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【结 构 式】

【分子编号】36757

【品名】ethyl (1S,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentanecarboxylate

【CA登记号】

【 分 子 式 】C15H29FO3Si

【 分 子 量 】304.4773632

【元素组成】C 59.17% H 9.6% F 6.24% O 15.76% Si 9.22%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XIIIa)

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

该中间体在本合成路线中的序号:(XIIIa)

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
Extended Information