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【结 构 式】 
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【分子编号】11387 【品名】2-Methylacrylaldehyde; Methacrylaldehyde 【CA登记号】78-85-3 |
【 分 子 式 】C4H6O 【 分 子 量 】70.09104 【元素组成】C 68.55% H 8.63% O 22.83% |
合成路线1
该中间体在本合成路线中的序号：(XII)The first total synthesis of hyperzine A as racemic is carried out as follows: The reaction of pyrrolidine (I) with cyclohexane-1,4-dione monoethyleneketal (II) by means of p-toluenesulfonic acid in refluxing benzene gives the enamine (III), which is cyclized with acrylamide (IV) in refluxing dioxane affording the bicyclic pyridone (V). The benzylation of (V) with benzyl chloride and KH in THF yields the N-benzyl derivative (VI), which is dehydrogenated by means of phenylselenium chloride in THF, followed by a treatment with NaIO4 in refluxing methanol to give the protected pyridone (VII). The debenzylation of (VII) with Pd(OH)2 in acetic acid yields the free pyridone (VIII), which is aromatized with methyl iodide and silver carbonate to the 2-methoxypyridine (IX). Elimination of the ketal group of (IX) with HCl in refluxing acetone affords the tetrahydroquinolone (X), which is carboxylated by means of dimethyl carbonate and KH to give 2-methoxy-6-oxo-5,6,7,8-tetrahydroquinoline-5-carboxylic acid methyl ester (XI). The cyclization of (XI) with 2-methylacrolein (XII) by means of sodium methoxide in methanol or tetramethylguanidine in dichloromethane yields the tricyclic compound (XIII), which is mesylated with mesyl chloride to the mesylate (XIV). Elimination of the mesyl group of (XIV) with refluxing acetic acid - sodium acetate affords the olefinic compound (XV), which is submitted to a Wittig condensation with ethylidenetriphenylphosphorane in ether giving the diolefinic compound (XVI) as a mixture of the E- and Z-isomers. Selective hydrolysis of (XVI) with NaOH in THF - methanol yields acid (XVII) as the E-isomer, which is treated with SOCl2 and sodium azide in a modified Curtius reaction to obtain the urethane (XVIII). Lastly trimethylsilyl iodide is used to effect both N- and O-deprotection.
| 【1】 Xia, Y.; Kozikowski, A.P.; A practical synthesis of the Chinese "nootropic" agent huperzine A: A possible lead in the treatment of Alzheimer's disease. J Am Chem Soc 1989, 111, 11, 4116. |
| 【2】 Qian, L.; Ji, R.; A total synthesis of (±)-huperzine A. Tetrahedron Lett 1989, 30, 16, 2089. |
| 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) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (II) | 11377 | 1,4-Dioxaspiro[4.5]decan-8-one | 4746-97-8 | C8H12O3 | 详情 | 详情 |
| (III) | 11378 | 1-(1,4-Dioxaspiro[4.5]dec-7-en-8-yl)pyrrolidine | C12H19NO2 | 详情 | 详情 | |
| (IV) | 11379 | 3-Butenamide | C4H7NO | 详情 | 详情 | |
| (V) | 11380 | 1',2',3',4',5',6',7',8'-Octahydrospiro[1,3-dioxlane-2,6'-quinolin]-2'-one | C11H15NO3 | 详情 | 详情 | |
| (VI) | 11381 | 1'-Benzyl-1',2',3',4',5',6',7',8'-Octahydrospiro[1,3-dioxlane-2,6'-quinolin]-2'-one | C18H21NO3 | 详情 | 详情 | |
| (VII) | 11382 | 1'-Benzyl-1',2',5',6',7',8'-Hexahydrospiro[1,3-dioxlane-2,6'-quinolin]-2'-one | C18H19NO3 | 详情 | 详情 | |
| (VIII) | 11383 | 1',2',5',6',7',8'-Hexahydrospiro[1,3-dioxlane-2,6'-quinolin]-2'-one | C11H13NO3 | 详情 | 详情 | |
| (IX) | 11384 | 2'-Methoxy-5',6',7',8'-tetrahydrospiro[1,3-dioxlane-2,6'-quinoline] | C12H15NO3 | 详情 | 详情 | |
| (X) | 11385 | 2-Methoxy-7,8-dihydro-6(5H)-quinolinone | C10H11NO2 | 详情 | 详情 | |
| (XI) | 11386 | methyl 2-methoxy-6-oxo-5,6,7,8-tetrahydro-5-quinolinecarboxylate | C12H13NO4 | 详情 | 详情 | |
| (XII) | 11387 | 2-Methylacrylaldehyde; Methacrylaldehyde | 78-85-3 | C4H6O | 详情 | 详情 |
| (XIII) | 11388 | methyl (1S)-10-hydroxy-5-methoxy-11-methyl-13-oxo-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-triene-1-carboxylate | C16H19NO5 | 详情 | 详情 | |
