WO2014190804A1 - Method for preparing crystal form f of erlotinib hcl - Google Patents

Method for preparing crystal form f of erlotinib hcl Download PDF

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WO2014190804A1
WO2014190804A1 PCT/CN2014/075094 CN2014075094W WO2014190804A1 WO 2014190804 A1 WO2014190804 A1 WO 2014190804A1 CN 2014075094 W CN2014075094 W CN 2014075094W WO 2014190804 A1 WO2014190804 A1 WO 2014190804A1
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erlotinib
alcohol
butanol
organic solvent
mixture
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PCT/CN2014/075094
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French (fr)
Chinese (zh)
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温特S.
商永严
塔拉韦拉埃斯卡萨尼P.
贝伦古尔马尔莫R.
郑国荣
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埃斯特维华义制药有限公司
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Publication of WO2014190804A1 publication Critical patent/WO2014190804A1/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

Definitions

  • the present invention relates to a novel process for the preparation of erlotinib hydrochloride Form F. Background technique
  • Erlotinib has the structure of the formula I, and its chemical name is N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine.
  • Erlotinib is an inhibitor of the erbB family of carcinogenic and proto-carcinogenic proteins, such as the epidermal growth factor receptor (EGFR).
  • EGFR epidermal growth factor receptor
  • erlotinib is used to treat excessive sputum conditions in humans, such as pain. Erlotinib with its salt
  • Erlotinib HCl (Erlinib HCl) can exist in different polymorphic forms which differ from each other in stability, physical properties, spectral data and preparation methods.
  • the erlotinib hydrochloride crystal form F is disclosed for the first time in the patent application WO2009025876A2.
  • erlotinib hydrochloride Form F was prepared by adding concentrated hydrochloric acid to a 1,3-dioxolane solution of erlotinib free base.
  • this preparation method was found to be unsuitable for industrial scale preparation of j3 ⁇ 4 because 1,3-dioxolane is a highly flammable solvent which is not suitable for industrial scale preparation.
  • the preparation method does not have reproducibility for obtaining erlotinib hydrochloride Form F.
  • the erlotinib hydrochloride crystal form prepared according to the method of WO2009025876A2 is F or G type as shown in Comparative Examples 1 to 4 below.
  • the method comprising the C 4 alcohol erlotinib imatinib free base is dissolved in an organic solvent is added to the vaporized hydrogen, and The formed erlotinib hydrochloride was crystallized.
  • the method of the invention further comprises converting erlotinib hydrochloride Form F to another crystalline form.
  • the invention provides the following technical solutions:
  • a method of preparing nylon erlotinib hydrochloride Form F comprising the erlotinib in the C 4 alcohol Mie imatinib free organic solvent is added to the dissolved hydrogen in the gasification, and the formed Erlotinib hydrochloride crystallizes.
  • the inventors have unexpectedly discovered that the key to solving the technical problems of the present invention lies in two parameters, namely the order of addition of vaporized hydrogen and the nature of the solvent medium.
  • the present invention will be selected in the C 4 alcohol erlotinib imatinib travel mu Mie organic solution was added to the hydrogen in the gasification, gasification of hydrogen rather than added to the organic solution (4 In the erlotinib in the alcohol.
  • hydrochloric acid was prepared by adding an organic solution of hydrogen peroxide to a solution of erlotinib free base in 2-methylpropanol.
  • erlotinib a mixture of Forms F, G and A is obtained instead of the desired single Form F.
  • the hydrogenated hydrogen participates in the reaction in the form of an organic solution, rather than participating in the reaction in the form of an aqueous solution.
  • the organic solution of hydrogen peroxide can be prepared by any suitable method known in the art, including, for example, but not limited to, the passage of a vaporized hydrogen gas into a target organic solvent, or commercially available.
  • the solvent medium suitable for the erlotinib free base in the process of the invention is ( 4 alcohol, an organic solvent suitable for dissolving the hydrogenated hydrogen as described below.
  • the crystal form A is obtained instead of the desired crystal form.
  • the erlotinib free base used as a starting material in the process of the invention can be prepared by any method known in the art, including, for example, but not limited to, the process described in Example 20 of U.S. Patent 5,747,498 A.
  • erlotinib free hydrazine is dissolved in an alcohol.
  • the dissolution of erlotinib is achieved at 70 to 100 e C.
  • C 4 alcohol is selected from 1-butanol, 2-butanol, tert-butanol, 2-propanol, and mixtures thereof.
  • the organic solvent is a mixture of one or more c 3 -6 alcohols with one or more solvents selected from the group consisting of: c 5 -8 alkanes, c 5 _ 8 . cycloalkyl, c 6 8 aromatic hydrocarbon, ⁇ : 41 () alkyl ethers, C 4 1Q cycloalkyl ether, d 4 C 2 4 alkyl carboxylic acid ester....
  • the organic solvent is one or more c 3 -6 alcohols with one or more
  • Suitable alcohols include but are not limited to the present invention is n-propanol, isopropanol, n-butanol and tert-butanol;
  • Example 8 5 _ Suitable alkanes include, but are not limited to, c-heptane and hexane;
  • suitable c 5 -8 cycloalkanes include, but are not limited to, cyclohexane;
  • suitable c 6 -8 aromatic hydrocarbons include, but are not limited to, benzene, toluene, and xylene; suitable.
  • alkyl ethers include but are not limited to acetate outfitting;.
  • Suitable C “Examples of cycloalkyl groups include, but are not limited to, ethers tetrahydrofuran; c acid suitable D_ 4
  • Example 2 _ 4 alkyl esters include, but are not limited to acetate, isopropyl Propyl ester.
  • the amount of hydrogenated hydrogen is from 1 to 1.5 molar equivalents, preferably 1.2 molar equivalents, relative to the erlotinib free base.
  • the process of the invention is carried out at 0 to 60 e C, preferably at 20 to 50 ° C, and most preferably at 30 e C.
