CN102040587A - Preparation method of imatinib mesylate - Google Patents
Preparation method of imatinib mesylate Download PDFInfo
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- CN102040587A CN102040587A CN2009101800751A CN200910180075A CN102040587A CN 102040587 A CN102040587 A CN 102040587A CN 2009101800751 A CN2009101800751 A CN 2009101800751A CN 200910180075 A CN200910180075 A CN 200910180075A CN 102040587 A CN102040587 A CN 102040587A
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Abstract
The invention relates to a preparation method of imatinib mesylate using N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine and 4-[(4-methyl piperazine-1-yl) methyl] benzoic acid hydrochloride as starting materials, and quality control method for intermediate in the preparation process and the final product. The overall yield of the process is about 40%, and the process is characterized in that reaction conditions are mild, operations are simple, column chromatography and other time and energy consuming steps can be avoided, quality of obtained products is stable, the purity is greater than 99%, the production cost is low, and the technology is stable and feasible.
Description
Technical field
This invention relates to imatinib mesylate preparation method, intermediate control method and in the application of field of medicaments.
Background technology
Imatinib mesylate is the derivative of aniline pyrimidine, be a specific tyrosine kinase inhibitor (tyrosine kinasesinhibitors, TKI).Be used for the treatment of chronic myelocytic leukemia (CML) by the FDA approval May calendar year 2001.Be used for the treatment of gastrointestinal stromal tumor (GIST) by FDA approval in 2003.
As first tumour generation coherent signal conduction depressant drug that gets the Green Light of the whole world, the consistent favorable comment of each side of international medical educational circles has been won in the listing of imatinib mesylate: on behalf of the brand-new antitumor drug of a class mechanism of action, it not only formally entered into clinical application thus, and itself has just indicated a kind of direction of disease therapeuticing medicine development, be drug target will tend to molecular level day by day, and this effective way that improves medication effect just and reduce its poison, side reaction.
Imatinib mesylate (Imatinib Mesylate), chemistry is by name: methyl 4-[(4-methyl isophthalic acid-piperazinyl)]-N-[4-methyl-3-[4-(3-pyridyl)-2-pyrimidyl] amino-phenyl]-the benzamide mesylate., its molecular structural formula is as follows:
About the synthetic method of imatinib mesylate, the domestic and foreign literature report is more.
The synthetic method that Chen Ao etc. delivered imatinib mesylate in 2007 (Chen Ao, Huang Hexiang etc.Synthesizing of imatinib mesylate.Meticulous and specialty chemicals, 2007,15 (8): 23-25), see Scheme1.
With 4-methyl-3-nitro aniline is starting raw material, makes imatinib mesylate through reactions such as condensation, reduction, cyclizations.Totally 6 steps reaction, total recovery 58.6%, there is following shortcoming in this method:
1) reactions steps is many, and the entire reaction time is long, and total reaction time surpasses 85h.
2) the 5th step reaction needed is used nitrogen protection.
3) the 5th step reaction product purity 98.3% (beige solid), purity 99.7% behind the purifying (off-white color solid), but document does not provide purification process, because next step direct and methylsulfonic acid salify, therefore the impurity of this step reaction is probably introduced in the product.
The synthetic method that Li Mingdong etc. delivered imatinib mesylate in 2008 (Li Mingdong, Li Dong etc.Synthesizing of imatinib mesylate.Chinese Pharmaceutical Journal, 2008,43 (3): 228-229), see Scheme2.
With 3-acetylpyridine, 2-methyl-5-nitro aniline etc. is raw material, through condensation, Cheng Huan, hydrogenation, acidylate, and then obtains imatinib mesylate with the methylsulfonic acid salify.Totally 6 steps reaction, total recovery is 27.0%, mainly there is following deficiency in this method:
1) reactions steps is many, and total reaction time is long.
2) need catalytic hydrogenation, for suitability for industrialized production is brought certain potential safety hazard.
