CN103570676B - The preparation of imatinib mesylate α crystallization and pharmaceutical composition thereof - Google Patents
The preparation of imatinib mesylate α crystallization and pharmaceutical composition thereof Download PDFInfo
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Abstract
The invention belongs to medical art, relate to preparation and the pharmaceutical composition thereof of imatinib mesylate α crystallization.The invention provides the preparation method of imatinib mesylate α crystallization, the method reactions steps provided is short, simple to operate, the solvent toxicity used is little, and environmental pollution is little, and total recovery is high, cost is low, obtained product purity is high, and be applicable to industrialization large-scale operation, the degree of crystallinity of the imatinib mesylate α crystallization of gained is more than 60%.The advantage of the pharmaceutical composition containing imatinib mesylate α crystallization provided by the invention is: overcome imatinib mesylate α crystallization poor fluidity, thermodynamic instability and bibulous shortcoming, the composition levels prepared is even, and long-term placement is stablized by force.
Description
Technical field
The invention belongs to medical art, relate to the preparation of imatinib mesylate α crystallization particularly, and the pharmaceutical composition containing imatinib mesylate α crystallization.
Background technology
Imatinib mesylate (ImatinibMesylate), chemistry 4-[(4-methyl isophthalic acid-piperazinyl) methyl]-N-by name [4-methyl-3-[[4-(3-pyridyl)-2-pyrimidyl] is amino] phenyl] benzamide methanesulfonate, its molecular structural formula is as follows:
It is the activeconstituents of medicine Gleevec (Glivec), is used for the treatment of chronic myelocytic leukemia (CML) and gastrointestinal stromal tumor (GIST) by FDA approval.
Imatinib mesylate can exist, as disclosed α crystallization and the β crystallization of imatinib mesylate in Chinese patent ZL98807303.X with multiple different crystallized form; The ε crystallization of imatinib mesylate and the form of δ crystallization is disclosed in patent application CN200680030515.X; The multiple crystallized forms such as F, G, H, I, K crystallization of imatinib mesylate are disclosed in patent application CN200680044007.7; The amorphous form of imatinib mesylate is disclosed in patent application CN200880018651.6.
The α crystallization of imatinib mesylate belongs to metastable state crystallization, needle-like crystal, mobility is poor, there is certain water absorbability simultaneously, these characteristics make the preparation of this crystallization there is certain technical difficulty, further, these characteristics of α crystallization also limit and this crystalline is become solid dosage medicine preparation.
It is generally acknowledged, stable crystal form has higher fusing point and less solubleness compared with metastable-state crystal.In actual drug R&D process, in order to make the steady quality of medicine, need the drug crystal forms that using state is stable; And for most medicine, more wish can there be larger solubleness, to ensure that medicine plays good therapeutic action.
Therefore, the pharmaceutical preparation providing a kind of stable imatinib mesylate containing α crystallization is badly in need of in this area, how in the preparation process of imatinib α crystallization and preparation thereof, overcome the defect of the stability of α crystallization own and physical properties aspect, the product meeting the α crystallization of the drug standard that preparation is applicable to suitability for industrialized production is crucial especially.
Summary of the invention
One aspect of the present invention relates to a kind of preparation method of imatinib mesylate α crystallization, and it comprises the steps:
4-[(4-methylpiperazine-1-yl) methyl] the phenylformic acid dihydrochloride of (a) formula I and sulfur oxychloride reaction, react complete, reaction mixture is cooled to less than 10 DEG C, filter, obtain 4-[(4-methylpiperazine-1-yl) methyl] the Benzoyl chloride dihydrochloride of formula II;
B N-(5-amino-2-methyl phenyl)-4-(3-the pyridyl)-2-PYRIMITHAMINE of () formula III and 4-[(4-methylpiperazine-1-yl) methyl] the Benzoyl chloride dihydrochloride of formula II react in pyridine, react complete, add water in reaction mixture, evaporated under reduced pressure, adds water in gained solid, and the ammoniacal liquor with 25% regulates pH=7.5 ~ 8.0, ethyl acetate is added in mixture, stirring is spent the night, and filters, obtains imatinib;
C () imatinib and methylsulfonic acid react in dehydrated alcohol, react complete, add the α crystalline seed of imatinib mesylate, stirring and crystallizing in reaction mixture, filter, obtain imatinib mesylate α crystallization.
