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【结 构 式】 
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【分子编号】15292 【品名】Indole; 1H-indole 【CA登记号】120-72-9 |
【 分 子 式 】C8H7N 【 分 子 量 】117.15032 【元素组成】C 82.02% H 6.02% N 11.96% |
合成路线1
该中间体在本合成路线中的序号：(I)Oxidative coupling of indole (I) and ethylenethiourea (II) with iodine and potassium iodide affords the hydroiodide salt (III) in 89% yield. The hydroiodide salt is converted into the hydrochloride salt on an ion exchange column or through the base.
| 【1】 Shah, .K.; Nagarajan, K.; Arya, V.P.; Parthasarathy, T.N.; Shenoy, S.J.; Kulkarni, Y.S.; Derivatives of 3-mercaptoindole - Synthesis of a potent vasoconstrictor, 3-(2-imidazolin-2-ylthio)indole(tinazole). Indian J Med 1981, 20B, 672-679. |
| 【2】 Arya, V.P.; Nagarajan, K. (Novartis Corp.); Condensed pyrrole mercapto compounds. DE 2427207; FR 2233047; JP 50035160; US 3954757 . |
| 【3】 Arya, V.P.; Tinazoline hydrochloride. Drugs Fut 1982, 7, 5, 325. |
| 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) | 31949 | Ethylenethiourea; 2-Imidazolidinethione | 96-45-7 | C3H6N2S | 详情 | 详情 |
| (III) | 31950 | 4,5-dihydro-1H-imidazol-2-yl 1H-indol-3-yl sulfide; 3-(4,5-dihydro-1H-imidazol-2-ylsulfanyl)-1H-indole | C11H11N3S | 详情 | 详情 | |
| (IV) | 31950 | 4,5-dihydro-1H-imidazol-2-yl 1H-indol-3-yl sulfide; 3-(4,5-dihydro-1H-imidazol-2-ylsulfanyl)-1H-indole | C11H11N3S | 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 cyclization of diethyl malonate (I) with cis-1,4-dichloro-2-butene (II) by means of LiH in DMF gives 3-cyclopentene-1,1-dicarboxylic acid diethyl ester (III), which is monodecarboxylated by hydrolysis with NaOH in ethanol, followed by heating at 170-180 C to yield 3-cyclopentene-1-carboxylic acid (IV). The reaction of (IV) with SOCl2 affords the acyl chloride (V), which by reaction with ethanol provides the ethyl ester (VI). The oxidation of (VI) with OsO4 and N-methylmorpholine N-oxide (NMMO) in acetone/water gives the dihydroxy compound (VII), which is further oxidized with NaIO4 in THF to yield the dialdehyde (VIII). The cyclization of (VIII) by means of glycine ethyl ester and acetonedicarboxylic acid affords the 9-azabicyclo[3,3,1]nonan-3-one derivative (IX), which is reduced with NaBH4 in ethanol to provide the corresponding alcohol (X). The protection of the OH group of (X) with dihydropyran and methanesulfonic acid gives the tetrahydropyranyl ether (XI), which is cyclized by means of tBuO-K in hot toluene, yielding the tricyclic ketone (XII). The deprotection of (XII) with 5N HCl affords the alcohol (XIII), which is finally esterified with 1H-indole-3-carbonyl chloride (XIV) by means of tetrafluoroboric acid and silver tetrafluoroborate in nitroethane. Alternatively, 1H-indole (XV) is condensed with oxalyl chloride (XVI) to give 3-indolylglyoxylyl chloride (XVII), which is used to acylate the alcohol (XIII) by means of tetrafluoroboric acid and silver tetrafluoroborate as before. Simultaneous decarbonylation takes place in this acylation reaction.
| 【1】 Gittos, M.W. (Merrell Pharmaceuticals, Inc.); Esters of hexahydro-8-hydroxy-2, 6-methano-2H-quinolizin-3(4H)-one and related compds.. AU 8780596; EP 0266730; JP 1988258476 . |
| 【2】 Gittos, M.W.; Fatmi, M.; Potent 5-HT3 antagonists incorporating a novel bridged pseudopelletierine ring system. Actual Chim Ther 1989, 16, 187. |
| 【3】 Gittos, M.W.; Fatmi, M.; Galvan, M.; Dolasetron Mesylate. Drugs Fut 1993, 18, 6, 506. |
| 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) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (II) | 50004 | cis-1,4-Dichloro-2-butene;(Z)-1,4-Dichlorobutene;(Z)-1,4-Dichloro-2-butene;(2Z)-1,4-Dichloro-2-butene;cis-1,2-Bis(chloromethyl)ethene | 1476-11-5 | C4H6Cl2 | 详情 | 详情 |
| (III) | 50000 | diethyl 3-cyclopentene-1,1-dicarboxylate | C11H16O4 | 详情 | 详情 | |
| (IV) | 50001 | 3-cyclopentene-1-carboxylic acid | C6H8O2 | 详情 | 详情 | |
| (V) | 50002 | 3-Cyclopentenecarboxylic acid | 7686-77-3 | C6H7ClO | 详情 | 详情 |
| (VI) | 13469 | ethyl 3-cyclopentene-1-carboxylate | C8H12O2 | 详情 | 详情 | |
| (VII) | 13470 | ethyl 3,4-dihydroxycyclopentanecarboxylate | C8H14O4 | 详情 | 详情 | |
| (VIII) | 13471 | ethyl 4-oxo-2-(2-oxoethyl)butanoate | C8H12O4 | 详情 | 详情 | |
| (IX) | 13472 | ethyl 9-(2-ethoxy-2-oxoethyl)-7-oxo-9-azabicyclo[3.3.1]nonane-3-carboxylate | C15H23NO5 | 详情 | 详情 | |
| (X) | 13473 | ethyl 9-(2-ethoxy-2-oxoethyl)-7-hydroxy-9-azabicyclo[3.3.1]nonane-3-carboxylate | C15H25NO5 | 详情 | 详情 | |
| (XI) | 13474 | ethyl 9-(2-ethoxy-2-oxoethyl)-7-(tetrahydro-2H-pyran-2-yloxy)-9-azabicyclo[3.3.1]nonane-3-carboxylate | C20H33NO6 | 详情 | 详情 | |
| (XII) | 50003 | 5-(tetrahydro-2H-pyran-2-yloxy)-8-azatricyclo[5.3.1.0(3,8)]undecan-10-one | C15H23NO3 | 详情 | 详情 | |
| (XIII) | 13475 | 5-Hydroxy-8-azatricyclo[5.3.1.0(3,8)]undecan-10-one | C10H15NO2 | 详情 | 详情 | |
| (XIV) | 17153 | 1H-indole-3-carbonyl chloride | C9H6ClNO | 详情 | 详情 | |
| (XV) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
| (XVI) | 29841 | Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride | 79-37-8 | C2Cl2O2 | 详情 | 详情 |
| (XVII) | 13476 | Indole-3-glyoxylyl chloride; 2-(1H-Indol-3-yl)-2-oxoacetyl chloride | 22980-09-2 | C10H6ClNO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The Friedel-Crafts condensation of indole (I) with 3-nitrobenzoyl chloride (II) by means of AlCl3 in dichloromethane gives 3-(3-nitrobenzoyl)indole (III), which is allowed to react with ethyl 4-bromobutyrate (IV) by means of K2CO3 in DMF to yield 4-[3-(3-nitrobenzoyl)indol-1-yl]butyric acid ethyl ester (V). The hydrolysis of (V) with NaOH in dioxane/water affords the corresponding butyric acid (VI), which is hydrogenated with H2 over Pd/C in methanol/dioxane yielding 3-[3-(3-aminobenzoyl)indol-1-yl]butyric acid (VII). Finally, this compound is condensed with bis(4-isobutylphenyl)chloromethane (VIII) by means of ethyldiisopropylamine in dichloromethane.
