Preparation method for Afatinib intermediate 6-nitryl-7-chlorol-4-quinazolinone

A technology of quinazolinone and afatinib, which is applied in the field of chemical synthesis, can solve the problems of high cost of formamidine acetate, difficulty in industrial production, environmental pollution, etc., and achieve the effects of low cost, reduced yield, and simple post-treatment

Inactive Publication Date: 2016-06-29
NANJING NORMAL UNIVERSITY
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  • Abstract
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Problems solved by technology

The cyclization reaction in this route mainly contains two kinds of methods, and a kind of raw material that uses is formamide and 2-amino-4-chlorobenzoic acid, but yield is low; Another kind of raw material that adopts is formamidine acetate and 2 -Amino-4-chlorobenzoic acid, but formamidine acetate is relatively expensive
At the same time, in the next step of nitration reaction, due to the adjacent paraposition effect of chlorine atoms, the nitration products generated are mixtures, and the proportion of the target product is low (about 70%). Only by crystallizing for many times can a relatively pure product be obtained, which is difficult in industrial production. If the waste liquid is not properly treated, it will also pollute the environment.

Method used

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  • Preparation method for Afatinib intermediate 6-nitryl-7-chlorol-4-quinazolinone

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Effect test

Embodiment 1

[0024] A preparation method of afatinib intermediate 6-nitro-7-chloro-4-quinazolinone, comprising the following steps:

[0025] Step (1): at room temperature, 2-amino-4-chlorobenzoic acid (100g, 0.583mol) was added to a 500ml round-bottom four-necked reaction flask, 300ml of acetic anhydride was added, vigorously stirred, refluxed for reaction, thin layer chromatography ( TLC) monitoring, the reaction was carried out for 5 hours; after the reaction, the reaction solution was poured into ice water, and a large amount of white solids were separated out, washed with water, and suction filtered to obtain 2-acetamido-4-chlorobenzoic acid (compound 2) 117g, yield 94.0 %. The product was used directly in the next reaction without purification.

[0026] The structural detection data of the 2-acetamido-4-chlorobenzoic acid prepared in this step are as follows:

[0027] m.p. is 208.2-208.9°C (literature value: 213-214°C);

[0028] 1 HNMR((CD3) 2 SO, 400MHz), δppm: 13.85(br,1H), 11....

Embodiment 2

[0036] Step (1) and step (3) are the same as in Example 1.

[0037] Step (2): under the condition of 20°C, add 30ml of concentrated sulfuric acid to the concentrated nitric acid (5.2g, 0.0536mol), and stir at room temperature for 1.5h to obtain a mixed acid system; under the condition of 8-10°C, add 2- Acetylamino-4-chlorobenzoic acid (10.4g, 0.0487mol) was reacted at room temperature and monitored by thin layer chromatography (TLC), after the reaction was completed, the reaction solution was poured into ice water, and a large amount of solid was precipitated; ethanol was recrystallized to obtain 0.53g The yellow solid was the product 2-amino-4-chloro-5-nitrobenzoic acid (compound 3), and the yield was 5.0%. The nuclear magnetic data and melting point data of the prepared 2-amino-4-chloro-5-nitrobenzoic acid are the same as those in Example 1.

Embodiment 3

[0039] Step (1) and step (2) are the same as in Example 1.

[0040] Step (3): under dry conditions, respectively, 2-amino-4-chloro-5-nitrobenzoic acid (3g, 13.85mmol), trimethyl orthoformate (6.4g, 60.67mmol), ammonium acetate (4.5g , 58.45mmol) was added to 50ml three-necked flask, then 20ml isopropanol was added, heated to reflux reaction, thin layer chromatography (TLC) monitoring, after the reaction was completed, the reaction solution was poured into ice water, washed with 100ml of water, suction filtered , and dried to obtain 1.9 g of 6-nitro-7-chloro-4-quinazolinone (compound 4) as a dark yellow solid with a yield of 61.0%. The nuclear magnetic data and melting point data of the prepared 6-nitro-7-chloro-4-quinazolinone are the same as those in Example 1.

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Abstract

The invention discloses a preparation method for an Afatinib intermediate 6-nitryl-7-chlorol-4-quinazolinone. An amino group is protected through amidation with 2-amino-4-chlorobenzoicacid as the raw material to obtain 2-acetamino-4-chlorobenzoicacid; then, 2-amino-4-chlorol-5-nitrobenzoic acid is obtained through nitration and hydrolysis; 2-amino-4-chlorol-5-nitrobenzoic acid and ammonium acetate are subjected to the trimethyl orthoformate reaction to obtain 6-nitryl-7-chlorol-4-quinazolinone. The operation method is easy and mild in experiment condition, the product purification is easy and convenient, and yield is high.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a method for synthesizing afatinib intermediate 6-nitro-7-chloro-4-quinazolinone. Background technique [0002] Afatinib is a new type of anti-lung cancer targeted drug, originally developed by Boehringer Ingelheim, Germany, and approved by the U.S. Food and Drug Administration (FDA) on July 12, 2013. At present, afatinib has been approved for first-line treatment in the United States, many European countries and Taiwan. [0003] Afatinib is an orally administered tyrosine kinase (TK) inhibitor that covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2) and HER4 (ErbB4), irreversibly inhibiting these kinases Autophosphorylation downregulates ErbB signaling, thereby inhibiting tumor growth. At the same time, afatinib can irreversibly bind to EGFR-HER2 tyrosine kinase and inhibit the activity of tyrosine kinase, thereby blocking EGFR-HER2-mediated tumor cell signal...

Claims

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Application Information

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IPC IPC(8): C07D239/88
CPCC07D239/88
Inventor 汪丽茜俞星辰汪卫敏肖亚平
Owner NANJING NORMAL UNIVERSITY
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