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【结 构 式】

【分子编号】11136

【品名】3,4,5-Trimethoxybenzaldehyde

【CA登记号】86-81-7

【 分 子 式 】C10H12O4

【 分 子 量 】196.20288

【元素组成】C 61.22% H 6.16% O 32.62%
与该中间体有关的原料药合成路线共 15 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15

合成路线1

该中间体在本合成路线中的序号：(I)

Synthesis of intermediate 1,4-bis(3,4,5-trimethoxyphenyl)butane-1,4-dione (V). This compound can be obtained by three related methods: 1. The Grignard reaction of 3,4,5-trimethoxybenzaldehyde (I) with vinylmagnesium bromide (II), followed by oxidation with MnO2, gives 1-(3,4,5-trimethoxyphenyl)-2-propen-1-one (III), which is then condensed with aldehyde (I) by means of the thiazolium salt (IV) to yield the target intermediate (V). 2. The condensation of 3,4,5-trimethoxyacetophenone (VI) with methylamine and formaldehyde gives 3-(dimethylamino)-1-(3,4,5-trimethoxyphenyl)-1-propanone (VII), which is treated with methyl iodide at 80 C to afford the previously reported propenone intermediate (III). 3.The direct dimerization of acetophenone (VI) by means of LDA and CuCl2 also gives the target intermediate (V). Synthesis of the target compound: The reduction of the butanedione intermediate (V) with LiAlH4 or NaBH4 gives (RS,RS)-1,4-bis(3,4,5-trimethoxyphenyl)butane-2,3-diol (IX), which is dehydrated to the target tetrahydrofuran by means of TFA, PdCl2/Cu(NO3)2 or MsCl/pyridine. Alternatively, the reduction of butanedione (V) can be performed stepwise, first with LiAlH(O-tBu)3 to give the intermediate hydroxyketone (VIII), which is reduced to the diol (IX). The isolation of the intermediate hydroxyketone (VIII) allows the separation of enantiomers offering the possibility of obtaining chiral forms of the target tetrahydrofuran.

参考文献 中间体
合成目标
【1】 Doebber, T.W.; Beattie, T.R.; Shen, T.-Y.; Hwang, S.-B.; Biftu, T. (Merck & Co., Inc.); New 2,5-diaryl tetrahydrofurans and analogs thereof as PAF antagonists. AU 8656430; EP 0199324; ES 8801909; JP 1987000077 .
【2】 Biftu, T.; Chabala, J.C.; Acton, J.; Kuo, C.-H.; Stevenson, R.; 2,5-DIARYLTETRAHYDROFURANS: PAF ANTAGONISTS. Drugs Fut 1989, 14, 4, 359.
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) 11136 3,4,5-Trimethoxybenzaldehyde 86-81-7 C10H12O4 详情 详情
(II) 16524 bromo(vinyl)magnesium 1826-67-1 C2H3BrMg 详情 详情
(III) 27941 1-(3,4,5-trimethoxyphenyl)-2-propen-1-one C12H14O4 详情 详情
(IV) 44365 3,4-diethyl-5-(2-hydroxyethyl)-1,3-thiazol-3-ium bromide C9H16BrNOS 详情 详情
(V) 44387 1,4-bis(3,4,5-trimethoxyphenyl)-1,4-butanedione C22H26O8 详情 详情
(VI) 44362 1-(3,4,5-trimethoxyphenyl)-1-ethanone 1136-86-3 C11H14O4 详情 详情
(VII) 44363 3-(dimethylamino)-1-(3,4,5-trimethoxyphenyl)-1-propanone C14H21NO4 详情 详情
(VIII) 44388 4-hydroxy-1,4-bis(3,4,5-trimethoxyphenyl)-1-butanone C22H28O8 详情 详情
(IX) 44389 (1R,4R)-1,4-bis(3,4,5-trimethoxyphenyl)-1,4-butanediol C22H30O8 详情 详情

合成路线2

该中间体在本合成路线中的序号：(IV)

A total synthesis of gomisin A has been published: The asymetric hydrogenation of 2-(carboxymethyl)-3-[3-methoxy-4,5-(methylenedioxy)phenyl]-2(E)-propenoic acid methyl ester (I) gives the (S)-isomer of the saturated hemiester (II), which by reduction with calcium borohydride is converted into the lactone (III). The aldol condensation with 3,4,5-trimethoxybenzaldehyde (IV), followed by dehydration with acetic anhydride, affords the benzylidene-lactone (V). The biphenyl cyclization of (V) with ferric perchlorate in dichloromethane - trifluoroacetic acid yields the dibenzocyclooctene compound (VI) (and its regioisomer). The reduction of (VI) with dibutylaluminum hydride affords diol (VII), which is acetylated with acetic anhydride to the diacetate (VIII). The reaction of (VIII) with ammonium formate and paladium chloride-triphenylphosphine complex and then with NaOH gives the exo-methylene derivative (IX), which is epoxidized with OsO4 - methanesulfonyl chloride and NaH to the epoxide (X). Finally, this compound is deprotected and submitted to ring-opening with LiAlH4.

