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【结 构 式】 
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【药物名称】Triptolide, PG-490 【化学名称】(-)-(3bS,4aS,5aS,6R,6aR,7aS,7bS,8aS,8bS)-3b,4,4a,6,6a,7a,7b,8b,9,10-Decahydro-6-hydroxy-6a-isopropyl-8b-methyltrisoxireno[4b,5:6,7:8a,9]phenanthro[1,2-c]furan-1(3H)-one 【CA登记号】38748-32-2 【 分 子 式 】C20H24O6 【 分 子 量 】360.41068 |
【开发单位】Kunming Institute of Botany (Originator), Pharmagenesis (Codevelopment) 【药理作用】IMMUNOMODULATING AGENTS, Immunosuppressants |
合成路线1
Total syntheses of both racemic triptolide and the levo-stereoisomer have been reported. L-dehydroabietic acid is used as the starting material. The phenol derivative of this acid (I) is converted to the trifluoroacetate (II). The latter is transformed into the isocyanate (III) by means of Curtius degradation by treating with thionyl chloride and sodium azide successively, followed by heating in toluene. The tertiary amine (IV) is formed on treatment of the isocyanate with lithium aluminum hydride in in refluxing tetrahydrofuran, and then with formic acid - formaldehyde The amine is oxidized with m-chloro perhenzoic acid, and the corresponding N-oxide is formed. Cope elimination of the N-oxide gives the olefin compound (V). Treatment of the latter with osmium tetroxide and sodium periodate affords the ketone (VI). The enolate of the compound (VI), on being generated by lithium diisopropylamide is transformed into the beta-hydroxy compound (VII) with formaldehyde. After the alcohol function has been blocked, the product is treated successively with benzyloxymethyllithium and hydrochloric acid in tetrahydrofuran and the triol monobenzyl ether (VIII) is formed. The primary alcoholic group is oxidized to the aldehyde by chromic anhydride in pyridine, and the phenol is acetylated with acetic anhydride in pyridine, and compound (IX) is afforded. Dehydration of this compound gives the unsaturated aldehyde (X). On oxidation of the aldehyde to the carboxylic acid, and then hydrogenolysis of the benzyloxy group, lactonization (XI) occurs spontaneously. A carbonyl group (XII) is introduced by oxidation with chromic anhydride in acetic acid. The acetyl group of compound (XII) is removed by saponification and the carbonyl function is reduced with sodium borohydride, and the diol (XIII) results. Treatment of the diol with sodium periodate gives the epoxy dienone (XIV). The latter is transformed into the bisoxide (XV) on treatment with hydrogen peroxide. L-Triptonide (XVI) is afforded on further oxidation with 3,5-dinitroperbenzoic acid. Reduction of triptonide with sodium borohydride gives 1-triptolide.
| 【1】 Chi, Y.S.; Kim, H.P.; Kang, S.S.; Chang, H.W.; Son, K.H.; Jong, H.G.; Koxue Tongbao 1977, 22, 10, 458-460. |
| 【2】 Liedtke, L.A.; Jernigan, D.; Strausbaugh, L.J.; J Am Chem Soc 1981, 2, 2, 121-131. |
| 【3】 Younes, B.; Lee, Y.-P.; Bajracharya, H.; Luchi, M.; Horvat, R.; J Am Chem Soc 1980, 102, 3, 1200-1201. |
| 【4】 Pagnano, P.J.; Gibson, J.K.; Cailey, C.F.; Buchanan, L.V.; J Am Chem Soc 1980, 102, 16, 5424-5425. |
| 【5】 Ruyun, J.; Triptolide. Drugs Fut 1985, 10, 7, 575. |
| 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) | 28062 | 3,5-dinitrobenzenecarboperoxoic acid | C7H4N2O7 | 详情 | 详情 | |
| (I) | 28047 | (1R,4aS,10aR)-8-hydroxy-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydro-1-phenanthrenecarboxylic acid | C20H28O3 | 详情 | 详情 | |
