Acetic Acid → HCID 22498150, compound

Acetic acid 6-allyl-3,4,5-tris-benzyloxy-tetrahydro-pyran-2-ylmethyl ester (from Example 7) (5 g, 9.7 mmol) was dissolved in dichloromethane (50 ml), water (50 ml), acetic acid (5 ml) and aliquat336 (1 ml) and cooled to 0° C. To this solution was added potassium permanganate (6.1 g, 38.7 mmol) portionwise with vigorous stirring, the resultant mixture allowed to warm to room temperature and stirring continued overnight. The reaction mixture was cooled to 0° C. and quenched with sodium sulfite (10 g), 5M hydrochloric acid (50 ml) was added and the mixture extracted with dichloromethane (4×50 ml). The combined organic extracts were washed with brine (100 ml), dried over sodium sulfate and evaporated. The residue was purified on a rapid vacuum silica gel (0.040-0.063 mm; 100 g) column (70×200 mm) eluted with dichloromethane (200 ml), 2.5% methanol dichloromethane (2×200 ml), 5% methanol in dichloromethane (2×200 ml), 10% methanol in dichloromethane (2×200 ml), 20% methanol in dichloromethane (2×200 ml) to give (6-acetoxymethyl-3,4,5-tris-benzyloxy-tetrahydro-pyran-2-yl)-acetic acid (tlc silica gel, Rf 0.6 in 10% MeOH/DCM, ESMS (−ve) 533 (M−H), 569 (M+Cl). This compound was reacted with sodium methoxide (1.3 g, 24 mmol) in methanol (10 ml) to give (3,4,5-tris-benzyloxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-acetic acid (tlc silica gel, Rf 0.5 in 10% MeOH/DCM, ESMS (−ve) 491 (M−H), 527 (M+Cl)) as an oil (3.1 g, 65%). This compound (3 g, 6 mmol), BOP reagent (2.87 g, 6.5 mmol) and the tosyl salt of glutamic acid, dibenzyl ester (4 g, 8 mmol) were combined in tetrahydrofuran (20 ml) and diisopropylethyalamine (3.5 ml, 20 mmol) added. After 4 hours the solvent was removed under reduced pressure and ethyl acetate (100 ml) added to the oily residue this mixture was subsequently washed with 1M hydrochloric acid (2×100 ml), saturated sodium bicarbonate (2×100 ml) and brine (100 ml), dried over anhydrous sodium sulfate, and evaporated to dryness. The residue was purified on a rapid vacuum silica gel (0.040-0.063 mm; 100 g) column (70×200 mm) eluted with light petroleum (200 ml), 10% ethyl acetate in light petroleum (200 ml), 20% ethyl acetate in light petroleum (200 ml), 30% ethyl acetate in light petroleum (200 ml), 40% ethyl acetate in light petroleum (200 ml), 50% ethyl acetate in light petroleum (4×200 ml) and 100% ethyl acetate (2×100 ml) to give 2-[2-(3,4,5-tris-benzyloxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-acetylamino]-pentanedioic acid dibenzyl ester (tlc silica gel, Rf 0.34 in 50% EtOAc/Light petroleum, ESMS (+ve) 802 (M+H), 824 (M+Na)) as an oil (1.4 g, 29%). This compound (2.4 g, 3.0 mmol) was dissolved in dry dichloromethane (10 ml) and triethylamine (557 μl, 4 mmol) and the mixture cooled to 0° C. whereupon phosphorous oxychloride (307 μl, 3.3 mmol) was added dropwise with stirring under an atmosphere of nitrogen. The mixture was allowed to warm to room temperature and stirred for 2 hours. The solvent was evaporated and the residue diluted with ether and centrifuged to remove insoluble salts. The supernatant was then evaporated and redissolved in a 1:1 mixture of acetone and water (20 ml) and kept at 45-50° C. for 2 hours. The solvent was removed under reduced pressure to give 2-[2-(3,4,5-tris-benzyloxy-6-phosphonooxymethyl-tetrahydro-pyran-2-yl)-acetylamino]-pentanedioic acid dibenzyl ester, ESMS (+ve) 882 (M+H). This compound was dissolved with 1% formic acid in 1:1 methanol and water (100 ml), 10% paladium on carbon (100 mg) added and hydrogenated at 40 psi overnight. The mixture was filtered through celite and the filtrate evaporated to dryness to give 2-[2-(3,4,5-trihydroxy-6-phosphonooxymethyl-tetrahydro-pyran-2-yl)-acetylamino]-pentanedioic acid, ESMS (−ve) 430 (M−H). From this was prepared the di sodium salt by dissolving this compound in a 1:1 solution of water and ethanol (2 ml) and dropwise addition of this solution to sodium acetate (541 mg, 6.6 mmol) dissolved in ethanol (50 ml). The resulting precipitate was isolated by centrifugation to give 2-[2-(3,4,5-trihydroxy-6-phosphonooxymethyl-tetrahydro-pyran-2-yl)-acetylamino]-pentanedioic acid, disodium salt as a white solid (732 mg, 51%). 1Hnmr (500 MHz, D2O): δ 1.75 (m, 1H), 1.94 (m, 1H), 2.13 (t, J=8.0 Hz, 2H), 2.52 (dd, J=6.5, 15.0 Hz, 1H), 2.64 (dd, J=8.5, 15.0 Hz, 1H), 3.54 (m, 1H), 3.64-3.73 (m, 2H), 3.76 (m, 1H), 3.85-3.97 (m, 2H), 4.03 (m, 1H), 4.21 (m, 1H).

1. temperatureThe reaction mixture was cooled to 0° C.
2. customquenched with sodium sulfite (10 g), 5M hydrochloric acid (50 ml)
3. additionwas added
4. extractionthe mixture extracted with dichloromethane (4×50 ml)
5. washThe combined organic extracts were washed with brine (100 ml)
6. dry with materialdried over sodium sulfate
7. customevaporated
8. customThe residue was purified on a rapid vacuum silica gel (0.040-0.063 mm; 100 g) column (70×200 mm)
9. washeluted with dichloromethane (200 ml), 2.5% methanol dichloromethane (2×200 ml), 5% methanol in dichloromethane (2×200 ml), 10% methanol in dichloromethane (2×200 ml)

ORD record

ord-4bb4a540e36544ceb958e96eece3dd89

Source dataset

uspto-grants-2005_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06878690B2