CN103588754A - Preparation method of imatinib - Google Patents
Preparation method of imatinib Download PDFInfo
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- CN103588754A CN103588754A CN201310537824.8A CN201310537824A CN103588754A CN 103588754 A CN103588754 A CN 103588754A CN 201310537824 A CN201310537824 A CN 201310537824A CN 103588754 A CN103588754 A CN 103588754A
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention relates to a preparation method of imatinib (I). Specifically, after a 6-methyl-N-(4-(pyridin-3-yl)pyrimidin-2-yl)-1,3-phenylenediamine reaction substrate (II) or a salt thereof is subjected to a reaction with p-halogenated methylbenzoyl halide in an inert solvent and in the presence of an alkali, any separation and purification treatment of an intermediate are not required, an in situ reaction with 1-methyl piperazine is directly carried out, and then the imatinib (I) target compound is obtained.
Description
Technical field
The invention belongs to the synthetic field of medicine, relate to particularly common name: imatinib, its chemical name is 4-[(4-methyl isophthalic acid-piperazinyl) methyl]-N-[4-methyl-3-[4-(3-pyridyl)-2-pyrimidyl] amino]-phenyl] benzamide (4-[(4-methylpiperazin-1-yl) methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl) pyrimidin-2-yl] amino}phenyl) benzamide) and preparation method.
Background technology
Gleevec (Imatinib mesylate) is a kind of oral tyrosine kinase inhibitor, by company of Switzerland Novartis (Novartis) research and development, be used for the treatment of the chronic phase patient after chronic myelocytic leukemia (CML) acute transformation phase, acceleration period or the alpha-interferon therapy failure of the Philadelphia chromosome positive.
Gleevec went on the market in the U.S. May calendar year 2001, go on the market November in the same year in Europe, and in April, 2002 Jing State Food and Drug Administration approval formally in Discussion on Chinese Listed, its trade name is " imatinib mesylate ", and it is a line medication for the treatment of at present chronic myelogenous leukemia (CML).
Imatinib is the 4-[(4-methyl isophthalic acid-piperazinyl of following formula) methyl]-N-[4-methyl-3-[4-(3-pyridyl)-2-pyrimidyl] amino]-phenyl] benzamide (I):
The preparation method of imatinib is a lot, is included in disclosed preparation method in patent US5521184, US6894051, GB2398565, WO2006071130, WO2006027795 and US2006149061.Its Patent US6894051 relates to the crystal formation of Gleevec.In these preparation methods, patent GB2398565 and WO2006071130 all need to use expensive BINAP (dinaphthalene hexichol phosphorus) for part carries out catalyzed coupling reaction, to be not suitable for suitability for industrialized production.Patent US2006149061 has mainly been to provide a kind of new intermediate preparation method of relevant imatinib, not only reacts step number long, and need to use the responsive reagent such as butyllithium, so be not suitable for very much industrial production.
Patent US5521184 relates to the chemical substance of this medicine, mainly by compound 6-methyl-N-(4-(pyridin-3-yl) pyrimidine-2-base)-1,3-phenylenediamine (II) with chloromethyl benzoic acid chlorides is reacted obtain N-(3-(4-(pyridin-3-yl) pyrimidine-2--amino)-4-aminomethyl phenyl)-4-chloromethyl) benzamide (III), then (III) again with methylpiperazine under triethylamine and methylene dichloride condition, altogether obtain imatinib through two-step reaction.The method flow process is as follows:
In synthesising process research, find that aforesaid method reaction step number is long, complex operation and need the plenty of time with the energy with separated and purify intermediates III, therefore wish from meeting industrial angle (reactions steps is short, reaction process is easy to operate, post-reaction treatment is convenient and production cost low), to find a new industrialized preparing process.
Summary of the invention
The object of the invention is to provide a kind of preparation method of imatinib of applicable suitability for industrialized production.
For achieving the above object, the inventor has designed the novel preparation method of the imatinib that is different from prior art, by reaction substrate (II) with to chloromethyl benzoic acid chlorides (VI) in inert solvent and under alkali effect, under proper temperature, reaction appropriate time after, do not need separating treatment gained intermediate, directly and 1-methylpiperazine reaction in－situ, then obtain the target compound of imatinib (I); Chemical reaction is shown in following formula:
Wherein, the salt of described reaction substrate (II) is selected from its hydrochloride, hydrobromate, nitrate, vitriol or hydrosulfate.
In one embodiment, the substituent X in the chemical formula of described halogenated methyl benzoyl halogen (VI), Y is selected from bromine or chlorine independently of one another, preferred X, Y is independently chlorine separately.
