CN111004293A - Purification method of clindamycin phosphate - Google Patents
Purification method of clindamycin phosphate Download PDFInfo
- Publication number
- CN111004293A CN111004293A CN201911149328.9A CN201911149328A CN111004293A CN 111004293 A CN111004293 A CN 111004293A CN 201911149328 A CN201911149328 A CN 201911149328A CN 111004293 A CN111004293 A CN 111004293A
- Authority
- CN
- China
- Prior art keywords
- clindamycin phosphate
- reverse micelle
- phase
- clindamycin
- crude
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/14—Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical
- C07H15/16—Lincomycin; Derivatives thereof
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for purifying clindamycin phosphate, which comprises the following process steps of dissolving surface active agent trioctylmethylammonium chloride (TOMAC) in organic solvent ethyl acetate to prepare a reverse micelle extraction system, dissolving surface active agent n-octyl- β -D-glucopyranoside (OGP) and crude clindamycin phosphate in purified water to be used as a water phase, mixing the reverse micelle extraction system with the water phase, extracting, standing for phase separation to obtain a reverse micelle extraction phase containing the clindamycin phosphate, and then adding inorganic salt to crystallize and separate the clindamycin phosphate from the reverse micelle extraction phase.
Description
Technical Field
The invention belongs to the technical field of antibiotic purification, and particularly relates to a purification method of clindamycin phosphate.
Background
Clindamycin phosphate (clindamycin phosphate) is a semisynthetic derivative of clindamycin, has the characteristics of good lipid solubility, high bioavailability and the like, and can be quickly hydrolyzed into clindamycin in vivo to show pharmacological activity. Compared with clindamycin, clindamycin phosphate has the characteristics of high antibacterial activity, quick absorption, strong fat solubility and permeability, less side effect and the like, is widely distributed in vivo, has high tissue concentration, and is particularly suitable for bone tissues; has strong antibacterial effect on various gram-positive bacteria and small side effect, is a broad-spectrum antibiotic with dual broad-spectrum characteristics of resisting anaerobic bacteria and aerobic bacteria, and is mainly used for treating infection caused by anaerobic bacteria and sensitive gram-positive bacteria clinically.
The traditional crystallization method of clindamycin phosphate is to heat, reflux and dissolve a crude product of clindamycin phosphate by ethanol, decolor the crude product by activated carbon, and perform gradient cooling crystallization to obtain a finished product of clindamycin phosphate. The crystallization method in the process has high requirements on equipment, and relates to a large amount of flammable and explosive organic solvent (ethanol), and certain safety risk exists in the crystallization process; and the sewage discharge is not beneficial to environmental protection.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide the method for purifying the clindamycin phosphate, which greatly reduces the using amount of organic solvent, reduces the discharge of industrial sewage, improves the production safety index, reduces the equipment requirement, saves energy, reduces consumption and can improve the product quality.
The technical scheme adopted for realizing the aim of the invention is as follows:
a purification method of clindamycin phosphate is characterized by comprising the following process steps:
dissolving surfactant trioctylmethylammonium chloride (TOMAC) in organic solvent ethyl acetate to prepare a reverse micelle extraction system;
dissolving n-octyl- β -D-glucopyranoside (OGP) as surfactant and clindamycin phosphate crude product in purified water as water phase;
and mixing the reverse micelle extraction system with a water phase, extracting, standing for phase separation to obtain a reverse micelle extraction phase containing the clindamycin phosphate, adding inorganic salt to crystallize and separate the clindamycin phosphate from the reverse micelle extraction phase, and separating.
In the reverse micelle extraction system, the concentration of trioctylmethylammonium chloride (TOMAC) is 10-50 mmol/L;
in the aqueous phase, the concentration of n-octyl- β -D-glucopyranoside (OGP) is 1-10 mmol/L.
In the water phase, the concentration of the clindamycin phosphate crude product is 50000-120000U/ml.
The mixing ratio of the reverse micelle extraction system to the water phase is 1: 1-5 in terms of volume ratio (v: v).
The extraction temperature is 20-40 ℃, and the extraction time is 10-40 min.
The addition amount of the inorganic salt is 5-15% of the feeding amount of the crude clindamycin phosphate product.
The inorganic salt is NaCl or Na2HPO4Or NaH2PO4。
The method adopts a reverse micelle extraction method to replace the traditional crystallization method, namely, trioctylmethylammonium chloride (TOMAC)/ethyl acetate is adopted as a reverse micelle extraction system, n-octyl- β -D-glucopyranoside (OGP) is adopted as an affinity cosurfactant to extract a clindamycin phosphate crude product, after the extraction is finished, inorganic salt (sodium salt) is added to crystallize and separate the clindamycin phosphate so as to separate the clindamycin phosphate from a reverse micelle system, wherein the introduced affinity cosurfactant is used for improving the extraction efficiency of the clindamycin phosphate.
