[(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 -Drug Synthesis Database

【结构式】

【分子编号】12253

【品名】[(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

【CA登记号】

【分子式】C₂₀H₂₃BrN₂O₆S

【分子量】499.3825

【元素组成】C 48.1% H 4.64% Br 16% N 5.61% O 19.22% S 6.42%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VIII)

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.

参考文献中间体

合成目标

【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：(IV)

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.

参考文献中间体

合成目标

【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

Extended Information