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Phosphate of epidermal growth factor receptor kinase inhibitor and preparation method thereof

A phosphate and compound technology, applied in the field of chemical medicine, can solve the problems of dose climbing, achieve low humidity, improve bioavailability, and facilitate industrial production

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

[0005] The study found that the free base form of CO1686 was used in early studies, but because of its hydrobromide salt form can improve drug availability and reduce variability, it was clinically switched to its hydrobromide salt in August 2013, but its dose remained the same. continue to climb

Method used

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  • Phosphate of epidermal growth factor receptor kinase inhibitor and preparation method thereof
  • Phosphate of epidermal growth factor receptor kinase inhibitor and preparation method thereof
  • Phosphate of epidermal growth factor receptor kinase inhibitor and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] The preparation method of formula (I) compound phosphate:

[0055] Dissolve 10.2 mg of the compound of formula (I) in 0.9 mL of acetone, add 0.09 mL of 0.2 mol / L phosphoric acid solution dropwise, stir and react at 50°C for 24 hours, and collect the solid to obtain it.

[0056] The phosphate product that above-mentioned method prepares, its 1 H NMR identification data are as follows:

[0057] 1 H NMR (400MHz, DMSO) δ10.17(s,1H),8.67(s,1H),8.28(s,1H),8.10(s,1H),7.74(s,1H),7.51(dd,J= 16.7,8.3Hz,2H),7.26(t,J=8.1Hz,2H),6.61(d,J=2.0Hz,1H),6.44(dd,J=17.0,10.1Hz,1H),6.26(dd, J=17.0, 1.8Hz, 2H), 5.76(dd, J=10.1, 1.9Hz, 1H), 3.77(s, 3H), 3.56(d, J=4.7Hz, 4H), 3.03(d, J=25.7 Hz,4H),2.07(d,J=15.7Hz,3H).

[0058] 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 followsfigure 1 , and its DSC graph is shown in figure 2 , and its TGA figure is shown in image 3 ,That 1 H NM...

Embodiment 2

[0063] The preparation method of formula (I) compound phosphate:

[0064] Dissolve 10.2 mg of the free base of the compound of formula (I) in 0.9 mL of tetrahydrofuran, add 0.09 mL of 0.2 mol / L phosphoric acid solution dropwise, stir and react at 50°C for 24 hours, and collect the solid to obtain it.

[0065] After testing, the solid obtained in this example is crystal form A, and its X-ray powder diffraction data are shown in Table 2.

[0066] Table 2

[0067] 2theta

[0068] 28.93

Embodiment 3

[0070] Comparative study on the solubility of phosphate and patent WO2013138502 hydrobromide:

[0071] Phosphate of the present invention and patent hydrobromide sample are formulated into saturated solution with FeSSIF (artificial intestinal fluid under the full stomach state) and water respectively, after 1 hour, after 4 hours, measure the amount in the saturated solution by high performance liquid chromatography content of the sample. The experimental results are shown in Table 3.

[0072] table 3

[0073]

[0074] As can be seen from the above comparison results, after being placed in FeSSIF and water for 1 hour, the phosphate of the present invention has a higher solubility than the patented hydrobromide after 4 hours.

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Abstract

The invention relates to phosphate of N-(3-(2-(4-(4-acetylpiperazine-1-yl)-2-methoxyphenylamino)-5-(trifluoromethyl)pyrimidine-4-yl-amino)phenyl)acrylamide), and a crystal form and a preparation method thereof. The phosphate of the compound as shown in a formula (I) which is described in the specification has favorable performance like good stability, low hygroscopicity and process developability and manageability; 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-(3-(2-(4-(4-acetylpiperazin-1-yl)-2-methoxyphenylamino)-5-(trifluoromethyl base) pyrimidin-4-ylamino) phenyl) acrylamide) phosphate salt and preparation method thereof. Background technique [0002] N-(3-(2-(4-(4-acetylpiperazin-1-yl)-2-methoxyphenylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)benzene Base) acrylamide) (aka CO1686), first developed by Clovis Oncology, is a novel oral, targeted covalent (irreversible mutant) third-generation dermal growth factor receptor ( EGFR) inhibitors, which can inhibit key activating mutations and T790 resistance mutations, and make wild-type EGFR signal idle. The drug is developed for the treatment of NSCLC patients with initial activating EGFR mutations and main resistance mutations T790M. May 20, 2014 The FDA has granted Breakthrough Therapy Designation to the experimental drug CO1686 as a monotherapy for the treatment of second-line...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/48A61K31/506A61P35/00
CPCC07D239/48C07B2200/13
Inventor 陈敏华张炎锋刘凯张晓宇王鹏李丕旭
Owner CRYSTAL PHARMATECH CO LTD
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