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【结 构 式】 
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【分子编号】19711 【品名】1H-pyrrole-2,5-dione 【CA登记号】541-59-3 |
【 分 子 式 】C4H3NO2 【 分 子 量 】97.07336 【元素组成】C 49.49% H 3.11% N 14.43% O 32.96% |
合成路线1
该中间体在本合成路线中的序号：(V)Reaction of 1,3,5,7-cyclooctatetraene (I) with maleimide (Step a, b), or maleic anhydride (Step c), in refluxing toluene affords the imide (II) or the anhydride (III) in 78 and 85% yields, respectively. Reaction of imide intermediate (II) with 1,4-dibromobutane gives the omega-haloalkylimide, which subsequently is reacted with 1-(2-pyrimidinyl)piperazine to yield Wy-47846 (Method A). Alternatively, Wy-47846 can be prepared via the reaction of (III) with 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine in refluxing pyridine (Method B), as shown in scheme. Wy-47846 is achiral.
| 【2】 Abou-Gharbia, M.; Moyer, J.A.; Haskins, J.T.; WY-47846. Drugs Fut 1989, 14, 5, 442. |
| 【1】 Abou-Gharbia, M.; et al.; Polycyclic aryl- and heteroarylpiperazyl imides as 5-HT1A receptor ligands and potential anxiolytic agents: synthesis and structure-activity relationship studies. J Med Chem 1988, 31, 7, 1382. |
| 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) | 20923 | 1,3,5,7-cyclooctatetraene | 629-20-9 | C8H8 | 详情 | 详情 |
| (II) | 20924 | bicyclo[4.2.0]octa-2,4-diene | C8H10 | 详情 | 详情 | |
| (III) | 20925 | (2R,6S,8R,11S)-4-azatetracyclo[5.4.2.0(2,6).0(8,11)]trideca-9,12-diene-3,5-dione | C12H11NO2 | 详情 | 详情 | |
| (IV) | 20926 | (2R,6S,8R,11S)-4-oxatetracyclo[5.4.2.0(2,6).0(8,11)]trideca-9,12-diene-3,5-dione | C12H10O3 | 详情 | 详情 | |
| (V) | 19711 | 1H-pyrrole-2,5-dione | 541-59-3 | C4H3NO2 | 详情 | 详情 |
| (VI) | 11182 | 2,5-Furandione; Maleic anhydride | 108-31-6 | C4H2O3 | 详情 | 详情 |
| (VII) | 11883 | 1,4-Dibromobutane; 1,4-Butylene bromide | 110-52-1 | C4H8Br2 | 详情 | 详情 |
| (VIII) | 11175 | 2-(1-Piperazinyl)pyrimidine; 2-Piperazinopyrimidine; N-(Pyrimidinyl)piperazine | 20980-22-7 | C8H12N4 | 详情 | 详情 |
| (IX) | 11181 | 4-[4-(2-Pyrimidinyl)piperazino]butylamine; 4-[4-(2-Pyrimidinyl)piperazino]-1-butanamine | 33386-20-8 | C12H21N5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XV)The Diels-Alder cyclization of 1-acetoxy-1,3-butadiene (XIV) with maleimide (XV) in toluene at 80 C gives racemic (3aRS,4RS,7aSR)-4-acetoxy-2,3,3a,4,7,7a-hexahydro-1H-isoindole-1,3-dione (XVI), which is reduced with LiAlH4 in THF to the racemic alcohol (XVII). Optical resolution of (XVII) with Di-p-toluoyl-L-tartaric acid in THF/ethanol/ /water yields the (3aS,4S,7aR)-isomer (XVIII), which is N-protected with tert-butoxycarbonyl anhydride to the protected compound (XIX). The Oppenauer oxidation of (XIX) catalized by aluminum isopropoxide affords the unsaturated ketone (XX), which is condensed with cyanacetic acid (XXI) by means of NaOH in toluene/water to afford the substituted cyanacetic derivative (XXII). The decarboxylation of (XXII) catalized by Cu2O in refluxing acetonitrile gives the suitably substituted ketone (XXIII), which is submitted to a Grignard condensation with 2-methoxy-phenylmagnesium bromide (XXIV) in THF yielding the alcohol (XXV) as a single isomer. The deprotection of (XXV) with HCl in THF affords compound (XXVI) with a free NH group, which is finally acylated with 2(S)-(2-methoxyphenyl)propionic acid (II) by means of SOCl2 and K2CO3 to obtain RPR-111905.