参考文献 中间体
合成目标
【1】 Mitsuhashi, H.; Wakamatsu, T.; Mukaiyama, C.; Tanaka, M.; Synthesis and optically pure gomisin A and schizandrin: The first total synthesis of gomisin A and schizandrin having naturally occurring configurations. Tetrahedron Lett 1992, 33, 29, 4165.
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) 11133 (E)-4-(7-Methoxy-1,3-benzodioxol-5-yl)-3-(methoxycarbonyl)-3-butenoic acid C14H14O7 详情 详情
(II) 11134 (3S)-4-Methoxy-3-[(7-methoxy-1,3-benzodioxol-5-yl)methyl]-4-oxobutyric acid C14H16O7 详情 详情
(III) 11135 (4S)-4-[(7-Methoxy-1,3-benzodioxol-5-yl)methyl]dihydro-2(3H)-furanone C13H14O5 详情 详情
(IV) 11136 3,4,5-Trimethoxybenzaldehyde 86-81-7 C10H12O4 详情 详情
(V) 11137 (4S)-4-[(7-Methoxy-1,3-benzodioxol-5-yl)methyl]-3-[(E)-(3,4,5-trimethoxyphenyl)methylidene]dihydro-2(3H)-furanone C23H24O8 详情 详情
(VI) 11138 (14aS)-6,7,8,9-Tetramethoxy-14,14a-dihydrobenzo[3,4]furo[3',4':6,7]cycloocta[1,2-f][1,3]benzodioxol-3(1H)-one C23H22O8 详情 详情
(VII) 11139 [(7S)-7-(Hydroxymethyl)-1,2,3,13-tetramethoxy-7,8-dihydrobenzo[3,4]cycloocta[1,2-f][1,3]benzodioxol-6-yl]methanol C23H26O8 详情 详情
(VIII) 11140 [(7S)-6-[(acetoxy)methyl]-1,2,3,13-tetramethoxy-7,8-dihydrobenzo[3,4]cycloocta[1,2-f][1,3]benzodioxol-7-yl]methyl acetate C27H30O10 详情 详情
(IX) 11141 [(7S)-1,2,3,13-Tetramethoxy-6-methylene-5,6,7,8-tetrahydrobenzo[3,4]cycloocta[1,2-f][1,3]benzodioxol-7-yl]methanol C23H26O7 详情 详情
(X) 11142 Methanesulfonic acid (6S,7R)-1,2,3,13-tetramethoxy-5,6,7,8-tetrahydrospiro[benzo[3,4]cycloocta[1,2-f][1,3]benzodioxole-6,2'-oxiran]-7-ylmethyl ester; Methanesulfonic acid (6S,7R)-1,2,3,13-tetramethoxy-5,6,7,8-tetrahydrospiro[benzo[3,4]cycloocta[1,2-f][1,3]benzodioxole-6,2'-oxiran]-7-yl methyl ester C24H28O10S 详情 详情

合成路线3

该中间体在本合成路线中的序号：(VII)

The O-silyl stilbene precursor (IV) was also synthesized by the Wittig reaction either between 3,4,5-trimethoxybenzaldehyde (VII) and the phosphonium salt (VIII) or between phosphonium bromide (IX) and 3-(tert-butyldimethylsilyloxy)-4-methoxybenzaldehyde (X), to furnish in both cases a mixture of the target Z-stilbene (IV) and its E-isomer (XI), which were separated by flash chromatography

参考文献 中间体
合成目标
【1】 Pettit, G.R.; Singh, S.B.; Boyd, M.R.; Hamel, E.; Pettit, R.K.; Schmidt, J.M.; Hogan, F.; Antineoplastic agents. 291. Isolation and synthesis of combretastatins A-4, A-5, and A-6. J Med Chem 1995, 38, 10, 1666.
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) 26118 tert-butyl[2-methoxy-5-[(E)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenoxy]dimethylsilane; tert-butyl(dimethyl)silyl 2-methoxy-5-[(E)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl ether C24H34O5Si 详情 详情
(VII) 11136 3,4,5-Trimethoxybenzaldehyde 86-81-7 C10H12O4 详情 详情
(VIII) 26117 (3-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzyl)(triphenyl)phosphonium bromide C32H38BrO2PSi 详情 详情
(IX) 19866 triphenyl(3,4,5-trimethoxybenzyl)phosphonium bromide C28H28BrO3P 详情 详情
(X) 26114 3-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzaldehyde C14H22O3Si 详情 详情
(XI) 60508 tert-butyl{2-methoxy-4-[(E)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenoxy}dimethylsilane; tert-butyl(dimethyl)silyl 2-methoxy-4-[(E)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl ether C24H34O5Si 详情 详情