| 【1】 Mealy, N.; Castaner, J.; FK-143. Drugs Fut 1996, 21, 5, 473. |
| 【2】 Golden, P.; Hashimoto, M.; Tanaka, H.; Sawada, Y.; Okada, S.; Sawada, K.; Kayakiri, N.; 4-(1-Benzoylindol-3-yl)butyric acids and FK143: Novel nonsteroidal inhibitors of steroid 5alpha-reductase (II). Chem Pharm Bull 1999, 47, 4, 481. |
| 【3】 Okada, S.; Sawada, K.; Kayakiri, N.; Saitoh, Y.; Tanaka, H.; Hashimoto, M. (Fujisawa Pharmaceutical Co., Ltd.); Indole derivs. EP 0458207; JP 1992244061; US 5212320; US 5312829 . |
| 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) | 15293 | 3-nitrobenzoyl chloride; m-nitrobenzoyl chloride | 121-90-4 | C7H4ClNO3 | 详情 | 详情 |
| (III) | 15294 | 1H-indol-3-yl(3-nitrophenyl)methanone | C15H10N2O3 | 详情 | 详情 | |
| (IV) | 11263 | ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate | 2969-81-5 | C6H11BrO2 | 详情 | 详情 |
| (V) | 15296 | ethyl 4-[3-(3-nitrobenzoyl)-1H-indol-1-yl]butanoate | C21H20N2O5 | 详情 | 详情 | |
| (VI) | 15297 | 4-[3-(3-nitrobenzoyl)-1H-indol-1-yl]butyric acid | C19H16N2O5 | 详情 | 详情 | |
| (VII) | 15298 | 4-[3-(3-aminobenzoyl)-1H-indol-1-yl]butyric acid | C19H18N2O3 | 详情 | 详情 | |
| (VIII) | 15299 | 1-[chloro(4-isobutylphenyl)methyl]-4-isobutylbenzene | C21H27Cl | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIV)Treatment of (R)-1-chloro-2,3-propanediol (I) with either K2CO3 or Cs2CO3 in CH2Cl2, followed by O-protection with Trt-Cl and Et3N in CH2Cl2, yields (S)-trityl glycidol (II). Alternatively, derivative (II) can also be obtained either by direct O-protection of (R)-glycidol (III) by means of Trt-Cl and Et3N in refluxing CH2Cl2 or by cyclization of protected propanediol derivative (IV)--obtained from treatment of compound (I) with Trt-Cl and Et3N in CH2Cl2--by means of KOH in EtOH. Reaction of (S)-trityl glycidol (II) with vinyl magnesium bromide (V) by means of CuI in THF provides (S)-1-(triphenylmethoxy)-4-penten-2-ol (VI), which is then condensed with allyl bromide (VII) with KOtBu or NaH in THF to afford compound (VIII). Ozonolysis of (VIII) in CH2Cl2/MeOH, followed by reductive quench with NaBH4 in NaOH, gives (S)-3-(2-hydroxyethoxy)-4-(triphenylmethoxy)-1-butanol (IX), which is then treated with MsCl/Et3N in CH2Cl2 to yield bismesylate (X). Coupling of compound (X) with 2,3-bis(1H-indol-3-yl)-N-methylmaleimide (XI) [obtained by treatment of dichloromaleic anhydride (XII) with methylamine hydrochloride by means of NaOMe in HOAc to furnish dichloro-N-methylmaleimide (XIII), followed by Grignard reaction of (XIII) with indole (XIV) in toluene/THF by means of EtMgBr in Et2O] by means of Cs2CO3 in DMF gives the 14-membered macrocycle (XV).
