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Salts and polymorphs of pyrimidine compound, and pharmaceutical composition and preparation method and application of salts and polymorphs of pyrimidine compound

A kind of technology of compound and crystal form, applied in the field of salts and polymorphs of pyrimidine compounds

Inactive Publication Date: 2019-07-16
INVENTISBIO CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] However, clinical studies have shown that many patients quickly (12-14 months) develop resistance to these small molecule inhibitors of EGFR, that is, acquired drug resistance

Method used

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  • Salts and polymorphs of pyrimidine compound, and pharmaceutical composition and preparation method and application of salts and polymorphs of pyrimidine compound
  • Salts and polymorphs of pyrimidine compound, and pharmaceutical composition and preparation method and application of salts and polymorphs of pyrimidine compound
  • Salts and polymorphs of pyrimidine compound, and pharmaceutical composition and preparation method and application of salts and polymorphs of pyrimidine compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0151] Embodiment 1, hydrochloride crystal form III

[0152] 1 (31.21mg, 1.0eq) was dissolved in a mixed solvent of acetonitrile and dichloromethane (48v, 3 / 1), and hydrochloric acid (1.1eq) was added with stirring at 50°C. After the reaction solution was cooled to room temperature, it was stirred for 30 minutes. The resulting clear solution was then washed with N 2 The stream was concentrated to about 32v and a solid precipitated out immediately. The resulting suspension was stirred overnight at room temperature, and the solid was collected by filtration and dried in vacuo at 50° C. for about 4 hours to obtain the hydrochloride salt form III. The sample is off-white solid, and XRPD, DSC, TGA, DVS and 1 H-NMR characterization.

[0153] The hydrochloride salt form III has a high melting point (273°C, Figure 5 ) crystals (Table 1 and Figure 4 ). The sample has slight hygroscopicity, and the weight gain is about 1.86% under the condition of 80% relative humidity ( Figu...

Embodiment 2

[0157] Embodiment 2, phosphate crystal form I

[0158] 1 (30.20mg, 1.0eq) was dissolved in acetone (26v). After adding phosphoric acid (1.1eq) under stirring at room temperature, sticky matter was precipitated immediately, and a solid precipitated after continued stirring for 2 hours. After the suspension was stirred at room temperature for 3 hours, the solid was collected by filtration and vacuum-dried overnight at 50°C to obtain phosphate crystal form I. The sample was an off-white solid, and XRPD, DSC, TGA, DVS and 1 H-NMR characterization.

[0159] Phosphate crystal form I is a crystal with high crystallinity (Table 2 and Figure 9 ), high melting point (238°C, Figure 10 ) crystals. The sample is slightly hygroscopic, and its weight gain is about 0.61% ( Figure 12 ). 1 H-NMR and TGA results showed that the sample had 0.7% residual solvent, but no significant weight loss before 150°C ( Figure 10 and Figure 11 ), indicating that the sample is anhydrous. After the...

Embodiment 3

[0163] Example 3, Form I of p-toluenesulfonate salt

[0164] 1 (31.60mg, 1.0eq) was dissolved in acetone (25v), and p-toluenesulfonic acid (1.1eq) was added with stirring at room temperature. After about 2 minutes, a solid precipitated out. The suspension continued to stir at room temperature for about 6 hours. The solid was collected by filtration and dried in vacuo at 50°C overnight to obtain Form I of p-toluenesulfonate salt. The sample was an off-white solid, and XRPD, DSC, TGA, DVS and 1 H-NMR characterization.

[0165] Form I of p-toluenesulfonate salt has a melting point of 172°C ( Figure 15 ) crystals (Table 3 and Figure 14 ). The sample is slightly hygroscopic, with a weight gain of about 0.55% ( Figure 17 ). TGA showed that the sample had no obvious weight loss before 200°C ( Figure 15 ); 1 H-NMR shows that the sample has about 0.3% residual solvent, and the ratio of free base and p-toluenesulfonic acid is 1:1 ( Figure 16 ). This sample is probably anh...

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Abstract

The present invention relates to salts of a compound 1, polymorphs of the compound 1, and a pharmaceutical composition comprising the salts and the polymorphs. The salts are preferably a hydrochloride, a phosphate, a p-toluenesulfonate, a besylate, a succinate, a sulfate, a monohydrobromide, a dihydrobromide, or the like. The invention also relates to a preparation method and application of the salts and the polymorphs and the pharmaceutical composition comprising the salts and the polymorphs.

Description

technical field [0001] The present invention relates to a salt and polymorphic form of a pyrimidine compound, a pharmaceutical composition containing them, a method for preparing various salts and polymorphic forms, and an application in preparing the pharmaceutical composition. [0002] Background of the invention [0003] Epidermal growth factor receptor (EGFR) is a receptor tyrosine protein kinase, a transmembrane protein belonging to the erbB receptor family. [0004] EGFR regulates cell proliferation, survival, adhesion, migration and differentiation, and it is overactivated or continuously activated in a variety of tumor cells, such as lung cancer, breast cancer, prostate cancer and other cells. Abnormal activation of EGFR plays a key role in the transformation and growth of tumors. Blocking the activation of EGFR has been clinically proven to be one of the effective methods for targeted therapy of tumor cells. EGFR is expressed in 50% of NSCLC (non-small cell lung ca...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04A61K31/506A61K45/06A61P35/00A61P35/02
CPCC07D403/04A61P35/00A61P35/02C07B2200/13
Inventor 代星江岳恒刘艳琴
Owner INVENTISBIO CO LTD
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