Synthesis of Carbovir and Abacavir from a Carbocyclic Precursor

Robert Vince1, Mei Hua1

1 Center for Drug Design, University of Minnesota, Minneapolis, Minnesota
Publication Name:  Current Protocols in Nucleic Acid Chemistry
Unit Number:  Unit 14.4
DOI:  10.1002/0471142700.nc1404s25
Online Posting Date:  July, 2006
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Abstract

A facile method for the synthesis of a carbocyclic analog of 2′,3′‐didehydro‐2′,3′‐dideoxy‐2‐amino‐6‐chloropurine is presented, starting from the versatile lactam, 2‐azabicyclo[2.2.1]hept‐5‐en‐3‐one. The corresponding anti‐HIV nucleoside analogs, carbovir and its derivative abacavir, are prepared directly from the 6‐chloro intermediate in one‐step reactions.

Keywords: carbocyclic nucleoside; HIV inhibitors; disubstituted purine analogs

     
 
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Table of Contents

  • Basic Protocol 1: Preparation of Carbovir and its 6‐Chloropurine Precursor
  • Basic Protocol 2: Preparation of Abacavir from the 6‐Chloropurine Precursor
  • Commentary
  • Literature Cited
  • Figures
     
 
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Materials

Basic Protocol 1: Preparation of Carbovir and its 6‐Chloropurine Precursor

  Materials
  • 2‐Azabicyclo[2.2.1]hept‐5‐en‐3‐one (Vince lactam; Sigma‐Aldrich)
  • 12 N HCl
  • 1 N dry HCl/methanol
  • Pyridine
  • Acetic anhydride
  • Ethyl acetate
  • Anhydrous calcium chloride
  • Sodium borohydride
  • Tetrahydrofuran (THF)
  • Barium hydroxide
  • Dry ice
  • Absolute ethanol
  • 1‐Butanol
  • 2‐Amino‐4,6‐dichloropyrimidine (Aldrich)
  • Triethylamine
  • Silica gel 60 (230 to 400 mesh; EM Science)
  • Chloroform (CHCl 3)
  • Methanol (MeOH)
  • p‐Chloroaniline
  • Ice‐salt bath
  • Sodium nitrite
  • Acetic acid
  • Sodium acetate trihydrate
  • Acetone
  • Zinc dust
  • Nitrogen source
  • Diethyl ether
  • Triethyl orthoformate
  • 3 N NaOH
  • Reflux condenser
  • Mechanical stirrer
  • Rotary evaporator
  • Büchner filter funnel
  • Silicon oil bath
  • 5.0 × 15–, 2.0 × 18–, 4.0 × 10–, 2.0 × 7.5–, and 5 × 5–cm columns
  • Silica gel 60 F 254 TLC plates (0.25‐mm layer; EM Science)
  • Additional reagents and equipment for column chromatography ( appendix 3E) and TLC ( appendix 3D)

Basic Protocol 2: Preparation of Abacavir from the 6‐Chloropurine Precursor

  Materials
  • 6‐Chloropurine precursor ( S.6; see protocol 1)
  • Ethanol
  • Cyclopropylamine
  • 1 N NaOH
  • Silica gel (230 to 400 mesh; EM Science)
  • Chloroform (CHCl 3)
  • Methanol (MeOH)
  • Acetonitrile
  • Silicon oil bath
  • Rotary evaporator
  • 2 × 13–cm column
  • Silica gel 60 F 254 TLC plate (0.25‐mm layer; EM Science)
  • Additional reagents and equipment for column chromatography ( appendix 3E) and TLC ( appendix 3D)
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Figures

Videos

Literature Cited

Literature Cited
   Jeong, L.S. and Lee, J.A. 2004. Recent advances in the synthesis of the carbocyclic nucleosides as potential antiviral agents. Antiviral Chem. Chemother. 15:235‐250.
   Rouhi, A.M. 2003. Cover Story. Chem. Eng. News 81:37‐52.
   Stinson, S.C. 1994. Market, environmental pressures spur change in fine chemicals industry. Chem. Eng. News 72:12‐26.
   Vince, R. and Daluge, S. 1978. Synthesis of carbocyclic aminonucleosides. J. Org. Chem. 43:2312‐2320.
   Vince, R. and Hua, M. 1990. Synthesis and anti‐HIV activity of carbocyclic 2′,3′‐didehydro‐2′,3′‐dideoxy‐2,6‐disubstituted purine nucleosides. J. Med. Chem. 33:17‐21.
   Vince, R., Hua, M., Brownell, J., Daluge, S., Lee, F.C., Shannon, W.M., Lavelle, G.C., Qualls, J., Weislow, O.S., Kiser, R., Canonico, C.G., Schultz, R.H., Narayanan, V.L., Mayo, L.G., Shoemaker, R.H., and Boyd, M.R. 1988. Potent and selective activity of a carbocyclic nucleoside analog (Carbovir: NSC 614846) against human immunodeficiency virus in vitro. Biochem. Biophys. Res. Commun. 156:1046‐1053.
   Zhu, Z.‐F. 2000. The latest progress in the synthesis of carbocyclic nucleosides. Nucleosides Nucleotides Nucleic Acids 19:651‐690.
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