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【结 构 式】 
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【药物名称】Eldecalcitol, ED-71 【化学名称】2beta-(3-Hydroxypropoxy)-1alpha,25-dihydroxyvitamin D3 【CA登记号】104121-92-8 【 分 子 式 】C30H50O5 【 分 子 量 】490.73 |
【开发单位】Chugai (Originator) 【药理作用】Bone Diseases, Treatment of, METABOLIC DRUGS, Treatment of Osteoporosis, Vitamin D Analogs |
合成路线1
The synthesis of the title compound has been reported starting from the known Diels-Alder adduct (I) of a cholestadiene derivative with 4-phenyl-1,2,4-triazolidinedione. Epoxide ring opening in (I) with 1,3-propanediol (II) in the presence of p-toluenesulfonic acid gave the 1,3-dihydroxy-2-(hydroxypropoxy) derivative (III). Subsequent retro-Diels-Alder reaction in (III) under reductive conditions furnished the cholestadiene compound (IV) (1). In a related sequence, initial retro-cycloaddition reaction in hot dimethylimidazolidinone, followed by ring opening of the resultant epoxide (V) with diol (II) provided an alternative access to diene (IV) (2). Conversion of diene (IV) to the title vitamin D3 analogue was effected by irradiation using a high pressure mercury lamp, followed by thermal isomerization in boiling THF
| 【1】 Miyamoto, K.; Kubodera, N.; Ochi, K.; Matsunaga, I.; Murayama, E. (Chugai Pharmaceutical Co. Ltd.); Vitamin D3 derivs. having a substituent at 2-position. EP 0184206; JP 1986267549; US 4666634 . |
| 【2】 Miyamoto, K.; et al.; Synthetic studies of vitamin D analogues. XIV. Synthesis and calcium regulating activity of vitamin D3 analogues bearing a hydroxyalkoxy group at the 2beta-position. Chem Pharm Bull 1993, 41, 6, 1111. |
| 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) | 59850 | (1S,2R,5R,6R,10R,11S,13S,14R,16S)-14-hydroxy-5-[(1R)-5-hydroxy-1,5-dimethylhexyl]-6,10-dimethyl-19-phenyl-12-oxa-17,19,21-triazaheptacyclo[14.5.2.0~1,9~.0~2,6~.0~10,16~.0~11,13~.0~17,21~]tricos-22-ene-18,20-dione | C35H47N3O5 | 详情 | 详情 | |
| (II) | 14685 | 1,3-propanediol; Trimethylene Glycol | 504-63-2 | C3H8O2 | 详情 | 详情 |
| (III) | 59851 | (1S,2R,5R,6R,10R,11R,12R,13R,15S)-11,13-dihydroxy-5-[(1R)-5-hydroxy-1,5-dimethylhexyl]-12-(3-hydroxypropoxy)-6,10-dimethyl-18-phenyl-16,18,20-triazahexacyclo[13.5.2.0~1,9~.0~2,6~.0~10,15~.0~16,20~]docos-21-ene-17,19-dione | C38H55N3O7 | 详情 | 详情 | |
| (IV) | 59852 | (1R,2R,3R,10R,13R,14R,17R)-17-[(1R)-5-hydroxy-1,5-dimethylhexyl]-2-(3-hydroxypropoxy)-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-1,3-diol | C30H50O5 | 详情 | 详情 | |
| (V) | 59853 | (2R,2aS,3aS,3bR,5aR,6R,8aR)-6-[(1R)-5-hydroxy-1,5-dimethylhexyl]-3b,5a-dimethyl-2,2a,3a,3b,3c,4,5,5a,6,7,8,8a-dodecahydro-1H-cyclopenta[7,8]phenanthro[3,4-b]oxiren-2-ol | C27H42O3 | 详情 | 详情 |
合成路线2
