CN101985442B - Convenient and quick method for preparing high-purity imatinib and mesylate thereof - Google Patents
Convenient and quick method for preparing high-purity imatinib and mesylate thereof Download PDFInfo
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- CN101985442B CN101985442B CN 201010286254 CN201010286254A CN101985442B CN 101985442 B CN101985442 B CN 101985442B CN 201010286254 CN201010286254 CN 201010286254 CN 201010286254 A CN201010286254 A CN 201010286254A CN 101985442 B CN101985442 B CN 101985442B
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Abstract
The invention discloses a method for synthesizing imatinib, which comprises the following step of: in the presence of a urea cation condensing agent, reacting N(5-amino-2-methylphenyl)-4-(3-pyridyl)-pyrimithamine (namely a compound shown in a formula I) with 4-(4-methylpiperazin methyl)-benzoic acid in an organic solvent to generate the imatinib. By adopting a specific coupling agent, the invention provides a method for synthesizing imatinib and mesylate thereof, which has the advantages of high efficiency, simple treatment, high product purity, low content of impurities of methyl-removed imatinib, good quality, and suitability for industrial production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, more particularly, relate to a kind of synthetic method that is suitable for imatinib and the mesylate thereof of suitability for industrialized production
Background technology
Imatinib mesylate (Imatinib mesylate, STI571) is by the tyrosine kinase inhibitor class medicine of company of Switzerland Novartis (Novartis) research and development.May calendar year 2001, imatinib mesylate obtains the U.S. FDA express train and examines, be used for alpha-interferon administration failure protoblast crisis stadium, chronic stadium, the granulocyte leukemia (CML) that accelerates stadium and the treatment of patients with gastrointestinal stromal tumors (GISTs), commodity are called imatinib mesylate (Glivec).The imatinib mesylate chemical name is 4-[(4-methyl isophthalic acid-piperazine) methyl]-4-[4-methyl-3-[[4-(3-pyridyl)-2-pyrimidyl] amino]-phenyl] the benzamide mesylate, chemical structure is:
The method of synthetic imatinib usually comprises following final step: N-(5-amino-2-methyl phenyl)-4-(3-pyridine)-PYRIMITHAMINE (formula I compound) and 4-(4-methylpiperazine methyl)-benzoic acid derivative (being formula II ' compound) reaction, thereby obtains imatinib.
This class synthetic method comprises indirect conjugation: Chinese patent CN 1043531C (June 2 1999 day for announcing) discloses N-(5-amino-2-methyl phenyl)-4-(3-pyridine)-PYRIMITHAMINE (formula I compound) and has reacted in the presence of pyridine with 4-(4-methylpiperazine methyl)-Benzoyl chloride, obtains imatinib;
Shen Xin etc. have described under the condition of organic solvent and highly basic existence and heating at Chinese patent application CN 101735196A (open day is on June 16th, 2010), N-(5-amino-2-methyl phenyl)-4-(3-pyridine)-PYRIMITHAMINE (being formula I compound) and 4-(4-methylpiperazine methyl)-benzoic ether (comprising methyl esters, ethyl ester, benzyl ester etc.) reaction obtain imatinib.
These class methods also comprise direct coupling method: RAMESH BABU POTLURI etc. have described application DCC and HOBt as coupling agent at Indian patent application IN 2007CH00006A (open day on November 28th, 2008), so that N-(5-amino-2-methyl phenyl)-4-(3-pyridine)-PYRIMITHAMINE (being formula I compound) and 4-(4-methylpiperazine methyl)-benzoic acid generate imatinib;
Amala etc. have described application DCC as coupling agent in Indian patent application IN 2007CH02524A (open day is on September 11st, 2009), so that N-(5-amino-2-methyl phenyl)-4-(3-pyridine)-PYRIMITHAMINE (being formula I compound) is reacted in acetonitrile with 4-(4-methylpiperazine methyl)-phenylformic acid, generate imatinib;
Castulik etc. have described at 4-chloro-2 at U.S. Patent application US 2009/0318692A (open day is on December 24th, 2009), 6-dimethoxy-1,3,5-triazine and N-methylmorpholine exist lower, N-in acetonitrile (5-amino-2-methyl phenyl)-4-(3-pyridine)-PYRIMITHAMINE (being formula I compound) and 4-(4-methylpiperazine methyl)-benzoic acid obtain imatinib;
Ivanov etc. are at Synthesis of imatinib:a convergent approach revisited, among Monatsh Chem. (2009) 140:619-623 application CDI (N has been described, N '-carbonyl dimidazoles) as condensing agent, N-in DMF (5-amino-2-methyl phenyl)-4-(3-pyridine)-PYRIMITHAMINE (being formula I compound) and 4-(4-methylpiperazine methyl)-benzoic acid obtain imatinib.