| (XIV) | 11389 | methyl (1S)-5-methoxy-11-methyl-10-[(methylsulfonyl)oxy]-13-oxo-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-triene-1-carboxylate | C17H21NO7S | 详情 | 详情 | |
| (XV) | 11390 | methyl (1S)-5-methoxy-11-methyl-13-oxo-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6,10-tetraene-1-carboxylate | C16H17NO4 | 详情 | 详情 | |
| (XVI) | 11391 | methyl (1R)-13-[(E)ethylidene]-5-methoxy-11-methyl-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6,10-tetraene-1-carboxylate | C18H21NO3 | 详情 | 详情 | |
| (XVII) | 11392 | (1R)-13-[(E)Ethylidene]-5-methoxy-11-methyl-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6,10-tetraene-1-carboxylic acid | C17H19NO3 | 详情 | 详情 | |
| (XVIII) | 11393 | ethyl 13-[(E)ethylidene]-5-methoxy-11-methyl-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6,10-tetraen-1-ylcarbamate | C19H24N2O3 | 详情 | 详情 | |
| (XIX) | 11394 | ethyl 13-[(E)ethylidene]-11-methyl-5-oxo-6-azatricyclo[7.3.1.0(2,7)]trideca-2(7),3,10-trien-1-ylcarbamate | C18H22N2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：A synthesis for optically pure (-)-huperzine A, through modification of the previously reported synthesis of (±)-huperzine A, has been described: Intermediate methyl ester (XI) of this synthesis [Drugs Fut 1990, 15(6): 616] is transesterified with (-)-8-phenylmenthol (A) in refluxing benzene to give the optical ester (XIa), suitable for a stereocontrolled cyclization. The cyclization of (XIa) with 2-methylacrolein, as in the previous synthesis, yields the tricyclic compound (XIIa) [an analogue of the previously reported (XII), but with the adequate absolute configuration]. The following step is dehydration to (XIVa), in the same way as in the case of (XIV) of the previous synthesis. From here, the previously reported synthetic route is repeated, finally yielding optically pure (-)-huperzine A. In some steps, separation of undesirable minor amounts of other enantiomers must be performed.
| 【1】 Yamada, F.; Kozikowski, A.P.; Reddy, E.R.; Pang, Y.P.; Miller, J.H.; McKinney, M.; A route to optically pure (-)-huperzine-A - Molecular modeling and invitro pharmacology. J Am Chem Soc 1991, 113, 12, 4695. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11387 | 2-Methylacrylaldehyde; Methacrylaldehyde | 78-85-3 | C4H6O | 详情 | 详情 | |
| (A) | 11396 | (1S,2S,4R)-4-Methyl-2-(1-methyl-1-phenylethyl)cyclohexanol | C16H24O | 详情 | 详情 | |
| (XIa) | 11397 | (1S,2S,4R)-4-methyl-2-(1-methyl-1-phenylethyl)cyclohexyl 2-methoxy-6-oxo-5,6,7,8-tetrahydro-5-quinolinecarboxylate | C27H33NO4 | 详情 | 详情 | |
| (XIIa) | 11398 | (1S,2S,4R)-4-methyl-2-(1-methyl-1-phenylethyl)cyclohexyl (1S,9R)-10-hydroxy-5-methoxy-11-methyl-13-oxo-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6-triene-1-carboxylate | C31H39NO5 | 详情 | 详情 | |
| (XIVa) | 11399 | (1S,2S,4R)-4-methyl-2-(1-methyl-1-phenylethyl)cyclohexyl (1S,9R)-5-methoxy-11-methyl-13-oxo-6-azatricyclo[7.3.1.0(2,7)]trideca-2,4,6,10-tetraene-1-carboxylate | C31H37NO4 | 详情 | 详情 | |
| (XI) | 11386 | methyl 2-methoxy-6-oxo-5,6,7,8-tetrahydro-5-quinolinecarboxylate | C12H13NO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The intermediate (XI) has been obtained as follows: The condensation of the chiral ketone (I) with unsaturated aldehyde (II) by means of chlorodicyclohexylborane (DCHBCl) gives the chiral heptenone (III), which is esterified with propanal and SmI3, yielding the ester (IV). The ketalization of (IV) with 2-(phenylselanyl)acetaldehyde diethyl acetal (V) by means of pyridinium p-toluenesulfonate (PPTS) affords the cyclic ketal (VI), which is oxidized with NaIO4 and condensed with the silylated enol ether (VII), providing the lactone (VIII). Methanolysis of the lactone (VII) with MeONa and silylation of the hydroxyester gives methyl ester (IX), which is hydrolyzed with KOH and reesterified with 2,6-dimethylphenol (X) and DCC, yielding the desired intermediate, the aryl ester (XI).
