CN103570673B - A kind of preparation method of imatinib mesylate alfa crystal form - Google Patents
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- 239000013078 crystal Substances 0.000 title claims abstract description 42
- 229960003685 imatinib mesylate Drugs 0.000 title claims abstract description 37
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 72
- 229960002411 imatinib Drugs 0.000 claims abstract description 27
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000005517 L01XE01 - Imatinib Substances 0.000 claims abstract description 25
- HJERCYPQHAGQIR-UHFFFAOYSA-N C(Cl)(Cl)Cl.CS(=O)(=O)O Chemical compound C(Cl)(Cl)Cl.CS(=O)(=O)O HJERCYPQHAGQIR-UHFFFAOYSA-N 0.000 claims abstract 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 44
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 21
- 239000011259 mixed solution Substances 0.000 claims description 15
- 239000003513 alkali Substances 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 238000000034 method Methods 0.000 abstract description 12
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- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
- 238000000113 differential scanning calorimetry Methods 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 3
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 3
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 3
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 3
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 3
- 125000005233 alkylalcohol group Chemical group 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 2
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 2
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
- 238000007707 calorimetry Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
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- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
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- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
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- 238000001727 in vivo Methods 0.000 description 1
- 230000006882 induction of apoptosis Effects 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- 150000003839 salts Chemical group 0.000 description 1
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- 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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Abstract
本发明涉及药物合成领域，公开了一种甲磺酸伊马替尼α晶型的制备方法。本发明所述制备方法为将伊马替尼碱与氯仿混合，与甲磺酸氯仿混合液反应，制得甲磺酸伊马替尼α晶型。本发明操作简单，收率高，工艺稳定，适合于甲磺酸伊马替尼α晶型的工业化生产。The invention relates to the field of drug synthesis, and discloses a preparation method of imatinib mesylate α crystal form. The preparation method of the invention is to mix the imatinib base with chloroform and react with the chloroform mesylate mixture to prepare the α crystal form of the imatinib mesylate. The invention has the advantages of simple operation, high yield and stable process, and is suitable for the industrialized production of the alpha crystal form of imatinib mesylate.
Description
技术领域technical field
本发明涉及药物合成领域，具体的说是涉及一种甲磺酸伊马替尼α晶型的制备方法。The invention relates to the field of drug synthesis, in particular to a preparation method of imatinib mesylate α crystal form.
背景技术Background technique
甲磺酸伊马替尼，英文名：Imatinib Mesilate，化学名：4-[(4-甲基-1-哌嗪)甲基]-N-[4-甲基-3-[[4-(3-吡啶)-2-嘧啶]氨基]苯基]-苯胺甲磺酸盐，分子式为C29H31N7O·CH4SO3，分子量为589.71，结构式如下：Imatinib mesilate, English name: Imatinib Mesilate, chemical name: 4-[(4-methyl-1-piperazine)methyl]-N-[4-methyl-3-[[4-( 3-pyridine)-2-pyrimidine]amino]phenyl]-aniline methanesulfonate, the molecular formula is C 29 H 31 N 7 O CH 4 SO 3 , the molecular weight is 589.71, and the structural formula is as follows:
。 .
它是瑞士诺华（Novartis）公司研究开发的一个信号转导抑制剂，于2001年5月10日在美国首次上市，目前已在美国、欧盟、日本和中国在内的60余个国家上市。It is a signal transduction inhibitor researched and developed by Novartis, Switzerland. It was first launched in the United States on May 10, 2001, and is currently listed in more than 60 countries including the United States, the European Union, Japan and China.
