WO2016177308A1 - 喹唑啉巴豆基化合物二马来酸盐的晶体及其制备方法和用途 - Google Patents

喹唑啉巴豆基化合物二马来酸盐的晶体及其制备方法和用途 Download PDF

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WO2016177308A1
WO2016177308A1 PCT/CN2016/080878 CN2016080878W WO2016177308A1 WO 2016177308 A1 WO2016177308 A1 WO 2016177308A1 CN 2016080878 W CN2016080878 W CN 2016080878W WO 2016177308 A1 WO2016177308 A1 WO 2016177308A1
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compound
formula
dimaleate salt
characteristic peaks
crystal
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PCT/CN2016/080878
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English (en)
French (fr)
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吕裕斌
殷建明
黄雪慧
李邦良
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杭州华东医药集团新药研究院有限公司
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Priority to JP2017558379A priority Critical patent/JP6752822B2/ja
Priority to ES16789302T priority patent/ES2745075T3/es
Priority to EP16789302.3A priority patent/EP3293181B1/en
Priority to US15/571,582 priority patent/US10065931B2/en
Publication of WO2016177308A1 publication Critical patent/WO2016177308A1/zh
Priority to US16/017,084 priority patent/US10640470B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • 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

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  • the present invention relates to a crystal of a dimaleate salt of a quinazoline crotonyl compound, a process for the preparation thereof and use thereof.
  • Patent document CN102838550A discloses a quinazoline crotonyl compound, a compound of formula I,
  • the compound of formula I has been shown to be an ideal highly potent dual irreversible tyrosine kinase inhibitor that inhibits kinase activity and phosphorylation by blocking competitive binding to ATP by acting on intracellular portions of EGFR, and blocks EGFR tyrosine The kinase ATP binding site thus achieves the purpose of specifically inhibiting EGFR.
  • the compounds are useful in the preparation of a variety of indications for the treatment or prevention of EGFR and HER2 kinase functions including, but not limited to, breast cancer, ovarian cancer, gastrointestinal cancer, esophageal cancer, lung cancer, head and neck squamous cell carcinoma, pancreatic cancer, epidermis
  • a variety of malignant tumor diseases such as squamous cell carcinoma, prostate cancer, glioma and nasopharyngeal cancer.
  • Patent Document Example 1 also discloses a method of synthesizing the above compound of the formula I, which gives a free base of the compound of the formula I.
  • the inventors have found that the free base has poor long-term storage stability and water solubility, and is not suitable for use as a raw material for preparation.
  • the inventors prepared various crystal forms of various salts of the compound of formula I, and studied the physicochemical properties and stability of these crystal forms.
  • the inventors have found that the dimaleate salt form K, Form G, Form E and Form F of the compound of Formula I have unexpectedly good effects in terms of storage stability and water solubility, wherein Form K and Form F It is especially suitable for use as a raw material for preparation.
  • the present invention provides a dimaleate salt form K of a compound of formula I,
  • the X-ray powder diffraction pattern (CuK ⁇ radiation) of the Form K has characteristic peaks at the following diffraction angle 2 ⁇ : 5.8 ⁇ 0.2°, 12.5 ⁇ 0.2°, 14.8 ⁇ 0.2°, 18.9 ⁇ 0.2°, 21.7 ⁇ 0.2° 23.6 ⁇ 0.2 °, 24.9 ⁇ 0.2 ° and 25.8 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern (CuK ⁇ radiation) of the Form K has a characteristic peak at the above diffraction angle 2 ⁇ , and the relative intensity is as follows:
  • the X-ray powder diffraction pattern (CuK ⁇ radiation) of the compound 2 of the compound of formula I, dimaleate further has characteristic peaks at the diffraction angle 2 ⁇ as follows: 17.4 ⁇ 0.2°, 18.0 ⁇ 0.2°, 20.3 ⁇ 0.2°, 24.3 ⁇ 0.2°, 26.4 ⁇ 0.2°, 27.3 ⁇ 0.2°, 28.3 ⁇ 0.2°, and 31.7 ⁇ 0.2°.
  • the X-ray powder diffraction pattern (CuK ⁇ radiation) of the compound B maleate salt form K of the formula I has a characteristic peak at the above diffraction angle 2 ⁇ , and the relative intensities are as follows:
  • the X-ray powder diffraction pattern (CuK ⁇ radiation) of the compound B maleate salt form K of the formula I further has characteristic peaks at the diffraction angle 2 ⁇ as follows: 21.1 ⁇ 0.2°, 22.7 ⁇ 0.2°, 29.2 ⁇ 0.2°, 30.3 ⁇ 0.2°, 32.7 ⁇ 0.2°, 33.1 ⁇ 0.2°, 36.5 ⁇ 0.2°, and 38.3 ⁇ 0.2°.
  • the X-ray powder diffraction pattern (CuK ⁇ radiation) of the compound B maleate salt form K of the formula I has a characteristic peak at the above diffraction angle 2 ⁇ , and the relative intensities are as follows:
  • the compound dimaleate salt form K of the formula I has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the crystalline form K has a melting point of 109.4 ⁇ 2 °C.
  • the crystal form K of the present invention shows an absorption peak in a spectrum measured by differential scanning calorimetry (DSC), and the absorption peak position is at 127 ⁇ 2 °C.
  • the compound dimaleate salt form K of the formula I has a thermogravimetric analysis (TGA) map substantially as shown in FIG.
  • the compound dimaleate salt form K of the formula I has a differential calorimetry (DSC) map substantially as shown in FIG.
