CN103588754B - Preparation method of imatinib - Google Patents
Preparation method of imatinib Download PDFInfo
- Publication number
- CN103588754B CN103588754B CN201310537824.8A CN201310537824A CN103588754B CN 103588754 B CN103588754 B CN 103588754B CN 201310537824 A CN201310537824 A CN 201310537824A CN 103588754 B CN103588754 B CN 103588754B
- Authority
- CN
- China
- Prior art keywords
- preparation
- reaction substrate
- reaction
- imatinib
- mol ratio
- 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.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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 pharmaceutical synthesis field, relate to common name particularly: imatinib, its chemical name is 4-[(4-methyl isophthalic acid-piperazinyl) methyl]-N-[4-methyl-3-[4-(3-pyridyl)-2-pyrimidyl] amino]-phenyl] preparation method of benzamide (4-[(4-methylpiperazin-1-yl) methyl]-N-(4-methyl-3-{ [4-(pyridin-3-yl) pyrimidin-2-yl] amino}phenyl) benzamide).
Background technology
Gleevec (Imatinib mesylate) is a kind of oral tyrosine kinase inhibitor, researched and developed by Novartis of Switzerland (Novartis) company, be used for the treatment of the chronic phase patient after the failure of chronic myelocytic leukemia (CML) acute transformation phase of Philadelphia Chromosome Positive, acceleration period or alpha-interferon therapy.
Gleevec goes on the market May calendar year 2001 in the U.S., November in the same year goes on the market in Europe, and in April, 2002 formal in Discussion on Chinese Listed through State Food and Drug Administration's approval, its trade name is " imatinib mesylate ", and it is a line medication for the treatment of chronic myelogenous leukemia (CML) at present.
Imatinib is 4-[(4-methyl isophthalic acid-piperazinyl) methyl]-N-[4-methyl-3-[4-(3-pyridyl)-2-pyrimidyl] the is amino]-phenyl of following formula] benzamide (I):
The preparation method of imatinib is a lot, is included in preparation method disclosed 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 needs 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 mainly provides a kind of new intermediate preparation method about imatinib, and not only reaction step number is long, and needs to use the sensitive agents such as butyllithium, is therefore very not suitable for 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 N-(3-(4-(pyridin-3-yl) pyrimidine-2--amino)-4-aminomethyl phenyl)-4-chloromethyl is obtained by reacting to chloromethyl benzoic acid chlorides) 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:
Find in synthesising process research that aforesaid method reaction step number is long, complex operation and need plenty of time and the energy with abstraction and purification intermediate 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 is low), the industrialized preparing process that new to be found.
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 present inventor devises the novel preparation method of the imatinib being different from prior art, namely by reaction substrate (II) with to halogenated methyl benzoyl halogen (VI) in inert solvent and under alkali effect, at moderate temperatures, after reacting appropriate time, do not need separating treatment gained intermediate, directly and 1-methylpiperazine reaction in－situ, the target compound of imatinib (I) is then obtained; 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, described to the substituent X in the chemical formula of halogenated methyl benzoyl halogen (VI), Y is selected from bromine or chlorine independently of one another, and preferred X, Y are 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 DEG C; Preferred room temperature.
In one embodiment, described appropriate time disappears with thin layer chromatography board and high performance liquid phase monitoring reaction substrate (II) and is as the criterion.In one embodiment, be 1:1-5:1 to the mol ratio of chloromethyl benzoic acid chlorides and described reaction substrate (II); 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
Compared with imatinib disclosed in prior art (I) preparation method, after the present invention adopts reaction substrate (II) and reacts under alkali effect halogenated methyl benzoyl halogen, do not need separating treatment, with 1-methylpiperazine reaction in－situ, obtain target compound imatinib (I), avoid the separation of intermediate on the one hand, substantially increase labour productivity.
Meanwhile, relative to the two-step reaction adopted in prior art, the inventive method product yield is high, and product purity is also high: product purity > 96%, the product purity > 99% obtained under optimum condition.
