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Pharmaceutical salt of EGFR inhibitor and crystal form, preparation method and application of pharmaceutical salt

A technology of inhibitors and medicinal salts, applied in the field of medicine, can solve the problems of lack of research and protection of medicinal forms of raw materials, meet the requirements of bioavailability and drug efficacy, high solubility and stability, and facilitate processing and operation Effect

Active Publication Date: 2017-09-19
WUXI SHUANGLIANG BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the above-mentioned application lacks the research and protection of the pharmaceutical form (such as the base crystal form) of the raw material drug, and needs to be further developed and improved.

Method used

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  • Pharmaceutical salt of EGFR inhibitor and crystal form, preparation method and application of pharmaceutical salt
  • Pharmaceutical salt of EGFR inhibitor and crystal form, preparation method and application of pharmaceutical salt
  • Pharmaceutical salt of EGFR inhibitor and crystal form, preparation method and application of pharmaceutical salt

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0070] The preparation method of the crystal form of the pharmaceutically acceptable salt of the EGFR inhibitor comprises:

[0071] The EGFR inhibitor in the form of free base and an acid form a salt in alcohol solvent or water, and then add (preferably dropwise) a ketone solvent for crystallization to obtain the crystalline form of the pharmaceutically acceptable salt of the EGFR inhibitor. The EGFR inhibitor in free base form and the acid preferably form equimolar salts.

[0072] Preferably, the alcoholic solvent has 1-6 carbon atoms; more preferably, the alcoholic solvent is methanol or ethanol.

[0073]Preferably, in the above preparation method, the amount ratio of the alcohol solvent to the EGFR inhibitor is 2-5ml:1g, preferably 3ml:1g.

[0074] Preferably, in the above preparation method, the ketone solvent has 3-6 carbon atoms; more preferably, the ketone solvent is acetone.

[0075] Preferably, in the above preparation method, the dosage ratio of the ketone solvent ...

Embodiment 1

[0088] Example 1: EGFR inhibitor mesylate (form A).

[0089] At room temperature, weigh the EGFR inhibitor (12.0 g, 24 mmol) in the form of free base, put it in a 500 mL single-necked bottle, and add 36 mL of ethanol. Add methanesulfonic acid (2.32g, 24mmol), stir and dissolve at 40-50°C. Then 240 mL of acetone was added dropwise, stirred at 0-5°C, and a gray solid was precipitated. Suction filtration, rinse the filter cake with a small amount of acetone, and dry in a vacuum oven at 60°C to obtain a light brown solid (10.1g, purity 99.0%, moisture 0.97%, melting point 150.5-152.8°C).

[0090] The structural confirmation data of the above products are as follows:

[0091] 1 H-NMR (400MHz, DMSO-d 6 ):δ9.47(1H,s),9.39(1H,s),9.30(1H,s),9.15(1H,s),8.62(1H,s),8.56~8.55(1H,d),8.48~ 8.47(1H,d),8.25~8.24(1H,d),8.06~8.04(1H,d),7.76(1H,s),7.33~7.30(1H,m),7.06(1H,s),6.83~ 6.79(1H,dd),6.46~6.41(1H,d),5.89~5.86(1H,d),4.00(3H,s),3.95(3H,s),3.27(4H,m),2.84(6H, s), 2.64(3H,s), 2.29(3H,s...

Embodiment 2

[0097] Example 2: EGFR inhibitor p-toluenesulfonate (form B).

[0098] At room temperature, weigh the EGFR inhibitor (9.0 g, 18 mmol) in the form of free base, put it in a 500 mL single-necked bottle, and add 27 mL of ethanol. Add p-toluenesulfonic acid monohydrate (4.56g, 18mmol), stir and dissolve at 40-50°C. Then 240 mL of acetone was added dropwise, and a gray solid was precipitated. After suction filtration, the filter cake was rinsed with a small amount of acetone and dried to obtain a light brown solid (10.1 g, purity 98.7%, moisture 0.57%, melting point 240.1-243.2°C).

[0099] The structural confirmation data of the above products are as follows:

[0100] 1 H-NMR (400MHz, DMSO-d 6 ):δ9.47(1H,s),9.37(1H,s),9.24(1H,s),9.14(1H,s),8.56~8.55(1H,d),8.48~8.47(1H,d), 8.24~8.23(1H,d),8.07~8.05(1H,d),7.77(1H,s),7.50~7.49(2H,d),7.30~7.29(1H,m),7.06(1H,s), 6.80~6.76(1H,dd),6.45~6.41(1H,d),5.88~5.86(1H,d),4.00(3H,s),3.95(3H,s),3.27(4H,m),2.84( 3H, s), 2.64(3H, s), 2.29(3H, ...

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Abstract

The invention provides pharmaceutical salt of an EGFR inhibitor and a crystal form, preparation method and application of the pharmaceutical salt. The structural formula of the EGFR inhibitor is as shown in formula I. The pharmaceutical salt is the mesylate, the tosilate, the phosphate, the hydrochloride or the citrate of the EGFR inhibitor. The pharmaceutical salt has the advantages that the pharmaceutical salt has the specific crystal form, the solubility and the stability of the pharmaceutical salt are higher than those of corresponding free alkali, the pharmaceutical salt is suitable for being used to prepare drugs for treating cancer (especially non-small-cell lung cancer), and the bioavailability and drug effect requirements are satisfied.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a medicinal salt of an EGFR inhibitor, its crystal form, a preparation method and an application. Background technique [0002] Targeted therapy targeting epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations is the current standard of care for patients with advanced non-small cell lung cancer (NSCLC). However, the drug effect of these drugs is generally very short-lived, and drug resistance will occur within 9 to 11 months. The reason is that cancer cells can evade the therapeutic activity of EGFR or ALK inhibitors by mutating and changing their growth patterns. It has been reported that for Asian patients with advanced NSCLC, 50% of the acquired resistance to anti-EGFR therapy is caused by the T790M mutation. [0003] In order to overcome the related drug resistance caused by T790M mutation, some irreversible ATP competitive inhibitors (such as ...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07C309/04C07C309/30C07C59/265A61P35/00
CPCC07D471/04C07B2200/13A61P35/00A61K31/437C07D403/04C07D403/02
Inventor 周平吴家权金深霜李莉
Owner WUXI SHUANGLIANG BIOTECH CO LTD
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