  • the invention also provides a preparation method of the compound dimaleate salt form K of the compound of the formula I, comprising the following steps:
  • the molar ratio of free base to maleic acid of the compound of formula I is 1: (1.95 - 2.05), preferably 1:2.
  • the amount of the maleic acid is the sum of the amounts of maleic acid used in the step (2) and the step (3).
  • the mixture is preferably heated to 45 to 55 °C.
  • the concentration of the free base of the compound of formula I in the mixture of the free base of the compound of formula I of step (1) and ethyl acetate is from 0.5 to 1.5 g/mL.
  • the ethyl acetate solution of maleic acid is added in a dropwise manner.
  • the concentrations of the ethyl acetate solution of maleic acid in steps (2) and (3) may be the same or different, and the concentration is 0.05-0.5 mol/L.
  • the volume ratio of the deionized water to ethyl acetate is (0.01-0.02):1.
  • the ethyl acetate here includes the total amount of ethyl acetate used in the steps (1) to (3).
  • the addition rate of the maleic acid ethyl acetate solution is preferably from 0.5 to 2 mL/min. It can be added in any suitable manner, such as by syringe.
  • the heating temperature is 40-60 ° C
  • the stirring time is 10-20 hours.
  • the temperature drop is preferably lowered to 5 to 30 ° C, more preferably to room temperature.
  • the separation may be carried out by a separation method conventional in the art, such as filtration, centrifugation or the like.
  • the invention also provides a dimaleate salt form E of a compound of formula I.
  • the X-ray powder diffraction pattern (CuK ⁇ radiation) of the Form E has characteristic peaks at the following diffraction angle 2 ⁇ : 4.5 ⁇ 0.2°, 12.0 ⁇ 0.2°, 18.2 ⁇ 0.2°, 19.8 ⁇ 0.2°, 20.6 ⁇ 0.2° 21.9 ⁇ 0.2°, 24.7 ⁇ 0.2°, 25.3 ⁇ 0.2°.
  • the relative intensities of the characteristic peaks of the X-ray powder diffraction pattern (CuK ⁇ radiation) of the Form E at the above diffraction angle 2 ⁇ are as follows:
  • the compound dimaleate salt form E of the formula I has an X-ray powder diffraction pattern substantially as shown in FIG.
  • thermogravimetric analysis (TGA) map substantially as shown in FIG.
  • the compound dimaleate salt Form E of Formula I has a differential calorimetry (DSC) map substantially as shown in FIG.
  • the invention also provides a preparation method of the crystal form E, comprising the following steps:
  • the invention also provides a dimaleate salt form F of a compound of formula I.
  • the X-ray powder diffraction pattern (CuK ⁇ radiation) of the Form F has characteristic peaks at the following diffraction angle 2 ⁇ : 5.1 ⁇ 0.2°, 11.5 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.7 ⁇ 0.2°, 19.7 ⁇ 0.2°. 23.3 ⁇ 0.2°, 25.0 ⁇ 0.2°, 26.2 ⁇ 0.2°.
  • the relative intensities of the characteristic peaks of the X-ray powder diffraction pattern (CuK ⁇ radiation) of the Form F at the above diffraction angle 2 ⁇ are as follows:
  • the compound dimaleate salt form F of formula I has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the compound dimaleate salt form F of formula I has a thermogravimetric analysis (TGA) map substantially as shown in FIG.
  • the compound dimaleate salt Form F of Formula I has a differential calorimetry (DSC) map substantially as shown in FIG.
  • the invention also provides a preparation method of the crystal form F, which comprises adding the crystal form E to an alcohol solvent, stirring, volatilizing the solvent or adding an anti-solvent to obtain the crystal form F.
  • the alcohol solvent is preferably ethanol.
  • the invention also provides a dimaleate salt form G of a compound of formula I.
  • the X-ray powder diffraction pattern (CuK ⁇ radiation) of the Form G has characteristic peaks at the following diffraction angle 2 ⁇ : 4.5 ⁇ 0.2°, 10.1 ⁇ 0.2°, 15.1 ⁇ 0.2°, 18.5 ⁇ 0.2°, 25.8 ⁇ 0.2° .
  • the relative intensity of the characteristic peak of the X-ray powder diffraction pattern (CuK ⁇ radiation) of the crystal form G at the above diffraction angle 2 ⁇ is as follows:
  • the X-ray powder diffraction pattern (CuK ⁇ radiation) of the Form G further has characteristic peaks at the following diffraction angle 2 ⁇ : 21.4 ⁇ 0.2°, 27.4 ⁇ 0.2°.
  • the X-ray powder diffraction pattern (CuK ⁇ radiation) of the compound dimaleate salt form G of the compound of formula I is at a relative intensity at the above characteristic peaks:
  • the compound dimaleate salt form G of formula I has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the compound dimaleate salt Form G of Formula I has a thermogravimetric analysis (TGA) map substantially as shown in FIG.
  • the compound dimaleate salt form G of formula I has a differential calorimetry (DSC) map substantially as shown in FIG.
  • the invention also provides a preparation method of the crystal form G, which comprises adding the crystal form E to a ketone solvent, stirring, volatilizing the solvent or adding an anti-solvent to obtain a crystal form G.
  • the ketone solvent is preferably acetone.
  • the characteristic peak relative intensity values of the above crystal forms may be within a certain range, for example, fluctuating within ⁇ 10%. In other cases, the characteristic peak relative intensity values of the above crystal forms may fluctuate within a larger range.
  • the crystal form K, the crystal form E, the form F, and the form G of the present invention are all substantially pure crystals, that is, crystals substantially free of other crystal forms.
