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【结 构 式】 
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【分子编号】15775 【品名】Allyltrimethylsilane; allyl(trimethyl)silane 【CA登记号】762-72-1 |
【 分 子 式 】C6H14Si 【 分 子 量 】114.26266 【元素组成】C 63.07% H 12.35% Si 24.58% |
合成路线1
该中间体在本合成路线中的序号：(II)A total synthesis of sufentanil has been described: The cyclization of 2-(2-thienyl)ethylamine (I) with allyltrimethylsilane (II) and formaldehyde gives 4-hydroxy-1-[2-(2-thienyl)ethyl]piperidine (III), which is oxidized with oxalyl chloride in DMSO/dichloromethane to 1-[2-(2-thienyl)ethyl]piperidin-4-one (IV). The epoxidation of (IV) by means of trimethylsulfonium iodide and the sodium salt of DMSO yields the spiro-epoxide (V), which is opened with aniline (VI) and boron trifluoride ethearate giving a 1.8:1 mixture of 4-(hydroxymethyl)-4-(phenylamino)piperidine (VII) and 4-hydroxy-4-(phenylamino)piperidine (VIII) that are conveniently separated. The methylation of the OH group of (VII) with diazomethane and SiO2 affords the methoxymethyl compound (IX), which is finally acylated with propionic anhydride to provide sufentanil.
| 【1】 Park, H.J.; Jeon, R.O.; Ryu, J.S.; Hyun, S.S.; Suh, Y.G.; Shin, D.Y.; Total synthesis of sufentanil. Arch Pharmacal Res 1999, 22, 4, 398. |
| 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) | 35253 | 2-(2-thienyl)ethylamine; 2-(2-thienyl)-1-ethanamine; 2-Thiophene ethylamine | 30433-91-1 | C6H9NS | 详情 | 详情 |
| (II) | 15775 | Allyltrimethylsilane; allyl(trimethyl)silane | 762-72-1 | C6H14Si | 详情 | 详情 |
| (III) | 35254 | 1-[2-(2-thienyl)ethyl]-4-piperidinol | C11H17NOS | 详情 | 详情 | |
| (IV) | 35255 | 1-[2-(2-thienyl)ethyl]-4-piperidinone | C11H15NOS | 详情 | 详情 | |
| (V) | 35256 | 6-[2-(2-thienyl)ethyl]-1-oxa-6-azaspiro[2.5]octane | C12H17NOS | 详情 | 详情 | |
| (VI) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (VII) | 35257 | [4-anilino-1-[2-(2-thienyl)ethyl]-4-piperidinyl]methanol | C18H24N2OS | 详情 | 详情 | |
| (VIII) | 35258 | 4-(anilinomethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinol | C18H24N2OS | 详情 | 详情 | |
| (IX) | 35259 | N-[4-(methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylamine; 4-(methoxymethyl)-N-phenyl-1-[2-(2-thienyl)ethyl]-4-piperidinamine | C19H26N2OS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The condensation of 4'-O-(benzyloxycarbonyl)-4'-demethylepipodophyllotoxin (I) with allyltrimethylsilane (II) by means of boron trifluoride ethearate in dichloromethane gives 4beta-allyl-4'-O-(benzyloxycarbonyl)-4'-demethyl-4-desoxypodophyllotoxin (III), which is oxidized with OsO4 and N-methylmorpholine (NMO) in acetone to the substituted acetaldehyde (IV). The reductocondensation of (IV) with N,N,N'-trimethylethylenediamine (V) by means of sodium cyanoborohydride and acetic acid in CHCl3 affords the protected final product (VI), which is finally hydrogenated with H2 over Pd/C in methanol.
