity sulfuric acid clopidogrel hydrogen compound of a kind of solvent residual amount that the present invention proposes and preparation method thereof is described by embodiment, person skilled obviously can change reduction bisulfate clopidogrel residual solvent method as herein described in content of the present invention, spirit and scope or suitably change and combination not departing from, and realizes the technology of the present invention.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they are all deemed to be included in spirit of the present invention, scope and content.
Claims (10)
1. bisulfate clopidogrel, Compound I, includes methyl iso-butyl ketone (MIBK) or ethyl acetate or methyl tertiary butyl ether, wherein methyl iso-butyl ketone (MIBK)≤500ppm, ethyl acetate≤420ppm, methyl tertiary butyl ether≤240ppm;
2. the preparation method of a bisulfate clopidogrel, comprise following steps: clopidogrel free alkali is dissolved in organic solvent, by above-mentioned solvent system mixture, at-20～20 DEG C of temperature, drop in vitriol oil organic solvent, stirring is separated out after solid, then be warming up to 15～50 DEG C continue to stir after 3～20 hours, filter, the dry bisulfate clopidogrel that to obtain.
3. preparation method according to claim 2, is characterized in that: for the preparation of Compound I claimed in claim 1.
4. according to the preparation method described in claim 2 or 3, it is characterized in that: described organic solvent is ketone, ester or ether solvent ketone preferable methyl isobutyl ketone, ester ethyl acetate, ether preferable methyl tertbutyl ether.
5. according to the preparation method described in claim 2 or 3, it is characterized in that: the mass percent concentration of described vitriol oil organic solvent is 1～30%, preferred concentration is 3～15%.
6. according to the preparation method described in claim 2 or 3, it is characterized in that: at-15～10 DEG C of temperature, add free alkali lye to vitriol oil organic solvent, time for adding preferably 0.5～5 hour, more preferably 1～3 hour.
7. according to the preparation method described in claim 2 or 3, it is characterized in that: it is 5～50% that described clopidogrel free alkali liquid is dissolved in its mass percent concentration in organic solvent, and preferred concentration is 5～25%.
8. according to the preparation method described in claim 2 or 3, it is characterized in that: described clopidogrel free alkali is 1: 1～1: 2 with the ratio of sulfuric acid amount of substance, the amount ratio of preferred substance is 1: 1～1: 1.5.
9. according to the preparation method described in claim 2 or 3, it is characterized in that: described intensification temperature is 20～40 DEG C.
10. according to the preparation method described in claim 2 or 3, it is characterized in that: described continuation churning time is 5～15 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410185431.XA CN103951675A (en) | 2014-04-29 | 2014-04-29 | Preparation method for clopidogrel hydrogen sulphate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410185431.XA CN103951675A (en) | 2014-04-29 | 2014-04-29 | Preparation method for clopidogrel hydrogen sulphate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103951675A true CN103951675A (en) | 2014-07-30 |
Family
ID=51329051
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410185431.XA Pending CN103951675A (en) | 2014-04-29 | 2014-04-29 | Preparation method for clopidogrel hydrogen sulphate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103951675A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104945413A (en) * | 2015-07-21 | 2015-09-30 | 浙江华海药业股份有限公司 | Preparation method of first hydrogen sulfate clopidogrel crystal form |
