WO2016101867A1 - 萘普替尼对甲苯磺酸盐的α晶型及制备方法和含有其的药物组合物 - Google Patents

萘普替尼对甲苯磺酸盐的α晶型及制备方法和含有其的药物组合物 Download PDF

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WO2016101867A1
WO2016101867A1 PCT/CN2015/098239 CN2015098239W WO2016101867A1 WO 2016101867 A1 WO2016101867 A1 WO 2016101867A1 CN 2015098239 W CN2015098239 W CN 2015098239W WO 2016101867 A1 WO2016101867 A1 WO 2016101867A1
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amino
fluorophenyl
ethoxy
quinazolinyl
chloro
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PCT/CN2015/098239
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French (fr)
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唐田
金锋
王彦青
吴婧
刘小柔
杨经安
冯汉林
于琳
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深圳市海王生物工程股份有限公司
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Priority to US15/539,070 priority Critical patent/US9957237B2/en
Publication of WO2016101867A1 publication Critical patent/WO2016101867A1/zh

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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
    • 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 belongs to the field of medical technology, and in particular to a novel crystalline form of naproxenil p-toluenesulfonate crystalline hydrate.
  • the compound is an inhibitor of a tyrosine kinase such as an epidermal growth factor receptor and can be used to treat or prevent diseases associated with tyrosine kinases such as epidermal growth factor receptors, such as cancer, particularly non-small cell lung cancer, colorectal cancer, Refractory non-small cell lung cancer, ovarian cancer, pancreatic cancer, breast cancer, glioma, brain tumor or neck cancer.
  • a tyrosine kinase such as an epidermal growth factor receptor
  • diseases associated with tyrosine kinases such as epidermal growth factor receptors, such as cancer, particularly non-small cell lung cancer, colorectal cancer, Refractory non-small cell lung cancer, ovarian cancer, pancreatic cancer, breast cancer, glioma, brain tumor or neck cancer.
  • One object of the present invention is to provide N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(two A new crystalline form of methylamino)-2-butenamide (napredniplatin) p-toluenesulfonate crystalline hydrate characterized by melting point, X-ray powder diffraction (XRD), differential scanning Calorimetric analysis (DSC), thermogravimetric analysis (TG), infrared spectroscopy (IR), and elemental analysis were performed, which have the properties required for the preparation of solid pharmaceutical formulations.
  • XRD X-ray powder diffraction
  • DSC differential scanning Calorimetric analysis
  • TG thermogravimetric analysis
  • IR infrared spectroscopy
  • a second object of the present invention is to provide N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4- Process for the preparation of a new crystalline form of (dimethylamino)-2-butenamide (napredniplatin) p-toluenesulfonate crystal hydrate.
  • a further object of the present invention is to provide a solution comprising the N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-
  • the present inventors prepared the N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(two)
  • the crude product is crystallized by recrystallization to obtain a new crystal form of 1.5 crystal water. That is, the alpha crystal form.
  • the characteristic diffraction peaks at 5.0 ⁇ 0.2, 17.6 ⁇ 0.2, and 18.7 ⁇ 0.2 (°) at 2 ⁇ are included, and the relative intensities (I/I 0 ) of these peaks are all greater than or equal to 20%.
  • the crystal may further comprise, in X-ray powder diffraction, 12.1 ⁇ 0.2, 14.5 ⁇ 0.2, 15.6 ⁇ 0.2, 20.1 ⁇ 0.2, 22.0 ⁇ 0.2, 25.4 ⁇ 0.2, 26.0 ⁇ 0.2, and 26.3 at 2 ⁇ . Characteristic diffraction peaks of ⁇ 0.2 (°), the relative intensities of these peaks are all greater than or equal to 7% (see Figure 1).
  • the alpha form of the invention can be characterized by an X-ray powder diffraction pattern. It is characterized in that its X-ray powder diffraction pattern has a characteristic peak represented by the above 2 ⁇ °, and its relative intensity is close to the following values:
  • the term "proximity” as used herein refers to the uncertainty of the relative intensity measurement. Those skilled in the art understand that the uncertainty of relative intensity is highly dependent on the measurement conditions. The uncertainty of the relative intensity is very dependent on the measurement conditions. The relative intensity value can vary, for example, within ⁇ 25% or preferably within ⁇ 10%.
