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【结 构 式】

【分子编号】53276

【品名】isopropyl (Z)-7-((1R,2R,3R,5S)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(trifluoromethyl)phenoxy]-1-butenyl}-3-hydroxycyclopentyl)-5-heptenoate

【CA登记号】n/a

【 分 子 式 】C38H63F3O6Si2

【 分 子 量 】729.0808296

【元素组成】C 62.6% H 8.71% F 7.82% O 13.17% Si 7.7%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(XXIII)

Synthesis of the alkenyl cuprate (XVII): Enzymatic acylation of the racemic acetylenic alcohol (VII) with vinyl butyrate (VIII) by means of Chirazyme L9 gives a mixture of the ester (R)-(IX) and the alcohol (S)-(X). Reaction of this mixture with Ms-Cl and TEA yields a mixture of ester (R)-(IX) and the mesylate (S)-(XI). Treatment of this mixture with butyric acid and TEA results in the acylation of mesylate (S)-(XI) with optical inversion, providing pure ester (R)-(IX). Enzymatic hydrolysis of (R)-(IX) with Chirazyme L2 affords the enantiomerically pure alcohol (R)-(XIII). Silylation of alcohol (XIII) with TBDMS-Cl and imidazole gives the silyl ether (XIV), which is iodinated with Cp2ZrCl2 and I2 to yield the iodovinyl derivative (XV). Finally, the reaction of compound (XV) with the lithium cuprate (XVI) ­prepared by lithiation of thiophene with BuLi followed by treatment with copper (I) cyanide­ affords the alkenyl cuprate (XVII). Condensation of the alkenyl cuprate (XVII) with the tricyclic ketone (VI) in toluene provides the bicyclic ketone (XVIII), which is submitted to a Baeyer-Villiger oxidation with peracetic acid to give a mixture of the regioisomeric lactones (XIX) and (XX). The minor and unwanted regioisomer (XIX) is selectively hydrolyzed by treatment with aqueous Na2CO3 and separated by crystallization. Reduction of lactone (XX) with DIBAL in toluene gives lactol (XXI), which is submitted to a Wittig condensation with (4-carboxybutyl)triphenylphosphonium bromide and t-BuOK in THF, followed by esterification with isopropyl iodide and DBU, yielding a mixture of the monosilylated compounds (XXIII) and (XXIV) due to migration of the silyl group on the cyclopentane ring. Finally, this mixture is deprotected with HCl in isopropanol.

1 Boulton, L.T.; Brick, D.; Fox, M.E.; et al.; Synthesis of the potent antiglaucoma agent, travoprost. Org Process Res Dev 2002, 6, 2, 138.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VI) 53260 (1R,3S,5R)-3-{[tert-butyl(dimethyl)silyl]oxy}tricyclo[3.2.0.0~2,7~]heptan-6-one n/a C13H22O2Si 详情 详情
(VII) 53262 1-[3-(trifluoromethyl)phenoxy]-3-butyn-2-ol 88462-65-1 C11H9F3O2 详情 详情
(VIII) 53263 n-Butyric acid vinyl ester; Vinyl n-butyrate; Vinyl butyrate 123-20-6 C6H10O2 详情 详情
(IX) 53264 (1R)-1-{[3-(trifluoromethyl)phenoxy]methyl}-2-propynyl butyrate n/a C15H15F3O3 详情 详情
(X) 53265 (2S)-1-[3-(trifluoromethyl)phenoxy]-3-butyn-2-ol n/a C11H9F3O2 详情 详情
(XI) 53266 (1S)-1-{[3-(trifluoromethyl)phenoxy]methyl}-2-propynyl methanesulfonate n/a C12H11F3O4S 详情 详情
(XII) 53267 Butanoic acid; Butyric acid; N-Butanic acid; N-Butanoic acid; n-Butyric acid; N-Ethylacetic acid; N-Propanecarboxylic acid; N-Propylformic acid 107-92-6 C4H8O2 详情 详情
(XIII) 53278 (2R)-1-[3-(trifluoromethyl)phenoxy]-3-butyn-2-ol n/a C11H9F3O2 详情 详情
(XIV) 53268 tert-butyl(dimethyl)[((1R)-1-{[3-(trifluoromethyl)phenoxy]methyl}-2-propynyl)oxy]silane; tert-butyl(dimethyl)silyl (1R)-1-{[3-(trifluoromethyl)phenoxy]methyl}-2-propynyl ether n/a C17H23F3O2Si 详情 详情
(XV) 53269 tert-butyl(dimethyl)silyl (1R,2E)-3-iodo-1-{[3-(trifluoromethyl)phenoxy]methyl}-2-propenyl ether; tert-butyl[((1R,2E)-3-iodo-1-{[3-(trifluoromethyl)phenoxy]methyl}-2-propenyl)oxy]dimethylsilane n/a C17H24F3IO2Si 详情 详情
(XVI) 53270 lithium cyano(2-thienyl)cuprate(1-) n/a C5H3CuLiNS 详情 详情
(XVII) 53271   n/a C22H27CuF3Li2NO2SSi 详情 详情
(XVIII) 53272 (5S)-5-{[tert-butyl(dimethyl)silyl]oxy}-7-{(E,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(trifluoromethyl)phenoxy]-1-butenyl}bicyclo[2.2.1]heptan-2-one n/a C30H47F3O4Si2 详情 详情
(XIX) 53273 (6S)-6-{[tert-butyl(dimethyl)silyl]oxy}-8-{(E,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(trifluoromethyl)phenoxy]-1-butenyl}-3-oxabicyclo[3.2.1]octan-2-one n/a C30H47F3O5Si2 详情 详情
(XX) 53274 (6S)-6-{[tert-butyl(dimethyl)silyl]oxy}-8-{(E,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(trifluoromethyl)phenoxy]-1-butenyl}-2-oxabicyclo[3.2.1]octan-3-one n/a C30H47F3O5Si2 详情 详情
(XXI) 53275 (6S)-6-{[tert-butyl(dimethyl)silyl]oxy}-8-{(E,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(trifluoromethyl)phenoxy]-1-butenyl}-2-oxabicyclo[3.2.1]octan-3-ol n/a C30H49F3O5Si2 详情 详情
(XXII) 13616 (4-Carboxybutyl)triphenylphosphonium bromide 17814-85-6 C23H24BrO2P 详情 详情
(XXIII) 53276 isopropyl (Z)-7-((1R,2R,3R,5S)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(trifluoromethyl)phenoxy]-1-butenyl}-3-hydroxycyclopentyl)-5-heptenoate n/a C38H63F3O6Si2 详情 详情
(XXIV) 53277 isopropyl (Z)-7-((1R,2R,3R,5S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(trifluoromethyl)phenoxy]-1-butenyl}-5-hydroxycyclopentyl)-5-heptenoate n/a C38H63F3O6Si2 详情 详情
Extended Information