CN105503825A - Preparation method of imatinib mesylate beta-form crystal - Google Patents
Preparation method of imatinib mesylate beta-form crystal Download PDFInfo
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- CN105503825A CN105503825A CN201510939648.XA CN201510939648A CN105503825A CN 105503825 A CN105503825 A CN 105503825A CN 201510939648 A CN201510939648 A CN 201510939648A CN 105503825 A CN105503825 A CN 105503825A
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- preparation
- imatinib mesylate
- imatinib
- crystal
- beta crystal
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a preparation method of an imatinib mesylate beta-form crystal. The method comprises the steps that imatinib alkali is suspended in organic solvent and cooled to 0-5 DEG C under the protection of nitrogen, a beta-form crystal is added, and methylsulfonic acid is dropwise added under the condition of heat preservation; after methylsulfonic acid is completely dropwise added, the temperature is raised to 20-30 DEG C, heat preservation crystallization is conducted for 2-6 h, and a white solid product is obtained after suction filtration and drying are conducted. According to the preparation method of the imatinib mesylate beta-form crystal, a one-pot method is adopted to direct prepare imatinib mesylate with the beta crystal form, other crystal forms or amorphous crystal transformation is not needed in the preparation process, the preparation technology is simple, the reaction conditions are mild, posttreatment is easy, the product purity is good, and the yield is high.
Description
Technical field
The present invention relates to a kind of preparation method of imatinib mesylate beta crystal, belong to medical art.
Background technology
Imatinib mesylate, chemical name is: 4-[(4-methyl isophthalic acid-piperazine) methyl]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] is amino] phenyl]-aniline mesylate, molecular formula is C
29h
31n
7oCH
4sO
3, molecular weight is 589.7.Structural formula is as follows:
Imatinib mesylate is the antitumour drug of Novartis Co., Ltd of Switzerland exploitation, is mainly used in leukemic treatment.Disclosed crystal formation has several crystal formation such as α, β, F, G, H, I, K at present, but other application are few except α, beta crystal.The imatinib mesylate that Novartis Co., Ltd of current Switzerland uses is beta crystal, introduce according in its patent CN1264375A, the advantages such as the imatinib mesylate of beta crystal has other crystal formation good fluidities relatively, and the more stable and water absorbability of thermodynamics is little, are convenient to store and processing.But the preparation method of disclosed imatinib mesylate beta crystal is less at present, and the imatinib mesylate introduced in patent CN1264375A prepares beta crystal method, and need to add water in preparation process solvent, crystallization time is long, complex process, and yield is not high.Patent CN102617549A describes a kind of method without the need to introducing beta crystal JZPD capsule imatinib mesylate beta crystal, but the method yield is lower.The preparation method of the imatinib mesylate beta crystal of above patent Introduction prepares beta crystal, complex operation by other crystal formations or unformed turn of crystalline substance, and yield losses is larger.
Summary of the invention
For the shortcoming existed in above preparation method, the invention provides a kind of preparation method of imatinib mesylate beta crystal.The method adopts imatinib alkali and methylsulfonic acid salify crystallization directly to obtain imatinib mesylate beta crystal, and the method preparation technology is simple, and product yield is high.
Technical scheme of the present invention is: a kind of preparation method of imatinib mesylate beta crystal, is characterized in that, by suspending imatinib base in organic solvent, nitrogen protection borehole cooling to 0 ~ 5 DEG C, add β type crystal seed, and insulation drips methylsulfonic acid; Dropwise, be warming up to 20 ~ 30 DEG C of insulation crystallization 2 ~ 6h, then after suction filtration, drying, obtain white solid product.
Above-mentioned organic solvent is C
2-5aliphatic alcohols (preferred Virahol, isopropylcarbinol), or C
2-5ethers (preferred tetrahydrofuran (THF), methyl tert-butyl ether), or DMF, N,N-dimethylacetamide, acetone, any one or any two or more mixed solvent in acetonitrile equal solvent.