In one embodiment, described alkali is selected from mineral alkali, organic bases or its mixing.
In one embodiment, described alkali is selected from Quilonum Retard, sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, triethylamine, Trimethylamine 99, N, one or more in N-diisopropyl ethyl amine, Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane (DABCO), other tertiary amine; Preferred sodium carbonate or salt of wormwood; More preferably salt of wormwood.
In one embodiment, described inert solvent is selected from one or more in tetrahydrofuran (THF), acetonitrile, Isosorbide-5-Nitrae-dioxane, toluene, ether, acetone, DMF, methyl-sulphoxide, methylene dichloride, chloroform and similar solvent.
In one embodiment, the mol ratio of described alkali and reaction substrate (II) is 2:1-8:1; Preferred 2:1-4:1.
In one embodiment, described proper temperature is 15 to 50 ℃; Preferred room temperature.
In one embodiment, described appropriate time disappears and is as the criterion with thin layer chromatography board and high performance liquid phase monitoring reaction substrate (II).In one embodiment, to the mol ratio of chloromethyl benzoic acid chlorides and described reaction substrate (II), be 1:1-5:1; Preferred 1:1-2:1.
In one embodiment, the mol ratio of 1-methylpiperazine and reaction substrate (II) is 10:1-2:1; More preferably 5:1-3:1.
Invention advantage and effect
Preparation method compares with the disclosed imatinib of prior art (I), after the present invention adopts reaction substrate (II) to react under alkali effect with to halogenated methyl benzoyl halogen, do not need separating treatment, with 1-methylpiperazine reaction in－situ, obtain target compound imatinib (I), avoid on the one hand the separation of intermediate, greatly improved labour productivity.
Meanwhile, with respect to the two-step reaction of available technology adopting, the inventive method product yield is high, and product purity is also high: product purity > 96%, the product purity > 99% obtaining under optimum condition.
Embodiment
Detailed description prepared by imatinib (I) below, specifically, by reaction substrate (II) with to chloromethyl benzoic acid chlorides (VI) in inert solvent and under alkali effect, under proper temperature, reaction appropriate time after, do not need separating treatment gained intermediate, directly and 1-methylpiperazine reaction in－situ, then obtain the target compound of imatinib (I); Chemical reaction is shown in following formula:
Substituent X in the chemical formula of wherein said halogenated methyl benzoyl halogen (VI), Y is selected from bromine or chlorine independently of one another.
Preferably, halogenated methyl benzoyl halogen is chloromethyl benzoic acid chlorides.
In preparation method of the present invention, reaction substrate (II), chloromethyl benzoic acid chlorides and 1-methylpiperazine can be bought or be prepared according to state of the art by market.
In the reaction of the inventive method, use organic bases or mineral alkali all can buy or prepare according to state of the art by market.
In a preferred embodiments of the inventive method, the alkali of use is salt of wormwood.
Following examples are only further to illustrate the present invention, there is no the intention that limit the invention to this specific embodiment.One skilled in the art would recognize that the present invention contained all possible alternatives, improvement project and equivalents within the scope of claims.
Embodiment
raw material and reagent:
Reaction substrate (II, chemistry 6-methyl-N-(4-(pyridin-3-yl) pyrimidine-2-base)-1 by name, 3-phenylenediamine) (Han Xiang bio tech ltd, Shanghai, 98%), to chloromethyl benzoic acid chlorides (Shanghai Bang Cheng Chemical Co., Ltd., 99%), N methyl piperazine (Shanghai De Mo Pharmaceutical Technology Co., Ltd, 99%), the solvent of other use and reagent Jun You Chemical Reagent Co., Ltd., Sinopharm Group provide.
embodiment 1: the preparation of imatinib (I)
Under nitrogen atmosphere, in 500 milliliters of there-necked flasks that mechanical stirrer is housed, add successively reaction substrate (II, 20.00g, 72mmol), tetrahydrofuran (THF) (300 milliliters), salt of wormwood (27.88g, 2.8eq).Then within half an hour, at room temperature slowly drip the tetrahydrofuran solution of chloromethyl benzoic acid chlorides (21.21g, 1.6eq) (50mL).After room temperature reaction 5 hours, add N methyl piperazine (46.06mL, 5.7eq).After room temperature reaction 18 hours, reaction solution is concentrated.600mL methylene dichloride and the dilution of 400mL water for residuum.After extracting and separating, methylene dichloride for water (100mL x3) extracts.The organic phase dried over mgso merging.After filtration, filtrate decompression is concentrated.200mL acetonitrile making beating for enriched material, filters, and with acetonitrile, washs.Filter cake, 65 ℃ of oven dry, obtains the imatinib (31.3g, 88%) of colorless solid, HPLC purity 99.8%.