  • the present invention also provides a composition comprising at least one of crystalline form K, crystalline form G, crystalline form E or crystalline form F of the compound of formula I, dimaleate.
  • the invention further provides the compound of formula I, dimaleate salt Form K, Form G, Form E or Form F, for the preparation of an indication for preventing or treating EGFR and HER2 kinase functions, including but not limited to breast
  • an indication for preventing or treating EGFR and HER2 kinase functions including but not limited to breast
  • drugs for various malignant diseases such as cancer, ovarian cancer, gastrointestinal cancer, esophageal cancer, lung cancer, head and neck squamous cell carcinoma, pancreatic cancer, epidermal squamous cell carcinoma, prostate cancer, glioma, and nasopharyngeal cancer.
  • the crystal form K of the dimaleate salt of the compound of the formula I of the present invention is compared to the free base of the compound of the formula I prepared in the prior art and compared to other crystal forms of the compound of the formula I obtained by the applicant of the present invention.
  • Form G, Form E or Form F has excellent storage stability and solubility, and is more suitable for use as a pharmaceutical raw material.
  • Figure 1 is an NMR spectrum of the free base of the compound of formula I;
  • Figure 2 is an NMR spectrum of Form K
  • Figure 3 is an XRPD pattern of Form K
  • Figure 4 is a TGA spectrum of Form K
  • Figure 5 is a DSC spectrum of Form K
  • Figure 6 is an XRPD pattern of Form E
  • Figure 7 is a TGA map of Form E
  • Figure 8 is a DSC spectrum of Form E
  • Figure 9 is an XRPD pattern of Form F
  • Figure 10 is a TGA map of Form F
  • Figure 11 is a DSC spectrum of Form F
  • Figure 12 is an XRPD pattern of Form G
  • Figure 13 is a TGA map of Form G
  • Figure 14 is a DSC spectrum of Form G
  • Figure 15 is a comparison chart of XRPD patterns of the free base of the compound of the formula I after storage for one week at 25 ° C / 60% R.H., and one week after storage at 40 ° C / 75% R.H.
  • Figure 16 is a comparison chart of XRPD patterns of the crystalline form K of the compound of the formula I after storage for one week at 25 ° C / 60% R.H., and one week after storage at 40 ° C / 75% R.H.
  • Figure 17 is a comparison chart of XRPD patterns of the crystalline form F of the compound of the formula I after storage for one week at 25 ° C / 60% R.H., and one week after storage at 40 ° C / 75% R.H.
  • Figure 18 is an XRPD pattern of the crystalline form K of the compound of Formula I after six months at K40 ° C / 75% R.H.;
  • Figure 19 is a graph showing the results of the competition for the stability of the crystalline form K and the crystalline form F of the compound of the formula I in Test Example 2, wherein the spectra 1-5 represent the XRPD patterns of the samples numbered 1-5 in Test Example 2;
  • Figure 20 is a graph showing the results of the competition for the stability of the crystal form K and the crystal form G of the compound of the formula I in Test Example 4, wherein the map 1 is the XRPD pattern of the crystal form G, the map 2 is the XRPD pattern of the crystal form K, and the map 3 is the stable form of the crystal form. XRPD pattern of the crystal after the sex test.
  • the DSC spectra were acquired by TA Q200 and TA Q2000 differential scanning calorimeter.
  • the TGA spectra were collected by TA Q500 and TA Q5000 thermogravimetric analyzer. The scanning parameters are shown in Table 2.
  • DSC showed that the melting point of Form K was 109.48 ° C and showed an absorption peak at 127 ⁇ 2 ° C.
  • TGA showed that Form K had two steps of weight loss with 0.3% and 1.9% weight loss, respectively.
  • Form F was similar to the NMR spectrum of Form K in Example 1, demonstrating that Form F is the dimaleate salt of the compound of Formula I.
  • the melting point of the crystalline form F was 155.6 ° C
  • the enthalpy value was 108.1 J/g
  • the weight loss was 0.4%.
  • XRPD X-ray powder diffraction analysis
  • TGA thermogravimetric analysis
  • DSC differential thermal analysis
  • Test Example 1 Storage stability test of the free base, crystalline form K and crystalline form F of the compound of the formula I
  • the XRPD pattern of the compound of formula I was significantly changed after storage for one week at 25 ° C / 60% RH and 40 ° C / 75% RH (see Figure 15), showing the crystal form stability of the free base of the compound of formula I. Poor, not suitable as a raw material for preparation.
  • Form C and Form F were each stored at 25 ° C / 60% R. H. and 40 ° C / 75% R. H. for one week, and the XRPD patterns of Form K and Form F were substantially identical, as shown in Figures 16 and 17, respectively. It is shown that Form K and Form F are stable for at least one week at 25 ° C / 60% R. H. and 40 ° C / 75% R. H.
  • Test Example 2 One of the comparative tests for the competition stability between Form K and Form F
  • Form K About 10 mg was weighed, and a suspension was formed by adding a different water activity saturated solution of Form K, and then Form F (about 10 mg) was added. After stirring at room temperature for 12 hours, the solid was centrifuged and tested for XRPD. The results are shown in Table 4 and Figure 19. From the results, it is understood that the crystal form K is thermodynamically more stable than the form F when the water activity is 0.15 or more at room temperature.
  • Form F did not change, indicating that Form F had good kinetic stability at 25 ° C / 60% R.H.
  • Form K was weighed into a saturated aqueous solution of Form K to form a suspension, and then Form G (about 10 mg) was added. After stirring at room temperature for 12 hours, the solid was centrifuged and tested for XRPD, and the results are shown in Fig. 20.
