|
【结 构 式】 
|
【分子编号】17523 【品名】[(2S,3S,4S,5R)-5-(acetoxy)-3,4-bis(benzoyloxy)tetrahydro-2-furanyl]methyl benzoate 【CA登记号】6974-32-9 |
【 分 子 式 】C28H24O9 【 分 子 量 】504.49316 【元素组成】C 66.66% H 4.8% O 28.54% |
合成路线1
该中间体在本合成路线中的序号：(III)The synthesis of [1'-14C]-labeled stavudine has been published: The reaction of labeled D-ribofuranose (I) first with methanol and acetyl chloride and then with benzoyl chloride gives 2,3,5-tri-O-benzoyl-1-O-methyl-D-ribofuranoside (II), which is acetylated with acetic anhydride and acetic acid to 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranoside (III). The condensation of (III) with thymine (IV) by means of hexamethyldisylazane (HMDS), trimethylsilyl chloride (TMS-Cl) and trifluoromethanesulfonic acid, followed by a basic hydrolysis with NaOMe affords 1-(beta-D-ribofuranosyl)thymine (V), which is treated with methanesulfonyl chloride in pyridine giving the trimesylate (VI). The reaction of (VI) with sodium benzoate in hot DMF yields the benzoylated internal ether (VII), which is treated with acetyl bromide in acetic acid/HBr affording 1-[2-bromo-2-deoxy-5-O-benzoyl-3-O-(methanesulfonyl)-beta-D-ribofuranos yl]thymine (VIII). The reaction of (VIII) with Zn in the same solvent as before gives 5'-O-benzoylstavudine (IX), which is finally debenzoylated with NaOCH3 in methanol.
| 【1】 Discordia, R.P.; Synthesis of 1'-[C-14]-Stavudine(R) (d4T). J Label Compd Radiopharm 1996, 38, 7, 613. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 10016 | D-Ribose; (3R,4S,5R)-5-(Hydroxymethyl)tetrahydro-2,3,4-furantriol; (2R,3R,4R)-2,3,4,5-Tetrahydroxypentanal | 50-69-1 | C5H10O5 | 详情 | 详情 |
| (I) | 45109 | (3R,4S,5R)-5-(hydroxymethyl)tetrahydro-2,3,4-furantriol | C5H10O5 | 详情 | 详情 | |
| (II) | 12247 | [(2R,3R,4R)-3,4-bis(benzoyloxy)-5-methoxytetrahydro-2-furanyl]methyl benzoate | C27H24O8 | 详情 | 详情 | |
| (II) | 45110 | [(2R,3R,4R)-3,4-bis(benzoyloxy)-5-methoxytetrahydro-2-furanyl]methyl benzoate | C27H24O8 | 详情 | 详情 | |
| (III) | 17523 | [(2S,3S,4S,5R)-5-(acetoxy)-3,4-bis(benzoyloxy)tetrahydro-2-furanyl]methyl benzoate | 6974-32-9 | C28H24O9 | 详情 | 详情 |
| (III) | 45111 | [(2R,3R,4R,5S)-5-(acetoxy)-3,4-bis(benzoyloxy)tetrahydro-2-furanyl]methyl benzoate | C28H24O9 | 详情 | 详情 | |
| (IV) | 12204 | 5-Methyl-2,4(1H,3H)-pyrimidinedione; Thymine | 65-71-4 | C5H6N2O2 | 详情 | 详情 |
| (V) | 12206 | 1-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione; 5-Methyluridine | 1463-10-1 | C10H14N2O6 | 详情 | 详情 |
| (V) | 45112 | 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione | C10H14N2O6 | 详情 | 详情 | |
| (VI) | 12251 | 1-[(2R,3R,4R,5R)-3,4-Bis[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-5-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione | C19H32N2O6S3 | 详情 | 详情 | |
| (VI) | 45113 | 1-[(2R,3R,4R,5R)-3,4-bis[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-5-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione | C19H32N2O6S3 | 详情 | 详情 | |
| (VII) | 12252 | ((2R,3R,3aS,9aR)-7-methyl-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-6-oxo-2,3,3a,9a-tetrahydro-6H-furo[2',3':4,5][1,3]oxazolo[3,2-a]pyrimidin-2-yl)methyl benzoate | C20H22N2O6S | 详情 | 详情 | |
| (VII) | 45114 | ((2R,3R,3aS,9aR)-7-methyl-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-6-oxo-2,3,3a,9a-tetrahydro-6H-furo[2',3':4,5][1,3]oxazolo[3,2-a]pyrimidin-2-yl)methyl benzoate | C20H22N2O6S | 详情 | 详情 | |
| (VIII) | 12253 | [(2R,3R,4R,5R)-4-bromo-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C20H23BrN2O6S | 详情 | 详情 | |
