CN103058901A - Refining method of tiopronin - Google Patents
Refining method of tiopronin Download PDFInfo
- Publication number
- CN103058901A CN103058901A CN2012105950444A CN201210595044A CN103058901A CN 103058901 A CN103058901 A CN 103058901A CN 2012105950444 A CN2012105950444 A CN 2012105950444A CN 201210595044 A CN201210595044 A CN 201210595044A CN 103058901 A CN103058901 A CN 103058901A
- Authority
- CN
- China
- Prior art keywords
- solvent
- tiopronin
- alkane
- purification process
- kinds
- 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.)
- Pending
Links
- YTGJWQPHMWSCST-UHFFFAOYSA-N CC(C(NCC(O)=O)=O)S Chemical compound CC(C(NCC(O)=O)=O)S YTGJWQPHMWSCST-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention relates to the application of a method for refining tiopronin through component solvent. Tiopronin is resolved in mixed solvent of ester solvent and oxazolidinone solvent or mixed solvent of ester solvent, oxazolidinone solvent and aliphatic alkane solvent, and the effect of removing impurities of tiopronin can be achieved through a crystallization procedure; and through the method, the effect of removing the impurity of a-chloro propionyl glycine in tiopronin is remarkable. The method has the advantages that the process procedures are simple, the operation is easy and the product yield is high.
Description
Technical field
The invention belongs to field of medicine and chemical technology, relate to a kind of process for purification of tiopronin.
Technical background
Tiopronin (Tiopronin), chemistry N-(2-mercapto radical propionyl group) by name-glycine is a kind of novel glycine derivative that contains free sulfhydryl groups, can be widely used as chemotherapy and radiation therapy protective reagents, liver protectant and heavy metal detoxification agent.Tiopronin toxicity is lower, and the long-term treatment of suitable chronic disease abroad is widely used clinically.The mid-90 in 20th century, domestic approval production, now clinically widespread use, tiopronin is the compound with following chemical structure.
The synthetic method of tiopronin, bibliographical information is more.Synthetic route mainly contains two large classes: a class is take the alpha-mercapto propionic acid as starting raw material, and through benzyl protection, make acyl chlorides, with the glycine condensation, the deprotection base makes target compound again, and wherein the deprotection base will react by the sodium in-55 ℃ of lower and liquefied ammonia.Another kind of with alpha-brominated propionyl glycine and compound (such as the thiobenzoic acid) condensation that contains potential sulfydryl, then ammonia solves target compound.First kind severe reaction conditions is difficult to suitability for industrialized production; The domestic supply of Equations of The Second Kind desired raw material seldom, and preparation difficulty, toxicity is large.There is patent report α in Japan, and the two propionyl glycine of α '-dithio prepare target compound through electrolytic reduction, but the electrolytic reduction equipment requirements are high, also is difficult to scale operation.
At present domestic the reaction with sulfur oxychloride take α-chloro-propionicacid cheap and easy to get as starting raw material makes α-chlorpromazine chloride, get the alpha-chloro Propionylglycine with the glycine condensation again, then with the sodium disulfide condensation, intermediate namely gets tiopronin without separation with zinc powder reduction.This technique is simple, and product yield is higher.It is not high that yet this method building-up process synthesizes product purity, particularly synthetic intermediate impurity alpha-chloro Propionylglycine is restive, domestic literature all is to control by technological process mostly at present, make with extra care with ethyl acetate, this method technological process control difficulty is large, production cycle is long, and production cost is large.Ethyl acetate is refining undesirable to the control of intermediate impurity alpha-chloro Propionylglycine, often surpasses national standard.
Summary of the invention
The invention provides a kind of brand-new process for purification, can effectively control the purity of impurity (alpha-chloro Propionylglycine) by this method, and yield is high, and process for refining is simple, and the tiopronin after making with extra care can be used as the production that bulk drug carries out the preparations such as capsule.