A different synthetic strategy used 3,4:5,6-O-diisopropylidene-D-mannitol (VI) as the starting material. Dehydration of (VI) by means of dimethylformamide dimethylacetal and Ac2O provided olefin (VII). Selective hydrolysis of the terminal acetonide of (VII) was achieved by means of 80% AcOH to afford diol (VIII). Conversion of (VIII) to the primary tosylate (IX), followed by treatment with Na2CO3 gave epoxide (X). Oxirane ring opening in (X) with NaCN furnished the beta-hydroxy nitrile (XI). This was then protected as the unsymmetric acetal (XII) by acid-catalyzed addition of ethyl vinyl ether. Partial reduction of the nitrile function of (XII) with DIBAL in toluene at -78 C gave rise to aldehyde (XIII), which was further derivatized as the corresponding oxime (XIV). The nitrile oxide generated by treatment of oxime (XIV) with NaOCl and Et3N underwent a dipolar cycloaddition to the olefin, leading to isoxazoline (XV)
| 【1】 Takahashi, T.; Shiono, M. (Kuraray Co., Ltd.); Cyclohexanetriol derivs.. EP 0503630 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 18762 | 1-Ethoxyethylene; Ethyl vinyl ether；Ethoxyethene | 109-92-2 | C4H8O | 详情 | 详情 |
| (VI) | 59854 | C12H22O6 | 详情 | 详情 | ||
| (VII) | 59855 | C12H20O4 | 详情 | 详情 | ||
| (VIII) | 59856 | (1R)-1-[(4R,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl]-1,2-ethanediol | C9H16O4 | 详情 | 详情 | |
| (IX) | 59857 | (2R)-2-[(4R,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl]-2-hydroxyethyl 4-methylbenzenesulfonate | C16H22O6S | 详情 | 详情 | |
| (X) | 59858 | (4R,5R)-2,2-dimethyl-4-[(2R)oxiranyl]-5-vinyl-1,3-dioxolane | C9H14O3 | 详情 | 详情 | |
| (XI) | 59859 | (3R)-3-[(4R,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl]-3-hydroxypropanenitrile | C10H15NO3 | 详情 | 详情 | |
| (XII) | 59860 | (3R)-3-[(4R,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl]-3-(1-ethoxyethoxy)propanenitrile | C14H23NO4 | 详情 | 详情 | |
| (XIII) | 59861 | (3R)-3-[(4R,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl]-3-(1-ethoxyethoxy)propanal | C14H24O5 | 详情 | 详情 | |
| (XIV) | 59862 | (3R)-3-[(4R,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl]-3-(1-ethoxyethoxy)propanal oxime | C14H25NO5 | 详情 | 详情 | |
| (XV) | 59863 | (3aR,4R,8bR)-2,2-dimethyl-3a,4,5,8,8a,8b-hexahydro[1,3]dioxolo[4,5-e][2,1]benzisoxazol-4-yl 1-ethoxyethyl ether; (3aR,4R,8bR)-4-(1-ethoxyethoxy)-2,2-dimethyl-3a,4,5,8,8a,8b-hexahydro[1,3]dioxolo[4,5-e][2,1]benzisoxazole | C14H23NO5 | 详情 | 详情 |
合成路线3
Hydrogenolysis of the isoxazoline ring of (XV) in the presence of Raney-nickel and boric acid generated the (hydroxymethyl)cyclohexanone (XVI). After hydroxyl group protection of (XVI) as the silyl ether (XVII), Peterson olefination of the ketone function of (XVII) with the lithium derivative of ethyl trimethylsilylacetate (XVIII) furnished the unsaturated ester (XIX). Desilylation of (XIX) gave the primary alcohol (XX), which was dehydrated to (XXI) by treatment with methanesulfonyl chloride and pyridine. The 1-(ethoxy)ethoxy protecting group of (XXI) was then replaced by a silyl ether (XXII) by acidic ketal hydrolysis, followed by treatment with tert-butyldiphenylsilyl chloride and imidazole. Subsequent acetonide (XXII) hydrolysis gave diol (XXIII), which was regioselectively mono-silylated providing intermediate (XXIV)