| 【1】 Leeson, P.A.; Castaner, J.; TOP-53. Drugs Fut 1996, 21, 11, 1136. |
| 【2】 Terada, T.; Fujimoto, K.; Nomura, M.; Yamashita, J.; Takeda, S.; Kobunai, T.; Yamaguchi, H.; Wierzba, K. (Taiho Pharmaceutical Co., Ltd.); 4-Desoxy-4-epipodophyllotoxin deriv. or pharmaceutically aceptable salt thereof. EP 0522173; JP 1993503298; WO 9212982 . |
| 【3】 Terada, T.; Fujimoto, K.; Nomura, M.; Yamashita, J.; Wierzba, K.; Shibata, J.; Sugimoto, Y.; Yamada, Y.; Antitumor agents. 3. Synthesis and biological activity of 4beta-alkyl derivatives containing hydroxy, amino, and amido groups of 4'-O-demethyl-4-desoxypodophyllotoxin as antitumor agents. J Med Chem 1993, 36, 12, 1689-99. |
| 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) | 15774 | 4-[(5R,5aR,8aR,9S)-9-hydroxy-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl]-2,6-dimethoxyphenyl benzyl carbonate | C29H26O10 | 详情 | 详情 | |
| (II) | 15775 | Allyltrimethylsilane; allyl(trimethyl)silane | 762-72-1 | C6H14Si | 详情 | 详情 |
| (III) | 15776 | 4-[(5R,5aR,8aR,9S)-9-allyl-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl]-2,6-dimethoxyphenyl benzyl carbonate | C32H30O9 | 详情 | 详情 | |
| (IV) | 15777 | 4-[(5R,5aR,8aR,9S)-6-oxo-9-(2-oxoethyl)-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl]-2,6-dimethoxyphenyl benzyl carbonate | C31H28O10 | 详情 | 详情 | |
| (V) | 15778 | N-[2-(dimethylamino)ethyl]-N-methylamine; N,N,N'-trimethyl-1,2-ethanediamine; N(1),N(1),N(2)-trimethyl-1,2-ethanediamine | 142-25-6 | C5H14N2 | 详情 | 详情 |
| (VI) | 15779 | 4-((5R,5aR,8aR,9S)-9-[2-[[2-(dimethylamino)ethyl](methyl)amino]ethyl]-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl)-2,6-dimethoxyphenyl benzyl carbonate | C36H42N2O9 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：Coupling of dihydroartemisinin (I) with allyl trimethylsilane in the presence of boron trifluoride etherate gave the 10beta-allyl deoxo derivative (II). Subsequent ozonization of the allyl double bond of (II), followed by reductive treatment with NaBH4, provided alcohol (III). Finally, alkylation of (III) with 2-fluorobenzyl bromide (IV) in the presence of NaH furnished the corresponding 2-fluorobenzyl ether.
| 【1】 Searle, N.L.; Maggs, J.L.; Kan, K.-W.; Ward, S.A.; O'Neill, P.M.; Raynes, K.; Park, K.; Storr, R.C.; Novel, potent, semisynthetic antimalarial carba analogues of the first-generation 1,2,4-trioxane artemether. J Med Chem 1999, 42, 26, 5487. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15775 | Allyltrimethylsilane; allyl(trimethyl)silane | 762-72-1 | C6H14Si | 详情 | 详情 | |
| (I) | 22370 | Dihydroartemisinin; (1R,4S,5R,8S,9R,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecan-10-ol | C15H24O5 | 详情 | 详情 | |
| (II) | 38773 | (1R,4S,5R,8S,9R,10R,12R,13R)-10-allyl-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadecane | C18H28O4 | 详情 | 详情 | |
| (III) | 38774 | 2-[(1R,4S,5R,8S,9R,10R,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0(4,13).0(8,13)]hexadec-10-yl]-1-ethanol | C17H28O5 | 详情 | 详情 | |