Embodiment
Here is detailed description prepared by imatinib (I), specifically, by reaction substrate (II) with to halogenated methyl benzoyl halo (VI) in inert solvent and under alkali effect, at moderate temperatures, after reacting appropriate time, do not need separating treatment gained intermediate, directly and 1-methylpiperazine reaction in－situ, the target compound of imatinib (I) is then obtained; Chemical reaction is shown in following formula:
Wherein said to the substituent X in the chemical formula of halogenated methyl benzoyl halogen (VI), Y is selected from bromine or chlorine independently of one another.Preferably, be chloromethyl benzoic acid chlorides to halogenated methyl benzoyl halogen.
With regard in preparation method of the present invention, reaction substrate (II), chloromethyl benzoic acid chlorides and 1-methylpiperazine are bought by market or are prepared according to state of the art.
In the reaction of the inventive method, use organic bases or mineral alkali all buy by market or prepare according to state of the art.
In a preferred embodiments of the inventive method, the alkali of use is salt of wormwood.
Following examples are only illustrate the present invention further, there is no the intention limiting the invention to this specific embodiment.One skilled in the art would recognize that and present invention encompasses all possible alternatives, improvement project and equivalents in Claims scope.
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%), other solvent used and reagent Jun You Chemical Reagent Co., Ltd., Sinopharm Group provide.
embodiment 1: the preparation of imatinib (I)
Under nitrogen atmosphere, be equipped with in the there-necked flask of mechanical stirrer toward 500 milliliters and add reaction substrate (II, 20.00g, 72mmol), tetrahydrofuran (THF) (300 milliliters) successively, salt of wormwood (27.88g, 2.8eq).Then, within half an hour, the tetrahydrofuran solution (50mL) to chloromethyl benzoic acid chlorides (21.21g, 1.6eq) is at room temperature slowly dripped.Room temperature reaction, after 5 hours, adds N methyl piperazine (46.06mL, 5.7eq).Room temperature reaction is after 18 hours, and reaction solution concentrates.Residuum 600mL methylene dichloride and the dilution of 400mL water.After extracting and separating, aqueous phase methylene dichloride (100mL x 3) extracts.The organic phase dried over mgso merged.After filtration, filtrate reduced in volume.Enriched material 200mL acetonitrile making beating, filters, uses acetonitrile wash.Filter cake, 65 DEG C 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 500 milliliters, the hydrochloride (22.63g, 72mmol), the tetrahydrofuran (THF) (300 milliliters) that add reaction substrate II in the there-necked flask of mechanical stirrer are successively housed, salt of wormwood (27.88g, 2.8eq).Then, within half an hour, the tetrahydrofuran solution (50mL) to chloromethyl benzoic acid chlorides (21.21g, 1.6eq) is at room temperature slowly dripped.Room temperature reaction, after 5 hours, adds N methyl piperazine (46.06mL, 5.7eq).Room temperature reaction is after 18 hours, and reaction solution concentrates.Residuum 600mL methylene dichloride and the dilution of 400mL water.After extracting and separating, aqueous phase methylene dichloride (100mL x 3) extracts.The organic phase dried over mgso merged.After filtration, filtrate reduced in volume.Enriched material 200mL acetonitrile making beating, filters, uses acetonitrile wash.Filter cake, 65 DEG C 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, be equipped with in the there-necked flask of mechanical stirrer toward 100 milliliters and add reaction substrate (II, 2.0g, 7.2mmol), tetrahydrofuran (THF) (30 milliliters) successively, sodium carbonate (2.75g, 3.6eq).Then, within half an hour, the tetrahydrofuran solution (5mL) to chloromethyl benzoic acid chlorides (2.38g, 1.8eq) is at room temperature slowly dripped.After 6 hours, N methyl piperazine (4.6mL, 5.7eq) is added 30 DEG C of reactions.50 DEG C of reactions after 18 hours, reaction solution concentrates.Residuum 60mL methylene dichloride and the dilution of 40mL water.After extracting and separating, aqueous phase methylene dichloride (15mL x 3) extracts.The organic phase dried over mgso merged.After filtration, filtrate reduced in volume.Enriched material 20mL acetonitrile making beating, filters, uses acetonitrile wash.Filter cake, 65 DEG C 