CN102796079B - A kind of preparation method of methanesulfonic acid fluorine imatinib - Google Patents
A kind of preparation method of methanesulfonic acid fluorine imatinib Download PDFInfo
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- CN102796079B CN102796079B CN201110146396.7A CN201110146396A CN102796079B CN 102796079 B CN102796079 B CN 102796079B CN 201110146396 A CN201110146396 A CN 201110146396A CN 102796079 B CN102796079 B CN 102796079B
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Abstract
The preparation method that the present invention relates to a kind of methanesulfonic acid fluorine imatinib.This preparation method shortens the response time, improves yield and safety is better, be more suitable for industrialized production.
Description
Technical field
The preparation method that the present invention relates to new type anticancer medicine methanesulfonic acid fluorine imatinib, this medicine is particularly well-suited to the treatment of chronic myelocytic leukemia.
Background technology
The chemical name of methanesulfonic acid fluorine imatinib is 4-[(4-methyl isophthalic acid-piperazinyl) methyl]-N-[6-methyl-5-[(4-(3-pyridine radicals)-2-pyrimidine radicals) amino] pyridin-3-yl]-3-(trifluoromethyl)-benzamide methanesulfonate.
In recent years, Gleevec has another name called imatinib becomes the first-line drug for the treatment of chronic myelocytic leukemia, but creates drug resistance after some patient's medication.Research shows, second filial generation Gleevec can better solve drug resistance problems.Namely methanesulfonic acid fluorine imatinib is the medicament for treatment of leukemia of new generation of exploitation on Gleevec basis, is mainly used in the treatment of chronic myelocytic leukemia, is currently under I phase clinical stage.
The preparation method that WO2006069525 discloses amino-metadiazine compound, and relate to the method preparing product by condensation reaction, also disclose some concrete condensing agents.But under normal circumstances, it is to be ensured that product quality, the use of condensing agent can cause cumbersome post-reaction treatment, specifically it is through silica gel column chromatography and removes a large amount of by-products produced due to the use of condensing agent, eventually increase production cost, and affect reaction yield, be not suitable for industrialized production.
Summary of the invention
The method that it is an object of the invention to provide the synthesizing methanesulfonic acid fluorine imatinib of a kind of simplicity, this response time is short, and it is convenient to process, and yield is high, is suitable for industrialized production.
The preparation method that the invention discloses the methanesulfonic acid fluorine imatinib shown in a kind of formula (I).
The method is as follows:
Carboxyl compound shown in formula (II) forms amido link with the amino-compound shown in formula (III) under condensing agent and solvent exist, reactant liquor adds the direct crystallize of alkali and obtains formula (IV) fluorine imatinib free alkali, then becomes salt to obtain methanesulfonic acid fluorine imatinib with methanesulfonic acid.
In above-mentioned reaction, formula (II) is from produced compounds, and formula (III) is outsourcing compound.Original technique is that first formula (II) and thionyl chloride be obtained by reacting acyl chlorides, then with formula (III) condensation under pyridine environment, organic solvent processes, and column chromatography obtains free alkali, then becomes salt to obtain methanesulfonic acid fluorine imatinib.
Technique is optimized by we, still with formula (II), formula (III) for raw material, adopts easy-to-handle condensing agent, reacts in solvent.
In above-mentioned prioritization scheme, condensing agent mainly has DCC, DIC, TBTU, HBTU, PyBOP, EDC hydrochlorate, or they and the combination of HOBt or HOAt, Ph3The combination of P and DIAD, Ph3The combination of P and DEAD or selected from CDI, wherein we prefer that EDC hydrochlorate.
Solvent mainly includes DMF, acetonitrile, oxolane, dichloromethane, chloroform, ethyl acetate, dioxane, pyridine and/or water, and wherein preferred water is as reaction dissolvent.
In such scheme, the inventory mol ratio of formula (II), formula (III) and condensing agent is 1～2: 1: 1～2, is wherein preferably 1.2: 1: 2.
In such scheme, reaction temperature is room temperature (10-30 DEG C).
Reaction terminates, and adds organic base as buffer solvent, adds inorganic base and regulates pH crystallize, is filtrated to get fluorine imatinib free alkali, and wherein organic base has pyridine, triethylamine, piperidines, it is preferred to pyridine；Inorganic base has ammonia, sodium hydroxide, sodium carbonate, it is preferred to ammonia.
The present invention adopts condensation reaction to prepare product, and the post processing of condensation reaction is optimized, thus greatly simplifiing operating process, improve product yield, reduces production cost.
Detailed description of the invention
In order to illustrate in greater detail the present invention, provide and following prepare example.But the scope of the present invention is not limited to this.
Embodiment one
By formula (III) compound (44.48g, 0.16mol), formula (II) compound (87.8g, content 74%, 0.192mol), EDC hydrochlorate (61.1g, 0.32mol), put into reaction bulb.Add purified water 450ml, be stirred at room temperature to molten clearly, TLC detect raw material (III) react completely, about 2-3h.