As preferably, in step (a), the mass ratio of 4-[(4-methylpiperazine-1-yl) methyl] phenylformic acid dihydrochloride and sulfur oxychloride is 1: 13.47; Reaction is under reflux conditions carried out.
As preferably, the mass ratio of formula II compound in step (b) and N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE is 1: 0.75; The mass ratio of formula II compound and pyridine is 1: 5.86; Temperature of reaction is about 25 DEG C.
As preferably, the imatinib in step (c) and the mass ratio of methylsulfonic acid are 1: 0.19, and the mass ratio of imatinib and total ethanol is 1: 10.9; Reaction is under reflux conditions carried out; Crystallization Process carries out at about 25 DEG C.
In a specific embodiment of the present invention, the preparation method of imatinib mesylate α crystallization, it comprises the steps:
A 4-[(4-methylpiperazine-1-yl) methyl] the phenylformic acid dihydrochloride of () formula I and sulfur oxychloride mixing, be heated to about 78 DEG C, back flow reaction 31 hours, stop heating, cool to about 0 DEG C, filter, obtain formula II compound;
N-(5-amino-2-methyl phenyl)-4-(3-the pyridyl)-2-PYRIMITHAMINE of (b) formula III and pyridine mixing, stir 20 minutes, dissolve, cool to about 0 DEG C, add formula II compound, control reacting liquid temperature below 20 DEG C, about 25 DEG C are warming up to after reinforced, react about 8 hours, add water, about 65 DEG C evaporated under reduced pressure, add water, be heated to about 50 DEG C, stirring and dissolving, be cooled to about 10 DEG C, add water stirring about 10 minutes, pH=7.5 ~ 8.0 are regulated with 25% ammoniacal liquor, stir 5 hours, add ethyl acetate stirring again to spend the night, filter, obtain imatinib,
C () dehydrated alcohol and imatinib mixing, be warming up to about 60 DEG C, stir 1 hour, drip the mixed solution of methylsulfonic acid and dehydrated alcohol, drip to finish and be warming up to about 78 DEG C, reflux about 20 minutes, about Temperature fall to 60 DEG C, add imatinib mesylate α crystalline seed, stirring and crystallizing, when being cooled to about 25 DEG C, then continues stirring and crystallizing 0.5 hour, filter, obtain imatinib mesylate α crystallization.
Wherein, in step (a), the mass ratio of 4-[(4-methylpiperazine-1-yl) methyl] phenylformic acid dihydrochloride and sulfur oxychloride is 1: 13.47.
The mass ratio of formula II compound in step (b) and N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE is 1: 0.75; The mass ratio of formula II compound and pyridine is 1: 5.86.
Imatinib in step (c) and the mass ratio of methylsulfonic acid are 1: 0.19, and the mass ratio of imatinib and total ethanol is 1: 10.9.
The method that the crystal seed of imatinib mesylate α crystallization can provide according to prior art obtains, and adds speed and purity that crystal seed can improve crystallization, and it is favourable for particularly adding the higher crystal seed of degree of crystallinity for the purity of crystallization.
The advantage preparing the method for imatinib mesylate α crystallization provided by the invention is: reactions steps is short, simple to operate, and the solvent toxicity of use is little, and environmental pollution is little, and total recovery is high, and cost is low, and obtained product purity is high, is applicable to industrialization large-scale operation.The degree of crystallinity of the imatinib mesylate α crystallization of gained more than 60%, preferably more than 70, more preferably more than 80%, most preferably more than 90%.The imatinib mesylate α crystallization prepared with aforesaid method has higher chemical purity and degree of crystallinity, is particularly suitable as bulk drug pharmaceutical compositions.
