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【结 构 式】 
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【分子编号】11749 【品名】4-Phenyl-3H-1,2,4-triazole-3,5(4H)-dione; 4-Phenyl-1,2,4-triazoline-3,5-dione 【CA登记号】4233-33-4 |
【 分 子 式 】C8H5N3O2 【 分 子 量 】175.14672 【元素组成】C 54.86% H 2.88% N 23.99% O 18.27% |
合成路线1
该中间体在本合成路线中的序号：(XXXVII)The synthesis of 22-oxacalcitriol labeled with tritium at the 2beta-position has been performed as follows: The condensation of 3beta-(tert-butyldimethylsilyloxy)pregn-5-en-20(S)-ol (XXVI) with N,N-dimethylacrylamide (XV) by means of NaH in THF gives the propionamide derivative (XXVII), which is submitted to a Grignard alkylation with CH3MgBr and CeCl3 in ethyl ether yielding the 3-hydroxy-3-methylbutoxy derivative (XXVIII). The desilylation of (XXVIII) with tetrabutylammonium fluoride in THF affords the 3beta-hydroxy compound (XXIX), which is oxidized with cyclohexanone in refluxing toluene catalyzed by aluminum isopropoxide giving the enone compound (XXX). The dehydrogenation of (XXX) with dichlorodicyanobenzoquinone (DDQ) in refluxing dioxane yields the 1,4-dien-3-one compound (XXXI), which is isomerized by means of sodium ethoxide in DMSO to the 1,5-dien-3-one isomer (XXXII). The reduction of (XXXII) with NaBH4 in methanol affords the corresponding 3beta-hydroxy compound (XXXIII), which is selectively acetylated with acetic anhydride in pyridine to the 3beta-acetoxy compound (XXXIV). The dehydrogenation of (XXXIV) with N-bromosuccinimide (NBS) and tetrabutylammonium fluoride in refluxing CCl4 affords the 1,5,7-triene compound (XXXV), which is deacetylated with LiAlH4/NaOH in THF giving the corresponding 3beta-hydroxy compound (XXXVI). The protection of the conjugated diene system of (XXXVI) by a Diels-Alder cycloaddition with 4-phenyl-2,5-dihydro-1H-1,2,4-triazole-2,5-dione (XXXVII) in dichloromethane yields the adduct (XXXVIII), which is treated with trimethylsilyl chloride and imidazole in DMF (in order to protect the 3beta-hydroxy group) affording (XXXIX). The selective epoxidation of the 1-double bond of (XXXIX) with m-chloroperbenzoic acid (MCPBA) in dichloromethane gives the 1alpha,2alpha-epoxy derivative (XL), which is desilylated with TBAF in THF to the 1alpha,2alpha-epoxy-3beta-hydroxy adduct (XLI). The deprotection of the conjugated diene system of (XLI) by a retro Diels-Alder reaction (heating at 140 C in 1,3-dimethylimidazolidin-2-one) yields 1alpha,2alpha-epoxy-3beta-hydroxy-20(S)-(3-hydroxy-3-methylbutoxy) pregna-5,7-diene (XLII), which is submitted to a epoxy ring opening with tritiated NaB3H4 affording the 2beta-tritiated pregnadiene (XLIII). Finally, this compound is irradiated in ethanol with a 400 W high-pressure mercury lamp provided with a Vycor filter.
| 【1】 Watanabe, H.; Akiyama, M.; Kawanishi, T.; Kubodera, N.; Synthesis of tritiated 1alpha,25-dihydroxy-22-oxavitamin D3. J Label Compd Radiopharm 1995, 36, 7, 645-54. |
| 【2】 Leeson, P.A.; Martel, A.M.; Castaner, J.; 22-Oxacalcitriol. Drugs Fut 1996, 21, 12, 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 |
|---|---|---|---|---|---|---|
| (XV) | 11727 | N,N-Dimethylacrylamide; N,N-Dimethyl-2-propenamide | 2680-03-7 | C5H9NO | 详情 | 详情 |
| (XXVI) | 11738 | (1S)-1-((3S,8S,9S,10R,13S,14S,17S)-3-[[tert-Butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-1-ethanol | C27H48O2Si | 详情 | 详情 | |
| (XXVII) | 11739 | 3-[[(1S)-1-((3S,8S,9S,10R,13S,14S,17S)-3-[[tert-Butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]-N,N-dimethylpropanamide | C32H57NO3Si | 详情 | 详情 | |
| (XXVIII) | 11740 | 4-[[(1S)-1-((3S,8S,9S,10R,13S,14S,17S)-3-[[tert-Butyl(dimethyl)silyl]oxy]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl]oxy]-2-methyl-2-butanol | C32H58O3Si | 详情 | 详情 | |