| 【1】 Takahashi, T.; Shiono, M. (Kuraray Co., Ltd.); Cyclohexanetriol derivs.. EP 0503630 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 59863 | (3aR,4R,8bR)-2,2-dimethyl-3a,4,5,8,8a,8b-hexahydro[1,3]dioxolo[4,5-e][2,1]benzisoxazol-4-yl 1-ethoxyethyl ether; (3aR,4R,8bR)-4-(1-ethoxyethoxy)-2,2-dimethyl-3a,4,5,8,8a,8b-hexahydro[1,3]dioxolo[4,5-e][2,1]benzisoxazole | C14H23NO5 | 详情 | 详情 | |
| (XVI) | 59864 | (3aR,7R,7aR)-7-(1-ethoxyethoxy)-4-(hydroxymethyl)-2,2-dimethyltetrahydro-1,3-benzodioxol-5(4H)-one | C14H24O6 | 详情 | 详情 | |
| (XVII) | 59865 | (3aR,7R,7aR)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-7-(1-ethoxyethoxy)-2,2-dimethyltetrahydro-1,3-benzodioxol-5(4H)-one | C20H38O6Si | 详情 | 详情 | |
| (XVIII) | 49044 | ethyl 2-(trimethylsilyl)acetate | C7H16O2Si | 详情 | 详情 | |
| (XIX) | 59867 | ethyl 2-[(3aR,7R,7aR)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-7-(1-ethoxyethoxy)-2,2-dimethyltetrahydro-1,3-benzodioxol-5(4H)-ylidene]acetate | C24H44O7Si | 详情 | 详情 | |
| (XX) | 59866 | ethyl 2-[(3aR,7R,7aR)-7-(1-ethoxyethoxy)-4-(hydroxymethyl)-2,2-dimethyltetrahydro-1,3-benzodioxol-5(4H)-ylidene]acetate | C18H30O7 | 详情 | 详情 | |
| (XXI) | 59868 | ethyl 2-[(3aR,7R,7aR)-7-(1-ethoxyethoxy)-2,2-dimethyl-4-methylenetetrahydro-1,3-benzodioxol-5(4H)-ylidene]acetate | C18H28O6 | 详情 | 详情 | |
| (XXII) | 59869 | ethyl 2-[(3aR,7R,7aS)-7-{[tert-butyl(diphenyl)silyl]oxy}-2,2-dimethyl-4-methylenetetrahydro-1,3-benzodioxol-5(4H)-ylidene]acetate | C30H38O5Si | 详情 | 详情 | |
| (XXIII) | 59870 | ethyl 2-((3R,4S,5R)-5-{[tert-butyl(diphenyl)silyl]oxy}-3,4-dihydroxy-2-methylenecyclohexylidene)acetate | C27H34O5Si | 详情 | 详情 | |
| (XXIV) | 59871 | ethyl 2-((3R,4R,5R)-3,5-bis{[tert-butyl(diphenyl)silyl]oxy}-4-hydroxy-2-methylenecyclohexylidene)acetate | C43H52O5Si2 | 详情 | 详情 |
合成路线4
Reduction of the ester function of (XXIV) by means of DIBAL afforded alcohol (XXV), which was further protected as the tetrahydropyranyl ether (XXVI). The free secondary hydroxyl of (XXVI) was then alkylated with allyl bromide (XXVII) and NaH to produce the allyl ether (XXVIII). Selective olefin hydroboration at the allyl ether moiety of (XXVIII), followed by oxidative work-up gave rise to the primary alcohol (XXIX). After silylation of (XXIX), the tetrahydropyranyl ether was hydrolyzed with ethanolic HCl providing the tris-O-silylated compound (XXX)
| 【1】 Takahashi, T.; Shiono, M. (Kuraray Co., Ltd.); Cyclohexanetriol derivs.. EP 0503630 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIV) | 59871 | ethyl 2-((3R,4R,5R)-3,5-bis{[tert-butyl(diphenyl)silyl]oxy}-4-hydroxy-2-methylenecyclohexylidene)acetate | C43H52O5Si2 | 详情 | 详情 | |
