CN105237529A - Refining method for high-purity anhydrous dasatinib - Google Patents
Refining method for high-purity anhydrous dasatinib Download PDFInfo
- Publication number
- CN105237529A CN105237529A CN201510722820.6A CN201510722820A CN105237529A CN 105237529 A CN105237529 A CN 105237529A CN 201510722820 A CN201510722820 A CN 201510722820A CN 105237529 A CN105237529 A CN 105237529A
- Authority
- CN
- China
- Prior art keywords
- dasatinib
- solvent
- purity anhydrous
- acetate
- ether
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention provides a refining method for high-purity anhydrous dasatinib. The method comprises the following steps: adding crude dasatinib into dimethyl formamide (DMF) and carrying out heating, dissolving and clarifying; then adding at least one solvent selected from the group consisting of methyl tert-butyl ether, isopropyl ether, ethyl ether, tetrahydrofuran, ethyl formate, methyl acetate, ethyl acetate, propyl acetate and isopropyl acetate into an obtained heated solution, wherein a volume ratio of the heated solution to the solvent is 1: 1-5; and after the temperature of an obtained mixed solution is reduced, carrying out crystallization, filtering and drying so as to obtain the high-purity anhydrous dasatinib, wherein a feeding mass-volume ratio of the dasatinib to the solvent is 1: 2-20. The high-purity anhydrous dasatinib prepared by using the method provided by the invention has the following advantages: chromatographic purity reaches up to 99.9%; maximum individual impurity is less than 0.05%; meanwhile, the method has the advantages of high refining yield, simple operation in preparation process, stable process and significant applicability to industrial mass production.
Description
Technical field:
The present invention relates to the preparation field of Dasatinib, refer more particularly to a kind of preparation method of high-purity anhydrous Dasatinib.
Background technology
Dasatinib (dasatinib), trade(brand)name Sprycel, a kind of oral tyrosine kinase inhibitor researched and developed by Bristol-Myers Squibb Co., the preferential examination & approval of this medicine on June 28th, 2006 by U.S. FDA, for to the past Endodontic failure or all stadium patients of Adult chronic's myelogenous leukemia (CML) of not tolerating, the acute lymphoblastic leukemia adult patient of Philadelphia Chromosome Positive being also used for the treatment of other therapy resistances simultaneously or not tolerating.
Yuan Yan producer Bristol Myers Squibb (BMS) company discloses the structure (as follows) of chemistry N-(2-chloro-6-aminomethyl phenyl)-2-by name [[6-[4-(2-hydroxyethyl) piperazine-1-base]-2-methylpyrimidine-4-base] is amino]-1,3-thiazoles-5-methane amide and additive salt thereof and preparation method in CN1348370A.
Dasatinib
CN102838595A discloses a kind of preparation method of Dasatinib, using the chloro-6-aminomethyl phenyl of 2-amino-N-(2-)-5-thiazole carboxamides obtains Dasatinib as starting raw material, but do not relate to the process for refining of Dasatinib.
CN102838594A discloses a kind of preparation and process for purification of Dasatinib, and namely mainly adopt the mixed solvent heating for dissolving of 95% second alcohol and water, cooling crystallization obtains anhydrous Dasatinib.Because its preferred solvent is dimethyl sulfoxide (DMSO) (DMSO), volume is approximately 3 times amount of raw material weight, and make initial action liquid concentration very large, add that the viscosity of DMSO own is large, cause and stir difficulty, reaction efficiency is not high.In addition, DMSO has special physicochemical property: boiling point is high, and viscosity is large, and poor stability, eliminates very difficult, even if washing also will repeatedly be washed, easily causes loss of product.The method is selected to react about 80 DEG C temperature, makes DMSO in a heated condition, due to inadequate to alkaline stability, easily produces self disproportionation reaction.In addition, the aftertreatment of the method adds viscosity Virahol larger equally in the cooling condition, and both mix mutually, makes the precipitation product in reaction system be difficult to suction filtration or centrifugal, operational difficulty.Meanwhile, refining yield can only reach about 74.0%.
