[(2R,3R,4S,5R)-3,5-bis(benzoyloxy)-4-fluorotetrahydro-2-furanyl]methyl benzoate -Drug Synthesis Database

【结构式】

【分子编号】17698

【品名】[(2R,3R,4S,5R)-3,5-bis(benzoyloxy)-4-fluorotetrahydro-2-furanyl]methyl benzoate

【CA登记号】

【分子式】C₂₆H₂₁FO₇

【分子量】464.4469432

【元素组成】C 67.24% H 4.56% F 4.09% O 24.11%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(II)

The reaction of 1,3,5-tri-O-benzoyl-2-O-(trifluoromethanesulfonyl)-alpha-D-ribofuranose (I) with labeled tetrabutylammonium fluoride in acetonitrile gives 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranose (II), which is treated with HBr/HOAc in dichloroethane to yield 3,5-di-O-benzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranosyl bromide (III). The condensation of (III) with thymine bis trimethylsilyl ether (IV) in dichloroethane affords a mixture of protected nucleoside alpha and beta anomers (V) and (VI), which, without separation, is deprotected with NaOMe in methanol and submitted to HPLC chromatographic separation to provide the target unprotected and labeled beta anomer.

参考文献中间体

合成目标

【1】 Alauddin, M.M.; et al.; Synthesis of [18F]-labeled 2'-deoxy-2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil ([18F]-FMAU). J Label Compd Radiopharm 2002, 45, 7, 583.

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)	56869	(2R,3R,4R,5R)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]-3-{[(trifluoromethyl)sulfonyl]oxy}tetrahydro-2-furanyl benzoate		C₂₇H₂₁F₃O₁₀S	详情	详情
(II)	17698	[(2R,3R,4S,5R)-3,5-bis(benzoyloxy)-4-fluorotetrahydro-2-furanyl]methyl benzoate		C₂₆H₂₁FO₇	详情	详情
(II)	56870	(2R,3S,4R,5R)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]-3-fluorotetrahydro-2-furanyl benzoate		C₂₆H₂₁FO₇	详情	详情
(III)	17524	[(2S,3S,4R,5S)-3-(benzoyloxy)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl benzoate		C₁₉H₁₆BrFO₅	详情	详情
(III)	56871	(2R,3R,4S,5R)-2-[(benzoyloxy)methyl]-5-bromo-4-fluorotetrahydro-3-furanyl benzoate		C₁₉H₁₆BrFO₅	详情	详情
(IV)	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
(V)	56872	(2R,3R,4S,5S)-2-[(benzoyloxy)methyl]-4-fluoro-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-furanyl benzoate		C₂₄H₂₁FN₂O₇	详情	详情
(V)	56874	(2R,3R,4S,5S)-2-[(benzoyloxy)methyl]-4-fluoro-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-furanyl benzoate		C₂₄H₂₁FN₂O₇	详情	详情
(VI)	56873	(2R,3R,4S,5R)-2-[(benzoyloxy)methyl]-4-fluoro-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-furanyl benzoate		C₂₄H₂₁FN₂O₇	详情	详情
(VI)	56875	(2R,3R,4S,5R)-2-[(benzoyloxy)methyl]-4-fluoro-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-3-furanyl benzoate		C₂₄H₂₁FN₂O₇	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XI)

The reaction of 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranose (XI) with HBr in acetic acid gives the bromosugar (XII), which is methylated with methanol/K2CO3 in THF, yielding the 1-O-methyl glucoside (XIII). The selective benzoylation of (XIII) with benzoyl chloride in pyridine at -30 C affords the 5-O-benzoyl glucoside (XIV), which is treated with CS2/methyl iodide and NaH in DMF, giving compound (XV). The reduction of (XV) with tributyltin hydride and AIBN in refluxing toluene yields the 3-deoxy glucoside (XVI), which is condensed with 6-chloropurine (V) in refluxing hexamethyldisylazane, affording 9-(5-O-benzoyl-2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)adenine (XVII). Finally, this compound is debenzoylated with methanolic ammonia at 100 C in a sealed tube.