| (IV) | 38775 | 1-(bromomethyl)-2-fluorobenzene | 446-48-0 | C7H6BrF | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)Pyridine-2,6-dicarboxylic acid (I) was hydrogenated to the corresponding piperidine, which was subsequently protected as the N-benzyloxycarbonyl derivative (II). The dicarboxylic acid (II) was converted into the cyclic anhydride (III) upon heating with Ac2O. Anhydride (III) was then dissolved in MeOH to produce the mono ester (IV). The electrochemical oxidation of acid (IV) in methanol gave rise to the methoxypiperidine (V). The methoxy group of (V) was then displaced by allyl trimethylsilane (VI) in the presence of TiCl4 to furnish the allyl piperidine (VII), which was further oxidized to diol (VIII) employing OsO4 and N-methylmorpholine-N-oxide. Then, oxidative cleavage of diol (VIII) by means of NaIO4 gave aldehyde (IX). After aldehyde (IX) ketalization with trimethyl orthoformate, basic hydrolysis of the methyl ester group provided carboxylic acid (X). This was activated as the mixed anhydride with isobutyl chloroformate and then treated with ammonia to afford amide (XI). The cyclization of the ketal amide (XI) upon treatment with pyridinium p-toluenesulfonate gave rise to the bicyclic derivative (XII). Upon bromination of (XII) in the presence of NaOMe, the bicyclic compound (XII) rearranged to the ketal lactam (XIII). Alkylation of the lactam nitrogen of (XIII) with ethyl bromoacetate and NaH produced ester (XIV), which was then hydrolyzed to the carboxylic acid (XV).
| 【1】 Tada, H.; Kalish, V.; Kato, S.; Villafranca, J.E.; Tatlock, J.H.; Linton, M.A.; Kawakami, H. (Agouron Pharmaceuticals, Inc.); Cpds., compsns., and methods for stimulating neuronal growth and elongation. WO 0004020 . |
| 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) | 43290 | 2,6-pyridinedicarboxylic acid | 499-83-2 | C7H5NO4 | 详情 | 详情 |
| (II) | 43291 | 1-[(benzyloxy)carbonyl]-2,6-piperidinedicarboxylic acid | C15H17NO6 | 详情 | 详情 | |
| (III) | 43292 | benzyl 2,4-dioxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate | C15H15NO5 | 详情 | 详情 | |
| (IV) | 43293 | 1-[(benzyloxy)carbonyl]-6-(methoxycarbonyl)-2-piperidinecarboxylic acid | C16H19NO6 | 详情 | 详情 | |
| (V) | 43294 | 1-benzyl 2-methyl 6-methoxy-1,2-piperidinedicarboxylate | C16H21NO5 | 详情 | 详情 | |
| (VI) | 15775 | Allyltrimethylsilane; allyl(trimethyl)silane | 762-72-1 | C6H14Si | 详情 | 详情 |
| (VII) | 43295 | 1-benzyl 2-methyl (2S,6R)-6-allyl-1,2-piperidinedicarboxylate | C18H23NO4 | 详情 | 详情 | |
| (VIII) | 43296 | 1-benzyl 2-methyl (2S,6R)-6-(2,3-dihydroxypropyl)-1,2-piperidinedicarboxylate | C18H25NO6 | 详情 | 详情 | |
| (IX) | 43297 | 1-benzyl 2-methyl (2S,6R)-6-(2-oxoethyl)-1,2-piperidinedicarboxylate | C17H21NO5 | 详情 | 详情 | |
| (X) | 43298 | (2S,6R)-1-[(benzyloxy)carbonyl]-6-(2,2-dimethoxyethyl)-2-piperidinecarboxylic acid | C18H25NO6 | 详情 | 详情 | |
| (XI) | 43299 | benzyl (2S,6R)-2-(aminocarbonyl)-6-(2,2-dimethoxyethyl)-1-piperidinecarboxylate | C18H26N2O5 | 详情 | 详情 | |
| (XII) | 43300 | benzyl 2-oxo-3,10-diazabicyclo[4.3.1]dec-4-ene-10-carboxylate | C16H18N2O3 | 详情 | 详情 | |
| (XIII) | 43301 | benzyl 2-(dimethoxymethyl)-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate | C18H24N2O5 | 详情 | 详情 | |