| 【1】 Paterson, I.; et al.; Total synthesis of the antimicrotubule agent (+)-discodermolide using boron-mediated aldol reactions of chiral ketones. Angew Chem. Int Ed Engl 2000, 39, 2, 377. |
| 【2】 Paterson, I.; Florence, G.J.; Synthesis of (+)-discodermolide and analogues by control of asymmetric induction in aldol reactions of gamma-chiral (Z)-enals. Tetrahedron Lett 2000, 41, 35, 6935. |
| 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) | 42614 | (2S)-1-[(4-methoxybenzyl)oxy]-2-methyl-3-pentanone | C14H20O3 | 详情 | 详情 | |
| (II) | 11387 | 2-Methylacrylaldehyde; Methacrylaldehyde | 78-85-3 | C4H6O | 详情 | 详情 |
| (III) | 42615 | (2S,4S,5R)-5-hydroxy-1-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-6-hepten-3-one | C18H26O4 | 详情 | 详情 | |
| (IV) | 42616 | (1R)-1-[(1R,2S,3S)-2-hydroxy-4-[(4-methoxybenzyl)oxy]-1,3-dimethylbutyl]-2-methyl-2-propenyl propionate | C21H32O5 | 详情 | 详情 | |
| (V) | 42617 | 1-[(2,2-diethoxyethyl)selanyl]benzene; 1-ethoxy-2-(phenylselanyl)ethyl ethyl ether | C12H18O2Se | 详情 | 详情 | |
| (VI) | 42618 | (4R,5S,6S)-4-isopropenyl-6-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-5-methyl-2-[(phenylselanyl)methyl]-1,3-dioxane; (2S)-2-[(4S,5S,6R)-6-isopropenyl-5-methyl-2-[(phenylselanyl)methyl]-1,3-dioxan-4-yl]propyl 4-methoxybenzyl ether | C26H34O4Se | 详情 | 详情 | |
| (VII) | 42619 | tert-butyl[(1-methoxyvinyl)oxy]dimethylsilane; tert-butyl(dimethyl)silyl 1-methoxyvinyl ether | C9H20O2Si | 详情 | 详情 | |
| (VIII) | 42620 | (7S,8R)-8-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-5,7-dimethyl-3,4,7,8-tetrahydro-2H-oxocin-2-one | C20H28O4 | 详情 | 详情 | |
| (IX) | 42621 | methyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate | C27H46O5Si | 详情 | 详情 | |
| (X) | 37388 | 2,6-dimethylphenol | 576-26-1 | C8H10O | 详情 | 详情 |
| (XI) | 42622 | 2,6-dimethylphenyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate | C34H52O5Si | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXVIII)Synthesis of the target (+)-Discodermolide: The reaction of 3-hydroxy-2(S)-methylpropionic acid methyl ester (I) with p-methoxybenzyl trichloroacetimidate gives the benzyl ether (XXVI), which is condensed with ethylmagnesium bromide in THF to yield the chiral ketone (XXVII). The reaction of (XXVII) with 2-methylpropenal (XXVIII) by means of (c-Hex)2B-Cl and TEA in ethyl ether affords the chiral hydroxyketone (XXIX), which is reduced with SmI2 and propanal to provide the beta-diol monoester (XXX). The methanolysis of (XXX) by means of K2CO3 furnishes the diol (XXXI), which can also be obtained directly by reduction of (XXIX) with Me4NBH(OAc)3 in acetonitrile/AcOH. The reaction of (XXXI) with the diethylacetal (XXXII) and PPTS in refluxing toluene gives the phenylselenoacetal (XXXIII), which is oxidized with NaIO4 and treated with DBU to achieve a Claisen rearrangement and yield the eight member lactone (XXXIV). The hydrolysis of (XXXIV) with KOH in refluxing aqueous methanol affords the hydroxyacid (XXXV), which is esterified with 2,6-dimethylphenol (XXXVI) by means of DCC and DMAP in dichloromethane to provide the phenyl ester (XXXVII). The reaction of (XXXVII) with Tbdms-OTf and lutidine gives the silylated ester (XXXVIII). Alternatively, the methanolysis of the lactone (XXXIV) with NaOMe in methanol gives the hydroxyester (XXXIX), which is treated with Tbdms-OTf as before to yield the silylated ester (XL). The hydrolysis of the ester (XL) with KOH in refluxing aqueous methanol affords the silylated hydroxyacid (XLI), which is esterified with 2,6-dimethylphenol (XXXVI) by means of DCC and DMAP to provide the already reported phenyl ester (XXXVIII).
