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Preparation method of antitumor drug AZD9291

An anti-tumor drug and intermediate technology, which is applied in the field of preparation of anti-tumor drug AZD9291, can solve the problems of long synthesis route, low total yield, unsuitable for industrial production and the like, and achieves high total yield, convenient operation and easy industrialization. production effect

Active Publication Date: 2017-09-29
山东四环药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The synthetic route is long, the total yield is low, and it is not suitable for industrial production

Method used

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  • Preparation method of antitumor drug AZD9291
  • Preparation method of antitumor drug AZD9291
  • Preparation method of antitumor drug AZD9291

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Embodiment 1: the preparation of compound intermediate 1 to intermediate 3

[0053] 1) Preparation of intermediate 1:

[0054] Add 40g (0.164mol) of SM1, 30.6g (0.164mol) of SM2 and 62.3g (0.328mol) of p-toluenesulfonic acid monohydrate into 200ml of isobutanol, heat up to reflux, react for 6h, a yellow solid precipitates out, and drops to After filtering at room temperature, washing with isopropanol, and vacuum drying at 50°C, 54.8 g of a yellow solid was obtained, with a yield of 85.0%.

[0055] 2) Preparation of intermediate 2:

[0056] Method 1: 50g (0.127mol) intermediate 1, 15.0g (0.147mol) N,N,N'-trimethylethylenediamine, 1g cuprous bromide and 19.65g (0.152mol) N,N-di Add isopropylethylamine to 350ml of N,N-dimethylformamide, rise to 100°C and react for 3 hours, cool down to room temperature and filter to remove cuprous bromide, add 80ml of water, a large amount of solids precipitate, filter, wash with water, 45 °C and dried under vacuum to obtain 57.2 g of o...

Embodiment 2

[0060] Embodiment 2: Synthesis of AZD9291

[0061] Add 3.37g (28mmol) of pivaloyl chloride and 4.13g (30mmol) of potassium carbonate to 60ml of 1,4-dioxane, add 2.02g (28mmol) of acrylic acid to the above solution at 0°C, and stir for 1h to prepare Mixed anhydride solution, 6.17g (13.8mmol) of intermediate 3 prepared in Example 1 was added to the mixed anhydride solution at 0°C, and the disappearance of the raw material was monitored by TLC. Add water and stir for 0.5 h, extract with 100 ml of ethyl acetate, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate in vacuo at 45°C to obtain crude AZD9291. Recrystallized with 50ml of acetonitrile to obtain 6.29g of brown solid; yield 91.3%, purity 99.8%.

[0062] The preparation of intermediate 2 is calculated by method 1, and the total yield of product is 71.7%. The preparation of intermediate 2 is calculated by method 2, and the total yield of product is 63.2%.

Embodiment 3

[0063] Embodiment 3: the synthesis of AZD9291

[0064] Add 3.2g (28mmol) of methanesulfonyl chloride and 2.22g (30mmol) of lithium carbonate to 100ml of acetonitrile, stir at 10°C, add 2.02g (28mmol) of acrylic acid to the above solution, and stir for 1.5h. 6.17g (13.8mmol) of intermediate 3 was added to the mixed anhydride solution at 0°C, and the disappearance of the raw material was monitored by TLC. Add water and stir for 1 h, extract with 100 ml of ethyl acetate, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate in vacuo at 45°C to obtain crude AZD9291. Recrystallize with 50ml of acetonitrile to obtain 6.35g of brown solid, yield 92.2%, purity 99.8%, HPLC spectrum as Figure 5 shown. The preparation of intermediate 2 is calculated by method 1, and the total yield of product is 72.4%. The preparation of intermediate 2 is calculated by method 2, and the total yield of product is 63.8%.

[0065] That 1 H NMR, 13 C-NMR, IR and ESI...

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Abstract

The invention discloses a preparation method of antitumor drug AZD9291. The method is as follows: reaction of 4-fluoro-2-methoxy-5-nitroaniline and 3-(2-chloro-pyrimidine-4-yl)-1-methylindole to obtain an intermediate 1; reaction of the intermediate 1 and N, N, N '-trimethylethylenediamine to obtain a compound intermediate 2; hydrogenation reduction of the intermediate 2 to obtain a compound intermediate 3, further introduction of acryloyl group into the intermediate 3 to obtain the AZD9291, and the method is characterized in that activator cuprous bromide is added into the preparing process of the intermediate 2; palladium carbon is used for catalytic hydrogenation reduction, and a mixed anhydride solution of acrylic acid is used for introduction of the acryloyl group of the AZD9291. The method effectively reduces waste solid generation, and improves the purity and the yield of the product.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of antitumor drug AZD9291. Background technique [0002] Lung cancer is one of the most common malignant tumors in the world, and it has become the first cause of death from malignant tumors in urban population in my country. Non-small cell lung cancer includes squamous cell carcinoma (squamous cell carcinoma), adenocarcinoma, and large cell carcinoma. Compared with small cell carcinoma, its cancer cells grow and divide more slowly, and spread and metastasize relatively later. Non-small cell lung cancer accounts for about 80% of all lung cancers, and about 75% of the patients are in the advanced stage when they are discovered, and the 5-year survival rate is very low. In recent years, many targeted new drugs have been developed to target cancer-causing gene mutations. Compared with traditional chemotherapy, targeted drugs mainly aff...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04A61P35/00
CPCC07D403/04
Inventor 张晓君刘慧敏郭建军李刚宁尚恩
Owner 山东四环药业股份有限公司
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