In conclusion, the purification method of clindamycin phosphate is beneficial to improving the purity of the product, avoids the use of flammable and explosive organic solvents, reduces the discharge of sewage, thereby reducing the environmental protection pressure, reducing the production cost and simultaneously reducing the safety risk of the production environment.
Detailed Description
The present invention will now be described in detail by way of examples, which are intended to illustrate the invention and not to limit the invention. The scope and core content of the invention are to be determined by the claims.
The clindamycin phosphate crude product used by the invention is prepared by adopting the currently disclosed synthetic method, and can also be prepared according to the following method: adding clindamycin hydrochloride alcoholate and acetone into a dried enamel glass reaction kettle, cooling to the temperature of less than or equal to-5 ℃, and then dropwise adding phosphorus oxychloride; keeping the temperature between 0 and-5 ℃ for reaction for 0.5 to 1h, after the lamella chromatography shows that the trimethylene protection reaction is complete, adding phosphorus oxychloride at the temperature of less than or equal to-10 ℃, and then dropwise adding pyridine at the temperature of less than or equal to-10 ℃. Then reacting at 0-5 ℃ for at least 2h until the thin plate chromatography shows that the reaction is complete. Adding quantitative purified water into a hydrolysis kettle, and cooling to 0-5 ℃ by using jacket brine for later use. And (3) sucking the reaction liquid into a cooled hydrolysis kettle, controlling the temperature in the kettle to be 25-30 ℃ for hydrolysis for at least 4h, and performing thin-plate chromatography to show that the reaction is complete. Adding Na2CO3Adjusting the pH value in the kettle to 3-4, after adjustment, recovering acetone remained in water in vacuum at the temperature of less than 50 ℃, adding activated carbon into the concentrated solution for decolorization and then performing filter pressing, diluting the filtrate with process water, separating the filtrate by using a macroporous adsorption resin column, washing with purified water, and analyzing methanol, wherein the washing and analyzing flow rates are 400-600L/h. Transferring the methanol analysis solution to a concentration kettle, and carrying out reduced pressure distillation to recover the methanol until the methanol is dry. Adding ethanol, stirring for 0.5-1.0 h at 5-10 ℃, and centrifuging to obtain a clindamycin phosphate crude product. The yield is 70.0-85.0%.
The clindamycin phosphate crude products mentioned in the following examples and comparative examples are clindamycin hydrochloride hydrate crude products prepared by the method.
Example 1
Dissolving TOMAC in ethyl acetate to prepare a 15mmol/L TOMAC ethyl acetate solution serving as a reverse micelle extraction system; using OGP as an affinity cosurfactant, dissolving the crude clindamycin phosphate and OGP in purified water to prepare mixed solutions with the concentrations of about 50000U/ml and 3mmol/L respectively as water phases. Mixing the TOMAC reverse micelle extraction system and the water phase according to the volume ratio of 1:2, stirring and extracting the crude clindamycin phosphate for 15min at the temperature of 25 ℃, standing and phase-separating to obtain a reverse micelle extraction phase containing the clindamycin phosphate. After extraction, adding 15% (weight) NaCl of the crude clindamycin phosphate product to crystallize and separate clindamycin phosphate from reverse micelle so as to separate the clindamycin phosphate from the reverse micelle system. Filtering and drying to obtain the finished product. The extraction yield was 93.43%, with clindamycin B phosphate being 0.89%.
Example 2
Dissolving TOMAC in ethyl acetate to prepare a 30mmol/L TOMAC ethyl acetate solution serving as a reverse micelle extraction system; using OGP as an affinity cosurfactant, dissolving crude clindamycin phosphate and OGP in purified water to prepare mixed solutions with the concentrations of about 80000U/ml and 6mmol/L respectively as water phases. Mixing the TOMAC reverse micelle extraction system and the water phase according to the volume ratio of 1:3, stirring and extracting the crude clindamycin phosphate product for 25min at the temperature of 30 ℃, standing and carrying out phase separation to obtain a reverse micelle extraction phase containing the clindamycin phosphate. After extraction, adding the crude clindamycin phosphate product with the dosage of 12 percent (by weight) of NaCl (or Na)2HPO4Or NaH2PO4) The clindamycin phosphate is crystallized and separated out from the reverse micelle, so that the clindamycin phosphate and the reverse micelle system are separated. Filtering and drying to obtain the finished product. The extraction yield was 94.12% and the clindamycin B phosphate was 0.85%.
