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Preparation method of osimertinib mesylate process impurity

A methoxyl and methylamino technology, applied in the field of drug synthesis, can solve the problems of impurity reporting and process impurity non-reporting, etc.

Inactive Publication Date: 2018-05-11
BEIJING CREATRON INST OF PHARMA RES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] At present, there is no report on some process impurities produced in this process route, especially there is no report on impurities A, B, C, and D disclosed in this patent

Method used

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  • Preparation method of osimertinib mesylate process impurity
  • Preparation method of osimertinib mesylate process impurity
  • Preparation method of osimertinib mesylate process impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1: Preparation of N-(4-fluoro-2-methoxy-5-nitro-phenyl)-4-(1-methylindol-3-yl)-pyrimidin-2-amine (MRTN -1)

[0053] Add 1,4-dioxane (2.06L) into the 5L reaction flask, and add 3-(2-chloropyrimidin-4-yl)-1-methylindole (SM1) (175.90g) in sequence under stirring 4-Fluoro-2-methoxy-5-nitroaniline (SM2) (161.20g) and p-toluenesulfonic acid (164.80g) were heated up to 85-90°C, and kept at this temperature for 5h. Cool down to room temperature, add a mixture of 25% ammonia (147.50 g) and water (686.00 mL) dropwise, keep the temperature not exceeding 20° C., and stir for 2 h after dropping. After suction filtration, the filter cake was rinsed with 1,4-dioxane to obtain the crude intermediate I. Add the crude intermediate I to a 5L three-necked flask, add dichloromethane (2.00L), stir and beat for 2 hours below 20°C. Suction filtration, rinse the filter cake with dichloromethane, and blow-dry the material at 45°C-50°C for 6h-10h to obtain a yellow-brown solid (260.00...

Embodiment 2

[0054] Example 2: N 4 -(2-Dimethylaminoethyl)-2-methoxy-N 4 -Methyl-N 1 Preparation of -[4-(1-methylindol-3-yl)-pyrimidin-2-yl]-5-nitro-benzene-1,4-diamine (MRTN-2)

[0055] Under nitrogen atmosphere, N-(4-fluoro-2-methoxy-5-nitro-phenyl)-4-(1-methylindole-3- base)-pyrimidin-2-amine (200.80g), N,N-dimethylacetamide (DMA, 1.95L), N,N',N'-trimethyl-ethylenediamine (SM3) (62.60g ), DIPEA (85.70g), after adding, heat up to 85°C, keep warm at 85°C-90°C, react for 5h-6h, TLC monitors the reaction, almost no intermediate I remains, the reaction is complete, cool down to room temperature, add water dropwise (975.00mL), after dropping, stir at 20°C to 30°C for 2h. After suction filtration, the filter cake was rinsed with ethanol (1.00 L) to obtain a light red wet material with a HPLC normalized purity of 98.44%. That is, get MRTN-2: N 4 -(2-Dimethylaminoethyl)-2-methoxy-N 4 -Methyl-N 1 -[4-(1-Methylindol-3-yl)-pyrimidin-2-yl]-5-nitro-benzene-1,4-diamine. 1 H-NMR (400Mz, DMSO-d...

Embodiment 3

[0056] Example 3: N 1 -(2-Dimethylaminoethyl)-5-methoxy-N 1 -Methyl-N 4 Preparation of -[4-(1-methylindol-3-yl)-pyrimidin-2-yl]-benzene-1,2,4-triamine (MRTN-3)

[0057] Put the wet material of MRTN-2 in Example 2 into the reaction flask, add ethanol (3.00L), replace the nitrogen, add stannous chloride (575.41g), and drop concentrated hydrochloric acid (163.16mL ), after dropping, stir for 10min. The temperature was raised to reflux, and the reaction was carried out at reflux for 3 hours. TLC monitored that there was no remaining raw material, and the temperature was lowered to room temperature. Suction filtration, rinse the filter cake with ethanol (500.00mL), and drain. While stirring, the filter cake was added to 5% aqueous sodium hydroxide solution, followed by dichloromethane (2.00 L), stirred for 10 min, and allowed to stand to separate layers. Collect the organic phase, filter the aqueous phase, extract the filtrate with 500.00 mL of dichloromethane, combine the org...

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Abstract

The invention relates to a process impurity of a medicine osimertinib mesylate used for non-small cell lung cancer. The impurity is selected from a compound A: N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindole-3-yl)-pyrimidine-2-yl]amino}phenyl)-acetamide, a compound B: 4-((2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1-H-indole-3-yl)pyrimidine)-2-yl)amino)phenyl)carbamyl)-4-methylene-pentanoic acid, a compound C: N1,N1,N2-trimethyl-N2-(4-(1-methyl-indole-3-yl)pyrimidine-2-yl)-ethylenediamine and a compound D: N-(2-dimethylamino-4-methoxy-5-{[4-(1-methylindole-3-yl)-pyrimidine-2-yl]amino}phenyl)acrylamide.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to process impurities and preparation thereof in the production process of raw materials, in particular to a process impurity and a preparation method of osimertinib mesylate. This application claims the priority of the application number 201610929934.2 filed on October 31, 2016. Background technique [0002] Osimertinib mesylate, a targeted anticancer drug developed by AstraZeneca, is an epidermal growth factor receptor (EGFR) inhibitor for the treatment of EGFR-T790 mutation-positive non-small cell lung cancer . The drug was approved for marketing by the U.S. Food and Drug Administration (FDA) on November 13, 2015, approved by the European Medicines Agency (EMA) on February 2, 2016, and approved by the Japanese Medicines and Medical Devices Administration in March 2016. (PMDA) approved listing, the listed product name is Tagrisso. [0003] The chemical name of Osimertinib Mesylate (...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04G01N30/02
CPCC07D403/04G01N30/02
Inventor 贾慧娟武凯洋王艳鑫
Owner BEIJING CREATRON INST OF PHARMA RES CO LTD
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