Further aspect of the present invention provides a kind of pharmaceutical composition containing imatinib mesylate α crystallization, and it contains following composition: imatinib mesylate α crystallization, Microcrystalline Cellulose, polyvinylpolypyrrolidone, Magnesium Stearate and micropowder silica gel.Except mentioned component, pharmaceutical composition can also containing other pharmaceutical excipients such as correctivess.
Pharmaceutical composition containing imatinib mesylate α crystallization of the present invention, wherein in mass, the amount of micropowder silica gel is 1%-10%, is preferably 3%-6%.
Pharmaceutical composition containing imatinib mesylate α crystallization of the present invention is tablet or capsule, is preferably capsule.
In a specific embodiment of the present invention, capsule preparations containing imatinib mesylate α crystallization of the present invention consists of the following composition: imatinib mesylate α crystallization, Microcrystalline Cellulose, polyvinylpolypyrrolidone, Magnesium Stearate and micropowder silica gel, wherein in mass, the amount of micropowder silica gel is 1%-10%, is preferably 3%-6%.
In a specific embodiment of the present invention, capsule preparations containing imatinib mesylate α crystallization of the present invention consists of the following composition: the imatinib mesylate α crystallization of 51.5%-53.5% in mass, the Microcrystalline Cellulose of 38.5%-39.6%, the polyvinylpolypyrrolidone of 3.9%-4.0%, the Magnesium Stearate of 0.4%-0.5% and the micropowder silica gel of 3%-5.5%.
Further aspect of the present invention provides a kind of preparation method of the pharmaceutical composition containing imatinib mesylate α crystallization, and it comprises the step of micropowder silica gel, Microcrystalline Cellulose, polyvinylpolypyrrolidone drying.
In a specific embodiment of the present invention, the preparation method of the pharmaceutical composition containing imatinib mesylate α crystallization, it comprises the steps:
(1) micropowder silica gel, Microcrystalline Cellulose, polyvinylpolypyrrolidone being dried to moisture at 105 DEG C is about 1.0, and crosses 60 mesh sieves respectively;
(2) take imatinib mesylate α crystallization, micropowder silica gel, Microcrystalline Cellulose and polyvinylpolypyrrolidone according to recipe quantity, mix;
(3) material under step 2 and recipe quantity Magnesium Stearate are mixed;
(4) detect intermediates content and moisture, moisture controlled is between 1.5-2.0;
(5) according to intermediates content filled capsules.
The advantage of the pharmaceutical composition containing imatinib mesylate α crystallization provided by the invention is: overcome imatinib mesylate α crystallization poor fluidity, thermodynamic instability and bibulous shortcoming, the composition levels prepared is even, and long-term placement is stablized by force.
Detect the content of moisture and intermediate in the present invention, make with the following method.
1. water content detection
1.1 reagent and test solution: anhydrous methanol, karl Fischer reagent.
1.2 instruments and apparatus: electronic analytical balance, moisture content tester.
1.3 working method: the fine powder got under assay item is about 200mg, detect according to Q/SOP08000086 " aquametry working specification " first method A.
2. intermediates content measures
2.1 instruments and apparatus: high performance liquid chromatograph, measuring bottle, electronic analytical balance, acidometer, ultrasonic apparatus, whizzer, octadecylsilane chemically bonded silica post.
2.2 reagent and test solution: imatinib mesylate reference substance, perfluorooctane sulfonate, phosphoric acid, methyl alcohol, 0.1mol/L hydrochloric acid soln.
2.3 moving phases: get perfluorooctane sulfonate 7.5g, the 1000ml that adds water dissolves, and is mobile phase A with phosphoric acid adjust pH to 2.5, and methyl alcohol is Mobile phase B, and according to the form below carries out linear gradient elution.