| (XXV) | 59872 | (1R,2R,6R)-2,6-bis{[tert-butyl(diphenyl)silyl]oxy}-4-[(Z)-2-hydroxyethylidene]-3-methylenecyclohexanol | C41H50O4Si2 | 详情 | 详情 | |
| (XXVI) | 59873 | (1R,2R,6R)-2,6-bis{[tert-butyl(diphenyl)silyl]oxy}-3-methylene-4-[(Z)-2-(tetrahydro-2H-pyran-2-yloxy)ethylidene]cyclohexanol | C46H58O5Si2 | 详情 | 详情 | |
| (XXVII) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XXVIII) | 59874 | ({(1R,2R,3R)-2-(allyloxy)-3-{[tert-butyl(diphenyl)silyl]oxy}-4-methylene-5-[(Z)-2-(tetrahydro-2H-pyran-2-yloxy)ethylidene]cyclohexyl}oxy)(tert-butyl)diphenylsilane; allyl (1R,2R,6R)-2,6-bis{[tert-butyl(diphenyl)silyl]oxy}-3-methylene-4-[(Z)-2-(tetrahydro-2H-pyran-2-yloxy)ethylidene]cyclohexyl ether | C49H62O5Si2 | 详情 | 详情 | |
| (XXIX) | 59875 | 3-({(1R,2R,6R)-2,6-bis{[tert-butyl(diphenyl)silyl]oxy}-3-methylene-4-[(Z)-2-(tetrahydro-2H-pyran-2-yloxy)ethylidene]cyclohexyl}oxy)-1-propanol | C49H64O6Si2 | 详情 | 详情 | |
| (XXX) | 59876 | 2-[(3R,4R,5R)-3,5-bis{[tert-butyl(diphenyl)silyl]oxy}-4-(3-{[tert-butyl(diphenyl)silyl]oxy}propoxy)-2-methylenecyclohexylidene]-1-ethanol | C60H74O5Si3 | 详情 | 详情 |
合成路线5
Allyl alcohol (XXX) was converted to chloride (XXXI) by means of N-chlorosuccinimide and dimethylsulfide. Displacement of the chloride ion of (XXXI) with lithium diphenylphosphide, followed by H2O2 oxidation of the resulting phosphine gave the phosphine oxide (XXXII). This was subjected to a Wittig condensation with the functionalized indanone (XXXIII) to produce the triene adduct (XXXIV). Final desilylation of (XXXIV) to the title compound was effected by treatment with tetrabutylammonium fluoride in THF
| 【1】 Takahashi, T.; Shiono, M. (Kuraray Co., Ltd.); Cyclohexanetriol derivs.. EP 0503630 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXX) | 59876 | 2-[(3R,4R,5R)-3,5-bis{[tert-butyl(diphenyl)silyl]oxy}-4-(3-{[tert-butyl(diphenyl)silyl]oxy}propoxy)-2-methylenecyclohexylidene]-1-ethanol | C60H74O5Si3 | 详情 | 详情 | |
| (XXXI) | 59877 | tert-butyl({(1R,2R,3R)-3-{[tert-butyl(diphenyl)silyl]oxy}-2-(3-{[tert-butyl(diphenyl)silyl]oxy}propoxy)-5-[(Z)-2-chloroethylidene]-4-methylenecyclohexyl}oxy)diphenylsilane; (1R,2R,6R)-2,6-bis{[tert-butyl(diphenyl)silyl]oxy}-4-[(Z)-2-chloroethylidene]-3-methylenecyclohexyl 3-{[tert-butyl(diphenyl)silyl]oxy}propyl ether | C60H73ClO4Si3 | 详情 | 详情 | |
| (XXXII) | 59878 | 2-[(3R,4R,5R)-3,5-bis{[tert-butyl(diphenyl)silyl]oxy}-4-(3-{[tert-butyl(diphenyl)silyl]oxy}propoxy)-2-methylenecyclohexylidene]ethyl(diphenyl)phosphine oxide; {2-[(3R,4R,5R)-3,5-bis{[tert-butyl(diphenyl)silyl]oxy}-4-(3-{[tert-butyl(diphenyl)silyl]oxy}propoxy)-2-methylenecyclohexylidene]ethyl}(oxo)diphenylphosphorane | C72H83O5PSi3 | 详情 | 详情 | |