合成路线4

该中间体在本合成路线中的序号：(VIII)

Heating p-fluorobenzaldehyde (I) with propionic anhydride (II) in the presence of sodium propionate affords methyl cinnamic acid derivative (III), which is then hydrogenated over Pd/C in EtOH to provide methyl hydrocinnamic acid derivative (IV). Ring closure of (IV) is then performed by heating with polyphosphoric acid to yield methylindanone derivative (V). Condensation of (V) with cyanoacetic acid (VI) by means of ammonium acetate and HOAc in refluxing toluene, followed by treatment with KOH in refluxing EtOH, provides acetic acid derivative (VII), which is then condensed with 3,4,5-trimethoxybenzaldehyde (VIII) by heating with NaOMe in MeOH to give substituted benzylidene derivative (IX). The target product can be finally obtained either by direct condensation of (IX) with benzylamine (XI) by means of DMAP and EDC in DMA or by first conversion of (IX) into the corresponding acetyl chloride by reaction with oxalyl chloride in refluxing THF, followed by coupling with benzylamine (XI) in CH2Cl2. Alternatively, the desired compound can also be obtained by coupling of acetic acid derivative (VII) with benzylamine (XI) by means of DMAP, EDC in DMA to afford N-benzyl acetamide derivative (XII), followed by condensation with 3,4,5-trimethoxybenzaldehyde (VIII) by heating with NaOMe in MeOH.

参考文献 中间体
合成目标
【1】 Sperl, G.; Gross, P.; Brendel, K.; Pamucku, R.; Piazza, G.A. (University of Arizona); Substd. benzylidene indenyl formamides, acetamides and propionamides. WO 9747303 .
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) 12337 4-fluorobenzaldehyde 459-57-4 C7H5FO 详情 详情
(II) 20095 propionic anhydride 123-62-6 C6H10O3 详情 详情
(III) 48870 (Z)-3-(4-fluorophenyl)-2-methyl-2-propenoic acid C10H9FO2 详情 详情
(IV) 48871 3-(4-fluorophenyl)-2-methylpropionic acid C10H11FO2 详情 详情
(V) 48872 6-Fluoro-2-methylindanone C10H9FO 详情 详情
(VI) 48873 2-Oxopropionitrile; Acetylcyanide; Pyruvonitrile C3H3NO 详情 详情
(VII) 48874 2-(5-fluoro-2-methyl-1H-inden-3-yl)acetic acid C12H11FO2 详情 详情
(VIII) 11136 3,4,5-Trimethoxybenzaldehyde 86-81-7 C10H12O4 详情 详情
(IX) 48875 2-[5-fluoro-2-methyl-1-[(E)-(3,4,5-trimethoxyphenyl)methylidene]-1H-inden-3-yl]acetic acid C22H21FO5 详情 详情
(X) 48876 2-[5-fluoro-2-methyl-1-[(E)-(3,4,5-trimethoxyphenyl)methylidene]-1H-inden-3-yl]acetyl chloride C22H20ClFO4 详情 详情
(XI) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(XII) 48877 N-benzyl-2-(5-fluoro-2-methyl-1H-inden-3-yl)acetamide C19H18FNO 详情 详情

合成路线5

该中间体在本合成路线中的序号：(IX)

Protection of 3,4,5-trimethoxybenzaldehyde (IX) with ethylene glycol (X) affords acetal (XI). After lithiation of (XI) by means of butyllithium, addition to veratraldehyde (XII) furnishes carbinol (XIII). Finally, cyclization of hydroxy acetal (XIII) with alkyne (VIII) under acidic conditions provides the title naphthol derivative.

