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Synthesis method of cediranib

A synthetic method, the technology of cediranib, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of difficult product purification, large solid residue, and difficult post-processing.

Inactive Publication Date: 2014-01-29
CHEMPROSPECT PHARMTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The zinc powder reduction used in this method is difficult to post-process and produces a large amount of solid residue. Using formamide as a cyclization reagent requires high temperature (190°C) and long-term reaction, which is easy to carbonize the product and generate impurities.
WO2006117552A1 uses iron powder for reduction, and also uses formamide as a cyclization reagent, which will lead to difficult post-processing and difficult purification of the product

Method used

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  • Synthesis method of cediranib
  • Synthesis method of cediranib
  • Synthesis method of cediranib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] 1) Chemical synthesis of 2-(2,3-difluoro-6-nitrophenyl)-3-acetoacetate (X1)

[0087] 68 g (1 mol) of sodium ethoxide was dissolved in 300 ml of anhydrous tetrahydrofuran, cooled to 10 °C with mechanical stirring, 130 g (1 mol) of ethyl acetoacetate was added, and the addition was completed in about 1 hour, and the temperature was controlled below 35 °C. 88.5 g (0.5 mol) of 1,2,3-trifluoro-4-nitrobenzene was dissolved in 200 ml of THF, and added dropwise into the above reaction solution under ice bath conditions. The reaction was naturally raised to room temperature and stirred for 5 h, and the reaction was completed by TLC monitoring.

[0088] Pour into 500ml of 1N aqueous hydrochloric acid for quenching, extract with ethyl acetate (1L*3), combine the organic phases, wash the organic phases with saturated brine, spin dry to obtain 241g of product, yield: 84%.

[0089] The structure of the product was confirmed by NMR:

[0090] 1 H NMR Spectrum (CDCl 3 ): δppm 13.21(s,...

Embodiment 2

[0146] As described in Example 1, the difference is that sodium hydride is used in step (1), the molar ratio of the reaction materials is the same, and 125 g of the product is obtained by the reaction, and the yield is 44%.

Embodiment 3

[0148] As described in Example 1, the difference is that potassium tert-butoxide is used in step (1), the molar ratio of the reaction materials is the same, and 153 g of the product is obtained after the reaction, and the yield is 54%.

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Abstract

The invention discloses a preparation method of cediranib, which comprises the following steps of using trifluoro-nitrobenzene as a raw material and performing acetyl methyl adding, substitution, cyclization and protection to obtain a segment 1; and then using methyl vanillate as the raw material, performing benzyl bromine protection, nitro adding, reduction, unique cyclization and chlorination to obtain a segment 2; and performing nucleophilic substitution and deprotection on the two segments to obtain the final product cediranib. Compared with other methods, the preparation method of the cediranib has the advantages of mild reaction condition, high yield and scale amplification, and raw materials can be obtained easily.

Description

technical field [0001] The invention relates to the preparation of cediranib (Cediranib), which belongs to the field of pharmaceutical chemical synthesis. Background technique [0002] Cediranib (tentative trade name Recentin), also known as AZD2171, is a potent inhibitor of pan-vascular endothelial growth factor (pan-VEGF) receptor tyrosine kinase. This is an oral chemotherapy drug that AstraZeneca is developing as a possible treatment for cancer. [0003] In antitumor treatment, chemotherapy is a widely used systemic treatment, which can be used alone or in combination with other methods, even for middle and advanced cancers that cannot be treated by surgery. In recent years, with the rapid development of chemotherapy pharmacology and cell molecular biology, chemotherapy drugs are transitioning from traditional cytotoxic drugs to new anticancer drugs with multiple links and new targets, and cancer cell differentiation inducers, telomerase inhibitors, etc. agent, tumor ge...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/12
Inventor 李宏松张淑娴欧贤飞程哲超
Owner CHEMPROSPECT PHARMTECH
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