| (XIV) | 43302 | benzyl 2-(dimethoxymethyl)-3-(2-ethoxy-2-oxoethyl)-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate | C22H30N2O7 | 详情 | 详情 | |
| (XV) | 43303 | 2-[9-[(benzyloxy)carbonyl]-2-(dimethoxymethyl)-4-oxo-3,9-diazabicyclo[3.3.1]non-3-yl]acetic acid | C20H26N2O7 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)Pyridine-2,6-dicarboxylic acid (I) was hydrogenated to the corresponding piperidine, which was subsequently protected as the N-benzyloxycarbonyl derivative (II). The dicarboxylic acid (II) was converted into the cyclic anhydride (III) upon heating with Ac2O. Anhydride (III) was then dissolved in MeOH to produce the mono ester (IV). The electrochemical oxidation of acid (IV) in methanol gave rise to the methoxypiperidine (V). The methoxy group of (V) was then displaced by allyl trimethylsilane (VI) in the presence of TiCl4 to furnish the allyl piperidine (VII), which was further oxidized to diol (VIII) employing OsO4 and N-methylmorpholine-N-oxide. Then, oxidative cleavage of diol (VIII) by means of NaIO4 gave aldehyde (IX). After aldehyde (IX) ketalization with trimethyl orthoformate, basic hydrolysis of the methyl ester group provided carboxylic acid (X). This was activated as the mixed anhydride with isobutyl chloroformate and then treated with ammonia to afford amide (XI). The cyclization of the ketal amide (XI) upon treatment with pyridinium p-toluenesulfonate gave rise to the bicyclic derivative (XII). Upon bromination of (XII) in the presence of NaOMe, the bicyclic compound (XII) rearranged to the ketal lactam (XIII). Alkylation of the lactam nitrogen of (XIII) with ethyl bromoacetate and NaH produced ester (XIV), which was then hydrolyzed to the carboxylic acid (XV).
| 【1】 Tada, H.; Kalish, V.; Kato, S.; Villafranca, J.E.; Tatlock, J.H.; Linton, M.A.; Kawakami, H. (Agouron Pharmaceuticals, Inc.); Cpds., compsns., and methods for stimulating neuronal growth and elongation. WO 0004020 . |
| 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) | 43290 | 2,6-pyridinedicarboxylic acid | 499-83-2 | C7H5NO4 | 详情 | 详情 |
| (II) | 43291 | 1-[(benzyloxy)carbonyl]-2,6-piperidinedicarboxylic acid | C15H17NO6 | 详情 | 详情 | |
| (III) | 43292 | benzyl 2,4-dioxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate | C15H15NO5 | 详情 | 详情 | |
| (IV) | 43293 | 1-[(benzyloxy)carbonyl]-6-(methoxycarbonyl)-2-piperidinecarboxylic acid | C16H19NO6 | 详情 | 详情 | |
| (V) | 43294 | 1-benzyl 2-methyl 6-methoxy-1,2-piperidinedicarboxylate | C16H21NO5 | 详情 | 详情 | |
| (VI) | 15775 | Allyltrimethylsilane; allyl(trimethyl)silane | 762-72-1 | C6H14Si | 详情 | 详情 |
| (VII) | 43295 | 1-benzyl 2-methyl (2S,6R)-6-allyl-1,2-piperidinedicarboxylate | C18H23NO4 | 详情 | 详情 | |
| (VIII) | 43296 | 1-benzyl 2-methyl (2S,6R)-6-(2,3-dihydroxypropyl)-1,2-piperidinedicarboxylate | C18H25NO6 | 详情 | 详情 | |
| (IX) | 43297 | 1-benzyl 2-methyl (2S,6R)-6-(2-oxoethyl)-1,2-piperidinedicarboxylate | C17H21NO5 | 详情 | 详情 | |
| (X) | 43298 | (2S,6R)-1-[(benzyloxy)carbonyl]-6-(2,2-dimethoxyethyl)-2-piperidinecarboxylic acid | C18H25NO6 | 详情 | 详情 | |
