Process Improvement on the Synthesis of Efinaconazole
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O626;R914.5

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    Abstract:

    To explore a new route for the synthesis of efinaconazole, intermediate 4-[(R)-2-hydroxypropiony]morpholine(Ⅱ)was prepared from starting materials R-methyl lactate by amination with morpholine, (2R)-2’,4’-difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2- lyoxy)propiophenone(Ⅳ) was synthesized by reacting with 2,4-difluorophenyl magnesium bromide after hydroxy group was protected. Precursor (2R,3R) -2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)- 2,3-butanediol(Ⅶ) was obtained via Corey-Chaykovsky epoxidation, trizole alkylation and deprotection in one pot reation. After reacting with methanesulfonyl chloride , epoxidation and subsequent alkylation with 4-methylenepiperidine, the product efinaconazole(Ⅰ) was acquired. The total yield of efinaconazole(Ⅰ) was increased from 17% to 24% with purity of more than 99% determined by HPLC. The stucture of product was characterized by means of 1HNMR, ESI-MS and polarimetry.

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History
  • Received:December 05,2015
  • Revised:January 27,2016
  • Adopted:February 03,2016
  • Online: March 10,2016
  • Published:
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