  • the above ⁇ crystal form has an X-ray powder diffraction pattern shown in Fig. 1 .
  • the present invention employs differential scanning calorimetry (DSC) technique for N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl ]-4-(Dimethylamino)-2-butenamide (napredniplatin) is characterized by the alpha crystal form of 1.5 crystal hydrates of p-toluenesulfonate (see Figure 2) with differential scanning The maximum endothermic heat is at 133 °C. The endothermic process appears as an endothermic peak on the DSC spectrum;
  • the present invention employs a thermogravimetric analysis technique for N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-( Dimethylamino)-2-butenamide (napredniplatin) is characterized by the alpha crystal form of 1.5 crystal hydrates of tosylate (see Figure 3), which is characterized by thermogravimetry (TG). It shows a weight loss of 2.5% at 169 ° C, indicating that crystal water is lost at this temperature.
  • TG thermogravimetry
  • the elemental analysis data of the ⁇ crystal form of the present invention is in agreement with the theoretical value (within ⁇ 0.3% difference), further confirming that the compound contains 1.5 crystal water (see the table below).
  • the above N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4 is prepared.
  • -(Dimethylamino)-2-butenamide (napredniplatin) p-toluenesulfonate 1.5 crystal hydrates of the alpha crystalline form comprises: N-[4-[(3-chloro-4) -fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(dimethylamino)-2-butenamide (napredniplatin) p-toluene
  • the crude acid salt is added to a mixed solvent of a C 1 -C 4 alkyl alcohol and water or added to a mixed solvent of a C 3 -C 4 alkyl ketone and water, and heated to reflux until dissolved; after the solution is
  • the solid was collected by filtration, and the collected solid was dried under reduced pressure to give crystals.
  • the alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol and butanol, preferably ethanol; the volume ratio of alcohol to water (V/V) is from 11:1 to 20:1; the ketone is selected from the group consisting of acetone, Methyl ethyl ketone and n-butyl ketone, etc., preferably acetone, the volume ratio of ketone to water (V / V) is from 11:1 to 20:1; the ratio of the crude product to the solvent is weight to volume ratio (W / V) is 1 (g): 5 to 30 (ml), preferably 1:12 (g/ml).
  • the solution is preferably heated to 50 to 80 ° C, more preferably, the alcohol and water mixed solvent is heated to 70 ° C, and the ketone and water mixed solvent is heated to 60 ° C.
  • the precipitation is carried out for 2 to 8 hours, more preferably 4 hours.
  • the precipitation temperature is 0 to 40 ° C, preferably 5 to 15 ° C.
  • the drying temperature is 30 to 60 ° C, preferably 45 ° C.
  • a N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl group of the present invention] A pharmaceutical composition of the alpha form of 1,4-(dimethylamino)-2-butenamide (napredniplatin) p-toluenesulfonate 1.5 crystalline hydrate.
  • the composition contains the novel crystalline form of the compound and, optionally, a pharmaceutically acceptable carrier and/or excipient.
  • the above pharmaceutical composition can be further formulated into a form ready for administration according to a conventional formulation method, including an oral or parenteral administration form.
  • a therapeutically effective amount of N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazoline should be included.
  • therapeutically effective amount is meant that at this dose, the compounds of the invention are capable of ameliorating or alleviating the symptoms of the disease, or are capable of inhibiting or blocking the progression of the disease.
  • the present invention N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(dimethylamino)-
  • 2-butenamide (napredniplatin) p-toluenesulfonate alpha crystal form is consistent with naproxenil p-toluenesulfonate for the treatment of hyperproliferative diseases, preferably the hyperproliferative diseases
  • hyperproliferative diseases for cancer, including but not limited to non-small cell lung cancer, colorectal cancer, refractory non-small cell lung cancer, pancreatic cancer, ovarian cancer, breast cancer, glioma, brain cancer or cervical cancer.
  • the present invention produces N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(dimethyl Amino)-2-butenamide (naprednisol) p-toluenesulfonate alpha crystal form with stable morphology and defined melting point, good chemical stability, high temperature resistance and light, this new crystalline form N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(dimethylamino)-2- Butenamide (napredniplatin) p-toluenesulfonate has the properties required for the preparation of solid preparations, and is convenient to store, easier to produce, and easier to control.