| (II) | 28048 | (1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-8-[(2,2,2-trifluoroacetyl)oxy]-1,2,3,4,4a,9,10,10a-octahydro-1-phenanthrenecarboxylic acid | C22H27F3O4 | 详情 | 详情 | |
| (III) | 28049 | (4bS,8R,8aR)-8-isocyanato-2-isopropyl-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydro-1-phenanthrenyl 2,2,2-trifluoroacetate | C22H26F3NO3 | 详情 | 详情 | |
| (IV) | 28050 | (4bS,8R,8aR)-8-(dimethylamino)-2-isopropyl-4b,8-dimethyl-4b,5,6,7,8,8a,9,10-octahydro-1-phenanthrenol | C21H33NO | 详情 | 详情 | |
| (V) | 28051 | (4bS,8aS)-2-isopropyl-4b-methyl-8-methylene-4b,5,6,7,8,8a,9,10-octahydro-1-phenanthrenol | C19H26O | 详情 | 详情 | |
| (VI) | 28052 | (4aS,10aR)-8-hydroxy-7-isopropyl-4a-methyl-3,4,4a,9,10,10a-hexahydro-1(2H)-phenanthrenone | C18H24O2 | 详情 | 详情 | |
| (VII) | 28053 | (1R,2S,4aS,10aR)-1,2-bis(hydroxymethyl)-7-isopropyl-4a-methyl-1,2,3,4,4a,9,10,10a-octahydro-1,8-phenanthrenediol | C20H30O4 | 详情 | 详情 | |
| (VIII) | 28054 | (1R,2S,4aS,10aR)-1-[(benzyloxy)methyl]-2-(hydroxymethyl)-7-isopropyl-4a-methyl-1,2,3,4,4a,9,10,10a-octahydro-1,8-phenanthrenediol | C27H36O4 | 详情 | 详情 | |
| (IX) | 28055 | (4bS,7S,8R,8aR)-8-[(benzyloxy)methyl]-8-hydroxy-7-(hydroxymethyl)-2-isopropyl-4b-methyl-4b,5,6,7,8,8a,9,10-octahydro-1-phenanthrenyl acetate | C29H38O5 | 详情 | 详情 | |
| (X) | 28056 | (4bS,8aR)-8-[(benzyloxy)methyl]-7-(hydroxymethyl)-2-isopropyl-4b-methyl-4b,5,6,8a,9,10-hexahydro-1-phenanthrenyl acetate | C29H36O4 | 详情 | 详情 | |
| (XI) | 28057 | (3bR,9bS)-7-isopropyl-9b-methyl-1-oxo-1,3,3b,4,5,9b,10,11-octahydrophenanthro[1,2-c]furan-6-yl acetate | C22H26O4 | 详情 | 详情 | |
| (XII) | 28058 | (3bR,9bS)-7-isopropyl-9b-methyl-1,5-dioxo-1,3,3b,4,5,9b,10,11-octahydrophenanthro[1,2-c]furan-6-yl acetate | C22H24O5 | 详情 | 详情 | |
| (XIII) | 28059 | (3bR,5S,9bS)-5,6-dihydroxy-7-isopropyl-9b-methyl-3b,4,5,9b,10,11-hexahydrophenanthro[1,2-c]furan-1(3H)-one | C20H24O4 | 详情 | 详情 | |
| (XIV) | 28060 | (5aS,9aR,10aS,11aR)-8-isopropyl-5a-methyl-4,5,5a,10a,11,11a-hexahydro-1H-oxireno[2',3':8a,9]phenanthro[1,2-c]furan-3,9-dione | C20H22O4 | 详情 | 详情 | |
| (XV) | 28061 | (1aS,2aR,3aS,4aR,9aS,10aS)-1a-isopropyl-9a-methyl-1a,4,4a,5,8,9,9a,10a-octahydro-2H-dioxireno[2',3':6,7:2',3':8a,9]phenanthro[1,2-c]furan-2,7(3aH)-dione | C20H22O5 | 详情 | 详情 | |
| (XVI) | 28063 | (3bS,4aR,5aR,6aS,7aS,7bR,8aR,8bS)-6a-isopropyl-8b-methyl-3b,4,4a,7a,7b,8b,9,10-octahydrotrioxireno[2',3':6,7:2',3':8a,9:2',3':4b,5]phenanthro[1,2-c]furan-1,6(3H,6aH)-dione | C20H22O6 | 详情 | 详情 |
合成路线2
An enantioselective total synthesis of chloride (MOM-Cl) and NaH in THF gives the methoxymethyl ether (II), which is methylated with n-BuLi and methyl iodide in THF yielding the 6-methyl derivative (III). The condensation of (III) with 3-methyl-2-butenyl bromide (IV) by means of s-BuLi in THF affords compound (V), which is deprotected with LiBF4 and TMSCl in acetonitrile to give the phenol (VI). Methylation of (VI) with dimethyl sulfate and K2CO3 in refluxing acetone provides the ether (VII), which is hydroxylated at the terminal methyl group with SeO2 and tert-butyl hydroperoxide (TBHP) in dichloromethane giving alcohol (VIII). The reaction of (VIII) with methanesulfonyl chloride and then with LiBr affords the corresponding alkenyl bromide (IX), which is condensed with methyl acetoacetate (X) by means of NaH and n-BuLi in THF providing the ketoester (XI).