2.4 need testing solutions: get the trial-product fine powder appropriate (being about equivalent to imatinib 50mg) mixed, accurately weighed, put in 100ml measuring bottle, solubilizing agent 80ml, supersound process 10 minutes, lets cool, and is diluted to scale, shake up, get above-mentioned solution, put in tool plug centrifuge tube, centrifugal to clarification, get supernatant liquor, as need testing solution.(preparing two parts)
2.5 reference substance solution: the imatinib mesylate reference substance being dried to constant weight of learning from else's experience 105 DEG C is about 15mg, accurately weighed, and put in 25ml measuring bottle, solubilizing agent dissolves and is diluted to scale, in contrast product solution.(preparing two parts altogether)
Hydrochloric acid soln-the methyl alcohol (4: 6) of 2.6 solvents: 0.1mol/L (9 → 1000).
2.7 chromatographic conditions: take octadecylsilane chemically bonded silica as weighting agent, determined wavelength is 267nm, and column temperature is 40 DEG C; Flow velocity is 1.2ml/min.
2.8 working method: detect according to Q/SOP08000063 " high performance liquid chromatography working specification ", precision measures need testing solution and reference substance solution 10 μ l injection liquid chromatography respectively, record color atlas; By external standard method with calculated by peak area, to obtain final product.(conversion factor of imatinib mesylate and imatinib is 0.837)
2.9 calculation formula:
In formula: 0.99861---reference substance purity;
F
on averagethe mean value of-correction factor;
A
contrast---the peak area of reference substance solution main peak;
A
sample---the peak area of need testing solution main peak;
W
contrast---the sample weighting amount (mg) of reference substance;
W
sample---the sample weighting amount (mg) of trial-product;
Accompanying drawing explanation
The X-ray diffracting spectrum of Fig. 1: imatinib mesylate α crystallization
Embodiment
If no special instructions, the solvent used in the present invention is all commercially available unprocessed direct use.The object of embodiment is in order to content of the present invention is described better, does not mean that and limits scope of the present invention.
The preparation of embodiment 1 imatinib mesylate α crystallization
(1) synthesis of 4-[(4-methylpiperazine-1-yl) methyl] Benzoyl chloride dihydrochloride (formula II)
Reaction formula:
Charging capacity:
In the reactor of 200L, add 4-[(4-methylpiperazine-1-yl) methyl] phenylformic acid dihydrochloride and sulfur oxychloride, be heated to about 78 DEG C, back flow reaction 31 hours, it is complete that TLC shows (developping agent: ethanol/methylene/triethylamine=1/10/1, Rf ≈ 0.5) raw material reaction.Stop heating, cool to about 0 DEG C, filter, filter cake sherwood oil (60 DEG C ~ 90 DEG C) washing 2 times, about 25 DEG C drying under reduced pressure 5 hours, obtain white solid, yield 90.4%, fusing point 318 ~ 325 DEG C.
(2) synthesis of imatinib free alkali
Reaction formula:
Feed intake:
In 100L reactor, add pyridine and N-(5-amino-2-methyl phenyl)-4-(3-pyridine)-2-PYRIMITHAMINE, stir 20 minutes, dissolve, cool to about 0 DEG C, add formula II compound, control reacting liquid temperature below 20 DEG C.Be warming up to about 25 DEG C after reinforced, react about 8 hours, it is complete that TLC shows (methylene chloride/methanol/triethylamine=40/1/1, Rf ≈ 0.8) raw material reaction.Add 8kg water, about 65 DEG C evaporated under reduced pressure.Add 30kg water, be heated to about 50 DEG C, stirring and dissolving, be transferred in 200L reactor.Be cooled to about 10 DEG C, then add 50kg water and stir about 10 minutes, regulate pH=7.5 ~ 8.0 with 25% ammoniacal liquor, stirs 5 hours, then add the stirring of 35kg ethyl acetate and spend the night.Filter, filter cake 80kg purified water stirring at room temperature 5 hours, filter, filter cake, in 75 DEG C of dryings 10 hours, obtains faint yellow solid, yield 92.7%, fusing point: 221 ~ 223 DEG C, [M+1] +=494.3, HPLC:99.55%.
