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

【结构式】

【分子编号】17691

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

【CA登记号】

【分子式】C₁₄H₁₄BrFO₅

【分子量】361.1645632

【元素组成】C 46.56% H 3.91% Br 22.12% F 5.26% O 22.15%

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：(IV)

The TLC monitored reaction of 1,3-di-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranose (III) with 30% HBr in acetic acid gives the bromosugar (IV), which is condensed with 6-chloropurine (V) in refluxing dichloromethane, yielding the chloropurine derivative (VI). The reaction of (VI) with methanolic NH3 at 100 C in a steel bomb affords 9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine (VII), which is selectively silylated with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole in DMF, giving the 5'-O-silyl derivative (VIII). The reaction of (VIII) with phenyl chlorothioformate by means of dimethylaminopyridine in DMF yields the thiocarbonate (IX), which is reduced with tributyltin hydride and AIBN in hot toluene, affording 9-[2,3-dideoxy-2-fluoro-5-O-(tert-butyldimethylsilyl)-beta-D-arabinofuranosyl]adenine (X). Finally, this compound is desilylated with tetrabutylammonium fluoride in THF.

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】 Ford, H. Jr.; Driscoll, J.S.; Aoki, S.; Kelley, J.A.; Johns, D.G.; Roth, J.S.; Tseng, C.K.-H.; Broder, S.; Marquez, V.E.; Mitsuya, H.; Acid-stable 2'-fluoro purine dideoxynucleosides as active agents against HIV. J Med Chem 1990, 33, 3, 978-85.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	17690	[(2R,3R,4S)-5-(acetoxy)-4-fluoro-3-[(1-hydroxyvinyl)oxy]tetrahydro-2-furanyl]methyl benzoate		C₁₆H₁₇FO₇	详情	详情
(IV)	17691	[(2R,3R,4S)-3-(acetoxy)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl benzoate		C₁₄H₁₄BrFO₅	详情	详情
(V)	17692	6-Chloropurine; 6-chloro-9H-purine	87-42-3	C₅H₃ClN₄	详情	详情
(VI)	17693	[(2R,3R,4S,5R)-3-(acetoxy)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl benzoate		C₁₉H₁₆ClFN₄O₅	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
(VIII)	17695	(2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-fluorotetrahydro-3-furanol		C₁₆H₂₆FN₅O₃Si	详情	详情
(IX)	17696	O-[(2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-fluorotetrahydro-3-furanyl] O-phenyl carbonothioate		C₂₃H₃₀FN₅O₄SSi	详情	详情
(X)	17697	9-[(2R,3S,5S)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorotetrahydro-2-furanyl]-9H-purin-6-ylamine; 9-[(2R,3S,5S)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorotetrahydro-2-furanyl]-9H-purin-6-amine		C₁₆H₂₆FN₅O₂Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

Reaction of 1,2:5,6-di-O-isopropylidene-3-O-tosyl-a-D-allofuranose (I) with KF in acetamide at 210 oC gives 3-deoxy-3-fluoro-1,2:5,6-di-O-isopropylidene-a-D-glucofuranose (II), which is treated with a 1:1 mixture of metha-nol and 0.7% aqueous H2SO4 to yield 3-deoxy-3-fluoro-1,2-isopropylidene-a-D-glucofuranose (III). Selective acylation of the sugar (III) with benzoyl chloride in pyridine affords the 6-O-benzoyl derivative (IV), which is treated with Amberlite IR-100 (H+) ion-exchange resin in hot dioxane to provide 6-O-benzoyl-3-deoxy-3-fluoro-D-glucofuranose (V). The oxidative cleavage of glucofuranose (V) by means of KIO4 in water results in rearrangement to give 5-O-benzoyl-2-deoxy-2-fluoro-3-O-formyl-D- arabinofuranose (VI), which is deformylated by means of NaOMe in methanol to provide 5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranose (VII). Acylation of the arabinofuranose (VII) with acetic anhydride in pyridine affords the 1,3-di-O-acetyl derivative (VIII), which is treated with HBr in AcOH/CH2Cl2 to yield 3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl bromide (IX) (1). Condensation of compound (IX) with 2-chloroadenine (X) by means of potassium tert-butoxide in different solvents gives the acylated 2-chloroadenosine derivative (XI), which is finally deacylated by means of NaOMe in methanol.