CN103408542A discloses a kind of exquisite method of Dasatinib, namely Dasatinib crude product is first suspended in a certain amount of dehydrated alcohol by main employing, then a certain amount of DMF is added, heat and dissolve after clarification until system, also to distill a part of solvent, after cooling, then add a certain amount of poor solvent, after product is separated out, filter out product.This process for refining yield is low, and generally about 74%, and technological operation is loaded down with trivial details, brings very burden to amplification suitability for industrialized production.
Summary of the invention:
The object of the invention is to provide a kind of to overcome above deficiency, the method refining effect is good, and yield is high, simultaneously simple to operate, is easy to the process for purification of the high-purity anhydrous Dasatinib of suitability for industrialized production.
The object of the present invention is achieved like this:
The process for purification of the high-purity anhydrous Dasatinib of the present invention, the method is after Dasatinib crude product being added in DMF heating for dissolving clarification, the at least one solvent in methyl tertiary butyl ether, isopropyl ether, ether, tetrahydrofuran (THF), ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate is added again in this hot solution, the volume ratio of hot melt liquid and solvent is 1:1 ~ 5, crystallization after the temperature of reduction mixing solutions, filtration drying both obtains; When feeding intake, the mass volume ratio of Dasatinib and solvent is 1:2 ~ 20.
In above-mentioned method, solvent is at least one in methyl tertiary butyl ether, isopropyl ether, propyl acetate.
Add at 75-90 DEG C in DMF by Dasatinib crude product in above-mentioned method, heating for dissolving is clarified.
Mass volume ratio 1:5 ~ 8 of Dasatinib and solvent when feeding intake in above-mentioned method, the solid Dasatinib of such as 1g adds the solvent of 10mL, and the mass volume ratio of the two is 1:10, and other roughly the same.
The temperature reducing mixing solutions in above-mentioned method rolls over crystalline substance after 15-30 DEG C.
The anhydrous Dasatinib yield adopting process for purification of the present invention obtained is high, and chromatographic purity is up to 99.9%, and maximum list is assorted is less than 0.05%, and simple to operate, process stabilizing, is easy to industrialized production.
Embodiment
Embodiment 1:
In the Dasatinib crude product of 50g, add the DMF of 150mL, and be heated to 75 DEG C, stir until system dissolves clarification, then the methyl tertiary butyl ether of 300mL is slowly added, finish, system is stirred lower nature and is down to 20 DEG C, then stirring and crystallizing 1 hour, filter, gained solid is dry under vacuo, obtains highly finished product 45.6g, yield 91.0%, chromatographic purity 99.9%, maximum list assorted 0.05%.
Embodiment 2:
In the Dasatinib crude product of 40g, add the DMF of 95mL, and be heated to 90 DEG C, stir until system dissolves clarification, then the isopropyl ether of 160mL is slowly added, finish, system is stirred lower nature and is down to 30 DEG C, then stirring and crystallizing 1 hour, filter, gained solid is dry under vacuo, obtains highly finished product 34.8g, yield 87.0%, chromatographic purity 99.9%, maximum list assorted 0.04%.
Embodiment 3:
In the Dasatinib crude product of 100g, add the DMF of 300mL, and be heated to 80 DEG C, stir until system dissolves clarification, then the methyl tertiary butyl ether of 700mL and the mixing solutions (v/v=1:1) of isopropyl ether is slowly added, finish, system is stirred lower nature and is down to 25 DEG C, then stirring and crystallizing 2 hours, filter, gained solid is dry under vacuo, obtains highly finished product 88.0g, yield 88.0%, chromatographic purity 99.9%, maximum list assorted 0.04%.