| (XXIX) | 11741 | (3S,8S,9S,10R,13S,14S,17S)-17-[(1S)-1-(3-Hydroxy-3-methylbutoxy)ethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-ol | C26H44O3 | 详情 | 详情 | |
| (XXX) | 11742 | (8S,9S,10R,13S,14S,17S)-17-[(1S)-1-(3-Hydroxy-3-methylbutoxy)ethyl]-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one | C26H42O3 | 详情 | 详情 | |
| (XXXI) | 11743 | (8S,9S,10S,13S,14S,17S)-17-[(1S)-1-(3-Hydroxy-3-methylbutoxy)ethyl]-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C26H40O3 | 详情 | 详情 | |
| (XXXII) | 11744 | (8S,9S,10S,13S,14S,17S)-17-[(1S)-1-(3-Hydroxy-3-methylbutoxy)ethyl]-10,13-dimethyl-4,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C26H40O3 | 详情 | 详情 | |
| (XXXIII) | 11745 | (3R,8S,9S,10S,13S,14S,17S)-17-[(1S)-1-(3-Hydroxy-3-methylbutoxy)ethyl]-10,13-dimethyl-4,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-ol | C26H42O3 | 详情 | 详情 | |
| (XXXIV) | 11746 | (3R,8S,9S,10S,13S,14S,17S)-17-[(1S)-1-(3-hydroxy-3-methylbutoxy)ethyl]-10,13-dimethyl-4,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-yl acetate | C28H44O4 | 详情 | 详情 | |
| (XXXV) | 11747 | (3R,9S,10R,13S,14S,17S)-17-[(1S)-1-(3-hydroxy-3-methylbutoxy)ethyl]-10,13-dimethyl-4,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-3-yl acetate | C28H42O4 | 详情 | 详情 | |
| (XXXVI) | 11748 | (3R,9S,10R,13S,14S,17S)-17-[(1S)-1-(3-Hydroxy-3-methylbutoxy)ethyl]-10,13-dimethyl-4,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-3-ol | C26H40O3 | 详情 | 详情 | |
| (XXXVII) | 11749 | 4-Phenyl-3H-1,2,4-triazole-3,5(4H)-dione; 4-Phenyl-1,2,4-triazoline-3,5-dione | 4233-33-4 | C8H5N3O2 | 详情 | 详情 |
| (XXXVIII) | 11750 | (1S,2R,5S,6S,9R,10R,13R,15S)-13-Hydroxy-5-[(1S)-1-(3-hydroxy-3-methylbutoxy)ethyl]-6,10-dimethyl-18-phenyl-16,18,20-triazahexacyclo[13.5.2.0(1,9).0(2,6).0(10,15).0(16,20)]docosa-11,21-diene-17,19-dione | C34H45N3O5 | 详情 | 详情 | |
| (XXXIX) | 11751 | (1S,2R,5S,6S,9R,10R,13R,15S)-13-[[tert-Butyl(dimethyl)silyl]oxy]-5-[(1S)-1-(3-hydroxy-3-methylbutoxy)ethyl]-6,10-dimethyl-18-phenyl-16,18,20-triazahexacyclo[13.5.2.0(1,9).0(2,6).0(10,15).0(16,20)]docosa-11,21-diene-17,19-dione | C40H59N3O5Si | 详情 | 详情 | |
| (XL) | 11752 | (1S,2R,5S,6S,9R,10R,11R,13R,14R,16S)-14-[[tert-Butyl(dimethyl)silyl]oxy]-5-[(1S)-1-(3-hydroxy-3-methylbutoxy)ethyl]-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 | C40H59N3O6Si | 详情 | 详情 | |
| (XLI) | 11753 | (1S,2R,5S,6S,9R,10R,11R,13S,14R,16S)-14-Hydroxy-5-[(1S)-1-(3-hydroxy-3-methylbutoxy)ethyl]-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 | C34H45N3O6 | 详情 | 详情 | |
| (XLII) | 11754 | (2R,2aS,3aR,3bR,3cS,5aS,6S,8aS)-6-[(1S)-1-(3-Hydroxy-3-methylbutoxy)ethyl]-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 | C26H40O4 | 详情 | 详情 | |
| (XLIII) | 11755 | (1S,3R,9S,10R,13S,14S,17S)-17-[(1S)-1-(3-Hydroxy-3-methylbutoxy)ethyl]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-1,3-diol | C26H42O4 | 详情 | 详情 | |
| (XLIII) | 45071 | (1S,3R,9S,10R,13S,14S,17S)-17-[(1S)-1-(3-hydroxy-3-methylbutoxy)ethyl]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-1,3-diol | C26H42O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)The reaction of ergosta-4,6,22-trien-3-one (I) with DDQ and 5-sulfosalicylic acid in refluxing dioxane gives ergosta-1,4,6,22-tetraen-3-one (II), which is acylated with isopropenyl acetate and Ts-OH in refluxing butyl acetate yielding 3-acetoxyergosta-1,3,5,7,22-pentaene (III). The reduction of (III) with calcium borohydridde in ethanol affords ergosta-1,5,7,22-tetraen-3beta-ol (IV), which is condensed with 4-phenyl-3H-4,5-dihydro-1,2,4-triazole-3,5-dione (V) in ethyl acetate yielding the Diels-Alder adduct (VI). The silylation of (VI) with TBDMS-Cl and imidazole affords the silyl ether (VII), which is epoxidized with MCPBA in chloroform giving the 1alpha,2alpha-22,23-diepoxide (VIII). The elimination of the silyl group with TBAF in THF gives the 3beta-alcohol (IX).