| (XXXIII) | 59905 | (1R,3aR,7aR)-1-{(1R)-1,5-dimethyl-5-[(triethylsilyl)oxy]hexyl}-7a-methyloctahydro-4H-inden-4-one | C24H46O2Si | 详情 | 详情 | |
| (XXXIV) | 59879 | C81H112O5Si4 | 详情 | 详情 |
合成路线6
Preparation of the allyl alcohol precursor (XXX) was further reported by an alternative method described in the two following schemes: The symmetrical epoxide (XXXV) was cleaved by 1,3-propanediol (II) in the presence of potassium tert-butoxide to give the diol (XXXVI). After protection of the primary alcohol of (XXXVI) as the pivalate ester (XXXVII), the benzyl ether groups of (XXXVII) were removed by hydrogenation in the presence of palladium hydroxide to provide (XXXVIII). Protection of the vicinal diol moiety of (XXXVII) as the corresponding acetonide (XXXIX) was achieved by treatment with 2,2-dimethoxypropane and p-TsOH. Subsequent Swern oxidation of the primary alcohol function of (XXXIX) gave aldehyde (XL). Addition of vinylmagnesium bromide to aldehyde (XL) afforded the allylic alcohol (XLI) as a diastereomeric mixture. Esterification of (XLI) with pivaloyl chloride provided dipivalate ester (XLII). Epoxide (XLIII) was then prepared by acidic acetonide (XLII) hydrolysis, followed by cyclization of the resultant vicinal diol under Mitsunobu conditions to afford epoxide (XLIII). Addition of the O-protected lithium acetylide (XLIV) to epoxide (XLIII) furnished the acetylene adduct (XLV)
| 【1】 Hatakeyama, S.; Ikeda, T.; Maeyama, J.; Esumi, T.; Iwabuchi, Y.; Irie, H.; Convergent synthesis of 1alpha, 25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D3 (ED-71). Bioorg Med Chem Lett 1997, 7, 22, 2871. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 14685 | 1,3-propanediol; Trimethylene Glycol | 504-63-2 | C3H8O2 | 详情 | 详情 |
| (XXXV) | 25266 | benzyl [(2S,3S)-3-[(benzyloxy)methyl]oxiranyl]methyl ether; (2S,3S)-2,3-bis[(benzyloxy)methyl]oxirane | C18H20O3 | 详情 | 详情 | |
| (XXXVI) | 46308 | (2R,3S)-1,4-bis(benzyloxy)-3-(3-hydroxypropoxy)-2-butanol | C21H28O5 | 详情 | 详情 | |
| (XXXVII) | 46309 | 3-([(1S,2R)-3-(benzyloxy)-1-[(benzyloxy)methyl]-2-hydroxypropyl]oxy)propyl pivalate | C26H36O6 | 详情 | 详情 | |
| (XXXVIII) | 59880 | 3-{[(1S,2R)-2,3-dihydroxy-1-(hydroxymethyl)propyl]oxy}propyl pivalate | C12H24O6 | 详情 | 详情 | |
| (XXXIX) | 46310 | 3-([(1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethyl]oxy)propyl pivalate | C15H28O6 | 详情 | 详情 | |
| (XL) | 46311 | 3-([(1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxoethyl]oxy)propyl pivalate | C15H26O6 | 详情 | 详情 | |
| (XLI) | 46312 | 3-([(1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxy-3-butenyl]oxy)propyl pivalate | C17H30O6 | 详情 | 详情 | |
| (XLII) | 59883 | 3-({(1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-[(2,2-dimethylpropanoyl)oxy]-3-butenyl}oxy)propyl pivalate | C22H38O7 | 详情 | 详情 | |