| 【1】 Paterson, I.; Florence, G.J.; Gerlach, K.; Scott, J.P.; Sereinig, N.; A practical synthesis of (+)-discodermolide and analogues: Fragment union by complex aldol reactions. J Am Chem Soc 2001, 123, 39, 9535. |
| 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) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
| (XXVI) | 42654 | methyl (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanoate | C13H18O4 | 详情 | 详情 | |
| (XXVII) | 42614 | (2S)-1-[(4-methoxybenzyl)oxy]-2-methyl-3-pentanone | C14H20O3 | 详情 | 详情 | |
| (XXVIII) | 11387 | 2-Methylacrylaldehyde; Methacrylaldehyde | 78-85-3 | C4H6O | 详情 | 详情 |
| (XXIX) | 42615 | (2S,4S,5R)-5-hydroxy-1-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-6-hepten-3-one | C18H26O4 | 详情 | 详情 | |
| (XXX) | 62842 | (1R)-1-{(1R,2S,3S)-2-hydroxy-4-[(4-methoxybenzyl)oxy]-1,3-dimethylbutyl}-2-methyl-2-propenyl butyrate | C22H34O5 | 详情 | 详情 | |
| (XXXI) | 62843 | (3R,4R,5S,6S)-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-1-heptene-3,5-diol | C18H28O4 | 详情 | 详情 | |
| (XXXII) | 62844 | 1-[(2,2-dipropoxyethyl)selanyl]benzene; 2-(phenylselanyl)-1-propoxyethyl propyl ether | C14H22O2Se | 详情 | 详情 | |
| (XXXIII) | 42618 | (4R,5S,6S)-4-isopropenyl-6-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-5-methyl-2-[(phenylselanyl)methyl]-1,3-dioxane; (2S)-2-[(4S,5S,6R)-6-isopropenyl-5-methyl-2-[(phenylselanyl)methyl]-1,3-dioxan-4-yl]propyl 4-methoxybenzyl ether | C26H34O4Se | 详情 | 详情 | |
| (XXXIV) | 42620 | (7S,8R)-8-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-5,7-dimethyl-3,4,7,8-tetrahydro-2H-oxocin-2-one | C20H28O4 | 详情 | 详情 | |
| (XXXV) | 62845 | (Z,6S,7R,8S)-7-hydroxy-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoic acid | C20H30O5 | 详情 | 详情 | |
| (XXXVI) | 37388 | 2,6-dimethylphenol | 576-26-1 | C8H10O | 详情 | 详情 |
| (XXXVII) | 62847 | 2,6-dimethylphenyl (Z,6S,7R,8S)-7-hydroxy-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate | C28H38O5 | 详情 | 详情 | |
| (XXXVIII) | 42622 | 2,6-dimethylphenyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate | C34H52O5Si | 详情 | 详情 | |
| (XXXIX) | 62846 | methyl (Z,6S,7R,8S)-7-hydroxy-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate | C21H32O5 | 详情 | 详情 | |
| (XL) | 42621 | methyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate | C27H46O5Si | 详情 | 详情 | |
| (XLI) | 62848 | (Z,6S,7R,8S)-7-{[tert-butyl(dimethyl)silyl]oxy}-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoic acid | C26H44O5Si | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)Boron-catalyzed condensation of propionyl oxazolidinone (I) with acrolein (II) stereoselectively provided the aldol product (III), and further methanolysis afforded beta-hydroxy ester (IV). A second aldol condensation of (IV) with methacrolein (V) furnished a difficultly separable mixture of diols (VI). Conversion of (VI) to the corresponding acetonides by treatment with 2-methoxypropene (VII) allowed chromatographical separation of the required major isomer (VIII). Hydrolysis of the acetonide, followed by ring-closing metathesis of diene (XI) in the presence of Grubbs catalyst gave rise to cyclopentene (XII). Selective silylation of the less hindered allylic hydroxyl of (XII) with tert-butyldimethylsilyl chloride yielding (XIII) and subsequent oxidation of the remaining alcohol group with MnO2 then provided ketone (XIV). Conjugate addition of lithium di-n-butylcuprate to the unsaturated ketone, followed by phenylselenylation of the intermediate enolate with PhSeBr yielded alpha-selenyl ketone (XV). Oxidative elimination of the phenylselenyl group gave a (1:1) mixture of the required unsaturated ketone (XVII) and its exomethylene isomer (XVI). Isomerization of (XVI) to the desired endo isomer (XVII) was carried out by treatment with RhCl3.
