CN108640900A - A kind of purification process of Erdosteine - Google Patents
A kind of purification process of Erdosteine Download PDFInfo
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- CN108640900A CN108640900A CN201810577239.3A CN201810577239A CN108640900A CN 108640900 A CN108640900 A CN 108640900A CN 201810577239 A CN201810577239 A CN 201810577239A CN 108640900 A CN108640900 A CN 108640900A
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- Prior art keywords
- erdosteine
- purification process
- aqueous solution
- crude product
- acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/36—Nitrogen atoms
Abstract
The present invention provides a kind of purification process of Erdosteine, include the following steps：1）Prepare Erdosteine crude product aqueous solution：Erdosteine crude product is dissolved in weakly acidic pH to the aqueous solution of alkalinity, addition can be extracted with the organic solvent of water stratification, obtain Erdosteine crude product aqueous solution, and the volume ratio of organic solvent and alkaline aqueous solution is 0.05~20：1；2）Prepare Erdosteine fine work：The Erdosteine crude product aqueous solution that step 1) obtains is adjusted with acid to acidity, solid, filtering is precipitated, drying obtains Erdosteine fine work.The present invention is based on the particularity for containing " carboxyl " group in Erdosteine structure, the column chromatography method for being not suitable for industrialized production greatly without operation difficulty is purified, only purified by " alkali soluble acid is heavy ", purification process is easy to operate, the impurity in Erdosteine crude product can be effectively removed, last Erdosteine fine work purity can reach 99.4% or more, and list is miscellaneous to be less than 0.1%, and high income, it is suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of purification process of Erdosteine, belong to pharmaceutical chemistry technical field.
Background technology
Erdosteine（Erdosteine）, chemical entitled：（±）- N- [2-(carboxymethyl sulfydryl)-acetyl group]-high half Guang
Propylhomoserin thiolactone, molecular formula are：C8H11NO4S2, molecular weight：249.3 No. CAS：84611-23-4, structural formula are as follows：
Erdosteine is Italian Edmond Pharma and the mucolytic drugs that Refarmed companies of Switzerland develop, main use
Treatment when thick sputum is not easy expectoration when acute and chronic bronchitis, the diseases such as obstructive lung disease.
There is no the report of special Erdosteine purification process in existing literature, and common purification process is recrystallization,
Recrystallization solvent is generally ethyl alcohol, acetone etc..The Erdosteine of the prior art readily available 95%, but to be further purified
When obtaining 99% or higher Erdosteine, general purification process is often extremely difficult to desired effect.
The method that the prior art commonly obtains the compound of high-purity for example has column chromatography method.The separation of column chromatography is former
Reason is that adsorption capacity on filler is different and detached according to substance, entire chromatography process be total material Adsorption and desorption,
It adsorbs again, desorption process again.Column chromatography method is used to need to consider column effect to reach different material Adsorption and desorption, adsorb again, again
Desorption ability is different, and separation process needs a large amount of eluting solvent, is easily introduced new impurity；And every time purifying bulk it is small,
Operating time is very long, cumbersome right
Operating personnel are more demanding, and hardly possible is suitable for industrialized production.
Therefore, it is badly in need of proposing that new technical solution optimizes the purification process of Erdosteine.
Invention content
The purpose of the present invention is overcoming the deficiencies of the prior art and provide, one kind is efficient, easy to operate to be suitable for industrialization rule
The purification process of the Erdosteine of mould production.
It is an unexpected discovery of the invention that containing the particularity of " carboxyl " group in Erdosteine structure, pass through " alkali soluble acid is heavy "
Purification process, end product quality can be controlled in highest list miscellaneous 0.1% hereinafter, 99% or more content, and equipment investment is few,
Production cost is low, and process stabilizing is simultaneously suitble to industrialized production.
Technical scheme is as follows：
A kind of purification process of Erdosteine, includes the following steps：
1）Prepare Erdosteine crude product aqueous solution：Erdosteine crude product is dissolved in weakly acidic pH to the aqueous solution of alkalinity
In, addition can be extracted with the organic solvent of water stratification, obtain Erdosteine crude product aqueous solution, the Erdosteine
The purity of crude product is 90%~98%, and the volume ratio of organic solvent and alkaline aqueous solution is 0.05~20：1；
2）Prepare Erdosteine fine work：The Erdosteine crude product aqueous solution that step 1) obtains is adjusted with acid to acidity, is precipitated solid
Body, filtering, drying obtain Erdosteine fine work.
Preferably,
The step 1）Process is as follows：Erdosteine crude product is added to the water, adjusts pH to 5~14 with inorganic base, stirring is molten
Solution, addition and the immiscible organic solvent of water, are extracted, obtain Erdosteine crude product aqueous solution.
The step 1）In, inorganic base includes sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, hydroxide
One or more of ammonium, sodium carbonate, sodium bicarbonate, potassium carbonate and saleratus.