  • Example 1 is an X-ray diffraction spectrum of a polymorph type ⁇ obtained in Example 1 of the present invention
  • Figure 2 is a DSC chart of the polymorph type ⁇ obtained in Example 1 of the present invention.
  • Figure 3 is a TG spectrum of polymorph type ⁇ obtained in Example 1 of the present invention.
  • Figure 4 is an IR spectrum of the polymorph ⁇ obtained in Example 1 of the present invention.
  • Fig. 5 is an HPLC chart of the polymorph ⁇ obtained in Example 1 of the present invention.
  • N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(dimethylamino)-2- Butenamide (Naproxil) is based on N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine, and is similar to the method of WO2007085638.
  • the salt forming process refers to the preparation method of the patent WO2012121764.
  • the obtained compound was 1.5 water of N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4- (Dimethylamino)-2-butenamide p-toluenesulfonate crystal form a.
  • Detection conditions Cu target K ⁇ ray, voltage 40kV, current 40mA, divergence slit 1/32°, anti-scatter slit 1/16°, anti-scatter slit 7.5mm, 2 ⁇ range: 3°-50°, step size 0.02 °, each step of stay time 40S.
  • Test basis The results of the IXFX ray powder diffraction method in the Appendix of the People's Republic of China (2010 Edition 2): Figure 1.
  • Test sample quality Sample 1: 2.27 mg (using an aluminum sample pan)
  • Test basis General rules for thermal analysis methods of JY/T 014-1996
  • thermogravimetric analyzer
  • Test basis General rules for thermal analysis methods of JY/T 014-1996
  • Test basis GB/T 6040-2002 General rules for infrared spectrum analysis
  • Test basis "Chinese Pharmacopoeia" two appendix VD high performance liquid chromatography
  • the obtained compound was N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4- (Dimethylamino)-2-butenamide p-toluenesulfonate crystal form ⁇ .
  • the obtained crystal forms ⁇ and ⁇ were investigated for stability (10-day accelerated test), and the water, purity, and maximum heterogeneity of the new crystal form were observed at 40 ° C, 60 ° C, humidity 75%, 92.5%, and light conditions.
  • the total impurity was compared with the data for 0 days, and the results showed that the obtained crystal form was stable.
  • the free base N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(dimethylamino
  • the degradation of 2-butene amide at 60 ° C indicates that high temperature has an effect on the stability of the free base.
  • the free base is based on N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine, and the method similar to patent WO2007085638 is used. preparation.
  • the purpose of developing the crystal form is mainly to solve the problem of dissolution and increase the dissolution.
  • the dissolution of prescriptions 1 to 2 was above 80% in 15 minutes.
  • the prescription 3 has a dissolution rate of less than 70% in 15 minutes.
  • the indicators of prescription 1 are better than prescription 3, so the products of ⁇ crystal form and free base are not only different in melting point, solubility, crystal solubility, etc.
  • the stability of the latter and the dissolution of the preparation The test indexes such as compressibility and disintegration degree are not as good as the crystal form of 1.5 crystal hydrate ⁇ of naproxenil p-toluenesulfonate of the present invention.

