A systematic study towards the synthesis, isolation and recrystallization of Atovaquone, an antimalarial drug: a sustainable synthetic pathway

Authors

  • Sanjay SDM Institute of Technology, Ujire.
  • Shashiprabha SDM College (Autonomous), Ujire.
  • Shridhara ArkGen Pharma Private Limited, Bangalore.
  • Nagarajan Retired Consultant for Alkem Labs and KOP Research Centre, Bangalore.
  • Ranganathan Retired Head of R & D, Alkem Labs and KOP Research Centre, Bangalore.

Keywords:

2-[trans-4-(4-chlorophenyl) cyclohexyl]-3-hydroxy-1, 4-naphthoquinone(Atovaquone), reaction optimization, isolation, recrystallization

Abstract

In the present work, studies were conducted towards the synthesis of Atovaquone 5 with systematic reaction and recrystallization condition optimization to isolate 5 in high yield with better purity. Synthesis of 5 was done by the hydrolysis of 2-[trans-4-(4-chlorophenyl) cyclohexyl]-3-chloro-1,4-naphthoquinone 4, which was isolated by the decarboxylative condensation of trans-4-(4-chlorophenyl) cyclohexane carboxylic acid 3 with naphthoquinone moiety. After the hydrolysis of 4, isolation of crude 5 was done by the use of acetic acid instead of dilute hydrochloric acid, product 5 was isolated in good purity with very less polar impurities. The use of a large volume of solvent becomes a bottleneck for the commercial synthesis of 5. Our efforts towards optimization of hydrolysis reaction and recrystallization of 5 with the use of small volume of solvent combination had made the process to be more cost effective and commercially viable for large scale manufacturing.

Author Biographies

Sanjay, SDM Institute of Technology, Ujire.

Department of Chemistry, Sri Dharmasthala Manjunatheshwara Institute of Technology (Affiliated to Visvesvaraya Technological University, Belagavi), Ujire - 574 240, Karnataka, India.

Shashiprabha, SDM College (Autonomous), Ujire.

PG Department of Chemistry, Sri Dharmasthala Manjunatheshwara College (Autonomous), Ujire-574 240, Karnataka, India.

Shridhara, ArkGen Pharma Private Limited, Bangalore.

Technical Coordinator, ArkGen Pharma Private Limited, Peenya Industrial Area, Bangalore-560 058, Karnataka, India.

Nagarajan, Retired Consultant for Alkem Labs and KOP Research Centre, Bangalore.

Retired Consultant for Alkem Labs and KOP Research Centre, Bangalore, Karnataka, India.

Ranganathan, Retired Head of R & D, Alkem Labs and KOP Research Centre, Bangalore.

Retired Head of R & D, Alkem Labs and KOP Research Centre, Bangalore, Karnataka, India.

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Published

2022-01-01