The step 1）In, the organic solvent with water stratification includes in esters, ethers, alkanes and arene
It is one or more of.
The step 1）In, organic solvent esters include ethyl acetate, Ethyl formate, methyl acetate and isopropyl acetate
One or more of.
The step 1）In, organic solvent ethers includes ether, methyl phenyl ethers anisole, isopropyl ether, methyl tertiary butyl ether(MTBE) and tetrahydrochysene
One or more of furans.
The step 1）In, organic solvent alkanes include n-hexane, dichloromethane, hexahydrotoluene, hexamethylene, penta
One or more of alkane, heptane and octane.
The step 1）In, organic solvent arene includes one or both of toluene, dimethylbenzene.
The step 2）Process is as follows：The Erdosteine crude product aqueous solution that step 1) obtains is adjusted to pH with inorganic acid
To 1~6, solid, filtering is precipitated in stirring, and drying obtains Erdosteine fine work.
The step 2）In, inorganic acid includes one kind or several in hydrochloric acid, nitric acid, boric acid, sulfuric acid, carbonic acid and phosphoric acid
Kind.
The step 2）In, the temperature that solid is precipitated in stirring is 0 DEG C~40 DEG C.It is preferred that 25 ± 5 DEG C.
The present invention has the following technical effect that：
The present invention is based on the particularity for containing " carboxyl " group in Erdosteine structure, are not suitable for work greatly without operation difficulty
The column chromatography method of industry metaplasia production is purified, and is only purified by " alkali soluble acid is heavy ", purification process is easy to operate, Neng Gouyou
Impurity in effect removal Erdosteine crude product, last Erdosteine fine work purity can reach 99.4% or more, and list is miscellaneous to be less than 0.1%,
And high income, it is suitable for industrialized production.
Specific implementation mode
It is described further below with reference to specific embodiment, to fully understand the purposes, features and effects of the present invention.
Embodiment 1
In the present embodiment, the purification process of Erdosteine includes the following steps：
1）10Kg Erdosteine crude products are added in 200L reaction kettles, 100L purified waters are added, with 1% NaOH aqueous solution tune
PH to 8.5 is saved, then 20L ethyl acetate is added in the stirring and dissolving at 25 ± 5 DEG C, stir 10min, static layering 20min, point
Liquid repeats above-mentioned extracting and washing twice, and liquid separation obtains Erdosteine crude product aqueous solution.
2）By Erdosteine crude product aqueous solution salt acid for adjusting pH to 2.5 obtained above, the stirring and crystallizing at 25 ± 5 DEG C
5h, filtering, drying obtain Erdosteine fine work 9.2Kg, and yield 92%, HPLC purity 99.7%, miscellaneous highest list is 0.07%.
Embodiment 2
In the present embodiment, the purification process of Erdosteine includes the following steps：
1）10Kg Erdosteine crude products are added in 200L reaction kettles, 100L purified waters are added, with sodium bicarbonate aqueous solution tune
Save pH to 5.0, the stirring and dissolving at 25 ± 5 DEG C, then be added 5L isopropyl ethers, stir 10min, static layering 20min, liquid separation,
Repeat above-mentioned extracting and washing twice, liquid separation obtains Erdosteine crude product aqueous solution.
2）By Erdosteine crude product aqueous solution phosphorus acid for adjusting pH to 1.0 obtained above, the stirring and crystallizing at 25 ± 5 DEG C
5h, filtering, drying obtain Erdosteine fine work 8.9Kg, and yield 89%, HPLC purity 99.5%, miscellaneous highest list is 0.05%.
Embodiment 3
In the present embodiment, the purification process of Erdosteine includes the following steps：
1）10Kg Erdosteine crude products are added in 200L reaction kettles, add 100L purified waters, it is water-soluble with 1% potassium hydroxide
Liquid adjusts pH to 14, and then 2000L dichloromethane is added in the stirring and dissolving at 25 ± 5 DEG C, stir 10min, static layering
20min, liquid separation repeat above-mentioned extracting and washing twice, and liquid separation obtains Erdosteine crude product aqueous solution.
2）By Erdosteine crude product aqueous solution sulphur acid for adjusting pH to 6.0 obtained above, the stirring and crystallizing at 25 ± 5 DEG C
5h, filtering, drying obtain Erdosteine fine work 9.0Kg, and yield 90%, HPLC purity 99.4%, miscellaneous highest list is 0.08%.
Embodiment 4
In the present embodiment, the purification process of Erdosteine includes the following steps：
1）10Kg Erdosteine crude products are added in 200L reaction kettles, 100L purified waters are added, with ammonium hydroxide aqueous solution tune
Save pH to 9.5, the stirring and dissolving at 25 ± 5 DEG C, then be added 100L toluene, stir 10min, static layering 20min, liquid separation,
Repeat above-mentioned extracting and washing twice, liquid separation obtains Erdosteine crude product aqueous solution.
