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WO2012071980A1 - 一种甲磺酸伊马替尼α晶型的制备方法 - Google Patents

一种甲磺酸伊马替尼α晶型的制备方法 Download PDF

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Publication number
WO2012071980A1
WO2012071980A1 PCT/CN2011/082267 CN2011082267W WO2012071980A1 WO 2012071980 A1 WO2012071980 A1 WO 2012071980A1 CN 2011082267 W CN2011082267 W CN 2011082267W WO 2012071980 A1 WO2012071980 A1 WO 2012071980A1
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Prior art keywords
imatinib
acetone
monomer
sulfonate
crystal form
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French (fr)
Inventor
张新余
徐建康
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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Zhejiang Jiuzhou Pharmaceutical Co Ltd
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Priority to EP11844916.4A priority Critical patent/EP2647632B1/en
Priority to US13/989,643 priority patent/US8871930B2/en
Publication of WO2012071980A1 publication Critical patent/WO2012071980A1/zh
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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
    • C07D401/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the present invention relates to the field of pharmaceutical synthesis, and in particular to a method for preparing a crystalline form of imatinib sulfonate. Background technique
  • Imatinib Mesilate English name: Imatinib Mesilate, chemical name: 4-[(4-mercapto-1-piperazine) fluorenyl] - N -[4-mercapto-3-[[4-( 3-pyridine)-2-pyrimidinium]amino]phenyl]-benzene OOSHM amine sulfonate, the molecular formula is C 29 H 31 N 7 0-CH 4 S0 3 ,
  • Imatinib sulfonate is a signal transduction inhibitor developed by Novartis in Switzerland. It was first listed in the United States on May 10, 2001. It is currently in the United States, the European Union, Japan and China. The other countries are listed.
  • imatinib eric acid can inhibit Bcr-Abl tyrosine kinase at the cellular level in vitro and in vivo, and can selectively inhibit Bcr-Abl positive cell line cells and Ph chromosome positive chronic myeloid leukemia, acute Proliferation of fresh cells from lymphocytic leukemia patients and induction of apoptosis.
  • it inhibits the platelet-derived growth factor (PDGF) receptor, stem cell factor (SCF), and the tyrosine kinase of the c-Kit receptor, thereby inhibiting cell behavior mediated by PDGF and stem cell factors.
  • PDGF platelet-derived growth factor
  • SCF stem cell factor
  • Imatinib sulfonate is a small molecule targeted anti-tumor drug, suitable for patients with chronic stage of chronic myeloid leukemia (CML) blast crisis, accelerated phase or failure of ⁇ -interferon therapy and inoperable resection or metastasis Patients with malignant gastrointestinal stromal tumors (GIST).
  • CML chronic myeloid leukemia
  • GIST malignant gastrointestinal stromal tumors
  • U.S. Patent No. 5,521,184 first describes imatinib and its salt forms.
  • the imatinib sulfonate alpha, beta, alpha 2, H1, I, II, ⁇ , ⁇ crystal forms are disclosed in the international patent applications WO99/03854, WO2005/077933, WO2004/106326, WO2006/054314, and WO2007/023182.
  • US Patent Application No. US20060223816 provides a process for preparing a stable, fluid, and pharmaceutically acceptable imatinib sulfonate alpha crystalline form, specifically by mixing imatinib base monomer with an organic solvent and heating to at least a portion of the yttrium.
  • the matrine base monomer is dissolved in an organic solvent; the imatinib sulfonate ⁇ crystal form seed crystal is added; the hydrazine acid is dissolved in an organic solvent, and then slowly added dropwise to the imatinib base monomer solution; The reaction solution was cooled to precipitate crystals of imatinib sulfonate, and the crystal form of imatinib sulfonate ⁇ was obtained by separation.
  • the patent application organic solvent is ketones including methyl ethyl ketone and decyl isobutyl ketone, the reaction temperature is higher, and imatinib monomer is sensitive to heat, easy to thermally degrade, and the product yield is low, only 85% ⁇ 90%. Summary of the invention
  • the object of the present invention is to provide a process for preparing a crystalline form of imatinib sulfonate having a high yield.
