CN104250290A - Method for separating and purifying caspofungin or its salt - Google Patents
Method for separating and purifying caspofungin or its salt Download PDFInfo
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- CN104250290A CN104250290A CN201310266048.2A CN201310266048A CN104250290A CN 104250290 A CN104250290 A CN 104250290A CN 201310266048 A CN201310266048 A CN 201310266048A CN 104250290 A CN104250290 A CN 104250290A
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Abstract
The invention provides a method for separating and purifying caspofungin or its salt, which comprises the following steps: separating caspofungin or its pharmaceutically acceptable salt in a reversed column chromatography, then recrystallizing, and drying to obtain caspofungin or its pharmaceutically acceptable salt with high purity. The prepared end product has the advantages of high purity and low production cost, the medicine quality is increased, operation is simple, and the method is suitable for industrial production.
Description
Technical field
The present invention relates to the separation purification method of Caspofungin or its pharmacy acceptable salt.
Background technology
Caspofungin (Caspofungin) is that lung reads rhzomorph B0(Pneumocandin B0) semi-synthetic derivative, there is spectrum antifungal activity.Its acetate February calendar year 2001 in U.S.'s Initial Public Offering.The structural formula of Caspofungin is such as formula shown in I:
Caspofungin is semi-synthetic lipopeptid (echinocandin) compound being synthesized by Glarea Lozoyensis tunning and come, and its preparation method is open in the many sections of patents such as WO9421677, EP620232, WO9624613.By fermentation with semi-synthetic after Caspofungin have to pass through separation and purification and just can reach medicinal standard.
Disclose with the method for preparation HPLC purifying Caspofungin in US5552521, with C18 post for stationary phase, with acetonitrile/water/acetic acid for eluent.The method only can obtain the product that purity is 78%.Disclose in CN102153616 to punch the method for resin separation purification Caspofungin, but the product that this method obtains all needs could obtain higher purity by recrystallization, separation and purification operation so repeatedly, too much carry out more than refrigerating temperature, add the possibility that Caspofungin impurity produces, be unfavorable for that very much the quality of the finished product and security control.Not only increase production cost, and mostly be high-pressure system, not easily amplify production.
The method of the Caspofungin of purifying disclosed in prior art, also mostly there is production prices costliness, product yield or purity can not meet quality product and security needs, therefore need one more convenient, purification efficiency is high, is suitable for the purification process of industrialized Caspofungin and salt thereof.
Summary of the invention
The object of the present invention is to provide the separation purification method of a kind of Caspofungin or its pharmacy acceptable salt.
Described pharmacy acceptable salt comprises the salt formed with following acid: hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid, toxilic acid, citric acid, acetic acid, tartrate, succsinic acid, oxysuccinic acid etc., the salt preferably formed with acetic acid.
Described method comprises the following steps:
Step 1): get Caspofungin or its pharmacy acceptable salt crude product, loading is to reversed phase chromatography post;
Pre-treatment volume percent is the ethanol dress post of 90%, then is the ethanol-formic acid solution balance pillar of 35% ︰ 10% by volume percent, and loading chromatography process carries out at normal temperatures and pressures, and moving phase speed is 110mL/min.
Described Caspofungin crude product preparation method can refer to method disclosed in Chinese patent 200680042233.1 and prepares.
Described reverse chromatography column filler is C4-C18 reverse phase silica gel filler, is more preferably C18 reverse phase silica gel filler.
The particle diameter of the post material of described reversed phase chromatography post is 10-100um, is preferably 20-50um, is more preferably 30-40um.
Further, the aperture of described reverse phase silica gel filler is 50-300, and preferred 100-200, is more preferably 120-150.
Described reverse silicagel column filler can be purchased from the filler of UniSilTM 10-RPC, the UniSil TM 15-RPC of Suzhou Nano-Micro Bio-technology Co., Ltd., UniSil TM 20-RPC, UniSil TM 30-RPC, UniSil TM 40-RPC or UniSil TM 50-RPC model, the filler of preferred UniSil TM 30-RPC or UniSil TM 40-RPC model, the more preferably filler of UniSil TM 30-RPC model.
Step 2) use A solvent washing pillar, then resolve with B solvent, Fractional Collections elutriant, elutriant is evaporated to 1/3rd of cumulative volume;
Described A solvent refers to that volume percent is the EtOH-MeOH solution of 40%-50% ︰ 10%-20%, is preferably 45% ︰ 15%.