参考文献 中间体
合成目标
【1】 Mori, S.; Takechi, S.; Kida, S.; Mizui, T.; Ichihashi, T. (Shionogi & Co. Ltd.); Lignan analog, production thereof, and hypolipidemic drug. EP 0597107; EP 0701991; JP 1993310634; US 5731455; WO 9308155 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 57432 methyl 6-ethyl-4-oxo-2-octynoate C11H16O3 详情 详情
(IX) 11136 3,4,5-Trimethoxybenzaldehyde 86-81-7 C10H12O4 详情 详情
(X) 11295 Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol 107-21-1 C2H6O2 详情 详情
(XI) 57434 2-(3,4,5-trimethoxyphenyl)-1,3-dioxolane; 4-(1,3-dioxolan-2-yl)-2,6-dimethoxyphenyl methyl ether C12H16O5 详情 详情
(XII) 18304 3,4-Dimethoxybenzaldehyde; Veratraldehyde 120-14-9 C9H10O3 详情 详情
(XIII) 57435 (3,4-dimethoxyphenyl)[6-(1,3-dioxolan-2-yl)-2,3,4-trimethoxyphenyl]methanol C21H26O8 详情 详情

合成路线6

该中间体在本合成路线中的序号：(I)

Addition of ethylmagnesium bromide to 3,4,5-trimethoxybenzaldehyde (I) gave secondary alcohol (II), which was converted into ketone (III) by Swern oxidation with DMSO and oxalyl chloride. Piperidinium acetate-catalyzed aldol condensation of propiophenone (III) with 3-hydroxy-4-methoxybenzaldehyde (IV), with water removal over 4 Å molecular sieves, gave the corresponding chalcone, obtained as a mixture of geometric isomers, from which the major E-isomer was separated by column chromatography.

参考文献 中间体
合成目标
【1】 Ducki, S.; Forrest, R.; Hadfield, J.A.; Kendall, A.; Lawrence, N.J.; McGown, A.T.; Rennison, D.; Potent antimitotic and cell growth inhibitory properties of substituted chalcones. Bioorg Med Chem Lett 1998, 8, 9, 1051.
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) 11136 3,4,5-Trimethoxybenzaldehyde 86-81-7 C10H12O4 详情 详情
(II) 18453 1-(3,4,5-trimethoxyphenyl)-1-propanol C12H18O4 详情 详情
(III) 18454 1-(3,4,5-trimethoxyphenyl)-1-propanone C12H16O4 详情 详情
(IV) 18455 3-hydroxy-4-methoxybenzaldehyde; Isovanillin 621-59-0 C8H8O3 详情 详情

合成路线7

该中间体在本合成路线中的序号：(I)

Reduction of 3,4,5-trimethoxybenzaldehyde (I) with NaBH4 provided benzyl alcohol (II). After conversion of (II) to the benzyl chloride (III) using SOCl2, its reaction with PPh3 (IV) in refluxing xylene afforded phosphonium salt (V). Subsequent Wittig reaction of the corresponding ylide with 4,4-(ethylenedioxy)cyclohexanone (VI) produced the benzylidene derivative (VII), which was reduced to benzyl compound (VIII) by catalytic hydrogenation over Pd/C. The ketal protecting group of (VIII) was then removed by acid hydrolysis to yield cyclohexanone (IX). Finally, the target tetrahydroquinazoline was obtained by condensation of (IX) with cyanoguanidine (X) at 180 C.

参考文献 中间体
合成目标
【1】 Papoulis, A.T.; Queener, S.F.; Rosowsky, A.; Forsch, R.A.; Synthesis and antiparasitic and antitumor activity. J Med Chem 1999, 42, 6, 1007.
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) 11136 3,4,5-Trimethoxybenzaldehyde 86-81-7 C10H12O4 详情 详情
(II) 23613 (3,4,5-trimethoxyphenyl)methanol 3840-31-1 C10H14O4 详情 详情
(III) 14072 3,4,5-Trimethoxybenzyl chloride; 5-(Chloromethyl)-1,2,3-trimethoxybenzene; 4-(Chloromethyl)-2,6-dimethoxyphenyl methyl ether 3840-30-0 C10H13ClO3 详情 详情
(IV) 23605 trimethylphosphine 594-09-2 C3H9P 详情 详情
(V) 23615 triphenyl(3,4,5-trimethoxybenzyl)phosphonium C28H28O3P 详情 详情
(VI) 11377 1,4-Dioxaspiro[4.5]decan-8-one 4746-97-8 C8H12O3 详情 详情
(VII) 23616 4-(1,4-dioxaspiro[4.5]dec-8-ylidenemethyl)-2,6-dimethoxyphenyl methyl ether; 8-(3,4,5-trimethoxybenzylidene)-1,4-dioxaspiro[4.5]decane C18H24O5 详情 详情
(VIII) 23617 4-(1,4-dioxaspiro[4.5]dec-8-ylmethyl)-2,6-dimethoxyphenyl methyl ether; 8-(3,4,5-trimethoxybenzyl)-1,4-dioxaspiro[4.5]decane C18H26O5 详情 详情
(IX) 23618 4-(3,4,5-trimethoxybenzyl)cyclohexanone C16H22O4 详情 详情
(X) 23611 N-cyanoguanidine 461-58-5 C2H4N4 详情 详情