  • the temperature of the process embodiments described herein of the present invention refers to a C 4 alcohol erlotinib in a mixture of organic solvent for the nylon run off mu gasification and causing hydrogen erlotinib hydrochloride crystallization temperature.
  • the crystallization process of the invention is carried out under agitation.
  • the mash is kept for 30 to 90 minutes during which time a solid product precipitates.
  • the method of the present invention further comprises recovering the erlotinib hydrochloride crystal form by conventional methods such as filtration, washing and drying. .
  • the C 4 alcohol erlotinib was washed with erlotinib hydrochloride Form F.
  • the C 4 alcohol is preferably selected from 1-butanol, 2-butanol, tert-butanol, 2-propanol, and Its mixture.
  • drying can be carried out under reduced pressure until the residual solvent content is reduced to the desired amount.
  • the method of the invention further comprises converting erlotinib hydrochloride Form F to another crystalline form.
  • the other crystal forms include, but are not limited to, Forms A, 8, and (.
  • the crystal forms A, B, F and G referred to herein represent known crystal forms which have been reported in the literature, respectively, having XRPD characteristic peaks as defined in WO2009025876A2, namely: Form A: at 5.7, 9.8, 10.1 , 10.3, 18.9, 19.5, 21.3, 24.2, 26.2 and 29.2 ⁇ 0.2° 2 ⁇ have XRPD characteristic peaks.
  • Form B at 6.3, 7.8, 9.5, 12.5, 13.4, 20.2, 21.1, 22.4 and 28.9 ⁇ 0.2.
  • Form F at 5.6, 9.7, 11.2, 16.9, 21.1, 24.0, 25.3 and 26.0 ⁇ 0.2. 2 ⁇ has XRPD characteristic peaks.
  • Form G at 5.9, 9.7, 11.7, 12.7, 16.2 and 23.3 ⁇ 0.2. There are XRPD characteristic peaks at 2 ⁇ .
  • WO2009025876A2 is hereby incorporated by reference in its entirety.
  • Form C refers to 5.6, 5.8, 9.6, 19.5, 22.6 and 24.6 ⁇ 0.2.
  • a crystal form having an XRPD characteristic peak at 2 ⁇ further having an XRPD characteristic peak at 11.2, 16.2, 23.4 and 24.1 ⁇ 0.2 0 2 , having an X-ray powder diffraction pattern substantially as shown in Fig. 1.
  • the process of the present invention is more suitable for large scale preparation than prior art processes and is more reproducible in obtaining erlotinib hydrochloride Form F.
  • Figure 1 is an X-ray powder diffraction pattern of Form C prepared in accordance with the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS
  • An X-ray powder diffraction pattern was obtained using a PANalytical-X'Pert diffractometer (using CuKa-auxiliary).
  • the system is concealed as ⁇ - ⁇ , transmission geometry and mounted with 3152/63 focused X-ray mirror, 0.5 ° divergence and anti-scatter slit and 0.02 rad (rad) The incident soller slit.
  • the sample was loaded onto a PW3064/60 reflection/transmission rotary table.
  • the detector is a 3018/00 PIXcel detector fitted with a 2 mm anti-scatter slit for transmission and a 0.02 Radsole slit.
  • Approximately 10-20 mg of sample was loaded between the two transparent membranes using a standard sample holder. Data was collected using an X'Pert data collector (version 2.2 g ) and the data was processed with background correction against blank samples of the membrane.
  • Erlotinib free base (0.55 g ) was dissolved in 2-methylpropanol (20 mL) by heating to 60 C with stirring. The resulting solution was cooled to 50 C, and hydrogenated hydrogen (0.28 ml, 5.8 M isopropanol, 1.2 molar equivalents) was added dropwise over 15 minutes. The mixture was stirred at 50 ° C for 1 hour, filtered and washed with 2-methylpropanol (2 mL). The collected solid was vacuum dried at 50 e C. The product was analyzed by X-ray powder diffraction to determine a mixture of Forms F, G and A. Yield: 0.53 g (90%).
  • Erlotinib free hydrazine (1.0-1.2 g ) was added to the solvent shown in Table 2 below (corresponding amounts are shown in Table 2), heated and dissolved at 80-100 °C. The solution was added to a mechanically stirred hydrogenated gas (0.55 0.62 mL, 5.7 M isopropanol, 1.2 molar equivalents) in a solvent (5 mL) as shown in Table 2 at 30 ° C for 30 minutes. in. The mixture was stirred at 30 C for 1 hour, filtered and washed with a solvent (2 mL). The collected solid was vacuum dried at 50 °C. The product was analyzed by powder X-ray diffraction to determine the crystal form F. Table 2
  • the tour erlotinib mu base (10 g) was added to 2-methyl-propanol (100 mL) was heated and dissolved at 70 e C. The resulting solution was added to mechanically stirred hydrogenation (4.7 mL, 6 M isopropanol, 1.1 molar equivalents) in isopropyl acetate (50 mL) and 2-methylpropane at 30 ° C over 15 min. A mixed solution of alcohol (50 mL). The mixture was stirred at 30 Torr for 30 min, filtered and washed with EtOAc EtOAc. The collected solid was vacuum dried at 60 C. The product was analyzed by powder X-ray diffraction to determine the crystal form F. Yield: 9.55 g (87%).
  • Example 6 Erlotinib HCl Form F (100 m g ) was suspended in acetone (1 mL) and stirred at room temperature for 2 hours. The mixture was filtered and washed with acetone (1 mL ⁇ 2) and dried in vacuo at 60 ° C for 16 hours. The product was analyzed by powder X-ray diffraction and determined to be Form A.
  • Erlotinib HCl Form F (200 m g ) was suspended in ethanol (1 mL) and stirred at 60 ° C for 17 hours. The mixture was filtered and dried under vacuum at room temperature. The product was analyzed by powder X-ray diffraction and determined to be Form B.
  • Erlotinib HCl Form F (200 m g ) was suspended in 2-pentanol (2 mL) and stirred at room temperature for 1 hour. The mixture was filtered and dried under vacuum at room temperature for 16 h. The product was analyzed by powder X-ray diffraction to determine the crystal form C.

Abstract

The present invention relates to a new method for preparing crystal form F of erlotinib HCl. The method comprises adding an erlotinib free alkali in a C4 alcohol into hydrogen chloride dissolved in an organic solvent, and crystallizing the resulting erlotinib HCl. The method of the invention has the advantages of being suitable for large-scale preparation and having reproducibility. Furthermore, the method of the present invention also comprises the conversion of the crystal form F of erlotinib HCl into other crystal forms.