| 【1】 Ye, X.-Y.; Yang, D.; Xu, M.; Enantioselective total synthesis of (-)-triptolide, (-)-triptonide, (+)-triptophenolide, and (+)-triptoquinomide. J Org Chem 2000, 65, 7, 2208. |
| 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) | 37653 | 2-isopropylphenol | 88-69-7 | C9H12O | 详情 | 详情 |
| (II) | 37654 | 1-isopropyl-2-(methoxymethoxy)benzene; (2-isopropylphenoxy)methyl methyl ether | C11H16O2 | 详情 | 详情 | |
| (III) | 37655 | 1-isopropyl-2-(methoxymethoxy)-3-methylbenzene; (2-isopropyl-6-methylphenoxy)methyl methyl ether | C12H18O2 | 详情 | 详情 | |
| (IV) | 12989 | 4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene | 870-63-3 | C5H9Br | 详情 | 详情 |
| (V) | 37656 | 1-isopropyl-2-(methoxymethoxy)-3-(4-methyl-3-pentenyl)benzene; [2-isopropyl-6-(4-methyl-3-pentenyl)phenoxy]methyl methyl ether | C17H26O2 | 详情 | 详情 | |
| (VI) | 37657 | 2-isopropyl-6-(4-methyl-3-pentenyl)phenol | C15H22O | 详情 | 详情 | |
| (VII) | 37658 | 1-isopropyl-2-methoxy-3-(4-methyl-3-pentenyl)benzene; 2-isopropyl-6-(4-methyl-3-pentenyl)phenyl methyl ether | C16H24O | 详情 | 详情 | |
| (VIII) | 37659 | (E)-5-(3-isopropyl-2-methoxyphenyl)-2-methyl-2-penten-1-ol | C16H24O2 | 详情 | 详情 | |
| (IX) | 37660 | 2-[(E)-5-bromo-4-methyl-3-pentenyl]-6-isopropylphenyl methyl ether; 1-[(E)-5-bromo-4-methyl-3-pentenyl]-3-isopropyl-2-methoxybenzene | C16H23BrO | 详情 | 详情 | |
| (X) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (XI) | 35414 | methyl (E)-9-(3-isopropyl-2-methoxyphenyl)-6-methyl-3-oxo-6-nonenoate | C21H30O4 | 详情 | 详情 |
合成路线3
The transesterification of ketoester (XI) with the menthol derivative (XII) gives the chiral ester (XIII), which is cyclized by means of manganic acetate and ytterbium trifluoromethanesulfonate in trifluoroethanol yielding the octahydrophenanthrene (XIV). The enolization of (XIV) with KHMDS and N,N-bis(trifluoromethylsulfonyl)aniline in THF affords the enol triflate (XV), which is reduced at the ester group with DIBAL in dichloromethane giving the hydroxymethyl derivative (XVI). The cyclization of (XVI) with CO by means of Pd(PPh3)4 and tributylamine in acetonitrile yields the cyclic lactone (XVII), which is oxidized with CrO3 in acetic acid affording the furophenanthrenedione (XVIII). Demethylation of (XVIII) with BBr3 in dichloromethane gives the phenolic intermediate (XIX), which is reduced with NaBH4 in methanol to yield the diol (XX). The selective epoxidation of (XX) with NaIO4 in methanol/water gives the ketoepoxide (XXI), which by a new epoxidation with trifluoroacetone and oxone in aqueous acetonitrile affords the diepoxide (XXII). A further new epoxidation of (XXII) with H2O2 and NaOH in methanol gives the keto-triepoxide (XXIII), which is finally reduced to (-)-triptolide with NaBH4 and Eu(FOD)3 in methanol.