| (XLIII) | 46314 | 3-([(1R)-2-[(2,2-dimethylpropanoyl)oxy]-1-[(2R)oxiranyl]-3-butenyl]oxy)propyl pivalate | C19H32O6 | 详情 | 详情 | |
| (XLIV) | 59881 | {3-[(4-methoxybenzyl)oxy]-1-propynyl}lithium | C11H11LiO2 | 详情 | 详情 | |
| (XLV) | 59882 | 3-({(1R,2R)-1-{1-[(2,2-dimethylpropanoyl)oxy]-2-propenyl}-2-hydroxy-6-[(4-methoxybenzyl)oxy]-4-hexynyl}oxy)propyl pivalate | C30H44O8 | 详情 | 详情 |
合成路线7
Basic hydrolysis of the pivalate esters of (XLV) followed by protection with tert-butyldimethylsilyl chloride provided the trisilylated derivative (XLVI). The p-methoxybenzyl protecting group of (XLVI) was then removed by treatment with DDQ, yielding (XLVII). Red-Al reduction of the propargyl alcohol (XLVII), followed by iodination produced the vinyl iodide (XLVIII). Intramolecular cyclization of iodide (XLVIII) under Heck reaction conditions gave rise to the key allyl alcohol intermediate (XXX), along with its undesired diastereoisomer (XLIX), which was separated by column chromatography
| 【1】 Hatakeyama, S.; Ikeda, T.; Maeyama, J.; Esumi, T.; Iwabuchi, Y.; Irie, H.; Convergent synthesis of 1alpha, 25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D3 (ED-71). Bioorg Med Chem Lett 1997, 7, 22, 2871. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXX) | 59876 | 2-[(3R,4R,5R)-3,5-bis{[tert-butyl(diphenyl)silyl]oxy}-4-(3-{[tert-butyl(diphenyl)silyl]oxy}propoxy)-2-methylenecyclohexylidene]-1-ethanol | C60H74O5Si3 | 详情 | 详情 | |
| (XLV) | 59882 | 3-({(1R,2R)-1-{1-[(2,2-dimethylpropanoyl)oxy]-2-propenyl}-2-hydroxy-6-[(4-methoxybenzyl)oxy]-4-hexynyl}oxy)propyl pivalate | C30H44O8 | 详情 | 详情 | |
| (XLVI) | 59884 | (5R,6R)-5,7-bis{[tert-butyl(dimethyl)silyl]oxy}-6-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-8-nonen-2-ynyl 4-methoxybenzyl ether; (6R)-6-{(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-3-pentynyl}-2,2,3,3,12,12,13,13-octamethyl-5-vinyl-4,7,11-trioxa-3,12-disilatetradecane | C38H70O6Si3 | 详情 | 详情 | |
| (XLVII) | 59885 | (5R,6R)-5,7-bis{[tert-butyl(dimethyl)silyl]oxy}-6-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-8-nonen-2-yn-1-ol | C30H62O5Si3 | 详情 | 详情 | |
| (XLVIII) | 59886 | (2Z,5R,6R)-5,7-bis{[tert-butyl(dimethyl)silyl]oxy}-6-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-3-iodo-2,8-nonadien-1-ol | C30H63IO5Si3 | 详情 | 详情 | |
| (XLIX) | 59887 | 2-[(3S,4R,5R)-3,5-bis{[tert-butyl(diphenyl)silyl]oxy}-4-(3-{[tert-butyl(diphenyl)silyl]oxy}propoxy)-2-methylenecyclohexylidene]-1-ethanol | C60H74O5Si3 | 详情 | 详情 |
合成路线8