Embodiment 4:
In the Dasatinib crude product of 120g, add the DMF of 340mL, and be heated to 85 DEG C, stir until system dissolves clarification, then the methyl tertiary butyl ether of 800mL and the mixing solutions (v/v=1:1) of ethyl acetate is slowly added, finish, system is stirred lower nature and is down to 15 DEG C, then stirring and crystallizing 2 hours, filter, gained solid is dry under vacuo, obtains highly finished product 106.8g, yield 89.0%, chromatographic purity 99.9%, maximum list assorted 0.05%.
Embodiment 5:
In the Dasatinib crude product of 150g, add the DMF of 400mL, and be heated to 80 DEG C, stir until system dissolves clarification, then the methyl tertiary butyl ether of 820mL and the mixing solutions (v/v/v=1:1:1) of isopropyl ether and ethyl acetate is slowly added, finish, system is stirred lower nature and is down to 25 DEG C, then stirring and crystallizing 3 hours, filter, gained solid is dry under vacuo, obtains highly finished product 130.5g, yield 87.0%, chromatographic purity 99.9%, maximum list assorted 0.04%.
Above-described embodiment is described further foregoing of the present invention, but this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to above-described embodiment.All technology realized based on foregoing all belong to protection scope of the present invention.
Claims (5)
1. the process for purification of high-purity anhydrous Dasatinib, the method is after Dasatinib crude product being added in DMF heating for dissolving clarification, the at least one solvent in methyl tertiary butyl ether, isopropyl ether, ether, tetrahydrofuran (THF), ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate is added again in this hot solution, the volume ratio of hot melt liquid and solvent is 1:1 ~ 5, crystallization after the temperature of reduction mixing solutions, filtration drying both obtains; When feeding intake, the mass volume ratio of Dasatinib and solvent is 1:2 ~ 20.
2. the process for purification of high-purity anhydrous Dasatinib as claimed in claim 1, is characterized in that in described method, solvent is at least one in methyl tertiary butyl ether, isopropyl ether, propyl acetate.
3. the process for purification of high-purity anhydrous Dasatinib as claimed in claim 1 or 2, described in is characterized in that
In method, Dasatinib crude product is added in DMF 75-90 DEG C of heating for dissolving clarifications.
4. the process for purification of high-purity anhydrous Dasatinib as claimed in claim 1 or 2, mass volume ratio 1:5 ~ 8 of Dasatinib and solvent when it is characterized in that feeding intake in described method.
5. the process for purification of high-purity anhydrous Dasatinib as claimed in claim 1 or 2, is characterized in that the temperature reducing mixing solutions in described method rolls over crystalline substance after 15-30 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510722820.6A CN105237529A (en) | 2015-10-29 | 2015-10-29 | Refining method for high-purity anhydrous dasatinib |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510722820.6A CN105237529A (en) | 2015-10-29 | 2015-10-29 | Refining method for high-purity anhydrous dasatinib |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105237529A true CN105237529A (en) | 2016-01-13 |
Family
ID=55035397
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510722820.6A Pending CN105237529A (en) | 2015-10-29 | 2015-10-29 | Refining method for high-purity anhydrous dasatinib |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105237529A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108239086A (en) * | 2016-12-27 | 2018-07-03 | 四川科伦药物研究院有限公司 | A kind of preparation method of Dasatinib N-6 anhydrous crystal forms |
| CN111217807A (en) * | 2018-11-26 | 2020-06-02 | 安礼特（上海）医药科技有限公司 | Dasatinib amorphous form and preparation method thereof |