Described B solvent refers to that volume percent is the EtOH-MeOH solution of 60%-70% ︰ 10%, is preferably 65% ︰ 10%.
Step 3), in above-mentioned concentrated solution, drips anti-solvent, separates out solid, filters to obtain Caspofungin or its salt.
Described reverse solvent is ethyl acetate or methyl acetate solvent, ethyl acetate solvent.
Separation condition gentleness of the present invention is easy to operate, applicant finds, method of the present invention solves the problem that a small amount of impurity can not be removed, the target product purity after separation is made to reach more than 95%, the quality not only increasing product also avoid the problems such as complicated operation in prior art, product purity be low, the quality of product is protected, realizes industrialization and produce the production cost greatly reducing product.
embodiment:
embodiment 1:
Get 5g Caspofungin dissolving crude product in the solution of 400ml 45% alcohol-water (V/V), then adjust pH4.0 with formic acid, filter to obtain 400ml filtrate, the upper reversed-phase column of above-mentioned filtrate.
Get the C18 filler that 300g reverse phase silica gel UniSil TM 20-RPC aperture is 100, with 95% ethanolic soln dress post, column type is 300mm × 15mm × 5 um, is then the ethanol-formic acid solution balance pillar of 35% ︰ 10% by volume percent.Under normal temperature and pressure, moving phase speed is that 110mL/min loading is complete, rinse with the EtOH-MeOH solution 1500ml that volume percent is 45% ︰ 15% again, then resolve with the EtOH-MeOH solution 1500ml that volume percent is 65% ︰ 10%, start after wash-out 1000ml to collect, amount to after collecting 1500ml and stop collecting, merge and collect liquid, at 60 DEG C, be evaporated to 500ml.
To in above-mentioned concentrated solution, drip ethyl acetate solvent 120ml, leave standstill 3h and separate out solid, filter Caspofungin 3.85g, HPLC detection purity is 96.7%.
embodiment 2:
Get 5g Caspofungin dissolving crude product in the solution of 400ml 45% alcohol-water (V/V), then adjust pH4.0 with formic acid, filter to obtain 400ml filtrate, the upper reversed-phase column of above-mentioned filtrate.
Get the C8 filler that 300g reverse phase silica gel UniSil TM 10-RPC aperture is 100, with 95% ethanolic soln dress post, column type is 250mm × 20mm × 5 um, is then the ethanol-formic acid solution balance pillar of 35% ︰ 10% by volume percent.Under normal temperature and pressure, moving phase speed is that 110mL/min loading is complete, rinse with the EtOH-MeOH solution 1600ml that volume percent is 40% ︰ 10% again, then resolve with the EtOH-MeOH solution 1500ml that volume percent is 60% ︰ 10%, start after wash-out 1000ml to collect, amount to after collecting 1500ml and stop collecting, merge and collect liquid, at 50 DEG C, be evaporated to 500ml.
To in above-mentioned concentrated solution, drip ethyl acetate solvent 150ml, leave standstill 3h and separate out solid, filter Caspofungin 3.69g, HPLC detection purity is 97.5%.
embodiment 3:
Get 5g Caspofungin dissolving crude product in the solution of 500ml 45% alcohol-water (V/V), then adjust pH4.0 with formic acid, filter to obtain 500ml filtrate, the upper reversed-phase column of above-mentioned filtrate.
Get the C4 filler that 300g reverse phase silica gel UniSil TM 50-RPC aperture is 100, with 95% ethanolic soln dress post, column type is 250mm × 20mm × 5 um, is then the ethanol-formic acid solution balance pillar of 35% ︰ 10% by volume percent.Under normal temperature and pressure, moving phase speed is that 110mL/min loading is complete, rinse with the EtOH-MeOH solution 1500ml that volume percent is 50% ︰ 20% again, then resolve with the EtOH-MeOH solution 1500ml that volume percent is 70% ︰ 10%, start after wash-out 1000ml to collect, amount to after collecting 1500ml and stop collecting, merge and collect liquid, at 50 DEG C, be evaporated to 500ml.