  • FaSSIF and FeSSIF are according to the literature Study of a Standardized Taurocholate - Lecithin Powder for Preparing the Biorelevant Media FeSSIF and FaSSIF (Kloefer, B., van Hoogevest, P., Moloney, R., Kuentz, M., Leigh, ML, & Dressman, J. (2010). Dissolution Technologies, Aug.

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Abstract

本发明公开了一种式I所示化合物的二马来酸盐晶型K、晶型E、晶型F和晶型G，并公开了它们的制备方法和用途。所述晶型K、晶型E、晶型F和晶型G具有优良的储存稳定性和溶解性，更适合作为制剂原料使用。

Description

喹唑啉巴豆基化合物二马来酸盐的晶体及其制备方法和用途 技术领域
本发明涉及喹唑啉巴豆基化合物的二马来酸盐的晶体及其制备方法和用途。
背景技术
专利文献CN102838550A公开了一种喹唑啉巴豆基化合物——式I化合物，
Figure PCTCN2016080878-appb-000001
所述式I化合物被证明是理想的高效双重非可逆性酪氨酸激酶抑制剂，可通过作用于EGFR细胞内部分与ATP竞争性结合，抑制激酶的活性和磷酸化，并封闭EGFR酪氨酸激酶ATP结合位点从而达到特异性抑制EGFR的目的。该化合物可用于制备治疗或预防各种与EGFR和HER2激酶功能有关的适应症，包括但不限于乳腺癌、卵巢癌、胃肠癌、食管癌、肺癌、头颈部鳞癌、胰腺癌、表皮鳞癌、前列腺癌、神经胶质瘤和鼻咽癌等多种恶性肿瘤疾病。
上述专利文献实施例1还公开了合成上述式I化合物的方法，该方法得到了一种式I化合物游离碱。发明人发现，该游离碱的长期储存稳定性和水溶解性较差，不适合作为制剂原料使用。
因此，需要一种具有更优异的物理性质的、适合制剂应用的式I化合物原料。
发明内容
发明人制备了式I化合物的多种盐的多种晶型，并对这些晶型的理化性质、稳定性进行了研究。发明人发现，式I化合物的二马来酸盐晶型K，晶型G、晶型E和晶型F在储存稳定性和水溶性方面具有意外的良好效果，其中晶型K和晶型F尤其适合作为制剂原料使用。
因此，本发明的目的在于提供一种式I化合物的二马来酸盐晶型K、晶型G、晶型E和晶型F及其制备方法和用途。
本发明提供一种式I所示化合物的二马来酸盐晶型K，
Figure PCTCN2016080878-appb-000002
所述晶型K的X-射线粉末衍射图(CuKα辐射)在以下衍射角2θ处具有特征峰：5.8±0.2°、12.5±0.2°、14.8±0.2°、18.9±0.2°、21.7±0.2°、23.6±0.2°、24.9±0.2°和25.8±0.2°。
优选地，所述晶型K的X-射线粉末衍射图(CuKα辐射)在上述衍射角2θ处具有特征峰，且相对强度如下：
Figure PCTCN2016080878-appb-000003
优选地，所述式I化合物二马来酸盐晶型K的X-射线粉末衍射图(CuKα辐射)进一步可在如下衍射角2θ处具有特征峰：17.4±0.2°、18.0±0.2°、20.3±0.2°、24.3±0.2°、26.4±0.2°、27.3±0.2°、28.3±0.2°和31.7±0.2°。
优选地，所述式I化合物二马来酸盐晶型K的X-射线粉末衍射图(CuKα辐射)在上述衍射角2θ处具有特征峰，且相对强度如下：
Figure PCTCN2016080878-appb-000004
优选地，所述式I化合物二马来酸盐晶型K的X-射线粉末衍射图(CuKα辐射)进一步在如下衍射角2θ处具有特征峰：21.1±0.2°、22.7±0.2°、29.2±0.2°、30.3±0.2°、32.7±0.2°、33.1±0.2°、36.5±0.2°和38.3±0.2°。
优选地，所述式I化合物二马来酸盐晶型K的X-射线粉末衍射图(CuKα辐射)在上述衍射角2θ处具有特征峰，且相对强度如下：
Figure PCTCN2016080878-appb-000005
非限制性地，所述式I化合物二马来酸盐晶型K具有基本上如图3所示的X-射线粉末衍射图。
进一步地，所述晶型K的熔点为109.4±2℃。
进一步地，本发明晶型K以差示扫描量热法(DSC)测定的图谱中显示有一个吸收峰，且该吸收峰位置在127±2℃处。
非限制性地，所述式I化合物二马来酸盐晶型K具有基本上如图4所示的热失重分析(TGA)图。
非限制性地，所述式I化合物二马来酸盐晶型K具有基本上如图5所示的差示量热扫描(DSC)图。
本发明还提供所述式I化合物二马来酸盐晶型K的制备方法，包括如下步骤：
(1)将式I化合物的游离碱与乙酸乙酯混合，并将混合液加热至40-60℃；
(2)向步骤(1)所得混合液中缓慢加入马来酸的乙酸乙酯溶液，至出现沉淀停止，加入去离子水；
(3)向步骤(2)所得反应体系中再加入马来酸的乙酸乙酯溶液，加热搅拌，降温析晶，分离晶体，得到所述晶型K。
其中，所述式I化合物的游离碱可根据现有方法，例如专利文献CN102838550A实施例1公开的方法合成得到。
