CN102796079A - Method for preparing flumatinib mesylate - Google Patents
Method for preparing flumatinib mesylate Download PDFInfo
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- CN102796079A CN102796079A CN2011101463967A CN201110146396A CN102796079A CN 102796079 A CN102796079 A CN 102796079A CN 2011101463967 A CN2011101463967 A CN 2011101463967A CN 201110146396 A CN201110146396 A CN 201110146396A CN 102796079 A CN102796079 A CN 102796079A
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- fluorine imatinib
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- methylsulfonic acid
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Abstract
The invention relates to a method for preparing flumatinib mesylate. By the method for preparing flumatinib mesylate, the reaction time is shortened, the yield is increased, the safety is better, and the method is more suitable for industrial production.
Description
Technical field
The present invention relates to the preparation method of new type anticancer medicine methylsulfonic acid fluorine imatinib, this medicine is specially adapted to the treatment of chronic myelocytic leukemia.
Background technology
The chemical name of methylsulfonic acid fluorine imatinib is 4-[(4-methyl isophthalic acid-piperazinyl) methyl]-N-[6-methyl-5-[(4-(3-pyridyl)-2-pyrimidyl) amino] pyridin-3-yl]-3-(trifluoromethyl)-BM mesylate.
In recent years, Gleevec has another name called the line medicine that imatinib becomes the treatment chronic myelocytic leukemia, but has produced resistance after some patient's medication.Research shows that s-generation Gleevec can better solve the resistance problem.Methylsulfonic acid fluorine imatinib promptly is the medicament for treatment of leukemia of on the Gleevec basis, developing of new generation, is mainly used in the treatment of chronic myelocytic leukemia, is in I phase clinical stage at present.
WO2006069525 discloses the preparation method of amino-metadiazine compound, and relates to the method for preparing product through condensation reaction, discloses some concrete condensing agents simultaneously.But generally; Guarantee quality product; The use of condensing agent can cause more loaded down with trivial details post-reaction treatment, and concrete is exactly to remove because a large amount of by products that the use of condensing agent produces finally can increase production cost through silica gel column chromatography; And influence reaction yield, be not suitable for suitability for industrialized production.
Summary of the invention
The object of the present invention is to provide a kind of method of easy synthesizing methanesulfonic acid fluorine imatinib, this reaction times is short, convenient processing, and yield is high, is fit to suitability for industrialized production.
The invention discloses the preparation method of the methylsulfonic acid fluorine imatinib shown in a kind of formula (I).
This method is as follows:
Aminocompound shown in carboxylic compound shown in the formula (II) and the formula (III) forms amido linkage in the presence of condensing agent and solvent, reaction solution adds the direct crystallization of alkali and obtains formula (IV) fluorine imatinib free alkali, obtains methylsulfonic acid fluorine imatinib with the methylsulfonic acid salify then.
In the above-mentioned reaction, formula (II) is the self-control compound, and formula (III) is the outsourcing compound.Original technology is at first formula (II) and sulfur oxychloride reaction to be obtained acyl chlorides, and again with formula (III) condensation under the pyridine environment, organic solvent is handled, and column chromatography obtains free alkali, and salify obtains methylsulfonic acid fluorine imatinib then.
We optimize technology, are raw material with formula (II), formula (III) still, adopt easy-to-handle condensing agent, in solvent, react.
In the above-mentioned prioritization scheme, condensing agent mainly contains DCC, DIC, TBTU, HBTU, PyBOP, EDC hydrochloride, perhaps combination, the Ph of they and HOBt or HOAt
3The combination of P and DIAD, Ph
3The combination of P and DEAD or be selected from CDI, wherein our preferred EDC hydrochloride.
Solvent mainly comprises DMF, acetonitrile, THF, methylene dichloride, trichloromethane, ETHYLE ACETATE, dioxane, pyridine and/or water, and wherein preferably water is as reaction solvent.
In the such scheme, the charging capacity mol ratio of formula (II), formula (III) and condensing agent is 1～2: 1: 1～2, wherein be preferably 1.2: 1: 2.
In the such scheme, temperature of reaction is room temperature (10-30 a ℃).
Reaction finishes, and adds organic bases as buffer solvent, adds mineral alkali again and regulates the pH crystallization, filters and obtains fluorine imatinib free alkali, and wherein organic bases has pyridine, triethylamine, piperidines, is preferably pyridine; Mineral alkali has ammoniacal liquor, sodium hydroxide, yellow soda ash, is preferably ammoniacal liquor.
The present invention adopts condensation reaction to come preparing product, and the aftertreatment of condensation reaction is optimized, thereby has greatly simplified operating process, improved product yield, reduces production costs.
Embodiment
In order to illustrate in greater detail the present invention, provide following preparation instance.But scope of the present invention is not to be defined in this.
Embodiment one
With formula (III) compound (44.48g, 0.16mol), formula (II) compound (87.8g, content 74%, 0.192mol), (61.1g 0.32mol), drops into reaction flask to the EDC hydrochloride.Add purified water 450ml, stirring at room is clear to dissolving, and TLC detects raw material (III) and reacts completely, approximately 2-3h.
Reaction finishes, diatomite filtration, 200ml washing.Filtrating adds pyridine 220ml, and agitation and dropping 25% strong aqua (110ml) is separated out a large amount of solids, and this moment, pH was about 12.Add 1500ml water, continue stirring and crystallizing 2h.