Chinese patent CN03803556.1 discloses synthesizing imatinib, sees Scheme3.
With 3-bromo-4-monomethylaniline and 4-(4-methyl-piperazinyl-methyl) methyl benzoate is starting raw material, obtains the imatinib free alkali through aminolysis, catalytic hydrogenation and PYRIMITHAMINE reaction.The shortcoming of this method is as follows:
1) trimethyl aluminium that uses is utmost point inflammable substance, brings potentially dangerous for big production.
2) use expensive palladium catalyst, and need catalytic hydrogenation, for suitability for industrialized production is brought certain potential safety hazard.
3) need carry out the purifying of product by column chromatography.
Chinese patent CN200710067344.4 discloses a kind of preparation method of imatinib, sees Scheme4.
With 4-(4-methyl-piperazine-1-ylmethyl) Benzoyl chloride and 3-nitro-4-methyl-aniline is raw material, and reaction makes the imatinib free alkali through 3 steps, and total recovery is 51.2%.The deficiency of this method is to have used hypertoxic sodium cyanide.
Chinese patent CN200810033189.9 discloses synthesizing imatinib, sees Scheme5.
So that N-(4-methyl-3-3 aminophenyl)-4-(4-methyl-piperazinyl-1-methyl)-benzamide is a raw material, under the effect of polypeptide condensing agent and organic bases,, obtain imatinib with 4-methyl-(3-pyridyl)-2-pyrimidone reaction.The shortcoming of this method is:
1) condensing agent BOP costs an arm and a leg (5g, 176 yuan), is not suitable for suitability for industrialized production.
2) need the control low-temp reaction.
3) only wash removal of impurities with water after the reaction, be drying to obtain the finished product, be difficult to remove byproduct of reaction, unreacted reagent.
PCT patent WO 2004/108699 discloses the preparation method of imatinib, sees Scheme6.
With 2-amino-4-nitrotoluene is starting raw material, obtains the imatinib free alkali through condensation, Cheng Huan, reduction, acidylate, totally 5 steps reaction, and total recovery 14.1%, mainly there is following deficiency in this method:
1) needs to use the centrifugation apparatus that adapts in big the production.
2) total recovery is relatively low.
Summary of the invention
The purpose of this invention is to provide the simple to operate of a kind of suitable suitability for industrialized production, cost is lower, the preparation method of the imatinib mesylate that process controllability is good.
Another object of the present invention provides the quality control method of intermediate and finished product in the above-mentioned imatinib mesylate preparation process.
In order to reach the object of the invention the technical solution used in the present invention be:
The preparation method of first kind of imatinib mesylate is characterized in that may further comprise the steps:
(1) with the N-shown in the structural formula (I) (5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE (hereinafter to be referred as intermediate compound I), with the 4-[(4-methylpiperazine-1-yl shown in the structural formula (II)) methyl] phenylformic acid dihydrochloride (hereinafter to be referred as intermediate II), in organic solvent, under the catalyzer existence condition, react, obtain the imatinib shown in the structural formula (III).
Described organic solvent is dimethyl formamide (DMF), chloroform, dimethyl sulfoxide (DMSO) (DMSO), acetonitrile, tetrahydrofuran (THF), methylene dichloride, benzene or toluene.
Described catalyzer is N-hydroxy-succinamide, dicyclohexyl carbodiimide.
Described being reflected under 10～200 ℃ of conditions carried out, and preferred condition is 20～50 ℃.
The ratio of the amount of substance of described intermediate compound I, intermediate II, N-hydroxy-succinamide, dicyclohexyl carbodiimide is 1: 1.2～20: 0.02～1: 0.5～5, and preferred ratio is 1: 1.2～1.5: 0.04～0.07: 1～1.2.
(2) with the first step reaction product water dissolution, add activated carbon decolorizing and filtration, regulate pH to alkalescence with ammoniacal liquor, to filter, drying obtains the imatinib free alkali.