| 【1】 Ye, X.-Y.; Yang, D.; Xu, M.; Enantioselective total synthesis of (-)-triptolide, (-)-triptonide, (+)-triptophenolide, and (+)-triptoquinomide. J Org Chem 2000, 65, 7, 2208. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 35414 | methyl (E)-9-(3-isopropyl-2-methoxyphenyl)-6-methyl-3-oxo-6-nonenoate | C21H30O4 | 详情 | 详情 | |
| (XII) | 35415 | (1S,2R,5S)-5-methyl-2-(1-methyl-1-phenylethyl)cyclohexanol | 65253-04-5 | C16H24O | 详情 | 详情 |
| (XIII) | 35416 | (1S,2R,5S)-5-methyl-2-(1-methyl-1-phenylethyl)cyclohexyl (E)-9-(3-isopropyl-2-methoxyphenyl)-6-methyl-3-oxo-6-nonenoate | C36H50O4 | 详情 | 详情 | |
| (XIV) | 35417 | (1S,2R,5S)-5-methyl-2-(1-methyl-1-phenylethyl)cyclohexyl (1R,4aS,10aS)-7-isopropyl-8-methoxy-4a-methyl-2-oxo-1,2,3,4,4a,9,10,10a-octahydro-1-phenanthrenecarboxylate | C36H48O4 | 详情 | 详情 | |
| (XV) | 35418 | (1S,2R,5S)-5-methyl-2-(1-methyl-1-phenylethyl)cyclohexyl (4aS,10aR)-7-isopropyl-8-methoxy-4a-methyl-2-[[(trifluoromethyl)sulfonyl]oxy]-3,4,4a,9,10,10a-hexahydro-1-phenanthrenecarboxylate | C37H47F3O6S | 详情 | 详情 | |
| (XVI) | 35419 | (4aS,10aR)-1-(hydroxymethyl)-7-isopropyl-8-methoxy-4a-methyl-3,4,4a,9,10,10a-hexahydro-2-phenanthrenyl trifluoromethanesulfonate | C21H27F3O5S | 详情 | 详情 | |
| (XVII) | 35420 | (3bR,9bS)-7-isopropyl-6-methoxy-9b-methyl-3b,4,5,9b,10,11-hexahydrophenanthro[1,2-c]furan-1(3H)-one | C21H26O3 | 详情 | 详情 | |
| (XVIII) | 35421 | (3bR,9bS)-7-isopropyl-6-methoxy-9b-methyl-3,3b,4,9b,10,11-hexahydrophenanthro[1,2-c]furan-1,5-dione | C21H24O4 | 详情 | 详情 | |
| (XIX) | 35422 | (3bR,9bS)-6-hydroxy-7-isopropyl-9b-methyl-3,3b,4,9b,10,11-hexahydrophenanthro[1,2-c]furan-1,5-dione | C20H22O4 | 详情 | 详情 | |
| (XX) | 28059 | (3bR,5S,9bS)-5,6-dihydroxy-7-isopropyl-9b-methyl-3b,4,5,9b,10,11-hexahydrophenanthro[1,2-c]furan-1(3H)-one | C20H24O4 | 详情 | 详情 | |
| (XXI) | 28060 | (5aS,9aR,10aS,11aR)-8-isopropyl-5a-methyl-4,5,5a,10a,11,11a-hexahydro-1H-oxireno[2',3':8a,9]phenanthro[1,2-c]furan-3,9-dione | C20H22O4 | 详情 | 详情 | |
| (XXII) | 35423 | (1aS,1bS,6bS,7aS,8aS,11aS)-10-isopropyl-1b-methyl-1b,3,6,6b,7,7a-hexahydrodioxireno[2',3':8a,9:2',3':4b,5]phenanthro[1,2-c]furan-4,9(2H,11aH)-dione | C20H22O5 | 详情 | 详情 | |
| (XXIII) | 37661 | (3bS,4aS,5aS,6aS,7aS,7bS,8aS,8bS)-6a-isopropyl-8b-methyl-3b,4,4a,7a,7b,8b,9,10-octahydrotrioxireno[2',3':6,7:2',3':8a,9:2',3':4b,5]phenanthro[1,2-c]furan-1,6(3H,6aH)-dione | C20H22O6 | 详情 | 详情 |