| 【1】 Faul, M.M.; Sullivan, K.A.; Neel, D.A.; Krumrich, C.A.; Jirousek, M.R.; Winneroski, L.L.; Gillig, J.R.; Rito, C.J.; Macrocyclic bisindolylmaleimides: Synthesis by inter- and intramolecular alkylation. J Org Chem 1998, 63, 6, 1961. |
| 【2】 Engel, G.L.; Farid, N.A.; Faul, M.M.; Jirousek, M.R.; Richardson, L.A.; Winneroski, L.L. Jr. (Eli Lilly and Company); Protein kinase C inhibitor. EP 0776895; JP 1999500149; US 5710145; WO 9718809 . |
| 【3】 Faul, M.M.; Winneroski, L.L. Jr.; Krumrich, C.A. (Eli Lilly and Company); Intermediates and their use to prepare N,N'-bridged bisindolylmaleimides. US 5721272 . |
| 【4】 Rito, C.J.; Mcdonald, J.H. III; Jirousek, M.R.; Winneroski, L.L. Jr.; Heath, W.F. Jr.; Faul, M.M. (Eli Lilly and Company); Improved synthesis of bisindolylmaleimides. EP 0657411; US 5541347 . |
| 【5】 Faul, M.M.; Winneroski, L.L. Jr.; Krumrich, C.A. (Eli Lilly and Company); Intermediates and their use to prepare N,N'-bridged bisindolylmaleimides. EP 0776899 . |
| 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) | 49696 | (S)-(+)-Alpha-Chlorohydrin; (S)-(+)-3-Chloro-1,2-propanediol; (S)-3-Chloro-1,2-propanediol | 60827-45-4 | C3H7ClO2 | 详情 | 详情 |
| (II) | 41006 | (2S)-oxiranylmethyl trityl ether; (2S)-2-[(trityloxy)methyl]oxirane | C22H20O2 | 详情 | 详情 | |
| (III) | 19241 | (2S)oxiranylmethanol | 60456-23-7 | C3H6O2 | 详情 | 详情 |
| (IV) | 51942 | (2R)-1-chloro-3-(trityloxy)-2-propanol | C22H21ClO2 | 详情 | 详情 | |
| (V) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (VI) | 41007 | (2S)-1-(trityloxy)-4-penten-2-ol | C24H24O2 | 详情 | 详情 | |
| (VII) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (VIII) | 41008 | 1-[[[(2S)-2-(allyloxy)-4-pentenyl]oxy](diphenyl)methyl]benzene; allyl (1S)-1-[(trityloxy)methyl]-3-butenyl ether | C27H28O2 | 详情 | 详情 | |
| (IX) | 41010 | (3S)-3-(2-hydroxyethoxy)-4-(trityloxy)-1-butanol | C25H28O4 | 详情 | 详情 | |
| (X) | 51943 | (7S)-2,11-dimethyl-2,11-dimethylene-7-[(trityloxy)methyl]-3,6,10-trioxa-2lambda(6),11lambda(6)-dithia-1,11-dodecadiene; 2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]ethyl (1S)-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-1-[(trityloxy)methyl]propyl ether | C31H40O4S2 | 详情 | 详情 | |
| (XI) | 51012 | 5-(tert-butyl) 1-(2,3,5,6-tetrafluorophenyl) (2S)-2-[[(2S)-2-[[(benzyloxy)carbonyl]amino]-5-(tert-butoxy)-5-oxopentanoyl]amino]pentanedioate | C32H38F4N2O9 | 详情 | 详情 | |
| (XII) | 21947 | 3,4-dichloro-2,5-furandione | 1122-17-4 | C4Cl2O3 | 详情 | 详情 |
| (XIII) | 41029 | 3,4-dichloro-1-methyl-1H-pyrrole-2,5-dione | C5H3Cl2NO2 | 详情 | 详情 | |
| (XIV) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
| (XV) | 41016 | (18S)-4-methyl-18-[(trityloxy)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.1(7,14).0(2,6).0(8,13).0(22,27)]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione | C46H39N3O4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XXXI)The intermediate (XI), 3,4-bis(3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione, has been obtained as follows: Reaction of 2,3-dichloromaleic anhydride (XXIX) with methylamine and NaOMe in acetic acid gives 3,4-dichloro-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione (XXX), which is then condensed with indole (XXXI) by means of ethylmagnesium bromide in refluxing toluene/THF to the target compound (XI).
| 【1】 Sorbera, L.A.; Rabasseda, X.; Silvestre, J.S.; Castañer, J.; LY-333531 Mesylate Hydrate. Drugs Fut 2000, 25, 10, 1017-1026. |
| 【2】 Rito, C.J.; Mcdonald, J.H. III; Jirousek, M.R.; Winneroski, L.L. Jr.; Heath, W.F. Jr.; Faul, M.M. (Eli Lilly and Company); Improved synthesis of bisindolylmaleimides. EP 0657411; US 5541347 . |
| 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) | 41012 | 3,4-di(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione | 113963-68-1 | C21H15N3O2 | 详情 | 详情 |
| (XXIX) | 21947 | 3,4-dichloro-2,5-furandione | 1122-17-4 | C4Cl2O3 | 详情 | 详情 |
| (XXX) | 41029 | 3,4-dichloro-1-methyl-1H-pyrrole-2,5-dione | C5H3Cl2NO2 | 详情 | 详情 | |
| (XXXI) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)A new strategy for the synthesis of a key intermediate in the preparation of LY-333531 has been described: Condensation of indole (I) with the tosylate (II) by means of NaH in DMF gives 4-(1-indolyl)butane-1,2-diol (III), which is monotritylated with trityl bromide yielding ether (IV). Alkylation of compound (IV) with tert-butyl bromoacetate (V) and NaH in THF affords the hydroxyacetic derivative (VI), which is reduced with LiBH4 in THF/EtOH to provide the carbinol (VII). Reaction of compound (VII) with Ms2O and pyridine in THF gives the mesylate (VIII), which is condensed with oxalyl chloride (IX) in ethyl ether to yield the oxoacetyl chloride (X). The alcoholysis of (X) with NaOMe in methanol affords the oxoacetate (XI), which is finally cyclized with 2-(3-indolyl)acetamide (XII) by means of NaH in DMF to provide the target intermediate (XIII).
| 【1】 Faul, M.M.; Kumrich, C.A.; Cyclization strategies for the synthesis of macrocyclic bisindolylmaleimides. J Org Chem 2001, 66, 6, 2024. |
| 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) | 48674 | 2-(2,2-diethyl-1,3-dioxolan-4-yl)ethyl 4-methylbenzenesulfonate | C16H24O5S | 详情 | 详情 | |
| (III) | 48675 | 4-(1H-indol-1-yl)-1,2-butanediol | C12H15NO2 | 详情 | 详情 | |
| (IV) | 48676 | 4-(1H-indol-1-yl)-1-(trityloxy)-2-butanol | C31H29NO2 | 详情 | 详情 | |
| (V) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (VI) | 48677 | tert-butyl 2-[3-(1H-indol-1-yl)-1-[(trityloxy)methyl]propoxy]acetate | C37H39NO4 | 详情 | 详情 | |
| (VII) | 48678 | 2-[3-(1H-indol-1-yl)-1-[(trityloxy)methyl]propoxy]-1-ethanol | C33H33NO3 | 详情 | 详情 | |
| (VIII) | 48679 | 2-[3-(1H-indol-1-yl)-1-[(trityloxy)methyl]propoxy]ethyl methanesulfonate | C34H35NO5S | 详情 | 详情 | |
| (IX) | 29841 | Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride | 79-37-8 | C2Cl2O2 | 详情 | 详情 |
| (X) | 48680 | 2-[3-[3-(2-chloro-2-oxoacetyl)-1H-indol-1-yl]-1-[(trityloxy)methyl]propoxy]ethyl methanesulfonate | C36H34ClNO7S | 详情 | 详情 | |
| (XI) | 48681 | methyl 2-[1-[3-[2-[(methylsulfonyl)oxy]ethoxy]-4-(trityloxy)butyl]-1H-indol-3-yl]-2-oxoacetate | C37H37NO8S | 详情 | 详情 | |
| (XII) | 48682 | Indole-3-acetamide;3-Indoleacetamide;2-(1H-indol-3-yl) | 879-37-8 | C10H10N2O | 详情 | 详情 |
| (XIII) | 48683 | 18-[(trityloxy)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.1(7,14).0(2,6).0(8,13).0(22,27)]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione | C45H37N3O4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)The target compound was obtained by several related ways. Indolylethanol (III) was either prepared by alkylation of indole (I) with methyl bromoacetate, followed by reduction of the resulting indolylacetate (II) with LiAlH4 or by alkylation of (I) with 2-bromoethanol. Alkylation of (III) with 4-fluorobenzaldehyde (IV) in the presence of NaH or condensation with 4-hydroxybenzaldehyde (V) under Mitsunobu conditions provided ether (VII). Alternatively, (VII) was prepared by alkylation of indole (I) with 4-(bromoethoxy)benzaldehyde (VI). Then, Knoevenagel condensation of aldehyde (VII) with 2,4-thiazolidinedione (VIII) in the presence of piperidinium benzoate in refluxing toluene with azeotropic removal of water yielded benzylidene compound (IX). Reduction of the olefinic double bond by either hydrogenation in the presence of an excess of Pd/C or by chemical reduction with Mg in MeOH provided the target benzyl compound. Alternatively, indolylethanol (III) was condensed with hydroxybenzyl compound (X) in the presence of tributyl phosphine and 1,1'-(azodicarbonyl)dipiperidine (ADDP) in benzene to give (XI), which was finally deprotected by hydrogenation in the presence of an excess of Pd/C in dioxan.