Description

一种制备盐酸厄洛替尼晶型 F的方法 技术领域  Method for preparing erlotinib hydrochloride crystal form F
本发明涉及一种制备盐酸厄洛替尼晶型 F的新方法。 背景技术  The present invention relates to a novel process for the preparation of erlotinib hydrochloride Form F. Background technique
厄洛替尼具有下式 I 结构，其化学名称为 N-(3-乙炔基苯基) -6,7- 双 (2-甲氧基乙氧基 )-4-喹唑啉胺。厄洛替尼是致癌和原致癌的蛋白賂氨 酸激酶的 erbB族的抑制剂，所述蛋白賂氨酸激酶例如为表皮生长因子 受体（ EGFR )。 因此厄洛替尼用于治疗人的过度坩殖性病症，例如痛 症。 厄洛替尼以其盐  Erlotinib has the structure of the formula I, and its chemical name is N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. Erlotinib is an inhibitor of the erbB family of carcinogenic and proto-carcinogenic proteins, such as the epidermal growth factor receptor (EGFR). Thus erlotinib is used to treat excessive sputum conditions in humans, such as pain. Erlotinib with its salt
Figure imgf000002_0001
式 I 。 盐酸厄洛替尼（ Erlotinib HC1 )可以不同的多晶型物形式存在，这 些多晶型物在稳定性、 物理性质、 光谱数据和制备方法方面彼此不同。
Figure imgf000002_0001
Formula I. Erlotinib HCl (Erlinib HCl) can exist in different polymorphic forms which differ from each other in stability, physical properties, spectral data and preparation methods.
盐酸厄洛替尼晶型 F首次在专利申请 WO2009025876A2中公开。 在该专利申请的实施例 7至 11中描述了通过将浓盐酸加入到厄洛替尼 游离碱的 1,3-二氧戊环溶液中来制备盐酸厄洛替尼晶型 F。然而，发现 该制备方法不适合工业规模化制备 j¾是因为 1,3-二氧戊环是一种不适 用于工业规模化制备的高度易燃溶剂。 另外，该制备方法对于获得盐 酸厄洛替尼晶型 F不具有重现性。如下文对比实施例 1 ~ 4所示，根据 WO2009025876A2的方法制备得到的盐酸厄洛替尼晶型是 F或 G型。  The erlotinib hydrochloride crystal form F is disclosed for the first time in the patent application WO2009025876A2. In Examples 7 to 11 of this patent application, erlotinib hydrochloride Form F was prepared by adding concentrated hydrochloric acid to a 1,3-dioxolane solution of erlotinib free base. However, this preparation method was found to be unsuitable for industrial scale preparation of j3⁄4 because 1,3-dioxolane is a highly flammable solvent which is not suitable for industrial scale preparation. In addition, the preparation method does not have reproducibility for obtaining erlotinib hydrochloride Form F. The erlotinib hydrochloride crystal form prepared according to the method of WO2009025876A2 is F or G type as shown in Comparative Examples 1 to 4 below.
因此有必要开发出一种适合工业化规横制备盐酸厄洛替尼晶型 F 且具有良好重现性的可靠方法。 发明内容  Therefore, it is necessary to develop a reliable method suitable for industrial preparation of erlotinib hydrochloride Form F with good reproducibility. Summary of the invention
本发明的目的在于提供一种制备盐酸厄洛替尼晶型 F的新方法， 该方法克服了现有技术的缺陷并允许以良好的收率在工业规模上获得 所需的晶型 F。 通过提供一种制备盐酸厄洛替尼晶型 F的方法来实现该目的，所 述方法包括将在 C4醇中的厄洛替尼游离碱加入到溶于有机溶剂的氣化 氢中，并使所形成的盐酸厄洛替尼结晶。 It is an object of the present invention to provide a novel process for the preparation of erlotinib hydrochloride Form F which overcomes the deficiencies of the prior art and allows the desired Form F to be obtained on an industrial scale in good yield. By providing a method for preparing nylon erlotinib hydrochloride Form F to achieve this object, the method comprising the C 4 alcohol erlotinib imatinib free base is dissolved in an organic solvent is added to the vaporized hydrogen, and The formed erlotinib hydrochloride was crystallized.
另外，本发明方法进一步包含将盐酸厄洛替尼晶型 F转化为其它 晶型。 本发明提供如下技术方案：  Additionally, the method of the invention further comprises converting erlotinib hydrochloride Form F to another crystalline form. The invention provides the following technical solutions:
1. 一种制备盐酸厄洛替尼晶型 F 的方法，所述方法包括将在 C4 醇中的厄洛替尼游离搣加入到溶于有机溶剂的氣化氢中，并使所形成 的盐酸厄洛替尼结晶。 A method of preparing nylon erlotinib hydrochloride Form F, said method comprising the erlotinib in the C 4 alcohol Mie imatinib free organic solvent is added to the dissolved hydrogen in the gasification, and the formed Erlotinib hydrochloride crystallizes.
2. 根据技术方案 1所述的方法，其中所述 C4醇选自 1-丁醇、 2- 丁醇、 叔丁醇、 2-甲基丙醇及其混合物。 2. The method according to aspect 1, wherein the C 4 alcohol is selected from 1-butanol, 2-butanol, tert-butanol, 2-propanol, and mixtures thereof.
3. 根据技术方案 1或 2所述的方法，其中所述有机溶剂选自一种 或更多种 C3_6醇。 3. The method according to claim 1 or 2, wherein the organic solvent is selected from one or more C 3 -6 alcohols.
4. 根据技术方案 1 - 3中任一项所述的方法，其中所述有机溶剂是 一种或更多种 C3_6醇与选自以下的一种或更多种溶剂的混合物： C5_8 烷烃、 C5.8环烷烃、 C6.8芳香烃、 。烷基酸、 。环烷基麒、 d.4羧 酸 C2-烧基酷。 4. According to Scenario 1 - The method as claimed in any one of 3, wherein said organic solvent is one or more C 3 _ 6 alcohol and selected from one or more solvents of a mixture of: C 5 _ 8 alkanes, C 5. 8 cycloalkane, C 6. 8 aromatic hydrocarbons. Alkyl acid, . Cycloalkyl hydrazine, d. 4 carboxylic acid C 2 - burnt base.
