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Method for synthesizing Vandetanib compound

A synthetic method, the technique of vandetanib, applied in the field of synthesis of vandetanib compounds, can solve the problems of cumbersome synthetic routes, high production costs, harmful environment, etc., and achieve the advantages of reduced process steps, short preparation cycle and easy operation Effect

Active Publication Date: 2016-01-20
山东罗欣乐康制药有限公司 +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The purpose of the present invention is to provide a new synthetic method of vandetanib compound, to solve the problems in the prior art that the synthetic route is too complicated, the production cost is high, and harmful to the environment

Method used

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  • Method for synthesizing Vandetanib compound
  • Method for synthesizing Vandetanib compound
  • Method for synthesizing Vandetanib compound

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Embodiment 1

[0049] Embodiment 1: the preparation of Vandetanib

[0050]Step 1): Add 45.0g (300mmol) of compound I, 49.7g (360mmol) of potassium carbonate, and 450ml of DMF to the reaction flask, and stir at a temperature of 15°C for about 30 minutes. After the solution is dissolved, add 110.9g (300mmol) of compound II and heat up React at 80°C for 10 hours. After the reaction is completed, add the reaction liquid to 20 times of water to precipitate a solid, which is filtered and dried to obtain 98.9 g of Compound III, with a yield of 95.2% and a purity of 99.62% (HPLC);

[0051] Step 2): Compound III 90.1g (260mmol) was dissolved in 300ml of acetic acid, stirred, and 68% HNO was slowly added to the reaction flask 3 17.0ml and 98% H 2 SO 4 55.7ml of the mixture was added within 0.5 hours and reacted at 0°C for 1 hour. After the reaction was completed, it was cooled to room temperature. Add ice water to cool, adjust the pH to neutral with 20% sodium hydroxide aqueous solution, stir for 5...

Embodiment 2

[0057] Embodiment 2: the preparation of Vandetanib

[0058] Step 1): Add 45.0g (300mmol) of compound I, 49.7g (360mmol) of potassium carbonate, and 675ml of DMF to the reaction flask, and stir at a temperature of 15°C for about 30 minutes. After the solution is dissolved, add 221.7g (600mmol) of compound II and heat React at 100°C for 5 hours. After the reaction is completed, add the reaction liquid to 20 times of water, and a solid precipitates, which is filtered and dried to obtain 101.1 g of Compound III, with a yield of 97.3% and a purity of 99.62% (HPLC);

[0059] Step 2): Compound III 90.1g (260mmol) was dissolved in 300ml of acetic acid, stirred, and 68% HNO was slowly added to the reaction flask 3 34.0ml and 98% H 2 SO 4 111.4ml of the mixture was added within 1 hour and reacted at 20°C for 2 hours. After the reaction was complete, it was cooled to room temperature. Add ice water to cool, adjust the pH to neutral with 20% sodium hydroxide aqueous solution, stir for ...

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Abstract

The invention discloses a method for synthesizing a Vandetanib compound. A compound I is adopted as an initial raw material, condensation, nitration, hydrogenation and reduction, addition, oxidation, hydrolysis and addition reactions are carried out, and the Vandetanib compound is prepared. According to the method for synthesizing the Vandetanib compound, the initial raw material is simple, cheap and easy to obtain, and compared with an existing route that loop closing and chlorination are carried out in sequence, and finally ammoniation is carried out, steps are reduced, the yield is increased, the reaction process is easy to operate, and the preparation period is short. Meanwhile, use of phosphorus trichloride or phosphorus pentachloride or thionyl chloride or phosgene or phosphorus oxychloride or other chlorinating agents with corrosivity is avoided, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine and chemical industry, in particular to a method for synthesizing a vandetanib compound. Background technique [0002] Vandetanib (Vandetanib) is a multi-target tyrosine kinase inhibitor, which belongs to the aniline quinazoline compound, known as "second-generation Iressa", not only acts on EGFR, VEGFR and RET tyrosine in tumor cells It also inhibits other tyrosine kinases and serine / threonine kinases. Vandetanib is the first approved drug for the treatment of medullary thyroid cancer (medullary thyroid cancer), suitable for the treatment of unresectable, locally advanced or metastatic symptomatic or progressive medullary thyroid cancer. Its chemical name is: 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazoline, chemical structural formula as follows: [0003] [0004] The synthetic method of this compound is as follows at present: [0005] AstraZeneca US P...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 陈雨田松杨玉发
Owner 山东罗欣乐康制药有限公司
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