embodiment 2: the preparation of imatinib (I)
Under nitrogen atmosphere, toward the hydrochloride (22.63g, 72mmol), the tetrahydrofuran (THF) (300 milliliters) that add successively reaction substrate II in 500 milliliters of there-necked flasks that mechanical stirrer is housed, salt of wormwood (27.88g, 2.8eq).Then within half an hour, at room temperature slowly drip the tetrahydrofuran solution of chloromethyl benzoic acid chlorides (21.21g, 1.6eq) (50mL).After room temperature reaction 5 hours, add N methyl piperazine (46.06mL, 5.7eq).After room temperature reaction 18 hours, reaction solution is concentrated.600mL methylene dichloride and the dilution of 400mL water for residuum.After extracting and separating, methylene dichloride for water (100mL x3) extracts.The organic phase dried over mgso merging.After filtration, filtrate decompression is concentrated.200mL acetonitrile making beating for enriched material, filters, and with acetonitrile, washs.Filter cake, 65 ℃ of oven dry, obtains the imatinib (32.0g, 86%) of colorless solid, HPLC purity 99.8%.
embodiment 3: the preparation of imatinib (I)
Under nitrogen atmosphere, in 100 milliliters of there-necked flasks that mechanical stirrer is housed, add successively reaction substrate (II, 2.0g, 7.2mmol), tetrahydrofuran (THF) (30 milliliters), sodium carbonate (2.75g, 3.6eq).Then within half an hour, at room temperature slowly drip the tetrahydrofuran solution of chloromethyl benzoic acid chlorides (2.38g, 1.8eq) (5mL).30 ℃ of reactions, after 6 hours, add N methyl piperazine (4.6mL, 5.7eq).50 ℃ of reactions, after 18 hours, reaction solution is concentrated.60mL methylene dichloride and the dilution of 40mL water for residuum.After extracting and separating, methylene dichloride for water (15mL x3) extracts.The organic phase dried over mgso merging.After filtration, filtrate decompression is concentrated.20mL acetonitrile making beating for enriched material, filters, and with acetonitrile, washs.Filter cake, 65 ℃ of oven dry, obtains the imatinib (2.91g, 82%) of colorless solid, HPLC purity 98.2%.
embodiment 4: the preparation of imatinib (I)
Under nitrogen atmosphere, in 100 milliliters of there-necked flasks that mechanical stirrer is housed, add successively reaction substrate (II, 2.0g, 7.2mmol), acetonitrile (30 milliliters), salt of wormwood (2.79g, 2.8eq).Then within half an hour, at room temperature slowly drip the tetrahydrofuran solution of chloromethyl benzoic acid chlorides (2.72g, 2.0eq) (5mL).After room temperature reaction 5 hours, add N methyl piperazine (6.1mL, 7.5eq).45 ℃ of reactions, after 18 hours, reaction solution is concentrated.60mL methylene dichloride and the dilution of 40mL water for residuum.After extracting and separating, methylene dichloride for water (15mL x3) extracts.The organic phase dried over mgso merging.After filtration, filtrate decompression is concentrated.20mL acetonitrile making beating for enriched material, filters, and with acetonitrile, washs.Filter cake, 65 ℃ of oven dry, obtains the imatinib (3.02g, 85%) of colorless solid, HPLC purity 99.2%.
embodiment 5: the preparation of imatinib (I)
Under nitrogen atmosphere, in 100 milliliters of there-necked flasks that mechanical stirrer is housed, add successively reaction substrate (II, 2.0g, 7.2mmol), chloroform (30 milliliters), salt of wormwood (2.79g, 2.8eq).Then within half an hour, at room temperature slowly drip the tetrahydrofuran solution of chloromethyl benzoic acid chlorides (4.20g, 3.1eq) (5mL).After room temperature reaction 7 hours, add N methyl piperazine (2.4mL, 3.0eq).15 ℃ of reactions, after 18 hours, reaction solution is concentrated.60mL methylene dichloride and the dilution of 40mL water for residuum.After extracting and separating, methylene dichloride for water (15mL x3) extracts.The organic phase dried over mgso merging.After filtration, filtrate decompression is concentrated.20mL acetonitrile making beating for enriched material, filters, and with acetonitrile, washs.Filter cake, 65 ℃ of oven dry, obtains the imatinib (2.84g, 80%) of colorless solid, HPLC purity 99.0%.
