CN102924432A - Preparation method of high-purity thalidomide - Google Patents
Preparation method of high-purity thalidomide Download PDFInfo
- Publication number
- CN102924432A CN102924432A CN201210444163XA CN201210444163A CN102924432A CN 102924432 A CN102924432 A CN 102924432A CN 201210444163X A CN201210444163X A CN 201210444163XA CN 201210444163 A CN201210444163 A CN 201210444163A CN 102924432 A CN102924432 A CN 102924432A
- Authority
- CN
- China
- Prior art keywords
- thalidomide
- dimethyl sulfoxide
- dmso
- preparation
- hot
- 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
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to a preparation method of high-purity thalidomide by using thalidomide crude products. The preparation method comprises dissolving the thalidomide crude products in hot dimethyl sulfoxide or a mixed solvent of the hot dimethyl sulfoxide and fatty alcohol, using activated carbon to decolor, filtering when the hot dimethyl sulfoxide or the mixed solvent is hot, and using filter liquor to conduct cooling and devitrification. The method is environment-friendly, simple and convenient to operate and high in yield, and meets requirements for drug good manufacturing practice (GMP) industrial production. High performance liquid chromatography (HPLC) purity of prepared thalidomide is larger than 99.9%.
Description
Technical field
The invention belongs to chemistry or pharmaceutical chemistry field, be specifically related to a kind of preparation method of high purity Thalidomide.
Background technology
Thalidomide (Thalidomide) claims again thalidomide, chemical name: 2,6-dioxy-3-phthalimide phenylpiperidines, and its chemical structural formula is as follows:
Thalidomide by the exploitation of Pharmion company, is glutamic acid derivatives at first.Research finds, Thalidomide and antileprotic be with can reducing lepra reaction, so this product is used for the treatment of Various Types of Leprosy and reacts, and is better such as curative effects such as lymphadenectasis, erythema nodosum, heating, arthrodynia and neurodynias.2006, U.S. FDA was examined again and has been passed through Thalidomide and can treat multiple myeloma.In China, Thalidomide has also passed through the approval of Chinese Medical Association, and except can treating ENL, Thalidomide can be treated multiple myeloma in clinic diagnosis guide hematology fascicle; Thalidomide can be treated ankylosing spondylitis and Behcet disease in clinic diagnosis guide rheumatism credit volume.
The Thalidomide preparation method of bibliographical information has multiple.The preparation method of the Thalidomide that GB768821 provides is: N-O-phthalic glutamatic acid or N-O-phthalic glutamatic acid acid anhydride and urea, and thiocarbamide, perhaps dry ammonia obtains Thalidomide 170-180 ℃ of reaction.The method temperature of reaction is higher, and side reaction is many, and products therefrom need to carry out repeatedly recrystallization with ethanol in scale operation, could obtain pure Thalidomide.Because the solubleness of Thalidomide in ethanol is little, the required amount of alcohol of recrystallization is large, is unfavorable for industrializing implementation.
The preparation method of the Thalidomide that EP1004581 provides is: Pidolidone amine and N-ethoxycarbonyl phthalic acid imine reaction obtain N-phthalic acid glu famine, N-phthalic acid glu famine again with carbonyl dimidazoles under the catalysis of 4-methylamino pyridine in anhydrous tetrahydro furan back flow reaction obtained Thalidomide in 16 hours.This method is carried out in two steps, has increased operating process, and the reaction times is longer; In addition, product is directly separated out from reaction solution in this patent, and purity is not high.
The preparation method of the Thalidomide that CN1405166 provides is: at 120-150 ℃ of lower Tetra hydro Phthalic anhydride and the glu famine of adding, heated and stirred is reacted and after 20-40 minute temperature is slowly risen to 160-220 ℃; System is vacuumized stopped reaction after 2-20 hour; Add Isosorbide-5-Nitrae-dioxane heated and stirred to system and become solution, decompression steams Isosorbide-5-Nitrae-dioxane, adds acetone and stirs, and filters and water washing and precipitating, uses washing with acetone again, and vacuum-drying gets Thalidomide.The method operation is more loaded down with trivial details, and temperature of reaction is high, is unfavorable for industrializing implementation; In addition, it is not high to add acetone (solubleness of Thalidomide in acetone the is little) product purity that directly crystallization obtains from reaction mixture in the method aftertreatment.