合成路线8

该中间体在本合成路线中的序号：(VI)

The acetylation of 2-(4-aminophenyl)acetic acid (I) with acetic anhydride, followed by nitration with nitric acid in acetic acid and treatment with HCl in ethanol gives 2-(4-amino-3-nitrophenyl)acetic acid ethyl ester (II), which is reduced at the nitro group, and cyclized with SOCl2 yielding the benzothiadiazole (III). The condensation of (III) with 3-fluoro-4-methoxyphenacyl bromide (IV) by means of potassium tert-butoxide affords the 4-oxobutyrate (V), which is condensed with 3,4,5-trimethoxybenzaldehyde (VI) by means of sodium methopxide in methanol to provide the the dihydrofuranone (VII). Finally, this compound is treated with NaOH in methanol to promote the opening of the lactone ring yielding the target compound.

参考文献 中间体
合成目标
【1】 Mederski, W.W.K.R.; Osswald, M.; Dorsch, D.; Anzali, S.; Christadler, M.; Schmitges, C.J.; Wilm, C.; Endothelin antagonists: Evaluation of 2,1, 3-benzothiadiazole as a methylendioxyphenyl bioisoster. Bioorg Med Chem Lett 1998, 8, 1, 17.
【2】 Mederski, W.W.K.R.; Dorsch, D.; Osswald, M.; Anzali, S.; Christadler, M.; Schmitges, C.J.; Schelling, P.; Wilm, C.; Fluck, M.; 3. Endothelin antagonists: Discovery of EMD 122946, a highly potent and orally active ETA selective antagonist. Bioorg Med Chem Lett 1998, 8, 13, 1771.
【3】 Dorsch, D.; Osswald, M.; Mederski, W.; Wilm, C.; Schmitges, C.; Christadler, M.; Anzali, S. (Merck Patent GmbH); 2,1,3-Benzothia(oxa)diazole derivs. having an endothelin receptor antagonistic effect. DE 19607096; EP 0882030; WO 9730982 .
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) 21229 2-(4-Aminophenyl)acetic acid 5345-54-0 C8H9NO2 详情 详情
(II) 26095 ethyl 2-(4-amino-3-nitrophenyl)acetate C10H12N2O4 详情 详情
(III) 26096 ethyl 2-(2,1,3-benzothiadiazol-5-yl)acetate C10H10N2O2S 详情 详情
(IV) 26097 2-bromo-1-(3-fluoro-4-methoxyphenyl)-1-ethanone C9H8BrFO2 详情 详情
(V) 26098 ethyl 2-(2,1,3-benzothiadiazol-5-yl)-4-(3-fluoro-4-methoxyphenyl)-4-oxobutanoate C19H17FN2O4S 详情 详情
(VI) 11136 3,4,5-Trimethoxybenzaldehyde 86-81-7 C10H12O4 详情 详情
(VII) 26099 3-(2,1,3-benzothiadiazol-5-yl)-5-(3-fluoro-4-methoxyphenyl)-5-hydroxy-4-(3,4,5-trimethoxybenzyl)-2(5H)-furanone C27H23FN2O7S 详情 详情

合成路线9

该中间体在本合成路线中的序号：(VI)

Isovanillin (I) was protected as the silyl ether (II) and subsequently reduced to the benzyl alcohol (III). After conversion of (III) to bromide (IV), its reaction with triphenylphosphine gave phosphonium bromide (V). The ylide resulting from deprotonation of (V) with n-butyllithium was then condensed with 3,4,5-trimethoxybenzaldehyde (VI) to afford the required E-stilbene (VII) along with the corresponding Z-isomer, which were separated by column chromatography. Asymmetric Sharpless dihydroxylation of (VII) by means of AD mix-alpha provided the (1S,2S)-diol (VIII). Finally, desilylation of (VIII) using tetrabutylammonium fluoride afforded the target phenol.