Filter the 500ml water washing.Filtration cakes torrefaction gets 89.0g to constant weight, yield 99%, and HPLC 99.5%, and single assorted 0.2%.
1H?NMR(500MHz，d
6-DMSO，25℃)：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
With formula (III) compound (55.6g, 0.2mol), formula (II) compound (109.8g, content 74%, 0.24mol), (45.9g 0.24mol), drops into reaction flask to the EDC hydrochloride.Add purified water 560ml, stirring at room is clear to dissolving, and TLC detects raw material (III) and reacts completely, approximately 2-3h.
Reaction finishes, diatomite filtration, 250ml washing.Filtrating adds pyridine 275ml, and agitation and dropping 25% strong aqua (138ml) is separated out a large amount of solids, and this moment, pH was about 12.Add 1850ml water, continue stirring and crystallizing 2h.
Filter the 620ml water washing.Filtration cakes torrefaction gets 106.2g to constant weight, yield 94.5%, and HPLC 99.5%, and single assorted 0.2%.
Claims (9)
1. the preparation method of the methylsulfonic acid fluorine imatinib shown in the formula (I),
It comprises that the aminocompound shown in carboxylic compound shown in the formula (II) and the formula (III) forms amido linkage in the presence of condensing agent and solvent; Reaction solution adds the direct crystallization of alkali and obtains formula (IV) fluorine imatinib free alkali, obtains methylsulfonic acid fluorine imatinib with the methylsulfonic acid salify then
2. method according to claim 1, wherein said condensing agent are selected from DCC, DIC, TBTU, HBTU, PyBOP, EDC hydrochloride, perhaps combination and the Ph of they and HOBt or HOAt
3The combination of P and DIAD and Ph
3The combination of P and DEAD perhaps is selected from CDI.
3. method according to claim 2, the preferred EDC hydrochloride of wherein selected condensing agent.
4. method according to claim 1, wherein said reaction solvent are DMF, acetonitrile, THF, methylene dichloride, trichloromethane, ETHYLE ACETATE, dioxane, pyridine and/or water.
5. method according to claim 4, wherein said reaction solvent are water.
6. method according to claim 1, wherein said alkali is selected from the mixture of organic bases and mineral alkali.
7. method according to claim 6, wherein said organic bases is selected from pyridine, triethylamine or piperidines, is preferably pyridine; Mineral alkali is selected from ammoniacal liquor, sodium hydroxide or yellow soda ash, is preferably ammoniacal liquor.
8. one kind prepares the method for compound according to claim 1, and this method comprises the following steps:
1) in solvent, add carboxylic acid cpd (II), aminocompound (III) and condensing agent respectively, room temperature or heating be stirring reaction down;
2) above-mentioned reaction solution adding organic bases and mineral alkali carry out crystallization, obtain fluorine imatinib free alkali (IV);
3) fluorine imatinib free alkali (IV) is at water/acetone system crystallization.
9. pharmaceutical composition that is used to treat chronic myelocytic leukemia, this pharmaceutical composition contain treat significant quantity methylsulfonic acid fluorine imatinib as claimed in claim 1 as effective constituent and pharmaceutically acceptable carrier.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103509007A (en) * | 2012-06-19 | 2014-01-15 | 江苏豪森医药集团连云港宏创医药有限公司 | Flumatinib mesylate crystal form and preparation method and use thereof |
| CN103509006A (en) * | 2012-06-19 | 2014-01-15 | 江苏豪森医药集团连云港宏创医药有限公司 | Flumatinib mesylate crystal form, and preparation method and use thereof |
| CN105884746A (en) * | 2016-05-05 | 2016-08-24 | 江苏豪森药业集团有限公司 | Synthesizing method of flumatinib |
| 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 |
| CN107648237A (en) * | 2016-07-26 | 2018-02-02 | 江苏豪森药业集团有限公司 | Pharmaceutical composition of amino-metadiazine compound and preparation method thereof |
| CN110687238A (en) * | 2019-11-20 | 2020-01-14 | 江苏豪森药业集团有限公司 | Detection method of flumatinib mesylate related substances |
| CN111072636A (en) * | 2019-12-16 | 2020-04-28 | 江苏豪森药业集团有限公司 | Synthesis method of flumatinib |
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103509007A (en) * | 2012-06-19 | 2014-01-15 | 江苏豪森医药集团连云港宏创医药有限公司 | Flumatinib mesylate crystal form and preparation method and use thereof |
| CN103509006A (en) * | 2012-06-19 | 2014-01-15 | 江苏豪森医药集团连云港宏创医药有限公司 | Flumatinib mesylate crystal form, and preparation method and use thereof |
| 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 |
| 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 |
| CN105884746A (en) * | 2016-05-05 | 2016-08-24 | 江苏豪森药业集团有限公司 | Synthesizing method of flumatinib |
| 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 |
| CN107648237A (en) * | 2016-07-26 | 2018-02-02 | 江苏豪森药业集团有限公司 | Pharmaceutical composition of amino-metadiazine compound and preparation method thereof |
| 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 |
| CN110687238A (en) * | 2019-11-20 | 2020-01-14 | 江苏豪森药业集团有限公司 | Detection method of flumatinib mesylate related substances |
| 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 |
| CN111072636A (en) * | 2019-12-16 | 2020-04-28 | 江苏豪森药业集团有限公司 | Synthesis method of flumatinib |
| 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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