CN111647030A - Method for improving purity of clindamycin hydrochloride - Google Patents
Method for improving purity of clindamycin hydrochloride Download PDFInfo
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- CN111647030A CN111647030A CN202010561572.2A CN202010561572A CN111647030A CN 111647030 A CN111647030 A CN 111647030A CN 202010561572 A CN202010561572 A CN 202010561572A CN 111647030 A CN111647030 A CN 111647030A
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- clindamycin
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- clindamycin hydrochloride
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- 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
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- 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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for improving the purity of clindamycin hydrochloride, which comprises the steps of taking clindamycin hydrochloride containing impurities such as dehydroclindamycin, clindamycin B, epimeddium and the like as a raw material, dissolving the raw material in water, adding a raney nickel catalyst, introducing hydrogen for reaction, filtering the raney nickel catalyst, adjusting the pH of filtrate, removing or reducing the clindamycin B and the epimeddium, and crystallizing to obtain the high-purity clindamycin hydrochloride. The method for improving the purity of clindamycin hydrochloride provided by the invention has the advantages that the Raney nickel catalyst is used for hydrogenation reaction, the dehydroclindamycin can be removed, the Raney nickel catalyst is easy to recover, no solid waste is generated, the clindamycin B and the epimeddin are removed by using the solubility difference of the clindamycin, the clindamycin B and the epimeddin under the alkaline condition, the impurities of the clindamycin hydrochloride are reduced, the quality and the purity of the clindamycin hydrochloride are improved, the cost is low, the method is suitable for industrial production, the hydrogenation reaction pressure is low, the safe production coefficient is high, the technological process is short, and the yield is high.
Description
Technical Field
The invention belongs to the technical field of organic matter purification, and particularly relates to a method for improving the purity of clindamycin hydrochloride.
Background
Clindamycin hydrochloride belongs to lincomycin antibiotics, is a derivative of lincomycin, has the same antibacterial spectrum as lincomycin, and has the antibacterial activity 4-8 times stronger than that of lincomycin. The clindamycin hydrochloride has quick action, no first-pass effect, difficult loss of medicine content and reliable curative effect. Has high antibacterial activity against gram-positive bacteria such as Staphylococcus (including penicillin-resistant strains), Streptococcus, Corynebacterium diphtheriae, Bacillus anthracis, etc. The antibacterial agent also has good antibacterial activity on gram-negative anaerobes, and the bacteroides comprise bacteroides fragilis, clostridium, peptococcus, clostridium perfringens and the like, and are mostly highly sensitive to clindamycin hydrochloride. Gram-negative aerobic bacteria include haemophilus influenzae, neisseria and mycoplasma, all resistant to clindamycin hydrochloride. The clindamycin hydrochloride has no cross drug resistance with penicillin, chloramphenicol, cephalosporins and tetracyclines, has partial cross drug resistance with macrolides, and has complete cross drug resistance with lincomycin. The action mechanism is that the peptide chain is prevented from being prolonged by combining with bacterial ribosome 50S subunit, thereby inhibiting the protein synthesis of bacterial cells, and the peptide chain is a bacteriostatic agent, but has bactericidal effect on certain bacteria at high concentration.
Clindamycin hydrochloride mainly contains the following impurities: dehydroclindamycin, clindamycin B, epimeclindamycin, and the like.
The invention discloses a Chinese patent with publication number CN102964402A, namely clindamycin hydrochloride without dehydroclindamycin, a preparation method and application thereof, and discloses a method for removing dehydroclindamycin by adopting palladium-carbon as a catalyst to carry out hydrogenation reaction. However, palladium carbon is expensive and has high industrialization cost, and the reaction pressure is high due to the use of a solvent in the reaction, which causes certain danger. The invention discloses a Chinese patent with publication number CN107200758A, which discloses a method for preparing high-purity clindamycin and clindamycin salt, and discloses a method for reducing clindamycin B by dissociating clindamycin hydrochloride in alkaline water, extracting with a solvent, concentrating the solvent, and then adding another solvent for crystallization.
Disclosure of Invention
In order to solve the technical problems in the prior art, the invention aims to provide a method for improving the purity of clindamycin hydrochloride.