Described water consumption is 2～10 times of amounts of the first step reaction product, and preferable amount is 4 times of amounts.
Described activated carbon dosage is 0.01%～5%, and preferable amount is 0.5%.
Described pH value is 8～11, and preferred pH value is 10.
(3) the imatinib free alkali that the reaction of second step is obtained is suspended in the organic solvent, and to wherein adding methylsulfonic acid, stirring reaction concentrates reaction solution, filters, and obtains imatinib mesylate.
Described organic solvent is Virahol, dehydrated alcohol, methyl alcohol, methylene dichloride, chloroform.
Described consumption of organic solvent is 5～20 times of amounts of imatinib free alkali, and preferred consumption is 8～12 times of amounts.
The ratio of the amount of substance of described imatinib free alkali, methylsulfonic acid is 1: 1～1.2, and preferred ratio is 1: 1.012.
Described concentrating degree is to be concentrated into 1/10～1/4 of original volume, is preferably 1/5.
(4) imatinib mesylate that three-step reaction is obtained is suspended in the poor solvent, be heated to backflow, slowly drip and just add water to dissolving fully, room temperature is placed crystallization, filters drying, obtain the imatinib mesylate of pharmaceutically useful purity＞99%, total recovery is about 40%, if the non-compliant requirement of synthetic imatinib mesylate, can dry again and the same method recrystallization.
Described poor solvent is ethanol, methyl alcohol, Virahol, acetone.
Described poor solvent consumption is 10～30 times of amounts, and preferred consumption is 18～22 times of amounts.
The preparation method of second kind of imatinib mesylate is characterized in that may further comprise the steps:
(1) with intermediate II, do not stopping to add thionyl chloride under the stirring, be heated to boiling, it is an amount of slowly to drip DMF, keep the boiling state reaction, the reclaim under reduced pressure thionyl chloride, remaining thionyl chloride is taken out of with the toluene azeotropic that repeatedly reduces pressure, and obtains the 4-[(4-methylpiperazine-1-yl shown in the structural formula (IV)) methyl] the Benzoyl chloride dihydrochloride.
The ratio of the amount of substance of described intermediate II, thionyl chloride is 1: 10～20, and preferred ratio is 1: 15.
The consumption of described catalyzer DMF is 0.1%～0.5% of a thionyl chloride consumption, and preferred amount is 0.2%.
(2) get intermediate compound I, it is an amount of to add organic solvent, stirs and makes suspendible, adds the acyl chlorides that above-mentioned the first step reaction generates, and adds an amount of pyridine as catalyzer, and the heated and stirred reaction is filtered, and obtains the imatinib hydrochloride.
The ratio of the amount of substance of the acyl chlorides that described intermediate compound I, the first step reaction generate is 1: 1～2, and preferred ratio is 1: 1.5.
Described organic solvent is dimethyl formamide (DMF), chloroform, dimethyl sulfoxide (DMSO) (DMSO), acetonitrile, tetrahydrofuran (THF), methylene dichloride, benzene or toluene.
Described consumption of organic solvent is 4～10 times of amounts of intermediate compound I, is preferably 5 times of amounts.
Described pyridine consumption is 10%～30% of a consumption of organic solvent, and preferred amount is 14%.
Described heated and stirred is reflected under 10～200 ℃ of conditions carries out, and preferred condition is 70～90 ℃.
(3) (2), (3), (4) operation steps of the later same first kind of preparation method of treatment step.
In each step of above-mentioned two kinds of preparation methods, use high performance liquid chromatography that each step reaction is monitored, and product is carried out purity test.Chromatographic process is:
With the octadecylsilane chemically bonded silica is weighting agent; Mobile phase A is perfluoroetane sulfonic acid sodium solution (gets perfluorooctane sulfonate 5g, add water 1000ml dissolving, regulate pH value to 2.5 with trifluoroacetic acid), and Mobile phase B is methyl alcohol-acetonitrile (1: 1), linear gradient elution.Flow velocity is per minute 1.0ml; The detection wavelength is 267nm.
