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Preparation method of apatinib intermediate

A technology of apatinib and intermediates, applied in the field of pharmaceutical chemical synthesis, can solve problems such as loss of economy, high energy consumption, unsafe concentration of nitro compounds, etc., and achieve concise process steps, avoid post-processing, and high-quality Effect

Inactive Publication Date: 2020-10-13
SUZHOU FUSHILAI PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Due to the need to use a large amount of nitric acid and concentrated sulfuric acid, it is uneconomical, especially the concentration of nitro compounds in the post-treatment is unsafe and consumes a lot of energy in production, so the following route of this patent needs to be optimized.

Method used

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  • Preparation method of apatinib intermediate
  • Preparation method of apatinib intermediate
  • Preparation method of apatinib intermediate

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Embodiment 1

[0026] A) nitration reaction, promptly prepares 1-(4-nitrophenyl) cyclopentacarbonitrile incipient product, also promptly prepares the incipient product of Apatinib intermediate, uses 1-phenyl-1-cyclohexanecarbonitrile as Compound (II) is added dropwise in the mixed acid of phosphoric acid, nitric acid and sulfuric acid and stirred to react to obtain the incipient wet product of apatinib intermediate as compound (I), the reaction formula is as follows:

[0027]

[0028] The detailed nitration reaction operation process of present embodiment 1 is: add mass percent concentration and be that 85% phosphoric acid (181.8g, 1.8eq.) and mass percent concentration are 68% nitric acid (97.4g, 1.2eq. ), lower the temperature to 5±5°C, dropwise add sulfuric acid (341.6g, 3.9eq.) with a mass percentage concentration of 98%, control the temperature NMT 25°C, then lower the temperature to 0±5°C, add dropwise 001S1 (150.0g, 876mmol, 1.0eq.), control the temperature not more than 15°C (targ...

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Abstract

A preparation method of an apatinib intermediate belongs to the technical field of chemical synthesis of medicines. The preparation method comprises the following steps: nitration reaction: dropwise adding 1-phenyl-1-cyclohexonitrile as a compound II into a mixed acid of phosphoric acid, nitric acid and sulfuric acid, and stirring for reaction to obtain an apatinib intermediate primary product asa compound I; and refining: refining the obtained apatinib intermediate primary product by using a refining solvent to obtain an apatinib intermediate finished product serving as a compound I. The usage amount of nitric acid and concentrated sulfuric acid is remarkably reduced, and the pressure on the environment influence is reduced; the purity is high; the preparation cost is reduced; the stepsare simple and reasonable, the operation is convenient, and tedious post-treatment is avoided; and the preparation method is beneficial for obtaining raw material medicines with higher quality.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and relates to a preparation method of an apatinib intermediate. Background technique [0002] During the growth and metastasis of malignant tumors, tumor angiogenesis plays a very important role. When the volume of the tumor grows more than 1mm 3 When cancer occurs, new blood vessels need to be formed or branches sprout from existing blood vessels to provide enough blood to support the survival of tumor cells. The growth rate and metastasis tendency of tumors are related to the levels of pro-angiogenic factors and the number of new microvessels. Since Folkman put forward the hypothesis of "anti-angiogenesis therapy" in the early 1970s, people's understanding of this field has made great progress. Inhibiting tumor angiogenesis has been recognized as a new anti-cancer strategy. [0003] Tyrosine kinase vascular endothelial growth factor (VEGF) and its receptor (VEGFR) ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C253/30C07C253/34C07C255/46
CPCC07C253/30C07C253/34C07C2601/08C07C255/46
Inventor 吕习周石晓青赵雪峰
Owner SUZHOU FUSHILAI PHARMA CO LTD
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