| 【1】 Tachibana, Y.; A convenient syntesis of a 1alpha-hydroxyvitamin D2. Bull Chem Soc Jpn 1988, 61, 11, 3915. |
| 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) | 34578 | (10R,13R,14S,17R)-10,13-dimethyl-17-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]-1,2,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C28H42O | 详情 | 详情 | |
| (II) | 34579 | (10S,13R,14S,17R)-10,13-dimethyl-17-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-3-one | C28H40O | 详情 | 详情 | |
| (III) | 34580 | (10R,13R,14R,17R)-10,13-dimethyl-17-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]-10,11,12,13,14,15,16,17-octahydro-9H-cyclopenta[a]phenanthren-3-yl acetate | C30H42O2 | 详情 | 详情 | |
| (IV) | 34581 | (3R,10R,13R,14R,17R)-10,13-dimethyl-17-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]-4,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthren-3-ol | C28H42O | 详情 | 详情 | |
| (V) | 11749 | 4-Phenyl-3H-1,2,4-triazole-3,5(4H)-dione; 4-Phenyl-1,2,4-triazoline-3,5-dione | 4233-33-4 | C8H5N3O2 | 详情 | 详情 |
| (VI) | 34582 | (1S,2R,5R,6R,10R,13R,15S)-13-hydroxy-6,10-dimethyl-18-phenyl-5-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]-16,18,20-triazahexacyclo[13.5.2.0(1,9).0(2,6).0(10,15).0(16,20)]docosa-11,21-diene-17,19-dione | C36H47N3O3 | 详情 | 详情 | |
| (VII) | 34583 | (1S,2R,5R,6R,10R,13R,15S)-13-[[tert-butyl(dimethyl)silyl]oxy]-6,10-dimethyl-18-phenyl-5-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]-16,18,20-triazahexacyclo[13.5.2.0(1,9).0(2,6).0(10,15).0(16,20)]docosa-11,21-diene-17,19-dione | C42H61N3O3Si | 详情 | 详情 | |
| (VIII) | 34584 | (1S,2R,5R,6R,10R,11R,13R,14R,16S)-14-[[tert-butyl(dimethyl)silyl]oxy]-5-((1S)-1-[3-[(1R)-1,2-dimethylpropyl]-2-oxiranyl]ethyl)-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, | C42H61N3O5Si | 详情 | 详情 | |
| (IX) | 34585 | (1S,2R,5R,6R,10R,11R,13S,14R,16S)-5-((1S)-1-[3-[(1R)-1,2-dimethylpropyl]-2-oxiranyl]ethyl)-14-hydroxy-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 | C36H47N3O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)Addition of methyl propiolate (I) to 2,4-hexadienal (II) using lithium hexamethyldisilazide afforded diene (III). Subsequent cycloaddition of (III) to 4-phenyl urazole (IV) in the presence of iodobenzene diacetate produced the corresponding triazolopyridazine as a diastereomeric mixture, from which the required cis isomer was isolated by flash chromatography.
| 【1】 McMillan, M.; Cudaback, E.; Misra-Press, A.; et al.; Synthesis and biological studies of a novel inhibitor of NF-kappaB. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 213. |
| 【2】 Eguchi, M.; Qabar, M.N.; Ferguson, M.D.; Babu, S.; Boatman, P.D. Jr.; McMillan, M.K.; Kahn, M.; Ogbu, C.O.; Lum, C.T.; Meara, J.P.; Kim, H.-O.; Urban, J. (Molecumetics Ltd.); Use of beta-sheet mimetics as protease and kinase inhibitors and as inhibitors of transcription factors. US 6117896; WO 9805333 . |
| 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) | 19588 | methyl propiolate | 922-67-8 | C4H4O2 | 详情 | 详情 |
| (II) | 29433 | (2E,4E)-2,4-hexadienal | 142-83-6 | C6H8O | 详情 | 详情 |
| (III) | 29434 | methyl (5E,7E)-4-hydroxy-5,7-nonadien-2-ynoate | C10H12O3 | 详情 | 详情 | |
| (IV) | 11749 | 4-Phenyl-3H-1,2,4-triazole-3,5(4H)-dione; 4-Phenyl-1,2,4-triazoline-3,5-dione | 4233-33-4 | C8H5N3O2 | 详情 | 详情 |