参考文献 中间体
合成目标
【1】 Pettit, G.R.; Singh, S.B.; Boyd, M.R.; Hamel, E.; Pettit, R.K.; Schmidt, J.M.; Hogan, F.; Antineoplastic agents. 291. Isolation and synthesis of combretastatins A-4, A-5, and A-6. J Med Chem 1995, 38, 10, 1666.
【2】 Pettit, G.R.; et al.; Antineoplastic agents. 410. Asymmetric hydroxylation of trans-combretastatin A-4. J Med Chem 1999, 42, 8, 1459.
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) 18455 3-hydroxy-4-methoxybenzaldehyde; Isovanillin 621-59-0 C8H8O3 详情 详情
(II) 26114 3-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzaldehyde C14H22O3Si 详情 详情
(III) 26115 (3-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)methanol C14H24O3Si 详情 详情
(IV) 26116 4-(bromomethyl)-2-[[tert-butyl(dimethyl)silyl]oxy]phenyl methyl ether; [5-(bromomethyl)-2-methoxyphenoxy](tert-butyl)dimethylsilane C14H23BrO2Si 详情 详情
(V) 26117 (3-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzyl)(triphenyl)phosphonium bromide C32H38BrO2PSi 详情 详情
(VI) 11136 3,4,5-Trimethoxybenzaldehyde 86-81-7 C10H12O4 详情 详情
(VII) 26118 tert-butyl[2-methoxy-5-[(E)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenoxy]dimethylsilane; tert-butyl(dimethyl)silyl 2-methoxy-5-[(E)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl ether C24H34O5Si 详情 详情
(VIII) 26119 (1S,2S)-1-(3-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-1,2-ethanediol C24H36O7Si 详情 详情

合成路线10

该中间体在本合成路线中的序号：(XVIII)

In a related procedure, iodination of acetophenone (XI) gave (XII). Subsequent alkylation of (XII) with dibromoethane afforded bromoethyl ether (XIII), which was converted to sulfide (XIV) by condensation with 4-chlorothiophenol (IX). Mannich reaction of (XIV) with paraformaldehyde and dimethylamine hydrochloride produced tertiary amine (XV), which was quaternized to (XVI) with MeI. Elimination in the resulting ammonium salt (XVI) produced vinyl ketone (XVII). Diketone (XIX) was then obtained by condensation with trimethoxybenzaldehyde (XVIII) in the presence of thiazolium salt (IV). Reduction of both ketone groups of (XIX) using NaBH4 yielded diol (XX), which was further cyclized with orthophosphoric acid in refluxing benzene to furnish a diastereomeric mixture of cis and trans diaryltetrahydrofurans (XXI). Iodine displacement in (XXI) with CuCN produced the corresponding diastereomeric mixture of cyanides, from which the target trans isomer was isolated by column chromatography.

参考文献 中间体
合成目标
【1】 Ram, B.; et al.; (±)-Trans-2-[3-methoxy-4-(4-chlorophenyl thioethoxy)-5-cyanophenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran, a potent PAF-receptor antagonist. Tetrahedron 1999, 55, 33, 10163.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10252 1,2-Dibromoethane; Ethylene dibromide 106-93-4 C2H4Br2 详情 详情
(IV) 27942 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride 4568-71-2 C13H16ClNOS 详情 详情
(IX) 27947 4-chlorobenzenethiol 106-54-7 C6H5ClS 详情 详情
(XI) 22604 1-(4-hydroxy-3-methoxyphenyl)-1-ethanone；Acetovanillone;4’-hydroxy-3’-methoxyacetophenone;1-(4-hydroxy-3-methoxyphenyl)ethanone 498-02-2 C9H10O3 详情 详情
(XII) 27949 1-(4-hydroxy-3-iodo-5-methoxyphenyl)-1-ethanone C9H9IO3 详情 详情
(XIII) 27950 1-[4-(2-bromoethoxy)-3-iodo-5-methoxyphenyl]-1-ethanone C11H12BrIO3 详情 详情
(XIV) 27951 1-(4-[2-[(4-chlorophenyl)sulfanyl]ethoxy]-3-iodo-5-methoxyphenyl)-1-ethanone C17H16ClIO3S 详情 详情
(XV) 27952 1-(4-[2-[(4-chlorophenyl)sulfanyl]ethoxy]-3-iodo-5-methoxyphenyl)-3-(dimethylamino)-1-propanone C20H23ClINO3S 详情 详情
(XVI) 27953 3-(4-[2-[(4-chlorophenyl)sulfanyl]ethoxy]-3-iodo-5-methoxyphenyl)-N,N,N-trimethyl-3-oxo-1-propanaminium iodide C21H26ClI2NO3S 详情 详情
(XVII) 27954 1-(4-[2-[(4-chlorophenyl)sulfanyl]ethoxy]-3-iodo-5-methoxyphenyl)-2-propen-1-one C18H16ClIO3S 详情 详情
(XVIII) 11136 3,4,5-Trimethoxybenzaldehyde 86-81-7 C10H12O4 详情 详情
(XIX) 27955 1-(4-[2-[(4-chlorophenyl)sulfanyl]ethoxy]-3-iodo-5-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione C28H28ClIO7S 详情 详情
(XX) 27956 1-(4-[2-[(4-chlorophenyl)sulfanyl]ethoxy]-3-iodo-5-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanediol C28H32ClIO7S 详情 详情
(XXI) 27957 2-(4-[2-[(4-chlorophenyl)sulfanyl]ethoxy]-3-iodo-5-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran C28H30ClIO6S 详情 详情

合成路线11

该中间体在本合成路线中的序号：(IV)

Condensation of 3-methoxysalicylaldehyde (I) with cyanoacetamide (II) in the presence of piperidine gave rise to the carbamoyl iminochromene (III). Subsequent condensation of (III) with 3,4,5-trimethoxybenzaldehyde furnished the title compound.

