6-chloro-9-(trimethylsilyl)-9H-purine -Drug Synthesis Database

【结构式】

【分子编号】17727

【品名】6-chloro-9-(trimethylsilyl)-9H-purine

【CA登记号】

【分子式】C₈H₁₁ClN₄Si

【分子量】226.7405

【元素组成】C 42.38% H 4.89% Cl 15.64% N 24.71% Si 12.39%

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：(XLIV)

The reaction of 2,3-O-isopropylidene-D-ribofuranose (XXXV) with 4-methylbenzoyl chloride (XXXVI) by means of pyridine in butyl acetate gives 2,3-O-isopropylidene-5-O-(4-methylbenzoyl)-D-ribofuranose (XXXVII), which is methylated by means of NaH and dimethylsulfate in THF to yield the expected methyl ribofuranoside (XXXVIII). The hydrolysis of the acetonide group of (XXXVIII) with trifluoromethanesulfonic acid in acetonitrile affords 1-O-methyl-5-O-(4-methylbenzoyl)-alpha-D-ribofuranose (XXXIX), which is treated with SO2Cl2/triethylamine in butyl acetate to give the cyclic sulfate (XL). The reduction of (XL) with NaBH4 in THF yields 3-deoxy-1-O-methyl-5-O-(4-methylbenzoyl)-alpha-D-ribofuranose (XLI), which is treated with trifluoromethanesulfonic anhydride and tetrabutylammonium fluoride in dichloromethane/pyridine to afford 2,3-dideoxy-2-fluoro-1-O-methyl-alpha-D-arabinofuranose (XLII). The reaction of (XLII) with HBr in acetic acid as before gives the bromosugar (XLIII), which is condensed with 6-chloro-9-(trimethylsilyl)purine (XLIV) in dichloromethane to yield 6-chloro-9-[2,3-dideoxy-2-fluoro-5-O-(4-methylbenzoyl)-beta-D-arabinofuranosyl]purine (XLV). Finally, this compound is treated with ammonia in methanol at 90 C.

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】 Saischek, E.; Dax, K.; Braun, W.; Fuchs, F.; Saischek, G. (Chevron Research Co.); D-Xylofuranose derivs., method of preparing them, their use, and novel intermediate compounds for the method. WO 9606851 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IXL)	17722	[(2R,3S,4R,5S)-3,4-dihydroxy-5-methoxytetrahydro-2-furanyl]methyl 4-methylbenzoate		C₁₄H₁₈O₆	详情	详情
(XXXV)	17718	(3aR,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol		C₈H₁₄O₅	详情	详情
(XXXVI)	17719	p-Toluoyl chloride; 4-methylbenzoyl chloride	874-60-2	C₈H₇ClO	详情	详情
(XXXVII)	17720	[(3aR,4R,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl 4-methylbenzoate		C₁₆H₂₀O₆	详情	详情
(XXXVIII)	17721	[(3aR,4R,6S,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl 4-methylbenzoate		C₁₇H₂₂O₆	详情	详情
(XL)	17723	[(3aR,4R,6S,6aR)-6-methoxy-2,2-dioxotetrahydro-2lambda(6)-furo[3,4-d][1,3,2]dioxathiol-4-yl]methyl 4-methylbenzoate		C₁₄H₁₆O₈S	详情	详情
(XLI)	17724	[(2S,4R,5S)-4-hydroxy-5-methoxytetrahydro-2-furanyl]methyl 4-methylbenzoate		C₁₄H₁₈O₅	详情	详情
(XLII)	17725	[(2S,4S,5S)-4-fluoro-5-methoxytetrahydro-2-furanyl]methyl 4-methylbenzoate		C₁₄H₁₇FO₄	详情	详情
(XLIII)	17726	[(2S,4S,5S)-5-bromo-4-fluorotetrahydro-2-furanyl]methyl 4-methylbenzoate		C₁₃H₁₄BrFO₃	详情	详情
(XLIV)	17727	6-chloro-9-(trimethylsilyl)-9H-purine		C₈H₁₁ClN₄Si	详情	详情
(XLV)	17728	[(2S,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluorotetrahydro-2-furanyl]methyl 4-methylbenzoate		C₁₈H₁₆ClFN₄O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

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