CN102260241 provides a kind of preparation method of highly purified Thalidomide alpha-crystal form: use pyridine, and perhaps DMF, perhaps dimethyl sulfoxide (DMSO) isopolarity dissolution with solvents Thalidomide (crude product) adds pure crystallization again.The HPLC purity of gained Thalidomide is greater than 99.7%, even reaches more than 99.9%.The polar solvent amount that the method is used for the dissolving Thalidomide be Thalidomide weight 5-10 doubly, the pure consumption (volume) that is used for crystallization be 10-24 times of Thalidomide weight.Solvent load is large, and its mother liquor is mixed solvent, and it is large to recycle difficulty, is unfavorable for industrializing implementation.
Wait the people eastwards in " research of R-or-S-Thalidomide new synthetic process " (chemical research and application, the 18th volume o. 11th), adopt DMF-distilled water that Thalidomide is carried out recrystallization.But DMF toxicity is larger, belongs to two kind solvents of ICH in requiring, limit the quantity of low (0.088%), therefore with its recrystallization exist product be difficult for drying qualified, be unfavorable for the deficiency such as environmental protection.
By the Thalidomide preparation method of existing bibliographical information, the product purity that directly obtains from reaction solution is not high, and major impurity wherein is: phthaloyl-L-glutamine gln, and its chemical structural formula is as follows:
In order to obtain meeting the product of medicinal requirements, must make with extra care gained Thalidomide crude product, remove impurity.Yet existing technology exist recrystallisation solvent toxicity greatly, the weak point such as not environmental protection, solvent load be large.As everyone knows, in production of raw medicine, final step refining reaction solvent for use is difficult to avoid form the residual of trace level in finished product, thereby may has side effects to the patient.In order to reduce this risk, have under the prerequisite of technological feasibility, bulk drug is refining should to adopt low toxicity or nontoxic solvent as far as possible.Therefore invent a kind of environmental protection, easy and simple to handle, and be suitable for extremely being necessary by the industrialized preparing process of GMP requirement preparation high purity Thalidomide.
Research is found, Thalidomide is soluble in dimethyl sulfoxide (DMSO), and its solubleness temperature influence is very large, and dimethyl sulfoxide (DMSO) belongs to three kind solvents in the ICH requirement, toxicity is lower, its PDE value is 50mg/ days, and residue limits is 0.5% in the product, so dimethyl sulfoxide (DMSO) is the preferred solvent of recrystallization purifying Thalidomide.
Because dimethyl sulfoxide (DMSO) is larger to Thalidomide solubleness, in order to improve Thalidomide recrystallization yield, can substitute dimethyl sulfoxide (DMSO) with the mixed solvent of dimethyl sulfoxide (DMSO) and Fatty Alcohol(C12-C14 and C12-C18).Fatty Alcohol(C12-C14 and C12-C18) is selected from methyl alcohol, ethanol, n-propyl alcohol, the 2-propyl alcohol, propyl carbinol, and the 2-butanols a kind of, two or more, preferred alcohol.The blending ratio of dimethyl sulfoxide (DMSO) and Fatty Alcohol(C12-C14 and C12-C18) is 1: 1 to 100: 1 (weight ratio).
Summary of the invention
The object of the present invention is to provide a kind ofly to prepare the method for high purity Thalidomide by the Thalidomide crude product, the method is environmentally friendly, and is easy and simple to handle, and yield is higher, the requirement of the drug's GMP suitability for industrialized production that is content with very little.Thalidomide obtained by this method, HPLC purity is greater than 99.9%.
In order to realize purpose of the present invention, provide following several technical scheme:
Scheme one
The preparation method of a kind of high purity Thalidomide of the present invention comprises the Thalidomide dissolving crude product in the dimethyl sulfoxide (DMSO) of heat, with activated carbon decolorizing, and filtered while hot, filtrate cooling crystallization.
Among the above-mentioned preparation method, the consumption of dimethyl sulfoxide (DMSO) is 1 to 5 times (weight ratio) of Thalidomide, preferred 2 to 3 times.
Among the above-mentioned preparation method, solvent temperature is 80 ℃ to 120 ℃.