To in above-mentioned concentrated solution, drip methyl acetate solvent 120ml, leave standstill 3h and separate out solid, filter Caspofungin 4.02g, HPLC detection purity is 95.3%.
embodiment 4:
Get 5g Caspofungin dissolving crude product in the solution of 500ml 45% alcohol-water (V/V), then adjust pH4.0 with formic acid, filter to obtain 500ml filtrate, the upper reversed-phase column of above-mentioned filtrate.
Get the C18 filler that 300g reverse phase silica gel UniSil TM 30-RPC aperture is 100, with 95% ethanolic soln dress post, column type is 250mm × 15mm × 5 um, is then the ethanol-formic acid solution balance pillar of 35% ︰ 10% by volume percent.Under normal temperature and pressure, moving phase speed is that 110mL/min loading is complete, rinse with the EtOH-MeOH solution 1500ml that volume percent is 45% ︰ 15% again, then resolve with the EtOH-MeOH solution 1500ml that volume percent is 65% ︰ 10%, start after wash-out 1000ml to collect, amount to after collecting 1500ml and stop collecting, merge and collect liquid, at 50 DEG C, be evaporated to 500ml.
To in above-mentioned concentrated solution, drip methyl acetate solvent 120ml, leave standstill 3h and separate out solid, filter Caspofungin 3.67g, HPLC detection purity is 97.6%.
embodiment 5:
Get 5g Caspofungin dissolving crude product in the solution of 500ml 45% alcohol-water (V/V), then adjust pH4.0 with formic acid, filter to obtain 500ml filtrate, the upper reversed-phase column of above-mentioned filtrate.
Get the C18 filler that 300g reverse phase silica gel UniSil TM40-RPC aperture is 100, with 95% ethanolic soln dress post, column type is 250mm × 15mm × 5 um, is then the ethanol-formic acid solution balance pillar of 35% ︰ 10% by volume percent.Under normal temperature and pressure, moving phase speed is that 110mL/min loading is complete, rinse with the EtOH-MeOH solution 1500ml that volume percent is 45% ︰ 15% again, then resolve with the EtOH-MeOH solution 1500ml that volume percent is 70% ︰ 10%, start after wash-out 1200ml to collect, amount to after collecting 1500ml and stop collecting, merge and collect liquid, at 50 DEG C, be evaporated to 500ml.
To in above-mentioned concentrated solution, drip methyl acetate solvent 120ml, leave standstill 3h and separate out solid, filter Caspofungin 3.75g, HPLC detection purity is 97.1%.
embodiment 6:
Get 5g caspofungin acetate dissolving crude product in the solution of 400ml 45% alcohol-water (V/V), then adjust pH4.0 with formic acid, filter to obtain 400ml filtrate, the upper reversed-phase column of above-mentioned filtrate.
Get the C18 filler that 300g reverse phase silica gel UniSil TM15-RPC aperture is 100, with 95% ethanolic soln dress post, column type is 250mm × 15mm × 5 um, is then the ethanol-formic acid solution balance pillar of 35% ︰ 10% by volume percent.Under normal temperature and pressure, moving phase speed is that 110mL/min loading is complete, rinse with the EtOH-MeOH solution 1500ml that volume percent is 45% ︰ 15% again, then resolve with the EtOH-MeOH solution 1500ml that volume percent is 70% ︰ 10%, start after wash-out 1000ml to collect, amount to after collecting 1500ml and stop collecting, merge and collect liquid, at 50 DEG C, be evaporated to 500ml.
To in above-mentioned concentrated solution, drip methyl acetate solvent 130ml, leave standstill 3h and separate out solid, filter Caspofungin 2.68g, HPLC detection purity is 96.9%.
It should be noted that and the foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, all any amendments done within the spirit and principles in the present invention, equivalent replacement and improvement etc., all should be included within protection scope of the present invention.
Claims (10)
1. a separation purification method for Caspofungin or its pharmacy acceptable salt, is characterized in that comprising the following steps:
1) get Caspofungin or its pharmacy acceptable salt crude product, loading is to reversed phase chromatography post;
2) with A solvent washing pillar, then resolve with B solvent, collect elutriant and concentrate;
3) in above-mentioned concentrated solution, drip anti-solvent, separate out solid, filter to obtain Caspofungin or its salt.
2. the method for claim 1, it is characterized in that the reverse chromatography column filler described in step 1) is C4-C18 reverse phase silica gel filler, packing material size is 10-100um, and aperture is 50-300.