(3) synthesis of imatinib mesylate α crystallization
Reaction formula:
Feed intake:
In 200L reactor, add 73kg dehydrated alcohol and 8.5kg imatinib free alkali, be warming up to about 60 DEG C and stir 1 hour.Drip the mixed solution of 1.65kg methylsulfonic acid and 20kg dehydrated alcohol, drip to finish and be warming up to about 78 DEG C, reflux about 20 minutes.Nitrogen press filtration, in another 200 liters of dry reaction stills, is stirred, Temperature fall to 60 DEG C left and right interpolation α crystal seed, stirring and crystallizing.When being cooled to about 25 DEG C, continue stirring and crystallizing again 0.5 hour, filter, a small amount of cold washing with alcohol of filter cake, 60 DEG C of dryings 10 hours, obtain pale yellow crystals shape solid, yield 92.6%, fusing point: 221 ~ 229 DEG C, the visible Fig. 1 of X-ray powder diffraction pattern, [M+1] +=494.3, HPLC:99.9%.
In the purity testing of imatinib mesylate, determine that chromatographic condition is as follows:
Instrument: Shimadzu LC-20AD type high performance liquid chromatograph
Detector: Shimadzu SPD-20A ultraviolet absorption detector
Data handling system: LCsolutionVersion1.21SP1
Chromatographic column: WatersSunFireTMC18 (5 μm, 4.6mm × 250mm)
Moving phase: A: ion pair reagent: perfluorooctane sulfonate 7.5g, the 1000ml that adds water dissolves, with phosphoric acid adjust pH to 2.5.
B: methyl alcohol
Gradient elution is carried out according to following program:
Embodiment 2: the preparation containing imatinib mesylate α crystallization capsule
Table 2.1 imatinib mesylate α crystallization capsule prescription
(1) micropowder silica gel, Microcrystalline Cellulose, polyvinylpolypyrrolidone being dried to moisture at 105 DEG C is about 1.0, and crosses 60 mesh sieves respectively;
(2) take imatinib mesylate, micropowder silica gel, Microcrystalline Cellulose and polyvinylpolypyrrolidone according to recipe quantity, mix;
(3) material under step 2 and recipe quantity Magnesium Stearate are mixed;
(4) detect intermediates content and moisture, moisture controlled is between 1.5-2.0;
(5) according to intermediates content filled capsules.
The preparation of the capsule of embodiment 3 containing imatinib mesylate α crystallization
Table 3.1 α crystalline imatinib mesylate capsule prescription
(1) micropowder silica gel, Microcrystalline Cellulose, polyvinylpolypyrrolidone being dried to moisture at 105 DEG C is about 1.0, and crosses 60 mesh sieves respectively;
(2) take imatinib mesylate, micropowder silica gel, Microcrystalline Cellulose and polyvinylpolypyrrolidone according to recipe quantity, mix;
(3) material under step 2 and recipe quantity Magnesium Stearate are mixed;
(4) detect intermediates content and moisture, moisture controlled is between 1.5-2.0;
(5) according to intermediates content filled capsules.
The stability study of the capsule of embodiment 4 containing imatinib mesylate α crystallization
1. sample source: each three batches of the imatinib mesylate capsule preparing specification and 100mg specification according to the method for embodiment 2
Lot number: 090701,090702,090703, specification: 50mg, in batches: 40,000/batches
Lot number: 090704,090705,090706, specification: 100mg, in batches: 40,000/batches
Packaging: aluminum-plastic packaged
2. investigate project: proterties, moisture, dissolution rate, related substance, content, crystallization.
