86304-28-1

Usage

Originator

Buciclovir,Astra Lakemedel

Manufacturing Process

Preparation of R-(+)-9-(3,4-dihydroxybutyl)guanine: Step A: preparation of R-(+)-1,2,4-butantriol: R-(+)-Dimethyl maleate (1.62, 10 mmol), prepared according to Boger, D.L. and Panek, J.S., J. Org. Chem. 1981, 46, 1208-10, was dissolved in THF (10 ml) and added dropwise to a prewarmed suspension of lithium aluminium hydride (0.63 g, 16.5 mmol) in THF (15 ml). The reaction mixture was stirred overnight at 55°C. After sequential addition of water (0.62 ml), 10% sodium hydroxide (1.20 ml) and water (1.90 ml) the mixture was filtered and the solid residue was boiled twice with THF (2x20 ml) and filtered. The combined filtrates were pooled and evaporated under reduced pressure (30°C) leaving crude 1,2,4-butantriol (0.7 g, 6.6 mmol) 66%. Step B: preparation of R-(+)-isopropylidenbutan 1,2,4-triol: R-(+)-1,2,4-butantriol (0.7 g, 6.6 mmol), prepared as described in step (a) above, was stirred for 1.5 hr in acetone (50 ml) containing 3 drops of conc. perchloric acid a satured solution of sodium bicarbonate in water (5 ml) was added and the stirring was continued for additional 10 min. The precipitate was filtered off and the filtrate evaporated under reduced pressure [2.7 kPa,(20 mm Hg), 30°C]. The residue was taken up in ethyl acetate, washed with satured aqueous sodium bicarbonate (5 ml) and brine (5 ml), and dried over magnesium sulfate. Evaporation of the solvent and distillation gave the title compound as a colourless oil (0.3 g, 2.05 mmol, 31%): b.p. 104°- 106°C/20 mm Hg; nD 20=1.4390. Step C: preparation of R-(+)-4-bromo-isopropylidenebutan-1,2-diol: R-(+)-Isopropylidene-butan-1,2,4-triol (0.3 g, 2.05 mmol) and triphenylphosphine (0.63 g, 2.4 mmol) were dissolved in methylene chloride (5 ml) and cooled to 0°C. N-Bromosuccinimide (0.38 g, 2.16 mmol) was added in small portions with stirring at 0°C. After additional 1 hr of stirring at 0°C hexane (15 ml) was added and the resulting precipitate was removed by filtration and washed twice with hexane (2x5 ml). The combined hexane solution was passed through a short column of silica gel (5 g). Elution with hexane (15 ml) gave after evaporation and distillation the title compound as a colorless oil (0.2 g, 0.96 mmol, 47%): b.p. 74°-76°C/20 mm Hg, nD 20=1.4630. [α]D 20=+27.7° (C=20, CHCl3). Step D: preparation of R(+)-4-(2-amino-6-chloropurin-9-yl)isopropylidenebutane- 1,2-diol: 2-Amino-6-chloropurin (162 mg, 0.96 mmol), R-(+)-4-bromo-isopropylidenebutandiol (200 mg, 0.96 mmol) and potassium carbonate (132 mg) was mixed in DMF (10 ml). After stirring for 16 hr the reaction mixture was filtered through celite and the solvent evaporated under reduced pressure [13 Pa (0.1 mm Hg), 50°C]. The residue was triturated with warm chloroform (5 ml) and undissolved material was filtered off. Evaporation of the solvent gave a pale yellow crystalline solid consisting mainly of the 9- and 7-isomers. These were separated by silica gel flash chromatography. Elution with chloroform/methanol (15:1) gave the title compound in pure form (106 mg, 0.36 mmol, 37%): MP: 129°-130°C, [α]D 21 =+57.5° (C=6.97, CHCl3). Step E: preparation of R-(+)-9-(3,4-dihydroxybutyl)guanine: R-(+)-4-(2-Amino-6-chloropurin-9-yl)isopropylidene-butane-1,2-diol (100 mg, 0.33 mmol) prepared according to step (d) above was dissolved in hydrochloric acid (1 mol/L) and refluxed for 1 hr. The solution was concentrated in vacuum and the residue dissolved in water (5 ml) and made alkaline by addition of aqueous ammonium hydroxide. After evaporation the solid residue was recrystallized from water giving the title compound as white needles (40 mg, 0.17 mmol, 51%). [α]D 21=+30.8° (C=0.25, water). (+/-)- Form had MP: 260°-261°C.

InChI:InChI=1/C9H13N5O3/c10-9-12-7-6(8(17)13-9)11-4-14(7)2-1-5(16)3-15/h4-5,15-16H,1-3H2,(H3,10,12,13,17)/t5-/m1/s1

Upstream product

• 19916-73-5 2-Amino-6-benzyloxypurine 

Relevant academic research and scientific papers

Synthesis of Chiral Acyclic Nucleosides by Sharpless Asymmetric Dihydroxylation: Access to Cidofovir and Buciclovir

An efficient method to construct chiral acyclic nucleosides via Sharpless asymmetric dihydroxylation of N-allylpyrimidines or N-alkenylpurines is reported. A range of chiral acyclic nucleosides with two adjacent hydroxyl groups present on the side chains could be produced in good yields (up to 97% yield) and excellent enantioselectivities (90-99% ee). The synthetic utility of the reaction was demonstrated by the catalytic asymmetric synthesis of (S)-Cidofovir and (R)-Buciclovir.