Although in above-mentioned prior art, disclose several different methods,, these synthetic methods are existent defect all, and for example severe reaction conditions (needing heating or highly basic) or non-ambient are friendly in the indirect conjugation; Directly how coupling method aftertreatment complexity, reaction generation impurity particularly easily generate demethyl imatinib impurity and are difficult to the shortcomings such as removal and purification.Therefore, still have in the art such needs: a kind of efficient, process simple, product purity is high, the content of demethyl imatinib impurity is few, the measured synthetic method that is suitable for imatinib or its mesylate of suitability for industrialized production of matter.
Summary of the invention
The present invention by adopt specific coupling agent provide a kind of efficient, process the synthetic method that content simple, demethyl imatinib impurity is few, be suitable for imatinib or its mesylate of suitability for industrialized production, successfully solved the deficiencies in the prior art.
The method that the purpose of this invention is to provide a kind of synthetic imatinib or its mesylate.
Specifically, the invention provides a kind of synthetic method of imatinib, it is included in urea positive ion condensing agent and exists lower, N-in organic solvent (5-amino-2-methyl phenyl)-4-(3-pyridine)-PYRIMITHAMINE (being formula I compound) and 4-(4-methylpiperazine methyl)-benzoic acid generate imatinib.
The synthetic method of imatinib provided by the present invention, described reaction randomly are to carry out under the condition that organic bases exists.Here, described organic bases is selected from diisopropylethylamine, triethylamine, N-methylmorpholine, pyridine; Preferably be selected from diisopropylethylamine or triethylamine.
In imatinib synthetic method provided by the invention, described urea positive ion condensing agent is selected from 2-(1H-benzo trisazo-L-1-yl)-1,1,3,3-tetramethyl-urea Tetrafluoroboric acid ester (TBTU), O-(benzotriazole-1-yl)-N, N, N ', N '-dipyrryl urea phosphofluoric acid ester (HBPYU), (benzotriazole-1-base oxygen base) two piperidines carbon hexafluorophosphates (HBPiPU), 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU), benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HBTU), 6-Chloro-Benzotriazole-1,1,3,3-tetramethyl-urea phosphofluoric acid ester (HCTU), tetramethyl-fluoro urea phosphofluoric acid ester (TFFH), the O-[(ethoxy carbonyl) cyano group methylamine]-N, N, N ', N '-tetramethyl-sulphur urine Tetrafluoroboric acid ester (TOTU), 1-(chloro-1-pyrrolidyl methylene radical) tetramethyleneimine hexafluorophosphate (PyCIU), tetramethyl-fluoro urea phosphofluoric acid ester (TFFH), two (tetramethylene) Fluoro-formamide (BTFFH), O-(benzotriazole-1-yl)-1,3-dimethyl-1,3-dimethylene urea phosphofluoric acid ester (HBMDU), or O-(7-azepine benzo triazol-1-yl)-1,1,3,3-two (tetramethylene) urea phosphofluoric acid ester (HAPyU), O-(7-azepine benzo triazol-1-yl)-1, the 3-dimethylene) phosphofluoric acid ester (HAMDU), more preferably, be selected from 2-(1H-benzo trisazo-L-1-yl)-1,1,3,3-tetramethyl-urea Tetrafluoroboric acid ester (TBTU), benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HBTU), or 6-Chloro-Benzotriazole-1,1,3,3-tetramethyl-urea phosphofluoric acid ester (HCTU), or 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU).