Among the above-mentioned preparation method, filtrate cooling crystallization, wherein recrystallization temperature is-10 ℃ to 30 ℃, preferred-5 ℃ to 5 ℃.
Among the above-mentioned preparation method, behind the Thalidomide crystallization, can be through processes such as further filtering separation, dryings.
Above-mentioned preparation method's gained Thalidomide HPLC purity is greater than 99.9%.
Among the above-mentioned preparation method, the Thalidomide crude product comprises and uses existing Thalidomide preparation method, the product that directly crystallization obtains from reaction mixture, and perhaps its related substances does not meet the Thalidomide product of standards of pharmacopoeia requirement.
Scheme two
The preparation method of a kind of high purity Thalidomide of the present invention comprises the Thalidomide dissolving crude product in the mixed solvent of the dimethyl sulfoxide (DMSO) of heat and Fatty Alcohol(C12-C14 and C12-C18), with activated carbon decolorizing, and filtered while hot, filtrate cooling crystallization.
Among the above-mentioned preparation method, Fatty Alcohol(C12-C14 and C12-C18) wherein is for being selected from methyl alcohol, ethanol, n-propyl alcohol, the 2-propyl alcohol, propyl carbinol, and the 2-butanols a kind of, two or more, preferred alcohol.
Among the above-mentioned preparation method, wherein the blending ratio of dimethyl sulfoxide (DMSO) and Fatty Alcohol(C12-C14 and C12-C18) is 1: 1 to 100: 1 (weight ratio).
Among the above-mentioned preparation method, wherein the consumption of dimethyl sulfoxide (DMSO) and Fatty Alcohol(C12-C14 and C12-C18) mixed solvent is 1 to 10 times (weight ratio) of Thalidomide, preferred 2 to 5 times.
Among the above-mentioned preparation method, wherein solvent temperature is reflux temperature.
Among the above-mentioned preparation method, wherein recrystallization temperature is-10 ℃ to 30 ℃, preferred-5 ℃ to 5 ℃.
Among the above-mentioned preparation method, behind the Thalidomide crystallization, can be through processes such as further filtering separation, dryings.
Above-mentioned preparation method's gained Thalidomide HPLC purity is greater than 99.9%.
Among the above-mentioned preparation method, the Thalidomide crude product comprises and uses existing Thalidomide preparation method, the product that directly crystallization obtains from reaction mixture, and perhaps its related substances does not meet the Thalidomide product of standards of pharmacopoeia requirement.
Embodiment
The following example is used for further explaining or understanding content of the present invention, but can not limits the scope of the invention.
Embodiment 1: the preparation of Thalidomide crude product
In reactor, drop into 10kgN-O-phthalic glutamatic acid acid anhydride, be heated to melting, pass into ammonia.After reaction is finished, reaction solution is put into water, stir simultaneously.Cooled and filtered, filter cake washes with water, obtains Thalidomide crude product 10kg.
Thalidomide crude product HPLC content 97.3%.HPLC testing conditions: take octadecylsilane chemically bonded silica as weighting agent; Acetonitrile-water-phosphoric acid (5: 95: 0.1) is mobile phase A, and acetonitrile-water-phosphoric acid (15: 85: 0.1) is Mobile phase B, and flow velocity is 1.5ml/min, and column temperature is 35.0 ℃, and the detection wavelength is 237nm; External standard method.
Embodiment 2: the preparation of high purity Thalidomide
Thalidomide crude product 100g (HPLC 97.3%) adds 200g dimethyl sulfoxide (DMSO) and 1g gac, is heated to 100 ℃ of dissolvings, suction filtration while hot, and filtrate is cooled to 0 ℃, suction filtration, the washing with alcohol filter cake, 80 ℃ of dryings obtain Thalidomide 65g.HPLC content 100.2%, testing conditions is with embodiment 1.
Embodiment 3: the preparation of high purity Thalidomide
Thalidomide crude product 100g (HPLC 97.3%) adds 200g dimethyl sulfoxide (DMSO), 2g ethanol and 1g gac, and reflux 30 minutes makes the Thalidomide dissolving.Suction filtration while hot, filtrate is cooled to 5 ℃, suction filtration, the washing with alcohol filter cake, 80 ℃ of dryings obtain Thalidomide 65g.HPLC content 100.2%, testing conditions is with embodiment 1.
