CN105859682A - Synthetic method of imatinib mesylate - Google Patents
Synthetic method of imatinib mesylate Download PDFInfo
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- CN105859682A CN105859682A CN201510022641.1A CN201510022641A CN105859682A CN 105859682 A CN105859682 A CN 105859682A CN 201510022641 A CN201510022641 A CN 201510022641A CN 105859682 A CN105859682 A CN 105859682A
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Abstract
The invention provides a synthetic method of a molecular targeted therapeutic drug imatinib mesylate aiming at chronic myelogenous leukemia and gastrointestinal stromal tumor, and belongs to the field of pharmaceutical synthesis. The method comprises the following steps: a reaction is carried out for 4-(chloromethyl)benzoic acid and oxalyl chloride in order to obtain 4-(chloromethyl)benzoyl chloride; and in the effects of a catalyst, reactions of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine are carried out with 4-(chloromethyl)benzoyl chloride, N-methylpiperazine, and methanesulfonic acid in order, 4-chloromethyl-N-[4-methyl-3-[4-(3-pyridyl)-2-pyrimidinyl]amino-phenyl]-benzamide, 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[4-(3-pyridyl)-2-pyrimidinyl]amino-phenyl]-benzamide and 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[4-(3-pyridyl)-2-pyrimidinyl]amino-phenyl]-benzamide methanesulfonate are obtained step by step, and imatinib mesylate is obtained (as shown in figure). The synthetic method has the advantages of simple process, operation convenience, low cost and high yield.
Description
Technical field
The present invention relates to a kind of synthetic method of imatinib mesylate, belong to pharmaceutical synthesis field.
Background technology
Imatinib mesylate (Imatinib Mesylate), chemical name 4-[(4-methyl isophthalic acid-piperazinyl) methyl]-N-[4-methyl-3-[4-(3-pyridine radicals)-2-pyrimidine radicals] methanesulfonylamino-phenyl]-benzamide methanesulfonate, belong to anilino-pyrimidine analog derivative, first developed by Novartis Co., Ltd of Switzerland, synthesized the earliest in 1992, and obtain FDA approval list marketing in calendar year 2001 in the U.S., subsequently in Europe, Japan, more than 60 countries such as China get permission list marketing, clinical treatment chronic myelogenous leukemia and the gastrointestinal stromal tumor of being mainly used in.
Imatinib mesylate is as the pioneering molecular targeted therapy in the whole world, it is a kind of highly effective Small molecular TYR inhibitors of kinases, it only can not affect normal cell for sick cell over the course for the treatment of, start new era of tumor cells targeted therapy, also open a kind of new direction of disease therapeuticing medicine development, namely effect target starts to trend towards molecular level simultaneously. Based on its significant curative effect and lower side effect, imatinib mesylate, once listing, just obtains the accreditation of extensive patients and the consistent favorable comment of industry, has very wide market prospects.
The synthetic method of traditional imatinib mesylate exists many unfavorable factors such as technique is tediously long, complicated operation, contaminated environment, post processing trouble; Meanwhile, because it is expensive, many patients can not get effective treatment because high treatment cost cannot be born, and limit its potential applicability in clinical practice to a certain extent; Therefore, make great efforts to probe into a kind of synthetic method of cheap efficient imatinib mesylate, reduce treatment cost, very necessary, there is great Research Significance and realistic meaning.
Summary of the invention
The object of the present invention is to provide the synthetic method of the imatinib mesylate that a kind of technique is simple, cost is low, yield is high.
