CN105001243A - Method for industrially preparing chromatographically pure vinorelbine - Google Patents
Method for industrially preparing chromatographically pure vinorelbine Download PDFInfo
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- CN105001243A CN105001243A CN201510398974.4A CN201510398974A CN105001243A CN 105001243 A CN105001243 A CN 105001243A CN 201510398974 A CN201510398974 A CN 201510398974A CN 105001243 A CN105001243 A CN 105001243A
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- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/04—Dimeric indole alkaloids, e.g. vincaleucoblastine
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Abstract
The invention discloses a method for industrially preparing chromatographically pure vinorelbine. The method comprises: (1) preparing a chromatographic column by using a silica gel obtained by swelling an organic solvent A as chromatographic column filler; (2) adding a vinorelbine coarse product organic solvent A solution into the chromatographic column; (3) eluting the chromatographic column by using a gradient elution method, sequentially using a mixed liquid of the organic solvent A/an organic solvent B with gradually decreased volume ratio as an eluant to elute, collecting a principle component effluent, and finally underwashing residues; and (4) carrying out concentration at a reduced pressure to recover the eluant so as to obtain high purity vinorelbine. A product provided by the invention is high in purity, and according to the method, the purity of vinorelbine can reach over 98% and the yield of vinorelbine is 60-98%. A stationary phase is stable and can be repeatedly used.
Description
Technical field
The present invention relates to the separating and purifying technology of vinorelbine, particularly relate to a kind of method of preparing chromatograph in industry purifying vinorelbine, belong to chemical pharmacy field.
Background technology
Vinorelbine (English name: vinorelbine) is the plant antitumor drug of the listing nineties in last century, so far be still the front-line chemotherapeutic agents of the common cancer such as mammary cancer, nonsmall-cell lung cancer of the comprehensive cancer Guidelines recommend of American National, and be widely used in other malignant tumours such as ovarian cancer, lymphoma.It by with tubulin binding, make cell in mitotic division process microtubule formed obstacle, structural formula is as follows:
Vinorelbine
Domestic to vinorelbine technical grade separation purification method research few.Chinese patent CN10781322A discloses a kind of separation purification method of vinorelbine crude product, and crude product, after alkali alumina post wash-out, obtains just sterling, then through C
18reverse phase filler post wash-out, elutriant is through dichloromethane extraction, obtain vinorelbine sterling by recrystallizing methanol again;
Chinese patent CN 102199165A discloses the technique that vinorelbine crude product obtains high purity product after silica gel column chromatography, alkali alumina column chromatography, but this processing step is various, and production cost is high, is not suitable for suitability for industrialized production.
Chinese patent CN103788117A discloses the lab scale purifying process of vinorelbine as intermediates, and through silica gel column chromatography, product purity can reach more than 99%, but yield is only about 27%, and this process economy is low, is not suitable for suitability for industrialized production.
The present invention have studied a kind of method that preparing chromatograph in industry prepares high purity vinorelbine, product purity high (more than 98%), and process recovery ratio is stablized, and is applicable to industrialized production.
Summary of the invention
The difficult problems such as, complex process low for vinorelbine purification efficiency, the object of this invention is to provide a kind of high purity, strong operability, are applicable to the purification process of the vinorelbine of suitability for industrialized production.
To achieve these goals, the present invention adopts following technical scheme:
A purification process for vinorelbine, comprises the steps:
(1) silica gel after adopting organic solvent A swelling is chromatographic column filler preparative chromatography post;
(2) above-mentioned chromatographic column is added by organic solvent A by after vinorelbine dissolving crude product;
(3) adopt the method for gradient elution to carry out wash-out to chromatographic column, carry out wash-out with organic solvent A/organic solvent B mixed solution that volume ratio reduces gradually as elutriant successively, collect main composition effluent liquid, finally wash lower residue with solvent;
(4) concentrating under reduced pressure reclaims eluent, and obtain high purity vinorelbine, purity 98 more than wt%, yield is 60 ~ 98%.
