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Two new synthetic routes for a key benzofuran intermediate for fruquintinib synthesis were developed. These routes offer improved yields and utilize cost-effective starting materials, enhancing pharmaceutical manufacturing.

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Area of Science:

  • Organic Chemistry
  • Medicinal Chemistry
  • Process Chemistry

Background:

  • Fruquintinib is an important anti-cancer drug.
  • Efficient synthesis of its key benzofuran intermediate is crucial for large-scale production.
  • Current industrial routes may face challenges in cost-effectiveness or yield.

Purpose of the Study:

  • To develop practical and efficient synthetic routes for a key benzofuran intermediate used in fruquintinib preparation.
  • To explore alternative starting materials and chemical transformations for improved synthesis.
  • To optimize the overall yield and cost-effectiveness of the intermediate synthesis.

Main Methods:

  • Route 1: Michael addition and intramolecular Heck cyclization using 2-bromo-5-methoxyphenol and a 2-butynoic acid derivative.
  • Route 2: Condensation, base-catalyzed rearrangement, nitrile conversion, and demethylation starting from 2-hydroxy-4-methoxybenzaldehyde.
  • Utilized readily available monoprotected resorcinol derivatives and cost-effective starting materials.

Main Results:

  • Route 1 yielded the benzofuran intermediate in 45% over three steps or 58% over five steps.
  • Route 2 provided the target intermediate in an improved 60% overall yield over five steps.
  • Route 2 demonstrated superior cost-effectiveness by employing less expensive starting materials.

Conclusions:

  • Two viable synthetic strategies for the benzofuran intermediate were successfully established.
  • The second route offers a more economical and higher-yielding alternative for industrial application.
  • These advancements contribute to more efficient manufacturing of fruquintinib.