| (XI) | 43299 | benzyl (2S,6R)-2-(aminocarbonyl)-6-(2,2-dimethoxyethyl)-1-piperidinecarboxylate | C18H26N2O5 | 详情 | 详情 | |
| (XII) | 43300 | benzyl 2-oxo-3,10-diazabicyclo[4.3.1]dec-4-ene-10-carboxylate | C16H18N2O3 | 详情 | 详情 | |
| (XIII) | 43301 | benzyl 2-(dimethoxymethyl)-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate | C18H24N2O5 | 详情 | 详情 | |
| (XIV) | 43302 | benzyl 2-(dimethoxymethyl)-3-(2-ethoxy-2-oxoethyl)-4-oxo-3,9-diazabicyclo[3.3.1]nonane-9-carboxylate | C22H30N2O7 | 详情 | 详情 | |
| (XV) | 43303 | 2-[9-[(benzyloxy)carbonyl]-2-(dimethoxymethyl)-4-oxo-3,9-diazabicyclo[3.3.1]non-3-yl]acetic acid | C20H26N2O7 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)Treatment of L-arabinose (I) with tert-butyldiphenylsilyl chloride and imidazole provided the mono-silylated furanose (II). The free hydroxyl groups of (II) were subsequently acylated with Ac2O, yielding the triacetate (III). Introduction of an allyl group in (III) by using the silyl reagent (IV) and boron trifluoride produced the allyl derivative (V) as a diastereomeric mixture. After basic hydrolysis of the acetate esters of (V), the required diastereoisomer (VI) was isolated by means of flash chromatography. Regioselective silylation of diol (VI) with tert-butyldiphenylsilyl chloride furnished (VII). Following methylation of the remaining free hydroxyl, the resultant methyl ether (VIII) was desilylated with methanolic HCl, giving diol (IX). Protection of the primary alcohol of (IX) was accomplished by acylation with pivaloyl chloride in pyridine, yielding (X). The secondary alcohol group of (X) was then converted to the benzyl ether (XI). Subsequent Sharpless asymmetric dihydroxylation of the allyl moiety of (XI) produced glycol (XII).
| 【1】 Littlefield, B.A.; Zheng, W.; Seletsky, B.M.; Yu, M.J.; Palme, M.H.; Towle, M.J. (Eisai Co., Ltd.); Macrocyclic analogs and methods of their use and preparation. US 6214865; WO 9965894 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Va) | 52367 | 4-(acetyloxy)-2-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-5-(2-propenyl)tetrahydro-3-furanyl acetate | C28H36O6Si | 详情 | 详情 | |
| (Vb) | 52368 | 4-(acetyloxy)-2-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-5-(2-propenyl)tetrahydro-3-furanyl acetate | C28H36O6Si | 详情 | 详情 | |
| (I) | 52364 | 2,3,4,5-tetrahydroxypentanal | C5H10O5 | 详情 | 详情 | |
| (II) | 52365 | 5-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)tetrahydro-2,3,4-furantriol | C21H28O5Si | 详情 | 详情 | |
| (III) | 52366 | 2,4-bis(acetyloxy)-5-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)tetrahydro-3-furanyl acetate | C27H34O8Si | 详情 | 详情 | |
| (IV) | 15775 | Allyltrimethylsilane; allyl(trimethyl)silane | 762-72-1 | C6H14Si | 详情 | 详情 |
| (VI) | 52369 | 2-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-5-(2-propenyl)tetrahydro-3,4-furandiol | C24H32O4Si | 详情 | 详情 | |
| (VII) | 52370 | 4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-2-(2-propenyl)tetrahydro-3-furanol | C30H46O4Si2 | 详情 | 详情 | |