In above-mentioned preparation method:
In step (1), adopt silica gel to be 100 ~ 400 orders;
In step (1), described organic solvent A is the one in methylene dichloride, propyl carbinol, Methyl isobutyl ketone, ethyl acetate, chloroform, dioxane;
In step (2), vinorelbine applied sample amount is 1 ~ 6 (w/w%), and inlet amount is 1 ~ 12% of preparative chromatography column volume;
In step (3), described organic solvent B is the one in acetone, acetonitrile, dimethyl formamide, methyl alcohol, methyl-sulphoxide;
In step (3), constant pressure and flow pump is adopted to enter eluent, eluent is followed successively by solvent orange 2 A: B=99:1 ~ 75:1 (v/v), solvent orange 2 A: B=65:1 ~ 45:1 (v/v), solvent orange 2 A: B=45:1 ~ 15:1 (v/v), eluting agent is 200 ~ 500% of column volume, and elution flow rate is 1 ~ 10% of per minute wash-out column volume; The pressure that preparative chromatography post runs is 0.1 ~ 0.7 MPa;
In step (3), elutriant Fractional Collections, collects and divides two sections, and first paragraph collects solvent orange 2 A: B=65:1 ~ 45:1 (v/v) cut, is the vinorelbine elutriant that content is lower; Second segment collects solvent orange 2 A: B=45:1 ~ 15:1 (v/v) cut, is mainly high density vinorelbine elutriant.
In step (3), adopt solvent orange 2 A: B=15:1 ~ 5:1 (v/v) wash-out residue.
The present invention for starting raw material, by silica gel preparing chromatograph in industry purifies and separates, realizes the preparation of high purity vinorelbine with vinorelbine crude product.Tool of the present invention has the following advantages:
1, product purity is high, and the method can make the purity of vinorelbine reach more than 98%, and yield is 60 ~ 98%.Stationary phase is stablized, reusable;
2, the eluent that the present invention uses easily reclaims, can Reusability, and production cost is low;
3, technological process is simple, and the disposable input of equipment is little, and energy consumption is low, workable, is applicable to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the liquid-phase chromatographic analysis collection of illustrative plates of the vinorelbine crude material that the embodiment of the present invention 1 adopts.
Fig. 2 is the liquid-phase chromatographic analysis collection of illustrative plates of the vinorelbine product that the embodiment of the present invention 1 obtains.
Embodiment
embodiment 1
1) take 5.96 kg 300 order silica gel, add chloroform and stir, discharge bubble in silica gel, then installed to equably in preparative chromatography by silica gel, column dimension is Φ 20cm × 52cm, after the compacting of stationary phase silica gel, rinse 2h with eluent, obtain the preparative chromatography post installed;
2) dissolved by 270g vinorelbine crude product (purity is 67.00%) chloroform, charging, inlet amount is 300ml;
3) constant pressure and flow pump is adopted to enter eluent, first use chloroform: methyl alcohol=90:1 solvent elution 2 bed, use chloroform instead: methyl alcohol=40:1 solvent elution 3 bed also collects elutriant a, use chloroform instead again: methyl alcohol=30:1 solvent elution 4 bed also collects elutriant b, finally uses chloroform instead: residue in the elution preparative chromatography post of methyl alcohol=15:1;
4) reclaim under reduced pressure elutriant b, obtains vinorelbine 116g, and liquid chromatographic detection purity is 99.72%, and yield is 63.94%.
As shown in Figure 1, the liquid-phase chromatographic analysis collection of illustrative plates of vinorelbine product as shown in Figure 2 for the liquid-phase chromatographic analysis collection of illustrative plates of vinorelbine crude material.
embodiment 2
1) take 6.05 kg 400 order silica gel, add chloroform and stir, discharge bubble in silica gel, then installed to equably in preparative chromatography by silica gel, column dimension is Φ 20cm × 52cm, after the compacting of stationary phase silica gel, rinse 2h with eluent, obtain the preparative chromatography post installed;
2) dissolved by 268g vinorelbine crude product (purity is 67%) chloroform, charging, inlet amount is 280ml;
3) constant pressure and flow pump is adopted to enter eluent, first use chloroform: methyl alcohol=95:1 solvent elution 2 bed, use chloroform instead: methyl alcohol=45:1 solvent elution 3 bed also collects elutriant a, use chloroform instead again: methyl alcohol=35:1 solvent elution 4 bed also collects elutriant b, finally uses chloroform instead: residue in the elution preparative chromatography post of methyl alcohol=15:1;
4) reclaim under reduced pressure elutriant b, obtains vinorelbine 178g, and liquid chromatographic detection purity is 99.1%, and yield is 98.24%.