参考文献中间体

合成目标

【1】 Siddiqui, M.A.; Marquez, V.E.; Driscoll, J.S.; Barchi, J.J. Jr.; Wysocki, R.J. Jr.; A more expedient approach to the synthesis of anti-HIV-active 2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl nucleosides. Synthesis 1991, 11, 11, 1005-8.
【2】 Castaner, J.; Graul, A.; Silvestre, J.S.; Lodenosine. Drugs Fut 1998, 23, 11, 1176-1189.
【3】 Driscoll, J.S.; Roth, J.S.; Broder, S.; Kelley, J.A.; Tseng, C.K.-H.; Mitsuya, H.; Marquez, V.E.; 2',3'-Dideoxy-2'-fluoro-ara-A, an acid-stable purine nucleoside active against human immunodeficiency virus (HIV). Biochem Pharmacol 1987, 36, 17, 2719-22.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	17692	6-Chloropurine; 6-chloro-9H-purine	87-42-3	C₅H₃ClN₄	详情	详情
(XI)	17698	[(2R,3R,4S,5R)-3,5-bis(benzoyloxy)-4-fluorotetrahydro-2-furanyl]methyl benzoate		C₂₆H₂₁FO₇	详情	详情
(XII)	17699	(2R,3R,4S)-5-bromo-4-fluoro-2-(hydroxymethyl)tetrahydro-3-furanol		C₅H₈BrFO₃	详情	详情
(XIII)	17700	(2R,3R,4S,5R)-4-fluoro-2-(hydroxymethyl)-5-methoxytetrahydro-3-furanol		C₆H₁₁FO₄	详情	详情
(XIV)	17701	[(2R,3R,4S,5R)-4-fluoro-3-hydroxy-5-methoxytetrahydro-2-furanyl]methyl benzoate		C₁₃H₁₅FO₅	详情	详情
(XV)	17702	((2R,3R,4S,5R)-4-fluoro-5-methoxy-3-[[(methylsulfanyl)carbothioyl]oxy]tetrahydro-2-furanyl)methyl benzoate		C₁₅H₁₇FO₅S₂	详情	详情
(XVI)	17703	[(2S,4S,5R)-4-fluoro-5-methoxytetrahydro-2-furanyl]methyl benzoate		C₁₃H₁₅FO₄	详情	详情
(XVII)	17704	[(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl benzoate		C₁₇H₁₄ClFN₄O₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XI)

The controlled reaction of 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranose (XI) with HBr in acetic acid gives the bromosugar (XXII), which is condensed with 6-chloropurine (V) as before, yielding 6-chloro-9-(3,5-di-O-benzoyl-2-deoxy-2-fluoro-beta-D-arabinofuranosyl)purine (XXIII). Finally, this compound is treated with ammonia in methanol as before to afford intermediate 9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine (VII).

参考文献中间体

合成目标

【1】 Castaner, J.; Graul, A.; Silvestre, J.S.; Lodenosine. Drugs Fut 1998, 23, 11, 1176-1189.
【2】 Marquez, V.E.; Design, synthesis, and antiviral activity of nucleoside and nucleotide analogs. ACS Symp Ser 1989, 401, 140-55.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	17692	6-Chloropurine; 6-chloro-9H-purine	87-42-3	C₅H₃ClN₄	详情	详情
(VII)	17694	(2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)tetrahydro-3-furanol		C₁₀H₁₂FN₅O₃	详情	详情
(XI)	17698	[(2R,3R,4S,5R)-3,5-bis(benzoyloxy)-4-fluorotetrahydro-2-furanyl]methyl benzoate		C₂₆H₂₁FO₇	详情	详情
(XXII)	17705	[(2R,3R,4S,5R)-3-(benzoyloxy)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl benzoate		C₁₉H₁₆BrFO₅	详情	详情
(XXIII)	17706	[(2R,3R,4S,5R)-3-(benzoyloxy)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl benzoate		C₂₄H₁₈ClFN₄O₅	详情	详情

Extended Information