embodiment 6: the preparation of imatinib (I)
Under nitrogen atmosphere, in 100 milliliters of there-necked flasks that mechanical stirrer is housed, add successively reaction substrate (II, 2.0g, 7.2mmol), Isosorbide-5-Nitrae-dioxane (30 milliliters), DABCO (3.23g, 4.0eq).Then within half an hour, at room temperature slowly drip the tetrahydrofuran solution of chloromethyl benzoic acid chlorides (2.12g, 1.6eq) (5mL).After room temperature reaction 6 hours, add N methyl piperazine (8.1mL, 10.0eq).50 ℃ of reactions, after 18 hours, reaction solution is concentrated.60mL methylene dichloride and the dilution of 40mL water for residuum.After extracting and separating, methylene dichloride for water (15mL x3) extracts.The organic phase dried over mgso merging.After filtration, filtrate decompression is concentrated.20mL acetonitrile making beating for enriched material, filters, and with acetonitrile, washs.Filter cake, 65 ℃ of oven dry, obtains the imatinib (2.70g, 76%) of colorless solid, HPLC purity 98.2%.
Claims (10)
1. the preparation method of an imatinib, it is characterized in that, by reaction substrate (II) or its salt with to chloromethyl benzoic acid chlorides (VI) in inert solvent and under alkali effect, under proper temperature, reaction appropriate time after, do not need separating treatment gained intermediate, directly and 1-methylpiperazine reaction in－situ, then obtain the target compound of imatinib (I); Chemical reaction is shown in following formula:
Wherein, the salt of described reaction substrate (II) is selected from its hydrochloride, hydrobromate, nitrate, vitriol or hydrosulfate.
2. preparation method as claimed in claim 1, is characterized in that, the substituent X in the chemical formula of described halogenated methyl benzoyl halogen (VI), and Y is selected from bromine or chlorine independently of one another, preferred X, Y is independently chlorine separately.
3. preparation method as claimed in claim 2, is characterized in that, described alkali is selected from mineral alkali, organic bases or its mixing.
4. preparation method as claimed in claim 2, it is characterized in that, described alkali is selected from Quilonum Retard, sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, triethylamine, Trimethylamine 99, N, one or more in N-diisopropyl ethyl amine, DABCO, other tertiary amine; Preferred sodium carbonate or salt of wormwood; More preferably salt of wormwood.
5. preparation method as claimed in claim 2, it is characterized in that, described inert solvent is selected from one or more in tetrahydrofuran (THF), acetonitrile, Isosorbide-5-Nitrae-dioxane, toluene, ether, acetone, DMF, methyl-sulphoxide, methylene dichloride, chloroform and similar solvent.
6. preparation method as claimed in claim 2, is characterized in that, the mol ratio of described alkali and reaction substrate (II) is 2:1-8:1; Preferred 2:1-4:1.
7. preparation method as claimed in claim 2, is characterized in that, described proper temperature is 15 to 50 ℃; Preferred room temperature.
8. preparation method as claimed in claim 2, is characterized in that, described appropriate time disappears and is as the criterion with thin layer chromatography board and high performance liquid phase monitoring reaction substrate (II).
9. preparation method as claimed in claim 2, is characterized in that, to the mol ratio of chloromethyl benzoic acid chlorides and described reaction substrate (II), is 1:1-5:1; Preferred 1:1-2:1.
10. preparation method as claimed in claim 2, is characterized in that, the mol ratio of 1-methylpiperazine and reaction substrate (II) is 10:1-2:1; More preferably 5:1-3:1.
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| CN201310537824.8A CN103588754B (en) | 2013-11-04 | 2013-11-04 | Preparation method of imatinib |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1630648A (en) * | 2002-02-07 | 2005-06-22 | 诺瓦提斯公司 | N-phenyl-2-pyrimidine-amine derivatives |
| CN1646519A (en) * | 2002-01-23 | 2005-07-27 | 诺瓦提斯公司 | N-oxyde of N-phenyl-2-pyrimidine-amine derivatives |
| CN103145693A (en) * | 2013-03-29 | 2013-06-12 | 成都百裕科技制药有限公司 | Preparation method of imatinib |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1646519A (en) * | 2002-01-23 | 2005-07-27 | 诺瓦提斯公司 | N-oxyde of N-phenyl-2-pyrimidine-amine derivatives |
| CN1630648A (en) * | 2002-02-07 | 2005-06-22 | 诺瓦提斯公司 | N-phenyl-2-pyrimidine-amine derivatives |
| CN103145693A (en) * | 2013-03-29 | 2013-06-12 | 成都百裕科技制药有限公司 | Preparation method of imatinib |
Non-Patent Citations (1)
| Title |
|---|
| 刘娥: "甲磺酸伊马替尼的合成", 《化学与生物工程》, vol. 29, no. 11, 31 December 2012 (2012-12-31), pages 36 - 38 * |
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