embodiment 3
1) take 5.98 kg 200 order silica gel, add chloroform and stir, discharge bubble in silica gel, then installed to equably in preparative chromatography by silica gel, column dimension is Φ 20cm × 52cm, after the compacting of stationary phase silica gel, rinse 2h with eluent, obtain the preparative chromatography post installed;
2) dissolved by 290g vinorelbine crude product (purity is 79.21%) chloroform, charging, inlet amount is 320ml;
3) constant pressure and flow pump is adopted to enter eluent, first use chloroform: methyl alcohol=90:1 solvent elution 3 bed, use chloroform instead: methyl alcohol=40:1 solvent elution 3 bed also collects elutriant a, use chloroform instead again: methyl alcohol=30:1 solvent elution 4 bed also collects elutriant b, finally uses chloroform instead: residue in the elution preparative chromatography post of methyl alcohol=10:1;
4) reclaim under reduced pressure elutriant b, obtains vinorelbine 187g, and liquid chromatographic detection purity is 98.31%, and yield is 80.03%.
embodiment 4
1) take 5.96 kg 300 order silica gel, add methylene dichloride and stir, discharge bubble in silica gel, then installed to equably in preparative chromatography by silica gel, column dimension is Φ 20cm × 52cm, after the compacting of stationary phase silica gel, rinse 2h with eluent, obtain the preparative chromatography post installed;
2) dissolved by 290g vinorelbine crude product (purity is 79.21%) methylene dichloride, charging, inlet amount is 320ml;
3) constant pressure and flow pump is adopted to enter eluent, first use methylene dichloride: acetonitrile=80:1 solvent elution 2 bed, use methylene dichloride instead: acetonitrile=35:1 solvent elution 3 bed also collects elutriant a, use methylene dichloride instead again: acetonitrile=25:1 solvent elution 4 bed also collects elutriant b, finally uses methylene dichloride instead: residue in the elution preparative chromatography post of acetonitrile=5:1;
4) reclaim under reduced pressure elutriant b, obtains vinorelbine 212g, and liquid chromatographic detection purity is 98.18%, and yield is 90.62%.
embodiment 5
1) take 5.97 kg 400 order silica gel, add methylene dichloride and stir, discharge bubble in silica gel, then installed to equably in preparative chromatography by silica gel, column dimension is Φ 20cm × 52cm, after the compacting of stationary phase silica gel, rinse 2h with eluent, obtain the preparative chromatography post installed;
2) dissolved by 255g vinorelbine crude product (purity is 79.65%) methylene dichloride, charging, inlet amount is 290ml;
3) constant pressure and flow pump is adopted to enter eluent, first use methylene dichloride: acetonitrile=85:1 solvent elution 3 bed, use methylene dichloride instead: acetonitrile=45:1 solvent elution 4 bed also collects elutriant a, use methylene dichloride instead again: acetonitrile=30:1 solvent elution 4 bed also collects elutriant b, finally uses methylene dichloride instead: residue in the elution preparative chromatography post of acetonitrile=5:1;
4) reclaim under reduced pressure elutriant b, obtains vinorelbine 189.5g, and liquid chromatographic detection purity is 98.12%, and yield is 91.55%.
embodiment 6
1) take 6.20 kg 300 order silica gel, add ethyl acetate and stir, discharge bubble in silica gel, then installed to equably in preparative chromatography by silica gel, column dimension is Φ 20cm × 52cm, after the compacting of stationary phase silica gel, rinse 2h with eluent, obtain the preparative chromatography post installed;
2) by 250g vinorelbine crude product (purity is 79.65%) acetic acid ethyl dissolution, charging, inlet amount is 290ml;
3) constant pressure and flow pump is adopted to enter eluent, first use ethyl acetate: methyl alcohol=99:1 solvent elution 2 bed, use ethyl acetate instead: methyl alcohol=50:1 solvent elution 3 bed also collects elutriant a, use ethyl acetate instead again: methyl alcohol=35:1 solvent elution 3 bed also collects elutriant b, finally uses ethyl acetate instead: residue in the elution preparative chromatography post of methyl alcohol=10:1;
4) reclaim under reduced pressure elutriant b, obtains vinorelbine 196.6g, and liquid chromatographic detection purity is 98.35%, and yield is 97.1%.