The present invention is dissolved in the crude product tiopronin in three kinds of solvent solvents of esters solvent, two kinds of solvent solvents of alkane ketone or esters solvent, alkane ketone, fat alkane kind solvent, makes with extra care purifying by crystallization technique, and concrete steps are as follows:
1. in reactor, add the crude product tiopronin, add esters solvent, two kinds of solvent solvents of alkane ketone or esters solvent, alkane ketone, three kinds of solvent solvents of fat alkane kind solvent, temperature rising reflux 0.5-2 hour;
2. stir and be cooled to room temperature, be incubated 0.5-2 hour, continue to be cooled to 0-5 ℃, stir insulation 2-8 hour, filter;
3. wet product carry out drip washing with normal hexane, get the refining sample of tiopronin through vacuum-drying.
The tiopronin raw material that the present invention adopts is to be the crude product that starting raw material prepares by α-chloro-propionicacid, as refining raw material, tiopronin purity 96.5% gets final product, and wherein impurity alpha-chloro Propionylglycine≤0.28% gets final product, by refining, product can satisfy the state-promulgated pharmacopoeia standard.
Solvent as crystallization, otherwise tiopronin is reacted, can use esters solvent, alkane ketone and three kinds of solvent solvents of fat alkane kind solvent, perhaps two kinds of solvent solvents of esters solvent and alkane ketone are preferentially selected esters solvent, alkane ketone and three kinds of solvent solvents of fat alkane class.
Esters solvent can be ethyl acetate, isopropyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, propyl propionate, isopropyl propionate, n-butyl propionate or isobutyl propionate, and is wherein best with ethyl acetate.
The alkane ketones solvent can be acetone, butanone or 2 pentanone, and is wherein best with acetone.
Fat alkanes solvent is weak polar solvent, can be normal butane, 2-methylbutane, uncle's butane, 2,2-dimethylbutane, 2,3-dimethylbutane, Skellysolve A, 2,2-dimethylpentane, 2,3-dimethylpentane, 2, the 4-dimethylpentane,, 3, one of 3-dimethylpentane, normal hexane, hexanaphthene, normal heptane, octane, octane-iso, isononane or positive nonane, wherein best with normal hexane.
The esters solvent volumetric usage is 2～5 times of tiopronin weight in the treating process, wherein with 3 times of the bests.
The esters solvent volumetric usage is 2～5 times of tiopronin weight in the treating process, is preferably 3～4 times.
When adopting two kinds of mixed solvents of esters solvent, alkane ketones solvent, esters solvent is 3～8: 1 with alkane ketones solvent mixed volume ratio, is preferably 3～6 in the treating process: 1, and more preferably 3: 1.
When adopting the mixed solvent of esters solvent, alkane ketone and three kinds of solvents of fat alkane class, esters solvent is 4～8: 1 with alkane ketones solvent mixed volume ratio, is preferably 6: 1 in the treating process.
The 0.5-2 that fatty alkanes solvent volume consumption is tiopronin weight in the treating process times, 1 times of optimal selection.
The consumption of ester class, alkane ketone and three kinds of solvent solvent volume of fat alkane kind solvent is preferential in the treating process selects 6: 1: 2.
From mixed solvent, separate out the tiopronin crystal, more satisfactory with the mode of cooling, tiopronin solution is cooled to 0-10 ℃, under agitation slowly lower the temperature the crystallization effect for well with 10-15 ℃/speed at one hour rating cooling.
The crystal of separating out filters separation in 0-5 ℃, select 0-5 ℃ an amount of solvent of normal hexane to carry out drip washing, and the product dissolvent residual adopts 50 ℃, pressure≤0.1mpa, and the method for vacuum-drying 24-48h is removed.
Embodiment
Below by specific embodiment the present invention is further described, but the present invention is not only limited to following instance.
The crude product tiopronin is to be that starting raw material prepares gained by α-chloro-propionicacid, and as refining crude product, tiopronin purity 96.5% gets final product, wherein impurity alpha-chloro Propionylglycine≤0.28%.(filter technique because decolouring is arranged in the crude product tiopronin preparation process, insoluble impurities is not arranged in the crude product, do not operate except insoluble impurities in the example.)