  • the present invention adopts the following technical solutions:
  • a crystal form of imatinib sulfonate ⁇ is prepared by mixing imatinib monomer with acetone and then reacting with sulfonic acid at 20 to 60 ° C to obtain imatinib sulfonate ⁇ Crystal form.
  • the imatinib monomer is mixed with acetone to form a suspension liquid, and the imatinib monomer is uniformly dispersed and fully reacted with hydrazine acid.
  • the solubility of imatinib monomer in acetone, methyl ethyl ketone and decyl isobutyl ketone is different, and the solubility of imatinib monomer in acetone is compared with methyl ketone and decyl isobutyl ketone.
  • the preparation method of the present invention mixes imatinib monomer with acetone to form a suspension liquid, which reduces the large amount of imatinib monomer dissolved in the solvent. The resulting imatinib monomer feedstock is lost, thereby increasing the yield.
  • acetone, butanone and decyl isobutyl ketone have different boiling points, butanone has a boiling point of 79.6 ° C, fluorenyl isobutyl ketone has a boiling point of 115.8 ° C, and acetone has a boiling point of only 56.48 ° C. It is obviously lower than methyl ethyl ketone and decyl isobutyl ketone.
  • the use of acetone as a solvent can lower the reaction temperature and reduce the thermal degradation loss of imatinib monomer, thereby increasing the yield.
  • the preparation method of the present invention is a reaction at 20 to 60 °C.
  • the mass ratio of the imatinib monomer to acetone is
  • the mass ratio of the imatinib monomer to acetone is 1: 15-30.
  • the molar ratio of the imatinib monomer to the ruthenium acid is 1: 1.0 ⁇ 1.5. More preferably, the molar ratio of the imatinib monomer to the ruthenium acid is 1:1.
  • the reaction time is 1 to 36 hours. More preferably, the reaction time is 4 to 10 hours.
  • sulfonic acid is a colorless or slightly brown oily liquid at normal temperature, it has a large viscosity and is diluted with an organic solvent to be diluted, so that the imatinib monomer can be more fully reacted with hydrazine sulfonic acid.
  • the imatinib monomer has low solubility in acetone and less thermal degradation loss, in a preferred embodiment, the sulfonic acid and acetone are first mixed to form a mixture of sulfonic acid and acetone, and then with Ima. The fentanyl monomer is reacted with an acetone mixture.
  • the mass ratio of the trace acid to acetone is 1: 15-20. More preferably, the mass ratio of the sulfonic acid to acetone is 1:15.
  • a seed crystal is an insoluble additive added to form a crystal nucleus during crystallization. Seed crystals can accelerate or promote the growth of enantiomeric crystals of the same crystalline or stereo configuration.
  • the preparation method of the present invention further comprises adding crystal form of imatinib alpha crystal form.
  • the mass ratio of the imatinib sulfonate ⁇ crystal form to the imatinib monomer is preferably 1:300 to 1000.
  • the preparation method of the present invention further comprises filtering the prepared crystal form of imatinib sulfonate ⁇ , Wash and dry.
  • the filtration is cooled to 20 ⁇ 25 ° C, and filtered under nitrogen protection. Due to the stable chemical nature of nitrogen, it is difficult to react with other substances and is often used as a shielding gas.
  • the washing is preferably acetone rinsing.
  • the drying is dried at 60 °C.
  • the preparation method of the invention can reduce the loss of imatinib monomer raw material by using acetone as a solvent, the boiling point of acetone is 56.48 ° C, and the acetone vaporizes and volatilizes at 60 ° C to remove the imatinib ⁇ crystal form product.
  • the solvent in the product increases the purity of the product. More preferably, the drying is vacuum drying at 60 °C.
  • the present invention detects by powder X-ray diffraction that the product prepared by the preparation method of the present invention is a crystalline form of imatinib sulfonate alpha and is subjected to differential scanning. The melting point of the crystal was measured by a calorimetry (DSC).
  • the preparation method of the invention has lower reaction temperature, greatly reduces the degradation of imatinib and improves the yield, and experiments show that the preparation method of the invention prepares the imatinib sulphate ⁇ crystal form, the product The yield is greater than 97%.
