【结 构 式】 ![]() |
【分子编号】12254 【品名】[(2S,5R)-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2,5-dihydro-2-furanyl]methyl benzoate 【CA登记号】 |
【 分 子 式 】C17H16N2O5 【 分 子 量 】328.32452 【元素组成】C 62.19% H 4.91% N 8.53% O 24.37% |
合成路线1
该中间体在本合成路线中的序号:(IX)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:(III)An improved process for the preparation of high purity stavudine in a good yield was reported: The reaction of 5-methyluridine (I) with mesyl chloride and NMM in acetone, followed by a treatment with 6N NaOH gives the 2,2'-anhydro-5-methyluridine derivative (II), which is treated successively with potassium benzoate in DMF, HBr in acetic acid, and finally with Zn in DMF to yield 2',3'-anhydro-5'-O-benzoylthymidine (III). Finally, this compound is debenzoylated with hot butylamine.
【1】 Reddy, J.P.; Quinlan, S.L.; Reid, J.G.; Renner, D.A.; Weaver, D.G.; Stark, D.R.; Chen, B.-C.; Independent syntesis and fate studies of impurities in process intermediates of the anti-AIDS drug d4T. Org Process Res Dev 1998, 2, 3, 203. |
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) | 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 |
(II) | 41035 | (2R,3R,3aS,9aR)-7-methyl-2-[[(methylsulfonyl)oxy]methyl]-6-oxo-2,3,3a,9a-tetrahydro-6H-furo[2',3':4,5][1,3]oxazolo[3,2-a]pyrimidin-3-yl methanesulfonate | C12H16N2O9S2 | 详情 | 详情 | |
(III) | 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 |
合成路线3
该中间体在本合成路线中的序号:(V)The sulfonation of 5-methyluridine (I) with MsCl and NMM in acetone gives the trimesylate (II) which is treated with sodium benzoate in hot acetamide to yield the cyclic benzoylated anhydro compound (III). The reaction of (III) with acetyl bromide in methanol/ethyl acetate affords the bromo derivative (IV), which is debrominated with Zn in the same solvent with a catalytic amount of HOAc to furnish the unsaturated sugar derivative (V). Finally this compound is debenzoylated with hot butylamine.
【1】 Chen, B.-C.; et al.; 5-Benzoyl-2'alpha-bromo-3'-O-methanesulfonylthymidine: A superior nucleoside for the synthesis of the anti-AIDS drug d4T(stavudine). Tetrahedron Lett 1995, 36, 44, 7957. |
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) | 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 |
(II) | 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 | |
(III) | 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 | |
(IV) | 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 | |
(V) | 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 |
合成路线4
该中间体在本合成路线中的序号:(IX)Finally this compound can be deprotected by conventional methods: (a) The acylation of 1,2-O-isopropylidene-alpha-D-xylofuranose (I) with benzoyl chloride and pyridine gives the 5-O-benzoyl derivative (II), which is acylated again with Ac2O in pyridine to yield the 3-O-acetyl-5-O-benzoyl derivative (III). The reaction of (III) with Ac2O in acetic acid affords the triacetyl derivative (IV) which is condensed with fully silylated thymine (V) by means of SnCl4 in acetone to provide the corresponding adduct (VI). The selective hydrolysis of the acetate groups of (VI) with sulfuric acid in hot acetonitrile gives 1-(5-O-benzoyl-beta-D-xylofuranosyl)thymine (VII), which is treated with MsCl and pyridine to yield the dimesylate (VIII). The reaction of (VIII) with NaI in refluxing dimethoxyethane affords, after column chromatography, 5'-O-benzoyl-3'-deoxy-2',3'-dideoxythymidine (IX), which is finally deprotected with NaOMe in methanol. (b) The reaction of the 5-O-benzoyl derivative (II) with MsCl and pyridine gives the mesylate (X), which is acylated with Ac2O in HOAc to yield 1,2-di-O-acetyl-5-O-benzoyl-3-O-(methylsulfonyl)-alpha-D-xylofuranose (XI). The condensation of (XI) with the fully silylated thymine (V) by means of SnCl4 in acetone affords the expected adduct (XII), which is treated with H2SO4 in hot MeCN to provide 1-(5'-O-benzoyl-3'-O-(methylsulfonyl)-beta-D-xylofuranosyl)thymine (XIII). Finally this compound is treated with MsCl and pyridine to yield the dimesylate (VIII), already reported. (c) The 1-(5-O-benzoyl-beta-D-xylofuranosyl)thymine (VII) can also be treated with TsCl and pyridine to give the ditosylate (XIV), which is then treated with NaI in refluxing dimethoxyethane to yield 5'-O-benzoyl-3'-deoxy-2',3'-dideoxythymidine (IX), already reported.
【1】 Spirikhin, L.V.; Mustafin, A.G.; Tolstikov, G.A.; Abdrakhumanov, L.B.; Gataullin, R.R.; Transformations of beta-D-xylofuranosyl nucleosides. Synthesis of 3'-deoxy-2,3-didehydrothymidine (D4T). Russian J Org Chem 1996, 32, 12, 1787. |
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) | 41907 | (3aR,5R,6S,6aR)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol | 20031-21-4 | C8H14O5 | 详情 | 详情 |
(II) | 41908 | [(3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzoate | C15H18O6 | 详情 | 详情 | |
(III) | 41909 | [(3aR,5R,6S,6aR)-6-(acetoxy)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzoate | C17H20O7 | 详情 | 详情 | |
(IV) | 41910 | [(2R,3S,4R,5R)-3,4,5-tris(acetoxy)tetrahydro-2-furanyl]methyl benzoate | C18H20O9 | 详情 | 详情 | |
(V) | 41900 | 5-methyl-2,4-bis[(trimethylsilyl)oxy]pyrimidine; 5-methyl-2-[(trimethylsilyl)oxy]-4-pyrimidinyl trimethylsilyl ether | 7288-28-0 | C11H22N2O2Si2 | 详情 | 详情 |
(VI) | 41911 | [(2R,3S,4R,5R)-3,4-bis(acetoxy)-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C21H22N2O9 | 详情 | 详情 | |
(VII) | 41912 | [(2R,3R,4R,5R)-3,4-dihydroxy-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C17H18N2O7 | 详情 | 详情 | |
(VIII) | 41913 | [(2R,3S,4R,5R)-3,4-bis[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C23H30N2O7S2 | 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 | |
(X) | 41914 | ((3aR,5R,6S,6aR)-2,2-dimethyl-6-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]tetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methyl benzoate | C18H24O6S | 详情 | 详情 | |
(XI) | 41915 | ((2R,3S,4R,5R)-4,5-bis(acetoxy)-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]tetrahydro-2-furanyl)methyl benzoate | C19H24O8S | 详情 | 详情 | |
(XII) | 41916 | [(2R,3S,4R,5R)-4-(acetoxy)-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C22H26N2O8S | 详情 | 详情 | |
(XIII) | 41917 | [(2R,3R,4R,5R)-4-hydroxy-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C20H24N2O7S | 详情 | 详情 | |
(XIV) | 41918 | ((2R,3S,4R,5R)-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-3,4-bis[[(4-methylphenyl)sulfonyl]oxy]tetrahydro-2-furanyl)methyl benzoate | C31H30N2O11S2 | 详情 | 详情 |