Abstract

本发明提供化合物N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺对甲苯磺酸盐1.5个结晶水合物的多晶型α，其具有稳定的形态和确定的熔点，化学稳定性好，耐高温和光照，适于制药用途。

Description

萘普替尼对甲苯磺酸盐的α晶型及制备方法和含有其的药物组合物 技术领域
本发明属于医药技术领域，具体地说，涉及萘普替尼对甲苯磺酸盐结晶水合物的新晶型。
背景技术
式(1)的化合物N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺(萘普替尼)对甲苯磺酸盐结晶水合物适用于治疗哺乳动物中的过度增殖性疾病，例如癌症。
Figure PCTCN2015098239-appb-000001
式(1)
该化合物是酪氨酸激酶例如表皮生长因子受体的抑制剂并可用来治疗或预防与酪氨酸激酶例如表皮生长因子受体有关的疾病，如癌症，特别是非小细胞肺癌、结肠直肠癌、顽固性非小细胞肺癌、卵巢癌、胰腺癌、乳腺癌、神经胶质瘤、脑瘤或颈部癌症。
发明内容
本发明的一个目的是提供N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺(萘普替尼)对甲苯磺酸盐结晶水合物的一种新晶型，其结晶的特征通过熔点、X-射线粉末衍射(XRD)、差示扫描量热分析(DSC)、热重分析(TG)、红外光谱(IR)、元素分析进行了表征，该晶型具备制备固体药物制剂所需要的性能。
本发明的第二个目的是提供N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺(萘普替尼)对甲苯磺酸盐结晶水合物新晶型的制备方法。
本发明的再一个目的是提供含有所述N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺(萘普替尼)对甲苯磺酸盐结晶水合物新晶型的药物组合物。
本发明人在制备所述N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺(萘普替尼)对甲苯磺酸盐结晶水合物的过程中，通过重结晶的方法对该物质粗品进行结晶，获得1.5个结晶水的新晶型，即α晶型。通过对该结晶进行熔点测量、X-射线粉末衍射、DSC、TG、IR、元素分析等检测和分析，确证获得的结晶是一种新型的结晶，称为N-[4-[(3-氯-4-氟苯基)氨]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺对甲苯磺酸盐1.5个结晶水的α晶型。
根据本发明的一方面，N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺(萘普替尼)对甲苯磺酸盐1.5个结晶水合物的α晶型，当用Cu辐射源进行X-射线粉末衍射时，所述的α晶型包括在位于2θ为5.0±0.2、17.6±0.2、18.7±0.2(°)的特征衍射峰，这些峰的相对强度(I/I0)均大于或等于20％。更进一步地，所述结晶在X-射线粉末衍射中还可以进一步包含位于2θ为12.1±0.2、14.5±0.2、15.6±0.2、20.1±0.2、22.0±0.2、25.4±0.2、26.0±0.2和26.3±0.2(°)的特征衍射峰，这些峰的相对强度均大于或等于7％(见图1)。
其中“±0.2”为允许的测量误差范围。
本发明的α晶型可以通过X-射线粉末衍射图谱进行表征。其特征在于其X射线粉末衍射图谱具有上述2θ°表示的特征峰，其相对强度接近下列数值：
Figure PCTCN2015098239-appb-000002
Figure PCTCN2015098239-appb-000003
此处的术语“接近”是指相对强度测量值的不确定性。本领域技术人员理解相对强度的不确定性非常依赖于测量条件。相对强度的不确定性非常依赖于测量条件。相对强度值可以例如在±25％范围内改变或优选在±10％范围内改变。
上述α晶型具有图1所示的X射线粉末衍射图谱。
本发明采用差示扫描量热(DSC)技术对N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺(萘普替尼)对甲苯磺酸盐1.5个结晶水合物的α晶型进行表征(见图2)，其中具有差示扫描量热的吸热最大值在133℃。该吸热过程在DSC谱图上表现为一吸热峰；
本发明采用热重分析技术对N-[4-[(3-氯-4-氟苯基)氨]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺(萘普替尼)对甲苯磺酸盐1.5个结晶水合物的α晶型进行表征(见图3)，其中其特征在于热重谱图(TG)显示在169℃失重2.5％，说明该温度下有结晶水失去。
