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New erlotinib hydrochloride crystal form and preparation method thereof

A technology of erlotinib hydrochloride and crystal form, applied in the field of medicinal chemistry, can solve the problems of environmental hazards, unsuitable for industrial production, high price of trifluorotoluene, etc., and achieve the effects of low toxicity, good solubility and stable crystal form

Active Publication Date: 2015-05-13
SHANDONG JINCHENG PHARMACEUTICAL GROUP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, trifluorotoluene is used as a solvent in the preparation of the crystal form, and trifluorotoluene is expensive, not suitable for industrial production, and has great harm to the environment

Method used

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  • New erlotinib hydrochloride crystal form and preparation method thereof
  • New erlotinib hydrochloride crystal form and preparation method thereof
  • New erlotinib hydrochloride crystal form and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Preparation method of new crystal form of erlotinib hydrochloride

[0036] Add 5.0 g of erlotinib base into a dry and clean 250 mL four-neck flask, add 75 mL of ethanol, heat to 40°C, and stir for 30 min. After the solid dissolves, heat filter to remove insoluble matter. Pass in dry HCl gas under slow stirring, stir for 0.5h; cool to 3±3°C under stirring, stir for 1h; filter, rinse with 5mL ethanol, and dry the filter cake in a blast oven at 35°C for 6h to obtain erlohydrochloride A new crystal form of tinib.

[0037] The product quality is 5.40g, the yield is 99%, and the HPLC purity is 99.7%.

[0038] Carry out X-ray powder diffraction detection to present embodiment product, obtain as follows figure 1 and as figure 2 , carry out DSC detection to the present embodiment product, and as image 3 .

Embodiment 2

[0040] Preparation method of new crystal form of erlotinib hydrochloride

[0041] Add 5.0g of erlotinib base into a dry and clean 250mL four-necked bottle, add 75mL of methanol, heat to 40°C, stir for 30min, after the solid dissolves, heat filter to remove the insoluble matter, and pass in dry HCl under slow stirring Gas, stirred for 1h, cooled to 3±3°C under stirring, filtered for 1h, rinsed with 5mL of methanol, and the filter cake was dried in a blast oven at 30°C for 6h to obtain a new crystal form of erlotinib hydrochloride.

[0042] The quality of the product is 5.41 g, the yield is 99%, and the HPLC purity is 99.7%.

Embodiment 3

[0044] Preparation method of new crystal form of erlotinib hydrochloride

[0045] Add 5.0g of erlotinib base into a dry and clean 250mL four-necked bottle, add 75mL of isopropanol, heat to 50°C, and stir for 30min. HCl gas, stirred for 1.5h, cooled to room temperature under stirring, continued to cool to 7±3°C, continued to stir for 2h, filtered, rinsed with 5mL isopropanol, and dried the filter cake in a blast oven at 50°C for 8h to obtain A new crystal form of erlotinib hydrochloride.

[0046] The quality of the product is 5.41 g, the yield is 99%, and the HPLC purity is 99.7%.

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Abstract

The present invention relates to a new erlotinib hydrochloride crystal form and a preparation method thereof, wherein the 2theta characteristic peaks are positioned at 9.395+ / -0.2 DEG, 13.197+ / -0.2 DEG, 15.507+ / -0.2 DEG, 16.797+ / -0.2 DEG, 20.019+ / -0.2 DEG, 20.511+ / -0.2 DEG, 20.944+ / -0.2 DEG, 22.273+ / -0.2 DEG, 22.795+ / -0.2 DEG, 24.270+ / -0.2 DEG, and 24.969+ / -0.2 DEG in an x-ray powder diffraction pattern. The preparation method comprises: (1) adding erlotinib base to a solvent, and stirring until the erlotinib base is dissolved; (2) introducing dry HCl gas until no solid is precipitated, and stirring; (3) cooling under stirring to achieve a temperature of 0-10 DEG C; and (4) filtering and drying to obtain the product. According to the present invention, the crystal form is single, and stability is good; and the alcohol is adopted as a solvent, such that characteristics of low toxicity, simple method, high product purity and easy industrial production are provided.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a new crystal form of erlotinib hydrochloride and a preparation method thereof. Background technique [0002] Erlotinib hydrochloride, trade name: Tarceva, chemical name: 4-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)quinazoline-hydrochloride 4-amine. Erlotinib hydrochloride, first listed in the United States in 2004, is a reversible epidermal growth factor tyrosinase (EGFR) inhibitor for locally advanced and or metastatic non-small cell lung cancer. The structural formula is as follows: [0003] [0004] According to literature and related patent reports, erlotinib hydrochloride has various crystal forms, including amorphous form, A crystal form, B crystal form, E crystal form, M crystal form, N crystal form, and P crystal form. The physical and chemical properties of each crystal form are quite different. For example, compared with crystal form A, crystal form B is ther...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/94
Inventor 伊茂聪马庆双张新余于兆涛
Owner SHANDONG JINCHENG PHARMACEUTICAL GROUP CO LTD
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