研究发现，甲磺酸伊马替尼在体内外均可在细胞水平上抑制Bcr-Abl酪氨酸激酶，能选择性抑制Bcr-Abl阳性细胞系细胞和Ph染色体阳性的慢性粒细胞白血病、急性淋巴细胞白血病病人的新鲜细胞的增殖和诱导其凋亡。此外，它还可抑制血小板衍化生长因子（PDGF）受体、干细胞因子(SCF)，c-Kit受体的酪氨酸激酶，从而抑制由PDGF和干细胞因子介导的细胞行为。甲磺酸伊马替尼属于小分子靶向抗肿瘤药，适用于慢性粒细胞白血病(CML)急变期、加速期或α-干扰素治疗失败后的慢性期患者和不能手术切除或发生转移的恶性胃肠道间质肿瘤（GIST）患者。Studies have found that imatinib mesylate can inhibit Bcr-Abl tyrosine kinase at the cellular level both in vivo and in vitro, and can selectively inhibit Bcr-Abl positive cell line cells and Ph chromosome-positive chronic myelogenous leukemia, acute Proliferation and induction of apoptosis in fresh cells from patients with lymphocytic leukemia. In addition, it can inhibit platelet-derived growth factor (PDGF) receptor, stem cell factor (SCF), c-Kit receptor tyrosine kinase, thereby inhibiting the cell behavior mediated by PDGF and stem cell factor. Imatinib mesylate is a small-molecule targeted antineoplastic drug, suitable for chronic myeloid leukemia (CML) patients in the blast phase, accelerated phase, or chronic phase after failure of α-interferon therapy and those who cannot be surgically removed or have metastases Patients with malignant gastrointestinal stromal tumors (GIST).
美国专利US5521184最早描述了伊马替尼及其盐形式。国际专利申请WO99/03854、WO2005/077933、WO2004/106326、WO2006/054314和WO2007/023182公开了甲磺酸伊马替尼α、β、α2、H1、Ⅰ、Ⅱ、δ、ε晶型。US Patent No. 5,521,184 first described imatinib and its salt forms. International patent applications WO99/03854, WO2005/077933, WO2004/106326, WO2006/054314 and WO2007/023182 disclose α, β, α2, H1, I, II, δ, ε crystal forms of imatinib mesylate.
US7300938公开了一种在氯类溶剂如氯仿中，伊马替尼碱与甲磺酸反应制备甲磺酸伊马替尼H1晶型的方法。US7300938 discloses a method for preparing the H1 crystal form of imatinib mesylate by reacting imatinib base with methanesulfonic acid in a chlorine solvent such as chloroform.
WO99/03854公开了甲磺酸伊马替尼α晶型和β晶型的制备方法。其中，α晶型用乙醇作溶剂，与伊马替尼碱混合成悬浮液，加入甲磺酸，后经过一系列后处理操作制备得到。但是该方法制备得到的α晶型不稳定，在自然状态下易吸湿和呈无定型，不适于药物应用。WO99/03854 discloses the preparation method of imatinib mesylate α crystal form and β crystal form. Among them, the α crystal form is prepared by using ethanol as a solvent, mixing with imatinib base to form a suspension, adding methanesulfonic acid, and then undergoing a series of post-processing operations. However, the α crystal form prepared by this method is unstable, easily hygroscopic and amorphous in a natural state, and is not suitable for pharmaceutical application.
WO2005095379公开了在烷基醇类或烷基醇和烷基酸酯的混合溶液中制备甲磺酸伊马替尼α晶型，这样使用烷基醇和烷基酸酯的混合溶液不利于生成α晶型，反而导致生成混晶。WO2005095379 discloses the preparation of the α crystal form of imatinib mesylate in an alkyl alcohol or a mixed solution of an alkyl alcohol and an alkyl ester, so that the use of a mixed solution of an alkyl alcohol and an alkyl ester is not conducive to the formation of the α crystal form , but lead to the formation of mixed crystals.
WO2011099039公开了以伊马替尼碱为原料，叔丁醇为溶剂制备甲磺酸伊马替尼α晶型的方法。具体为：将伊马替尼碱用叔丁醇溶解成悬浮液，在30～60℃滴加甲磺酸和叔丁醇的混合溶液，加热混合物至回流，冷却、过滤、结晶、干燥。该制备方法中要求伊马替尼碱的纯度大于99%，溶剂的水分含量大约在0.01至0.015，滴加甲磺酸和叔丁醇混合溶液时间为1～4小时，碱是甲磺酸质量的2～10倍。该方法对原料的纯度要求高，还需控制溶剂水分含量，操作复杂，不适于工业化生产。WO2011099039 discloses a method for preparing the α crystal form of imatinib mesylate by using imatinib base as a raw material and tert-butanol as a solvent. Specifically: dissolving imatinib base in tert-butanol into a suspension, adding dropwise a mixed solution of methanesulfonic acid and tert-butanol at 30-60° C., heating the mixture to reflux, cooling, filtering, crystallizing, and drying. In this preparation method, the purity of imatinib base is required to be greater than 99%, the moisture content of the solvent is about 0.01 to 0.015, the time for adding the mixed solution of methanesulfonic acid and tert-butanol is 1 to 4 hours, and the alkali is the mass of methanesulfonic acid. 2 to 10 times of that. This method has high requirements on the purity of the raw materials, and also needs to control the moisture content of the solvent, the operation is complicated, and it is not suitable for industrial production.