Above-mentioned consumption of organic solvent is 5 ~ 15ml/g (in imatinib alkali), preferably 5 ~ 10ml/g.
The add-on of above-mentioned imatinib mesylate β type crystal seed is 0.1 ~ 1.0wt% (in imatinib alkali).
The mol ratio of above-mentioned methylsulfonic acid and imatinib alkali is 1.0 ~ 1.1:1.
The time for adding of above-mentioned methylsulfonic acid is 20-30 minute.
The invention has the beneficial effects as follows:
1, preparation method of the present invention is water-less environment, and under water-less environment, imatinib mesylate is more stable, should not degrade.
2, the present invention adopts " one kettle way " directly obtained beta crystal imatinib mesylate, need not other crystal formations or unformed turn of crystalline substance obtain, preparation technology is simple, reaction conditions is gentle, and aftertreatment is simple, the purity good (purity >=99.95%) of product, yield high (yield >=98.0%).
Accompanying drawing explanation
Fig. 1 is the X-diffracting spectrum of the imatinib mesylate beta crystal in patent CN1264375A;
Fig. 2 is the X-diffracting spectrum of the imatinib mesylate beta crystal that the embodiment of the present invention 1 prepares.
Embodiment
Below in conjunction with specific embodiment, the present invention is further illustrated, but protection scope of the present invention is not limited thereto:
Embodiment 1:
Be suspended in 800ml acetone by imatinib alkali 100g, nitrogen protection borehole cooling to 0 DEG C, add 0.5g β type crystal seed, insulation drips 20g methylsulfonic acid, within 30 minutes, dropwises; Dropwise, be warming up to 20 DEG C ~ 30 DEG C insulation crystallization 4h, then after suction filtration, drying, obtain white solid product 118.0g, yield 98.8%, quality 99.95%.
As shown in Figure 2, the relative line intensities of the imatinib mesylate beta crystal in patent CN1264375A as shown in Figure 1 for the X-diffracting spectrum of the imatinib mesylate beta crystal that the embodiment of the present invention 1 prepares.Under the θ of refraction angle 2, the relative line intensities of the x-ray diffraction pattern of the present invention and documents is as shown in table 1, and the relative line intensities that the spectral line in x-ray diffraction pattern of the present invention has is 20 or higher.The X-diffraction data of the imatinib mesylate beta crystal in the imatinib mesylate beta crystal prepared by the present invention and patent CN1264375A is contrasted, and the crystal formation demonstrating imatinib mesylate prepared by the present invention is beta crystal.
Table 1 the present invention compares with the relative line intensities of the x-ray diffraction pattern of documents
Embodiment 2:
Be suspended in by imatinib alkali 1.0Kg in the mixed solvent (2.5L ethanol and 2.5L Virahol) of 5L ethanol and Virahol, nitrogen protection borehole cooling to 5 DEG C, adds 2g β type crystal seed, and insulation drips 199g methylsulfonic acid, within 25 minutes, dropwises; Dropwise, be warming up to 20 DEG C ~ 30 DEG C insulation crystallization 6h, then after suction filtration, drying, obtain white solid product 1.175Kg, yield 98.3%, quality 99.96%.
Embodiment 3:
Be suspended in by imatinib alkali 1.0Kg in the mixed solvent (3L acetonitrile and 3L ethanol) of 6L acetonitrile and ethanol, nitrogen protection borehole cooling to 5 DEG C, adds 5g β type crystal seed, and insulation drips 205g methylsulfonic acid, within 20 minutes, dropwises; Dropwise, be warming up to 20 DEG C ~ 30 DEG C insulation crystallization 6h, then after suction filtration, drying, obtain white solid product 1.179Kg, yield 98.7%, quality 99.96%.