In imatinib synthetic method provided by the invention, described organic solvent is selected from methylene dichloride, chloroform, toluene, dimethylbenzene, DMF (DMF), DMAC (N,N-dimethylacetamide) etc.; Preferably, be selected from methylene dichloride or DMF.
In imatinib synthetic method provided by the invention, described 4-(4-methylpiperazine methyl)-phenylformic acid randomly is its pharmaceutical acceptable acid salt form, can be selected from hydrochloride, vitriol etc., is preferably dihydrochloride.
The invention provides a kind of synthetic method of imatinib mesylate, being included in urea positive ion condensing agent exists lower, N-in organic solvent (5-amino-2-methyl phenyl)-4-(3-pyridine)-PYRIMITHAMINE (being formula I compound) and 4-(4-methylpiperazine methyl)-benzoic acid generate imatinib; Then, the imatinib that obtains is reacted with methylsulfonic acid again, obtain imatinib mesylate.
The synthetic method of imatinib mesylate provided by the present invention, described N-(5-amino-2-methyl phenyl)-4-(3-pyridine)-PYRIMITHAMINE (being formula I compound) randomly is to carry out under the condition that organic bases exists with 4-(4-methylpiperazine methyl)-benzoic reaction.Here, described organic bases is selected from diisopropylethylamine, triethylamine, N-methylmorpholine, pyridine; Preferably be selected from diisopropylethylamine.
In imatinib mesylate synthetic method provided by the invention, described urea positive ion condensing agent is selected from 2-(1H-benzo trisazo-L-1-yl)-1,1,3,3-tetramethyl-urea Tetrafluoroboric acid ester (TBTU), O-(benzotriazole-1-yl)-N, N, N ', N '-dipyrryl urea phosphofluoric acid ester (HBPYU), (benzotriazole-1-base oxygen base) two piperidines carbon hexafluorophosphates (HBPiPU), 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU), benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HBTU), 6-Chloro-Benzotriazole-1,1,3,3-tetramethyl-urea phosphofluoric acid ester (HCTU), tetramethyl-fluoro urea phosphofluoric acid ester (TFFH), the O-[(ethoxy carbonyl) cyano group methylamine]-N, N, N ', N '-tetramethyl-sulphur urine Tetrafluoroboric acid ester (TOTU), 1-(chloro-1-pyrrolidyl methylene radical) tetramethyleneimine hexafluorophosphate (PyCIU), tetramethyl-fluoro urea phosphofluoric acid ester (TFFH), two (tetramethylene) Fluoro-formamide (BTFFH), O-(benzotriazole-1-yl)-1,3-dimethyl-1,3-dimethylene urea phosphofluoric acid ester (HBMDU), O-(7-azepine benzo triazol-1-yl)-1,1,3,3-two (tetramethylene) urea phosphofluoric acid ester (HAPyU), O-(7-azepine benzo triazol-1-yl)-1, the 3-dimethylene) phosphofluoric acid ester (HAMDU), more preferably, be selected from 2-(1H-benzo trisazo-L-1-yl)-1,1,3,3-tetramethyl-urea Tetrafluoroboric acid ester (TBTU), benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HBTU), or 6-Chloro-Benzotriazole-1,1,3,3-tetramethyl-urea phosphofluoric acid ester (HCTU), or 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU).
In imatinib mesylate synthetic method provided by the invention, described organic solvent is selected from methylene dichloride, chloroform, toluene, dimethylbenzene, DMF, DMAC etc.; Preferably, be selected from methylene dichloride or DMF.
In imatinib mesylate synthetic method provided by the invention, described 4-(4-methylpiperazine methyl)-phenylformic acid randomly is its pharmaceutical acceptable acid salt form, can be selected from hydrochloride, vitriol etc., is preferably dihydrochloride.