鉴于已有技术中存在的一系列问题，有必要对甲磺酸伊马替尼α晶型的制备方法作进一步改进，开发产品收率高、工艺稳定、适合工业化生产的甲磺酸伊马替尼α晶型的制备方法。In view of a series of problems existing in the prior art, it is necessary to further improve the preparation method of imatinib mesylate α crystal form, and develop imatinib mesylate with high product yield, stable process and suitable for industrialized production. A preparation method of Ni-alpha crystal form.
发明内容Contents of the invention
本发明提供了一种甲磺酸伊马替尼α晶型的制备方法，该方法操作简单，收率高，适于工业化生产。The invention provides a method for preparing α crystal form of imatinib mesylate. The method is simple in operation and high in yield, and is suitable for industrial production.
本发明采用的技术方案为：The technical scheme adopted in the present invention is:
伊马替尼碱与氯仿混合后，与甲磺酸和氯仿的混合溶液反应，制得甲磺酸伊马替尼α晶型。After the imatinib base is mixed with chloroform, it reacts with the mixed solution of methanesulfonic acid and chloroform to prepare the α crystal form of imatinib mesylate.
作为优选，伊马替尼碱与氯仿混合，氯仿与伊马替尼碱的质量比为1～40：1。Preferably, the imatinib base is mixed with chloroform, and the mass ratio of the chloroform to the imatinib base is 1-40:1.
作为优选，甲磺酸和氯仿的混合溶液中，氯仿与甲磺酸的质量比为24.6：1。Preferably, in the mixed solution of methanesulfonic acid and chloroform, the mass ratio of chloroform to methanesulfonic acid is 24.6:1.
经过发明人实验，伊马替尼碱与氯仿混合后，加热可以使伊马替尼碱溶清在氯仿中，后与甲磺酸和氯仿的混合溶液充分反应，析出甲磺酸伊马替尼α晶型。After the inventor's experiment, after the imatinib base is mixed with chloroform, heating can make the imatinib base dissolve in the chloroform, and then fully react with the mixed solution of methanesulfonic acid and chloroform to separate out imatinib mesylate Alpha crystal form.
作为优选，仲丁醇与伊马替尼碱混合后，加热到50～70℃。Preferably, after the sec-butanol and imatinib base are mixed, they are heated to 50-70°C.
本发明的一种实施方式为：伊马替尼碱与氯仿混合后，加热到50～70℃，与甲磺酸和氯仿的混合溶液反应，经过简单的后处理后，得到甲磺酸伊马替尼α晶型。One embodiment of the present invention is: after imatinib base is mixed with chloroform, heated to 50-70°C, reacted with a mixed solution of methanesulfonic acid and chloroform, and after simple post-treatment, ima mesylate is obtained The α-crystal form of tinib.
本发明所述的简单后处理为对制得的甲磺酸伊马替尼α晶型进行过滤、洗涤、干燥。The simple post-treatment of the present invention is to filter, wash and dry the prepared imatinib mesylate α crystal form.
过滤优选为冷却至25℃，干燥氮气保护下过滤，由于氮气的化学性质稳定，不易与其他物质发生反应，常用作保护气，干燥的氮气没有水分，使晶型更稳定。Filtration is preferably cooled to 25°C and filtered under the protection of dry nitrogen. Because the chemical properties of nitrogen are stable, it is not easy to react with other substances. It is often used as a protective gas. Dry nitrogen has no moisture and makes the crystal form more stable.
洗涤优选为氯仿淋洗。Washing is preferably chloroform rinse.
干燥优选为在65℃下真空干燥。Drying is preferably vacuum drying at 65°C.