Embodiment 4:
Be suspended in 100ml tetrahydrofuran solvent by imatinib alkali 10g, nitrogen protection borehole cooling to 2 DEG C, add 0.05g β type crystal seed, insulation drips 2.08g methylsulfonic acid, within 25 minutes, dropwises; Dropwise, be warming up to 20 DEG C ~ 30 DEG C insulation crystallization 3h, then after suction filtration, drying, obtain white solid product 11.72g, yield 98.1%, quality 99.95%.
Claims (8)
1. a preparation method for imatinib mesylate beta crystal, is characterized in that, by suspending imatinib base in organic solvent, nitrogen protection borehole cooling to 0 ~ 5 DEG C, add β type crystal seed, and insulation drips methylsulfonic acid; Dropwise, be warming up to 20 ~ 30 DEG C of insulation crystallization 2 ~ 6h, then after suction filtration, drying, obtain white solid product.
2. the preparation method of a kind of imatinib mesylate beta crystal as claimed in claim 1, is characterized in that, in imatinib alkali, the add-on of described imatinib mesylate β type crystal seed is 0.1 ~ 1.0wt%.
3. the preparation method of a kind of imatinib mesylate beta crystal as claimed in claim 1, is characterized in that, the mol ratio of described methylsulfonic acid and imatinib alkali is 1.0 ~ 1.1:1.
4. as the preparation method of a kind of imatinib mesylate beta crystal in claim 1-3 as described in any one, it is characterized in that, described organic solvent is C
2-5aliphatic alcohols, C
2-5ethers, DMF, N,N-dimethylacetamide, acetone, any one or any two or more mixed solvent in acetonitrile.
5. the preparation method of a kind of imatinib mesylate beta crystal as claimed in claim 4, is characterized in that, described C
2-5aliphatic alcohols organic solvent be Virahol or isopropylcarbinol.
6. the preparation method of a kind of imatinib mesylate beta crystal as claimed in claim 4, is characterized in that, described C
2-5ether organic solvent be tetrahydrofuran (THF) or methyl tert-butyl ether.
7. the preparation method of a kind of imatinib mesylate beta crystal as claimed in claim 4, is characterized in that, in imatinib alkali, described consumption of organic solvent is 5 ~ 15ml/g.
8. the preparation method of a kind of imatinib mesylate beta crystal as claimed in claim 7, is characterized in that, in imatinib alkali, described consumption of organic solvent is 5 ~ 10ml/g.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510939648.XA CN105503825B (en) | 2015-12-16 | 2015-12-16 | A kind of preparation method of imatinib mesylate beta crystal |
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| CN201510939648.XA CN105503825B (en) | 2015-12-16 | 2015-12-16 | A kind of preparation method of imatinib mesylate beta crystal |
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| CN105503825A true CN105503825A (en) | 2016-04-20 |
| CN105503825B CN105503825B (en) | 2019-01-11 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1264375A (en) * | 1997-07-18 | 2000-08-23 | 诺瓦提斯公司 | Crystal modification of N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
| CN102617549A (en) * | 2012-03-02 | 2012-08-01 | 瑞阳制药有限公司 | Method for preparing imatinib mesylate beta crystalline form |
-
2015
- 2015-12-16 CN CN201510939648.XA patent/CN105503825B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1264375A (en) * | 1997-07-18 | 2000-08-23 | 诺瓦提斯公司 | Crystal modification of N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
| CN102617549A (en) * | 2012-03-02 | 2012-08-01 | 瑞阳制药有限公司 | Method for preparing imatinib mesylate beta crystalline form |
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| CN105503825B (en) | 2019-01-11 |
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Effective date of registration: 20200224 Address after: No. 10678, Wenliang Road, Dongjia street, Licheng District, Jinan City, Shandong Province Patentee after: Shandong Anxin Pharmaceutical Co., Ltd Address before: 250105 No. 849 Dong Jia town, Licheng District, Shandong, Ji'nan Patentee before: QILU TIANHE PHARMACEUTICAL Co.,Ltd. |