| 【1】 Lohray, B.B.; et al.; Novel indole containing thiazolidinedione derivatives as potent euglycemic and hypolipidaemic agents. Bioorg Med Chem Lett 1997, 7, 7, 785. |
| 【2】 Rao, K.N.; Reddy, A.K.; Reddy, P.G.; Vikramadityan, R.K.; Madhavan, G.R.; Bhushan, V.; Rajagopolan, R.; Mamidi, R.N.V.S.; Rajesh, B.M.; Jajoo, H.K.; Rao, B.P.; Murali, N.; Chakrabarti, R.; Subramaniam, S.; Lohray, B.B.; Novel euglycemic and hypolipidemic agent. J Med Chem 1998, 41, 10, 1619. |
| 【3】 Fujita, T.; Fujimoto, K.; Yoshioka, T.; Yanagisawa, H.; Fujiwara, T.; Horikoshi, H.; Oguchi, M.; Wada, K. (Sankyo Co., Ltd.); Heterocyclic cpds. having antidiabetic activity, their preparation and their use. CA 2146701; EP 0676398; JP 1995330728; US 5624935; US 5834501; US 5962470; US 6117893 . |
| 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) | 18795 | methyl 2-(1H-indol-1-yl)acetate | C11H11NO2 | 详情 | 详情 | |
| (III) | 18796 | 2-(1H-indol-1-yl)-1-ethanol | C10H11NO | 详情 | 详情 | |
| (IV) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (V) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (VI) | 18799 | 4-(2-bromoethoxy)benzaldehyde | 52191-15-8 | C9H9BrO2 | 详情 | 详情 |
| (VII) | 18800 | 4-[2-(1H-indol-1-yl)ethoxy]benzaldehyde | C17H15NO2 | 详情 | 详情 | |
| (VIII) | 10883 | 1,3-Thiazolane-2,4-dione; 2,4-Thiazolidinedione | 2295-31-0 | C3H3NO2S | 详情 | 详情 |
| (IX) | 18802 | 5-((E)-[4-[2-(1H-indol-1-yl)ethoxy]phenyl]methylidene)-1,3-thiazolidine-2,4-dione | C20H16N2O3S | 详情 | 详情 | |
| (X) | 18803 | 5-(4-hydroxybenzyl)-3-trityl-1,3-thiazolidine-2,4-dione | C29H23NO3S | 详情 | 详情 | |
| (XI) | 18804 | 5-[4-[2-(1H-indol-1-yl)ethoxy]benzyl]-3-trityl-1,3-thiazolidine-2,4-dione | C39H32N2O3S | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)Friedel Crafts acylation of indole (II) with tert-leucine N-carboxyanhydride (I) in the presence of AlCl3 gave aminoketone (III). Subsequent condensation of (III) with the succinate building block (IV) in DMF afforded succinamide (V). Further deprotection of the tert-butyl ester of (V) by treatment with trifluoroacetic acid provided carboxylic acid (VI), which was coupled with O-tert-butyldimethylsilyl hydroxylamine (VII) in the presence of EDC and HOBt to yield, after desilylation, the target hydroxamic acid.
| 【1】 Sheppard, G.S.; Florjancic, A.S.; Giesler, J.R.; Xu, L.; Guo, Y.; Davidsen, S.K.; Marcotte, P.A.; Elmore, I.; Albert, D.H.; Terrance, J.M.; Bouska, J.J.; Goodfellow, C.L.; Morgan, D.W.; Summers, J.B.; Aryl ketones as novel replacements for the C-terminal amide bond of succinyl hydroxamate MMP inhibitors. Bioorg Med Chem Lett 1998, 8, 22, 3251. |
| 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) | 21638 | (4S)-4-(tert-butyl)-1,3-oxazolidine-2,5-dione | C7H11NO3 | 详情 | 详情 | |
| (II) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
| (III) | 21640 | (2S)-2-amino-1-(1H-indol-3-yl)-3,3-dimethyl-1-butanone | C14H18N2O | 详情 | 详情 | |
| (IV) | 21641 | 1-(tert-butyl) 4-(2,3,4,5,6-pentafluorophenyl) (2S,3R)-2-allyl-3-isobutylbutanedioate | C21H25F5O4 | 详情 | 详情 | |
| (V) | 21642 | tert-butyl (2S)-2-[(1R)-1-([[(1S)-1-(1H-indol-3-ylcarbonyl)-2,2-dimethylpropyl]amino]carbonyl)-3-methylbutyl]-4-pentenoate | C29H42N2O4 | 详情 | 详情 | |
| (VI) | 21643 | (2S)-2-[(1R)-1-([[(1S)-1-(1H-indol-3-ylcarbonyl)-2,2-dimethylpropyl]amino]carbonyl)-3-methylbutyl]-4-pentenoic acid | C25H34N2O4 | 详情 | 详情 | |
| (VII) | 21644 | (Aminooxy)(tert-butyl)dimethylsilane; O-[tert-Butyl(dimethyl)silyl]hydroxylamine | 41879-39-4 | C6H17NOSi | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(II)Friedel Crafts acylation of indole (II) with phenylalanine N-carboxyanhydride (I) in the presence of AlCl3 gave aminoketone (III). Subsequent condensation of (III) with the succinate building block (IV) in DMF afforded succinamide (V). Further deprotection of the tert-butyl ester of (V) by treatment with trifluoroacetic acid provided carboxylic acid (VI), which was coupled with O-tert-butyldimethylsilyl hydroxylamine (VII) in the presence of EDC and HOBt to yield, after desilylation, the target hydroxamic acid.
