[(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methanol -Drug Synthesis Database

【结构式】

【分子编号】17712

【品名】[(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methanol

【CA登记号】

【分子式】C₁₀H₁₀ClFN₄O₂

【分子量】272.6662632

【元素组成】C 44.05% H 3.7% Cl 13% F 6.97% N 20.55% O 11.74%

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：(XXIX)

The selective silylation of 2-deoxy-2-fluoro-1-O-methyl-beta-D-arabinofuranose (XIII) with tert-butyldiphenylsilyl chloride (TBDPS-Cl) and imidazole in DMF gives the 5-O-silylated sugar (XXIV), which is treated with CS2/NaH/methyl iodide in DMF to yield compound (XXV). The reduction of (XXV) with tributyltin hydride and AIBN in refluxing toluene affords 2,3-dideoxy-2-fluoro-5-O-(tert-butyldiphenylsilyl)-beta-D-arabinofuranose (XXVI), which is treated with HBr in acetic acid to yield the bromosugar (XXVII). The condensation of (XXVII) with 6-chloropurine (V) in hot acetonitrile gives 6-chloro-9-[2,3-dideoxy-2-fluoro-5-O-(tert-butyldiphenylsilyl)-beta-D-arabinofuranosyl]purine (XXVIII), which is desilylated with tetrabutylammonium fluoride in THF, yielding 6-chloro-9-[2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl]purine (XXIX). Finally, this compound is treated with methanolic ammonia at 105 C as before.

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.; Siddiqui, M.A.; Driscoll, J.S.; Wysocki, R.J. Jr. (US Department of Health & Human Services); 2'-Fluorofuranosyl derivs. and methods for preparing 2'-fluoropyrimidine and 2'-fluoropurine nucleosides. US 5817799 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XXIV)	17707	(2R,3R,4S,5R)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)-4-fluoro-5-methoxytetrahydro-3-furanol	C₂₂H₂₉FO₄Si	详情	详情
(XXV)	17708	O-[(2R,3R,4S,5R)-2-([[tert-butyl(diphenyl)silyl]oxy]methyl)-4-fluoro-5-methoxytetrahydro-3-furanyl] S-methyl carbonodithioate	C₂₄H₃₁FO₄S₂Si	详情	详情
(XXVI)	17709	tert-butyl(diphenyl)silyl [(2S,4S,5R)-4-fluoro-5-methoxytetrahydro-2-furanyl]methyl ether; tert-butyl[[(2S,4S,5R)-4-fluoro-5-methoxytetrahydro-2-furanyl]methoxy]diphenylsilane	C₂₂H₂₉FO₃Si	详情	详情
(XXVII)	17710	[[(2S,4S)-5-bromo-4-fluorotetrahydro-2-furanyl]methoxy](tert-butyl)diphenylsilane; [(2S,4S)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl tert-butyl(diphenyl)silyl ether	C₂₁H₂₆BrFO₂Si	详情	详情
(XXVIII)	17711	tert-butyl(diphenyl)silyl [(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl ether; 9-[(2R,3S,5S)-5-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3-fluorotetrahydro-2-furanyl]-6-chloro-9H-purine	C₂₆H₂₈ClFN₄O₂Si	详情	详情
(XXIX)	17712	[(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methanol	C₁₀H₁₀ClFN₄O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

The reaction of inosine (I) with trimethyl orthoacetate and AcOH, followed by a treatment with acetyl bromide, gives 3'-beta-bromo-3'-deoxyinosine (II), which is debrominated by means of Bu3SnH and AIBN in toluene to yield 3'-deoxyinosine (III). The reaction of (III) with SOCl2 /DMF in refluxing dichloromethane or with POCl3 /TEA in refluxing acetonitrile yields the 6-chloropurine (IV), which is deacetylated with NaOMe in methanol to afford the dihydroxy compound (V). The selective tritylation of the primary OH group of (V) with Tr-Cl and collidine in acetonitrile provides the trityl ether (VI), which is fluorinated with diethylaminosulfur trifluoride (DAST) and pyridine in dichloromethane to give the 3'-beta-fluoro derivative (VII). The reaction of (VII) with ammonia in THF gives the tritylated fluoroadenosine (VIII), which is finally deprotected with HCl in methanol/water to provide the target lodenosine. Alternatively, conversion of (VII) into lodenosine can be performed by first removal of the trityl protecting group with HCl in MeOH/toluene yielding compound (IX), whose chlorine atom is finally displaced with ammonia in MeOH/toluene