本发明方法中，式I化合物的游离碱与马来酸的摩尔比为1:(1.95-2.05)，优选为1:2。其中所述马来酸的量为步骤(2)和步骤(3)中所用的马来酸的用量之和。
步骤(1)中，优选将混合液加热至45-55℃。
优选地，步骤(1)式I化合物的游离碱与乙酸乙酯的混合液中，式I化合物的游离碱的浓度为0.5～1.5g/mL。
优选地，步骤(2)中，所述马来酸的乙酸乙酯溶液的加入方式为滴加。
优选地，步骤(2)和(3)中所述马来酸的乙酸乙酯溶液的浓度可以相同或不同，且浓度为0.05-0.5mol/L。
本发明方法中，所述去离子水与乙酸乙酯的体积比为(0.01-0.02):1。这里的乙酸乙酯包括步骤(1)-(3)采用的乙酸乙酯总量。
步骤(3)中，所述马来酸的乙酸乙酯溶液的加入速度优选为0.5-2mL/min。可采用任何合适的方式加入，例如用注射器加入。
优选地，步骤(3)中，所述加热温度为40-60℃，所述搅拌时间为10～20小时。
优选地，步骤(3)中，所述降温优选降至5-30℃，更优选降至室温。
步骤(3)中，所述分离可采用本领域常规的分离方法，例如过滤、离心等。
本发明还提供一种式I所示化合物的二马来酸盐晶型E。
所述晶型E的X-射线粉末衍射图(CuKα辐射)在以下衍射角2θ处具有特征峰：4.5±0.2°、12.0±0.2°、18.2±0.2°、19.8±0.2°、20.6±0.2°、21.9±0.2°、24.7±0.2°、25.3±0.2°。
优选地，所述晶型E的X-射线粉末衍射图(CuKα辐射)在上述衍射角2θ处的特征峰的相对强度如下：
Figure PCTCN2016080878-appb-000006
Figure PCTCN2016080878-appb-000007
非限制性地，所述式I化合物二马来酸盐晶型E具有基本上如图6所示的X-射线粉末衍射图。
非限制性地，所述式I化合物二马来酸盐晶型E具有基本上如图7所示的热失重分析(TGA)图。
非限制性地，所述式I化合物二马来酸盐晶型E具有基本上如图8所示的差示量热扫描(DSC)图。
本发明还提供所述晶型E的制备方法，包括如下步骤：
(1)将式I化合物与乙酸乙酯混合，搅拌；
(2)向步骤(1)所得混合物中加入马来酸乙酸乙酯溶液，搅拌，得到式I化合物的二马来酸盐晶型E。
本发明还提供一种式I所示化合物的二马来酸盐晶型F。
所述晶型F的X-射线粉末衍射图(CuKα辐射)在以下衍射角2θ处具有特征峰：5.1±0.2°、11.5±0.2°、17.5±0.2°、18.7±0.2°、19.7±0.2°、23.3±0.2°、25.0±0.2°、26.2±0.2°。
优选地，所述晶型F的X-射线粉末衍射图(CuKα辐射)在上述衍射角2θ处的特征峰的相对强度如下：
Figure PCTCN2016080878-appb-000008
非限制性地，所述式I化合物二马来酸盐晶型F具有基本上如图9所示的X-射线粉末衍射图。
非限制性地，所述式I化合物二马来酸盐晶型F具有基本上如图10所示的热失重分析(TGA)图。
非限制性地，所述式I化合物二马来酸盐晶型F具有基本上如图11所示的差示量热扫描(DSC)图。
本发明还提供所述晶型F的制备方法，包括将晶型E加入醇类溶剂中，搅拌，挥发溶剂或者加反溶剂，得到晶型F。所述醇类溶剂优选为乙醇。
本发明还提供一种式I所示化合物的二马来酸盐晶型G。
所述晶型G的X-射线粉末衍射图(CuKα辐射)在以下衍射角2θ处具有特征峰：4.5±0.2°、10.1±0.2°、15.1±0.2°、18.5±0.2°、25.8±0.2°。
优选地，所述晶型G的X-射线粉末衍射图(CuKα辐射)在上述衍射角2θ处的特征峰的相对强度如下：
Figure PCTCN2016080878-appb-000009
所述晶型G的X-射线粉末衍射图(CuKα辐射)进一步在以下衍射角2θ处具有特征峰：21.4±0.2°、27.4±0.2°。
优选地，所述式I化合物二马来酸盐晶型G的X-射线粉末衍射图(CuKα辐射)上述特征峰处的相对强度为：
21.4±0.2°      1.21
27.4±0.2°      3.5。
非限制性地，所述式I化合物二马来酸盐晶型G具有基本上如图12所示的X-射线粉末衍射图。
非限制性地，所述式I化合物二马来酸盐晶型G具有基本上如图13所示的热失重分析(TGA)图。
非限制性地，所述式I化合物二马来酸盐晶型G具有基本上如图14所示的差示量热扫描(DSC)图。
本发明还提供所述晶型G的制备方法，包括将晶型E加入酮类溶剂中，搅拌，挥发溶剂或者加入反溶剂，得到晶型G。
所述酮类溶剂优选为丙酮。
需要说明的是，上述晶型K、晶型E、晶型F、晶型G的特征峰的相对强度值仅是本发明某些实施方式中测定得到的，并不是绝对的。本领域技术人员理解，由于择优取向，同一晶型在不同测试条件下(例如测量仪器、方法、操作等方面)，相对强度会发生改变。
上述晶型的特征峰相对强度值可在一定范围内，例如在±10％范围内波动。在另一些情况下，上述晶型的特征峰相对强度值可在更大范围内波动。
本发明的晶型K、晶型E、晶型F、晶型G均为基本上纯的晶体，即基本不含有其他晶型的晶体。
本发明还提供一种组合物，所述组合物中含有所述式I化合物二马来酸盐晶型K、晶型G、晶型E或晶型F中的至少一种。