Embodiment 1
With 80g crude product tiopronin (purity 96.8%,) place the 1000ml four-hole boiling flask, add ethyl acetate 240ml, acetone 40ml, temperature rising reflux 0.5 hour, stirring is cooled to 30 ℃ of room temperatures, be incubated 0.5 hour, continue to be cooled to 0-5 ℃, stir insulation 2 hours, filter, wet product carry out drip washing with a small amount of 0-5 ℃ normal hexane, sample must be made with extra care sample 65.6g, yield 82% in 45 ℃ of vacuum-drying 6-8 hours, purity 98.8%, single assorted content meets State Food and Drug Administration's medicine tentative standard (YBH 12042005).
Embodiment 2
With 80g crude product tiopronin (purity 96.8%,) place the 1000ml four-hole boiling flask, add ethyl acetate 320ml, acetone 40ml, temperature rising reflux 2 hours, stirring is cooled to 30 ℃ of room temperatures, be incubated 1 hour, continue to be cooled to 0-5 ℃, stir insulation 5 hours, filter, wet product carry out drip washing with a small amount of 0-5 ℃ normal hexane, sample must be made with extra care sample 60.3g, yield 75.4% in 45 ℃ of vacuum-drying 6-8 hours, purity 99.1%, single assorted content meets State Food and Drug Administration's medicine tentative standard (YBH 12042005).
Embodiment 3
With 80g crude product tiopronin (purity 96.8%,) place the 1000ml four-hole boiling flask, add ethyl acetate 240ml, acetone 80ml, temperature rising reflux 1 hour, stirring is cooled to 30 ℃ of room temperatures, be incubated 2 hours, continue to be cooled to 0-5 ℃, stir insulation 8 hours, filter, wet product carry out drip washing with a small amount of 0-5 ℃ normal hexane, sample must be made with extra care sample 63.8g, yield 79.7% in 45 ℃ of vacuum-drying 6-8 hours, purity 99.3%, single assorted content meets State Food and Drug Administration's medicine tentative standard (YBH 12042005).
Embodiment 4
With 80g crude product tiopronin (purity 96.8%,) place the 1000ml four-hole boiling flask, add ethyl acetate 320ml, normal hexane 80ml, acetone 40ml, temperature rising reflux 1 hour, stirring is cooled to 30 ℃ of room temperatures, be incubated 1 hour, continue to be cooled to 0-5 ℃, stir insulation 2 hours, filter, wet product carry out drip washing with a small amount of 0-5 ℃ normal hexane, sample must be made with extra care sample 70.5g, yield 88.1% in 45 ℃ of vacuum-drying 6-8 hours, purity 98.9%, single assorted content meets State Food and Drug Administration's medicine tentative standard (YBH 12042005).
Embodiment 5
With 80g crude product tiopronin (purity 96.8%,) place the 1000ml four-hole boiling flask, add ethyl acetate 160ml, normal hexane 160ml, acetone 40ml, temperature rising reflux 0.5 hour, stirring is cooled to 30 ℃ of room temperatures, be incubated 0.5 hour, continue to be cooled to 0-5 ℃, stir insulation 4 hours, filter, wet product carry out drip washing with a small amount of 0-5 ℃ normal hexane, sample must be made with extra care sample 72.9g, yield 91.1% in 45 ℃ of vacuum-drying 6-8 hours, purity 98.5%, single assorted content meets State Food and Drug Administration's medicine tentative standard (YBH 12042005).
Embodiment 6
With 80g crude product tiopronin (purity 96.8%,) place the 1000ml four-hole boiling flask, add ethyl acetate 240ml, normal hexane 80ml, acetone 40ml, temperature rising reflux 1 hour, stirring is cooled to 30 ℃ of room temperatures, be incubated 1 hour, continue to be cooled to 0-5 ℃, stir insulation 2 hours, filter, wet product carry out drip washing with a small amount of 0-5 ℃ normal hexane, sample must be made with extra care sample 72.2g, yield 90.2% in 45 ℃ of vacuum-drying 6-8 hours, purity 98.8%, single assorted content meets State Food and Drug Administration's medicine tentative standard (YBH 12042005).