| 【1】 Sunazuka, T.; et al.; Total synthesis of (+)-madindoline A and (-)-madindoline B, potent, selective inhibitors of interleukin 6. Determination of the relative and absolute configurations. J Am Chem Soc 2000, 122, 9, 2122. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIa) | 36695 | methyl (2R,3R)-3-hydroxy-2-[(1R)-1-hydroxy-2-propenyl]-2,4-dimethyl-4-pentenoate | C11H18O4 | 详情 | 详情 | |
| (VIb) | 36696 | methyl (2S,3R)-3-hydroxy-2-[(1R)-1-hydroxy-2-propenyl]-2,4-dimethyl-4-pentenoate | C11H18O4 | 详情 | 详情 | |
| (VIc),(XI) | 36697 | methyl (2S,3S)-3-hydroxy-2-[(1R)-1-hydroxy-2-propenyl]-2,4-dimethyl-4-pentenoate | C11H18O4 | 详情 | 详情 | |
| (I) | 11535 | (4S)-4-Isopropyl-3-propionyl-1,3-oxazolidin-2-one | 77877-19-1 | C9H15NO3 | 详情 | 详情 |
| (II) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (III) | 36693 | (4S)-3-[(2S,3R)-3-hydroxy-2-methyl-4-pentenoyl]-4-isopropyl-1,3-oxazolidin-2-one | C12H19NO4 | 详情 | 详情 | |
| (IV) | 36694 | methyl (2S,3R)-3-hydroxy-2-methyl-4-pentenoate | C7H12O3 | 详情 | 详情 | |
| (V) | 11387 | 2-Methylacrylaldehyde; Methacrylaldehyde | 78-85-3 | C4H6O | 详情 | 详情 |
| (VII) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (VIII) | 36698 | methyl (4S,5R,6R)-4-isopropenyl-2,2,5-trimethyl-6-vinyl-1,3-dioxane-5-carboxylate | C14H22O4 | 详情 | 详情 | |
| (IX) | 36699 | methyl (4R,5R,6R)-4-isopropenyl-2,2,5-trimethyl-6-vinyl-1,3-dioxane-5-carboxylate | C14H22O4 | 详情 | 详情 | |
| (X) | 36700 | methyl (4R,5S,6R)-4-isopropenyl-2,2,5-trimethyl-6-vinyl-1,3-dioxane-5-carboxylate | C14H22O4 | 详情 | 详情 | |
| (XII) | 36701 | methyl (1S,2S,5R)-2,5-dihydroxy-1,3-dimethyl-3-cyclopentene-1-carboxylate | C9H14O4 | 详情 | 详情 | |
| (XIII) | 36702 | methyl (1R,2S,5R)-5-[[tert-butyl(dimethyl)silyl]oxy]-2-hydroxy-1,3-dimethyl-3-cyclopentene-1-carboxylate | C15H28O4Si | 详情 | 详情 | |
| (XIV) | 36703 | methyl (1S,5R)-5-[[tert-butyl(dimethyl)silyl]oxy]-1,3-dimethyl-2-oxo-3-cyclopentene-1-carboxylate | C15H26O4Si | 详情 | 详情 | |
| (XV) | 36704 | methyl (1S,5R)-4-butyl-5-[[tert-butyl(dimethyl)silyl]oxy]-1,3-dimethyl-2-oxo-3-(phenylselanyl)cyclopentanecarboxylate | C25H40O4SeSi | 详情 | 详情 | |
| (XVI) | 36705 | methyl (1S,2R)-3-butyl-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-4-methylene-5-oxocyclopentanecarboxylate | C19H34O4Si | 详情 | 详情 | |
| (XVII) | 36706 | methyl (1S,2R)-3-butyl-2-[[tert-butyl(dimethyl)silyl]oxy]-1,4-dimethyl-5-oxo-3-cyclopentene-1-carboxylate | C19H34O4Si | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)The stereocontrolled reaction of 3-pentanone (I) with 2-methylpropionaldehyde (II) by means of (+)-bis(diisopinocampheyl)borane triflate and DIEA in THF, followed by silylation with Tes-Cl and imidazole gives the silylated heptenone (III), which is condensed with 3-benzyloxypropionaldehyde (IV) by means of chlorodicyclohexylborane yielding the diol (V). The protection of the hydroxy groups of (V) with 2,2-dimethoxypropane and camphorsulfonic acid (CSA) with simultaneous desilylation affords the isopropylidene ketal (VI), which is acylated with propionic anhydride and triethylamine giving the propionate (VII). The Claisen rearrangement of (VII) by means of LDA and TBDMS-Cl in HMPT yields the carboxylic acid (VIII), which by regio- and stereoselective hydroboration of its double bond with BH3, followed by oxidation with N-methylmorpholine N-oxide (NMO) and tetrapropylammonium perruthenate (TPAP) in dichloromethane affords the lactone (IX). The reaction of (IX) with Me2Al-NH2, followed by debenzylation with H2 over Pd/C provides the dihydroxyamide (X), which is oxidized with Dess-Martin periodinane (DMP) in dichloromethane giving the keto aldehyde (XI). The cyclization of (XI) with HF in acetonitrile yields the spiro carbaldehyde (XII), which is silylated with Tes-OTf in dichloromethane providing the silyl ether (XIII).