本发明提供了一种用氯仿作溶剂制备甲磺酸伊马替尼α晶型的方法，该方法制得的甲磺酸伊马替尼α晶型收率高，而且操作简单，适合工业化生产。The invention provides a method for preparing the α crystal form of imatinib mesylate by using chloroform as a solvent. The yield of the α crystal form of imatinib mesylate prepared by the method is high, and the operation is simple, which is suitable for industrial production .
附图说明Description of drawings
图1示本发明实施例1制备的甲磺酸伊马替尼α晶型粉末X射线衍射图谱。Figure 1 shows the powder X-ray diffraction pattern of imatinib mesylate α crystal form prepared in Example 1 of the present invention.
图2示本发明实施例1制备的甲磺酸伊马替尼α晶型DSC图谱。Figure 2 shows the DSC spectrum of imatinib mesylate α crystal form prepared in Example 1 of the present invention.
具体实施方式Detailed ways
为了进一步理解本发明，下面结合实施例对本发明提供的一种甲磺酸伊马替尼α晶型的制备方法进行详细说明。需要理解的是，这些实施例描述只是为进一步详细说明本发明的特征，而不是对本发明范围或本发明权利要求范围的限制。In order to further understand the present invention, the preparation method of the α crystal form of imatinib mesylate provided by the present invention will be described in detail below in conjunction with the examples. It should be understood that the descriptions of these embodiments are only for further detailing the characteristics of the present invention, rather than limiting the scope of the present invention or the scope of the claims of the present invention.
实施例1：Example 1:
在500ml的四口反应瓶中投入25g伊马替尼碱和400g氯仿，加热至50℃，保温。向反应瓶中滴入甲磺酸（4.875g）与氯仿（120g）的混合溶液，2h滴加完毕，保温3h，自然冷却至25℃，氮气保护下抽滤，用25ml氯仿淋洗，抽干后置于65℃的真空烘箱中烘12h，得甲磺酸伊马替尼α晶型28.37g，收率95.0%。利用粉末X-射线衍射法和差示扫描量热法（DSC）测定制备的甲磺酸伊马替尼α晶型。XRPD图谱见图1，反射角2θ为：4.965，10.536，11.325, 11.956,12.269, 12.993，13.944，14.988，15.443， 16.596，17.803，18.709， 19.163，19.909，21.369，21.724，21.955，22.745，23.223，23.810，25.052，26.431，27.435，28.086，28.576，28.967，30.054，30.469，32.140，32.672，33.954。DSC图谱见图2，峰值为227.0℃。Put 25g of imatinib base and 400g of chloroform into a 500ml four-necked reaction flask, heat to 50°C, and keep warm. Add the mixed solution of methanesulfonic acid (4.875g) and chloroform (120g) dropwise into the reaction bottle, after 2h dropwise addition, keep warm for 3h, cool naturally to 25°C, filter under nitrogen protection, rinse with 25ml chloroform, and drain Then put it in a vacuum oven at 65°C for 12 hours to obtain 28.37 g of imatinib mesylate α crystal form, with a yield of 95.0%. The α crystal form of imatinib mesylate was determined by powder X-ray diffraction and differential scanning calorimetry (DSC). XRPD图谱见图1，反射角2θ为：4.965，10.536，11.325, 11.956,12.269, 12.993，13.944，14.988，15.443， 16.596，17.803，18.709， 19.163，19.909，21.369，21.724，21.955，22.745，23.223，23.810 , 25.052, 26.431, 27.435, 28.086, 28.576, 28.967, 30.054, 30.469, 32.140, 32.672, 33.954. The DSC spectrum is shown in Fig. 2, and the peak value is 227.0°C.
实施例2：Example 2:
在1000ml的四口反应瓶中投入25g伊马替尼碱和600g氯仿，加热到60℃，保温。向反应瓶中滴入甲磺酸（4.875g）与氯仿（120g）的混合溶液，2h滴加完毕，保温3h，自然冷却至25℃，氮气保护下抽滤，用25ml氯仿淋洗，抽干后置于65℃的真空烘箱中烘12h，得甲磺酸伊马替尼α晶型28.26g，收率94.6%。利用差示热量扫描法（DSC）测定制备的甲磺酸伊马替尼α晶型。差示扫描量热法图谱峰值为226.5℃。Put 25g of imatinib base and 600g of chloroform into a 1000ml four-necked reaction flask, heat to 60°C, and keep warm. Add the mixed solution of methanesulfonic acid (4.875g) and chloroform (120g) dropwise into the reaction bottle, after 2h dropwise addition, keep warm for 3h, cool naturally to 25°C, filter under nitrogen protection, rinse with 25ml chloroform, and drain Then put it in a vacuum oven at 65°C for 12 hours to obtain 28.26 g of imatinib mesylate α crystal form, with a yield of 94.6%. The α crystal form of imatinib mesylate was determined by differential calorimetry (DSC). The peak value of the differential scanning calorimetry spectrum is 226.5°C.
