ethyl (1R,3S)-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-3-fluorocyclopentanecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】36758

【品名】ethyl (1R,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 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XIIIb)

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.

参考文献中间体

合成目标

【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：(XIIIb)

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.

参考文献中间体

合成目标

【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