(1S,2S,3S,5S)-5-(2-Amino-6-(benzyloxy)-9H-purin-9-yl)-3-(benzyloxy)-2-(benzyloxymethyl)cyclopentanol

Uses

(2R,3R,5R)-5-[2-Amino-6-(phenylmethoxy)-9H-purin-9-yl]-3-(phenylmethoxy)-2-[(phenylmethoxy)methyl]-cyclopentanol is an intermediate in the preparation of ent-Entecavir (E558905).

Synthesis

To the reaction flask was added 100 mL of toluene and 0.1 g of tetrabutylammonium bromide and stirred for 10 minutes. Subsequently, 50 g of 30% KOH aqueous solution and 10 g of (1S,2R,3S,5R)-3-(phenylmethoxy)-2-[(phenylmethoxy)methyl]-6-oxabicyclo[3.1.0]hexane were added and stirred until completely dissolved. The reaction mixture was warmed to 80 °C and stirred over heat for 6 hours. The reaction progress was monitored by TLC during the reaction (unfolding agent: ethyl acetate/n-heptane=1:1, (1S,2R,3S,5R)-3-(phenylmethoxy)-2-[(phenylmethoxy)methyl]-6-oxabicyclo[3.1.0]hexane had an Rf value of 0.7, and the target product (1S,2S,3S,5S)-5-(2-amino-6-benziloxy-9H- purin-9-yl)-3-benzyloxy-2-benzyloxymethylcyclopentanol had an Rf value of 0.3) to ensure that the residue of the raw material was less than 1%. After completion of the reaction, the heating was stopped and the reaction mixture was allowed to stand and stratify. The aqueous layer was separated and the organic layer was washed twice with potable water. The toluene solution was concentrated and the solvent was removed to give 12 g of crude product. After purification by column chromatography, the eluate was concentrated and dried to give 6 g of white solid target product with 99.9% purity by HPLC (target product retention time 6 min, raw material retention time 10 min).

References

[1] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 2, p. 127 - 132
[2] Patent: US5206244, 1993, A
[3] Patent: CN107513065, 2017, A. Location in patent: Paragraph 0013-0014; 0015-0016; 0017-0018