| 【1】 Nicolaou, K.C.; et al.; Total synthesis of sanglifehrin A. Angew Chem. Int Ed Engl 1999, 38, 16, 2447. |
| 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) | 32415 | Propione; Dimethylacetone; Diethyl ketone; 3-Pentanone | 96-22-0 | C5H10O | 详情 | 详情 |
| (II) | 11387 | 2-Methylacrylaldehyde; Methacrylaldehyde | 78-85-3 | C4H6O | 详情 | 详情 |
| (III) | 32416 | (4R,5R)-4,6-dimethyl-5-[(triethylsilyl)oxy]-6-hepten-3-one | C15H30O2Si | 详情 | 详情 | |
| (IV) | 14688 | 3-(benzyloxy)propanal | C10H12O2 | 详情 | 详情 | |
| (V) | 32417 | (3S,4S,5S,6S,7R)-1-(benzyloxy)-4,6,8-trimethyl-7-[(triethylsilyl)oxy]-8-nonene-3,5-diol | C25H44O4Si | 详情 | 详情 | |
| (VI) | 31418 | [6-(benzyloxy)-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl][3-methoxy-4-(1-pyrrolidinylmethyl)phenyl]methanone | C34H31NO4S | 详情 | 详情 | |
| (VII) | 31419 | 4-[6-(benzyloxy)-3-[3-methoxy-4-(1-pyrrolidinylmethyl)benzyl]-1-benzothiophen-2-yl]phenol | C34H33NO3S | 详情 | 详情 | |
| (VIII) | 31420 | methyl (2S)-3-hydroxy-2-(tritylamino)propanoate | C23H23NO3 | 详情 | 详情 | |
| (IX) | 32421 | (3S,5S,6S)-6-((1S)-1-[(4S,5R,6S)-6-[2-(benzyloxy)ethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl]ethyl)-3-ethyl-5-methyltetrahydro-2H-pyran-2-one | C26H40O5 | 详情 | 详情 | |
| (X) | 32422 | (2S,4S,5S,6R)-2-ethyl-5-hydroxy-6-[(4R,5R,6S)-6-(2-hydroxyethyl)-2,2,5-trimethyl-1,3-dioxan-4-yl]-4-methylheptanamide | C19H37NO5 | 详情 | 详情 | |
| (XI) | 32423 | (2S,4S,6S)-2-ethyl-4-methyl-5-oxo-6-[(4S,5R,6S)-2,2,5-trimethyl-6-(2-oxoethyl)-1,3-dioxan-4-yl]heptanamide | C19H33NO5 | 详情 | 详情 | |
| (XII) | 32424 | 2-[(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl]acetaldehyde | C16H27NO4 | 详情 | 详情 | |
| (XIII) | 32425 | 2-[(2S,3S,4S,5S,6R,9S,11S)-9-ethyl-3,5,11-trimethyl-8-oxo-4-[(triethylsilyl)oxy]-1-oxa-7-azaspiro[5.5]undec-2-yl]acetaldehyde | C22H41NO4Si | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(V)The regiocontrolled condensation of 3-pentanone (IV) with methacrolein (V) catalyzed by (+)-Ipc2B-OTf and DIEA in THF gives the chiral 3-heptenone (VI), which is reductocondensed with 3-benzyloxypropanal (VII) by means of Cy2BCl, Et3N and LiBH4 in ethyl ether to afford the partially protected tetrol (VIII). The ketalization of (VIII) with 2,2-dimethoxypropane and CSA in acetone provides the desilylated cyclic ketal (IX), which is esterified with butyric anhydride and Et3N to the butyrate (X). The isomerization of (X) by means of LDA, and TBDMS-Cl in HMPA/THF, followed by a treatment in hot toluene yields the chiral undecenoic acid (XI), which is reduced by means of borane in THF to the undecanediol (XII). The lactonization of (XII) by means of NMO and tetrapropylammonium perruthenate (TPAP) in dichloromethane affords the lactone (XIII), which is treated with Me2Al-NH2 in dichloromethane to give the amide (XIV). The debenzylation of (XIV) with H2 over Pd(OH)2 in ethanol yields the dihydroxyamide (XV), which is oxidized with Dess Martin periodinane (DMP) and pyridine in dichloromethane affording the ketoaldehyde (XVI). Spirocyclization of (XVI) catalyzed by HF in acetonitrile gives the aldehydic spirolactam (XVII). Alternatively, the oxidation of the secondary alcohol of (XIV) with pyridinium dichromate (PDC) in dichloromethane yields the ketoamide (XVIII), which is submitted to spirocyclization with HF as before, and hydrogenolytic debenzylation to afford the intermediate spirolactam (XIX). The oxidation of (XIX) with O2 catalyzed by RuCl2 (PPh)3 in benzene gives the previously reported aldehydic spirolactam (XVII).