参考文献中间体

合成目标

【1】 Bauta, W.E.; Schulmeier, B.E.; Cantrell, W.R. Jr.; Lovett, D.; Puente, J. (Ilex Oncology, Inc.); Process for preparing purine nucleosides. US 2003114663; WO 0311877 .
【2】 Clayton, S.D., Montgomery, J.A., Riordan, J.M., Secrist, J.A. III., Shortnacy-Fowler, A.T.; Synthesis and biologic activity of 2'-fluoro-2-halo derivatives of 9-beta-D-arabinofuranosyladenine. J Med Chem 1992, 35 (2): 397
【3】 Castaner, J., Chilman-Blair, K., Mealy, N.E.; Clofarabine. Drugs Fut 2004, 29 (2): 112
【4】 Fox, J.J., Reichman, U., Watanabe, K.A.; A practical synthesis of 2-deoxy-2-fluoro-D-arabinofuranose derivatives. Carbohydr Res 1975, 42 (2): 233
【5】 Montgomery, J.A., Secrist, J.A. III (Southern Research Institute); 2-Halo-9-(2-deoxy-2-fluoro-B-D-arabinofuranosyl) adenine nucleoside derivs.. JP 1993502014, US 5034518, WO 9014352
【6】 Montgomery, J.A., Secrist, J.A. III, Fowler, A.T. (Southern Research Institute); Methods for synthesizing 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-9H-purin-6-amine. WO 0160383, CA 2400470, EP 1261350

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
（X）	11644	6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine	10310-21-1	C₅H₄ClN₅	详情	详情
(I)	63931	(3aR,5R,6S,6aR)-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl 4-methylbenzenesulfonate		C₁₉H₂₆O₈S	详情	详情
(II)	63932	(3aR,5R,6S,6aS)-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-6-fluoro-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole		C₁₂H₁₉FO₅	详情	详情
(III)	63933	(1S)-1-[(3aR,5R,6S,6aS)-6-fluoro-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-1,2-ethanediol		C₉H₁₅FO₅	详情	详情
(IV)	63934	(2S)-2-[(3aR,5R,6S,6aS)-6-fluoro-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-2-hydroxyethyl benzoate		C₁₆H₁₉FO₆	详情	详情
(V)	63935	(2S)-2-[(2R,3R,4S)-3-fluoro-4,5-dihydroxytetrahydro-2-furanyl]-2-hydroxyethyl benzoate		C₁₃H₁₅FO₆	详情	详情
(VI)	63936	[(2R,3R,4S)-4-fluoro-3-(formyloxy)-5-hydroxytetrahydro-2-furanyl]methyl benzoate		C₁₃H₁₃FO₆	详情	详情
(VII)	63937	[(2R,3R,4S)-4-fluoro-3,5-dihydroxytetrahydro-2-furanyl]methyl benzoate		C₁₂H₁₃FO₅	详情	详情
(VIII)	63938	[(2R,3R,4S)-3,5-bis(acetyloxy)-4-fluorotetrahydro-2-furanyl]methyl benzoate		C₁₆H₁₇FO₇	详情	详情
(IX)	17691	[(2R,3R,4S)-3-(acetoxy)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl benzoate		C₁₄H₁₄BrFO₅	详情	详情
(XI)	63940	[(2R,3R,4S,5R)-3-(acetyloxy)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl benzoate		C₁₉H₁₇ClFN₅O₅	详情	详情
(XII)	25254	2,6-dichloro-9H-purine	5451-40-1	C₅H₂Cl₂N₄	详情	详情
(XIII)	63941	[(2R,3R,4S,5R)-3-(acetyloxy)-5-(2,6-dichloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl benzoate		C₁₉H₁₅Cl₂FN₄O₅	详情	详情
(XIV)	63942	(2R,3R,4S,5R)-5-(2-chloro-6-methoxy-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)tetrahydro-3-furanol		C₁₁H₁₂ClFN₄O₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

参考文献中间体

合成目标

【1】 Montgomery JA,Shortnacy-Fowler AT,et aL 1992.Synthesis and biological activity of 2'-fluoro-2-halo derivatives of 9-β-D-arabinofuranosyladerune.J.MaL Chem.35: 397-- 401.

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)	17691	[(2R,3R,4S)-3-(acetoxy)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl benzoate		C₁₄H₁₄BrFO₅	详情	详情
(II)	25254	2,6-dichloro-9H-purine	5451-40-1	C₅H₂Cl₂N₄	详情	详情
(III)	63941	[(2R,3R,4S,5R)-3-(acetyloxy)-5-(2,6-dichloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl benzoate		C₁₉H₁₅Cl₂FN₄O₅	详情	详情

Extended Information