The concrete synthetic method of imatinib mesylate of the present invention, comprises the following steps:
(1) under the effect of catalyst, p-chloromethyl benzoic acid and ethanedioly chloride react in aprotic solvent, generate compoundTo chloromethyl benzoic acid chlorides; Wherein the mol ratio of p-chloromethyl benzoic acid and acyl chlorides is 1:1 ~ 1.5, and reaction temperature is 0 ~ 50 DEG C, reaction time 3 ~ 16 h;
(2) under the effect of catalyst, N-(5-amino-2-methyl phenyl)-4-(3-pyridine radicals)-2-pyrilamine and compoundChloromethyl benzoic acid chlorides is reacted in aprotic solvent, generate compound4-chloromethyl-N-[4-methyl-3-[4-(3-pyridine radicals)-2-pyrimidine radicals] methanesulfonylamino-phenyl]-benzamide; Wherein N-(5-amino-2-methyl phenyl)-4-(3-pyridine radicals)-2-pyrilamine be 1:1 ~ 1.8 to the mol ratio of chloromethyl benzoic acid chlorides, reaction temperature is 0 ~ 90 DEG C, reaction time 1 ~ 20 h;
(3) compound4-chloromethyl-N-[4-methyl-3-[4-(3-pyridine radicals)-2-pyrimidine radicals] methanesulfonylamino-phenyl]-benzamide reacts in aprotic solvent with N methyl piperazine, generates compound4-[(4-methyl isophthalic acid-piperazinyl) methyl]-N-[4-methyl-3-[4-(3-pyridine radicals)-2-pyrimidine radicals] methanesulfonylamino-phenyl]-benzamide, i.e. Imatinib; Wherein the mol ratio of 4-chloromethyl-N-[4-methyl-3-[4-(3-pyridine radicals)-2-pyrimidine radicals] methanesulfonylamino-phenyl]-benzamide and N methyl piperazine is 1:1 ~ 10, and reaction temperature is room temperature to 100 DEG C, reaction time 2 ~ 15 h;
(4) compound4-[(4-methyl isophthalic acid-piperazinyl) methyl]-N-[4-methyl-3-[4-(3-pyridine radicals)-2-pyrimidine radicals] methanesulfonylamino-phenyl]-benzamide and Loprazolam directly react in proton solvent, generate target product compound4-[(4-methyl isophthalic acid-piperazinyl) methyl]-N-[4-methyl-3-[4-(3-pyridine radicals)-2-pyrimidine radicals] methanesulfonylamino-phenyl]-benzamide methanesulfonate, i.e. imatinib mesylate; Wherein the mol ratio of 4-[(4-methyl isophthalic acid-piperazinyl) methyl]-N-[4-methyl-3-[4-(3-pyridine radicals)-2-pyrimidine radicals] methanesulfonylamino-phenyl]-benzamide and Loprazolam is 1:1 ~ 1.5, reaction temperature is room temperature to 120 DEG C, reaction time 2 ~ 20 h.
In the reaction of step (1), catalyst used is dimethyl formamide, pyridine and lewis acid zinc chloride, stannic chloride, boron fluoride, ferric trichloride, alchlor, alchlor, boron chloride and Boron tribromide etc., wherein dimethyl formamide and zinc chloride the most conventional, and with catalytic effect the best of dimethyl formamide; Aprotic solvent used is one or more of carrene, chloroform, carbon tetrachloride, benzinum, benzene, toluene, chlorobenzene, oxolane, ethyl acetate etc.
In the reaction of step (2), catalyst used is the organic bases such as dimethylamine, diethylamine, triethylamine, pyridine, picoline, N ' N-dimethylaniline, N ' dinethylformamide, N ' N-dimethylacetylamide, TBAB, methyl tricapryl ammonium chloride, quinoline, pyrroles, wherein with catalytic effect the best of triethylamine; Aprotic solvent used is one or more of acetone, carrene, chloroform, carbon tetrachloride, benzinum, benzene, toluene, chlorobenzene, oxolane, ethyl acetate etc.
In the reaction of step (3), aprotic solvent used is one or more of acetone, carrene, chloroform, carbon tetrachloride, benzinum, benzene, toluene, chlorobenzene, oxolane, ethyl acetate etc.
In the reaction of step (4), proton solvent used is one or more of the alcohols solvents such as methyl alcohol, ethanol, isopropyl alcohol, n-butanol, the tert-butyl alcohol.