Claims (10)
1. the refining purification process of a tiopronin, comprise such as following steps: the crude product tiopronin is dissolved in esters solvent, two kinds of solvent solvents of alkane ketone or esters solvent, alkane ketone, three kinds of solvent solvents of fat alkane kind solvent, make with extra care purifying by crystallization technique, concrete steps are as follows:
1. in reactor, add the crude product tiopronin, add esters solvent, two kinds of solvent solvents of alkane ketone or esters solvent, alkane ketone, three kinds of solvent solvents of fat alkane kind solvent, temperature rising reflux 0.5-2 hour;
2. stir and be cooled to room temperature, be incubated 0.5-2 hour, continue to be cooled to 0-5 ℃, stir insulation 2-8 hour, filter;
3. wet product carry out drip washing with normal hexane, get the refining sample of tiopronin through vacuum-drying.
2. tiopronin as claimed in claim 1 is made with extra care purification process, its characteristics are: esters solvent is selected from one of ethyl acetate, isopropyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, propyl propionate, isopropyl propionate, n-butyl propionate or isobutyl propionate, is preferably ethyl acetate.
3. tiopronin as claimed in claim 1 is made with extra care purification process, and its characteristics are: the alkane ketones solvent is selected from one of acetone, butanone or 2 pentanone, is preferably acetone.
4. tiopronin as claimed in claim 1 is made with extra care purification process, its characteristics are: fatty alkanes solvent is weak polar solvent, be selected from normal butane, 2-methylbutane, uncle's butane, 2,2-dimethylbutane, 2,3-dimethylbutane, Skellysolve A, 2,2-dimethylpentane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3, one of 3-dimethylpentane, normal hexane, hexanaphthene, normal heptane, octane, octane-iso, isononane or positive nonane are preferably normal hexane.
5. the refining purification process of tiopronin as claimed in claim 1, its characteristics are: two kinds of solvent solvents of described esters solvent, alkane ketones solvent or esters solvent, alkane ketone, three kinds of solvent solvents of fat alkane class can adopt equal-volume to mix, and perhaps equal-volume does not mix.
6. the refining purification process of tiopronin as claimed in claim 1, its characteristics are: the esters solvent volumetric usage is 2～5 times of tiopronin weight, is preferably 3～4 times.
7. the refining purification process of tiopronin as claimed in claim 1, its characteristics are: the 0.5-2 that fatty alkanes solvent volume consumption is tiopronin weight doubly is preferably 1 times.
8. such as the refining purification process of claim 1 or 5 described tiopronins, its characteristics are: during two kinds of mixed solvents of described esters solvent, alkane ketones solvent, esters solvent is 3～8: 1 with alkane ketones solvent mixed volume ratio, is preferably 3～6: 1, and more preferably 3: 1.
9. such as the refining purification process of claim 1 or 5 described tiopronins, its characteristics are: during the mixed solvent of described esters solvent, alkane ketone and three kinds of solvents of fat alkane class, esters solvent is 4～8: 1 with alkane ketones solvent mixed volume ratio, is preferably 6: 1.