本发明的1.5个结晶水合物的α晶型的红外图谱如图4所示，其中在3419、3284、3052、2930、2732、2589、1695、1640、1575、1543、1524、1498、1452、1400、1368、1328、1266、1238、1218、1185、1160、1121、1033、1008、814、684、568、500cm-1有较强吸收峰。
本发明的α晶型的元素分析数据与理论值吻合(相差±0.3％以内)，进一步确证该化合物含有1.5个结晶水(见下表)。
Figure PCTCN2015098239-appb-000004
根据本发明的另一方面，制备上述N-[4-[(3-氯-4-氟苯基)氨]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺(萘普替尼)对甲苯磺酸盐1.5个结晶水合物的α晶型的方法包括：将N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(乙氧 基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺(萘普替尼)对甲苯磺酸盐粗品，加入到C1-C4烷基醇和水的混合溶剂中或加入到C3-C4烷基酮和水的混合溶剂中，加热回流至溶解；溶液澄清后开始降温，至析出固体，过滤收集固体，将收集的固体减压干燥即得α晶型。所述的醇选自甲醇、乙醇、丙醇、异丙醇和丁醇，优选为乙醇；醇与水的体积比(V/V)11:1～20:1；所述的酮选自丙酮、甲基乙基酮和正丁酮等，优选为丙酮，酮与水的体积比(V/V)为11:1～20:1；所述的粗品与溶剂的配比为重量体积比(W/V)为1(g)：5～30(ml)，优选为1:12(g/ml)。将溶液优选加热到50～80℃，更优选醇和水混合溶剂加热至70℃，酮和水混合溶剂加热至60℃。根据此实施方案，析固进行2～8小时，更优选为4小时。析固温度为0～40℃，优选5～15℃。析固完全后过滤，烘干温度为30～60℃，优选为45℃。
根据本发明的又一方面，提供含有本发明N-[4-[(3-氯-4-氟苯基)氨]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺(萘普替尼)对甲苯磺酸盐1.5个结晶水合物的α晶型的药物组合物。该组合物含有所述新晶型化合物和任选的药学上可接受的载体和/或赋形剂。
上述药物组合物可进一步按照常规制剂方法配制成可供给药的形式，包括经口或胃肠外给药形式。在可供给药的形式中，应包含治疗有效量的N-[4-[(3-氯-4-氟苯基)氨]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺(萘普替尼)对甲苯磺酸盐的α晶型。所谓“治疗有效量“是指在该剂量下，本发明的化合物能够改善或减轻疾病症状，或能够抑制或阻断疾病的发展。
根据经验并考虑本领域的标准方法和参考文献，本领域技术人员可以很容易地选择各种载体和/或赋形剂并确定其用量。
本发明N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺(萘普替尼)对甲苯磺酸盐α晶型的应用范围与萘普替尼对甲苯磺酸盐一致，用于治疗过度增殖性疾病，优选所述的过度增殖性疾病为癌症，包括但不限于非小细胞肺癌、结肠直肠癌、顽固性非小细胞肺癌、胰腺癌、卵巢癌、乳腺癌、神经胶质瘤、脑癌或颈部癌症。
本发明制备得到了N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺(萘普替尼)对甲苯磺酸盐的α晶型，其具有稳定的形态和确定的熔点，化学稳定性好，耐高温和光照，这种新晶型的 N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺(萘普替尼)对甲苯磺酸盐具备了制备固体制剂所需要的性能，且贮存方便，生产操作更为简便，质量更易控制。
附图说明
图1是本发明实施例1所得的多晶型α的X射线衍射图谱；
图2是本发明实施例1所得的多晶型α的DSC图谱；
图3是本发明实施例1所得的多晶型α的TG图谱；
图4是本发明实施例1所得的多晶型α的IR图谱；
图5是本发明实施例1所得的多晶型α的HPLC图谱。
具体实施方式
所有原料和试剂均为商业购买。
粗品制备：
N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺(萘普替尼)以N-(3-氯-4-氟苯基)-7-氟-6-硝基-4-喹唑啉胺为起始原料，参考专利WO2007085638类似的方法来制备，成盐过程参考专利WO2012121764的制备方法。
制备N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨 基)-2-丁烯酰胺(萘普替尼)对甲苯磺酸盐的α晶型
[实施例1]
取200g萘普替尼对甲苯磺酸盐粗品加入到反应瓶中，加入2400ml的丙酮和水的混合溶剂中(V/V＝12:1)，搅拌下升温回流至60℃。溶解后搅拌10min，再降温至5～15℃，至固体析出再搅拌析晶4h，抽滤，滤饼用丙酮淋洗。滤饼于45℃鼓风干燥，用五氧化二磷助干。得类白色固体163g，收率81.5％。用卡尔费休测定仪检测水分为3.3％。得到的化合物为1.5个结晶水的N-[4-[(3-氯-4-氟苯基)氨]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺对甲苯磺酸盐晶型α。