| 【1】 Sheppard, G.S.; Florjancic, A.S.; Giesler, J.R.; Xu, L.; Guo, Y.; Davidsen, S.K.; Marcotte, P.A.; Elmore, I.; Albert, D.H.; Terrance, J.M.; Bouska, J.J.; Goodfellow, C.L.; Morgan, D.W.; Summers, J.B.; Aryl ketones as novel replacements for the C-terminal amide bond of succinyl hydroxamate MMP inhibitors. Bioorg Med Chem Lett 1998, 8, 22, 3251. |
| 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) | 21645 | (4S)-4-benzyl-1,3-oxazolidine-2,5-dione | 14825-82-2 | C10H9NO3 | 详情 | 详情 |
| (II) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
| (III) | 21647 | (2S)-2-amino-1-(1H-indol-3-yl)-3-phenyl-1-propanone | C17H16N2O | 详情 | 详情 | |
| (IV) | 21641 | 1-(tert-butyl) 4-(2,3,4,5,6-pentafluorophenyl) (2S,3R)-2-allyl-3-isobutylbutanedioate | C21H25F5O4 | 详情 | 详情 | |
| (IV) | 21655 | 4-(tert-butyl) 1-(2,3,4,5,6-pentafluorophenyl) (2R,3S)-2-isobutyl-3-(4-pentenyl)butanedioate | C23H29F5O4 | 详情 | 详情 | |
| (V) | 21649 | tert-butyl (2S)-2-[(1R)-1-([[(1S)-1-benzyl-2-(1H-indol-3-yl)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]-4-pentenoate | C32H40N2O4 | 详情 | 详情 | |
| (V) | 21656 | tert-butyl (2S)-2-[(1R)-1-([[(1S)-1-benzyl-2-(1H-indol-3-yl)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]-6-heptenoate | C34H44N2O4 | 详情 | 详情 | |
| (VI) | 21650 | (2S)-2-[(1R)-1-([[(1S)-1-benzyl-2-(1H-indol-3-yl)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]-4-pentenoic acid | C28H32N2O4 | 详情 | 详情 | |
| (VI) | 21657 | (2S)-2-[(1R)-1-([[(1S)-1-benzyl-2-(1H-indol-3-yl)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]-6-heptenoic acid | C30H36N2O4 | 详情 | 详情 | |
| (VII) | 21644 | (Aminooxy)(tert-butyl)dimethylsilane; O-[tert-Butyl(dimethyl)silyl]hydroxylamine | 41879-39-4 | C6H17NOSi | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(II)Friedel Crafts acylation of indole (II) with phenylalanine N-carboxyanhydride (I) in the presence of AlCl3 gave aminoketone (III). Subsequent condensation of (III) with the succinate building block (IV) in DMF afforded succinamide (V). Further deprotection of the tert-butyl ester of (V) by treatment with trifluoroacetic acid provided carboxylic acid (VI), which was coupled with O-tert-butyldimethylsilyl hydroxylamine (VII) in the presence of EDC and HOBt to yield, after desilylation, the target hydroxamic acid.
| 【1】 Sheppard, G.S.; Florjancic, A.S.; Giesler, J.R.; Xu, L.; Guo, Y.; Davidsen, S.K.; Marcotte, P.A.; Elmore, I.; Albert, D.H.; Terrance, J.M.; Bouska, J.J.; Goodfellow, C.L.; Morgan, D.W.; Summers, J.B.; Aryl ketones as novel replacements for the C-terminal amide bond of succinyl hydroxamate MMP inhibitors. Bioorg Med Chem Lett 1998, 8, 22, 3251. |
| 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) | 21645 | (4S)-4-benzyl-1,3-oxazolidine-2,5-dione | 14825-82-2 | C10H9NO3 | 详情 | 详情 |
| (II) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
| (III) | 21647 | (2S)-2-amino-1-(1H-indol-3-yl)-3-phenyl-1-propanone | C17H16N2O | 详情 | 详情 | |
| (VII) | 21644 | (Aminooxy)(tert-butyl)dimethylsilane; O-[tert-Butyl(dimethyl)silyl]hydroxylamine | 41879-39-4 | C6H17NOSi | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(II)Friedel Crafts acylation of indole (II) with tert-leucine N-carboxyanhydride (I) in the presence of AlCl3 gave aminoketone (III). Subsequent condensation of (III) with the malate building block (IV) in DMF afforded amide (V). Further deprotection of the tert-butyl ester of (V) by treatment with trifluoroacetic acid provided carboxylic acid (VI), which was coupled with O-tert-butyldimethylsilyl hydroxylamine (VII) in the presence of EDC and HOBt to yield, after desilylation, the target hydroxamic acid.
| 【1】 Sheppard, G.S.; Florjancic, A.S.; Giesler, J.R.; Xu, L.; Guo, Y.; Davidsen, S.K.; Marcotte, P.A.; Elmore, I.; Albert, D.H.; Terrance, J.M.; Bouska, J.J.; Goodfellow, C.L.; Morgan, D.W.; Summers, J.B.; Aryl ketones as novel replacements for the C-terminal amide bond of succinyl hydroxamate MMP inhibitors. Bioorg Med Chem Lett 1998, 8, 22, 3251. |
| 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) | 21638 | (4S)-4-(tert-butyl)-1,3-oxazolidine-2,5-dione | C7H11NO3 | 详情 | 详情 | |
| (II) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
| (III) | 21640 | (2S)-2-amino-1-(1H-indol-3-yl)-3,3-dimethyl-1-butanone | C14H18N2O | 详情 | 详情 | |
| (IV) | 21662 | 1-(tert-butyl) 4-(2,3,4,5,6-pentafluorophenyl) (2S,3R)-2-hydroxy-3-isobutylbutanedioate | C18H21F5O5 | 详情 | 详情 | |
| (V) | 21663 | tert-butyl (2S,3R)-2-hydroxy-3-([[(1S)-1-(1H-indol-3-ylcarbonyl)-2,2-dimethylpropyl]amino]carbonyl)-5-methylhexanoate | C26H38N2O5 | 详情 | 详情 | |
| (VI) | 21664 | (2S,3R)-2-hydroxy-3-([[(1S)-1-(1H-indol-3-ylcarbonyl)-2,2-dimethylpropyl]amino]carbonyl)-5-methylhexanoic acid | C22H30N2O5 | 详情 | 详情 | |
| (VII) | 21644 | (Aminooxy)(tert-butyl)dimethylsilane; O-[tert-Butyl(dimethyl)silyl]hydroxylamine | 41879-39-4 | C6H17NOSi | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(III)The reaction of N-carbobenzoxy-4-piperidylacetic acid (I) with refluxing SOCl2 yields the corresponding acyl chloride (II), which by condensation with indole (III) by means of methylmagnesium iodide (A) in ether gives rise to 3-indolyl-(4-piperidylmethyl)ketone (IV). Finally, this compound is reduced with LiAlH4 in THF.