  • the invention has high process stability, simple operation cylinder, low cost, high-purity product of imatinib sulfonate ⁇ crystal form, and is suitable for industrial production of imatinib sulfonate, and has high economic benefit. . DRAWINGS
  • Figure 1 is a graph showing the powder X-ray diffraction pattern of the imatinib sulfonate ⁇ crystal form prepared in Example 1 of the present invention.
  • Fig. 2 is a DSC chart showing the crystal form of imatinib sulfonate ⁇ prepared in Example 1 of the present invention.
  • the invention discloses a preparation method of imatinib sulfonate ⁇ crystal form.
  • the reflection angle 2 ⁇ is approximately: 4.8, 10.4, 11.2, 11.9, 12.9, 13.8, 14.9, 16.4, 17.0, 18.1, 18.6, 19.0, 19.8, 21.2, 21.6, 22.6, 23.1, 23.7, 24.9 , 26.3, 28.5, 31.9, 32.5, 43.4 ⁇ 0.2.
  • the DSC spectrum is shown in Figure 2 with a peak at 229 °C.
  • the dried product of imatinib ⁇ crystal form was about 35.20 g, the yield was 98.21%, and the HPLC was 99.70%.
  • the prepared crystal form of imatinib sulfonate ⁇ was measured by powder X-ray diffractometry, and the results were the same as in Example 1, and the peak value of the differential scanning calorimetry graph was 227 °C.
  • Example 3
  • the type of dried product was about 35.22 g, the yield was 98.27%, and the HPLC was 99.87%.
  • the prepared imatinib oxime ⁇ crystal form was examined by powder X-ray diffractometry, and the results were the same as in Example 1.
  • the differential scanning calorimetry graph peak value was 228 °C.

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  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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Description

一种曱磺酸伊马替尼 0晶型的制备方法 本申请要求于 2010 年 11 月 30 日提交中国专利局、 申请号为 201010567773.x, 发明名称为"一种曱磺酸伊马替尼 α晶型的制备方法"的中国 专利申请的优先权， 其全部内容通过引用结合在本申请中。 技术领域
本发明涉及药物合成领域，具体涉及一种曱磺酸伊马替尼 α晶型的制备方 法。 背景技术