5. 根据技术方案 1 - 4中任一项所述的方法，其中所述有机溶剂是 一种或更多种 C3_6醇与一种或更多种 d_4羧酸 C2_4烷基酯的混合物。 The method according to any one of claims 1 to 4, wherein the organic solvent is one or more C 3 -6 alcohols and one or more d 4 carboxylic acids C 2 _ 4 alkane a mixture of base esters.
6. 根据技术方案 1 - 5中任一项所述的方法，其中在 0 ~ 60eC的温 度下进行所述方法。 6. The method according to any one of claims 1 to 5, wherein the method is carried out at a temperature of 0 to 60 e C.
7. 根据技术方案 1 - 6中任一项所述的方法，其中在 20 ~ 50°〇的 温度下进行所述方法。  The method according to any one of claims 1 to 6, wherein the method is carried out at a temperature of 20 to 50 °.
8. 根据技术方案 1 - 7中任一项所述的方法其中所述方法在 30°C 下进行。  The method according to any one of claims 1 to 7, wherein the method is carried out at 30 °C.
9. 根据技术方案 1 - 8中任一项所述的方法，其中相对于厄洛替尼 游离碱，氣化氢的用量是 1至 1.5摩尔当量，优选 1.2摩尔当量。  The method according to any one of claims 1 to 8, wherein the amount of the hydrogenated hydrogen is from 1 to 1.5 molar equivalents, preferably 1.2 molar equivalents, relative to the erlotinib free base.
10. 根据技术方案 1 - 9中任一项所述的方法，其还包括通过过滤、 洗涤和干燥来回收盐酸厄洛替尼晶型 F。 11. 根据技术方案 1 - 10中任一项所述的方法，其中用 c4 醇洗涤 盐酸厄洛替尼晶型 F。 10. The method of any one of claims 1-9, further comprising recovering erlotinib hydrochloride Form F by filtration, washing, and drying. The method according to any one of claims 1 to 10, wherein the erlotinib hydrochloride Form F is washed with c 4 alcohol.
12. 根据技术方案 1 - 11中任一项所述的方法，其中所述 C4醇选 自 1-丁醇、 2-丁醇、 叔丁醇、 2-甲基丙醇及其混合物。 The method of any one of claims 1 to 11, wherein the C 4 alcohol is selected from the group consisting of 1-butanol, 2-butanol, tert-butanol, 2-methylpropanol, and mixtures thereof.
13. 根据技术方案 1 - 12中任一项所述的方法，其还包括将盐酸厄 洛替尼晶型 F转化为其它晶型。  The method of any one of claims 1 to 12, further comprising converting erlotinib hydrochloride Form F to another crystalline form.
本发明人意外地发现，解决本发明的技术问颶的关键在于两种参 数，即氣化氢的加入顺序和溶剂介质的性质。  The inventors have unexpectedly discovered that the key to solving the technical problems of the present invention lies in two parameters, namely the order of addition of vaporized hydrogen and the nature of the solvent medium.
就氧化氢的加入顺序而言，本发明选择将在 C4醇中的厄洛替尼游 亩搣加入到氣化氢的有机溶液中，而不是将氣化氢的有机溶液加入到 在( 4醇中的厄洛替尼游禽碱中。 如下文对比实施例 5所示，当通过将 氣化氢的有机溶液加入到厄洛替尼游离碱的 2-甲基丙醇溶液中来制备 盐酸厄洛替尼时，获得的是晶型 F、 G和 A的混合物，而非所需的单 一晶型 F。 In terms of order of addition of hydrogen peroxide, the present invention will be selected in the C 4 alcohol erlotinib imatinib travel mu Mie organic solution was added to the hydrogen in the gasification, gasification of hydrogen rather than added to the organic solution (4 In the erlotinib in the alcohol. In the following, as shown in Comparative Example 5, hydrochloric acid was prepared by adding an organic solution of hydrogen peroxide to a solution of erlotinib free base in 2-methylpropanol. In the case of erlotinib, a mixture of Forms F, G and A is obtained instead of the desired single Form F.
在本发明方法中，氣化氢以有机溶液的形式参与反应，而非以水 溶液的形式参与反应。 氧化氢的有机溶液可以本领域已知的任何合适 方法来制备，例如包括但不限于将氣化氢气体通入目标有机溶剂中 ， 也可通过商购获得。  In the process of the present invention, the hydrogenated hydrogen participates in the reaction in the form of an organic solution, rather than participating in the reaction in the form of an aqueous solution. The organic solution of hydrogen peroxide can be prepared by any suitable method known in the art, including, for example, but not limited to, the passage of a vaporized hydrogen gas into a target organic solvent, or commercially available.
就溶剂介质而言，在本发明方法中，适用于厄洛替尼游离碱的溶 剂介质是 ( 4醇，适用于溶解氣化氢的有机溶剂如下文所述。 如下文对 比实施例 6 中所示，当通过将厄洛替尼游离碱的四氢呋喃溶液加入到 溶于四氢呋喃的氣化氢中来制备盐酸厄洛替尼时，获得的是晶型 A， 而非所需的晶型？。 In the case of the solvent medium, the solvent medium suitable for the erlotinib free base in the process of the invention is ( 4 alcohol, an organic solvent suitable for dissolving the hydrogenated hydrogen as described below. As in Comparative Example 6 below) It is shown that when erlotinib HCl is prepared by adding a solution of erlotinib free base in tetrahydrofuran to hydrogen sulfide dissolved in tetrahydrofuran, the crystal form A is obtained instead of the desired crystal form.
在本发明方法中用作起始原料的厄洛替尼游离碱可通过本领域已 知的任何方法来制备，例如包括但不限于美国专利 US5747498A中的 实施例 20所述方法。  The erlotinib free base used as a starting material in the process of the invention can be prepared by any method known in the art, including, for example, but not limited to, the process described in Example 20 of U.S. Patent 5,747,498 A.
在本发明的一种特别实施方式中，将厄洛替尼游离搣溶解在 醇 中。 优选在 70 ~ 100eC下实现厄洛替尼游亩搣的溶解。 In a particular embodiment of the invention, erlotinib free hydrazine is dissolved in an alcohol. Preferably, the dissolution of erlotinib is achieved at 70 to 100 e C.