| 【1】 Blancafort, P.; Owen, R.T.; Castañer, J.; Serradell, M.N.; Indalpine. Drugs Fut 1979, 4, 12, 873. |
| 【2】 Champseix, A.; et al.; US 4064255 . |
| 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) | 20225 | iodo(methyl)magnesium | 917-64-6 | CH3IMg | 详情 | 详情 |
| (I) | 39633 | 2-[1-(2-phenylacetyl)-4-piperidinyl]acetic acid | C15H19NO3 | 详情 | 详情 | |
| (II) | 39634 | 2-[1-(2-phenylacetyl)-4-piperidinyl]acetyl chloride | C15H18ClNO2 | 详情 | 详情 | |
| (III) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
| (IV) | 39635 | 1-(1H-indol-3-yl)-2-(4-piperidinyl)-1-ethanone | C15H18N2O | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(I)The acylation of indole (I) with 4-fluorobenzoyl chloride (II) by means of AlCl3 in dichloromethane gives 3-(4-fluorobenzoyl)indole (III), which is N-alkylated with ethyl iodide and K2CO3 in acetone yielding 1-ethyl-3-(4-fluorobenzoyl)indole (IV). The reduction of (IV) with NaBH4 in methanol affords the corresponding carbinol (V), which is finally treated with carbonyl diimidazole (VI) in THF.
| 【1】 Marchand, P.; Robert, J.-M.; Palzer, M.; Delovoye-Seiller, B.; Hartmann, R.W.; Le Baut, G.; Le Borgne, M.; New selective nonsteroidal aromatase inhibitors: Synthesis and inhibitory activity of 2, 3 or 5-(alpha-azolylbenzyl)-1H-indoles. Bioorg Med Chem Lett 1999, 9, 3, 333. |
| 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) | 17263 | 4-fluorobenzoyl chloride | 403-43-0 | C7H4ClFO | 详情 | 详情 |
| (III) | 29518 | (4-fluorophenyl)(1H-indol-3-yl)methanone | C15H10FNO | 详情 | 详情 | |
| (IV) | 29519 | (1-ethyl-1H-indol-3-yl)(4-fluorophenyl)methanone | C17H14FNO | 详情 | 详情 | |
| (V) | 29520 | (1-ethyl-1H-indol-3-yl)(4-fluorophenyl)methanol | C17H16FNO | 详情 | 详情 | |
| (VI) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(I)Treatment of an excess of indole (I) with dichloroacetyl chloride (II) in the presence of AlCl3 under Friedel-Crafts conditions produced the trimer intermediate (III), which was cyclized and acylated to yield the title indolyl quinoline.
| 【1】 Chakrabarti, G.; et al.; Indolylquinoline derivatives are cytotoxic to Leishmania donovani promastigotes and amastigotes in vitro and are effective in treating murine visceral leishmaniasis. J Antimicrob Chemother 1999, 43, 3, 359. |
| 【2】 Mahato, S.B.; et al.; Synthesis of indolylquinolines under Friedel-Crafts reaction conditions. Tetrahedron 1994, 50, 36, 10803. |
合成路线15
该中间体在本合成路线中的序号：(I)Treatment of an excess of indole (I) with chloroacetyl chloride (II) in the presence of AlCl3 under Friedel-Crafts conditions produced the trimer intermediate (III), which was cyclized and acylated to yield the title indolyl quinoline.
| 【1】 Chakrabarti, G.; et al.; Indolylquinoline derivatives are cytotoxic to Leishmania donovani promastigotes and amastigotes in vitro and are effective in treating murine visceral leishmaniasis. J Antimicrob Chemother 1999, 43, 3, 359. |
| 【2】 Mahato, S.B.; et al.; Synthesis of indolylquinolines under Friedel-Crafts reaction conditions. Tetrahedron 1994, 50, 36, 10803. |
合成路线16
该中间体在本合成路线中的序号：(I)The condensation of 1H-indole (I) with 4-chlorobenzyl chloride (II) by means of NaH in DMSO gives 1-(4-chlorobenzyl) indole (III), which is treated with oxalyl chloride in a hot aprotic solvent yielding the intermediate acid chloride (IV). Finally, this compound is treated with pyridin-4-amine (V) in the same solvent.
| 【1】 Lebaut, G.; Menciu, C.; Kutscher, B.; Emig, P.; Szelenyi, S.; Brune, K. (Asta Medica AG); N-Substd. indol-3-glyoxylamide with antiasthmatic, antiallergic and immunosuppressive/immunomodulating effect. DE 19636150; EP 0931063; JP 2000505098; US 6008231; WO 9809946 . |
| 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) | 10356 | 1-Chloro-4-(chloromethyl)benzene; 4-Chlorobenzyl chloride | 104-83-6 | C7H6Cl2 | 详情 | 详情 |
| (III) | 30441 | 1-(4-chlorobenzyl)-1H-indole | C15H12ClN | 详情 | 详情 | |
| (IV) | 30442 | 2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxoacetyl chloride | C17H11Cl2NO2 | 详情 | 详情 | |
| (V) | 25661 | 4-pyridinamine; 4-aminopyridine | 5044-74-5 | C5H6N2 | 详情 | 详情 |
合成路线17
该中间体在本合成路线中的序号：(I)Reaction of indole (I) with chloroacetyl chloride (II) in the presence of pyridine in toluene afforded the chloro ketone (III). This was then treated with sodium azide in aqueous acetone to furnish the azido ketone (IV). Hydrogenation of (IV) over Pd/C in the presence of a catalytic amount of HOAc gave rise to 3,5-bisindolyl pyrazine (V). Finally, N-methylation of the indole rings with iodomethane and K2CO3 yielded the title compound.
