Synthesis method of Osimertinib

A synthesis method and compound technology, applied in the field of medicine and chemical industry, can solve the problems of low utilization rate of atoms, smell affecting industrialization prospects, etc., and achieve the effect of short route, high yield and cost reduction

Active Publication Date: 2018-04-20
安庆奇创药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, an equivalent amount of dimethylamine is released during the cyclization of the guanidino compound with the corresponding 3-dimethylaminopropenone compound, which makes the atom utilization rate of the reaction lower, and the pungent smell of dimethylamine is also To a certain extent, it affects the industrialization prospect of this method

Method used

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  • Synthesis method of Osimertinib
  • Synthesis method of Osimertinib
  • Synthesis method of Osimertinib

Examples

Experimental program
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Effect test

Embodiment 1

[0033] Embodiment 1, the preparation of N-(4-fluoro-2-methoxy-5-nitrophenyl) formamide (II)

[0034] Acetic anhydride (1.53 g, 15 mmol) was added into a 25 mL three-neck flask, the temperature of the solution was controlled with an ice-water bath, and magnetic stirring was performed. Formic acid (1.38g, 30mmol) was slowly added dropwise in acetic anhydride, and the temperature of the reaction solution was controlled not to exceed 35°C. Stirring was continued for 15 min at room temperature. Then, 4-fluoro-2-methoxy-5-nitroaniline (I) (1.86 g, 10 mmol) was slowly added to the above solution in batches, and the reaction temperature was controlled not to exceed 35°C. After the addition of 4-fluoro-2-methoxy-5-nitroaniline (I) was completed, stirring was continued for 48 h, 10 mL of water was added, and stirring was continued for 1 h. A yellow solid precipitated out, which was filtered and washed with water until the washed water became neutral. Dry under reduced pressure at 45°...

Embodiment 2

[0035] Embodiment 2, the preparation of 3-(1-methyl-1H-indol-3-yl) prop-2-en-1-one (IV)

[0036] Under nitrogen protection, N-methylindole (III) (1.31 g, 10 mmol) was added into a 50 mL three-necked flask, dissolved in 20 mL of anhydrous dichloromethane, the temperature of the solution was controlled by an ice-water bath, and magnetically stirred. Aluminum trichloride (3.33 g, 25 mmol) was added to the above solution in batches, and the reaction temperature was controlled not to exceed 10°C. A dichloromethane solution of acryloyl chloride (1.80 g, 20 mmol of acryloyl chloride dissolved in 5 mL of anhydrous dichloromethane) was slowly added dropwise to the above reaction solution. After the dropwise addition, the resulting reaction solution was stirred at 0° C. for 2 h. After that, 10 mL of water was added to quench the reaction, dichloromethane was evaporated under reduced pressure, and 50 mL of ethyl acetate was added to dissolve the system, washed three times with saturated...

Embodiment 3

[0037] Example 3, Preparation of 2-(4-fluoro-2-methoxy-5-nitroanilino)-4-(1-methyl-1H-indol-3-yl)pyrimidine (V)

[0038] Under oxygen protection, in a 250mL single-necked bottle, 3-(1-methyl-1H-indol-3-yl)prop-2-en-1-one (IV) (1.85g, 10mmol), N- (4-Fluoro-2-methoxy-5-nitrophenyl)formamide (II) (3.21g, 15mmol), ammonium iodide (3.62g, 25mmol), sodium nitrite (0.14g, 2mmol), Morpholine (0.17g, 2mmol) was dissolved in 25mL of acetic acid, heated to 80°C, and stirred for 16h. After the reaction was completed, the reaction solution was slowly added dropwise to 100 mL of saturated sodium bicarbonate ice solution, and a yellow solid was precipitated, which was dried under reduced pressure at 45°C for 12 hours to obtain 2-(4-fluoro-2-methoxy-5-nitrate Anilino)-4-(1-methyl-1H-indol-3-yl)pyrimidine (V) 3.46g, yield 88%. 96% purity.

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Abstract

The invention discloses a synthesis method of Osimertinib. The method comprises the following steps that (1) 4-fluoro-2-methoxyl-5-nitroaniline is subjected to formylation to obtain N-(4-fluoro-2-methoxyl-5-nitrophenyl) methanamide; (2) N-methylindole is subjected to acylation reaction to prepare 3-(1-methyl-1H-indole-3-yl)prop-2-en-1-one; (3) products generated in the former two-step reactions are subjected to one-step cyclization to obtain 2-(4-fluoro-2- methoxyl-5- nitroanilino)-4-(1-methyl-1H-indole-3-yl) pyrimidine; (4) the product generated in the step (3) is sequentially subjected to nucleophilic substitution reaction, reduction reaction and condensation amidation reaction to obtain the Osimertinib. The method provided by the invention has the advantages that the raw materials can be easily obtained; the steps are simple; the yield is high; the reaction conditions are mild; the synthesis method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a method for synthesizing ostinib. Background technique [0002] Lung cancer has always been one of the most lethal and difficult-to-cure tumors. Common chemotherapy has the disadvantage of high toxicity and side effects. In recent years, studies have shown that one type of non-small cell lung cancer is caused by mutations in the epidermal growth hormone receptor (EGFR). Therefore, for this cancer-causing gene mutation, many targeted new drugs are constantly emerging for the treatment of lung cancer. Unfortunately, many of these drugs, such as gefitinib and er1otinib, are short-lived. Because the 790th position in the EGFR sequence of cancer cells is prone to mutations, changing from threonine to methine, thereby achieving the purpose of drug resistance of cancer cells. However, Ostinib (AZD9291) will not be interfered by this drug-resistant mutation,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04
CPCC07D403/04
Inventor 吴学平邢继刚储贻结时珠勇
Owner 安庆奇创药业有限公司
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