化合物性状鉴定如图1～图5所示。
实施例样品的测试条件：
(一)XRD：
检测仪器：锐影(Empyrean)X射线衍射仪
检测条件：Cu靶Kα射线，电压40kV，电流40mA，发散狭缝1/32°，防散射狭缝1/16°，防散射狭缝7.5mm，2θ范围：3°-50°，步长0.02°，每步停留时间40S。
检测依据：中华人民共和国(2010年版二部)附录ⅨFⅩ射线粉末衍射法检测结果：如图1。
(二)DSC：
检测仪器：德国NETZSCH公司DSC 204F1差示扫描量热仪
检测条件：气氛：N2(纯度：≥99.99％)，20ml/min
扫描程序：从室温以10℃/min升温至180℃，记录升温曲线。
检测样品质量：样品1：2.27mg(使用铝质样品盘)
检测依据：JY/T 014-1996热分析方法通则
检测结果：如图2。
(三)TG：
检测仪器：德国NETZSCH公司TG209热重分析仪
检测条件：气氛：空气，20ml/min
扫描程序：室温～700℃，升温速率：10℃/min。
检测依据：JY/T 014-1996热分析方法通则
检测结果：如图3。
(四)红外光谱：
检测仪器：FT-IR NICOLET6700(德国)
检测条件：溴化钾压片法
检测依据：GB/T 6040-2002红外光谱分析方法通则
检测结果：如图4。
(五)HPLC
检测仪器：Agilent 1260series(美国)
检测条件：
色谱柱：Waters C18
流动相A：乙腈-流动相B(70:30)
流动相B：0.05mol/l磷酸二氢铵溶液(pH＝7.3)
柱温：30℃检测波长：247nm。
检测依据：《中国药典》二部附录VD高效液相色谱法
检测结果：如图5
[实施例2]
取200g萘普替尼对甲苯磺酸盐粗品加入到反应瓶中，加入1600ml的丙酮和水的混合溶剂中(V/V＝10:1)，搅拌下升温回流至60℃。溶解后搅拌10min，再降温至5～15℃，至固体析出再搅拌析晶4h，抽滤，滤饼用丙酮淋洗。滤饼于45℃鼓风干燥，用五氧化二磷助干。得类白色固体154g，收率77.0％。用卡尔费休测定仪检测水分为4.4％。得到的化合物为2个结晶水的N-[4-[(3-氯-4-氟苯基)氨]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺对甲苯磺酸盐晶型β。
[其他实施例]
各取20g萘普替尼对甲苯磺酸盐粗品加入到反应瓶中，参考实施例1～2的实验操作进行以下实验：
Figure PCTCN2015098239-appb-000005
Figure PCTCN2015098239-appb-000006
N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁 烯酰胺(萘普替尼)对甲苯磺酸盐晶型的稳定性考察
[实施例3]
将获得的晶型α和β进行稳定性考察(10天的加速试验)，在40℃、60℃、湿度75％、92.5％、光照条件下对新晶型的水分、纯度、最大单杂及总杂与0天的数据进行对比，结果显示获得的晶型稳定。而游离碱(N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺)在60℃条件下，降解明显，说明高温对游离碱的稳定性有影响。
表1晶型α影响因素试验结果
Figure PCTCN2015098239-appb-000007
Figure PCTCN2015098239-appb-000008
表2晶型β影响因素试验结果
Figure PCTCN2015098239-appb-000009
表3游离碱影响因素试验结果
Figure PCTCN2015098239-appb-000010
游离碱的制备方法：游离碱以N-(3-氯-4-氟苯基)-7-氟-6-硝基-4-喹唑啉胺为起始原料，参考专利WO2007085638类似的方法来制备。
固体药物制剂的制备
【实施例4】固体药物制剂的制备
处方1：
制法：上述成分按照常规制剂方法进行混合、直接压片。
处方2：
Figure PCTCN2015098239-appb-000012
制法：萘普替尼对甲苯磺酸盐1.5个结晶水合物α晶型与甘露醇、乳糖、交联聚维酮按等量倍增法混合均匀，加入预先配好的HPMC溶液制成软材，20目筛制粒，60℃干燥30分钟，18目筛整粒，加入微粉硅胶，混合均匀，装入2#胶囊即可。
处方3：
Figure PCTCN2015098239-appb-000013
制法：上述成分按照常规制剂方法进行混合、直接压片。
【实施例5】影响因素对照试验
按实施例4中的处方1～3工艺制备3批样品，经基本项目考察合格后，分别进行光照，高温和高湿试验，考察样品的外观性状、含量和溶出度。影响因素的结果表明，样品在高温和光照条件下性质稳定，可以作为制剂参考处方和工艺，但处方3在25℃、RH75％以及25℃、RH92.5％条件下容易吸潮，在光照下容易产生降解产物。