| 【1】 Jiang, B.; Gu, X.-H.; Syntheses and cytotoxicity evaluation of bis(indolyl)thiazole, bis(indolyl)pyrazinone and bis(indolyl)pyrazine: Analogues of cytotoxic marine bis(indole) alkaloid. Bioorg Med Chem 2000, 8, 2, 363. |
| 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) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (III) | 46764 | 2-chloro-1-(1H-indol-3-yl)-1-ethanone | C10H8ClNO | 详情 | 详情 | |
| (IV) | 46765 | 2-azido-1-(1H-indol-3-yl)-1-ethanone | C10H8N4O | 详情 | 详情 | |
| (V) | 46766 | 3-[5-(1H-indol-3-yl)-2-pyrazinyl]-1H-indole | C20H14N4 | 详情 | 详情 |
合成路线18
该中间体在本合成路线中的序号：(I)Reaction of indole (I) with chloroacetyl chloride (II) in the presence of pyridine in toluene afforded the chloro ketone (III). This was then treated with sodium azide in aqueous acetone to furnish the azido ketone (IV). Hydrogenation of (IV) over Pd/C in the presence of HCl gave the amino ketone (V). The intermediate 3-indolylglyoxylic chloride (VI) was obtained by acylation of indole (I) with oxalyl chloride in CH2Cl2. Subsequent condensation between acid chloride (VI) and amino ketone (V) produced amide (VII). This was finally cyclized to the desired bisindolyl pyrazinone by treatment with ammonia in a pressure vessel.
| 【1】 Jiang, B.; Gu, X.-H.; Syntheses and cytotoxicity evaluation of bis(indolyl)thiazole, bis(indolyl)pyrazinone and bis(indolyl)pyrazine: Analogues of cytotoxic marine bis(indole) alkaloid. Bioorg Med Chem 2000, 8, 2, 363. |
| 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) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (III) | 46764 | 2-chloro-1-(1H-indol-3-yl)-1-ethanone | C10H8ClNO | 详情 | 详情 | |
| (IV) | 46765 | 2-azido-1-(1H-indol-3-yl)-1-ethanone | C10H8N4O | 详情 | 详情 | |
| (V) | 46767 | 2-amino-1-(1H-indol-3-yl)-1-ethanone | C10H10N2O | 详情 | 详情 | |
| (VI) | 13476 | Indole-3-glyoxylyl chloride; 2-(1H-Indol-3-yl)-2-oxoacetyl chloride | 22980-09-2 | C10H6ClNO2 | 详情 | 详情 |
| (VII) | 46768 | 2-(1H-indol-3-yl)-N-[2-(1H-indol-3-yl)-2-oxoethyl]-2-oxoacetamide | C20H15N3O3 | 详情 | 详情 |
合成路线19
该中间体在本合成路线中的序号：(IV)The methanolysis of anhydride (I) with dry refluxing methanol gives the monoester (II), which is treated with COCl2 to yield the acyl chloride (III). The condensation of (III) with indole (IV) by means of ZnCl2/MeMgCl and AlCl3 affords the adduct (V), which is N protected by means of Mom-Cl and NaH in THF to provide the intermediate (VI). The cyclization of (VI) by means of Temda and LiHMDS in THF gives the tetracyclic quinone (VII), which is finally deprotected with hot aq. HCl to provide the target Calothrixin B.
| 【1】 Bernardo, P.H.; et al.; A simple and concise route to calothrixin B. Tetrahedron Lett 2002, 43, 16, 2939. |
| 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) | 56959 | furo[3,4-c]quinoline-1,3-dione | C11H5NO3 | 详情 | 详情 | |
| (II) | 56960 | 4-(methoxycarbonyl)-3-quinolinecarboxylic acid | C12H9NO4 | 详情 | 详情 | |
| (III) | 56961 | methyl 3-(chlorocarbonyl)-4-quinolinecarboxylate | C12H8ClNO3 | 详情 | 详情 | |
| (IV) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
| (V) | 56962 | methyl 3-(1H-indol-3-ylcarbonyl)-4-quinolinecarboxylate | C20H14N2O3 | 详情 | 详情 | |
| (VI) | 56963 | methyl 3-{[1-(methoxymethyl)-1H-indol-3-yl]carbonyl}-4-quinolinecarboxylate | C22H18N2O4 | 详情 | 详情 | |
| (VII) | 46800 | 12-(methoxymethyl)-7H-indolo[3,2-j]phenanthridine-7,13(12H)-dione | C21H14N2O3 | 详情 | 详情 |
合成路线20
该中间体在本合成路线中的序号：(IV)The title compound was isolated from the fermentation broth of Streptomyces sp. strain HC-21. A synthetic method for the preparation of the title compound was also reported. Asymmetric dihydroxylation of ethyl crotonate (I) using commercial AD-mix-beta produced diol (II). This was converted to the (2S,3R)-epoxide (III) by bromination with HBr in HOAc followed by cyclization of the resultant bromohydrin in the presence of DBU. Epoxide ring opening with the organomagnesium reagent generated from indole (IV) and methylmagnesium bromide furnished the chiral indolylbutanoate (V). Cyclization of the hydroxy ester (V) with guanidine hydrochloride (VI) in the presence of potassium tert-butoxide yielded the amino oxazolone (VII). Finally, displacement of the amino- by a methylamino group was achieved by treatment with aqueous methylamine.
| 【1】 Kanamaru, T.; Nakao, M.; Tawada, H.; Kamiyama, K. (Takeda Chemical Industries, Ltd.); Oxazolone derivs. and their use as anti-Helicobacter pylori agent. EP 0923577; JP 1998279579; US 6169102; WO 9749703 . |
| 【2】 Kamiyama, K.; Nakayama, Y. (Takeda Chemical Industries, Ltd.); Process for producing indolmycins. WO 9952905 . |
| 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) | 52087 | Ethyl crotonate; trans-Ethyl crotonate; Crotonic acid ethyl ester | 623-70-1 | C6H10O2 | 详情 | 详情 |
| (II) | 52088 | ethyl (2S,3R)-2,3-dihydroxybutanoate | C6H12O4 | 详情 | 详情 | |
| (III) | 52089 | ethyl (2S,3R)-3-methyl-2-oxiranecarboxylate | C6H10O3 | 详情 | 详情 | |
| (IV) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
| (V) | 52090 | ethyl (2S,3R)-2-hydroxy-3-(1H-indol-3-yl)butanoate | C14H17NO3 | 详情 | 详情 | |
| (VI) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (VII) | 52091 | (5S)-2-amino-5-[(1R)-1-(1H-indol-3-yl)ethyl]-1,3-oxazol-4(5H)-one | C13H13N3O2 | 详情 | 详情 |
合成路线21
该中间体在本合成路线中的序号：(II)The condensation of the chiral epoxide (I) with indole (II) by means of methylmagnesium bromide in ethyl ether/dichloromethane gives the indolylbutyric ester (III), which is hydrolyzed with NaOH in ethanol/water and purified by crystallization to yield the corresponding butyric acid (IV). The esterification of (IV) with ethanol/HCl regenerates pure ester (III), which is cyclized with guanidine (V) by means of tBu-OK in tert-butanol to afford the oxazolone (VI). Finally the amino group of (VI) is methylated by means of methylamine in water to provide the target indolmycin.