参考文献 中间体
合成目标
【1】 Perry, P.J.; McGown, A.T.; Pavlidis, V.H.; Hadfield, J.A.; Synthesis and anticancer activities of 4-oxobenzopyrano[2,3-d]pyrimidines. Anti-Cancer Drugs 1999, 10, 6, 591.
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) 12620 o-Vanillin; 2-Hydroxy-3-methoxybenzaldehyde 148-53-8 C8H8O3 详情 详情
(II) 12122 Cyanoacetamide; 2-Cyanoacetamide 107-91-5 C3H4N2O 详情 详情
(III) 38139 2-imino-8-methoxy-2H-chromene-3-carboxamide C11H10N2O3 详情 详情
(IV) 11136 3,4,5-Trimethoxybenzaldehyde 86-81-7 C10H12O4 详情 详情

合成路线12

该中间体在本合成路线中的序号：(I)

The condensation between 3,4,5-trimethoxybenzaldehyde (I), 4-methylbenzenesulfinic acid (II) and formamide in the presence of camphorsulfonic acid gave tosyl-(3,4,5-trimethoxyphenyl)methylformamide (III), which was subsequently dehydrated to the isonitrile (IV) by treatment with POCl3 and Et3N. After conversion of 4-methoxy-3-nitrobenzaldehyde (V) to the corresponding imine with methylamine, its reaction with the tosylmethyl isonitrile (IV) gave rise to the diaryl imidazole (VI). The nitro group of (VI) was finally reduced to amine by using SnCl2 and HCl or ammonium formiate and Pd/C

参考文献 中间体
合成目标
【1】 Wang, L.; Woods, K.W.; Li, Q.; Barr, K.J.; McCroskey, R.M.; Hannick, S.M.; Gherke, L.; Credo, R.B.; Hui, Y.H.; Marsch, K.; Warner, R.; Lee, J.Y.; Zielinski-Mozng, N.; Frost, D.; Rosenberg, S.H.; Sham, H.L.; Potent, orally active heterocycle-based combretastatin A-4 analogues: Synthesis, structure-activity relationship, pharmacokinetics, and in vivo antitumor activity evaluation. J Med Chem 2002, 45, 8, 1697.
【2】 Wang, L.; Woods, K.W.; Li, Q.; Sham, H.L. (Abbott Laboratories Inc.); Imidazole antiproliferative agents. WO 0109103 .
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) 11136 3,4,5-Trimethoxybenzaldehyde 86-81-7 C10H12O4 详情 详情
(II) 25593 4-methylbenzenesulfinic acid C7H8O2S 详情 详情
(III) 49071 [(4-methylphenyl)sulfonyl](3,4,5-trimethoxyphenyl)methylformamide C18H21NO6S 详情 详情
(IV) 49072 2-[(4-methylphenyl)sulfonyl]-2-(3,4,5-trimethoxyphenyl)acetonitrile C18H19NO5S 详情 详情
(V) 18225 4-METHOXY-3-NITROBENZALDEHYDE 31680-08-7 C8H7NO4 详情 详情
(VI) 49073 2,3-dimethoxy-5-[5-(4-methoxy-3-nitrophenyl)-1-methyl-1H-imidazol-4-yl]phenyl methyl ether; 5-(4-methoxy-3-nitrophenyl)-1-methyl-4-(3,4,5-trimethoxyphenyl)-1H-imidazole C20H21N3O6 详情 详情

合成路线13

该中间体在本合成路线中的序号：(I)

Condensation of 3,4,5-trimethoxybenzaldehyde (I) with nitromethane in the presence of KOH produced the nitro alcohol (II), which was subsequently hydrogenated over Pd/C to afford amino alcohol (III). Acylation of (III) with 5-indolecarboxylic acid (IV) gave the corresponding amide (V). Oxazoline (VI) was then obtained by cyclization of (V) in the presence of Burgess reagent. Finally, N-methylation of the indole ring with MeI and KOH furnished the title compound.