本发明还提供所述式I化合物二马来酸盐晶型K、晶型G、晶型E或晶型F在制备预防或治疗与EGFR和HER2激酶功能有关的适应症，包括但不限于乳腺癌、卵巢癌、胃肠癌、食管癌、肺癌、头颈部鳞癌、胰腺癌、表皮鳞癌、前列腺癌、神经胶质瘤和鼻咽癌等多种恶性肿瘤疾病的药物中的用途。
与现有技术制备得到的式I化合物的游离碱相比，以及与本发明申请人试验得到的式I化合物的其他晶型相比，本发明的式I化合物二马来酸盐的晶型K、晶型G、晶型E或晶型F具有优异的储存稳定性和溶解性，更适合作为制药原料使用。
附图说明
图1为式I化合物的游离碱的NMR图谱；
图2为晶型K的NMR图谱；
图3为晶型K的XRPD图谱；
图4为晶型K的TGA图谱；
图5为晶型K的DSC图谱；
图6为晶型E的XRPD图谱；
图7为晶型E的TGA图谱；
图8为晶型E的DSC图谱；
图9为晶型F的XRPD图谱；
图10为晶型F的TGA图谱；
图11为晶型F的DSC图谱；
图12为晶型G的XRPD图谱；
图13为晶型G的TGA图谱；
图14为晶型G的DSC图谱；
图15为式I化合物游离碱分别在制备后、25℃/60％R.H.条件下存放一周后、40℃/75％R.H.条件下存放一周后的XRPD图谱对比图；
图16为式I化合物晶型K分别在制备后、25℃/60％R.H.条件下存放一周后、40℃/75％R.H.条件下存放一周后的XRPD图谱对比图；
图17为式I化合物晶型F分别在制备后、25℃/60％R.H.条件下存放一周后、40℃/75％R.H.条件下存放一周后的XRPD图谱对比图；
图18为式I化合物晶型K于K40℃/75％R.H.条件下放置六个月后的XRPD图谱；
图19为试验例2中式I化合物晶型K、晶型F竞争稳定性实验结果，其中图谱1-5表示试验例2中编号分别为1-5的样品的XRPD图谱；
图20为试验例4中式I化合物晶型K、晶型G竞争稳定性实验结果，其中图谱1为晶型G的XRPD图谱，图谱2为晶型K的XRPD图谱，图谱3为晶型竞争稳定性试验后晶体的XRPD图谱。
具体实施方式
以下结合具体实施例对本发明的技术方案做进一步详细说明。应当理解，这些实施例是用于示例性地说明本发明的基本原理、主要特征和优点，实施例中采用的具体实施条件可以在本领域范围内做适当调整，而本发明的保护范围不受实施例的限制。
以下实施例中，晶型的XRPD测定采用PANalytical Empyrean X射线粉末衍射分析仪，参数见表1。
表1
Figure PCTCN2016080878-appb-000010
DSC图谱采用TA Q200和TA Q2000差示扫描量热仪采集，TGA图谱采用TA Q500和TA Q5000热重分析仪采集，扫描参数见表2。
表2
Figure PCTCN2016080878-appb-000011
以下实施例中，式I化合物的游离碱是根据专利文献CN102838550A中实施例1记载的方法制备得到的。
以下实施例中，未注明的实施条件为常规实验中的条件。
实施例1 式I化合物二马来酸盐晶型K的制备和表征
称取13.5g式I化合物游离碱，置于500mL的三口烧瓶中，加入15mL乙酸乙酯，机械搅拌并且加热至50℃，可观察到溶液浑浊，逐滴加入0.2mol/L的马来酸乙酸乙酯溶液，至出现沉淀(约加入80mL)，然后加入3mL去离子水，接着用注射器以1mL/min的速度加入0.2mol/L马来酸的乙酸乙酯溶液约112mL，在温度约50℃下保温搅拌15小时，自然降温至室温，抽滤并于35℃下真空干燥5小时，得到式I化合物的二马来酸盐晶型K，其HPLC纯度99.3％。
对式I化合物游离碱和所得晶型K进行核磁测试，溶剂为MeOD，分别得到NMR图谱(分别为图1和图2)。从液态核磁共振的结果看，马来酸乙烯基上的两个氢的化学位移在6.3ppm左右，将其积分面积定义为1.0，游离碱上的一个H的化学位移在8.6ppm左右，积分面积为0.25，与马来酸上的乙烯基上的氢的化学计量比为1:4，由于乙烯基上是两个氢，所以式I化合物游离碱与马来酸按化学计量比为1:2成盐，从而证明晶型K是式I化合物的二马来酸盐。
晶型K进行X射线粉末衍射分析(XRPD)、热失重分析(TGA)和差热分析(DSC) 分析，实验结果分别见图3-5。
DSC显示晶型K的熔点为109.48℃，且在127±2℃处显示吸收峰。
TGA显示晶型K有两步失重，分别失重0.3％和1.9％。
实施例2 式I化合物二马来酸盐晶型E的制备和表征
将式I化合物的游离碱300.6mg加入到20mL的玻璃瓶中，向其中加入乙酸乙酯4mL。在50℃搅拌5分钟。向其中加入0.2mol/L马来酸的乙酸乙酯溶液6.6mL，50℃下搅拌反应24小时，得到式I化合物的二马来酸盐晶型E。
对晶型E进行核磁测试，其NMR图谱与实施例1中晶型K的NMR图谱相似，证明晶型E为式I化合物的二马来酸盐。
晶型E的X射线粉末衍射分析(XRPD)、热失重分析(TGA)和差热分析(DSC)实验结果分别见图6-8。
实施例3 式I化合物二马来酸盐晶型F的制备和表征
将8.3mg式I化合物二马来酸盐晶型E加入到3mL玻璃瓶中，加入0.5mL乙醇，加热至60℃使完全溶解，得到澄清溶液。将所得澄清溶液快速降温至5℃，析出固体，离心，得到晶型F。
对晶型F进行核磁测试，其NMR图谱与实施例1中晶型K的NMR图谱相似，证明晶型F为式I化合物的二马来酸盐。