Reaction terminates, and kieselguhr filters, and 200ml washes.Filtrate adds pyridine 220ml, agitation and dropping 25% strong aqua ammonia (110ml), precipitates out a large amount of solid, and now pH is about 12.Add 1500ml water, continue stirring and crystallizing 2h.
Filter, 500ml water washing.Filtration cakes torrefaction, to constant weight, obtains 89.0g, yield 99%, HPLC99.5%, list assorted 0.2%.
1HNMR (500MHz, d6-DMSO, 25 DEG C): δ: 2.357 (s, 3H), 2.426-2.449 (m, 3H), 2.814 (3, 3H), 2.907-2.931 (m, 2H), 3.073 (t, 2H), 3.405 (br, 1H), 3.793 (s, 2H), 7.525-7.551 (m, 2H), 7.944 (d, 1H), 8.291 (d, 1H), 8.320 (s, 1H), 8.516 (d, 1H), 8.579 (d, 1H), 8.625 (s, 1H), 8.649-8.653 (m, 1H), 8.699 (d, 1H), 9.260 (s, 1H), 9.301-9.304 (br, 1H), 10.706 (s, 1H) ppm.
Embodiment two
By formula (III) compound (55.6g, 0.2mol), formula (II) compound (109.8g, content 74%, 0.24mol), EDC hydrochlorate (45.9g, 0.24mol), put into reaction bulb.Add purified water 560ml, be stirred at room temperature to molten clearly, TLC detect raw material (III) react completely, about 2-3h.
Reaction terminates, and kieselguhr filters, and 250ml washes.Filtrate adds pyridine 275ml, agitation and dropping 25% strong aqua ammonia (138ml), precipitates out a large amount of solid, and now pH is about 12.Add 1850ml water, continue stirring and crystallizing 2h.
Filter, 620ml water washing.Filtration cakes torrefaction, to constant weight, obtains 106.2g, yield 94.5%, HPLC99.5%, list assorted 0.2%.
Claims (4)
1. a preparation method for the methanesulfonic acid fluorine imatinib shown in formula (I),
It includes the carboxyl compound shown in formula (II) and forms amido link with the amino-compound shown in formula (III) under condensing agent and solvent exist, reactant liquor adds the direct crystallize of alkali and obtains formula (IV) fluorine imatinib free alkali, then become salt to obtain methanesulfonic acid fluorine imatinib with methanesulfonic acid
Wherein, described condensing agent is selected from EDC hydrochlorate, and described reaction dissolvent is water, and described alkali is selected from the mixture of organic base and inorganic base, and described organic base is selected from pyridine, triethylamine or piperidines, and described inorganic base is selected from ammonia, sodium hydroxide or sodium carbonate.
2. method according to claim 1, wherein said organic base is pyridine.
3. method according to claim 1, wherein said inorganic base is ammonia.
4. the method preparing compound as claimed in claim 1, the method comprises the following steps:
1) being separately added into the lower stirring reaction of carboxylic acid compound (II), amino-compound (III) and condensing agent, room temperature or heating in a solvent, wherein said condensing agent is selected from EDC hydrochlorate, and described solvent is water；
2) above-mentioned reactant liquor addition organic base and inorganic base carry out crystallize, obtain fluorine imatinib free alkali (IV), and described organic base is selected from pyridine, triethylamine or piperidines, and described inorganic base is selected from ammonia, sodium hydroxide or sodium carbonate；
3) fluorine imatinib free alkali (IV) is at water/acetone system crystallize.
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Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103509006B (en) * | 2012-06-19 | 2016-11-16 | 江苏豪森药业集团有限公司 | Methanesulfonic acid fluorine imatinib crystal formation and its production and use |
| CN103509007B (en) * | 2012-06-19 | 2016-08-31 | 江苏豪森药业集团有限公司 | Methanesulfonic acid fluorine imatinib crystal formation and its production and use |
| CN105884746B (en) * | 2016-05-05 | 2018-09-21 | 江苏豪森药业集团有限公司 | The synthetic method of fluorine imatinib |
| CN107652269A (en) * | 2016-07-26 | 2018-02-02 | 江苏豪森药业集团有限公司 | Methanesulfonic acid fluorine imatinib purification of intermediate method |
| CN107648237B (en) * | 2016-07-26 | 2022-03-04 | 江苏豪森药业集团有限公司 | Pharmaceutical composition of aminopyrimidine compounds and preparation method thereof |
| CN110687238B (en) * | 2019-11-20 | 2022-04-19 | 江苏豪森药业集团有限公司 | Detection method of flumatinib mesylate related substances |
| CN111072636B (en) * | 2019-12-16 | 2022-08-23 | 江苏豪森药业集团有限公司 | Synthesis method of flumatinib |
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Address after: 222006 Jiangsu province Lianyungang Kaitai Dapu Road Industrial Area Applicant after: JIANGSU HANSOH PHARMACEUTICAL GROUP LIANYUNGANG HONGCHUANG PHARMACEUTICAL CO., LTD. Address before: 222006 Jiangsu province Lianyungang Kaitai Dapu Road Industrial Area Applicant before: Jiangsu Hansoh Pharmaceutical Group Lianyungang Hongchuang Medical Co., Ltd. |
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