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, be equipped with in the there-necked flask of mechanical stirrer toward 100 milliliters and add reaction substrate (II, 2.0g, 7.2mmol), acetonitrile (30 milliliters) successively, salt of wormwood (2.79g, 2.8eq).Then, within half an hour, the tetrahydrofuran solution (5mL) to chloromethyl benzoic acid chlorides (2.72g, 2.0eq) is at room temperature slowly dripped.Room temperature reaction, after 5 hours, adds N methyl piperazine (6.1mL, 7.5eq).45 DEG C of reactions after 18 hours, reaction solution concentrates.Residuum 60mL methylene dichloride and the dilution of 40mL water.After extracting and separating, aqueous phase methylene dichloride (15mL x 3) extracts.The organic phase dried over mgso merged.After filtration, filtrate reduced in volume.Enriched material 20mL acetonitrile making beating, filters, uses acetonitrile wash.Filter cake, 65 DEG C 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, be equipped with in the there-necked flask of mechanical stirrer toward 100 milliliters and add reaction substrate (II, 2.0g, 7.2mmol), chloroform (30 milliliters) successively, salt of wormwood (2.79g, 2.8eq).Then, within half an hour, the tetrahydrofuran solution (5mL) to chloromethyl benzoic acid chlorides (4.20g, 3.1eq) is at room temperature slowly dripped.Room temperature reaction, after 7 hours, adds N methyl piperazine (2.4mL, 3.0eq).15 DEG C of reactions after 18 hours, reaction solution concentrates.Residuum 60mL methylene dichloride and the dilution of 40mL water.After extracting and separating, aqueous phase methylene dichloride (15mL x 3) extracts.The organic phase dried over mgso merged.After filtration, filtrate reduced in volume.Enriched material 20mL acetonitrile making beating, filters, uses acetonitrile wash.Filter cake, 65 DEG C 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, be equipped with in the there-necked flask of mechanical stirrer toward 100 milliliters and add reaction substrate (II, 2.0g, 7.2mmol), Isosorbide-5-Nitrae-dioxane (30 milliliters) successively, DABCO (3.23g, 4.0eq).Then, within half an hour, the tetrahydrofuran solution (5mL) to chloromethyl benzoic acid chlorides (2.12g, 1.6eq) is at room temperature slowly dripped.Room temperature reaction, after 6 hours, adds N methyl piperazine (8.1mL, 10.0eq).50 DEG C of reactions after 18 hours, reaction solution concentrates.Residuum 60mL methylene dichloride and the dilution of 40mL water.After extracting and separating, aqueous phase methylene dichloride (15mL x 3) extracts.The organic phase dried over mgso merged.After filtration, filtrate reduced in volume.Enriched material 20mL acetonitrile making beating, filters, uses acetonitrile wash.Filter cake, 65 DEG C of oven dry, obtains the imatinib (2.70g, 76%) of colorless solid, HPLC purity 98.2%.
Claims (12)
1. the preparation method of an imatinib, it is characterized in that, by reaction substrate (II) or its salt and halogenated methyl benzoyl halogen (VI) in inert solvent and under alkali effect, at moderate temperatures, after reacting appropriate time, do not need separating treatment gained intermediate, directly and 1-methylpiperazine reaction in－situ, the target compound of imatinib (I) is then obtained; 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;
Substituent X in the chemical formula of described halogenated methyl benzoyl halogen (VI), Y is independently chlorine separately;
Described alkali is selected from sodium carbonate or salt of wormwood.
2. preparation method as claimed in claim 1, it is characterized in that, described alkali is selected from salt of wormwood.
3. preparation method as claimed in claim 1, is characterized in that, described inert solvent is selected from one or more of tetrahydrofuran (THF), acetonitrile, Isosorbide-5-Nitrae-dioxane, toluene, ether, acetone, DMF, methyl-sulphoxide, methylene dichloride or chloroform.
4. preparation method as claimed in claim 1, it is characterized in that, the mol ratio of described alkali and reaction substrate (II) is 2:1-8:1.
5. preparation method as claimed in claim 1, it is characterized in that, the mol ratio of described alkali and reaction substrate (II) is 2:1-4:1.
6. preparation method as claimed in claim 1, it is characterized in that, described proper temperature is 15 to 50 DEG C.
7. preparation method as claimed in claim 1, it is characterized in that, described proper temperature is room temperature.