参考文献 中间体
合成目标
【1】 Liu, G.; Jae, H.-S.; Szczepankiewicz, B.G.; et al.; New antimitotic agents with activity in multi-drug-resistant cell lines and in vivo efficacy in murine tumor models. J Med Chem 2001, 44, 25, 4416.
【2】 Woods, K.W.; Wang, L.; Kalvin, D.M.; Barr, K.J.; Li, Q.; Liu, G.; Gwaltney, S.L. II; Claiborne, A.K.; Jae, H.-S.; Sham, H.L. (Abbott Laboratories Inc.); Substd. oxazolines as antiproliferative agents. WO 0006556 .
【3】 Sham, H.L.; Jae, H.-S.; Li, Q.; Wang, L.; Woods, K.W.; Liu, G.; Barr, K.J.; Kalvin, D.M.; Gwaltney, S.L. II; Claiborne, A.K. (Abbott Laboratories Inc.); Oxazoline antiproliferative agents. US 6228868 .
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) 11136 3,4,5-Trimethoxybenzaldehyde 86-81-7 C10H12O4 详情 详情
(II) 48616 2-nitro-1-(3,4,5-trimethoxyphenyl)-1-ethanol C11H15NO6 详情 详情
(III) 48617 2-amino-1-(3,4,5-trimethoxyphenyl)-1-ethanol C11H17NO4 详情 详情
(IV) 48618 Indole-5-carboxylic acid 1670-81-1 C9H7NO2 详情 详情
(V) 48619 N-[2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-1H-indole-5-carboxamide C20H22N2O5 详情 详情
(VI) 48620 5-[5-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1,3-oxazol-2-yl]-1H-indole; 4-[2-(1H-indol-5-yl)-4,5-dihydro-1,3-oxazol-5-yl]-2,6-dimethoxyphenyl methyl ether C20H20N2O4 详情 详情

合成路线14

该中间体在本合成路线中的序号：(I)

By heating a mixture of 3,4,5-trimethoxybenzaldehyde (I), tetrahydro-1,4-oxazine (II) and precipitated sulfur, at 140 C

参考文献 中间体
合成目标
【1】 Banfi, S.; et al.; Research on 3,4,5-trimethoxy-benzamides. Note III. Synthesis and CNS depressant activity of new alkoxythiobenzamides. Chim Ther 1973, 4, 3, 462.
【2】 Castaner, J.; de Angelis, L.; Trithiozine. Drugs Fut 1976, 1, 8, 397.
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) 11136 3,4,5-Trimethoxybenzaldehyde 86-81-7 C10H12O4 详情 详情
(II) 10388 Morpholine 110-91-8 C4H9NO 详情 详情

合成路线15

该中间体在本合成路线中的序号：(I)

The condensation of 3,4,5-trimethoxybenzaldehyde (I) with 4-methylphenylsulfinic acid (II) and formamide by means of hot CSA gives the adduct (III), which is treated with POCl3 in DME to yield the isonitrile (IV). The reaction of benzaldehyde (V) with methylamine and AcOH in refluxing ethanol gives the enamine (VI), which is finally cyclized with isonitrile (IV) by means of K2CO3 in ethanol/DME to afford the target 1-methylimidazole.

参考文献 中间体
合成目标
【1】 Wang, L.; Woods, K.W.; Li, Q.; Barr, K.J.; McCroskey, R.M.; Hannick, S.M.; Gherke, L.; Credo, R.B.; Hui, Y.H.; Marsch, K.; Warner, R.; Lee, J.Y.; Zielinski-Mozng, N.; Frost, D.; Rosenberg, S.H.; Sham, H.L.; Potent, orally active heterocycle-based combretastatin A-4 analogues: Synthesis, structure-activity relationship, pharmacokinetics, and in vivo antitumor activity evaluation. J Med Chem 2002, 45, 8, 1697.
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) 11136 3,4,5-Trimethoxybenzaldehyde 86-81-7 C10H12O4 详情 详情
(II) 25593 4-methylbenzenesulfinic acid C7H8O2S 详情 详情
(III) 49071 [(4-methylphenyl)sulfonyl](3,4,5-trimethoxyphenyl)methylformamide C18H21NO6S 详情 详情
(IV) 49072 2-[(4-methylphenyl)sulfonyl]-2-(3,4,5-trimethoxyphenyl)acetonitrile C18H19NO5S 详情 详情
(V) 63173 3,4-bis[(E)-2-(methylamino)ethenyl]benzaldehyde C13H16N2O 详情 详情
(VI) 63174 (E)-N-methyl-2-{2-[(E)-2-(methylamino)ethenyl]-4-[(methylamino)methyl]phenyl}-1-ethenamine; N-{3,4-bis[(E)-2-(methylamino)ethenyl]benzyl}-N-methylamine C14H21N3 详情 详情
Extended Information