表4
考察指标 处方1 处方2 处方3
溶出度 好 好 差
可压性 好 / 较好
崩解度 好 较好 差
研制晶型的目的主要是解决溶出度的问题，增大溶出。按照2010版药典溶出度试验表明处方1～2其在15分钟溶出度均在80％以上。而处方3在15分钟溶出度只有70％以下。在辅料一致的前提下，处方1的各项考察指标优于处方3，因此α晶型与游离碱的产品不光在熔点、溶解度、晶体溶解度等方面有差异，后者的稳定性、制剂溶出度、可压性、崩解度等各项考察指标都不如本发明的萘普替尼对甲苯磺酸盐1.5个结晶水合物α晶型。
以上对本发明较佳实施方式的描述并不限制本发明，本领域技术人员可以根据本发明做出各种改变或变形，只要不脱离本发明的精神，均应属于本发明所附权利要求的范围。

Claims (8)

  1. 式(1)化合物N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺对甲苯磺酸盐的α晶型，所述α晶型为含1.5个结晶水的N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺对甲苯磺酸盐水合物，其具有2θ°为5.0±0.2、12.1±0.2、14.5±0.2、15.6±0.2、17.6±0.2、18.7±0.2、20.1±0.2、22.0±0.2、25.4±0.2、26.0±0.2和26.3±0.2表示的特征峰的X射线粉末衍射图谱
    Figure PCTCN2015098239-appb-100001
  2. 根据权利要求1所述的N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺对甲苯磺酸盐的α晶型，其特征在于，所述的2θ°的相对强度I/I0约为下列数值：
    Figure PCTCN2015098239-appb-100002
  3. 根据权利要求1-2任一项所述的N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(乙氧 基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺对甲苯磺酸盐的α晶型，其特征在于，所述α晶型的DSC扫描的最大吸热转变约在133℃。
  4. 根据权利要求1-2任一项所述的N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺对甲苯磺酸盐的α晶型，其特征在于热重谱图显示在169℃失重2.5％。
  5. 根据权利要求1-2任一项所述的N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺对甲苯磺酸盐的α晶型，其特征在于用KBr压片测得的红外吸收图谱，其在约3419、3284、3052、2930、2732、2589、1695、1640、1575、1543、1524、1498、1452、1400、1368、1328、1266、1238、1218、1185、1160、1121、1033、1008、814、684、568、500cm-1处有吸收峰。
  6. 制备权利要求1所述的N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺对甲苯磺酸盐的α晶型的方法，包括下述步骤：
    1)将N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺对甲苯磺酸盐粗品，加入到C1-C4烷基醇和水的混合溶剂中或加入到C3-C4烷基酮和水的混合溶剂中，加热回流至溶解；
    其中所述的烷基醇选自甲醇、乙醇、丙醇、异丙醇和丁醇，醇与水的体积比为11:1～20:1；
    所述的烷基酮选自丙酮、甲基乙基酮和正丁酮，酮与水的体积比为11:1～20:1；
    所述的粗品与溶剂的配比为重量体积比1(g)：5～30(ml)，加热温度为50～80℃；
    2)溶液澄清后开始降温，至析出固体，过滤收集固体，将收集的固体减压干燥即得α晶型；
    其中析固进行2～8小时，析固温度为0～40℃，析固完全后过滤，烘干温度为30～60℃。
  7. 权利要求6所述的制备方法，其中步骤1)中所述的烷基醇为乙醇，烷基酮为丙酮，粗品与溶剂的重量体积比为1:12(g/ml)，醇和水混合溶剂加热至70℃，酮和水混合溶剂加热至60℃；
    步骤2)中析固时间为4小时，析固温度为5～15℃，烘干温度为45℃
  8. 含有权利要求1所述的N-[4-[(3-氯-4-氟苯基)氨基]-7-[3-(乙氧基)-6-喹唑啉基]-4-(二甲基氨基)-2-丁烯酰胺对甲苯磺酸盐的α晶型的药物组合物。
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