3. imatinib mesylate capsule stability research
3.1 accelerated tests:
By imatinib mesylate capsule by commercially available prod packaging, temperature 40 DEG C ± 2 DEG C, place 6 months under the condition of relative humidity 75% ± 5%, in the 1st, 2,3, June samples detection respectively, and compares with 0 day detected result.Investigation the results are shown in Table 4.1, table 4.2.
3.2 test-results
Two each three batch samples of specification are temperature 40 DEG C ± 2 DEG C, and under the condition of relative humidity 75% ± 5%, place after 6 months, each test items such as related substance, crystallization, dissolution rate, content, moisture content, compared with 0 day initial results, all do not have considerable change.
These results suggest that, the pharmaceutical composition stability containing imatinib mesylate α crystallization of the present invention is better, and stability and water absorbability can reach requirement.Overcome imatinib mesylate α crystalline stability difference and bibulous defect.
Table 4.1 imatinib mesylate capsule (specification: 50mg) accelerated test investigates result
Table 4.2 imatinib mesylate capsule (specification: 100mg) accelerated test investigates result
The uniformity of dosage units of the capsule intermediate of embodiment 5 containing imatinib mesylate α crystallization and moisture content research
1 sample preparation and sampling
(1) micropowder silica gel, Microcrystalline Cellulose, polyvinylpolypyrrolidone being dried to moisture at 105 DEG C is about 1.0, and crosses 60 mesh sieves respectively;
(2) take imatinib mesylate 4.78kg, micropowder silica gel 262.4g, Microcrystalline Cellulose 3.56kg and polyvinylpolypyrrolidone 360g, mix;
(3) material under step 2 and Magnesium Stearate 40g are mixed;
(4) random sampling 10 point in step (3) intermediate mixture, often some sampling 6g, is No. 1-10 by sample number into spectrum, measures content and weight loss on drying.
2 content and weight loss on drying
| Sample | Content (in imatinib) | Weight loss on drying |
| 1 | 43.8％ | 2.4％ |
| 2 | 44.2％ | 2.5％ |
| 3 | 43.7％ | 2.5％ |
| 4 | 44.2％ | 2.5％ |
| 5 | 44.2％ | 2.5％ |
| 6 | 43.7％ | 2.5％ |
| 7 | 43.3％ | 2.6％ |
| 8 | 44.4％ | 2.6％ |
| 9 | 44.0％ | 2.5％ |
| 10 | 43.6％ | 2.5％ |
| Analyze | rsd 0.2％ |
Claims (4)
1. a preparation method for imatinib mesylate α crystallization, it comprises the steps:
4-[(4-methylpiperazine-1-yl) methyl] the phenylformic acid dihydrochloride of (a) formula I and sulfur oxychloride reaction, react complete, reaction mixture is cooled to less than 10 DEG C, filter, obtain 4-[(4-methylpiperazine-1-yl) methyl] the Benzoyl chloride dihydrochloride of formula II;
B N-(5-amino-2-methyl phenyl)-4-(3-the pyridyl)-2-PYRIMITHAMINE of () formula III and 4-[(4-methylpiperazine-1-yl) methyl] the Benzoyl chloride dihydrochloride of formula II react in pyridine, react complete, add water in reaction mixture, evaporated under reduced pressure, adds water in gained solid, and the ammoniacal liquor with 25% regulates pH=7.5 ~ 8.0, ethyl acetate is added in mixture, stirring is spent the night, and filters, obtains imatinib;
C () imatinib and methylsulfonic acid react in dehydrated alcohol, react complete, in reaction mixture, add the α crystalline seed of imatinib mesylate, stirring and crystallizing, filter, obtain imatinib mesylate α crystallization, wherein, the mass ratio of imatinib and methylsulfonic acid is 1:0.19, and the mass ratio of imatinib and total ethanol is 1:10.9, reaction is under reflux conditions carried out, and Crystallization Process carries out at about 25 DEG C
2. the preparation method of claim 1, wherein, in step (a), the mass ratio of 4-[(4-methylpiperazine-1-yl) methyl] phenylformic acid dihydrochloride and sulfur oxychloride is 1:13.47, and reaction is under reflux conditions carried out.