曱橫酸伊马替尼，英文名： Imatinib Mesilate,化学名： 4-[(4-曱基 -1-哌嗪) 曱基] -N-[4-曱基 -3-[[4-(3-吡啶) -2-嘧啶]氨基]苯基] -苯 OOSHM胺曱磺酸盐， 分子式为 C29H31N70-CH4S03,
Figure imgf000003_0001
曱磺酸伊马替尼是瑞士诺华（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。
研究发现， 曱橫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。 曱磺酸伊 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。
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公开了曱磺酸伊马替尼 α、 β、 α2、 Hl、 I 、 II、 δ、 ε晶型。 美国专利申请 US20060223816提供了制备稳定、 流动性好、 适合药用的曱磺 酸伊马替尼 α晶型的方法，具体为将伊马替尼碱单体与有机溶剂混合，加热至 至少部分伊马替尼碱单体溶于有机溶剂； 加入曱磺酸伊马替尼 α晶型晶种； 将 曱橫酸溶于有机溶剂，然后緩慢滴加到伊马替尼碱单体溶液中；将反应液冷却， 使曱磺酸伊马替尼晶体沉淀， 分离制得曱磺酸伊马替尼 α晶型。该专利申请有 机溶剂为酮类包括丁酮和曱基异丁基酮，反应温度较高， 而伊马替尼单体对热 敏感， 容易热降解， 产物收率较低， 仅为 85%~90%。 发明内容
本发明目的是提供一种收率高的曱磺酸伊马替尼 α晶型的制备方法。
为实现本发明的目的， 本发明采用如下技术方案：
一种曱磺酸伊马替尼 α晶型的制备方法为将伊马替尼单体与丙酮混合，然 后与曱磺酸在 20 ~ 60°C反应， 制得曱磺酸伊马替尼 α晶型。
反应式如下：
Figure imgf000004_0001
伊马替尼单体与丙酮混和后形成混悬液体，使伊马替尼单体均勾分散， 与 曱橫酸充分反应。伊马替尼单体在丙酮、丁酮和曱基异丁基酮三种溶剂中的溶 解度不同，与丁酮及曱基异丁基酮相比，伊马替尼单体在丙酮中的溶解度极小， 伊马替尼单体以 50倍质量的丁酮作溶剂 75°C回流， 即可溶解， 以 80倍质量 的曱基异丁基酮作溶剂 100 ~ 110°C反应也能溶解， 而以 165倍质量的丙酮作 溶剂 57°C回流， 几乎不溶， 以 250倍质量的丙酮作溶剂， 57°C回流， 虽有溶 解但不能澄清。 因伊马替尼单体在丙酮中的溶解度极小， 本发明所述制备方法 将伊马替尼单体与丙酮混合， 形成了混悬液体， 减少了伊马替尼单体大量溶入 溶剂造成的伊马替尼单体原料的损失， 从而提高收率。
另一方面， 丙酮、 丁酮和曱基异丁基酮三种溶剂的沸点不同， 丁酮沸点 为 79.6°C , 曱基异丁基酮沸点为 115.8°C , 而丙酮沸点仅为 56.48°C , 明显低于 丁酮和曱基异丁基酮， 以丙酮作为溶剂可降低反应温度， 减少伊马替尼单体的 热降解损失， 从而提高收率。
本发明所述制备方法为 20 ~ 60°C反应。
作为优选， 本发明所述制备方法， 所述伊马替尼单体与丙酮的质量比为
1 : 10 ~ 100。 更优选地是， 所述伊马替尼单体与丙酮的质量比为 1 : 15 ~ 30。
在一个优选的实施方案中， 本发明所述制备方法， 所述伊马替尼单体与曱 橫酸的摩尔比为 1 : 1.0 ~ 1.5。 更优选地是， 所述伊马替尼单体与曱橫酸的摩尔 比为 1 : 1。
作为优选， 本发明所述制备方法， 所述反应时间为 1 ~ 36h。 更优选地是， 所述反应时间为 4 ~ 10h。
由于曱磺酸常温下为无色或微棕色油状液体， 粘度较大， 与有机溶剂混合 后被稀释， 可使伊马替尼单体与曱磺酸反应更加充分。此外由于伊马替尼单体 在丙酮中溶解度小、 热降解损失少， 因此， 在一个优选的实施方案中， 先将曱 磺酸与丙酮混合形成曱磺酸与丙酮混合液，再与伊马替尼单体与丙酮混合液反 应。
作为优选， 所述曱蹟酸与丙酮的质量比为 1 : 15 ~ 20。 更优选地是， 所述曱 磺酸与丙酮的质量比为 1 : 15。
晶种是在结晶过程中为了形成晶核所加入的不溶的添加物。晶种可以加快 或促进与之晶型或立体构型相同的对映异构体结晶的生长。
在一个优选的实施方案中， 本发明所述制备方法，还包括加入曱橫酸伊马 替尼 α晶型晶种。作为优选，所述曱磺酸伊马替尼 α晶型晶种与伊马替尼单体 的质量比优选为 1 :300 ~ 1000。