Accompanying drawing explanation
Fig. 1 imatinib mesylate synthetic route chart of the present invention.
Detailed description of the invention
The present invention is set forth further below in conjunction with instantiation.
Embodiment 1
Synthesizing chloromethyl benzoic acid chlorides: add carrene 400 ml and p-chloromethyl benzoic acid 100 g successively in 1000 ml reaction bulbs, be placed in ice-water bath to stir, treat that temperature is down to 0 DEG C, start slowly to drip oxalyl chloride 90 g, in dropping process within temperature control to 20 DEG C; Drip and finish, add dimethyl formamide 4.8 g, be then slowly warming up to 25 DEG C, and insulated and stirred is reacted 6 h; Reaction terminates, and temperature control 40 DEG C of decompression distillation, obtain brown yellow oil liquid; In 1000 ml reaction bulbs, continue to add benzinum 200 ml, mix, be placed in cryosel water-bath and be cooled to-10 DEG C, insulated and stirred crystallization 4 h, crystallization is complete, rapid filtration under suction, filter cake is placed in vacuum drying chamber 40 DEG C of vacuum drying 12 h, obtain off-white color crystalline powder 98.4 g, be chloromethyl benzoic acid chlorides, yield is 88.8%.
Embodiment 2
Synthesizing of 4-chloromethyl-N-[4-methyl-3-[4-(3-pyridine radicals)-2-pyrimidine radicals] methanesulfonylamino-phenyl]-benzamide: add oxolane 850 ml and N-(5-amino-2-methyl phenyl)-4-(3-pyridine radicals)-2-pyrilamine 70 g successively in 2000 ml reaction bulbs, be placed in ice-water bath to stir, be cooled to 0 DEG C, slowly drip triethylamine 45 g, drip and finish, temperature control to 5 DEG C, insulated and stirred 1 h; Continue slowly to add chloromethyl benzoic acid chlorides 50 g, finish, be slowly warming up to 25 DEG C, insulated and stirred is reacted 5 h; Insulation reaction terminates, suction filtration, discards filtrate, and filter cake is transferred in 2000 ml reaction bulbs, and 800 ml add water, stirring at room temperature 2 h; Stir and terminate, suction filtration, discards filtrate, and filter cake is transferred in 2000 ml reaction bulbs, and add acetone 500 ml, be slowly heated to backflow, insulated and stirred is reacted 2 h; Reaction terminates, stop stirring, Temperature fall is to room temperature, rapid filtration under suction, filter cake is placed in vacuum drying chamber 60 DEG C of vacuum drying 12 h, obtain yellow crystalline powder 98.9 g, be 4-chloromethyl-N-[4-methyl-3-[4-(3-pyridine radicals)-2-pyrimidine radicals] methanesulfonylamino-phenyl]-benzamide, yield is 91.2%.
Embodiment 3
Synthesizing of Imatinib: add N methyl piperazine 200 ml in 1000 ml reaction bulbs, slowly be heated to 65 DEG C, then 4-chloromethyl-N-[4-methyl-3-[4-(3-pyridine radicals)-2-pyrimidine radicals] methanesulfonylamino-phenyl]-benzamide 80 g is added in batches, temperature control to 65 ~ 70 DEG C in reinforced process, finish insulated and stirred 3 h; Reaction terminates, and closes heating, in reaction bulb, adds purified water 400 ml, stirs 2 h, leaves standstill, naturally cools to room temperature; Suction filtration, and colourless to filtrate with purified water drip washing filter cake; Filter cake is transferred in reaction bulb, and add acetone 400 ml, be slowly heated to backflow, insulated and stirred is reacted 2 h; Reaction terminates, naturally cool to room temperature, suction filtration, filter cake is vacuum drying 12 h under 60 DEG C of conditions, obtain light yellow to creamy white crystals powder 85.9, be 4-[(4-methyl isophthalic acid-piperazinyl) methyl]-N-[4-methyl-3-[4-(3-pyridine radicals)-2-pyrimidine radicals] methanesulfonylamino-phenyl]-benzamide, yield is 93.5%.