8. preparation method as claimed in claim 1, is characterized in that, described appropriate time disappears with thin layer chromatography board and high performance liquid phase monitoring reaction substrate (II) and is as the criterion.
9. preparation method as claimed in claim 1, it is characterized in that, the mol ratio of described halogenated methyl benzoyl halogen and described reaction substrate (II) is 1:1-5:1.
10. preparation method as claimed in claim 1, it is characterized in that, the mol ratio of described halogenated methyl benzoyl halogen and described reaction substrate (II) is 1:1-2:1.
11. preparation methods as claimed in claim 1, is characterized in that, the mol ratio of 1-methylpiperazine and reaction substrate (II) is 10:1-2:1.
12. preparation methods as claimed in claim 1, is characterized in that, the mol ratio of 1-methylpiperazine and reaction substrate (II) is 5:1-3:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310537824.8A CN103588754B (en) | 2013-11-04 | 2013-11-04 | Preparation method of imatinib |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310537824.8A CN103588754B (en) | 2013-11-04 | 2013-11-04 | Preparation method of imatinib |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103588754A CN103588754A (en) | 2014-02-19 |
| CN103588754B true CN103588754B (en) | 2015-05-27 |
Family
ID=50079106
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310537824.8A Expired - Fee Related CN103588754B (en) | 2013-11-04 | 2013-11-04 | Preparation method of imatinib |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103588754B (en) |
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 |
-
2013
- 2013-11-04 CN CN201310537824.8A patent/CN103588754B/en not_active Expired - Fee Related
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 |
|---|
| 甲磺酸伊马替尼的合成;刘娥;《化学与生物工程》;20121231;第29卷(第11期);第36-38页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103588754A (en) | 2014-02-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102985416B (en) | Process of preparing a thrombin specific inhibitor | |
| CN104395284A (en) | Process for preparing quinoline derivatives | |
| CN102282134A (en) | Methods of preparing quinoline derivatives | |
| CN102336705B (en) | Method for preparing N-(3,5-dichloropyridyl-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzoyl amine | |
| JP6592085B2 (en) | Preparation method of revaprazan hydrochloride | |
| CN105566215A (en) | Preparation method of Stivarga | |
| CN106279104A (en) | A kind of process modification method preparing succinum love song Ge Lieting | |
| CN102367260A (en) | Synthesis method of 2-aminopyrimidine-5-boric acid | |
| CN104072492A (en) | Synthetic method of anti-tumor targeting therapy drug Tivozanib | |
| CN103058991A (en) | Preparation method of alpha-crystal form imatinib mesylate | |
| CN104910135A (en) | Preparation method of new crystal form of dexrabeprazole sodium | |
| CN103588754B (en) | Preparation method of imatinib | |
| CN101654416B (en) | N-[3-nitro-4-methyl-phenyl]-4-aldehyde group-benzamide and preparation method thereof as well as preparation method of derivatives thereof | |
| CN104356110B (en) | A kind of the sulphur induction tetrazine compound of 3,6 aromatic heterocycle Asymmetrical substitute 1,2,4,5 and its synthetic method | |
| CN104311485A (en) | Preparation method of medicine bosutinib for treating leukemia | |
| CN106045914A (en) | Method for synthesizing tri-substituted imidazole compounds | |
| CN103588765A (en) | Synthesis method for azilsartan medoxomil or salt thereof, intermediate of azilsartan medoxomil or salt thereof and synthesis method for intermediate | |
| CN103483314B (en) | Method for preparing imatinib mesylate in alpha crystal form conveniently and rapidly | |
| CN111349045A (en) | Synthetic method of lenvatinib and novel intermediate | |
| CN105949196B (en) | A kind of preparation method of MER/FLT3 double inhibitors intermediate | |
| CN104031031A (en) | Dabigatran etexilate preparation method | |
| CN102731474B (en) | Preparation method of imatinib | |
| CN106496118B (en) | A kind of quinolines enamine ketone compound and preparation method thereof | |
| CN103755657A (en) | Preparation method of rivaroxaban intermediate | |
| CN103724282A (en) | Synthesis method of quinazoline derivatives as pharmaceutical intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150527 Termination date: 20201104 |