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 42％ | 58％ |
| 15 | 42％ | 58％ |
| 25 | 13％ | 87％ |
| 30 | 42％ | 58％ |
| 40 | 42％ | 58％ |
Use this method can make intermediate compound I, intermediate II, imatinib, impurity A (shown in structural formula V), impurity B (shown in structural formula VI) resolution good, typical separate degree color atlas is seen accompanying drawing 1.The imatinib mesylate high-efficient liquid phase chromatogram that first kind, second kind preparation method makes is seen accompanying drawing 2, accompanying drawing 3 respectively.
This technology total recovery about 40%, adopt product that this explained hereafter goes out through check, proterties, fusing point, acidity, residue on ignition, heavy metal, arsenic salt, organic solvent residual, methylsulfonic acid content, related substance, content etc. are all up to specification, and with many batch samples quality test of this explained hereafter no significant difference as a result.
This technological reaction condition relaxes, time consumption and energy consumption steps such as no column chromatography, and the constant product quality of acquisition, cost is low, and process stabilizing is feasible.Use solvent in this technology and be two, three kind solvents, avoid having used a kind solvent, solvent had both reduced cost by recycling and reusing, and helped environment protection again.
Description of drawings
Fig. 1 intermediate compound I, intermediate II, imatinib, impurity A, impurity B mixing solutions high-efficient liquid phase chromatogram, wherein the peak of each material correspondence number and retention time are as follows respectively:
| Peak number | Retention | Corresponding compound | |
| 1 | 5.087 | Intermediate compound I | |
| 2 | 7.428 | |
|
| 3 | 11.148 | |
|
| 4 | 16.392 | |
|
| 5 | 28.062 | Impurity A |
The imatinib mesylate high-efficient liquid phase chromatogram that first kind of preparation method of Fig. 2 makes, the retention time of imatinib mesylate is 16.640min, normalization method purity is 99.50%.
The imatinib mesylate high-efficient liquid phase chromatogram that second kind of preparation method of Fig. 3 makes, the retention time of imatinib mesylate is 16.448min, normalization method purity is 99.47%.
The imatinib mesylate that Fig. 4 the present invention makes
1H NMR spectrogram
The imatinib mesylate that Fig. 5 the present invention makes
13C NMR spectrogram
Embodiment
Two kinds of methods that prepare imatinib mesylate of the present invention all adopt with the N-shown in the structural formula (I) (5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE (intermediate compound I), with the 4-[(4-methylpiperazine-1-yl shown in the structural formula (II)) methyl] phenylformic acid dihydrochloride (intermediate II) is as initial substance.
First kind of preparation method undertaken by following flow process 1:
Embodiment 1: first kind of preparation method of imatinib mesylate
(1) gets intermediate compound I (50.3g, 0.181mol), be suspended among dimethyl formamide (DMF) 250ml, do not stop to stir down, and the adding intermediate II (75.2g, 0.245mol), and N-hydroxy-succinamide (1.04g, 0.009mol), in 10 minutes, add dicyclohexyl carbodiimide (39.2g, DMF solution 0.190mol) under the stirring at room.In 20 ℃ of stirring reactions 17 hours, HPLC monitored reaction, after reaction is finished, filtered, and product 60 ℃ of drying under reduced pressure 6 hours, is obtained product 60.1g, was faint yellow solid.
(2) the faint yellow solid 60g that step (1) is made is dissolved in the 240ml water, adds 0.5% gac, and heating in water bath to 60 ℃ stirred filtration 30 minutes.Filtrate is regulated pH to 10.2 with ammoniacal liquor, and with sedimentation and filtration, vacuum-drying obtains imatinib free alkali 49.8g, is faint yellow solid.