本发明所述制备方法， 还包括对制得的曱磺酸伊马替尼 α晶型进行过滤、 洗涤、 干燥。
其中， 所述过滤为冷却至 20 ~ 25 °C , 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。
本发明所述制备方法， 所述洗涤优选为丙酮淋洗。
作为优选， 所述干燥为 60°C干燥。 本发明所述制备方法为了减少伊马替 尼单体原料的损失以丙酮作为溶剂， 丙酮沸点为 56.48°C , 60°C下丙酮汽化挥 发， 可除去曱磺酸伊马替尼 α晶型产物中的溶剂， 提高产物的纯度。 更优选地 是， 所述干燥为 60°C真空干燥。
根据特定的多晶型可产生不同的光谱的性质， 本发明通过粉末 X-射线衍 射检测了本发明所述制备方法制备的产物为曱磺酸伊马替尼 α晶型，并且通过 差示扫描量热法（DSC )测定了晶体的熔点。
本发明所述制备方法反应温度较低，极大减少了伊马替尼的降解，提高了 收率， 实验表明， 采用本发明所述制备方法制备曱磺酸伊马替尼 α晶型， 产物 收率大于 97%。 本发明工艺稳定性高， 操作筒单， 成本低， 能够得到高纯度的 曱磺酸伊马替尼 α晶型产物，适合于曱磺酸伊马替尼的工业化生产，具有很高 的经济效益。 附图说明
图 1示本发明实施例 1制备的曱磺酸伊马替尼 α晶型的粉末 X-射线衍射图谱。 图 2示本发明实施例 1制备的曱磺酸伊马替尼 α晶型的 DSC图谱。 具体实施方式
本发明公开了一种曱磺酸伊马替尼 α晶型的制备方法。本领域技术人员可 以借鉴本文内容， 适当改进工艺参数实现。 特别需要指出的是， 所有类似的替 换和改动对本领域技术人员来说是显而易见的， 它们都被视为包括在本发明。 本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发 明内容、精神和范围内对本文所述的方法进行改动或适当变更与组合， 来实现 和应用本发明技术。
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曱磺酸伊马 替尼 α晶型的制备方法进行详细说明，但是应当理解，这些描述只是为进一步 说明本发明的特征和优点， 而不是对本发明权利要求的限制。 实施例 1 :
向 500ml的四口反应瓶中投入伊马替尼单体 30g(60.77mmol), 加入丙酮
300g、 α型晶种 O.lg,加热到 55 ~ 60 °C ,搅拌中滴加曱磺酸 5.84g(60.77mmol )/ 丙酮 88.65g混合液， 2小时滴加完毕， 然后冷却到 20 ~ 25°C , 氮气保护下过 滤， 丙酮 50克淋洗， 滤饼 60°C真空干燥 12小时以上， 得曱橫酸伊马替尼 α 晶型干燥产品约 35.80g, 收率 99.89% , HPLC 99.91%。 利用粉末 X-射线衍射 法和差示扫描量热法 (DSC)测定制备的曱磺酸伊马替尼 α晶型。 XRPD图谱见 图 1 , 反射角 2 Θ约为： 4.8, 10.4, 11.2, 11.9, 12.9, 13.8, 14.9, 16.4, 17.0, 18.1 , 18.6, 19.0, 19.8, 21.2, 21.6, 22.6, 23.1 , 23.7, 24.9, 26.3 , 28.5 , 31.9, 32.5, 43.4±0.2。 DSC图谱见图 2, 峰值为 229 °C。 实施例 2:
向 500ml的四口反应瓶中投入伊马替尼单体 30g(60.77mmol), 加入丙酮 450g、 α型晶种 O.lg,加热到 40 ~ 45°C ,搅拌中滴加曱磺酸 5.84g(60.77mmol )/ 丙酮 116.8g混合液， 36小时滴加完毕， 然后冷却到 20 ~ 25°C , 氮气保护下过 滤， 丙酮 50克淋洗， 滤饼 60°C真空干燥 12小时以上， 得曱橫酸伊马替尼 α 晶型干燥产品约 35.20g, 收率 98.21% , HPLC 99.70% 。 粉末 X-射线衍射法 检测制备的曱磺酸伊马替尼 α晶型， 结果同实施例 1 , 差示扫描量热法图语峰 值为 227°C。 实施例 3:
向 500ml的四口反应瓶中投入伊马替尼单体 30g(60.77mmol), 加入丙酮