3. the preparation method of claim 1, wherein, the mass ratio of formula II compound in step (b) and N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE is 1:0.75, the mass ratio of formula II compound and pyridine is 1:5.86, and temperature of reaction is about 25 DEG C.
4. a preparation method for imatinib mesylate α crystallization, it comprises the steps:
A 4-[(4-methylpiperazine-1-yl) methyl] the phenylformic acid dihydrochloride of () formula I and sulfur oxychloride mixing, be heated to about 78 DEG C, back flow reaction 31 hours, stop heating, cool to about 0 DEG C, filter, obtain formula II compound;
N-(5-amino-2-methyl phenyl)-4-(3-the pyridyl)-2-PYRIMITHAMINE of (b) formula III and pyridine mixing, stir 20 minutes, dissolve, cool to about 0 DEG C, add formula II compound, control reacting liquid temperature below 20 DEG C, about 25 DEG C are warming up to after reinforced, react about 8 hours, add water, about 65 DEG C evaporated under reduced pressure, add water, be heated to about 50 DEG C, stirring and dissolving, be cooled to about 10 DEG C, add water stirring about 10 minutes, pH=7.5 ~ 8.0 are regulated with 25% ammoniacal liquor, stir 5 hours, add ethyl acetate stirring again to spend the night, filter, obtain imatinib,
C () dehydrated alcohol and imatinib mixing, be warming up to about 60 DEG C, stir 1 hour, drip the mixed solution of methylsulfonic acid and dehydrated alcohol, drip to finish and be warming up to about 78 DEG C, reflux about 20 minutes, about Temperature fall to 60 DEG C, add imatinib mesylate α crystalline seed, stirring and crystallizing, when being cooled to about 25 DEG C, then continues stirring and crystallizing 0.5 hour, filter, obtain imatinib mesylate α crystallization;
Wherein, in step (a), the mass ratio of 4-[(4-methylpiperazine-1-yl) methyl] phenylformic acid dihydrochloride and sulfur oxychloride is 1:13.47;
The mass ratio of formula II compound in step (b) and N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE is 1:0.75; The mass ratio of formula II compound and pyridine is 1:5.86;
Imatinib in step (c) and the mass ratio of methylsulfonic acid are 1:0.19, and the mass ratio of imatinib and total ethanol is 1:10.9.
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| CN101573350A (en) * | 2006-04-27 | 2009-11-04 | 西科尔公司 | Polymorphic forms of imatinib mesylate and processes for preparation of novel crystalline forms as well as amorphous and form alpha |
| CN102040587A (en) * | 2009-10-26 | 2011-05-04 | 韩南银 | Preparation method of imatinib mesylate |
| CN102617552A (en) * | 2012-04-06 | 2012-08-01 | 江南大学 | Crystallizing method for preparing alpha crystal form methanesulfonic acid imatinib |
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| CN101573350A (en) * | 2006-04-27 | 2009-11-04 | 西科尔公司 | Polymorphic forms of imatinib mesylate and processes for preparation of novel crystalline forms as well as amorphous and form alpha |
| CN102040587A (en) * | 2009-10-26 | 2011-05-04 | 韩南银 | Preparation method of imatinib mesylate |
| CN102617552A (en) * | 2012-04-06 | 2012-08-01 | 江南大学 | Crystallizing method for preparing alpha crystal form methanesulfonic acid imatinib |
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| 甲磺酸伊马替尼的合成;李铭东等;《中国药学杂志》;20080228;第43卷(第3期);第228-229页 * |
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