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Phosphate of epidermal growth factor receptor inhibitor, and crystal form and preparation method thereof

A phosphate and crystal form technology, which is applied in the field of chemical medicine, can solve the problems of high biotoxicity of methanesulfonic acid and unsuitability for drug synthesis, and achieve the goal of overcoming the high toxicity of methanesulfonic acid salt, meeting the requirements of bioavailability and drug efficacy, free Effect of improving alkali solubility

Inactive Publication Date: 2015-10-07
CRYSTAL PHARMATECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, methanesulfonic acid has high biological toxicity and is not suitable for pharmaceutical use in selected cases

Method used

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  • Phosphate of epidermal growth factor receptor inhibitor, and crystal form and preparation method thereof
  • Phosphate of epidermal growth factor receptor inhibitor, and crystal form and preparation method thereof
  • Phosphate of epidermal growth factor receptor inhibitor, and crystal form and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Preparation method of phosphate:

[0058] Dissolve 10.1 mg of free base of the compound of formula (I) in 0.5 mL of acetone, add 0.1 mL of 0.2 mol / L phosphoric acid solution dropwise, and react with stirring at room temperature for 24 hours to obtain phosphate.

[0059] The phosphate product prepared by the above method, its NMR identification data are as follows:

[0060] 1H NMR(400MHz,DMSO)δ10.04(s,1H),9.03(s,1H),8.63(s,1H),8.33(d,J=5.3Hz,1H),8.27(d,J=7.9Hz ,1H),7.91(s,1H),7.53(d,J=8.1Hz,1H),7.25(dd,J=8.7,6.3Hz,2H),7.16(t,J=7.5Hz,1H),7.03 (s,1H),6.55(d,J=10.3Hz,1H),6.29(dd,J=16.9,1.9Hz,1H),5.84–5.71(m,1H),3.92(s,3H),3.88( s,3H),3.04(s,2H),2.69(s,3H),2.62(s,2H),2.41(s,6H).

[0061] After testing, the solid obtained in this example is crystal form A, and its X-ray powder diffraction data are shown in Table 1. Its XRPD pattern is as follows figure 1 , and its DSC graph is shown in figure 2 , and its TGA figure is shown in image 3 .

[0062] Table 1 X-ray powde...

Embodiment 2

[0066] Preparation method of phosphate:

[0067] Dissolve 10.2 mg of the free base of the compound of formula (I) in 0.5 mL of ethanol, add dropwise 0.1 mL of 0.2 mol / L phosphoric acid solution, and stir at room temperature for 24 hours to obtain phosphate.

[0068] After testing, the solid obtained in this example is crystal form A, and its X-ray powder diffraction data are shown in Table 2.

[0069] Table 2 X-ray powder diffraction data of crystal form A

[0070] 2theta d interval strength% 7.43 11.91 31.68 8.17 10.83 28.63 8.57 10.32 16.45 9.76 9.06 100.00 10.70 8.27 57.18 11.85 7.47 7.92 12.25 7.22 13.48 12.85 6.89 3.59 13.60 6.51 22.65 15.20 5.83 15.23 16.37 5.41 35.12 16.78 5.28 19.18 17.49 5.07 17.43 19.51 4.55 41.64 21.51 4.13 24.69 22.56 3.94 20.93 23.55 3.78 13.26 24.47 3.64 37.67

[0071] 25.06 3.55 31.75 25.64 3.47 16.14 ...

Embodiment 3

[0073] Comparative study on dynamic solubility of compound phosphate and free base of formula (I):

[0074] The formula (I) compound phosphate and free base were respectively treated with H 2 O and SGF (simulated gastric fluid, artificial gastric juice) at pH 1.8 were prepared into a saturated solution, and the content was measured by high performance liquid chromatography (HPLC) after 1 hour, 4 hours and 24 hours respectively. The experimental results are shown in Table 3.

[0075] table 3

[0076]

[0077] The results showed that the solubility of phosphate in water was much higher than that of free base in water, and during the analysis, it was found that free base was degraded in SGF within 24 hours, and its stability in biological media was poor, which was not conducive to drug production. The invention overcomes the problems of low solubility of free base and instability in biological media by forming phosphate, and achieves the effect of improving bioavailability. ...

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Abstract

The invention relates to phosphate of a compound as shown in the formula (I) which is described in the specification, and a crystal form and a preparation method thereof. The phosphate of the compound has a stable crystal form; the crystal form has favorable performance like good solubility, low hygroscopicity and process developability; and the preparation method is simple and has low cost, so the method has an important value to optimization and development of the phosphate of the compound as a drug in the future.

Description

technical field [0001] The invention relates to the field of chemical medicine, in particular to N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindole-3- Base) pyrimidin-2-yl] amino} phenyl) prop-2-enamide phosphate, its crystal form and preparation method. Background technique [0002] Targeted therapy for 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 adenocarcinoma (NSCLC). However, the effects of these drugs are generally short-lived, with resistance developing within 9-11 months because cancer cells are able to evade the therapeutic activity of EGFR or ALK inhibitors by mutating and changing their growth patterns. [0003] For the second mutation of EGFR in lung cancer patients, there is currently no suitable drug to treat it. The compound of formula (I) (also known as AZD9291) developed by AstraZeneca (AZD9291) is an oral, irreversi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04A61K31/506A61P35/00
CPCA61K31/506C07D403/04C07B2200/13
Inventor 陈敏华张炎锋刘凯夏楠张晓宇王鹏李丕旭
Owner CRYSTAL PHARMATECH CO LTD
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