2）By Erdosteine crude product aqueous solution salt acid for adjusting pH to 3.5 obtained above, the stirring and crystallizing at 25 ± 5 DEG C
5h, filtering, drying obtain Erdosteine fine work 9.5Kg, and yield 95%, HPLC purity 99.9%, miscellaneous highest list is 0.03%.
Claims (11)
1. a kind of purification process of Erdosteine, which is characterized in that include the following steps：
1）Prepare Erdosteine crude product aqueous solution：Erdosteine crude product is dissolved in weakly acidic pH to the aqueous solution of alkalinity
In, addition can be extracted with the organic solvent of water stratification, obtain Erdosteine crude product aqueous solution, organic solvent and alkali
Property aqueous solution volume ratio be 0.05~20：1；
2）Prepare Erdosteine fine work：The Erdosteine crude product aqueous solution that step 1) obtains is adjusted with acid to acidity, is precipitated solid
Body, filtering, drying obtain Erdosteine fine work.
2. the purification process of Erdosteine according to claim 1, which is characterized in that the step 1）Process is as follows：
Erdosteine crude product is added to the water, adjusts pH to 5~14 with inorganic base, stirring and dissolving is added immiscible organic molten with water
Agent is extracted, and Erdosteine crude product aqueous solution is obtained.
3. the purification process of Erdosteine according to claim 2, which is characterized in that the step 1）In, inorganic base
Including sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, ammonium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and carbonic acid
One or more of hydrogen potassium.
4. the purification process of Erdosteine according to claim 1, which is characterized in that the step 1）In, with moisture
The organic solvent of layer includes one or more of esters, ethers, alkanes and arene.
5. the purification process of Erdosteine according to claim 4, which is characterized in that the step 1）In, You Jirong
Agent esters include one or more of ethyl acetate, Ethyl formate, methyl acetate and isopropyl acetate.
6. the purification process of Erdosteine according to claim 4, which is characterized in that the step 1）In, You Jirong
Agent ethers includes one or more of ether, methyl phenyl ethers anisole, isopropyl ether, methyl tertiary butyl ether(MTBE) and tetrahydrofuran.
7. the purification process of Erdosteine according to claim 4, which is characterized in that the step 1）In, You Jirong
Agent alkanes include one or more of n-hexane, dichloromethane, hexahydrotoluene, hexamethylene, pentane, heptane and octane.
8. the purification process of Erdosteine according to claim 4, which is characterized in that the step 1）In, You Jirong
Agent arene includes one or both of toluene, dimethylbenzene.
9. the purification process of Erdosteine according to claim 1, which is characterized in that the step 2）Process is as follows：
The Erdosteine crude product aqueous solution that step 1) obtains is adjusted to pH to 1~6 with inorganic acid, solid is precipitated in stirring, filters, drying
Obtain Erdosteine fine work.
10. the purification process of Erdosteine according to claim 9, which is characterized in that the step 2）In, inorganic acid
Including one or more of hydrochloric acid, nitric acid, boric acid, sulfuric acid, carbonic acid and phosphoric acid.
11. the purification process of Erdosteine according to claim 9, which is characterized in that the step 2）In, stirring analysis
The temperature for going out solid is 0 DEG C~40 DEG C.
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| CN201810577239.3A CN108640900A (en) | 2018-06-07 | 2018-06-07 | A kind of purification process of Erdosteine |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4411909A (en) * | 1981-03-19 | 1983-10-25 | Refarmed, Recherches Pharmaceutiques Et Medicales, S.A. | [(2-Oxo-3-tetrahydrothienylcarbamoyl)-alkylthio] acetic acids, their salts and esters, a process for preparation thereof and the pharmaceutical compositions containing same |
| KR100554108B1 (en) * | 2003-10-02 | 2006-02-22 | 주식회사 한서켐 | A process for preparing erdosteine |
| CN101941963A (en) * | 2010-04-22 | 2011-01-12 | 浙江康乐药业股份有限公司 | Synthesis method of erdosteine |
-
2018
- 2018-06-07 CN CN201810577239.3A patent/CN108640900A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4411909A (en) * | 1981-03-19 | 1983-10-25 | Refarmed, Recherches Pharmaceutiques Et Medicales, S.A. | [(2-Oxo-3-tetrahydrothienylcarbamoyl)-alkylthio] acetic acids, their salts and esters, a process for preparation thereof and the pharmaceutical compositions containing same |
| KR100554108B1 (en) * | 2003-10-02 | 2006-02-22 | 주식회사 한서켐 | A process for preparing erdosteine |
| CN101941963A (en) * | 2010-04-22 | 2011-01-12 | 浙江康乐药业股份有限公司 | Synthesis method of erdosteine |
Non-Patent Citations (3)
| Title |
|---|
| 张须学: "《天然药物化学》", 30 September 2012 * |
| 李飞等: "厄多司坦的合成", 《中国医药工业杂志》 * |
| 马丽等: "厄多司坦原料药中有关物质的测定方法", 《药学学报》 * |
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Application publication date: 20181012 |
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