The title compound was also prepared using solid-phase methodology within a parallel synthesis protocol for the construction of a combinatorial library of vitamin D3 analogues. The A-ring synthon (LVIII) was synthesized as follows. Esterification of the previously reported alcohol intermediate (L) with pivaloyl chloride gave pivalate ester (LI). Acetonide hydrolysis in (LI) and then selective mono-silylation of the resultant diol (LII) yielded (LIII). Michael addition of ethyl acrylate (LIV) to the free hydroxyl group of (LIII) furnished ester (LV). Subsequently reduction of methyl ester (LV), with simultaneous reductive cleavage of the pivaloyl group in the presence of LiAlH4 led to diol (LVI). Chlorination of the allylic alcohol of (LVI) by means of N-chlorosuccinimide and dimethylsulfide, followed by silylation of the remaining hydroxyl group gave (LVII). Conversion of chloride (LVII) into the phosphine oxide (LVIII) was then performed using a similar procedure as that for intermediate (XXXII)
| 【1】 Hijikuro, I.; Doi, T.; Takahashi, T.; Parallel synthesis of a vitamin D3 library in the solid-phase. J Am Chem Soc 2001, 123, 16, 3716. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (L) | 59888 | 2-[(3aR,7R,7aS)-7-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethyl-4-methylenetetrahydro-1,3-benzodioxol-5(4H)-ylidene]-1-ethanol | C18H32O4Si | 详情 | 详情 | |
| (LI) | 59889 | 2-[(3aR,7R,7aS)-7-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethyl-4-methylenetetrahydro-1,3-benzodioxol-5(4H)-ylidene]ethyl pivalate | C23H40O5Si | 详情 | 详情 | |
| (LII) | 59890 | 2-((3R,4S,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}-3,4-dihydroxy-2-methylenecyclohexylidene)ethyl pivalate | C20H36O5Si | 详情 | 详情 | |
| (LIII) | 59891 | 2-((3R,4R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-4-hydroxy-2-methylenecyclohexylidene)ethyl pivalate | C26H50O5Si2 | 详情 | 详情 | |
| (LIV) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (LV) | 59892 | 2-[(3R,4R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-4-(3-methoxy-3-oxopropoxy)-2-methylenecyclohexylidene]ethyl pivalate | C30H56O7Si2 | 详情 | 详情 | |
| (LVI) | 59893 | 3-({(1R,2R,6R)-2,6-bis{[tert-butyl(dimethyl)silyl]oxy}-4-[(Z)-2-hydroxyethylidene]-3-methylenecyclohexyl}oxy)-1-propanol | C24H48O5Si2 | 详情 | 详情 | |
| (LVII) | 59894 | tert-butyl({(1R,2R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-5-[(Z)-2-chloroethylidene]-4-methylenecyclohexyl}oxy)dimethylsilane; (1R,2R,6R)-2,6-bis{[tert-butyl(dimethyl)silyl]oxy}-4-[(Z)-2-chloroethylidene]-3-methylenecyclohexyl 3-{[tert-butyl(dimethyl)silyl]oxy}propyl ether | C30H61ClO4Si3 | 详情 | 详情 | |
| (LVIII) | 59895 | 2-[(3R,4R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-2-methylenecyclohexylidene]ethyl(diphenyl)phosphine oxide; {2-[(3R,4R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-2-methylenecyclohexylidene]ethyl}(oxo)diphenylphosphorane | C42H71O5PSi3 | 详情 | 详情 |
合成路线9