Embodiment 4
Synthesizing of imatinib mesylate: add isopropyl alcohol 600 ml and 4-[(4-methyl isophthalic acid-piperazinyl) methyl]-N-[4-methyl-3-[4-(3-pyridine radicals)-2-pyrimidine radicals] methanesulfonylamino-phenyl]-benzamide 50 g in 2000 ml reaction bulbs, stirring at room temperature 1 h is to even, fast drop Loprazolam 10 g, drip and finish, continue to add isopropyl alcohol 300 ml, slowly be heated to 65 DEG C, insulated and stirred 3 h; Reaction terminates, and is slowly down to room temperature, closes stirring, leaves standstill 12 h; Leave standstill and terminate, continue to stir 1 h, suction filtration, filter cake is vacuum drying 12 h under 60 DEG C of conditions, obtain creamy white crystals powder 54.9 g, be 4-[(4-methyl isophthalic acid-piperazinyl) methyl]-N-[4-methyl-3-[4-(3-pyridine radicals)-2-pyrimidine radicals] methanesulfonylamino-phenyl]-benzamide methanesulfonate, i.e. imatinib mesylate, yield is 92.1%.
Above content is in conjunction with concrete example further description made for the present invention, can not assert that synthetic method of the present invention is confined to these explanations. Under the prerequisite that does not depart from the inventive method design, the person skilled in field of the present invention can also be made some simple change replacements, and the protection domain of of the present invention synthetic method all should be considered as.
Claims (8)
1. a synthetic method for imatinib mesylate, is characterized in that: under the effect of catalyst, and p-chloromethyl benzoic acid and ethanedioly chloride react in aprotic solvent, generates compoundTo chloromethyl benzoic acid chlorides; Wherein the mol ratio of p-chloromethyl benzoic acid and acyl chlorides is 1:1 ~ 1.5, and reaction temperature is 0 ~ 50 DEG C, reaction time 3 ~ 16 h.
2. a synthetic method for imatinib mesylate, is characterized in that: under the effect of catalyst, N-(5-amino-2-methyl phenyl)-4-(3-pyridine radicals)-2-pyrilamine and compoundChloromethyl benzoic acid chlorides is reacted in aprotic solvent, generate compound4-chloromethyl-N-[4-methyl-3-[4-(3-pyridine radicals)-2-pyrimidine radicals] methanesulfonylamino-phenyl]-benzamide; Wherein N-(5-amino-2-methyl phenyl)-4-(3-pyridine radicals)-2-pyrilamine be 1:1 ~ 1.8 to the mol ratio of chloromethyl benzoic acid chlorides, reaction temperature is 0 ~ 90 DEG C, reaction time 1 ~ 20 h.
3. a synthetic method for imatinib mesylate, is characterized in that: compound4-chloromethyl-N-[4-methyl-3-[4-(3-pyridine radicals)-2-pyrimidine radicals] methanesulfonylamino-phenyl]-benzamide reacts in aprotic solvent with N methyl piperazine, generates compoundImatinib, i.e. 4-[(4-methyl isophthalic acid-piperazinyl) methyl]-N-[4-methyl-3-[4-(3-pyridine radicals)-2-pyrimidine radicals] methanesulfonylamino-phenyl]-benzamide; Wherein the mol ratio of 4-chloromethyl-N-[4-methyl-3-[4-(3-pyridine radicals)-2-pyrimidine radicals] methanesulfonylamino-phenyl]-benzamide and N methyl piperazine is 1:1 ~ 10, and reaction temperature is room temperature to 100 DEG C, reaction time 2 ~ 15 h.