晶型F的X射线粉末衍射分析(XRPD)、热失重分析(TGA)和差热分析(DSC)实验结果分别见图9-11。
根据DSC图和TGA图可知，晶型F熔点为155.6℃，焓值108.1J/g，失重0.4％。
实施例4 式I化合物二马来酸盐晶型G的制备和表征
称量11.3mg式I化合物的二马来酸盐晶型E至20mL玻璃瓶中，加入1.9mL丙酮，振荡将其完全溶解，边滴加反溶剂正庚烷边搅拌，直至有固体析出，离心，得到晶型G。
对晶型G进行核磁测试，其NMR图谱与实施例1中晶型K的NMR图谱相似，证明晶型G为式I化合物的二马来酸盐。
晶型G的X射线粉末衍射分析(XRPD)、热失重分析(TGA)和差热分析(DSC)分别见图12-14。
试验例1 式I化合物游离碱、晶型K、晶型F的储存稳定性试验
式I化合物游离碱分别在25℃/60％R.H.和40℃/75％R.H.条件下存放一周后，其XRPD图谱发生了明显改变(见图15)，显示式I化合物游离碱的晶型稳定性较差，不适合作为制剂原料。
晶型K、晶型F各自在25℃/60％R.H.和40℃/75％R.H.条件下存放一周，晶型K和晶型F的XRPD图谱基本一致，分别见图16和图17。显示晶型K和晶型F在25℃/60％R.H.和40℃/75％R.H.条件下至少可以稳定一周。
上述实验说明，式I化合物晶型K和晶型F比式I化合物游离碱具有更好的物理稳定 性。
式I化合物游离碱在40℃/75％R.H.条件下存放一周后，HPLC测定其化学含量降至初始含量的94.8％，显示其化学稳定性较差。
晶型K、晶型E、晶型F和晶型G在40℃/75％R.H.条件下存放一周后，HPLC测定化学含量稳定，显示这四种晶型化学稳定性良好。结果见表3。
表3
Figure PCTCN2016080878-appb-000012
晶型K在40℃/75％R.H.条件下放置六个月前后，其XRPD图谱基本一致，见图18。说明晶型K具有良好的物理和化学稳定性。
试验例2 晶型K与晶型F的竞争稳定性比较试验之一
称量约10mg晶型K，加入晶型K的不同水活度饱和溶液中形成悬浮液，然后加入晶型F(约10mg)。在室温下搅拌12小时后，离心分离固体并测试XRPD。结果见表4和图19。由结果可知，在室温条件下，水活度大于等于0.15时，晶型K比晶型F热力学上更稳定。
表4
样品编号 水活度 溶剂：水 晶型
1 0.00 IPA 晶型F
2 0.15 IPA:H2O 99:1 晶型K
3 0.39 IPA:H2O 24:1 晶型K
4 0.60 ACN:H2O 19:1 晶型K
5 0.80 ACN:H2O 9:1 晶型K
试验例3 晶型K与晶型F的竞争稳定性比较试验之二
称量约10mg晶型F，向其中加入约0.1mg晶型K，振动混合。然后将两份样品分别置于不同的环境中放置10天，测试XRPD。结果见表5。
表5
Figure PCTCN2016080878-appb-000013
由结果可知，在40℃/75％R.H.有晶型K存在时，晶型F转变为晶型K，即此时晶型 K比晶型F具有更好的热力学稳定性。
在25℃/60％R.H.有晶型K存在时，晶型F没有变化,说明晶型F在25℃/60％R.H.条件下具有良好的动力学稳定性。
试验例4 晶型K与晶型G的储存稳定性比较试验
称量约10mg晶型K加入晶型K的饱和水溶液中形成悬浮液，然后加入晶型G(约10mg)。在室温下搅拌12小时后，离心分离固体并测试XRPD，结果见图20。
由结果可知，晶型G在室温条件下转化为晶型K。因此，室温下在水中晶型K比晶型G热力学上更稳定。
试验例5 式I化合物的游离碱、晶型K和晶型F的溶解性
对式I化合物的游离碱、晶型K和晶型F在不同pH条件下，在水中、空腹状态下的模拟肠液(FaSSIF)、饱腹状态下的模拟肠液(FeSSIF)以及模拟胃液(SGF)中的溶解度进行了测试。其中FaSSIF和FeSSIF按照文献Study of a Standardized Taurocholate–Lecithin Powder for Preparing the Biorelevant Media FeSSIF and FaSSIF(Kloefer,B.,van Hoogevest,P.,Moloney,R.,Kuentz,M.,Leigh,M.L.,&Dressman,J.(2010).Dissolution Technologies,Aug.17(3),6-14.)记载的方法配制得到；SGF按照文献Albendazole Generics-A Comparative In Vitro Study(Galia E.,Horton,J and Dressman J.(1999)Pharmaceutical Research,16 (12),1871-1975)记载的方法制备得到。试验结果参见表6。
表6
Figure PCTCN2016080878-appb-000014

Claims (18)

  1. 一种式I所示化合物的二马来酸盐晶型K，
    Figure PCTCN2016080878-appb-100001
    所述晶型K的X-射线粉末衍射图(CuKα辐射)在以下衍射角2θ处具有特征峰：5.8±0.2°、12.5±0.2°、14.8±0.2°、18.9±0.2°、21.7±0.2°、23.6±0.2°、24.9±0.2°和25.8±0.2°。