| 【1】 Mutti, S.; et al.; Practical enantiospecific synthesis of RPR 111905: A novel non-peptide substance P antagonist. Tetrahedron Lett 1996, 37, 48, 8743. |
| 【2】 Achard, D.; Peyronel, J.-F.; Tabart, M. (Aventis Pharma SA); Perhydroisoindole derivs. as antagonists of substance P. FR 2727411; JP 1998509970; US 5739351; WO 9616939 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 19710 | (1E)-1,3-butadienyl acetate | 1515-76-0 | C6H8O2 | 详情 | 详情 |
| (XV) | 19711 | 1H-pyrrole-2,5-dione | 541-59-3 | C4H3NO2 | 详情 | 详情 |
| (XVI) | 19712 | (3aR,4S,7aR)-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-yl acetate | C10H11NO4 | 详情 | 详情 | |
| (XVII) | 19713 | (3aS,4S,7aR)-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-ol | C8H13NO | 详情 | 详情 | |
| (XIX) | 19715 | tert-butyl (3aS,4S,7aR)-4-hydroxy-1,3,3a,4,7,7a-hexahydro-2H-isoindole-2-carboxylate | C13H23NO3 | 详情 | 详情 | |
| (XX) | 19716 | tert-butyl (3aS,7aR)-4-oxo-1,3,3a,4,7,7a-hexahydro-2H-isoindole-2-carboxylate | C13H19NO3 | 详情 | 详情 | |
| (XXII) | 19718 | (2S)-2-[(3aR,5R,7aS)-2-(tert-butoxycarbonyl)-7-oxooctahydro-1H-isoindol-5-yl]-2-cyanoethanoic acid | C16H22N2O5 | 详情 | 详情 | |
| (XXIII) | 19719 | tert-butyl (3aS,6S,7aR)-6-(cyanomethyl)-4-oxooctahydro-2H-isoindole-2-carboxylate | C15H22N2O3 | 详情 | 详情 | |
| (XXV) | 19721 | tert-butyl (3aS,4S,6S,7aR)-6-(cyanomethyl)-4-hydroxy-4-(2-methoxyphenyl)octahydro-2H-isoindole-2-carboxylate | C22H30N2O4 | 详情 | 详情 | |
| (XXVI) | 19722 | 2-[(3aR,5S,7S,7aS)-7-hydroxy-7-(2-methoxyphenyl)octahydro-1H-isoindol-5-yl]acetonitrile | C17H22N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Maleimide (I) was brominated in the presence of benzoyl peroxide to give 3,4-dibromomaleimide (II). Alkylation of (II) with 4-(tert-butyl)benzyl bromide (III) in the presence of potassium carbonate afforded the N-(tert-butylbenzyl) derivative (IV). Coupling of the dibromomaleimide (IV) with the indolylmagnesium iodide resulting from 5-fluoroindole (V) and MeMgI furnished the bis-indolyl maleimide (VI). Oxidative cyclization of (VI) using dicyanodichlorobenzoquinone yielded the target indolopyrrolocarbazole system (VIII). Glycosylation of (VIII) with the protected fluoro glucose derivative (VIII) under Mitsunobu conditions afforded adduct (IX). The O-benzyl protecting groups were then removed by transfer hydrogenation with cyclohexene and Pd(OH)2 to give (X). The tert-butylbenzyl group was finally removed by basic hydrolysis followed by recyclization with fused ammonium acetate.
