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Preparation method of hydrochloric acid erlotinib crystal form F

A technology for erlotinib hydrochloride and crystal form, which is applied in the field of preparing erlotinib hydrochloride crystal form F, can solve the problem that it is not suitable for highly flammable solvents, is not suitable for industrial-scale preparation, and is not suitable for erlotinib hydrochloride crystal form F. No reproducibility, etc.

Active Publication Date: 2013-10-02
ESTEVE HUAYI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this preparation method was found to be unsuitable for industrial scale preparation because 1,3-dioxolane is a highly flammable solvent unsuitable for industrial scale preparation
In addition, the preparation method is not reproducible for obtaining erlotinib hydrochloride Form F

Method used

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  • Preparation method of hydrochloric acid erlotinib crystal form F
  • Preparation method of hydrochloric acid erlotinib crystal form F

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0053] The method of the present invention is illustrated in more detail by the following non-limiting examples. The following examples do not limit the invention in any way.

[0054] In the following comparative examples and examples, X-ray powder diffraction analysis was performed under the following conditions:

[0055] The X-ray powder diffraction pattern was obtained using a PANalytical-X’Pert diffractometer (using CuKα-radiation). The system is configured for θ-θ, transmission geometry and installed with a 3152 / 63 focusing X-ray mirror, 0.5o divergence and anti-scatter slits, and 0.02 rad incident soller slit . Load the sample on the PW3064 / 60 reflection / transmission rotating stage. The detector is a 3018 / 00 PIXcel detector, equipped with a 2 mm anti-scatter slit for transmission and a 0.02 rad Soler slit. Use a standard sample holder to load approximately 10-20 mg of sample between the two transparent films. The X'Pert data collector (version 2.2g) was used to collect d...

Embodiment 1～4

[0066] Erlotinib free base (1.0-1.2 g) was added to the solvent shown in Table 2 below (the corresponding amount is shown in Table 2), heated and dissolved at 80-100°C. At 30°C, the resulting solution was added to a mechanically stirred solution of hydrogen chloride (0.55~0.62 mL, 5.7M isopropanol, 1.2 molar equivalent) in the solvent (5 mL) shown in Table 2 within 30 minutes. The mixture was stirred at 30°C for 1 hour, filtered and washed with the solvent shown in Table 2 below (2 mL). The collected solid was vacuum dried at 50°C. The product was analyzed by powder X-ray diffraction and determined to be crystal form F.

[0067] Table 2

[0068] Example No. Solvent Volume (mL) Yield Crystal form 1 1-butanol10 1.01g (90%)F 2 2-butanol10 0.99g (88%)F 3 Tert-butanol15 0.97g (87%)F 4 2-methylpropanol10 1.00 g (82%) F

Embodiment 5

[0070] Erlotinib free base (10 g) was added to 2-methylpropanol (100 mL), heated at 70°C and dissolved. At 30°C, the resulting solution was added to mechanically stirred hydrogen chloride (4.7 mL, 6M isopropanol, 1.1 molar equivalent) in isopropyl acetate (50 mL) and 2-methylpropanol (50 mL) within 15 minutes. mL) of the mixed solution. The mixture was stirred at 30°C for 30 minutes, filtered and washed with 2-methylpropanol (20 mL). The collected solid was vacuum dried at 60°C. The product was analyzed by powder X-ray diffraction and determined to be crystal form F. Yield: 9.55g (87%).

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Abstract

The invention relates to a novel preparation method of hydrochloric acid erlotinib crystal form F. The method comprises steps that erlotinib free alkali in C4 alcohol is added into hydrogen chloride dissolved in an organic solvent, and the formed hydrochloric acid erlotinib is crystallized. The method has the advantages of suitability for mass production and good reproducibility. Furthermore, the invention also comprises a method of converting hydrochloric acid erlotinib crystal form F into other forms.

Description

technical field [0001] The invention relates to a new method for preparing crystal form F of erlotinib hydrochloride. Background technique [0002] Erlotinib has the following formula I structure, and its chemical name is N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. Erlotinib is an inhibitor of the erbB family of oncogenic and proto-oncogenic protein tyrosine kinases, such as the epidermal growth factor receptor (EGFR). Erlotinib is therefore useful in the treatment of hyperproliferative disorders, such as cancer, in humans. Erlotinib is sold as its hydrochloride salt. [0003] [0004] Formula I. [0005] Erlotinib HCl can exist in different polymorphic forms which differ from each other in terms of stability, physical properties, spectroscopic data and methods of preparation. [0006] The crystal form F of erlotinib hydrochloride was first disclosed in the patent application WO2009025876A2. The preparation of erlotinib hydrochloride form F by ad...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/94
CPCC07D239/94
Inventor S.温特商永严P.塔拉韦拉埃斯卡萨尼R.贝伦古尔马尔莫郑国荣
Owner ESTEVE HUAYI PHARMA
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