| CN107118221A (en) * | 2017-05-24 | 2017-09-01 | 常州制药厂有限公司 | A kind of bisulfate clopidogrel crystal formation I preparation methods |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007102037A2 (en) * | 2006-03-09 | 2007-09-13 | Richter Gedeon Nyrt. | A PROCESS FOR THE PREPARATION OF POLYMORPH FORM I OF (S)-(+)-METHYL-α-(2-CHLOROPHENYL)-6,7-DYHIDRO-THIENO-[3,2-c]PYRIDINE-5(4H)-ACETATE HYDROGEN SULFATE |
| CN102070648A (en) * | 2010-12-07 | 2011-05-25 | 天津红日药业股份有限公司 | Preparation method of clopidogrel hydrogen sulfate I |
| CN102875568A (en) * | 2012-09-06 | 2013-01-16 | 苏州晶云药物科技有限公司 | Method for preparing (+)-(S)-clopidogrel hydrogen sulfate pure crystal type I |
-
2014
- 2014-04-29 CN CN201410185431.XA patent/CN103951675A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007102037A2 (en) * | 2006-03-09 | 2007-09-13 | Richter Gedeon Nyrt. | A PROCESS FOR THE PREPARATION OF POLYMORPH FORM I OF (S)-(+)-METHYL-α-(2-CHLOROPHENYL)-6,7-DYHIDRO-THIENO-[3,2-c]PYRIDINE-5(4H)-ACETATE HYDROGEN SULFATE |
| CN102070648A (en) * | 2010-12-07 | 2011-05-25 | 天津红日药业股份有限公司 | Preparation method of clopidogrel hydrogen sulfate I |
| CN102875568A (en) * | 2012-09-06 | 2013-01-16 | 苏州晶云药物科技有限公司 | Method for preparing (+)-(S)-clopidogrel hydrogen sulfate pure crystal type I |
Non-Patent Citations (1)
| Title |
|---|
| 潘仙华等: "Ⅰ型氯吡格雷硫酸氢盐的合成及晶型转换", 《精细化工》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104945413A (en) * | 2015-07-21 | 2015-09-30 | 浙江华海药业股份有限公司 | Preparation method of first hydrogen sulfate clopidogrel crystal form |
| CN107118221A (en) * | 2017-05-24 | 2017-09-01 | 常州制药厂有限公司 | A kind of bisulfate clopidogrel crystal formation I preparation methods |
| CN107118221B (en) * | 2017-05-24 | 2021-09-07 | 常州制药厂有限公司 | Preparation method of clopidogrel hydrogen sulfate crystal form I |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103694106A (en) | Method for extracting and purifying dihydroartemisinic acid from artemisinin wax oil | |
| CN101863784B (en) | Methods for preparing and extracting betaine and betaine hydrochloride | |
| CN103739520B (en) | A kind of 3,4-dichlorobenzene isocyanic ester process for purification | |
| WO2022237690A1 (en) | Semi-synthetic method for dihydroquercetin | |
| CN102964240A (en) | Preparation method of high-purity glycolic acid crystals | |
| CN107556156B (en) | Method for extracting palmitoleic acid from natural vegetable oil | |
| CN103739484B (en) | The preparation method of 1,4-naphthalene dicarboxylic acids | |
| CN103951675A (en) | Preparation method for clopidogrel hydrogen sulphate | |
| CN102485723A (en) | Semi-synthesis of vinpocetine through one kettle way and preparation of water-soluble vinpocetine salt | |
| CN104557576A (en) | Method for preparing high-purity pregabalin | |
| CN103012288B (en) | Preparation method of 6-chloro-1,3-dimethyluracil | |
| CN105237339B (en) | The method that n-octacosanol is extracted by raw material of sugar refinery mix indicator technique | |
| CN102093263A (en) | Recycling method of levorotation camphorsulfonic acid serving as clopidogrel resolving agent | |
| CN103804310A (en) | Method for preparing high-purity 7-chloro-5-phenyl-benzodiazepine-2-one | |
| CN102757373B (en) | Method for preparing high-purity lutein ester from marigold flower particles | |
| CN100494153C (en) | Extraction separation technology of octagonal shickimmi oxalic acid | |
| CN108084238A (en) | A kind of preparation method of canrenone intermediate | |
| CN108084016A (en) | A kind of high-purity linoleic preparation method | |
| CN113004168A (en) | Production process of methoxyamine for synthesizing furan ammonium salt | |
| CN108299538B (en) | Method for removing isoursodesoxycholic acid in duck bile | |
| WO2013159347A1 (en) | Method for continuously producing high-content high-optical-purity lactate | |
| CN102731340A (en) | Preparation method of demethyl aureomycin hydrochloride | |
| CN101550144B (en) | Preparation technique for mezlocillin | |
| CN104447468A (en) | Deep processing method of lutein extract | |
| CN110862429A (en) | Preparation method of sodium aescinate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20140730 |