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A kind of synthetic method of vegfr inhibitor fruquintinib and its benzofuran intermediate

A synthetic method and inhibitor technology, applied in drug combination, organic chemistry, antineoplastic drugs, etc., can solve problems such as unpleasant odor, and achieve the effect of low cost, good reproducibility, and few synthesis steps

Active Publication Date: 2021-10-26
GUANGZHOU ANYANREN PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] 6-Hydroxy-N, the synthesis process of 2-dimethylbenzofuran-3-carboxamide As shown above, a large amount of sodium sulfide is produced in the process of synthesizing compound 11 and compound 12, which has a very unpleasant smell, resulting in The post-treatment of reaction needs to use excessive sodium hypochlorite solution to convert it into sodium sulfate, and the use of such strong oxidant as sodium hypochlorite will cause the product to be oxidatively decomposed, and its yield in this step is only 53% (and purity 92%)
This poses a great challenge to its industrial production

Method used

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  • A kind of synthetic method of vegfr inhibitor fruquintinib and its benzofuran intermediate
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  • A kind of synthetic method of vegfr inhibitor fruquintinib and its benzofuran intermediate

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Embodiment 1

[0074] Embodiment 1 of the present invention is: a synthesis method of a VEGFR inhibitor fruquintinib benzofuran intermediate, comprising the following steps:

[0075] S1, the synthesis of compound 1:

[0076]

[0077] Add 3-methoxyphenol (124.14g) and DMF (250mL) into the reaction flask, control the temperature at 30°C, add NBS (186.88g) in batches, keep warm for 2 hours after the addition, TLC reaction is complete, and the reaction solution Added in water (1000mL), a large amount of solid precipitated out, washed the solid with water, dried to obtain the crude product, crystallized with EA and n-heptane mixed solvent system (the volume ratio of EA and n-heptane was 1:5) to obtain the solid of compound 1 (142.1g, Yield 70.0%, purity greater than 85.0%).

[0078] S2, the synthesis of compound 2:

[0079]

[0080] Add compound 1 (101.5g), TEA (61.2g) and DCM (500mL) into the reaction flask, control the temperature at 30°C, add acetic anhydride (61.2g) dropwise, keep the...

Embodiment 2

[0093] Embodiment 2 of the present invention is: a method for synthesizing VEGFR inhibitor fruquintinib and intermediates, comprising the following steps:

[0094] S1. Compound 6 was synthesized by the method of Example 1 of the present invention.

[0095] S2, the synthesis of compound 7:

[0096]

[0097] Add compound 6 (10.2g) and acetone (100mL) into the reaction flask, replace with nitrogen, add compound 6A (11.2g), heat up to 60°C for 12 hours after the addition, TLC reaction is complete, cool down to 25°C, add water (300.0g), stirred for 30 minutes, the organic phase was washed once with saturated brine, dried and concentrated to dryness, crystallized with acetone and n-heptane mixed solvent system (the volume ratio of acetone and n-heptane was 2:7) to obtain compound 7 (17.5g , yield 89.0%, product purity greater than 99.0%).

[0098] The nuclear magnetic resonance spectrum of compound 7 prepared by the embodiment of the present invention two is shown in figure 1 ...

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Abstract

The invention discloses a synthesis method of VEGFR inhibitor fruquintinib and its benzofuran intermediate. The synthesis method of VEGFR inhibitor fruquintinib in the invention comprises the following steps: S1: halogenation; S2: acyl S3: coupling; S4: ring closure; S5: hydrolysis; S6: amination; S7: substitution. The present invention has few synthetic steps, and the process is simple and easy to operate; no expensive and dangerous compounds are used in the synthetic process, and there is no safety risk; the method uses commercially available starting materials, and the cost is low, which ensures good reproducibility of the synthetic route and is A process suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing VEGFR inhibitor fruquintinib and its benzofuran intermediate. Background technique [0002] Fruquintinib, developed by Hutchison Pharma, is a highly selective oral inhibitor of vascular endothelial growth factor receptor (VEGFR), which has the potential to become the world's best-in-class VEGFR inhibitor for the treatment of various solid tumors . High efficiency, low toxicity, and suitable for combination therapy are the excellent characteristics of fruquintinib that distinguish it from other approved small molecule VEGFR inhibitors. It is clinically used for the treatment of gastric cancer, advanced or metastatic colorectal cancer, and non-small cell lung cancer. On September 5, 2018, fruquintinib was approved for marketing by the Chinese Drug Evaluation Department, and the approved indication is metastatic colorectal cancer. 6-Hydroxy-N,2-dim...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/84C07D405/12A61P35/00
CPCA61P35/00C07D307/84C07D405/12
Inventor 戴洪果刘辉李权伟向进
Owner GUANGZHOU ANYANREN PHARMA TECH CO LTD
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