| 【1】 Saulnier, M.G.; Balasubramanian, N.; Frennesson, D.B.; St. Laurent, D.R.; Langley, D.R. (Bristol-Myers Squibb Co.); Cytotoxic amino sugar and related sugar derivs. of indolopyrrolocarbazoles. EP 0971717; JP 2000516250; WO 9807433 . |
| 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) | 19711 | 1H-pyrrole-2,5-dione | 541-59-3 | C4H3NO2 | 详情 | 详情 |
| (II) | 48178 | 3,4-dibromo-1H-pyrrole-2,5-dione | C4HBr2NO2 | 详情 | 详情 | |
| (III) | 20588 | 1-(bromomethyl)-4-(tert-butyl)benzene | 18880-00-7 | C11H15Br | 详情 | 详情 |
| (IV) | 48179 | 3,4-dibromo-1-[4-(tert-butyl)benzyl]-1H-pyrrole-2,5-dione | C15H15Br2NO2 | 详情 | 详情 | |
| (V) | 32388 | 5-Fluoroindole; 5-Fluoro-1H-indole | 399-52-0 | C8H6FN | 详情 | 详情 |
| (VI) | 48180 | 1-[4-(tert-butyl)benzyl]-3,4-bis(5-fluoro-1H-indol-3-yl)-1H-pyrrole-2,5-dione | C31H25F2N3O2 | 详情 | 详情 | |
| (VII) | 48181 | 6-[4-(tert-butyl)benzyl]-3,9-difluoro-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione | C31H23F2N3O2 | 详情 | 详情 | |
| (VIII) | 48182 | (3R,4R,5S,6R)-3,4-bis(benzyloxy)-6-[(benzyloxy)methyl]-5-fluorotetrahydro-2H-pyran-2-ol | C27H29FO5 | 详情 | 详情 | |
| (IX) | 48183 | 12-[(2R,3R,4R,5S,6R)-3,4-bis(benzyloxy)-6-[(benzyloxy)methyl]-5-fluorotetrahydro-2H-pyran-2-yl]-6-[4-(tert-butyl)benzyl]-3,9-difluoro-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione | C58H50F3N3O6 | 详情 | 详情 | |
| (X) | 48184 | 6-[4-(tert-butyl)benzyl]-3,9-difluoro-12-[(2R,3R,4R,5S,6R)-5-fluoro-3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione | C37H32F3N3O6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)Indole (I) is protected as the indole N-carboxylate (II) by treatment of its lithio derivative with carbon dioxide gas in cold THF. Subsequent metalation with tert-butyllithium, followed by addition to cyclopentanone (III) gives rise to the carbinol adduct (IV). Dehydration of (IV) under acidic conditions furnishes 2-(1-cyclopentenyl)indole (V). Diels-Alder condensation of (V) with maleimide (VI) at 190 C provides the pentacyclic system (VII). Further dehydrogenation of (VII) employing DDQ leads to the fused carbazole compound (VIII). Regioselective halogenation of (VIII) at position 3 by means of NBS yields the corresponding aryl bromide (IX). Then, displacement of the bromide group of (IX) with either CuCN or Zn(CN)2 produces nitrile (X). This is finally reduced to the primary amine by catalytic hydrogenation in the presence of Raney nickel and ammonia.
| 【1】 Chatterjee, S.; Ator, M.A.; Hudkins, R.L.; Bihovsky, R.; Dunn, D. (Cephalon, Inc.); Novel multicyclic cpds. and the use thereof. WO 0185686 . |
| 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) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
| (II) | 60168 | 1H-indole-1-carboxylate | C9H6NO2 | 详情 | 详情 | |
| (III) | 15113 | cyclopentanone | 120-92-3 | C5H8O | 详情 | 详情 |
| (IV) | 60169 | 1-(1H-indol-2-yl)cyclopentanol | C13H15NO | 详情 | 详情 | |
| (V) | 60170 | 2-(1-cyclopenten-1-yl)-1H-indole | C13H13N | 详情 | 详情 | |
| (VI) | 19711 | 1H-pyrrole-2,5-dione | 541-59-3 | C4H3NO2 | 详情 | 详情 |
| (VII) | 60171 | 3a,3b,4,5,6,6a,7,11c-octahydro-1H-cyclopenta[a]pyrrolo[3,4-c]carbazole-1,3(2H)-dione | C17H16N2O2 | 详情 | 详情 | |
| (VIII) | 60172 | 4,5,6,7-tetrahydro-1H-cyclopenta[a]pyrrolo[3,4-c]carbazole-1,3(2H)-dione | C17H12N2O2 | 详情 | 详情 | |
| (IX) | 60173 | 10-bromo-4,5,6,7-tetrahydro-1H-cyclopenta[a]pyrrolo[3,4-c]carbazole-1,3(2H)-dione | C17H11BrN2O2 | 详情 | 详情 | |
| (X) | 60174 | 1,3-dioxo-2,3,4,5,6,7-hexahydro-1H-cyclopenta[a]pyrrolo[3,4-c]carbazole-10-carbonitrile | C18H11N3O2 | 详情 | 详情 |