embodiment 7
1) take 6.10 kg 400 order silica gel, add ethyl acetate and stir, discharge bubble in silica gel, then installed to equably in preparative chromatography by silica gel, column dimension is Φ 20cm × 52cm, after the compacting of stationary phase silica gel, obtains the preparative chromatography post installed;
2) by 260g vinorelbine crude product (purity is 70.57%) acetic acid ethyl dissolution, charging, inlet amount is 280ml;
3) constant pressure and flow pump is adopted to enter eluent, first use ethyl acetate: methyl alcohol=98:1 solvent elution 2 bed, use ethyl acetate instead: methyl alcohol=48:1 solvent elution 3 bed also collects elutriant a, use ethyl acetate instead again: methyl alcohol=30:1 solvent elution 2 bed also collects elutriant b, finally uses ethyl acetate instead: residue in the elution preparative chromatography post of methyl alcohol=10:1;
4) reclaim under reduced pressure elutriant b, obtains vinorelbine 130g, and liquid chromatographic detection purity is 98.47%, and yield is 69.77%.
embodiment 8
1) take 5.90 kg 400 order silica gel, add chloroform and stir, discharge bubble in silica gel, then installed to equably in preparative chromatography by silica gel, column dimension is Φ 20cm × 52cm, after the compacting of stationary phase silica gel, rinse 2h with eluent, obtain the preparative chromatography post installed;
2) dissolved by 220g vinorelbine crude product (purity is 82.79%) chloroform, charging, inlet amount is 250ml;
3) constant pressure and flow pump is adopted to enter eluent, first use chloroform: acetone=75:1 solvent elution 3 bed, use chloroform instead: acetone=40:1 solvent elution 3 bed also collects elutriant a, use chloroform instead again: acetone=25:1 solvent elution 2 bed also collects elutriant b, finally uses chloroform instead: residue in the elution preparative chromatography post of acetone=5:1;
4) reclaim under reduced pressure elutriant b, obtains vinorelbine 122g, and liquid chromatographic detection purity is 98.43%, and yield is 65.93%.
embodiment 9
1) take 5.80 kg 300 order silica gel, add chloroform and stir, discharge bubble in silica gel, then installed to equably in preparative chromatography by silica gel, column dimension is Φ 20cm × 52cm, after the compacting of stationary phase silica gel, rinse 2h with eluent, obtain the preparative chromatography post installed;
2) dissolved by 216g vinorelbine crude product (purity is 79.19%) chloroform, charging, inlet amount is 240ml;
3) constant pressure and flow pump is adopted to enter eluent, first use chloroform: acetone=80:1 solvent elution 3 bed, use chloroform instead: acetone=45:1 solvent elution 3 bed also collects elutriant a, use chloroform instead again: acetone=30:1 solvent elution 2 bed also collects elutriant b, finally uses chloroform instead: residue in the elution preparative chromatography post of acetone=5:1;
4) reclaim under reduced pressure elutriant b, obtains vinorelbine 156g, and liquid chromatographic detection purity is 98.57%, and yield is 89.90%.
embodiment 10
1) take 6.20 kg 300 order silica gel, add chloroform and stir, discharge bubble in silica gel, then installed to equably in preparative chromatography by silica gel, column dimension is Φ 20cm × 52cm, after the compacting of stationary phase silica gel, rinse 2h with eluent, obtain the preparative chromatography post installed;
2) dissolved by 216g vinorelbine crude product (purity is 79.19%) chloroform, charging, inlet amount is 250ml;
3) constant pressure and flow pump is adopted to enter eluent, first use chloroform: acetone=75:1 solvent elution 3 bed, use chloroform instead: acetone=45:1 solvent elution 3 bed also collects elutriant a, use chloroform instead again: acetone=30:1 solvent elution 2 bed also collects elutriant b, finally uses chloroform instead: residue in the elution preparative chromatography post of acetone=5:1;
4) reclaim under reduced pressure elutriant b, obtains vinorelbine 160g, and liquid chromatographic detection purity is 98.1%, and yield is 91.76%.