900g、 α型晶种 O.lg,加热到 20 ~ 25°C ,搅拌中滴加曱磺酸 5.84g(60.77mmol )/ 丙酮 88.65g混合液， 4小时滴加完毕， 然后在氮气保护下过滤， 丙酮 50克淋 洗， 滤饼 60°C真空干燥 12 小时以上， 得曱磺酸伊马替尼 α晶型干燥产品约 35.00g, 收率 97.65%, HPLC 99.85%。 粉末 X-射线衍射法检测制备的曱磺酸 伊马替尼 α晶型， 结果同实施例 1, 差示扫描量热法图语峰值为 228°C。 实施例 4:
向 1000ml的四口反应瓶中投入伊马替尼单体 30g(60.77mmol), 加入丙酮 3000g、 α型晶种 0.1 g,加热到 40 ~45°C,搅拌中滴加曱磺酸 8.76g(91.16mmol )/ 丙酮 160g混合液， 10小时滴加完毕，然后冷却到 20~25°C,氮气保护下过滤， 丙酮 50克淋洗， 滤饼 60°C真空干燥 12小时以上， 得曱橫酸伊马替尼 α晶型 干燥产品约 34.80g, 收率 97.10% , HPLC 99.51%。 粉末 X-射线衍射法检测制 备的曱磺酸伊马替尼 α 晶型， 结果同实施例 1, 差示扫描量热法图语峰值为 229°C。 实施例 5:
向 500ml的四口反应瓶中投入伊马替尼单体 30g(60.77mmol), 加入丙酮 450g, 加热到 40 ~45°C, 搅拌中滴加曱磺酸 5.84g(60.77mmol )溶液， 6小时滴 加完毕， 然后冷却到 20~25°C, 氮气保护下过滤， 丙酮 50克淋洗， 滤饼 60°C 真空干燥 12 小时以上， 得曱磺酸伊马替尼 α 晶型干燥产品约 34.94g, 收率 97.5% , HPLC 99.34%。 粉末 X-射线衍射法检测制备的曱磺酸伊马替尼 α晶 型， 结果同实施例 1, 差示扫描量热法图语峰值为 227°C。 实施例 6:
向 500ml的四口反应瓶中投入伊马替尼单体 30g(60.77mmol), 加入丙酮 450g, 加热到 50~60°C, 搅拌中滴加曱磺酸 5.84g(60.77mmol ) I 丙酮 88.65g 混合液， 10 小时滴加完毕， 然后冷却到 20~25°C, 氮气保护下过滤， 丙酮 50克淋洗， 滤饼 60°C真空干燥 12小时以上，得曱磺酸伊马替尼 α晶型干燥产 品约 35.22g, 收率 98.27% , HPLC 99.87%。 粉末 X-射线衍射法检测制备的曱 磺酸伊马替尼 α晶型， 结果同实施例 1, 差示扫描量热法图语峰值为 228°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。本发明 提出的曱磺酸伊马替尼 α晶型的制备方法已通过实施例进行了描述，相关技术 人员明显能在不脱离本发明内容、精神和范围内对本文所述的曱磺酸伊马替尼 α晶型的制备方法进行改动或适当变更与组合， 来实现本发明技术。 特别需要 指出的是， 所有相类似的替换和改动对本领域技术人员来说是显而易见的， 它 们都被视为包括在本发明的精神、 范围和内容中。

Claims

权 利 要 求
1、 一种曱磺酸伊马替尼 α晶型的制备方法， 其特征在于， 将伊马替尼单 体与丙酮混合， 然后与曱磺酸在 20 ~ 60 °C反应， 制得曱磺酸伊马替尼 α晶型。
2、 根据权利要求 1所述制备方法， 其特征在于， 所述伊马替尼单体与丙 酮的质量比为 1 : 10 ~ 100。
3、 根据权利要求 2所述制备方法， 其特征在于， 所述伊马替尼单体与丙 酮的质量比为 1 : 15 ~ 30。
4、 根据权利要求 1所述制备方法， 其特征在于， 所述伊马替尼单体与曱 橫酸的摩尔比为 1 : 1.0 ~ 1.5。
5、根据权利要求 1所述制备方法，其特征在于，所述反应时间为 1 ~ 36h。
6、根据权利要求 5所述制备方法，其特征在于，所述反应时间为 4 ~ 10h。
7、 根据权利要求 1所述制备方法， 其特征在于， 所述曱磺酸为曱磺酸与 丙酮混合溶液。
8、 根据权利要求 1所述制备方法， 其特征在于， 还包括加入曱磺酸伊马 替尼 α晶型晶种。
9、 根据权利要求 1所述制备方法， 其特征在于， 还包括过滤、 洗涤、 干 燥步骤。
PCT/CN2011/082267 2010-11-30 2011-11-16 一种甲磺酸伊马替尼α晶型的制备方法 Ceased WO2012071980A1 (zh)

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