Embodiment 4: the preparation of high purity Thalidomide
Thalidomide crude product 100g (HPLC 97.3%) adds 200g dimethyl sulfoxide (DMSO), 20g ethanol and 1g gac, and reflux 30 minutes makes the Thalidomide dissolving.Suction filtration while hot, filtrate is cooled to 5 ℃, suction filtration, the washing with alcohol filter cake, 80 ℃ of dryings obtain Thalidomide 70g.HPLC content 100.0%, testing conditions is with embodiment 1.
Embodiment 5: the preparation of high purity Thalidomide
Thalidomide crude product 40g (HPLC 97.3%) adds 200g dimethyl sulfoxide (DMSO), 200g ethanol and 1g gac, and reflux 30 minutes makes the Thalidomide dissolving.Suction filtration while hot, filtrate is cooled to 5 ℃, suction filtration, the washing with alcohol filter cake, 80 ℃ of dryings obtain Thalidomide 30g.HPLC content 100.0%, testing conditions is with embodiment 1.
Embodiment 6: the preparation of high purity Thalidomide
Thalidomide crude product 100g (HPLC 97.3%) adds 200g dimethyl sulfoxide (DMSO), 20g methyl alcohol and 1g gac, and reflux 30 minutes makes the Thalidomide dissolving.Suction filtration while hot, filtrate is cooled to 5 ℃, suction filtration, the washing with alcohol filter cake, 80 ℃ of dryings obtain Thalidomide 70g.HPLC content 100.0%, testing conditions is with embodiment 1.
Claims (11)
1. the preparation method of a high purity Thalidomide, it comprises the dimethyl sulfoxide (DMSO) of Thalidomide dissolving crude product in heat, perhaps in the mixed solvent of the dimethyl sulfoxide (DMSO) of heat and Fatty Alcohol(C12-C14 and C12-C18), with activated carbon decolorizing, filtered while hot, the filtrate crystallization of lowering the temperature.
2. method according to claim 1 is characterized in that the dimethyl sulfoxide (DMSO) of Thalidomide dissolving crude product in heat, with activated carbon decolorizing, and filtered while hot, filtrate cooling crystallization.
3. method according to claim 2, the consumption that it is characterized in that dimethyl sulfoxide (DMSO) is 1 to 5 times (weight ratio) of Thalidomide.
4. method according to claim 3 is characterized in that solvent temperature is 80 ℃ to 120 ℃.
5. method according to claim 4 is characterized in that recrystallization temperature is-10 ℃ to 30 ℃.
6. method according to claim 1 is characterized in that the Thalidomide dissolving crude product in the mixed solvent of the dimethyl sulfoxide (DMSO) of heat and Fatty Alcohol(C12-C14 and C12-C18), with activated carbon decolorizing, and filtered while hot, filtrate cooling crystallization.
7. method according to claim 6 is characterized in that Fatty Alcohol(C12-C14 and C12-C18) is selected from methyl alcohol, ethanol, n-propyl alcohol, the 2-propyl alcohol, propyl carbinol, and the 2-butanols a kind of, two or more.
8. method according to claim 7, the blending ratio that it is characterized in that dimethyl sulfoxide (DMSO) and Fatty Alcohol(C12-C14 and C12-C18) is 1: 1 to 100: 1 (weight ratio).
9. method according to claim 8, the consumption that it is characterized in that dimethyl sulfoxide (DMSO) and Fatty Alcohol(C12-C14 and C12-C18) mixed solvent is 1 to 10 times (weight ratio) of Thalidomide.
10. method according to claim 9 is characterized in that solvent temperature is reflux temperature.