Example 3
TOMAC is dissolved in ethyl acetate to prepare a 45mmol/L TOMAC ethyl acetate solution which is used as a reverse micelle extraction system; dissolving crude clindamycin phosphate and OGP in purified water by taking OGP as an affinity cosurfactant to prepare mixed solutions with the concentrations of about 110000U/ml and 10mmol/L respectively as water phases. Mixing the TOMAC reverse micelle extraction system and the water phase according to the volume ratio of 1:5, stirring and extracting the crude clindamycin phosphate product for 40min at the temperature of 20 ℃, standing and carrying out phase separation to obtain a reverse micelle extraction phase containing the clindamycin phosphate. After extraction, adding 5% (weight) NaCl of the crude clindamycin phosphate product to crystallize and separate clindamycin phosphate from reverse micelle so as to separate the clindamycin phosphate from the reverse micelle system. Filtering and drying to obtain the finished product. The extraction yield was 94.81% and the clindamycin B phosphate was 0.87%.
Comparative example 1
Adding ethanol into the clindamycin phosphate crude product according to the proportion of 1:8 (m: v), heating, refluxing, dissolving, and slowly adding water until a clear solution is obtained. Then adding activated carbon to carry out decolorization treatment for 30min, transferring the decolorized solution into a crystallization kettle, reducing the temperature to 25 ℃ at a free cooling rate, and preserving the temperature for 3 h; then the temperature is reduced to 0 ℃ and the temperature is kept for 2 h. Centrifuging, rinsing with ethanol, and drying to obtain the final product. The crystal yield was 80.30% and the clindamycin B phosphate was 1.27%.
Comparative example 2
Adding ethanol into the clindamycin phosphate crude product according to the proportion of 1:9 (m: v), heating, refluxing, dissolving, and slowly adding water until a clear solution is obtained. Then adding activated carbon to carry out decoloring treatment for 40min, transferring the decoloring solution to a crystallization kettle, reducing the temperature to 30 ℃ at a free cooling rate, and preserving the temperature for 3 h; then the temperature is reduced to 3 ℃ and the temperature is preserved for 3 hours. Centrifuging, rinsing with ethanol, and drying to obtain the final product. The crystal yield was 82.14% and clindamycin B phosphate was 1.15%.
Claims (8)
1. A purification method of clindamycin phosphate is characterized by comprising the following process steps:
dissolving surfactant trioctylmethylammonium chloride in organic solvent ethyl acetate to prepare a reverse micelle extraction system;
dissolving n-octyl- β -D-glucopyranoside as a surfactant and a crude clindamycin phosphate in purified water to be used as a water phase;
and mixing the reverse micelle extraction system with a water phase, extracting, standing for phase separation to obtain a reverse micelle extraction phase containing the clindamycin phosphate, adding inorganic salt to crystallize and separate the clindamycin phosphate from the reverse micelle extraction phase, and separating.
2. The purification method of clindamycin phosphate according to claim 1, characterized in that the concentration of trioctylmethylammonium chloride in the reverse micelle extraction system is 10-50 mmol/L.
3. The purification method of clindamycin phosphate according to claim 1, wherein the concentration of n-octyl- β -D-glucopyranoside in the aqueous phase is 1 to 10 mmol/L.
4. The method for purifying clindamycin phosphate according to claim 1, wherein the concentration of the crude clindamycin phosphate in the aqueous phase is 50000-120000U/ml.
5. The purification method of clindamycin phosphate according to claim 1, wherein the mixing ratio of the reverse micelle extraction system to the water phase is 1: 1-5 in terms of volume ratio.
6. The purification method of clindamycin phosphate according to claim 1, wherein the extraction temperature is 20-40 ℃ and the extraction time is 10-40 min.
7. The method for purifying clindamycin phosphate according to claim 1, wherein the addition amount of the inorganic salt is 5 to 15 percent of the feeding amount of the crude clindamycin phosphate.