In order to achieve the purpose and achieve the technical effect, the invention adopts the technical scheme that:
a method for improving the purity of clindamycin hydrochloride comprises the following steps:
dissolving clindamycin hydrochloride containing impurities such as dehydroclindamycin, clindamycin B, epimeddium and the like in water; adding Raney nickel catalyst, and introducing hydrogen to react, so that dehydro-clindamycin reacts to generate clindamycin; filtering out Raney nickel catalyst, adjusting the pH value of the filtrate to be alkaline, and removing clindamycin B and epimeddin; then hydrochloric acid is added, and the required high-purity clindamycin hydrochloride is obtained through crystallization.
Further, the method comprises the following steps:
dissolving clindamycin hydrochloride containing impurities such as dehydroclindamycin, clindamycin B, epimeddium and the like in water;
adding Raney nickel catalyst, and introducing hydrogen to react for 8-10h to make dehydro-clindamycin react to generate clindamycin;
filtering to remove Raney nickel catalyst, adjusting the filtrate to alkalinity with dilute alkali solution, standing for crystallization, filtering, and removing clindamycin B and epimeddin;
adding acetone to dissolve, adding hydrochloric acid, crystallizing, filtering, washing and vacuum drying to obtain the required high-purity clindamycin hydrochloride.
Further, the weight ratio of the clindamycin hydrochloride containing impurities such as dehydroclindamycin, clindamycin B, epimeclindamycin and the like to water is 1: 2-4.
Furthermore, the addition amount of the Raney nickel catalyst is 1/100-1/200 of the weight of the clindamycin hydrochloride.
Furthermore, before introducing hydrogen, nitrogen is used for replacing air in the hydrogenation reactor for a plurality of times under a sealed condition, and then hydrogen is introduced, wherein the pressure in the reaction process is not more than 0.2 MPa.
Further, adjusting the pH value of the filtrate to 8-12 by using dilute alkali liquor.
Further, the dilute alkali solution is 10% sodium hydroxide solution or potassium carbonate solution or sodium carbonate solution and the like.
Compared with the prior art, the invention has the beneficial effects that:
the invention discloses a method for improving purity of clindamycin hydrochloride, which comprises the steps of taking clindamycin hydrochloride containing impurities such as dehydroclindamycin, clindamycin B, clindamycin epime and the like as a raw material, dissolving the clindamycin hydrochloride in water with 2-4 times of the weight of the clindamycin hydrochloride, adding a raney nickel catalyst of 1/100-1/200 in the weight of the clindamycin hydrochloride, introducing hydrogen for reacting for 8-10h to enable the dehydroclindamycin to react to generate the clindamycin, filtering out the raney nickel catalyst, adjusting the pH of filtrate to 8-12 by using dilute alkali liquor, removing or reducing the clindamycin B and the clindamycin epime, and crystallizing to obtain the high-purity clindamycin hydrochloride. The method for improving the purity of clindamycin hydrochloride provided by the invention adopts the Raney nickel catalyst to carry out hydrogenation reaction, so that dehydroclindamycin is generated into clindamycin, the Raney nickel catalyst is easy to recover, no solid waste is generated, the solubility difference of clindamycin, clindamycin B and epimembrin under an alkaline condition is utilized to remove or reduce clindamycin B and epimembrin, the impurities of clindamycin hydrochloride are reduced, the quality and the purity of clindamycin hydrochloride are improved, the hydrogenation reaction pressure is low, the safety production coefficient is improved, the whole process is short, the yield is high, the cost is low, the method is suitable for industrial production, and the method has a wide application prospect.
Detailed Description
The following detailed description of the embodiments of the present invention is provided to enable those skilled in the art to more easily understand the advantages and features of the present invention, and to clearly and clearly define the scope of the present invention.
Example 1
Dissolving 50g of clindamycin hydrochloride containing dehydro-clindamycin, clindamycin B and epimedamycin impurities in 100mL of purified water, adding a raney nickel catalyst-palladium carbon of 0.5g, introducing hydrogen under 0.2Mpa, reacting for 8 hours to ensure that the dehydro-clindamycin reacts to generate clindamycin, filtering out the raney nickel catalyst, dropwise adding 10% NaOH into the filtrate, adjusting the pH of the filtrate to 8, standing for crystallization, filtering to obtain clindamycin, drying, dissolving in 500mL of acetone solution, dropwise adding 18mL of concentrated HCl, crystallizing after 3-5min, washing with acetone after filtering, and drying in vacuum at 60 ℃ to obtain the required high-purity clindamycin hydrochloride.
In example 1, the removal rate of dehydrolincomycin was 99%, the removal rate of clindamycin B was 98%, the removal rate of epimeddium was 95%, and the yield was 98.5%.
Example 2
Dissolving 100g of clindamycin hydrochloride containing dehydroclindamycin, clindamycin B and epimeddium in 400mL of purified water, adding a raney nickel catalyst-palladium carbon of 0.5g, introducing hydrogen under 0.2Mpa, reacting for 10h to ensure that the dehydroclindamycin reacts to generate clindamycin, filtering the raney nickel catalyst, dropwise adding 10% NaOH into the filtrate, adjusting the pH of the filtrate to 12, standing for crystallization, filtering to obtain clindamycin, adding 1000mL of acetone for dissolution after spin-drying, dropwise adding 36mL of concentrated HCl, crystallizing after 5-8min, filtering, washing with acetone, and vacuum-drying at 60 ℃ to obtain clindamycin hydrochloride.
In this example 2, the removal rate of dehydrolincomycin is 99%, the removal rate of clindamycin B is 98.5%, the removal rate of epimeddium is 96%, and the yield is: 98 percent.
Example 3
Dissolving 100g of clindamycin hydrochloride containing dehydroclindamycin, clindamycin B and epimeddium in 300mL of purified water, adding 1.0g of raney nickel catalyst-palladium carbon, introducing hydrogen under 0.2Mpa, reacting for 9h to ensure that the dehydroclindamycin reacts to generate clindamycin, filtering the raney nickel catalyst, dropwise adding 10% NaOH into the filtrate, adjusting the pH to 11.5, standing for crystallization, filtering to obtain clindamycin, adding 1000mL of acetone for dissolution after spin-drying, dropwise adding 36mL of concentrated HCl, crystallizing after 5-8min, filtering, washing with acetone, and vacuum-drying at 60 ℃ to obtain clindamycin hydrochloride.
In this example 3, the removal rate of dehydrolincomycin is 99%, the removal rate of clindamycin B is 98.5%, the removal rate of epimeddium is 95.5%, and the yield is: 98 percent.
Example 4
Dissolving 100g of clindamycin hydrochloride containing dehydroclindamycin, clindamycin B and epimeddium in 300mL of purified water, adding 1.0g of raney nickel catalyst-palladium carbon, introducing hydrogen under 0.2Mpa, reacting for 9h to ensure that the dehydroclindamycin reacts to generate clindamycin, filtering the raney nickel catalyst, dropwise adding saturated potassium carbonate solution into the filtrate, adjusting the pH to 9, standing for crystallization, filtering to obtain clindamycin, adding 1000mL of acetone for dissolution after spin-drying, dropwise adding 36mL of concentrated HCl, crystallizing after 5-8min, filtering, washing with acetone, and vacuum drying at 60 ℃ to obtain clindamycin hydrochloride.
In this example 4, the removal rate of dehydrolincomycin is 99%, the removal rate of clindamycin B is 99%, the removal rate of epimeddium is 97%, and the yield is: 98.5 percent.
Example 5
Dissolving 100g of clindamycin hydrochloride containing dehydroclindamycin, clindamycin B and epimeddium in 300mL of purified water, adding 1.0g of raney nickel catalyst-palladium carbon, introducing hydrogen under 0.2Mpa, reacting for 9h to ensure that the dehydroclindamycin reacts to generate clindamycin, filtering out the raney nickel catalyst, dropwise adding saturated sodium carbonate solution into the filtrate, adjusting the pH to 9, standing for crystallization, filtering to obtain clindamycin, adding 1000mL of acetone for dissolution after spin-drying, dropwise adding 36mL of concentrated HCl, crystallizing after 5-8min, filtering, washing with acetone, and vacuum-drying at 60 ℃ to obtain the clindamycin hydrochloride.
In this example 5, the removal rate of dehydrolincomycin is 99%, the removal rate of clindamycin B is 99%, the removal rate of epimeddium clindamycin is 97.5%, and the yield is: 99 percent.
The parts of the invention which are not described in detail adopt the prior art, and the modules which are not described in detail only adopt the existing products, and are not described in detail herein.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes, which are made by the present specification, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.
Claims (6)
1. A method for improving the purity of clindamycin hydrochloride is characterized by comprising the following steps:
dissolving clindamycin hydrochloride containing impurities such as dehydroclindamycin, clindamycin B, epimeddium and the like in water;
adding Raney nickel catalyst, and introducing hydrogen to react, so that dehydro-clindamycin reacts to generate clindamycin;
filtering out Raney nickel catalyst, adjusting the pH value of the filtrate to be alkaline, and removing clindamycin B and epimeddin;
adding hydrochloric acid, and crystallizing to obtain the required high-purity clindamycin hydrochloride.
2. The method for improving the purity of clindamycin hydrochloride according to claim 1, which is characterized by comprising the following steps:
dissolving clindamycin hydrochloride containing impurities such as dehydroclindamycin, clindamycin B, epimeddium and the like in water with the weight 2-4 times of that of the clindamycin hydrochloride;
adding Raney nickel catalyst, and introducing hydrogen to react for 8-10h to make dehydro-clindamycin react to generate clindamycin;
filtering to remove Raney nickel catalyst, adjusting pH of the filtrate to alkalinity with dilute alkali solution, standing for crystallization, filtering, and removing clindamycin B and epimeddin;
adding acetone to dissolve, adding hydrochloric acid, crystallizing, filtering, washing and vacuum drying to obtain the required high-purity clindamycin hydrochloride.
3. The method for improving the purity of clindamycin hydrochloride according to claim 1 or 2, wherein the Raney nickel catalyst is added in an amount of 1/100-1/200 based on the weight of clindamycin hydrochloride.
4. The method for improving the purity of clindamycin hydrochloride according to claim 1 or 2, characterized in that before the hydrogen is introduced, nitrogen is used for replacing air in the hydrogenation reactor for a plurality of times under sealed conditions, and then the hydrogen is introduced, wherein the pressure in the reaction process is not more than 0.2 MPa.
5. The method for improving the purity of clindamycin hydrochloride according to claim 1 or 2, characterized in that the pH value of the filtrate is adjusted to 8-12 by using dilute alkali liquor.
6. The method for improving the purity of clindamycin hydrochloride according to claim 5, characterized in that the dilute alkali solution is 10% sodium hydroxide solution or potassium carbonate solution or sodium carbonate solution.
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| CN202010561572.2A CN111647030A (en) | 2020-06-18 | 2020-06-18 | Method for improving purity of clindamycin hydrochloride |
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| CN202010561572.2A CN111647030A (en) | 2020-06-18 | 2020-06-18 | Method for improving purity of clindamycin hydrochloride |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101891778A (en) * | 2010-06-17 | 2010-11-24 | 张家港市信谊化工有限公司 | Process for synthesizing clindamycin hydrochloride |
| CN102964400A (en) * | 2012-11-20 | 2013-03-13 | 广州白云山天心制药股份有限公司 | Preparation method and applications of dehydro-lincomycin-free lincomycin hydrochloride |
| CN102964402A (en) * | 2012-11-20 | 2013-03-13 | 广州白云山天心制药股份有限公司 | Dehydro-clindamycin-free clindamycin hydrochloride and preparation method and applications thereof |
| CN107200758A (en) * | 2017-05-17 | 2017-09-26 | 广州品红制药有限公司 | A kind of preparation method of high-purity clindamycin and clindamycin salt |
| CN108409812A (en) * | 2018-02-09 | 2018-08-17 | 新宇药业股份有限公司 | A kind of method of dehydrogenation lincomycin in reduction Lincomycin Hydrochloride |
-
2020
- 2020-06-18 CN CN202010561572.2A patent/CN111647030A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101891778A (en) * | 2010-06-17 | 2010-11-24 | 张家港市信谊化工有限公司 | Process for synthesizing clindamycin hydrochloride |
| CN102964400A (en) * | 2012-11-20 | 2013-03-13 | 广州白云山天心制药股份有限公司 | Preparation method and applications of dehydro-lincomycin-free lincomycin hydrochloride |
| CN102964402A (en) * | 2012-11-20 | 2013-03-13 | 广州白云山天心制药股份有限公司 | Dehydro-clindamycin-free clindamycin hydrochloride and preparation method and applications thereof |
| CN107200758A (en) * | 2017-05-17 | 2017-09-26 | 广州品红制药有限公司 | A kind of preparation method of high-purity clindamycin and clindamycin salt |
| CN108409812A (en) * | 2018-02-09 | 2018-08-17 | 新宇药业股份有限公司 | A kind of method of dehydrogenation lincomycin in reduction Lincomycin Hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| JOHN D. GINN ET AL.: "Intramolecular [4+2]-cycloaddition reactions of cyclic 2-thiomethyl-5-amidofurans", 《TETRAHEDRON LETTERS》 * |
| 陶慎熹等译: "《高等有机化学 反应、机理和结构（上册）》", 31 October 1981, 人民教育出版社 * |
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Application publication date: 20200911 |