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【结 构 式】 
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【药物名称】 【化学名称】[(1S,3S)-3-(6-Amino-9H-purin-9-yl)-1-fluorocyclopentyl]methanol 【CA登记号】 【 分 子 式 】C11H14FN5O 【 分 子 量 】251.26553 |
【开发单位】University of Georgia (Originator) 【药理作用】ANTIINFECTIVE THERAPY, Antiviral Drugs |
合成路线1
Horner-Emmons condensation of 2,3-isopropylidene-D-glyceraldehyde (I) with phosphonate (II) produced the unsaturated ester (IIIa-b). Ketal deprotection and lactone ring closure of (II) under acidic conditions, followed by O-silylation afforded (IV). The lactone function of (IV) was reduced with DIBAL and then with NaBH4-CeCl3 to produce the corresponding diol. Further silylation of the primary hydroxyl group furnished (V). Condensation of (V) with triethyl orthoacetate followed by Claisen rearrangement gave rise to the gamma,delta-unsaturated ester (VI). This was reduced to alcohol with LiAlH4 and then alkylated with benzyl bromide to yield benzyl ether (VII). Ozonization of (VII) in methanol at -78 C, followed by decomposition of the ozonide with dimethyl sulfide gave aldehyde (VIII). Horner-Emmons condensation of (VIII) with the sodium salt of triethyl phosphonoacetate (IX) produced the alpha,beta-unsaturated ester (X). Double bond hydrogenation in (X) with simultaneous benzyl group cleavage afforded hydroxy ester (XI), which was then converted to mesylate (XII). This was cyclized to the cyclopentane (XIIIa-b) by means of NaH in refluxing THF.
| 【1】 Hong, J.H.; et al.; Enantiomeric synthesis of 3'-fluoro-apionucleosides using claisen rearrangement. Tetrahedron Lett 1998, 39, 21, 3443. |
| 【2】 Gumina, G.; et al.; Stereoselective synthesis of carbocyclic L-4'-fluoro-2',3'-dideoxyadenosine. Org Lett 2000, 2, 9, 1229. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| (XIIIa) | 36757 | ethyl (1S,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentanecarboxylate | C15H29FO3Si | 详情 | 详情 | |
| (XIIIb) | 36758 | ethyl (1R,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentanecarboxylate | C15H29FO3Si | 详情 | 详情 | |
| (IIIa) | 36760 | ethyl (E)-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-fluoro-2-propenoate | C10H15FO4 | 详情 | 详情 | |
| (IIIb) | 36761 | ethyl (E)-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-fluoro-2-propenoate | C10H15FO4 | 详情 | 详情 | |
| (I) | 36759 | (4R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde | 15186-48-8 | C6H10O3 | 详情 | 详情 |
| (II) | 18192 | ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate | 2356-16-3 | C8H16FO5P | 详情 | 详情 |
| (IV) | 36762 | (5S)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluoro-2(5H)-furanone | C11H19FO3Si | 详情 | 详情 | |
| (V) | 36750 | (6S,7E)-8-fluoro-2,2,3,3,11,11,12,12-octamethyl-4,10-dioxa-3,11-disila-7-tridecen-6-ol | C17H37FO3Si2 | 详情 | 详情 | |
| (VI) | 36751 | ethyl (3S,4E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluoro-4-hexenoate | C21H43FO4Si2 | 详情 | 详情 | |
| (VII) | 36752 | benzyl (3S,4E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluoro-4-hexenyl ether; (E,8S)-8-[2-(benzyloxy)ethyl]-8-fluoro-2,2,3,3,11,11,12,12-octamethyl-4,10-dioxa-3,11-disila-6-tridecene | C26H47FO3Si2 | 详情 | 详情 | |
| (VIII) | 36753 | (2R)-4-(benzyloxy)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-fluorobutanal | C18H29FO3Si | 详情 | 详情 | |
| (IX) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (X) | 36754 | ethyl (E,4S)-6-(benzyloxy)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-fluoro-2-hexenoate | C22H35FO4Si | 详情 | 详情 | |
| (XI) | 36755 | ethyl (4R)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-fluoro-6-hydroxyhexanoate | C15H31FO4Si | 详情 | 详情 | |
| (XII) | 36756 | ethyl (4R)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-fluoro-6-[(methylsulfonyl)oxy]hexanoate | C16H33FO6SSi | 详情 | 详情 |
合成路线2
Hydrolysis of (XIIIa-b) to the carboxylic acid (XIVa-b), and further iodo decarboxylation yielded a mixture of epimeric iodides (XVa-b). From hydrolysis of the iodide group of (XVa-b) with NaHCO3 only the alpha-alcohol (XVI) was isolated. This was condensed with 6-chloropurine (XVII) under Mitsunobu conditions to give adduct (XVIII). The 6-chloro derivative (XVIII) was converted into the protected adenosine analogue (XIX) by treatment with methanolic ammonia in a steel bomb at 100 C. Finally, desilylation of (XIX) employing tetrabutylammonium fluoride furnished the title compound.
| 【1】 Gumina, G.; et al.; Stereoselective synthesis of carbocyclic L-4'-fluoro-2',3'-dideoxyadenosine. Org Lett 2000, 2, 9, 1229. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIIIa) | 36757 | ethyl (1S,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentanecarboxylate | C15H29FO3Si | 详情 | 详情 | |
| (XIIIb) | 36758 | ethyl (1R,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentanecarboxylate | C15H29FO3Si | 详情 | 详情 | |
| (XIVa) | 36763 | (1S,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentanecarboxylic acid | C13H25FO3Si | 详情 | 详情 | |
| (XIVb) | 36764 | (1R,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentanecarboxylic acid | C13H25FO3Si | 详情 | 详情 | |
| (XVa) | 36765 | tert-butyl[[(1S,3S)-1-fluoro-3-iodocyclopentyl]methoxy]dimethylsilane; tert-butyl(dimethyl)silyl [(1S,3S)-1-fluoro-3-iodocyclopentyl]methyl ether | C12H24FIOSi | 详情 | 详情 | |
| (XVb) | 36766 | tert-butyl[[(1S,3R)-1-fluoro-3-iodocyclopentyl]methoxy]dimethylsilane; tert-butyl(dimethyl)silyl [(1S,3R)-1-fluoro-3-iodocyclopentyl]methyl ether | C12H24FIOSi | 详情 | 详情 | |
| (XVI) | 36767 | (1R,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentanol | C12H25FO2Si | 详情 | 详情 | |
| (XVII) | 17692 | 6-Chloropurine; 6-chloro-9H-purine | 87-42-3 | C5H3ClN4 | 详情 | 详情 |
| (XVIII) | 36768 | 9-[(1S,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentyl]-6-chloro-9H-purine; tert-butyl(dimethyl)silyl [(1S,3S)-3-(6-chloro-9H-purin-9-yl)-1-fluorocyclopentyl]methyl ether | C17H26ClFN4OSi | 详情 | 详情 | |
| (XIX) | 36769 | 9-[(1S,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentyl]-9H-purin-6-amine; 9-[(1S,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentyl]-9H-purin-6-ylamine | C17H28FN5OSi | 详情 | 详情 |