(3) (49.8g 0.1009mol), is suspended in the 750ml methyl alcohol imatinib free alkali that step (2) is made, be heated to 70 ℃, slowly add methylsulfonic acid (9.84g, 0.1024mol), in 20 minutes, add, be heated to backflow, kept 20 minutes, be concentrated into about 350ml, be placed to room temperature, filter, obtain imatinib mesylate 53.1g, be buff powder.
(4) imatinib mesylate (53.1g that step (3) is made, 0.090mol), be suspended in the 500ml ethanol, be heated to backflow, do not stop to stir down dropping water and make just dissolving, filtered while hot, put coldly, crystallization filters, drying under reduced pressure obtains imatinib mesylate finished product 49.9g, is light yellow crystalline powder.
Second kind of preparation method undertaken by following flow process 2:
Embodiment 2: second kind of preparation method of imatinib mesylate
(1) gets intermediate II (2350g, 7.65mol), do not stop to stir down adding thionyl chloride 20L, be heated to boiling, slowly drip DMF 27ml, keep boiling state to react 2 hours down, the reclaim under reduced pressure thionyl chloride, repeatedly add an amount of toluene and evaporated under reduced pressure, to remove unnecessary thionyl chloride, vacuum-drying under 60 ℃ of conditions.
(2) (1450g 5.23mol), adds DMF 7.2L to get intermediate compound I, stirring makes dissolving, adds the acyl chlorides that above-mentioned reaction generates, and is heated to 70 ℃, add pyridine 1L, about 15 hours of stirring reaction is with HPLC monitoring reaction progress, after reaction is finished, be cooled to room temperature, stirred 2 hours, and filtered, product drying under reduced pressure under 60 ℃ of conditions.
(3) get the imatinib hydrochloride that above-mentioned reaction obtains, add entry 7.5L, stir and make dissolving, add 0.5% gac, be heated to 50 ℃, kept 30 minutes, filter, filtrate is regulated pH to about 10 with strong aqua, filter filter residue evaporated under reduced pressure, drying under reduced pressure under 50 ℃ of conditions.
(4) get the imatinib free alkali that above-mentioned reaction makes, be suspended in the 11.2L Virahol, to wherein adding methylsulfonic acid 220g, stirring reaction 2 hours.Reaction mixture is concentrated into about 2L, and cooling is filtered, with product at 60 ℃ of drying under reduced pressure.
(5) imatinib mesylate that above-mentioned reaction is obtained is suspended in the 25L ethanol, is heated under the reflux conditions, adds the about 350ml of entry and makes dissolving, and room temperature is placed and spent the night, and filters, at 60 ℃ of drying under reduced pressure, promptly.
It is an amount of to get this product, with DMSO-d
6Be solvent, make proton nmr spectra, the result: δ 10.177 (s, 1), 9.278～9.282 (d, 1), (8.975 s, 1), 8.683～8.695 (dd, 1), 8.475～8.521 (m, 2), 8.080～8.085 (d, 1), 7.947～7.968 (d, 2), 7.425～7.549 (m, 5), 7.200～7.221 (d, 1), 3.686 (s, 2), 3.376～3.402 (d, 2), (3.039 d, 2), 2.936～3.039 (bs, 4), 2.784 (s, 3), (2.382 bs, 2), accompanying drawing 4 is seen in 2.225 (s, 3).
It is an amount of to get this product, with DMSO-d
6Be solvent, make carbon-13 nmr spectra, the result: δ 165.5,162.0, and 161.6,159.9,151.7,148.5,138.2,137.6,135.0,134.6,132.7,130.5,129.4,128.2,124.3,117.8,117.3,108.0,61.0,53.0,49.6,42.7,25.9,18.1, see accompanying drawing 5.