| (VIII) | 45115 | [(2R,3R,4R,5R)-4-bromo-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C20H23BrN2O6S | 详情 | 详情 | |
| (IX) | 12254 | [(2S,5R)-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2,5-dihydro-2-furanyl]methyl benzoate | C17H16N2O5 | 详情 | 详情 | |
| (IX) | 45116 | [(2S,5R)-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2,5-dihydro-2-furanyl]methyl benzoate | C17H16N2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Previously, it was reported that D-ribose was synthesized from D-xylose, the epimer of D-ribose, via a stereoselective oxidation-reduction procedure, albeit in low yield. This strategy was adapted to prepare the L-ribose derivative (V) for the practical synthesis of L-FMAU as well as related nucleosides. After pyridinium dichromate (PDC) oxidation, ketone (III) was reduced to an alcohol using NaBH4. It should be mentioned that due to the stereoelectronic effects of the 1,2-O-isopropylidene group, the hydride preferentially attacks from the beta-face. After a series of reactions, compound (V) was obtained and treated with saturated hydrogen chloride in CH2Cl2 at 0 C followed by the migration of the benzoyl group and treatment with SO2Cl2 and imidazole in DMF/CH2Cl2 to give a imidazolyl intermediate. The imidazole derivative was fluorinated with a mixture of KHF2 and 48% HF/H2O to give 1,3,5-tri-O-benzoyl-2-fluoro-alpha-L-arabinofuranose, which was converted to bromosugar (VI) using 45% HBr/AcOH. Without further purification, the bromosugar was condensed with silylated thymine in anhydrous CHCl3 in refluxing conditions to give protected L-FMAU with high stereoselectivity, which was further treated with NH3/CH3OH for debenzoylation to give L-FMAU. Due to the availability and high cost of L-xylose, however, we have developed another procedure from L-arabinose. L-Arabinose is a natural sugar with reasonable cost. The anomeric position was protected with a benzyl group in acidic conditions to the pyranose form and the vicinal cis-hydroxy groups were protected with an isopropylidene group. In similar conditions as for L-xylose, PDC was used for the oxidation reaction to obtain ketone (IV), which was reduced with NaBH4 in methanol with high stereoselectivity as described for L-xylose. After deprotection of compound (IV) using 4% CF3CO2H, the resulting L-ribose was sequentially treated with 1% HCl/MeOH, BzCl/pyridine and H2SO4/AcO/AcOH to obtain compound (V). The remaining steps to L-FMAU were the same as described for the L-xylose route.
| 【1】 Oka, K.; Wada, H.; Synthesis of D-ribose from D-xylose. Yakugaku Zasshi 1963, 83, 890-1. |
| 【2】 Brundidge; Tann, C.H.; Brodfuehrer, P.R.; et al.; Fluorocarbohydrates in synthesis. An efficient synthesis of 1-(2-deoxy-2-fluoro-ß-D-arabinofuranosyl)-thymine (ß-D-FMAU). J Org Chem 1985, 50, 3644-6. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 17519 | (3R,4S,5R)tetrahydro-2H-pyran-2,3,4,5-tetrol; L-(-)-Xylose | 609-06-3 | C5H10O5 | 详情 | 详情 |
| (II) | 17520 | (3R,4S,5S)tetrahydro-2H-pyran-2,3,4,5-tetrol; L-(+)-Arabinose | 7296-56-2 | C5H10O5 | 详情 | 详情 |
| (III) | 17521 | [(3aS,5S,6aR)-2,2-dimethyl-6-oxotetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzoate | C15H16O6 | 详情 | 详情 | |
| (IV) | 17522 | (3aS,6S,7aR)-6-(benzyloxy)-2,2-dimethyldihydro-4H-[1,3]dioxolo[4,5-c]pyran-7(6H)-one | C15H18O5 | 详情 | 详情 | |
| (V) | 17523 | [(2S,3S,4S,5R)-5-(acetoxy)-3,4-bis(benzoyloxy)tetrahydro-2-furanyl]methyl benzoate | 6974-32-9 | C28H24O9 | 详情 | 详情 |
| (VI) | 17524 | [(2S,3S,4R,5S)-3-(benzoyloxy)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl benzoate | C19H16BrFO5 | 详情 | 详情 |