在本发明方法的一种特别实施方式中 ， C4醇选自 1-丁醇、 2-丁 醇、 叔丁醇、 2-甲基丙醇及其混合物。 根据一种优选的实施方式，将氣化氢溶解在选自 c3_6醇及其混合 物的有机溶剂中。 In one particular embodiment of the method of the present invention, C 4 alcohol is selected from 1-butanol, 2-butanol, tert-butanol, 2-propanol, and mixtures thereof. According to a preferred embodiment, the vaporized hydrogen dissolved in an organic solvent selected from c 3 _ 6 alcohol and mixtures thereof.
在另一种优选实施方式中，所述有机溶剂是一种或更多种 c3_6醇 与选自以下的一种或更多种溶剂的混合物： c5_8烷烃、 c5_8环烷 、 c6.8 芳香烃、 <：4.1()烷基醚、 C4.1Q环烷基醚、 d.4羧酸 C2.4烷基酯。在更优选 的实施方式中，所述有机溶剂是一种或更多种 c3_6醇与一种或更多种In another preferred embodiment, the organic solvent is a mixture of one or more c 3 -6 alcohols with one or more solvents selected from the group consisting of: c 5 -8 alkanes, c 5 _ 8 . cycloalkyl, c 6 8 aromatic hydrocarbon, <: 41 () alkyl ethers, C 4 1Q cycloalkyl ether, d 4 C 2 4 alkyl carboxylic acid ester.... In a more preferred embodiment, the organic solvent is one or more c 3 -6 alcohols with one or more
C1-4羧酸 C2.4烷基酯的混合物。 C 1-4 carboxylic acid C 2. 4 alkyl ester mixture.
对于本发明，合适的 c3_6醇的实例包括但不限于正丙醇、 异丙醇、 正丁醇和叔丁醇；合适的 c5_8烷烃的实例包括但不限于庚烷和己烷； 合适的 c5_8环烷烃的实例包括但不限于环己烷；合适的 c6_8芳香烃的 实例包括但不限于苯、 甲苯和二甲苯；合适的 。烷基醚的实例包括 但不限于乙艤；合适的 C"。环烷基醚的实例包括但不限于四氢呋喃； 合适的 d_4羧酸 c2_4烷基酯的实例包括但不限于乙酸异丙酯。 For Examples 3 _ 6 c Suitable alcohols include but are not limited to the present invention is n-propanol, isopropanol, n-butanol and tert-butanol; Example 8 5 _ Suitable alkanes include, but are not limited to, c-heptane and hexane; Examples of suitable c 5 -8 cycloalkanes include, but are not limited to, cyclohexane; examples of suitable c 6 -8 aromatic hydrocarbons include, but are not limited to, benzene, toluene, and xylene; suitable. Examples of alkyl ethers include but are not limited to acetate outfitting;. Suitable C "Examples of cycloalkyl groups include, but are not limited to, ethers tetrahydrofuran; c acid suitable D_ 4 Example 2 _ 4 alkyl esters include, but are not limited to acetate, isopropyl Propyl ester.
在一种特别的实施方式中，相对于厄洛替尼游离碱，氣化氢的用 量是 1至 1.5摩尔当量，优选 1.2摩尔当量。  In a particular embodiment, the amount of hydrogenated hydrogen is from 1 to 1.5 molar equivalents, preferably 1.2 molar equivalents, relative to the erlotinib free base.
在一种优选的实施方式中，在 0 ~ 60eC下实施本发明方法，优选在 20 ~ 50°C下实施本发明方法，最优选在 30eC下实施本发明方法。 这里 所述的本发明方法的实施温度是指将在 C4醇中的厄洛替尼游亩滅与氣 化氢的有机溶液混合以及使盐酸厄洛替尼结晶的温度。 In a preferred embodiment, the process of the invention is carried out at 0 to 60 e C, preferably at 20 to 50 ° C, and most preferably at 30 e C. The temperature of the process embodiments described herein of the present invention refers to a C 4 alcohol erlotinib in a mixture of organic solvent for the nylon run off mu gasification and causing hydrogen erlotinib hydrochloride crystallization temperature.
在一种特别的实施方式中，本发明的结晶过程在搅拌条件下进行。 优选地，保持撹拌 30 ~ 90分钟，期间沉淀析出固体产物。  In a particular embodiment, the crystallization process of the invention is carried out under agitation. Preferably, the mash is kept for 30 to 90 minutes during which time a solid product precipitates.
本发明的方法进一步包括通过常规方法例如过滤、 洗涤和干燥来 回收盐酸厄洛替尼晶型？。  The method of the present invention further comprises recovering the erlotinib hydrochloride crystal form by conventional methods such as filtration, washing and drying. .
在优选的实施方式中，用 C4醇洗涤盐酸厄洛替尼的晶型 F，该 C4 醇优选选自 1-丁醇、 2-丁醇、 叔丁醇、 2-甲基丙醇及其混合物。 In a preferred embodiment, the C 4 alcohol erlotinib was washed with erlotinib hydrochloride Form F., The C 4 alcohol is preferably selected from 1-butanol, 2-butanol, tert-butanol, 2-propanol, and Its mixture.
在优选实施方式中，可在减压下进行干燥直到残余溶剂含量降低 至所需的量。  In a preferred embodiment, drying can be carried out under reduced pressure until the residual solvent content is reduced to the desired amount.
在本发明的另一方面中， 本发明的方法还包括将将盐酸厄洛替尼 晶型 F转化为其它晶型。所述其它晶型包括但不限于晶型 A、 8和(。 本文中所涉及的晶型 A、 B、 F和 G分别表示已被文献报道的已知 晶型，其具有如 WO2009025876A2中所定义的 XRPD特征峰，即： 晶型 A： 在 5.7, 9.8, 10.1, 10.3, 18.9, 19.5, 21.3, 24.2, 26.2和 29.2士 0.2° 2Θ处具有 XRPD特征峰。 In another aspect of the invention, the method of the invention further comprises converting erlotinib hydrochloride Form F to another crystalline form. The other crystal forms include, but are not limited to, Forms A, 8, and (. The crystal forms A, B, F and G referred to herein represent known crystal forms which have been reported in the literature, respectively, having XRPD characteristic peaks as defined in WO2009025876A2, namely: Form A: at 5.7, 9.8, 10.1 , 10.3, 18.9, 19.5, 21.3, 24.2, 26.2 and 29.2 ± 0.2° 2Θ have XRPD characteristic peaks.