11. method according to claim 10 is characterized in that recrystallization temperature is-10 ℃ to 30 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210444163XA CN102924432A (en) | 2012-11-09 | 2012-11-09 | Preparation method of high-purity thalidomide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210444163XA CN102924432A (en) | 2012-11-09 | 2012-11-09 | Preparation method of high-purity thalidomide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102924432A true CN102924432A (en) | 2013-02-13 |
Family
ID=47639391
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210444163XA Pending CN102924432A (en) | 2012-11-09 | 2012-11-09 | Preparation method of high-purity thalidomide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102924432A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110498788A (en) * | 2018-05-16 | 2019-11-26 | 欣凯医药化工中间体（上海）有限公司 | A kind of preparation method of high-purity thalidomide alpha-crystal form |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1405166A (en) * | 2002-10-28 | 2003-03-26 | 中国科学院长春应用化学研究所 | Thalidomide and its derivatives preparation method |
| US20050272934A1 (en) * | 2004-06-01 | 2005-12-08 | Antibioticos S.P.A. | Process for the synthesis of thalidomide |
| WO2008035378A2 (en) * | 2006-09-20 | 2008-03-27 | Matrix Laboratories Ltd | An improved process for the preparation of thalidomide |
| CN102260241A (en) * | 2010-05-26 | 2011-11-30 | 重庆医药工业研究院有限责任公司 | Industrial preparation method of thalidomide of crystal form alpha |
| WO2011154739A1 (en) * | 2010-06-09 | 2011-12-15 | Generics [Uk] Limited | Crystalline forms of thalidomide and processes for their preparation |
-
2012
- 2012-11-09 CN CN201210444163XA patent/CN102924432A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1405166A (en) * | 2002-10-28 | 2003-03-26 | 中国科学院长春应用化学研究所 | Thalidomide and its derivatives preparation method |
| US20050272934A1 (en) * | 2004-06-01 | 2005-12-08 | Antibioticos S.P.A. | Process for the synthesis of thalidomide |
| WO2008035378A2 (en) * | 2006-09-20 | 2008-03-27 | Matrix Laboratories Ltd | An improved process for the preparation of thalidomide |
| CN102260241A (en) * | 2010-05-26 | 2011-11-30 | 重庆医药工业研究院有限责任公司 | Industrial preparation method of thalidomide of crystal form alpha |
| WO2011154739A1 (en) * | 2010-06-09 | 2011-12-15 | Generics [Uk] Limited | Crystalline forms of thalidomide and processes for their preparation |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110498788A (en) * | 2018-05-16 | 2019-11-26 | 欣凯医药化工中间体（上海）有限公司 | A kind of preparation method of high-purity thalidomide alpha-crystal form |
| CN110498788B (en) * | 2018-05-16 | 2021-09-17 | 欣凯医药化工中间体（上海）有限公司 | Preparation method of high-purity thalidomide alpha crystal form |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108129288B (en) | Synthesis method of trans-3-hydroxycyclobutylformic acid | |
| CN106256824B (en) | Preparation method of high-purity delafloxacin meglumine salt | |
| CN104177461B (en) | The preparation method of troxerutin | |
| CN106831772B (en) | Synthetic method of avibactam intermediate | |
| CN115011661A (en) | Synthetic method of 3 beta-ursodesoxycholic acid | |
| CN105198718A (en) | Preparation method for buparvaquone | |
| CN102924311A (en) | L-ornithine-L-aspartate preparation method | |
| CN107686530B (en) | A kind of synthetic method for the more glucose sodium that relaxes | |
| CN102924432A (en) | Preparation method of high-purity thalidomide | |
| CN104193674A (en) | Synthesis method of flunixin meglumine | |
| CN102260241A (en) | Industrial preparation method of thalidomide of crystal form alpha | |
| CN113620957B (en) | Preparation method of aminomethyl pyrazine compound | |
| CN106518939B (en) | Method for preparing Solithromycin compound | |
| CN103804265B (en) | The synthesis of a kind of Sulpiride or its optical isomer and post-processing approach | |
| CN102838586A (en) | Method for preparing lenalidomide | |
| CN103588802B (en) | A kind of purification process of solvent pairs recrystallization triisopropanolamine cyclic borate | |
| JP6234556B2 (en) | Method for preparing trihydroxyethyl rutoside | |
| CN112010805A (en) | Method for refining fasudil hydrochloride | |
| CN112194581A (en) | Preparation method of flurbiprofen axetil | |
| CN113185507A (en) | Lurasidone preparation method | |
| CN104650048B (en) | Purification method of olmesartan medoxomil condensation compound | |
| CN110862429A (en) | Preparation method of sodium aescinate | |
| CN104045639B (en) | A kind of preparation method of figured silk fabrics acyclovir | |
| CN108863946B (en) | Preparation method of dibazole impurity reference substance | |
| CN102206185A (en) | Process for refining bendazac lysine and analogs thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130213 |