3. the method for claim 1, it is characterized in that the reverse chromatography column filler described in step 1) is C18 reverse phase silica gel filler, packing material size is 20-50um, and aperture is 100-200.
4. the method for claim 1, it is characterized in that the reverse chromatography column filler described in step 1) is C18 reverse phase silica gel filler, packing material size is 30-40um, and aperture is 120-150.
5. the method for claim 1, is characterized in that the reverse silicagel column filler described in step 1) can be purchased from the filler of UniSilTM 10-RPC, the UniSil TM 15-RPC of Suzhou Nano-Micro Bio-technology Co., Ltd., UniSil TM 20-RPC, UniSil TM 30-RPC, UniSil TM 40-RPC or UniSil TM 50-RPC model.
6. the method for claim 1, is characterized in that step 2) described in A solvent refer to that volume percent is the EtOH-MeOH solution of 40%-50% ︰ 10%-20%.
7. the method for claim 1, is characterized in that step 2) described in A solvent refer to that volume percent is the EtOH-MeOH solution of 45% ︰ 15%.
8. the method for claim 1, is characterized in that step 2) described in B solvent refer to that volume percent is the EtOH-MeOH solution of 60%-70% ︰ 10%.
9. the method for claim 1, is characterized in that step 2) described in B solvent refer to that volume percent is the EtOH-MeOH solution of 65% ︰ 10%.
10. the method for claim 1, is characterized in that the reverse solvent described in step 3) is ethyl acetate or methyl acetate solvent.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104910258A (en) * | 2015-06-23 | 2015-09-16 | 苏州纳微科技有限公司 | Method for finely purifying caspofungin |
| CN114456092A (en) * | 2022-01-14 | 2022-05-10 | 江苏诺泰澳赛诺生物制药股份有限公司 | Method for separating and purifying cinacalcet intermediate impurities |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020188011A1 (en) * | 2001-04-20 | 2002-12-12 | King Ivan C. | Antiviral agents and methods of treating viral infections |
| CN102076707A (en) * | 2008-06-25 | 2011-05-25 | 特瓦药厂私人有限公司 | Caspofungin free of caspofungin impurity A |
| CN102153616A (en) * | 2010-12-27 | 2011-08-17 | 浙江海正药业股份有限公司 | Separation and purification method for cyclohexyl peptide compounds and salts thereof |
| CN103180336A (en) * | 2010-09-28 | 2013-06-26 | 中化帝斯曼制药有限公司荷兰公司 | Method for isolating cyclohexapeptide |
-
2013
- 2013-06-28 CN CN201310266048.2A patent/CN104250290A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020188011A1 (en) * | 2001-04-20 | 2002-12-12 | King Ivan C. | Antiviral agents and methods of treating viral infections |
| CN102076707A (en) * | 2008-06-25 | 2011-05-25 | 特瓦药厂私人有限公司 | Caspofungin free of caspofungin impurity A |
| CN103180336A (en) * | 2010-09-28 | 2013-06-26 | 中化帝斯曼制药有限公司荷兰公司 | Method for isolating cyclohexapeptide |
| CN102153616A (en) * | 2010-12-27 | 2011-08-17 | 浙江海正药业股份有限公司 | Separation and purification method for cyclohexyl peptide compounds and salts thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104910258A (en) * | 2015-06-23 | 2015-09-16 | 苏州纳微科技有限公司 | Method for finely purifying caspofungin |
| CN114456092A (en) * | 2022-01-14 | 2022-05-10 | 江苏诺泰澳赛诺生物制药股份有限公司 | Method for separating and purifying cinacalcet intermediate impurities |
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Address after: Suzhou City, Jiangsu Province, Suzhou Industrial Park 215123 Xinghu Street No. 218 Nano Technology Park building C25 Applicant after: Borui Pharmaceutical (Suzhou) Limited by Share Ltd Applicant after: Xintai Pharmaceutical (Suzhou) Co., Ltd. Address before: Xinghu Street Industrial Park of Suzhou city in Jiangsu province 215123 No. 218 BioBAY building C27 Applicant before: Borui Bio-medical Technology (Jiangsu) Co., Ltd. Applicant before: Xintai Pharmaceutical (Suzhou) Co., Ltd. |
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Application publication date: 20141231 |