Embodiment 3: imatinib mesylate HPLC purity detecting
Chromatographic condition:
Chromatographic column: Venusil C18 (250 * 4.6mm, 5 μ m)
Moving phase: perfluoroetane sulfonic acid sodium solution (get perfluorooctane sulfonate 7.5g, add water 1000ml dissolving)+methyl alcohol-acetonitrile (1: 1) with 10% phosphorus acid for adjusting pH value to 2.5, gradient elution, gradient condition is the same.
Column temperature: room temperature
Flow velocity: 1.0ml/min
Detect wavelength: 267nm
Sample size: 10 μ l
Mix the preparation of differentiating solution: get intermediate compound I, intermediate II, imatinib mesylate, each is an amount of for impurity A, impurity B, adds methyl alcohol and makes the solution that contains 0.1mg among every 1ml, as differentiating solution.
Precision is measured 10 μ l, injecting chromatograph, and the record color atlas, the result shows that the resolution at each peak is all good.
The preparation of need testing solution: it is an amount of to get the synthetic imatinib mesylate that makes, and adds methyl alcohol and makes the solution that contains 0.5mg among every 1ml, as need testing solution.
Precision is measured 10 μ l, injecting chromatograph, and the record color atlas, the result shows, the imatinib mesylate normalization method purity that first kind of preparation method makes is that the imatinib mesylate normalization method purity that 99.50%, the second kind of preparation method makes is 99.47%.
Embodiment 4: imatinib mesylate TLC purity detecting
Chromatographic condition:
Developping agent: in the double flute cylinder, with ethyl acetate-methyl alcohol (7: 3) be developping agent on one side, the other side adding ammoniacal liquor is an amount of, saturated 30 minutes.
Colour developing: ultra-violet lamp 254nm
Absolute point sample amount: 20 μ g, 40 μ g, 60 μ g, 80 μ g
The preparation of need testing solution: add methyl alcohol-chloroform (1: 1) and make the solution that contains imatinib 10mg among every 1ml approximately, as need testing solution.
Get above-mentioned need testing solution each 2 μ l, 4 μ l, 6 μ l, 8 μ l respectively, put on same silica gel G 254 thin layer plates, launch with above-mentioned developping agent, take out, dry, put under the ultra-violet lamp (254nm) and observe, the result shows that each spot rounding is not all observed tangible impurity spot.
Claims (10)
1. the preparation method of an imatinib mesylate is characterized in that may further comprise the steps:
(1) with the N-shown in the structural formula (I) (5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE, with the 4-[(4-methylpiperazine-1-yl shown in the structural formula (II)) methyl] the phenylformic acid dihydrochloride, in organic solvent, under the catalyzer existence condition, react, obtain the imatinib shown in the structural formula (III).
(2) the product water dissolution that step (1) is obtained adds activated carbon decolorizing and filtration, regulates pH to alkalescence with ammoniacal liquor, filters, and drying obtains the imatinib free alkali.
(3) the imatinib free alkali that step (2) is obtained is suspended in the organic solvent, and to wherein adding methylsulfonic acid, stirring reaction concentrates reaction solution, filters, and obtains imatinib mesylate.
(4) imatinib mesylate that step (3) is obtained is suspended in the poor solvent, be heated to backflow, slowly drip and just add water to dissolving fully, room temperature is placed crystallization, filter, drying obtains the imatinib mesylate of pharmaceutically useful purity＞99%, if the non-compliant requirement of synthetic imatinib mesylate can be dry again also by this method recrystallization again.
2. the preparation method of an imatinib mesylate is characterized in that may further comprise the steps:
(1) with the 4-[(4-methylpiperazine-1-yl shown in the structural formula (II)) methyl] the phenylformic acid dihydrochloride, do not stopping to add thionyl chloride under the stirring, be heated to boiling, it is an amount of slowly to drip DMF, keep the boiling state reaction, the reclaim under reduced pressure thionyl chloride, remaining thionyl chloride is taken out of with the toluene azeotropic that repeatedly reduces pressure, and obtains the 4-[(4-methylpiperazine-1-yl shown in the structural formula (IV)) methyl] the Benzoyl chloride dihydrochloride.