Claims (8)
1. a purification process for vinorelbine, is characterized in that comprising the steps:
(1) silica gel after adopting organic solvent A swelling is chromatographic column filler preparative chromatography post;
(2) above-mentioned chromatographic column is added by organic solvent A by after vinorelbine dissolving crude product;
(3) adopt the method for gradient elution to carry out wash-out to chromatographic column, carry out wash-out with organic solvent A/organic solvent B mixed solution that volume ratio reduces gradually as elutriant successively, collect main composition effluent liquid, finally wash lower residue with solvent;
(4) concentrating under reduced pressure reclaims eluent, and obtain high purity vinorelbine, purity 98 more than wt%, yield is 60 ~ 98%.
2. purification process according to claim 1, is characterized in that: in step (1), adopt silica gel to be 100 ~ 400 orders.
3. purification process according to claim 1, is characterized in that: in step (1), and described organic solvent A is the one in methylene dichloride, propyl carbinol, Methyl isobutyl ketone, ethyl acetate, chloroform, dioxane.
4. purification process according to claim 1, is characterized in that: in step (2), and described vinorelbine applied sample amount is 1 ~ 6 (w/w%), and inlet amount is 1 ~ 12% of preparative chromatography column volume.
5. purification process according to claim 1, is characterized in that: in step (3), and described organic solvent B is the one in acetone, acetonitrile, dimethyl formamide, methyl alcohol, methyl-sulphoxide.
6. purification process according to claim 1, it is characterized in that: in step (3), constant pressure and flow pump is adopted to enter eluent, eluent is followed successively by solvent orange 2 A: B=99:1 ~ 75:1 (v/v), solvent orange 2 A: B=65:1 ~ 45:1 (v/v), solvent orange 2 A: B=45:1 ~ 15:1 (v/v), eluting agent is 200 ~ 500% of column volume, and elution flow rate is 1 ~ 10% of per minute wash-out column volume; The pressure that preparative chromatography post runs is 0.1 ~ 0.7 MPa.
7. purification process according to claim 1, is characterized in that: in step (3), elutriant Fractional Collections, collects and divides two sections, and first paragraph collects solvent orange 2 A: B=65:1 ~ 45:1 (v/v) cut; Second segment collects solvent orange 2 A: B=45:1 ~ 15:1 (v/v) cut.
8. purification process according to claim 1, is characterized in that: in step (3), adopts solvent orange 2 A: B=15:1 ~ 5:1 (v/v) wash-out residue.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109206442A (en) * | 2017-06-29 | 2019-01-15 | 江苏汉邦科技有限公司 | A kind of preparation method of vinorelbine monomer |
| CN109988184A (en) * | 2017-12-29 | 2019-07-09 | 江苏豪森药业集团有限公司 | The purification process of vinorelbine |
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| CN101638413A (en) * | 2009-08-28 | 2010-02-03 | 广州汉方现代中药研究开发有限公司 | Separation and purification method for vinca alkaloids |
| CN104725405A (en) * | 2013-12-20 | 2015-06-24 | 中国医药研究开发中心有限公司 | Preparation method of vinorelbine |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101638413A (en) * | 2009-08-28 | 2010-02-03 | 广州汉方现代中药研究开发有限公司 | Separation and purification method for vinca alkaloids |
| CN104725405A (en) * | 2013-12-20 | 2015-06-24 | 中国医药研究开发中心有限公司 | Preparation method of vinorelbine |
Non-Patent Citations (1)
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| 李晓蕾: "抗肿瘤药长春碱的提取分离工艺研究", 《中国优秀硕士学位论文全文数据库 工程科技I辑》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109206442A (en) * | 2017-06-29 | 2019-01-15 | 江苏汉邦科技有限公司 | A kind of preparation method of vinorelbine monomer |
| CN109988184A (en) * | 2017-12-29 | 2019-07-09 | 江苏豪森药业集团有限公司 | The purification process of vinorelbine |
| CN109988184B (en) * | 2017-12-29 | 2021-12-17 | 江苏豪森药业集团有限公司 | Purification method of vinorelbine |
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