Attachment of the CD-ring synthon to the solid-phase support required the introduction of an appropriate spacer group. Coupling between methyl 4-hydroxybenzenesulfonate (LIX) and the tetrahydropyranyl-protected diol (LX) under Mitsunobu conditions afforded the alkoxy sulfonate (LXI). The sulfonate ester of (LXI) was hydrolyzed with LiCl in refluxing acetone, and the resulting sulfonic acid was converted to sulfonyl chloride (LXII) by PCl5 -in DMF. Coupling of the CD-ring alcohol (LXIII) with the sulfonyl chloride (LXII), followed by acidic tetrahydropyranyl group cleavage gave the sulfonate linker-bound CD synthon (LXIV). This was attached to a previously chlorinated diethylsilyl resin to furnish the resin-bound CD ring (LXV). Alternatively, resin (LXV) was prepared by a more general method consisting in the initial attachment of the sulfonate linker (LXII) to the resin support, and then loading alcohol (LXIII) to the resultant sulfonyl chloride resin (LXVI). Horner-Wadsworth-Emmons condensation of the resin-bound ketone (LXV) with the lithiated phosphine oxide (LVIII) yielded the triene compound (LXVII). Cleavage of the sulfonate resin and simultaneous introduction of the side chain substitution was achieved by copper-catalyzed displacement of sulfonate resin (LXVII) with the Grignard reagent (LXVIII). The silyl protecting groups were finally cleaved by treatment with CSA in aqueous methanol
| 【1】 Hijikuro, I.; Doi, T.; Takahashi, T.; Parallel synthesis of a vitamin D3 library in the solid-phase. J Am Chem Soc 2001, 123, 16, 3716. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (LVIII) | 59895 | 2-[(3R,4R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-2-methylenecyclohexylidene]ethyl(diphenyl)phosphine oxide; {2-[(3R,4R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-2-methylenecyclohexylidene]ethyl}(oxo)diphenylphosphorane | C42H71O5PSi3 | 详情 | 详情 | |
| (LIX) | 59896 | methyl 4-hydroxybenzenesulfonate | C7H8O4S | 详情 | 详情 | |
| (LX) | 59897 | 9-(tetrahydro-2H-pyran-2-yloxy)-1-nonanol | C14H28O3 | 详情 | 详情 | |
| (LXI) | 59898 | methyl 4-{[9-(tetrahydro-2H-pyran-2-yloxy)nonyl]oxy}benzenesulfonate | C21H34O6S | 详情 | 详情 | |
| (LXII) | 59899 | 4-{[9-(tetrahydro-2H-pyran-2-yloxy)nonyl]oxy}benzenesulfonyl chloride | C20H31ClO5S | 详情 | 详情 | |
| (LXIII) | 59900 | (1R,3aR,7aR)-1-[(1S)-2-hydroxy-1-methylethyl]-7a-methyloctahydro-4H-inden-4-one | C13H22O2 | 详情 | 详情 | |
| (LXIV) | 59901 | (2S)-2-[(1R,3aR,7aR)-7a-methyl-4-oxooctahydro-1H-inden-1-yl]propyl 4-[(9-hydroxynonyl)oxy]benzenesulfonate | C28H44O6S | 详情 | 详情 | |
| (LXV) | 59903 | (2S)-2-[(1R,3aR,7aR)-7a-methyl-4-oxooctahydro-1H-inden-1-yl]propyl 4-({9-[hydroxy(dipropyl)silyl]nonyl}oxy)benzenesulfonate | C34H58O6SSi | 详情 | 详情 | |
| (LXVI) | 59902 | {9-[4-(methylsulfonyl)phenoxy]nonyl}(dipropyl)silanol | C22H40O4SSi | 详情 | 详情 | |
| (LXVII) | 59904 | (2S)-2-((1R,3aS,7aR)-4-{(E)-2-[(3R,4R,5R)-3,5-bis{[tert-butyl(dimethyl)silyl]oxy}-4-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)-2-methylenecyclohexylidene]ethylidene}-7a-methyloctahydro-1H-inden-1-yl)propyl 4-({9-[hydroxy(dipropyl)silyl]nonyl}oxy)be | C64H118O9SSi4 | 详情 | 详情 |