  2. 根据权利要求1所述的晶型K，其特征在于，所述特征峰的相对强度为：
    Figure PCTCN2016080878-appb-100002
  3. 根据权利要求1或2所述的晶型K，其特征在于，所述晶型K的X-射线粉末衍射图(CuKα辐射)进一步在如下衍射角2θ处具有特征峰：17.4±0.2°、18.0±0.2°、20.3±0.2°、24.3±0.2°、26.4±0.2°、27.3±0.2°、28.3±0.2°和31.7±0.2°。
  4. 根据权利要求3所述的晶型K，其特征在于，下述特征峰的相对强度为：
    Figure PCTCN2016080878-appb-100003
  5. 根据权利要求4所述的晶型K，其特征在于，所述晶型K的X-射线粉末衍射图(CuKα辐射)进一步在如下衍射角2θ处具有特征峰：21.1±0.2°、22.7±0.2°、29.2±0.2°、30.3±0.2°、32.7±0.2°、33.1±0.2°、36.5±0.2°和38.3±0.2°。
  6. 根据权利要求5所述的晶型K，其特征在于，下述特征峰的相对强度为：
    Figure PCTCN2016080878-appb-100004
    Figure PCTCN2016080878-appb-100005
  7. 根据权利要求1-6任一项所述的晶型K的制备方法，包括如下步骤：
    (1)将式I化合物的游离碱与乙酸乙酯混合，并将混合液加热至40-60℃；
    (2)向步骤(1)所得混合液中缓慢加入马来酸的乙酸乙酯溶液，至出现沉淀停止，加入去离子水；
    (3)向步骤(2)所得反应体系中再加入马来酸的乙酸乙酯溶液，加热搅拌，降温析晶，分离晶体，得到所述晶型K。
  8. 根据权利要求7所述的制备方法，其特征在于，式I化合物与马来酸的摩尔比为1:(1.95～2.05)。
  9. 根据权利要求8所述的制备方法，其特征在于，所述去离子水与乙酸乙酯的体积比为(0.01～0.02):1。
  10. 根据权利要求9所述的制备方法，其特征在于，步骤(1)式I化合物与乙酸乙酯的混合液中，式I化合物的浓度为0.5～1.5g/mL；步骤(2)和(3)中所述马来酸的乙酸乙酯溶液的浓度为0.05～0.5mol/L。
  11. 一种式I所示化合物的二马来酸盐晶型E，
    Figure PCTCN2016080878-appb-100006
    所述晶型E的X-射线粉末衍射图(CuKα辐射)在以下衍射角2θ处具有特征峰：4.5±0.2°、12.0±0.2°、18.2±0.2°、19.8±0.2°、20.6±0.2°、21.9±0.2°、24.7±0.2°、25.3±0.2°。
  12. 根据权利要求11所述的晶型E，其特征在于，所述特征峰的相对强度为：
    Figure PCTCN2016080878-appb-100007
  13. 一种式I所示化合物的二马来酸盐晶型F，
    Figure PCTCN2016080878-appb-100008
    所述晶型F的X-射线粉末衍射图(CuKα辐射)在以下衍射角2θ处具有特征峰：5.1±0.2°、11.5±0.2°、17.5±0.2°、18.7±0.2°、19.7±0.2°、23.3±0.2°、25.0±0.2°、26.2±0.2°。
  14. 根据权利要求13所述的晶型F，其特征在于，所述特征峰的相对强度为：
    Figure PCTCN2016080878-appb-100009
  15. 一种式I所示化合物的二马来酸盐晶型G，
    Figure PCTCN2016080878-appb-100010
    所述晶型G的X-射线粉末衍射图(CuKα辐射)在以下衍射角2θ处具有特征峰：4.5±0.2°、10.1±0.2°、15.1±0.2°、18.5±0.2°、25.8±0.2°。
  16. 根据权利要求15所述的晶型G，其特征在于，所述特征峰的相对强度为：
    Figure PCTCN2016080878-appb-100011
  17. 一种组合物，所述组合物中含有根据权利要求1-6任一项所述的式I化合物二马来酸盐晶型K、根据权利要求7-10任一项所述制备方法制备得到的式I化合物二马来酸盐晶型K、根据权利要求11或12所述的式I化合物二马来酸盐晶型E、根据权利要求13或14所述的式I化合物二马来酸盐晶型F、根据权利要求15或16所述的式I化合物二马来酸盐晶型G中的一种或几种。
  18. 根据权利要求1-6任一项所述的式I化合物二马来酸盐晶型K、根据权利要求7-10任一项所述制备方法制备得到的式I化合物二马来酸盐晶型K、根据权利要求11或12所 述的式I化合物二马来酸盐晶型E、根据权利要求13或14所述的式I化合物二马来酸盐晶型F、根据权利要求15或16所述的式I化合物二马来酸盐晶型G用于制备预防或治疗与EGFR和HER2激酶功能有关的适应症的药物中的用途，其中所述与EGFR和HER2激酶功能有关的适应症选自乳腺癌、卵巢癌、胃肠癌、食管癌、肺癌、头颈部鳞癌、胰腺癌、表皮鳞癌、前列腺癌、神经胶质瘤和鼻咽癌中的一种或几种。
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