晶型 B：在 6.3, 7.8, 9.5, 12.5, 13.4, 20.2, 21.1, 22.4和 28.9 ± 0.2。 2Θ 处具有 XRPD特征峰。  Form B: at 6.3, 7.8, 9.5, 12.5, 13.4, 20.2, 21.1, 22.4 and 28.9 ± 0.2. There are XRPD characteristic peaks at 2Θ.
晶型 F：在 5.6, 9.7, 11.2, 16.9, 21.1, 24.0, 25.3和 26.0 ± 0.2。 2Θ处具 有 XRPD特征峰。  Form F: at 5.6, 9.7, 11.2, 16.9, 21.1, 24.0, 25.3 and 26.0 ± 0.2. 2Θ has XRPD characteristic peaks.
晶型 G：在 5.9, 9.7, 11.7, 12.7, 16.2和 23.3士 0.2。 2Θ处具有 XRPD 特征峰。  Form G: at 5.9, 9.7, 11.7, 12.7, 16.2 and 23.3 ± 0.2. There are XRPD characteristic peaks at 2 Θ.
通过引用将 WO2009025876A2整体并入本文。  WO2009025876A2 is hereby incorporated by reference in its entirety.
本文中所涉及的晶型 C指在 5.6, 5.8, 9.6, 19.5, 22.6和 24.6 ± 0.2。 2Θ处具有 XRPD特征峰的晶型，其在 11.2, 16.2, 23.4和 24.1 ± 0.2 0 2Θ 处进一步具有 XRPD特征峰，其具有基本如附图 1所示的 X-射线粉末 衍射图。 有益效果 Form C referred to herein refers to 5.6, 5.8, 9.6, 19.5, 22.6 and 24.6 ± 0.2. A crystal form having an XRPD characteristic peak at 2 进一步 further having an XRPD characteristic peak at 11.2, 16.2, 23.4 and 24.1 ± 0.2 0 2 , having an X-ray powder diffraction pattern substantially as shown in Fig. 1. Beneficial effect
与现有技术方法相比，本发明方法更适合于大规模制备，并且在 获得盐酸厄洛替尼晶型 F方面更具重现性。 附图说明  The process of the present invention is more suitable for large scale preparation than prior art processes and is more reproducible in obtaining erlotinib hydrochloride Form F. DRAWINGS
图 1 为本发明制备的晶型 C的 X-射线粉末衍射图。 具体实施方式 实施例  Figure 1 is an X-ray powder diffraction pattern of Form C prepared in accordance with the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS
通过以下非限制性实施例更详细地说明本发明的方法。 以下实施 例不以任何方式对本发明进行限制。  The method of the invention is illustrated in more detail by the following non-limiting examples. The following examples are not intended to limit the invention in any way.
在以下对比实施例和实施例中，按照下列条件进行 X-射线粉末衍 射分析：  In the following comparative examples and examples, X-ray powder diffraction analysis was carried out under the following conditions:
利用 PANalytical - X'Pert衍射仪（使用 CuKa-辅射）获得 X-射 线粉末衍射图。 该***配匿为 Θ-Θ，透射几何并安装有 3152/63 聚焦 X-射线镜，0.5°散度（ divergence )和抗散射狭缝以及 0.02 拉德（ rad ) 的入射索勒（ soller )狭缝。 将样品加载到 PW3064/60反射 /透射旋转 台上。 检测器是 3018/00 PIXcel检测器，安装有用于透射的 2 mm抗 散射狭缝和 0.02拉德索勒狭缝。使用标准的样品架将约 10-20 mg的样 品装载在两展透明膜之间。使用 X'Pert数据收集器（版本 2.2g)收集数 据，并对照膜的空白样品用背景校正处理数据。 An X-ray powder diffraction pattern was obtained using a PANalytical-X'Pert diffractometer (using CuKa-auxiliary). The system is concealed as Θ-Θ, transmission geometry and mounted with 3152/63 focused X-ray mirror, 0.5 ° divergence and anti-scatter slit and 0.02 rad (rad) The incident soller slit. The sample was loaded onto a PW3064/60 reflection/transmission rotary table. The detector is a 3018/00 PIXcel detector fitted with a 2 mm anti-scatter slit for transmission and a 0.02 Radsole slit. Approximately 10-20 mg of sample was loaded between the two transparent membranes using a standard sample holder. Data was collected using an X'Pert data collector (version 2.2 g ) and the data was processed with background correction against blank samples of the membrane.
在以下对比实施例和实施例中，氣化氢的摩尔当量，相对于厄洛 替尼游亩碱计。  In the following comparative examples and examples, the molar equivalents of hydrogenated hydrogen are relative to erlotinib.
对比实施例 1 ~ 4  Comparative Example 1 ~ 4
将厄洛替尼游亩碱 (250 mg)和 1,3-二氧戊环 (10 mL)加热至下表 1 中显示的温度，并在该温度下保持 1 小时。 然后加入盐酸 (0.053 mL, 37% 水溶液, 1摩尔当量)。将混合物搅拌 10分钟，以 2eC/min的降温 速率冷却至 0 C，在 0 C下保持 1小时，过滤并用 1,3-二氧戊环 (1 mL) 洗涤。对所收集的固体于 60°C进行莫空干燥。通过 X-射线粉末衍射对 产物进行分析，确定为下表 1中所显示的晶型。 1 shows the temperature erlotinib travel mu base (250 m g) and 1,3-dioxolane (10 mL) was heated to the following table, and maintained at this temperature for 1 hour. Hydrochloric acid (0.053 mL, 37% aqueous solution, 1 molar equivalent) was then added. The mixture was stirred for 10 minutes, cooled to 0 C at a reduced rate of 2 e C/min, kept at 0 C for 1 hour, filtered and washed with 1,3-dioxolane (1 mL). The collected solid was subjected to vacuum drying at 60 °C. The product was analyzed by X-ray powder diffraction and determined to be the crystalline form shown in Table 1 below.
表 1  Table 1
Figure imgf000007_0001
对比实施例 5
Figure imgf000007_0001
Comparative Example 5