| RU2777433C2 (en) * | 2019-07-04 | 2022-08-03 | Общество с ограниченной ответственностью "АКСЕЛЬФАРМ" | Method for obtaining anhydrous amorphous form of n-(2-chlorine-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolcarboxamide |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009053854A2 (en) * | 2007-10-23 | 2009-04-30 | Teva Pharmaceutical Industries Ltd. | Polymorphs of dasatinib and process for preparation thereof |
| CN102040596A (en) * | 2009-10-10 | 2011-05-04 | 上海希迪制药有限公司 | Dasatinib polymorph and preparation method thereof |
| CN103664929A (en) * | 2012-08-30 | 2014-03-26 | 石药集团中奇制药技术（石家庄）有限公司 | Dasatinib polycrystalline form medicament and preparation method thereof |
-
2015
- 2015-10-29 CN CN201510722820.6A patent/CN105237529A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009053854A2 (en) * | 2007-10-23 | 2009-04-30 | Teva Pharmaceutical Industries Ltd. | Polymorphs of dasatinib and process for preparation thereof |
| CN102040596A (en) * | 2009-10-10 | 2011-05-04 | 上海希迪制药有限公司 | Dasatinib polymorph and preparation method thereof |
| CN103664929A (en) * | 2012-08-30 | 2014-03-26 | 石药集团中奇制药技术（石家庄）有限公司 | Dasatinib polycrystalline form medicament and preparation method thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108239086A (en) * | 2016-12-27 | 2018-07-03 | 四川科伦药物研究院有限公司 | A kind of preparation method of Dasatinib N-6 anhydrous crystal forms |
| CN108239086B (en) * | 2016-12-27 | 2023-06-16 | 四川科伦药物研究院有限公司 | Preparation method of dasatinib N-6 anhydrous crystal |
| CN111217807A (en) * | 2018-11-26 | 2020-06-02 | 安礼特（上海）医药科技有限公司 | Dasatinib amorphous form and preparation method thereof |
| RU2777433C2 (en) * | 2019-07-04 | 2022-08-03 | Общество с ограниченной ответственностью "АКСЕЛЬФАРМ" | Method for obtaining anhydrous amorphous form of n-(2-chlorine-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolcarboxamide |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2980418C (en) | Preparation method of crystalline form a of pci-32765 | |
| CN105968093A (en) | Preparation method for trelagliptin succinate | |
| CN105061416B (en) | A kind of method for preparing flumioxazin | |
| CN105712984A (en) | Preparation method of Azilsartan | |
| CN102491918A (en) | Alanyl glutamine compound and preparation method thereof | |
| CN105566215A (en) | Preparation method of Stivarga | |
| CN102796079A (en) | Method for preparing flumatinib mesylate | |
| CN105237529A (en) | Refining method for high-purity anhydrous dasatinib | |
| CN105859686B (en) | Refining method of dabigatran etexilate free alkali | |
| CN102584693B (en) | Preparation method for high purity 2-chlorine-3-aminopyridine hydrochloride | |
| CN101735239B (en) | Preparation method of anhydrous olanzapine crystal form II | |
| CN104326954B (en) | A kind of synthetic method of Fudosteine | |
| WO2023170048A1 (en) | Crystallization of 4-hydroxyacetophenone from ethanol and ethyl acetate | |
| CN107814769B (en) | Purification method of bosutinib | |
| CN101391969B (en) | Method for preparing N-methyl-2-(2,4-dichlorophenoxy) acetamide | |
| CN104418810A (en) | New synthetic route of levosimendan | |
| CN107488178B (en) | Preparation method of high-purity pralatrexate intermediate | |
| CN105601545B (en) | A kind of synthetic method of sulphoamidine | |
| JP5501054B2 (en) | Method for producing 3,3-diaminoacrylic acid (1-diphenylmethylazetidin-3-yl) ester acetate | |
| JP6764998B2 (en) | How to make hydronidon | |
| CN104151299B (en) | Compound, crystal-form compound and preparation method thereof | |
| CN112028838B (en) | Preparation method of 2-ethoxy-5-fluorouracil impurity | |
| CN110483312A (en) | A kind of preparation method of high-purity hydrochloric acid Ivabradine and its intermediate | |
| CN105801559B (en) | The preparation method of 4- methyl -3- [[4- (3- pyridyl group) -2- pyrimidine radicals] amino] ethyl benzoate | |
| CN105884763A (en) | Method for purifying apixaban |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160113 |