参考文献中间体

合成目标

【1】 Takamatsu, S.; et al.; 9-(2,3-Dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)adenine (FddA) via a purine 3'-deoxynucleoside. J Org Chem 2001, 66, 22, 7469.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	38013	9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1,9-dihydro-6H-purin-6-one	C₁₀H₁₂N₄O₅	详情	详情
(II)	55505	[(2R,3S,4S,5R)-4-(acetyloxy)-3-bromo-5-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-2-furanyl]methyl acetate	C₁₄H₁₅BrN₄O₆	详情	详情
(III)	55506	(2R,3R,5S)-5-[(acetyloxy)methyl]-2-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate	C₁₄H₁₆N₄O₆	详情	详情
(IV)	55507	[(2S,4R,5R)-4-(acetyloxy)-5-(6-chloro-9H-purin-9-yl)tetrahydro-2-furanyl]methyl acetate	C₁₄H₁₅ClN₄O₅	详情	详情
(V)	48720	(2R,3R,5S)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3-furanol	C₁₀H₁₁ClN₄O₃	详情	详情
(VI)	48721	(2R,3R,5S)-2-(6-chloro-9H-purin-9-yl)-5-[(trityloxy)methyl]tetrahydro-3-furanol	C₂₉H₂₅ClN₄O₃	详情	详情
(VII)	48722	[(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl trityl ether; 6-chloro-9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purine	C₂₉H₂₄ClFN₄O₂	详情	详情
(VIII)	29876	9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-ylamine; 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-amine	C₂₉H₂₆FN₅O₂	详情	详情
(IX)	17712	[(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methanol	C₁₀H₁₀ClFN₄O₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(X)

The protection of 5(S)-(hydroxymethyl)tetrahydrofuran-2-one with Tbdps-Cl and imidazole gives the silyl ether (II), which is oxidized by means of LiHMDS and MoOPH in THF to yield 5(R)-(tert-butyldiphenylsilyloxymethyl)-3(R)-hydroxytetrahydrofuran-2-one (III). The fluorination of (III) by means of Et2N-SF3 (DAST) in dichloromethane affords 5(R)-(tert-butyldiphenylsilyloxymethyl)-3(S)-fluorotetrahydrofuran-2-one (IV), which is reduced with DIBAL to provide the alcohol (V). The acylation of (V) with Ac2O and pyridine gives the acetate (VI), which is converted into the bromide (VII) by reaction with Tms-Br and BiBr3. The condensation of (VII) with 6-chloro-9-(trimethylsilyl)purine (VIII) yields the glycosylated chloropurine (IX), which is then desilylated by means of TBAF in THF to afford the chloronucleoside (X). Finally, this compound is treated with ammonia in methanol at 100 C in a pressure vessel to provide the target Lodenosine.

参考文献中间体

合成目标

【1】 Choudhury, A.; et al.; A concise synthesis of anti-viral agent F-ddA, starting from (S)-dihydro-5-(hydroxymethyl)-2(3H)-furanone. Tetrahedron Lett 2003, 44, 2, 247.

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)	12008	(5S)-5-(Hydroxymethyl)dihydro-2(3H)-furanone; (S)-(+)-Dihydro-5-(hydroxymethyl)-2(3h)-furanone	32780-06-6	C₅H₈O₃	详情	详情
(II)	12215	(5S)-5-([[tert-Butyl(diphenyl)silyl]oxy]methyl)dihydro-2(3H)-furanone		C₂₁H₂₆O₃Si	详情	详情
(III)	61756	(3R,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-hydroxydihydro-2(3H)-furanone		C₂₁H₂₆O₄Si	详情	详情
(IV)	61757	(3S,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-fluorodihydro-2(3H)-furanone		C₂₁H₂₅FO₃Si	详情	详情
(V)	61758	(3S,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-fluorotetrahydro-2-furanol		C₂₁H₂₇FO₃Si	详情	详情
(VI)	61759	(2R,3S,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-fluorotetrahydro-2-furanyl acetate		C₂₃H₂₉FO₄Si	详情	详情
(VII)	61760	[(2S,4S,5R)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl tert-butyl(diphenyl)silyl ether; {[(2S,4S,5R)-5-bromo-4-fluorotetrahydro-2-furanyl]methoxy}(tert-butyl)diphenylsilane		C₂₁H₂₆BrFO₂Si	详情	详情
(VIII)	17727	6-chloro-9-(trimethylsilyl)-9H-purine		C₈H₁₁ClN₄Si	详情	详情
(IX)	61761	9-[(2R,3S,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-fluorotetrahydro-2-furanyl]-9H-purin-6-amine; 9-[(2R,3S,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-3-fluorotetrahydro-2-furanyl]-9H-purin-6-ylamine		C₂₆H₃₀FN₅O₂Si	详情	详情
(X)	17712	[(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methanol		C₁₀H₁₀ClFN₄O₂	详情	详情

Extended Information