| 【1】 Nicolaou, K.C.; et al.; Total synthesis of the novel immunosuppressant Sanglifehrin A. J Am Chem Soc 2000, 122, 16, 3830. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 32415 | Propione; Dimethylacetone; Diethyl ketone; 3-Pentanone | 96-22-0 | C5H10O | 详情 | 详情 |
| (V) | 11387 | 2-Methylacrylaldehyde; Methacrylaldehyde | 78-85-3 | C4H6O | 详情 | 详情 |
| (VI) | 32416 | (4R,5R)-4,6-dimethyl-5-[(triethylsilyl)oxy]-6-hepten-3-one | C15H30O2Si | 详情 | 详情 | |
| (VII) | 14688 | 3-(benzyloxy)propanal | C10H12O2 | 详情 | 详情 | |
| (VIII) | 32417 | (3S,4S,5S,6S,7R)-1-(benzyloxy)-4,6,8-trimethyl-7-[(triethylsilyl)oxy]-8-nonene-3,5-diol | C25H44O4Si | 详情 | 详情 | |
| (IX) | 32418 | (3R,4R)-4-[(4R,5R,6S)-6-[2-(benzyloxy)ethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl]-2-methyl-1-penten-3-ol | C22H34O4 | 详情 | 详情 | |
| (X) | 32419 | (1R)-1-((1S)-1-[(4S,5R,6S)-6-[2-(benzyloxy)ethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl]ethyl)-2-methyl-2-propenyl butyrate | C26H40O5 | 详情 | 详情 | |
| (XI) | 32420 | (2S,4E,6R)-6-[(4R,5R,6S)-6-[2-(benzyloxy)ethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl]-2-ethyl-4-methyl-4-heptenoic acid | C26H40O5 | 详情 | 详情 | |
| (XII) | 35875 | (2S,4S,5S,6R)-6-[(4R,5R,6S)-6-[2-(benzyloxy)ethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl]-2-ethyl-4-methyl-1,5-heptanediol | C26H44O5 | 详情 | 详情 | |
| (XIII) | 32421 | (3S,5S,6S)-6-((1S)-1-[(4S,5R,6S)-6-[2-(benzyloxy)ethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl]ethyl)-3-ethyl-5-methyltetrahydro-2H-pyran-2-one | C26H40O5 | 详情 | 详情 | |
| (XIV) | 35876 | (2S,4S,5S,6R)-6-[(4R,5R,6S)-6-[2-(benzyloxy)ethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl]-2-ethyl-5-hydroxy-4-methylheptanamide | C26H43NO5 | 详情 | 详情 | |
| (XV) | 32422 | (2S,4S,5S,6R)-2-ethyl-5-hydroxy-6-[(4R,5R,6S)-6-(2-hydroxyethyl)-2,2,5-trimethyl-1,3-dioxan-4-yl]-4-methylheptanamide | C19H37NO5 | 详情 | 详情 | |
| (XVI) | 32423 | (2S,4S,6S)-2-ethyl-4-methyl-5-oxo-6-[(4S,5R,6S)-2,2,5-trimethyl-6-(2-oxoethyl)-1,3-dioxan-4-yl]heptanamide | C19H33NO5 | 详情 | 详情 | |
| (XVII) | 32424 | 2-[(2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-3,5,11-trimethyl-8-oxo-1-oxa-7-azaspiro[5.5]undec-2-yl]acetaldehyde | C16H27NO4 | 详情 | 详情 | |
| (XVIII) | 35877 | (2S,4S,6S)-6-[(4S,5R,6S)-6-[2-(benzyloxy)ethyl]-2,2,5-trimethyl-1,3-dioxan-4-yl]-2-ethyl-4-methyl-5-oxoheptanamide | C26H41NO5 | 详情 | 详情 | |
| (XIX) | 35878 | (2S,3R,4S,5S,6R,9S,11S)-9-ethyl-4-hydroxy-2-(2-hydroxyethyl)-3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one | C16H29NO4 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XIII)In one strategy, bromination of 4-ethoxyacetophenone (I) with Br2 yields 2-bromo-1-(4-ethoxyphenyl)ethanone (II) along with the byproduct 2-bromo-1-(3-bromo-4-ethoxyphenyl)ethanone, which are separated using HPLC. Alkylation of propionaldehyde N,N-diisobutylenamine (III) with bromo ketone (II) and subsequent ketalization with neopentyl glycol (IV) using p-TsOH·H2O and, optionally, H2SO4 in MeCN gives monoprotected ketoaldehyde (V) (1). Finally, cyclization of ketoaldehyde derivative (V) with 4-aminobenzenesulfonamide (VI) in the presence of AcOH in PrOH/H2O at 90-100 °C furnishes apricoxib (1, 2).
