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A kind of synthetic method of antitumor drug

A technology for anti-tumor drugs and synthesis methods, applied in the directions of anti-tumor drugs, drug combinations, chemical instruments and methods, etc., can solve problems such as difficulties in industrial production of AZD9291, and achieve the effects of lowering temperature, saving costs, and mild reaction conditions

Active Publication Date: 2017-06-16
苏州东南药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] This route adopts the ferric ammonium reduction method to reduce the nitro group, and the post-reaction treatment must first be pretreated with an ion exchange resin, which makes the industrial production of AZD9291 very difficult.

Method used

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  • A kind of synthetic method of antitumor drug
  • A kind of synthetic method of antitumor drug
  • A kind of synthetic method of antitumor drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1: Preparation of compound 4-fluoro-2-methoxyl-5-nitroanilinocarbamate tert-butyl

[0040] Add 500mg (2.69mmol) of 4-fluoro-2-methoxy-5-nitroaniline, 586.24mg (2.69mmol) of Boc anhydride and 10ml of acetonitrile into a single-necked bottle, raise the temperature to 55°C for 6 hours, and spin off under reduced pressure. Acetonitrile, 5ml of ethyl acetate was added to dissolve the system, and 1ml of petroleum ether was slowly added under stirring to precipitate a solid, which was filtered to obtain 639mg of a yellow solid, with a yield of 84%.

Embodiment 2

[0041] Example 2: Preparation of compound 4-(N,N,N'-trimethylethylenediamine)-2-methoxyl-5-nitroaniline formate tert-butyl

[0042] Under nitrogen / argon protection, 200mg (0.698mmol) tert-butyl 4-fluoro-2-methoxy-5-nitroanilinocarbamate, 78.47mg (0.768mmol) N,N,N'-trimethyl Add ethylenediamine, 117.27mg (0.907mmol) N,N-diisopropylethylamine and 10ml N,N-methylacetamide into a 50ml single-necked flask, heat up to 45°C, stir for 2h, cool down to room temperature, add 40ml of water was extracted twice with 20ml of dichloromethane, the organic layers were combined, washed with saturated brine, dried, filtered with suction, and spin-dried with dichloromethane to obtain 252mg of a bright orange solid with a yield of 98%.

Embodiment 3

[0043] Embodiment 3: Preparation of compound 2-(N,N,N'-trimethylethylenediamino)-4-methoxy-5-carbamic acid tert-butyl aniline

[0044] Under nitrogen / argon protection, 500mg (1.3mmol) tert-butyl 4-(N,N,N'-trimethylethylenediamine)-2-methoxy-5-nitroaniline carbamate, 2.5 mg palladium carbon and 50ml methanol were added to a 100ml single-necked flask, the system was replaced with hydrogen three times, stirred and reacted at room temperature for 2 hours, a layer of diatomaceous earth was added on the filter paper, the system was filtered, and the mother liquor was spin-dried to obtain a brown oil 422.4 mg, yield 96%.

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PUM

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Abstract

The invention relates to a synthetic method of an anti-tumor medicine, namely N-[2-[[2-(dimethylamino) ethyl] methyl amino]-4-methoxy-5-[[4-(1-methyl-1H-indole-3-yl)-2-pyrimidyl] amino] phenyl]-2-acrylamide (AZD9291) and a key intermediate of the anti-tumor medicine. The synthetic method comprises the following steps: performing Boc acid anhydride protection on 4-fluoro-2-methoxy-5-nitroaniline to obtain 4-fluoro-2-methoxy-5-nitroanilino tert-butyl formate, then reacting with N,N,N'-trimethylethylenediamine to obtain 4-(N,N,N'-trimethylethylenediamino)-2-methoxy-5-nitroanilino tert-butyl formate, then reducing to obtain 2-(N,N,N'-trimethylethylenediamino)-4-methoxy-5-tert-butyl carbamate phenylamine, then completely reacting with acryloyl chloride and directly removing a Boc protecting group to obtain 2-methoxy-4-N,N,N'-trimethylethylenediamino-5-acrylamido phenylamine, and finally reacting with 3-(2-chloropyrimidine-4-yl)-1-methylindole to obtain AZD9291. A process disclosed by the invention is simple in step, relatively high in yield, mild in reaction condition and easy for realization of industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to a late-stage lung cancer drug N-[2-[[2-(dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-( 1-Methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-2-acrylamide (AZD9291). Background technique [0002] Lung cancer is one of the most difficult tumors to conquer. According to the basic pathological classification, lung cancer is divided into two categories: non-small cell lung cancer and small cell lung cancer. Lung cancer is mostly non-small cell lung cancer, which grows relatively slowly, and can be subdivided into squamous cell lung cancer, adenocarcinoma and large cell lung cancer. In recent years, many so-called targeted therapies have been emerging in response to cancer-causing gene mutations. Compared with common chemotherapy, targeted drugs mainly affect cancer cells with corresponding mutations, and have lower toxicity and higher efficiency. Literatu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/04C07C271/28C07C269/04C07C269/06C07C233/44C07C231/12A61P35/00
CPCY02P20/55
Inventor 吉民李元刘海东李锐蔡进胡海燕
Owner 苏州东南药业股份有限公司
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