(2) get the N-shown in the structural formula (I) (5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE, it is an amount of to add organic solvent, stirring makes suspendible, add 4-[(4-methylpiperazine-1-yl) methyl] the Benzoyl chloride dihydrochloride, add an amount of pyridine as catalyzer, the heated and stirred reaction is filtered, and obtains the imatinib hydrochloride.
(3) subsequent processing steps obtains pharmaceutically useful imatinib mesylate with (2), (3), (4) step of claim 1.
3. the method for claim 1, wherein in the step (1), described organic solvent is a kind of in dimethyl formamide (DMF), chloroform, dimethyl sulfoxide (DMSO) (DMSO), acetonitrile, tetrahydrofuran (THF), methylene dichloride, benzene or the toluene.Described catalyzer is N-hydroxy-succinamide, dicyclohexyl carbodiimide.Described being reflected under 10～200 ℃ of conditions carried out.Described N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE, 4-[(4-methylpiperazine-1-yl) methyl] ratio of amount of substance of phenylformic acid dihydrochloride, N-hydroxy-succinamide, dicyclohexyl carbodiimide is 1: 1.2～20: 0.02～1: 0.5～5.
4. the method for claim 1, wherein in the step (2), described water consumption is 2～10 times of amounts.Described activated carbon dosage is 0.01%～5%.Described pH value is 8～11.
5. the method for claim 1, wherein in the step (3), described organic solvent is a kind of in Virahol, dehydrated alcohol, methyl alcohol, methylene dichloride, the chloroform.Described consumption of organic solvent is 5～20 times of amounts of imatinib free alkali.The ratio of the amount of substance of described imatinib free alkali, methylsulfonic acid is 1: 1～1.2.
6. the method for claim 1, wherein in the step (4), described poor solvent is a kind of in ethanol, methyl alcohol, Virahol, the acetone.Described poor solvent consumption is 10～30 times of amounts.
7. methyl method as claimed in claim 2, wherein in the step (1), described 4-[(4-methylpiperazine-1-yl)] ratio of amount of substance of phenylformic acid dihydrochloride, thionyl chloride is 1: 10～20.The consumption of described catalyzer DMF is 0.1%～0.5% of a thionyl chloride consumption.
8. method as claimed in claim 2, wherein in the step (2), described N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE, 4-[(4-methylpiperazine-1-yl) methyl] ratio of amount of substance of phenylformic acid dihydrochloride is 1: 1～2.Described organic solvent is a kind of in dimethyl formamide (DMF), chloroform, dimethyl sulfoxide (DMSO) (DMSO), acetonitrile, tetrahydrofuran (THF), methylene dichloride, benzene or the toluene.Described consumption of organic solvent is 4～10 times of amounts.Described pyridine consumption is 10%～30% of a consumption of organic solvent.Described heated and stirred is reflected under 10～200 ℃ of conditions carries out.
9. the HPLC quality control method of imatinib mesylate synthetic intermediate and the finished product, it is characterized in that: (it is an amount of to get perfluorooctane sulfonate to use the perfluoroetane sulfonic acid sodium solution, be dissolved in water, with acid for adjusting pH value to 2.0～3.0) as water, use methyl alcohol, acetonitrile mixed solution as organic phase, linear gradient elution.
10. method as claimed in claim 9, wherein the perfluorooctane sulfonate consumption is 0.2%～1%, described acid is a kind of in trifluoroacetic acid, formic acid, acetate, phosphoric acid, the hydrochloric acid.The ratio of described methyl alcohol, acetonitrile is 1: 0.5～2.Described linear gradient is: in the time of 0 minute, water-organic phase (42: 58) kept 15 minutes, in 10 minutes organic phase from 58% linear change to 87%, again in 5 minutes from 87% linear change to 58%.
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