Compared with prior art, useful technique effect of the present invention is embodied in:
1, imatinib provided by the present invention and mesylate thereof prepare the yield height
N-(5-amino-2-methyl phenyl)-4-(3-pyridine)-PYRIMITHAMINE (being formula I compound) prepares the yield of imatinib up to 98% with 4-(4-methylpiperazine methyl)-benzoic acid.Report in the existing open source information that N-(5-amino-2-methyl phenyl)-4-(3-pyridine)-PYRIMITHAMINE (being formula I compound) all is lower than 80% with the highest yield that 4-(4-methylpiperazine methyl)-benzoic acid prepares imatinib.
2, preparation method's provided by the present invention yield feedstock conversion high, that participate in reaction is thorough, this so that reaction to generate product imatinib purity high, extremely be conducive to the raising of its quality product when refining.The made purity that obtains the imatinib mesylate product of the present invention is up to more than 99.8%, particularly " demethylation impurity " (CAS NO:404844-02-6, numbering: STI 509-00) and other single impurity all less than 0.1%; The content high quality of product is good.In known above-mentioned several preparation methods, be mostly during synthetic imatinib under the condition of strong acid heating, to react, generate " demethyl imatinib " so that demethylation easily occurs " N methyl piperazine intermediate " under this envrionment conditions.We adopt the method for condensing of urea positive ion to react under mild conditions, substantially can not generate " demethyl imatinib "; Provide " demethyl imatinib " impurity to contain few imatinib raw material during for salify, " demethyl imatinib " impurity in the end reaction generation finished product is less than the requirement that meets ICH below 0.05%, preparation method of the present invention more can reduce the detrimental impurity in the product, the level of improving the quality of products.
Therefore, the synthetic method productive rate of imatinib provided by the invention and mesylate thereof is high, and purity is high, is suitable for suitability for industrialized production.
Description of drawings
What Fig. 1 represented is the imatinib mesylate HPLC detected result of embodiment 1 and the preparation of embodiment 5 methods.
What Fig. 2 represented is the imatinib mesylate HPLC detected result of document CN 1043531C preparation.
What Fig. 3 represented is the imatinib mesylate HPLC detected result of document IN 2007CH02524A preparation.
Embodiment
Further specify embodiment of the present invention below by embodiment, for those of ordinary skills, the following example does not consist of the restriction to embodiment of the present invention.
One, the preparation of imatinib
Reaction equation:
In four-hole bottle, add 4-(4-methylpiperazine methyl)-phenylformic acid dihydrochloride (122g, 0.397mol), methylene dichloride (1000ml), the control room temperature drips diisopropylethylamine (138ml, 0.792mol), finished insulation reaction 1 hour.Add N-(5-amino-2-methyl phenyl)-4-(3-pyridine)-PYRIMITHAMINE (100g, 0.361mol), HBTU (150g, 0.396mol) and diisopropylethylamine (75ml, 0.431mol).Finishing insulation reaction spends the night.Add dilute sodium hydroxide (500ml) aqueous solution under the room temperature, stirred 1 hour.Suction filtration, suitable quantity of water and ethyl acetate drip washing get filter cake 1.
The mother liquor phase-splitting is told the organic phase anhydrous sodium sulfate drying, suction filtration.Filtrate decompression is concentrated into dried light yellow solid, adds ethyl acetate and stirs out crystalline substance.Suction filtration, an amount of ethyl acetate drip washing gets filter cake 2, and filter cake 1 and filter cake 2 are merged, and in 50 ℃ of dryings, gets light yellow solid target compound 174.5g (purity: 98.3%)." demethyl imatinib " do not detect.Yield: 98.0%.
In four-hole bottle, add 4-(4-methylpiperazine methyl)-phenylformic acid dihydrochloride (24.4g, 0.079mol), DMF (120ml), the control room temperature drips DIPEA (28ml, 0.161mol), adds rear insulated and stirred 30 minutes.Add N-(5-amino-2-methyl phenyl)-4-(3-pyridine)-PYRIMITHAMINE (20g, 0.072mol), HCTU (32.7g, 0.079mol) and DIPEA (15ml, 0.086mol).Add rear insulation reaction 8 hours.Reaction is finished, and add entry and stirred 30 minutes, suction filtration, filter cake washs with ethyl acetate, in 50 ℃ of dryings.Get light yellow solid target compound 33.1g (purity: 97.8%)." demethyl imatinib " do not detect.Yield: 93.1%.
Add 4-(4-methylpiperazine methyl)-phenylformic acid dihydrochloride (16.9g, 0.055mol) in four-hole bottle, dimethyl formamide (140ml) drips DIPEA (19ml, 0.055mol) under the control room temperature, finishes insulated and stirred 30 minutes.Add N-(5-amino-2-methyl phenyl)-4-(3-pyridine)-PYRIMITHAMINE (13.8g, 0.050mol), TBTU (17.7g, 0.055mol), temperature control 20-30 ℃ drips DIPEA (11ml, 0.063mol).Finishing insulation reaction spends the night.Add entry and stirred 1 hour, suction filtration, filter cake washs with ethyl acetate, in 50 ℃ of dryings.Get light yellow solid target compound 23.5g (purity: 97.5%)." demethyl imatinib " do not detect.Yield: 95.7%.
Add 4-(4-methylpiperazine methyl)-phenylformic acid dihydrochloride (10.1g, 0.033mol) in four-hole bottle, dimethyl formamide (50ml) drips triethylamine (9ml, 0.066mol) under the control room temperature, finishes insulated and stirred 30 minutes.Add N-(5-amino-2-methyl phenyl)-4-(3-pyridine)-PYRIMITHAMINE (8.3g, 0.030mol), HATU (12.5g, 0.033mol), temperature control 20-30 ℃ drips DIPEA (7.7ml, 0.033mol).Finishing insulation reaction spends the night.Add entry and stirred 1 hour, suction filtration, filter cake washs with ethyl acetate, in 50 ℃ of dryings.Get light yellow solid target compound 17.1g (purity: 97.2%)." demethyl imatinib " do not detect.Yield: 96.7%.
The preparation of imatinib mesylate
Reaction formula:
In four-hole bottle, add imatinib (170g, 0.344mol), Virahol (1700ml) and methylsulfonic acid (36.4g, 0.379mol).Be warming up to back flow reaction 2 hours.Be cooled to 0～5 ℃ of growing the grain 2 hours.Suction filtration, Virahol drip washing, 60 ℃ of reduced vacuum dryings.Get off-white color solid target thing 186.7g.Purity: 99.89% (single assorted less than 0.1%), wherein " demethyl imatinib " impurity: 0.01%.Yield: 92%.
We test according to the example that provides in the prior art, and imatinib and imatinib mesylate that different methods prepares tabulated, when preparing imatinib and imatinib mesylate, more different synthesis techniques produce the generation situation of " demethyl imatinib " amount:
Wherein the detection method condition of related substance (demethyl imatinib impurity) is:
Chromatographic column model and specification: Phenomenex Luna 5u C18 250mm * 4.6mm
Moving phase: perfluorooctane sulfonate (perfluorooctane sulfonate 7.5g adds 800ml water, transfers PH to 2.5, is settled to 1000ml): methyl alcohol=35: 65
Flow velocity: 1.2ml/min
Detect wavelength: 267nm.
Claims (13)
1. the synthetic method of an imatinib, it is included in urea positive ion condensing agent and exists lower, N-(5-amino-2-methyl phenyl in organic solvent)-the 4-(3-pyridine)-PYRIMITHAMINE and 4-(4-methylpiperazine methyl)-phenylformic acid or the reaction of its pharmaceutical acceptable acid salt form, generate imatinib;
Wherein, described urea positive ion condensing agent is selected from 2-(1H-benzo trisazo-L-1-yl)-1,1,3,3-tetramethyl-urea Tetrafluoroboric acid ester, benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester or 6-Chloro-Benzotriazole-1,1,3,3-tetramethyl-urea phosphofluoric acid ester or 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester.
2. method according to claim 1, wherein, described reaction is to carry out under the condition that organic bases exists, described organic bases is selected from diisopropylethylamine, triethylamine, N-methylmorpholine, or pyridine.
3. synthetic method according to claim 2, wherein, described organic bases is selected from diisopropylethylamine or triethylamine.
4. synthetic method according to claim 1, wherein, described organic solvent is selected from methylene dichloride, chloroform, toluene, dimethylbenzene, DMF, or DMAC.
5. synthetic method according to claim 4, wherein, described organic solvent is selected from methylene dichloride or DMF.
6. synthetic method according to claim 1, wherein, described 4-(4-methylpiperazine methyl)-phenylformic acid pharmaceutical acceptable acid salt form is selected from hydrochloride or vitriol.
7. the synthetic method of an imatinib mesylate, being included in urea positive ion condensing agent exists lower, N-(5-amino-2-methyl phenyl in organic solvent)-the 4-(3-pyridine)-PYRIMITHAMINE and 4-(4-methylpiperazine methyl)-phenylformic acid or the reaction of its pharmaceutical acceptable acid salt form, generate imatinib; Then, the imatinib that obtains is reacted with methylsulfonic acid again, obtain imatinib mesylate;
Wherein, described urea positive ion condensing agent is selected from 2-(1H-benzo trisazo-L-1-yl)-1,1,3,3-tetramethyl-urea Tetrafluoroboric acid ester, benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester or 6-Chloro-Benzotriazole-1,1,3,3-tetramethyl-urea phosphofluoric acid ester or 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester.
8. synthetic method according to claim 7, wherein, described N-(5-amino-2-methyl phenyl)-the 4-(3-pyridine)-PYRIMITHAMINE and 4-(4-methylpiperazine methyl)-reaction of phenylformic acid or its pharmaceutical acceptable acid salt form is to carry out under the condition that organic bases exists; Here, described organic bases is selected from diisopropylethylamine, triethylamine, N-methylmorpholine, or pyridine.
9. synthetic method according to claim 8, wherein, described organic bases is selected from diisopropylethylamine.
10. synthetic method according to claim 7, wherein, described organic solvent is selected from methylene dichloride, chloroform, toluene, dimethylbenzene, DMF, or DMAC.
11. synthetic method according to claim 10, wherein, described organic solvent is selected from methylene dichloride or DMF.
12. synthetic method according to claim 7, wherein, described 4-(4-methylpiperazine methyl)-phenylformic acid pharmaceutical acceptable acid salt form is selected from hydrochloride or sulfuric acid.
13. synthetic method according to claim 12, wherein, described 4-(4-methylpiperazine methyl)-phenylformic acid pharmaceutical acceptable acid salt form is dihydrochloride.
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| CN102206205A (en) * | 2011-04-12 | 2011-10-05 | 江苏中威药业有限公司 | Preparation method for imatinib |
| CN102796079B (en) * | 2011-05-27 | 2016-06-29 | 江苏豪森药业集团有限公司 | A kind of preparation method of methanesulfonic acid fluorine imatinib |
| CN104865321A (en) * | 2015-04-10 | 2015-08-26 | 江苏豪森药业股份有限公司 | High sensitivity analysis and detection method of imatinib related substance |
| CN106124662A (en) * | 2016-07-15 | 2016-11-16 | 江苏悦兴医药技术有限公司 | The high performance liquid chromatography method for detecting purity that a kind of 2 cyano group 4 pyridinecarboxylate are kept completely separate with its major impurity |
| CN109627985B (en) * | 2018-10-15 | 2021-08-24 | 哈尔滨工业大学无锡新材料研究院 | UV curing inhibition oxygen polymerization inhibition bionic adhesive and preparation method thereof |
| CN112552283A (en) * | 2020-12-07 | 2021-03-26 | 天津羲泽润科技有限公司 | Preparation method of novel tinib medicine |
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| CN101641345A (en) * | 2006-10-26 | 2010-02-03 | 西科尔公司 | Imatinib base, and imatinib mesylate and processes for preparation thereof |
| CN101677955A (en) * | 2007-03-12 | 2010-03-24 | 雷迪博士实验室有限公司 | imatinib mesylate |
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