| (VIII) | 52371 | (1,1-dimethylethyl)({[3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4-(methyloxy)-5-(2-propenyl)tetrahydro-2-furanyl]methyl}oxy)diphenylsilane; (1,1-dimethylethyl)(dimethyl)silyl 2-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-4-(methyloxy)-5-(2-propenyl)tetrahydro-3-furanyl ether | C31H48O4Si2 | 详情 | 详情 | |
| (IX) | 52372 | 2-(hydroxymethyl)-4-(methyloxy)-5-(2-propenyl)tetrahydro-3-furanol | C9H16O4 | 详情 | 详情 | |
| (X) | 52373 | [3-hydroxy-4-(methyloxy)-5-(2-propenyl)tetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate | C14H24O5 | 详情 | 详情 | |
| (XI) | 52374 | [4-(methyloxy)-3-[(phenylmethyl)oxy]-5-(2-propenyl)tetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate | C21H30O5 | 详情 | 详情 | |
| (XII) | 52375 | {5-(2,3-dihydroxypropyl)-4-(methyloxy)-3-[(phenylmethyl)oxy]tetrahydro-2-furanyl}methyl 2,2-dimethylpropanoate | C21H32O7 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IV)Treatment of L-arabinose (I) with tert-butyldiphenylsilyl chloride and imidazole provided the mono-silylated furanose (II). The free hydroxyl groups of (II) were subsequently acylated with Ac2O, yielding the triacetate (III). Introduction of an allyl group in (III) by using the silyl reagent (IV) and boron trifluoride produced the allyl derivative (V) as a diastereomeric mixture. After basic hydrolysis of the acetate esters of (V), the required diastereoisomer (VI) was isolated by means of flash chromatography. Regioselective silylation of diol (VI) with tert-butyldiphenylsilyl chloride furnished (VII). Following methylation of the remaining free hydroxyl group of (VII), the resultant methyl ether (VIII) was desilylated with methanolic HCl, giving diol (IX). Protection of the primary alcohol of (IX) was accomplished by acylation with pivaloyl chloride in pyridine, yielding (X). The secondary alcohol group of (X) was then converted to the benzyl ether (XI). Subsequent Sharpless asymmetric dihydroxylation of the allyl moiety of (XI) produced glycol (XII).
| 【1】 Littlefield, B.A.; Zheng, W.; Seletsky, B.M.; Yu, M.J.; Palme, M.H.; Towle, M.J. (Eisai Co., Ltd.); Macrocyclic analogs and methods of their use and preparation. US 6214865; WO 9965894 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Va) | 52367 | 4-(acetyloxy)-2-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-5-(2-propenyl)tetrahydro-3-furanyl acetate | C28H36O6Si | 详情 | 详情 | |
| (Vb) | 52368 | 4-(acetyloxy)-2-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-5-(2-propenyl)tetrahydro-3-furanyl acetate | C28H36O6Si | 详情 | 详情 | |
| (I) | 52364 | 2,3,4,5-tetrahydroxypentanal | C5H10O5 | 详情 | 详情 | |
| (II) | 52365 | 5-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)tetrahydro-2,3,4-furantriol | C21H28O5Si | 详情 | 详情 | |
| (III) | 52366 | 2,4-bis(acetyloxy)-5-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)tetrahydro-3-furanyl acetate | C27H34O8Si | 详情 | 详情 | |
| (IV) | 15775 | Allyltrimethylsilane; allyl(trimethyl)silane | 762-72-1 | C6H14Si | 详情 | 详情 |
| (VI) | 52369 | 2-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-5-(2-propenyl)tetrahydro-3,4-furandiol | C24H32O4Si | 详情 | 详情 | |