8. Process for the purification of clindamycin phosphate according to claim 1 or 7, characterized in that the inorganic salt is NaCl or Na2HPO4Or NaH2PO4。
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911149328.9A CN111004293B (en) | 2019-11-21 | 2019-11-21 | Purification method of clindamycin phosphate |
| PCT/CN2020/130604 WO2021098847A1 (en) | 2019-11-21 | 2020-11-20 | Clindamycin phosphate purification method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911149328.9A CN111004293B (en) | 2019-11-21 | 2019-11-21 | Purification method of clindamycin phosphate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111004293A true CN111004293A (en) | 2020-04-14 |
| CN111004293B CN111004293B (en) | 2022-12-27 |
Family
ID=70113172
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911149328.9A Active CN111004293B (en) | 2019-11-21 | 2019-11-21 | Purification method of clindamycin phosphate |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN111004293B (en) |
| WO (1) | WO2021098847A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112574260A (en) * | 2020-11-29 | 2021-03-30 | 宁夏泰益欣生物科技有限公司 | Purification method of tylosin tartrate |
| WO2021098847A1 (en) * | 2019-11-21 | 2021-05-27 | 宁夏泰益欣生物科技有限公司 | Clindamycin phosphate purification method |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IN184009B (en) * | 1995-12-29 | 2000-06-03 | Council Scient Ind Res | |
| CN101928307A (en) * | 2010-08-24 | 2010-12-29 | 安徽省皖北药业股份有限公司 | Crystallization method of clindamycin phosphate |
| CN103772454A (en) * | 2013-04-27 | 2014-05-07 | 杭州领业医药科技有限公司 | Refining method for clindamycin phosphate |
| CN107880083A (en) * | 2017-12-21 | 2018-04-06 | 广州白云山天心制药股份有限公司 | A kind of process for purification of clindamycin phosphate |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111004293B (en) * | 2019-11-21 | 2022-12-27 | 宁夏泰益欣生物科技股份有限公司 | Purification method of clindamycin phosphate |
-
2019
- 2019-11-21 CN CN201911149328.9A patent/CN111004293B/en active Active
-
2020
- 2020-11-20 WO PCT/CN2020/130604 patent/WO2021098847A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IN184009B (en) * | 1995-12-29 | 2000-06-03 | Council Scient Ind Res | |
| CN101928307A (en) * | 2010-08-24 | 2010-12-29 | 安徽省皖北药业股份有限公司 | Crystallization method of clindamycin phosphate |
| CN103772454A (en) * | 2013-04-27 | 2014-05-07 | 杭州领业医药科技有限公司 | Refining method for clindamycin phosphate |
| CN107880083A (en) * | 2017-12-21 | 2018-04-06 | 广州白云山天心制药股份有限公司 | A kind of process for purification of clindamycin phosphate |
Non-Patent Citations (3)
| Title |
|---|
| SING C. CHUO，ET AL.: "A new method of extraction of amoxicillin using mixed reverse micelles", 《COLLOIDS AND SURFACES A: PHYSICOCHEMICAL AND ENGINEERING ASPECTS》 * |
| 李夏兰，等: "反胶束萃取技术及其在抗生素分离上的应用", 《中国抗生素杂志》 * |
| 纪蓓，等: "反胶束萃取技术在生物工程中的应用", 《食品与发酵工业》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021098847A1 (en) * | 2019-11-21 | 2021-05-27 | 宁夏泰益欣生物科技有限公司 | Clindamycin phosphate purification method |
| CN112574260A (en) * | 2020-11-29 | 2021-03-30 | 宁夏泰益欣生物科技有限公司 | Purification method of tylosin tartrate |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2021098847A1 (en) | 2021-05-27 |
| CN111004293B (en) | 2022-12-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2014094405A1 (en) | Method for extraction and preparation of avermectin b2a | |
| CN111004293B (en) | Purification method of clindamycin phosphate | |
| CN102911036A (en) | Method for obtaining high pure dicarboxylic acid | |
| CN110002992A (en) | A kind of refining methd of positive long-chain biatomic acid | |
| CN102453011A (en) | Preparation method of high-purity naringenin | |
| CN106749258B (en) | Method for purifying ertapenem sodium | |
| CN109553645B (en) | Method for extracting low-content erythromycin A in fermentation solution | |
| CN103772186A (en) | Refining method of fermented organic acid | |
| CN113549031A (en) | Method for refining dipheny hydrochloride | |
| CN109134556B (en) | Hydrochloric acid crystallization separation and purification method of lincomycin | |
| CN111171096B (en) | Extraction method of pleocidin | |
| WO2020207130A1 (en) | Process for separating and purifying artemisinin | |
| CN105949253B (en) | A kind of purification process of Clindamycin Hydrochloride | |
| EP1756055A1 (en) | Process for the purification of tryptophan | |
| CN104292283B (en) | The purification process of nimoctin | |
| CN110041307A (en) | The preparation method of esomeprazole sulfide intermediate | |
| CN102432645A (en) | Purifying method for etimicin sulfate | |
| CN101792476B (en) | Method for extracting and separating fusidic acid | |
| CN109020933A (en) | A kind of purification process of Mycophenolic Acid | |
| CN110606844B (en) | Mupirocin purification method | |
| CN106928290A (en) | A kind of preparation method of high content rutin | |
| CN108976224B (en) | Method for extracting and purifying ergometrine from fermentation liquor | |
| CN105732547A (en) | Preparation method of dehydrated andrographolide diacid half ester basic salt | |
| CN110894207B (en) | Purification method of clindamycin palmitate hydrochloride | |
| CN116768910B (en) | Refining method of rifabutin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Address after: 750205 Yinchuan Biotechnology Park, Helan County, Yinchuan City, Ningxia Hui Autonomous Region Applicant after: Ningxia Taiyixin Biotechnology Co.,Ltd. Address before: 750205 Yinchuan Biotechnology Park, Helan County, Yinchuan City, Ningxia Hui Autonomous Region Applicant before: NINGXIA TAIYICIN BIOTECH Co.,Ltd. |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant |