CN107954892A - A kind of method of solvent residual amount in reduction quadracycline - Google Patents
A kind of method of solvent residual amount in reduction quadracycline Download PDFInfo
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- CN107954892A CN107954892A CN201711399757.2A CN201711399757A CN107954892A CN 107954892 A CN107954892 A CN 107954892A CN 201711399757 A CN201711399757 A CN 201711399757A CN 107954892 A CN107954892 A CN 107954892A
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- solvent
- quadracycline
- acetone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of method for reducing solvent residual amount in quadracycline, its method：Urea double salt is put into recrystallisation solvent first, add hydrochloric acid solution to adjust pH value 1.5~3.0 to dissolving to clarify, filtering, then add and adjust solvent, 20~50min is kept the temperature after being warming up to 35 DEG C~40 DEG C, subsequent slow cooling to room temperature filters, and material washed once through acetone, filter, drying obtains quadracycline finished product；The adjusting solvent is water, acetone or combination.The present invention controls crystalline rate, so as to achieve the purpose that to reduce dissolvent residual in quadracycline using the polarity for adjusting solvent adjustment recrystallisation solvent；Meanwhile novel solvent is not introduced, avoid product from there are other dissolvent residuals, reduce solvent consumption in production process, reduce the production cost of quadracycline finished product, improve product quality.
Description
Technical field
The present invention relates to technical field of medicine synthesis, and solvent residual amount in quadracycline is reduced more particularly to a kind of
Method.
Background technology
Quadracycline is first generation tetracycline antibiotics, is the hydrochloride of tetracycline base, it is with broad spectrum antibacterial
Feature, can resist such as Gram-negative and gram-positive bacteria, Chlamydia, mycoplasma, rickettsia bacterium and primary species parasite
Deng multiple-microorganism.In addition to the crowd of penicillin-susceptible, can much be treated by the use of tetracycline antibiotics as substitute
Some diseases.Since its cost is not high, purity is high, and toxic side effect is small, and storage period length, oral absorption percentage is significantly larger than Fourth Ring
Plain alkali, into after people's human body, blood concentration, drug usine level, bioavilability are above tetracycline base, and securely and reliably, curative effect
Definitely, therefore the treatment for human and animal's infection is now widely used for, particularly in some American-European countries still extensive
Use.
The main production process of quadracycline is at present:By using streptomyces aureus as obtained by production strain fermentation culture
The process generation tetracycline bases such as tetracycline fermentation liquor is acidified, extraction and crystallization, then by tetracycline base in organic solvent with
Urea molecule is complexed to form urea double salt, finally puts into butanol solvent the urea double salt formed, adds hydrochloric acid solution tune
PH value 1.5~3.0 to dissolving to be saved to clarify, filtering, filtrate controls crystallization rate by heating up, keeping the temperature and cool down, after completion of the reaction,
Reacting liquid filtering, after acetone washs qualification twice, filters, drying, obtains quadracycline finished product.Since pharmaceutical industry is special
It is required that to ensure that medicine exists the security and validity of human body,《Chinese Pharmacopoeia》The residual of middle regulation butanol is less than
5000ppm, the residual of acetone are less than 100ppm.Therefore, it is to be related to product matter to control quadracycline butanol and acetone residue
The important indicator of amount and safety.And during above-mentioned whole operation, cerium sulphate crystal not enough becomes more meticulous, and solvent polarity is not suitable for, institute
Dissolvent residual height is uneven in quadracycline finished product, it is impossible to ensure that quadracycline dissolvent residual 100% is qualified.
The content of the invention
The purpose of the present invention is that the defects of overcoming the above-mentioned prior art, there is provided one kind reduces solvent in quadracycline
The method of residual quantity, 100% qualification of quadracycline dissolvent residual is reached by this method, improves product quality and city
Field competitiveness.
The technical solution taken for achieving the above object is：
A kind of method of solvent residual amount in reduction quadracycline, it is characterised in that its processing step is：Urea is answered first
Salt is put into recrystallisation solvent, is added hydrochloric acid solution to adjust pH value 1.5~3.0 to dissolving and is clarified, filtering, then addition is adjusted molten
Agent, keeps the temperature 20~50min after being warming up to 35 DEG C~40 DEG C, subsequent slow cooling to room temperature filters, and material washed once through acetone,
Filter, drying obtains quadracycline finished product；
The adjusting solvent is water, acetone or combination.
The addition of the adjusting solvent is 0.1~0.5 times of tetracycline urea double salt inventory.
The recrystallisation solvent is butanol, its addition is 5~8 times of tetracycline urea double salt inventory.
The present invention adjusts solvent by being added on original Process ba- sis, utilizes the pole of the adjusting solvent adjustment recrystallisation solvent
Property, crystalline rate is controlled, so as to achieve the purpose that to reduce dissolvent residual in quadracycline；Meanwhile the present invention is new without introducing
Solvent, avoids product from having other dissolvent residuals, reduces solvent consumption in production process, reduces being produced into for quadracycline finished product
This, improves product quality.
Embodiment
The present invention is explained with example, it should be understood that example is to be used to illustrate rather than to this below
The limitation of invention.The scope of the present invention is determined with core content according to claims.
Embodiment 1：
150g tetracycline urea double salts are poured into 6 times of butanol solvents, add hydrochloric acid 70ml to adjust pH value 2.2, lysate passes through
After filter, 30ml water is added, 30min is kept the temperature after being warming up to 40 DEG C, subsequent slow cooling to room temperature filters, and material washs one through acetone
It is secondary, filter, drying obtains quadracycline finished product.After testing：Yield 93.8% is changed, butanol remains in quadracycline
800ppm, acetone residue 35ppm.
Embodiment 2：
150g tetracycline urea double salts are poured into 8 times of butanol solvents, add hydrochloric acid 66ml to adjust pH value 2.5, lysate passes through
After filter, 15ml water is added, 50min is kept the temperature after being warming up to 35 DEG C, subsequent slow cooling to room temperature filters, and material washs one through acetone
It is secondary, filter, drying obtains quadracycline finished product.Change yield 94.6%.Butanol remains 1500ppm, acetone residue 47ppm.
Embodiment 3：
150g tetracycline urea double salts are poured into 6 times of butanol solvents, add hydrochloric acid 70ml to adjust pH value 1.7, lysate passes through
After filter, 30ml acetone is added, 20min is kept the temperature after being warming up to 40 DEG C, subsequent slow cooling to room temperature filters, and material is washed through acetone
Once, filter, drying obtains quadracycline finished product.Change yield 95.1%.Butanol remains 2100ppm, acetone residue 58ppm.
Embodiment 4：
150g tetracycline urea double salts are poured into 5 times of butanol and acetone 30ml solvents, add hydrochloric acid 72ml to adjust pH value 2.5,
Lysate after filtering, is slowly added to water（45ml）And acetone（30ml）, 35min is kept the temperature after being warming up to 38 DEG C, is then slowly dropped
Temperature to room temperature filters, and material washed once through acetone, filters, and drying obtains quadracycline finished product.Change yield 95.3%.Fourth
Alcohol remains 1600ppm, acetone residue 38ppm.
Embodiment 5：
150g tetracycline urea double salts are poured into 6 times of butanol solvents, add hydrochloric acid 68ml to adjust pH value 1.9, lysate passes through
After filter, water is slowly added to（15ml）And acetone（15ml）Mixed solvent, keeps the temperature 50min, subsequent slow cooling after being warming up to 40 DEG C
Filtered to room temperature, material washed once through acetone, filter, and drying obtains quadracycline finished product.Change yield 95.0%.Butanol
Remain 1100ppm, acetone residue 32ppm.
Comparative example（Former technique）：
150g tetracycline urea double salts are poured into 6 times of butanol solvents, add hydrochloric acid 70ml to adjust pH value 1.9, lysate passes through
After filter, 30min is kept the temperature after being warming up to 40 DEG C, subsequent slow cooling to room temperature filters, and material washed once through acetone, filters, and dries
It is dry to obtain quadracycline finished product.Change yield 95.1%, butanol residual 2800ppm, acetone 86ppm.
Claims (3)
- A kind of 1. method for reducing solvent residual amount in quadracycline, it is characterised in that its processing step is：First by urea Double salt is put into recrystallisation solvent, is added hydrochloric acid solution to adjust pH value 1.5~3.0 to dissolving and is clarified, filtering, then addition is adjusted molten Agent, keeps the temperature 20~50min after being warming up to 35 DEG C~40 DEG C, subsequent slow cooling to room temperature filters, and material washed once through acetone, Filter, drying obtains quadracycline finished product；The adjusting solvent is water, acetone or combination.
- 2. the method described in accordance with the claim 1 for reducing solvent residual amount in quadracycline, it is characterised in that the adjusting The addition of solvent is 0.1~0.5 times of tetracycline urea double salt inventory.
- 3. the method described in accordance with the claim 1 for reducing solvent residual amount in quadracycline, it is characterised in that the crystallization Solvent is butanol, its addition is 5~8 times of tetracycline urea double salt inventory.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711399757.2A CN107954892A (en) | 2017-12-22 | 2017-12-22 | A kind of method of solvent residual amount in reduction quadracycline |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201711399757.2A CN107954892A (en) | 2017-12-22 | 2017-12-22 | A kind of method of solvent residual amount in reduction quadracycline |
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| CN107954892A true CN107954892A (en) | 2018-04-24 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112479924A (en) * | 2020-12-17 | 2021-03-12 | 宁夏启元药业有限公司 | Method for reducing residual butanol in tetracycline hydrochloride finished product |
| CN112521307A (en) * | 2020-12-17 | 2021-03-19 | 宁夏启元药业有限公司 | Separation method of tetracycline hydrochloride |
Citations (5)
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|---|---|---|---|---|
| CN101209978A (en) * | 2006-12-25 | 2008-07-02 | 林广德 | Method for synthesizing dexocycline hydrochloridele from 6-methyl terramycin salt of organic acid |
| CN101693669A (en) * | 2009-10-13 | 2010-04-14 | 浙江大学 | Minocycline hydrochloride hydrate crystal forms and preparation method thereof |
| CN102617396A (en) * | 2009-10-13 | 2012-08-01 | 浙江大学 | Minocycline hydrochloride hydrate crystal form and synthesis method thereof |
| CN103896798A (en) * | 2014-01-14 | 2014-07-02 | 李学强 | Tetracycline purifying process |
| CN105294481A (en) * | 2015-11-19 | 2016-02-03 | 宁夏启元药业有限公司 | Preparation method of tetracycline hydrochloride |
-
2017
- 2017-12-22 CN CN201711399757.2A patent/CN107954892A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101209978A (en) * | 2006-12-25 | 2008-07-02 | 林广德 | Method for synthesizing dexocycline hydrochloridele from 6-methyl terramycin salt of organic acid |
| CN101693669A (en) * | 2009-10-13 | 2010-04-14 | 浙江大学 | Minocycline hydrochloride hydrate crystal forms and preparation method thereof |
| CN102617396A (en) * | 2009-10-13 | 2012-08-01 | 浙江大学 | Minocycline hydrochloride hydrate crystal form and synthesis method thereof |
| CN103896798A (en) * | 2014-01-14 | 2014-07-02 | 李学强 | Tetracycline purifying process |
| CN105294481A (en) * | 2015-11-19 | 2016-02-03 | 宁夏启元药业有限公司 | Preparation method of tetracycline hydrochloride |
Non-Patent Citations (3)
| Title |
|---|
| 李武客，宋丹丹: "《基础化学实验教程 第2版》", 31 August 2014 * |
| 赵琰: "盐酸四环素反应结晶过程优化研究", 《工程科技Ⅰ辑》 * |
| 郑剑萍等: "盐酸四环素原料中的残留溶剂控制", 《科技与企业》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112479924A (en) * | 2020-12-17 | 2021-03-12 | 宁夏启元药业有限公司 | Method for reducing residual butanol in tetracycline hydrochloride finished product |
| CN112521307A (en) * | 2020-12-17 | 2021-03-19 | 宁夏启元药业有限公司 | Separation method of tetracycline hydrochloride |
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