| (VII) | 52370 | 4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-2-(2-propenyl)tetrahydro-3-furanol | C30H46O4Si2 | 详情 | 详情 | |
| (VIII) | 52371 | (1,1-dimethylethyl)({[3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4-(methyloxy)-5-(2-propenyl)tetrahydro-2-furanyl]methyl}oxy)diphenylsilane; (1,1-dimethylethyl)(dimethyl)silyl 2-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-4-(methyloxy)-5-(2-propenyl)tetrahydro-3-furanyl ether | C31H48O4Si2 | 详情 | 详情 | |
| (IX) | 52372 | 2-(hydroxymethyl)-4-(methyloxy)-5-(2-propenyl)tetrahydro-3-furanol | C9H16O4 | 详情 | 详情 | |
| (X) | 52373 | [3-hydroxy-4-(methyloxy)-5-(2-propenyl)tetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate | C14H24O5 | 详情 | 详情 | |
| (XI) | 52374 | [4-(methyloxy)-3-[(phenylmethyl)oxy]-5-(2-propenyl)tetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate | C21H30O5 | 详情 | 详情 | |
| (XII) | 52375 | {5-(2,3-dihydroxypropyl)-4-(methyloxy)-3-[(phenylmethyl)oxy]tetrahydro-2-furanyl}methyl 2,2-dimethylpropanoate | C21H32O7 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(III)The reaction of dihydroartemisinin (I) with benzoyl chloride in pyridine gives the benzoate (II), which is treated with alyltrimethylsilane (III) and ZnCl2 in dichloroethane to yield the allyl-artemisinin derivative (IV). The ozonolysis of the vinyl group of (IV), followed by reduction with NaBH4, affords the 2-hydroxyethyl derivative (V). The reaction of (V) with Ms-Cl and TEA provides the mesylate (VI), which is finally condensed with 1-[3-(trifluoromethyl)phenyl]piperazine (VII) in refluxing benzene to furnish the target piperazinylethyl derivative.
| 【1】 Hindley, S.; Bray, P.G.; Ward, S.A.; Searle, N.L.; Park, B.K.; Davies, J.; O'Neill, P.M.; Storr, R.C.; Mechanism-based design of parasite-targeted artemisinin derivatives: Synthesis and antimalarial activity of new diamine containing analogues. J Med Chem 2002, 45, 5, 1052. |
| 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) | 54785 | (1R,4S,5R,8S,9R,10S,12R,13R)-1,5,9,12-tetramethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0~4,13~.0~8,13~]hexadecan-10-ol | C16H26O5 | 详情 | 详情 | |
| (II) | 54786 | (1R,4S,5R,8S,9R,10S,12R,13R)-1,5,9,12-tetramethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0~4,13~.0~8,13~]hexadec-10-yl benzoate | C23H30O6 | 详情 | 详情 | |
| (III) | 15775 | Allyltrimethylsilane; allyl(trimethyl)silane | 762-72-1 | C6H14Si | 详情 | 详情 |
| (IV) | 54787 | (1R,4S,5R,8S,9R,10R,12R,13R)-10-allyl-1,5,9,12-tetramethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0~4,13~.0~8,13~]hexadecane | C19H30O4 | 详情 | 详情 | |
| (V) | 54788 | 2-[(1R,4S,5R,8S,9R,10R,12R,13R)-1,5,9,12-tetramethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0~4,13~.0~8,13~]hexadec-10-yl]-1-ethanol | C18H30O5 | 详情 | 详情 | |
| (VI) | 54789 | 2-[(1R,4S,5R,8S,9R,10R,12R,13R)-1,5,9,12-tetramethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0~4,13~.0~8,13~]hexadec-10-yl]ethyl methanesulfonate | C19H32O7S | 详情 | 详情 | |
| (VII) | 16172 | 1-[3-(trifluoromethyl)phenyl]piperazine; N-[3-(trifluoromethyl)phenyl]piperazine | 15532-75-9 | C11H13F3N2 | 详情 | 详情 |