实施例3：Example 3:
在1000ml的四口反应瓶中投入25g伊马替尼碱和1000g氯仿，加热到70℃，保温。向反应瓶中滴入甲磺酸（4.875g）与氯仿（120g）的混合溶液，2h滴加完毕，保温3h，自然冷却至25℃，氮气保护下抽滤，用25ml氯仿淋洗，抽干后置于65℃的真空烘箱中烘12h，得甲磺酸伊马替尼α晶型28.24g，收率94.5%。利用差示热量扫描法（DSC）测定制备的甲磺酸伊马替尼α晶型。差示扫描量热法图谱峰值为227.2℃。Put 25g of imatinib base and 1000g of chloroform into a 1000ml four-necked reaction flask, heat to 70°C, and keep warm. Add the mixed solution of methanesulfonic acid (4.875g) and chloroform (120g) dropwise into the reaction bottle, after 2h dropwise addition, keep warm for 3h, cool naturally to 25°C, filter under nitrogen protection, rinse with 25ml chloroform, and drain Then put it in a vacuum oven at 65°C for 12 hours to obtain 28.24 g of imatinib mesylate α crystal form, with a yield of 94.5%. The α crystal form of imatinib mesylate was determined by differential calorimetry (DSC). The peak value of the differential scanning calorimetry spectrum is 227.2°C.
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。The descriptions of the above embodiments are only used to help understand the method and core idea of the present invention. It should be pointed out that for those skilled in the art, without departing from the principle of the present invention, some improvements and modifications can be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.
Claims (4)
- A kind of 1. preparation method of imatinib mesylate alfa crystal form, it is characterised in that after Imatinib alkali is mixed with chloroform, 50 DEG C~70 DEG C are heated to, is reacted with the mixed solution of methanesulfonic acid and chloroform, prepares imatinib mesylate alfa crystal form；The chlorine Imitative and Imatinib alkali mass ratio is 16~40：1；In the mixed liquor of the methanesulfonic acid chloroform, the quality of chloroform and methanesulfonic acid Than for 24.6:1.
- A kind of 2. preparation method of imatinib mesylate alfa crystal form, it is characterised in that after Imatinib alkali is mixed with chloroform, 50 DEG C~70 DEG C are heated to, is reacted with the mixed solution of methanesulfonic acid and chloroform, prepares imatinib mesylate alfa crystal form；The chlorine Imitative and Imatinib alkali mass ratio is 16:1；In the mixed liquor of the methanesulfonic acid chloroform, the mass ratio of chloroform and methanesulfonic acid is 24.6:1。
- A kind of 3. preparation method of imatinib mesylate alfa crystal form, it is characterised in that after Imatinib alkali is mixed with chloroform, 50 DEG C~70 DEG C are heated to, is reacted with the mixed solution of methanesulfonic acid and chloroform, prepares imatinib mesylate alfa crystal form；The chlorine Imitative and Imatinib alkali mass ratio is 24：1；In the mixed liquor of the methanesulfonic acid chloroform, the mass ratio of chloroform and methanesulfonic acid is 24.6:1。
- A kind of 4. preparation method of imatinib mesylate alfa crystal form, it is characterised in that after Imatinib alkali is mixed with chloroform, 50 DEG C~70 DEG C are heated to, is reacted with the mixed solution of methanesulfonic acid and chloroform, prepares imatinib mesylate alfa crystal form；The chlorine Imitative and Imatinib alkali mass ratio is 40：1；In the mixed liquor of the methanesulfonic acid chloroform, the mass ratio of chloroform and methanesulfonic acid is 24.6:1。
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