Intermediate (V) can also be prepared by reaction of 1-(4-ethoxyphenyl)-2-buten-1-one (VII) with CH3NO2 in the presence of DBU in THF to produce nitro ketone (VIII). Subsequent treatment of nitro derivative (VIII) with neopentyl glycol (IV) and NaOMe and MeOH gives acetal (V) (2).
In an alternative strategy, condensation of 4-ethoxyacetaldehyde (IX) with 4-sulfamoylaniline (VI) in refluxing EtOH furnishes N-(4-ethoxybenzylidene)-4-sulfamoylaniline (X), which then condenses with trimethylsilyl cyanide (XI) in the presence of ZnCl2 in THF yielding α-amino nitrile (XII). Cyclization of this compound with methacrolein (XIII) using LiHMDS in THF affords apricoxib (3). Scheme 1.
| 【1】 Kojima, S., Ooyama, J. (Daiichi Sankyo Co., Ltd.). Process for production of brominated acetophenone. WO 2008020617. |
| 【2】 Fujimoto, K., Takebayashi, T., Noguchi, Y., Saitou, T. (Daiichi Sankyo Co., Ltd.). Production of 4-methyl-1,2-diarylpyrrole and intermediate for synthesizing the same. JP 2000080078. |
| 【3】 Kimura, T., Noguchi, Y., Nakao, A., Suzuki, K., Ushiyama, S., Kawara, A., Miyamoto, M. (Daiichi Sankyo Co., Ltd.). 1,2-Diphenylpyrrole derivatives, their preparation and their therapeutic uses. CA 2201812, EP 0799823, JP 1997823971, US 5908858. |
| 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) | 66028 | 4'-Ethoxyacetophenone; 1-(4-Ethoxyphenyl)ethan-1-one | 1676-63-7 | C10H12O2 | 详情 | 详情 |
| (II) | 66029 | 2-Bromo-1-(4-Ethoxyphenyl)Ethanone; Zinc02649911 | 51012-63-6 | C10H11BrO2 | 详情 | 详情 |
| (III) | 66030 | 2-methyl-N-(2-methylpropyl)-N-prop-1-enylpropan-1-amine | 100334-82-5 | C11H23N | 详情 | 详情 |
| (IV) | 12641 | Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol | 126-30-7 | C5H12O2 | 详情 | 详情 |
| (V) | 66031 | C18H26O4 | 详情 | 详情 | ||
| (VI) | 54719 | 4-Aminobenzenesulfonamide; p-Aminobenzene sulfonyl amide; p-Aminobenzenesulfonamide; p-Anilinesulfonamide; Sulfanilamide | 63-74-1 | C6H8N2O2S | 详情 | 详情 |
| (VII) | 66032 | C12H14O2 | 详情 | 详情 | ||
| (VIII) | 66033 | C13H17NO4 | 详情 | 详情 | ||
| (IX) | 66034 | 4-Ethoxybenzaldehyde; p-Ethoxybenzaldehyde | 10031-82-0 | C9H10O2 | 详情 | 详情 |
| (X) | 66035 | C15H16N2O3S | 详情 | 详情 | ||
| (XI) | 61447 | Trimethylsilyl cyanide; Cyanotrimethylsilane; TMSCN; Trimethylsilyl carbonitrile; Trimethylsilylnitrile; Cyantrimethylsilan; Trimethylsilylnitrile; Cyanotrimethylsilane; TRIMETHYLSILYLCYANIDE; Cyanotrimethylsilane; (CYANOTRIMETHYLSILANE) | 7677-24-9 | C4H9NSi | 详情 | 详情 |
| (XII) | 66036 | C16H17N2O3S | 详情 | 详情 | ||
| (XIII) | 11387 | 2-Methylacrylaldehyde; Methacrylaldehyde | 78-85-3 | C4H6O | 详情 | 详情 |