Acetic Acid → HCID 69734782, compound

Temperature

0 °C

Phosphoric acid 6-allyl-3,4,5-tris-benzyloxy-tetrahydro-pyran-2-ylmethyl ester diphenyl ester (prepared in Example 15) (10 g, 14.16 mmol) in dichloromethane (75 ml) water (75 ml) and acetic acid (15.6 ml) was added Aliquat 336 (0.93 g) and the reaction vessel was cooled to 0° C. and potassium permanganate (8.3 g, 52.7 mmol) was added in two portions. The ice bath was removed, and the reaction was stirred for 24 hours at room temperature. Sodium sulfite (9.31 g, 57.4 mmol) was added and the mixture was partitioned between water (150 ml) and dichloromethane (200 ml). The aqueous layer was extracted with dichloromethane (150 ml), and the combined organic extracts were washed with brine (200 ml), dried (sodium sulfate), filtered and evaporated under reduced pressure. The residue was chromatographed on a silica gel (0.040-0.063 mm) column (4×20 cm), eluted with ethylacetate:methanol (19:1) to give [3,4,5-tris-benzyloxy-6-(bis-phenoxy-phosphoryloxymethyl)-tetrahydro-pyran-2-yl]-acetic acid (9.6 g, 93.8%). To a stirred solution of this compound (9.0 g, 12.45 mmol) and BOP reagent (5.84 g, 13.16 mmol) in tetrahydrofuran (50 ml) at room temperature was added diisopropylethylamine (2.62 ml, 15.03 mmol). The resulting solution was stirred for 5 minutes, then sodium borohydride (490 mg, 12.9 mmol) was added. After stirring for 20 minutes, the solvent was evaporated and the residue was taken up in ethylacetate (300 ml) and washed with 5% hydrochloric acid (2×100 ml), saturated sodium bicarbonate (2×100 ml) and brine (100 ml), dried (sodium sulfate), filtered and evaporated. The residue was chromatographed on a silica gel (0.040-0.063 mm) column (4×20 cm), eluted with petroleum spirit (bp 60-80°): ethyl acetate (1:1) to give phosphoric acid diphenyl ester 3,4,5-tris-benzyloxy-6-(2-hydroxy-ethyl)-tetrahydro-pyran-2-ylmethyl ester (4.9 g, 56%), tlc silica gel, Rf0.42 (ethyl acetate/petroleum spirit bp 60-80 1:1). 1Hnmr (300 MHz, CDCl3): δ 1.65 (m, 1H), 1.98 (m, 1H), 3.50-3.80 (m, 5H), 4.00-4.30 (m, 3H), 4.45-4.68 (m, 6H), 4.85 (m, 1H), 7.00-7.70 (m, 25H); ESMS (+ve) 711 (M+H), 733 (M+Na). This compound (3.64 g, 5.13 mmol), tetramethylurea (600 mg, 5.17 mmol) and silver trifluoromethanesulfonate (1.32 g, 5.14 mmol) were dissolved in dichloromethane (100 ml) and stirred under nitrogen over molecular sieves (4A°, 5 g) for 1 hour at room temperature, and then cooled to −20° C. To this solution was added hepta-O-acetylmaltosyl bromide (prepared in Example 15) (5.82 g, 5.14 mmol) in dichloromethane (100 ml) dropwise. The mixture was stirred at −20° C. for 4 hours, then left overnight to reach room temperature, and filtered through celite. The filtrate was poured into ice-cold water and washed sequentially with saturated sodium bicarbonate (100 ml), water (50 ml), hydrochloric acid (100 ml), water (50 ml), saturated sodium bicarbonate (100 ml), and water (50 ml). The resulting solution was dried (sodium sulfate), filtered and evaporated under reduced pressure. The residue was chromatographed on a silica gel (0.040-0.063 mm) column (4×50 cm), eluted with petroleum spirit (bp 60-80°): ethyl acetate (3:2) to give phosphoric acid diphenyl ester 3,4,5-tris-benzyloxy-6-{2-[3,4-diacetoxy-6-bacetoxymethyl-5-(3,4,5-triacetoxy-6-acetoxymethyl-tetrahydro-pyran-2-yloxy)-tetrahydro-pyran-2-yloxy]-ethyl}-tetrahydro-pyran-2-ylmethyl ester (3.07 g, 34%). Treatment of this compound in a similar manner to that for phosphoric acid diphenyl ester mono-(6-{2-[3,4-diacetoxy-6-acetoxymethyl-5-(3,4,5-triacetoxyroxy-6-acetoxymethyl-tetrahydro-pyran-2-yloxy)-tetrahydro-pyran-2-yloxy]-propyl}-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl) ester in Example 15 gave phosphoric acid mono-(6-{2-[3,4-dihydroxy-6-hydroxymethyl-5-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-tetrahydro-pyran-2-yloxy]-ethyl}-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl) ester monosodium salt. (72% overall). 1Hnmr (300 MHz, D2O) ∂ 1.64-2.10 (m, 2H), 3.14 (m, 1H), 3.23 (m, 1H), 3.40-4.20 (m, 19H), 4.30 (m, 1H), 5.25 (m, 1H); ESMS (−ve) 611 (M−H).

1. customThe ice bath was removed
2. customthe mixture was partitioned between water (150 ml) and dichloromethane (200 ml)
3. extractionThe aqueous layer was extracted with dichloromethane (150 ml)
4. washthe combined organic extracts were washed with brine (200 ml)
5. dry with materialdried (sodium sulfate)
6. filtrationfiltered
7. customevaporated under reduced pressure
8. customThe residue was chromatographed on a silica gel (0.040-0.063 mm) column (4×20 cm)
9. washeluted with ethylacetate:methanol (19:1)

ORD record

ord-c13f793fee26439183abd611bb3ee44e

Source dataset

uspto-grants-2005_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06878690B2