搅拌下，通过加热至 60 C将厄洛替尼游离碱 (0.55 g)溶解在 2-甲基 丙醇 (20 mL)中。 将所得溶液冷却至 50 C，并于 15分钟内滴加氣化氢 (0.28ml, 5.8M异丙醇中， 1.2摩尔当量)。 将混合物在 50°C下撖拌 1小 时，过滤并用 2-甲基丙醇 (2 mL)洗涤。 对所收集的固体于 50eC进行真 空干燦。 通过 X-射线粉末衍射对产物进行分析，确定为晶型 F、 G和 A的混合物。 收率： 0.53 g (90%)。 对比实施例 6 将厄洛替尼游亩碱 (1.0 g)加入到四氢呋喃 （10 mL)中，在 60eC下加 热并溶解。在 30°〇下，将所得溶液于 20分钟内加入到机械搅拌的氣化 氢（ 0.55ml， 5.7M异丙醇中， 1.2庫尔当量）的四氢呋喃（ 5mL )溶液 中。将混合物在 30eC下搅拌 90分钟，过滤并用四氢呋喃 （2 mL)洗涤。 对所收集的固体于 60°C进行真空干燥。通过粉末 X-射线衍射对产物进 行分析，确定为晶型 A。 实施例 1 ~ 4 Erlotinib free base (0.55 g ) was dissolved in 2-methylpropanol (20 mL) by heating to 60 C with stirring. The resulting solution was cooled to 50 C, and hydrogenated hydrogen (0.28 ml, 5.8 M isopropanol, 1.2 molar equivalents) was added dropwise over 15 minutes. The mixture was stirred at 50 ° C for 1 hour, filtered and washed with 2-methylpropanol (2 mL). The collected solid was vacuum dried at 50 e C. The product was analyzed by X-ray powder diffraction to determine a mixture of Forms F, G and A. Yield: 0.53 g (90%). Comparative Example 6 The tour erlotinib mu base (1.0 g) was added to a tetrahydrofuran (10 mL) was heated and dissolved at 60 e C. The resulting solution was added to a stirred solution of mechanically hydrogenated hydrogen (0.55 ml, 5.7 M isopropanol, 1.2 kuel equivalent) in tetrahydrofuran (5 mL) over 30 min. The mixture was stirred at 30 e C 90 min, filtered and washed with tetrahydrofuran (2 mL). The collected solid was vacuum dried at 60 °C. The product was analyzed by powder X-ray diffraction and determined to be Form A. Example 1 ~ 4
将厄洛替尼游离搣 (1.0-1.2 g)加入到下表 2所示溶剂（对应用量如 表 2中所示）中，在 80-100°C下加热并溶解。 在 30°〇下，将所得溶液 于 30分钟内加入到机械搅拌的氣化氢 (0.55 0.62 mL, 5.7M异丙醇中， 1.2摩尔当量)在表 2中所示溶剂 (5 mL)的溶液中。 将混合物在 30 C下 搅拌 1小时，过滤并用下表 2中显示的溶剂洗涤 (2 mL)。 对所收集的 固体于 50°C进行真空干燥。通过粉末 X-射线衍射对产物进行分析，确 定为晶型F。 表 2 Erlotinib free hydrazine (1.0-1.2 g ) was added to the solvent shown in Table 2 below (corresponding amounts are shown in Table 2), heated and dissolved at 80-100 °C. The solution was added to a mechanically stirred hydrogenated gas (0.55 0.62 mL, 5.7 M isopropanol, 1.2 molar equivalents) in a solvent (5 mL) as shown in Table 2 at 30 ° C for 30 minutes. in. The mixture was stirred at 30 C for 1 hour, filtered and washed with a solvent (2 mL). The collected solid was vacuum dried at 50 °C. The product was analyzed by powder X-ray diffraction to determine the crystal form F. Table 2
Figure imgf000008_0001
Figure imgf000008_0001
实施例 5  Example 5
将厄洛替尼游亩碱 (10 g)加入到 2-甲基丙醇 (100 mL)中，在 70eC下 加热并溶解。在 30°〇下，将所得溶液于 15分钟内加入到机械搅拌的氣 化氢 (4.7 mL, 6M异丙醇中， 1.1摩尔当量)在乙酸异丙酯 （50 mL)和 2- 甲基丙醇 (50 mL)的混合溶液中。 将混合物在 30Ό下搅拌 30分钟，过 滤并用 2-甲基丙醇 (20 mL)洗涤。 对所收集的固体于 60 C进行真空干 燥。通过粉末 X-射线衍射对产物进行分析，确定为晶型 F。收率：9.55g (87%)。 实施例 6 将盐酸厄洛替尼晶型 F (100 mg)悬浮在丙酮 (1 mL)中，并在室温下 搅拌 2小时。过滤该混合物，并用丙酮 (1 mLx2)洗涤，在 60°C下真空 干燦 16小时。 通过粉末 X-射线衍射对产物进行分析，确定为晶型 A。 The tour erlotinib mu base (10 g) was added to 2-methyl-propanol (100 mL) was heated and dissolved at 70 e C. The resulting solution was added to mechanically stirred hydrogenation (4.7 mL, 6 M isopropanol, 1.1 molar equivalents) in isopropyl acetate (50 mL) and 2-methylpropane at 30 ° C over 15 min. A mixed solution of alcohol (50 mL). The mixture was stirred at 30 Torr for 30 min, filtered and washed with EtOAc EtOAc. The collected solid was vacuum dried at 60 C. The product was analyzed by powder X-ray diffraction to determine the crystal form F. Yield: 9.55 g (87%). Example 6 Erlotinib HCl Form F (100 m g ) was suspended in acetone (1 mL) and stirred at room temperature for 2 hours. The mixture was filtered and washed with acetone (1 mL×2) and dried in vacuo at 60 ° C for 16 hours. The product was analyzed by powder X-ray diffraction and determined to be Form A.
实施例 7  Example 7
将盐酸厄洛替尼晶型 F(200 mg)悬浮在乙醇 (1 mL)中，并在 60°C 下搅拌 17小时。过滤该混合物，并在室温下进行真空干燥。 通过粉末 X-射线衍射对产物进行分析，确定为晶型 B。 Erlotinib HCl Form F (200 m g ) was suspended in ethanol (1 mL) and stirred at 60 ° C for 17 hours. The mixture was filtered and dried under vacuum at room temperature. The product was analyzed by powder X-ray diffraction and determined to be Form B.
实施例 8  Example 8
将盐酸厄洛替尼晶型 F (200 mg)悬浮在 2-戊醇 (2 mL)中并在室温 下搅拌 1小时。将混合物过滤并在室温下真空干燦 16小时。通过粉末 X-射线衍射对产物进行分析，确定为晶型 C。 Erlotinib HCl Form F (200 m g ) was suspended in 2-pentanol (2 mL) and stirred at room temperature for 1 hour. The mixture was filtered and dried under vacuum at room temperature for 16 h. The product was analyzed by powder X-ray diffraction to determine the crystal form C.
本发明上述实施方式和实施例的描述仅出于阐释和说明的目的， 并非以任何方式限制本发明。 很明显，本领域技术人灵根据本发明上 下文的教导可进行多种改动和变化。 这些改动和变化均落在权利要求 所限定的本发明精神和范围内。  The above description of the embodiments and the examples of the invention are intended to be illustrative and not restrictive. It will be apparent that various modifications and changes can be made in the art in accordance with the teachings of the invention. Such changes and modifications are intended to be included within the spirit and scope of the invention as defined by the appended claims.