10. the refining purification process of tiopronin as claimed in claim 9, its characteristics are: described esters solvent, alkane ketones solvent and fat alkane kind solvent volume ratio are 6: 1: 2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012105950444A CN103058901A (en) | 2012-12-31 | 2012-12-31 | Refining method of tiopronin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012105950444A CN103058901A (en) | 2012-12-31 | 2012-12-31 | Refining method of tiopronin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103058901A true CN103058901A (en) | 2013-04-24 |
Family
ID=48101835
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012105950444A Pending CN103058901A (en) | 2012-12-31 | 2012-12-31 | Refining method of tiopronin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103058901A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108658858A (en) * | 2017-06-27 | 2018-10-16 | 上海中西三维药业有限公司 | A kind of preparation method of the preparation and process for purification and its sulfate of hydroxychloroquine |
| CN110041191A (en) * | 2019-04-30 | 2019-07-23 | 湖南九典宏阳制药有限公司 | A kind of purification process of pelubiprofen |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101113141A (en) * | 2006-07-19 | 2008-01-30 | 南京圣和药业有限公司 | Optical active N-(alpha-mercapto radical propionyl group) aminoacetic acid |
| US20080220441A1 (en) * | 2001-05-16 | 2008-09-11 | Birnbaum Eva R | Advanced drug development and manufacturing |
-
2012
- 2012-12-31 CN CN2012105950444A patent/CN103058901A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080220441A1 (en) * | 2001-05-16 | 2008-09-11 | Birnbaum Eva R | Advanced drug development and manufacturing |
| CN101113141A (en) * | 2006-07-19 | 2008-01-30 | 南京圣和药业有限公司 | Optical active N-(alpha-mercapto radical propionyl group) aminoacetic acid |
Non-Patent Citations (2)
| Title |
|---|
| 夏玉宇: "《化验员实验手册（第二版）》", 1 March 2005, 化学工业出版社 * |
| 罗愉城等: "硫普罗宁合成工艺的改进", 《精细化工中间体》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108658858A (en) * | 2017-06-27 | 2018-10-16 | 上海中西三维药业有限公司 | A kind of preparation method of the preparation and process for purification and its sulfate of hydroxychloroquine |
| CN108658858B (en) * | 2017-06-27 | 2022-02-25 | 上海中西三维药业有限公司 | Preparation and refining method of hydroxychloroquine and preparation method of sulfate thereof |
| CN110041191A (en) * | 2019-04-30 | 2019-07-23 | 湖南九典宏阳制药有限公司 | A kind of purification process of pelubiprofen |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103910775A (en) | Synthesis method of 17alpha-hydroxyl progesterone | |
| CN105481952B (en) | Composition containing nitrogen heterocyclic hexapeptide precursor and preparation method and application thereof | |
| CN108676014A (en) | The method for purifying the method for everolimus intermediate and preparing everolimus | |
| CN105348351B (en) | The method for preparing 5ST | |
| CN103058901A (en) | Refining method of tiopronin | |
| CN103601735B (en) | A kind of method of mosictin of purifying | |
| CN107674107A (en) | A kind of process for purification of shellfish cholic acid difficult to understand | |
| CN109251157A (en) | (R)-Esomeprazole preparation method | |
| CN110128293B (en) | Medical intermediate impurity and preparation method and application thereof | |
| CN103119051A (en) | Preparation method of rocuronium | |
| CN101508709B (en) | Method for auxiliary extraction of aloin with mechanical force | |
| CN104231033A (en) | Preparation method of dutasteride | |
| CN102126970A (en) | Methods for separating leucine and arginine by selective precipitation | |
| CN104402758B (en) | A kind of preparation method of iohexol impurity | |
| CN112341510B (en) | Preparation method of betamethasone | |
| CN109503441A (en) | The preparation method of high-content Mercaptamine | |
| CN104693140B (en) | A kind of 5-Hydroxymethylthiazole purifying process | |
| CN102757373A (en) | Method for preparing high-purity lutein ester from marigold flower particles | |
| CN106946905B (en) | A kind of production method of mibemycin | |
| CN101307086B (en) | Process for purifying 3beta-cholest-5,24-diene-3-alcohol y solvent crystallization method | |
| CN112175034B (en) | Method for preparing 17 alpha-hydroxyprogesterone | |
| CN106831811B (en) | A method of preparing high-content nimoctin | |
| CN104558103B (en) | A kind of preparation method of argatroban intermediate | |
| CN108314651A (en) | A kind of new preparation process of huperzine | |
| CN104151396A (en) | Method for catalyzing and synthesizing S-acetyl-L-glutathione from mixed solvent |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C53 | Correction of patent of invention or patent application | ||
| CB02 | Change of applicant information |
Address after: 510990 No. 6, Industrial Avenue, Conghua Economic Development Zone, Guangdong, Guangzhou Applicant after: Guangdong Xianqiang Pharmaceutical Co., Ltd. Address before: 510620 Guangdong city of Guangzhou Province Sports West A Victoria Square No. 103 49 floor Applicant before: Xianqiang Pharmaceutical Co., Ltd., Guangdong |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: APPLICANT; FROM: XIANQIANG PHARMACEUTICAL CO., LTD., GUANGDONG TO: GUANGDONG XIANQIANG PHARMACEUTICAL CO., LTD. |
|
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130424 |