Acetic acid--water (1/1) → 4-(2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol, (1S,4R)-

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Reaction Conditions

Reaction Steps

A suspension of (1S,4R)-4-((2-Amino-6-chloro-5-((4-chlorophenyl)azo)-4-pyrimidinyl)amino)-2-cyclopentene-1-methanol hydrate (1.96 g, 5 mmol) in tetrahydrofuran (15 mL) was treated with acetic acid/water (1:1, 5 mL), then with zinc dust (1.63 g, 25 mmol) in portions so as to keep the pot temperature below 35° C. The deep yellow color faded after 10 min, and after an additional 50 min the solution was filtered to remove precipitated zinc salts. The filter cake was rinsed with tetrahydrofuran and the filtrate was refiltered to remove additional zinc salts, then concentrated in vacuo with addition of toluene to facilitate removal of water and acetic acid. The residue was rinse with toluene/hexane to separate some of the 4-chloroaniline byproduct taken up in triethyl orthoformate (40 mL), cooled on an ice bath (5° C.), and treated dropwise with concentrated hydrochloric acid (1.9 mL). The mixture was stirred at 5° C. for 5 h (tan suspension soon formed), slow warm to room temperature, and stirred far an additional 18 h, then cooled on an ice bath and filtered. The filter cake was rinsed with ether (save filtrate), ard the solid was taken up in water (30 mL), filtered, and the solids washed with water. The aqueous filtrate was basified with sodium carbonate to pH-9, then extracted with 5% isopropanol-chloroform (3×25 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to a residual tan foam (0.85 g). The organic filtrate from above was concentrated in vacuo an the residue taken up in 1N hydrochloric acid (30 mL), stirred far 1 h, filtered, and the filtrate adjusted to pH-6 with 5N sodium hydroxide (6 mL), then basified with sodium carbonate. This aqueous suspension was extracted with 5% isopropanol-chloroform (3×25 mL), and the combined organic extracts were dried (Na2SO4) and concentrated in vacuo to a tan foam (0.55 g). The two batches were combined, dissolved in warm chloroform, and loaded onto a silica gel column, which was eluted with 7% methanol-chloroform to afford pure fractions containing the subject compound. These were concentrated in vacuo and the residual foam crystallized am ethyl acetate (2 crops) to afford 0.86 g (65%) of the title compound as a pale tan solid; mp 160°-162° C. 1H-NMR (DMSO-d6)δ: 8.04(s,1H); 6.91(s,2H); 6.15(m, 1H); 5.90 (m, 1H); 5.45 (m, 1H); 4.73(t,1H,J=5 Hz); 3.45(t,2H,J=5 Hz); 2.80-2.95(m, 1H); 2.55-2.70(m, 1H); 1.60-1.70(m, 1H). Ms(Cl): m/z 170 (m-C5 ring, 100); 230 (m-Cl, 50); 266 (m+H+, 100). [α]20589 -104°, [α]20436 -267°(c=0.29, methanol).

Provenance & Evidence