4. a synthetic method for imatinib mesylate, is characterized in that: compound4-[(4-methyl isophthalic acid-piperazinyl) methyl]-N-[4-methyl-3-[4-(3-pyridine radicals)-2-pyrimidine radicals] methanesulfonylamino-phenyl]-benzamide and Loprazolam directly react in proton solvent, generate target product compound 4-[(4-methyl isophthalic acid-piperazinyl) methyl]-N-[4-methyl-3-[4-(3-pyridine radicals)-2-pyrimidine radicals] methanesulfonylamino-phenyl]-benzamide methanesulfonate, i.e. imatinib mesylate, is shown in following formula; Wherein the mol ratio of 4-[(4-methyl isophthalic acid-piperazinyl) methyl]-N-[4-methyl-3-[4-(3-pyridine radicals)-2-pyrimidine radicals] methanesulfonylamino-phenyl]-benzamide and Loprazolam is 1:1 ~ 1.5, reaction temperature is room temperature to 120 DEG C, reaction time 2 ~ 20 h.
5. the synthetic method of the imatinib mesylate according to right 1, it is characterized in that: catalyst used is dimethyl formamide, pyridine and lewis acid zinc chloride, stannic chloride, boron fluoride, ferric trichloride, alchlor, alchlor, boron chloride and Boron tribromide etc., wherein dimethyl formamide and zinc chloride the most conventional, and with catalytic effect the best of dimethyl formamide; Aprotic solvent used is one or more of carrene, chloroform, carbon tetrachloride, benzinum, benzene, toluene, chlorobenzene, oxolane, ethyl acetate etc.
6. the synthetic method of the imatinib mesylate according to right 2, it is characterized in that: catalyst used is the organic bases such as dimethylamine, diethylamine, triethylamine, pyridine, picoline, N ' N-dimethylaniline, N ' dinethylformamide, N ' N-dimethylacetylamide, TBAB, methyl tricapryl ammonium chloride, quinoline, pyrroles, wherein with catalytic effect the best of triethylamine; Aprotic solvent used is one or more of acetone, carrene, chloroform, carbon tetrachloride, benzinum, benzene, toluene, chlorobenzene, oxolane, ethyl acetate etc.
7. the synthetic method of the imatinib mesylate according to right 3, is characterized in that: aprotic solvent used is one or more of acetone, carrene, chloroform, carbon tetrachloride, benzinum, benzene, toluene, chlorobenzene, oxolane, ethyl acetate etc.
8. the synthetic method of the imatinib mesylate according to right 4, is characterized in that: proton solvent used is one or more of the alcohols solvents such as methyl alcohol, ethanol, isopropyl alcohol, n-butanol, the tert-butyl alcohol.
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| CN112359079A (en) * | 2020-11-10 | 2021-02-12 | 江苏八巨药业有限公司 | Preparation method of imatamine |
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| CN101735196A (en) * | 2008-11-12 | 2010-06-16 | 上海百灵医药科技有限公司 | Method for synthesizing Imatinib |
| CN101735197A (en) * | 2009-12-18 | 2010-06-16 | 天津市炜杰科技有限公司 | Method for synthesizing Imatinib |
| WO2013035102A1 (en) * | 2011-09-05 | 2013-03-14 | Natco Pharma Limited | Processes for the preparation of imatinib base and intermediates thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101735196A (en) * | 2008-11-12 | 2010-06-16 | 上海百灵医药科技有限公司 | Method for synthesizing Imatinib |
| CN101735197A (en) * | 2009-12-18 | 2010-06-16 | 天津市炜杰科技有限公司 | Method for synthesizing Imatinib |
| WO2013035102A1 (en) * | 2011-09-05 | 2013-03-14 | Natco Pharma Limited | Processes for the preparation of imatinib base and intermediates thereof |
Non-Patent Citations (3)
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| 姚正其主编: "《药物合成反应》", 30 September 2012, 中国医药科技出版社出版 * |
| 尹文萱主编: "《有机化学实验》", 31 October 2009, 中国矿业大学出版社 * |
| 郭家林等: "甲磺酸伊马替尼的合成", 《中国医药工业杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112359079A (en) * | 2020-11-10 | 2021-02-12 | 江苏八巨药业有限公司 | Preparation method of imatamine |
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