Claims

权利要求书 Claim
1. 一种制备盐酸厄洛替尼晶型 F 的方法，所述方法包括将在 醇中的厄洛替尼游离搣加入到溶于有机溶剂的氣化氢中，并使所形成 的盐酸厄洛替尼结晶。  A method for preparing erlotinib hydrochloride Form F, which comprises adding erlotinib free hydrazine in an alcohol to a hydrogenated hydrogen dissolved in an organic solvent, and forming the formed hydrochloric acid Lotitinib crystallizes.
2. 根据权利要求 1所述的方法，其中所述 C4醇选自 1-丁醇、 2- 丁醇、 叔丁醇、 2-甲基丙醇及其混合物。 2. The method according to claim 1, wherein the C 4 alcohol is selected from 1-butanol, 2-butanol, tert-butanol, 2-propanol, and mixtures thereof.
3. 根据权利要求 1所述的方法，其中所述有机溶剂选自一种或更 多种 C3_6醇。 3. The method according to claim 1, wherein said organic solvent is selected from one or more C 3 _ 6 alcohol.
4. 根据权利要求 1所述的方法，其中所述有机溶剂是一种或更多 种 C3_6醇与选自以下的一种或更多种溶剂的混合物： ( 5_8烷 、 C5_8环 烷烃、 C6_8芳香烃、 C4-1。烷基醚、 C4-1。环烷基醚、 d_4羧酸 C2_4烷基酯。 4. The method according to claim 1, wherein said organic solvent is a mixture of one or more C 3 _ 6 alcohol and selected from one or more solvents: (5 _ 8 alkyl, C 5 _ 8 cycloalkane, C 6 -8 aromatic hydrocarbon, C 4-1 alkyl ether, C 4-1 cycloalkyl ether, d 4 carbon carboxylic acid C 2 _ 4 alkyl ester.
5. 根据权利要求 4所述的方法，其中所述有机溶剂是一种或更多 种 C3_6醇与一种或更多种 d_4羧酸 C2_4烷基酯的混合物。 The method according to claim 4, wherein said organic solvent is one or more d_ 2 _ 4 alkyl esters of a mixture of C 3 _ 6-carboxylic acid 4-ol with one or more C.
6. 根据权利要求 1所述的方法，其中在 0 ~ 60eC下进行所述方法。 6. The method of claim 1 wherein the method is performed at 0 ~ 60 eC .
7. 根据权利要求 6所述的方法其中在 20 ~ 50eC下进行所述方法。 7. The method of claim 6 wherein the method is performed at 20 to 50 eC .
8. 根据权利要求 7所述的方法，其中在 30eC下进行所述方法。 8. The method of claim 7, wherein the method is performed at 30 e C.
9. 根据权利要求 1所述的方法，其还包括通过过滤、 洗涤和干燥 来回收盐酸厄洛替尼晶型 F。  9. The method of claim 1 further comprising recovering erlotinib hydrochloride Form F by filtration, washing, and drying.
10. 根据权利要求 9所述的方法，其中用 C4 醇洗涤盐酸厄洛替尼 晶型 F。 10. The method according to claim 9, wherein the C 4 alcohol erlotinib washed with erlotinib hydrochloride Form F.
11. 根据权利要求 10所述的方法，其中所述( 4醇选自 1-丁醇、 2- 丁醇、 叔丁醇、 2-甲基丙醇及其混合物。 11. The method of claim 10, wherein the ( 4 alcohol is selected from the group consisting of 1-butanol, 2-butanol, tert-butanol, 2-methylpropanol, and mixtures thereof.
12. 根据权利要求 1所述的方法，其还包括将将盐酸厄洛替尼晶型 F转化为其它晶型。  12. The method of claim 1 further comprising converting erlotinib hydrochloride Form F to another crystalline form.
PCT/CN2014/075094 2013-05-28 2014-04-10 Method for preparing crystal form f of erlotinib hcl WO2014190804A1 (en)

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CN103333124B (en) * 2013-05-28 2015-03-25 埃斯特维华义制药有限公司 Preparation method of hydrochloric acid erlotinib crystal form F

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5747498A (en) * 1996-05-28 1998-05-05 Pfizer Inc. Alkynyl and azido-substituted 4-anilinoquinazolines
CN1276370A (en) * 1999-03-31 2000-12-13 辉瑞产品公司 Process for preparing anticancer compound, and intermediate
CN1751032A (en) * 2003-02-17 2006-03-22 霍夫曼-拉罗奇有限公司 Polymorph of {6,7-bis(2-methoxy-ethoxy)-quinazolin-4-yl}-(3e)
WO2007060691A2 (en) * 2005-11-23 2007-05-31 Natco Pharma Limited A novel process for the preparation of erlotinib
WO2008102369A1 (en) * 2007-02-21 2008-08-28 Natco Pharma Limited Novel polymorphs of erlotinib hydrochloride and method of preparation
WO2009025876A2 (en) * 2007-08-23 2009-02-26 Plus Chemicals, S.A. Crystalline forms of erlotinib hcl and formulations thereof
CN103333124A (en) * 2013-05-28 2013-10-02 埃斯特维华义制药有限公司 Preparation method of hydrochloric acid erlotinib crystal form F

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007138613A2 (en) * 2006-05-25 2007-12-06 Vittal Mallya Scientific Research Foundation A process for synthesis of [6,7-bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)amine hydrochloride
CN101602734B (en) * 2009-04-24 2011-07-20 浙江九洲药业股份有限公司 Method for preparing Erlotinib hydrochloride crystal form A

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5747498A (en) * 1996-05-28 1998-05-05 Pfizer Inc. Alkynyl and azido-substituted 4-anilinoquinazolines
CN1276370A (en) * 1999-03-31 2000-12-13 辉瑞产品公司 Process for preparing anticancer compound, and intermediate
CN1751032A (en) * 2003-02-17 2006-03-22 霍夫曼-拉罗奇有限公司 Polymorph of {6,7-bis(2-methoxy-ethoxy)-quinazolin-4-yl}-(3e)
WO2007060691A2 (en) * 2005-11-23 2007-05-31 Natco Pharma Limited A novel process for the preparation of erlotinib
WO2008102369A1 (en) * 2007-02-21 2008-08-28 Natco Pharma Limited Novel polymorphs of erlotinib hydrochloride and method of preparation
WO2009025876A2 (en) * 2007-08-23 2009-02-26 Plus Chemicals, S.A. Crystalline forms of erlotinib hcl and formulations thereof
CN103333124A (en) * 2013-05-28 2013-10-02 埃斯特维华义制药有限公司 Preparation method of hydrochloric acid erlotinib crystal form F

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