| 【1】 Hasuoka, A.; et al.; Development of a stereoselective practical synthetic route to indolmycin, a candidate anti-H. pylori agent. Chem Pharm Bull 2001, 49, 12, 1604. |
| 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) | 52089 | ethyl (2S,3R)-3-methyl-2-oxiranecarboxylate | C6H10O3 | 详情 | 详情 | |
| (II) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
| (III) | 52090 | ethyl (2S,3R)-2-hydroxy-3-(1H-indol-3-yl)butanoate | C14H17NO3 | 详情 | 详情 | |
| (IV) | 58332 | (rac)-2-hydroxy-3-(1H-indol-3-yl)butanoic acid | C12H13NO3 | 详情 | 详情 | |
| (V) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (VI) | 52091 | (5S)-2-amino-5-[(1R)-1-(1H-indol-3-yl)ethyl]-1,3-oxazol-4(5H)-one | C13H13N3O2 | 详情 | 详情 |
合成路线22
该中间体在本合成路线中的序号：(II)The condensation of trans-epoxide (I) with indole (II) gives the racemic indolylbutyric acid (III), which is submitted to optical resolution with (+)-alpha-phenylethylamine to yield the (2S,3R)-enantiomer (2S,3R) (III). Finally, this compound is cyclized with N,N'.dimethylguanidine (IV) by means of Et-ONa in refluxing ethanol to afford the target indolmycin.
| 【1】 Preobrazhenskaya, M.N.; et al.; Total synthesis of antibiotic indolmycin and its stereoisomers. Tetrahedron 1968, 24, 6131. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (2S,3R)(III) | 58333 | (2S,3R)-2-hydroxy-3-(1H-indol-3-yl)butanoic acid | C12H13NO3 | 详情 | 详情 | |
| (I) | 52089 | ethyl (2S,3R)-3-methyl-2-oxiranecarboxylate | C6H10O3 | 详情 | 详情 | |
| (II) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
| (III) | 58332 | (rac)-2-hydroxy-3-(1H-indol-3-yl)butanoic acid | C12H13NO3 | 详情 | 详情 | |
| (IV) | 58334 | N,N'-dimethylguanidine | C3H9N3 | 详情 | 详情 |
合成路线23
该中间体在本合成路线中的序号：(I)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 |
合成路线24
该中间体在本合成路线中的序号：(XIV)Condensation of methyl 5,6-dihydropyrrolo[3,2,1-ij]quinolin-1-ylacetate (I) with methyl (3-indolyl)glyoxylate (II) in the presence of LDA in THF affords the butenedioate derivative (III), which can also be prepared by condensation of methyl 5,6-dihydropyrrolo[3,2,1-ij] quinoline-1-glyoxylate (IV) with methyl 3-indolylacetate (V) in the presence of LDA in THF. Hydrogenation of alkene (III) over Pd/C gives the saturated diester (VI), which upon cyclocondensation with benzylamine in THF yields the 1-benzyl-2,5-pyrrolidinedione derivative (VII). Debenzylation of compound (VII) by means of H2 over Pd/C then provides the 2,3-diarylsuccinimide (VIII) as a cis/trans mixture. Alternatively, succinimide (VIII) can be produced by the direct cyclocondensation of diester (VI) with NH3 in MeOH at elevated temperature. Isomerization of intermediate (VIII) with t-BuOK in t-BuOH or THF/t-BuOH leads to the (±)-trans-isomer, racemic tivantinib (IX) . Resolution of racemate (IX) can be effected by means of chiral preparative SFC or MCC , or by fractional crystallization with (1S,2S)-(+)-pseudoephedrine .
Racemic tivantinib (IX) can also be obtained by the following methods:
Reduction of the maleimide derivative (X) with Mg in refluxing MeOH produces the trans-succinimide (IX) . Alternatively, the reduction of maleimide (X) by catalytic hydrogenation over Pd/C in MeOH or Pd(OH)2/C in toluene provides the (±)-cis-succinimide (XI), which can be isomerized to the corresponding trans-succinimide (IX) by treatment with t-BuOK in t-BuOH at 50 °C . Similarly, reduction of the maleimide (X) with Zn(Hg) in HCl/EtOH leads to a mixture of cis- and trans-maleimides . The tricyclic compound (IX) can also be obtained by intramolecular Heck reaction of the 1-allyl-7-bromoindole derivative (XII) in the presence of 9-BBN and Pd(PPh3)4 . In a further method, condensation of 1-benzyl-3,4-dibromopyrrole-2,5-dione (XIII) with indole (XIV) using methyl magnesium bromide yields 1-benzyl-3-bromo-4-(3-indolyl)pyrrole-2,5-dione (XV), which by Suzuki coupling with 5,6-dihydropyrrolo[3,2,1-ij]quinolin-1-ylboronic acid (XVI) in the presence of Pd(PPh3)4 or by condensation with 5,6-dihydropyrrolo[3,2,1-ij]quinoline (XVII) by means of LiHMDS affords the maleimide (XVIII). Finally, adduct (XVIII) is reduced with Mg in refluxing MeOH, followed by debenzylation with H2 over Pd/C in MeOH (IX) .
| 【1】 Li, C.J., Ashwell, M.A., Hill, J., Moussa, M.M., Munshi, N. (ArQule, Inc.). Maleimide derivatives, pharmaceutical compositions and methods for treatment of cancer. CN 10194970, EP 1846406, EP 2289892, JP 2008530026, US 2006223760, US 7713969, WO 2006086484. |
| 【2】 Chan, T.C.K., France, D.S., Ishii, K. (ArQule, Inc.; Kyowa Hakko Kirin Co., Ltd.). Combinational compositions and methods for treatment of cancer. KR 2011118817, US 2010297075, WO 2010093789. |
| 【3】 Reed, D.P., Barnes, N.R., Kane, J.C., Lee, C.A., Chen, J.-X., Redmon, M.P.(ArQule, Inc.). Purified pyrroloquinolinyl-pyrrolidine-2,5-dione compositions and methods for preparing and using same. US 201116022, WO 2011079142. |
| 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) | 68951 | methyl 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetate | C14H15NO2 | 详情 | 详情 | |
| (II) | 68952 | methyl (3-indolyl)glyoxylate;methyl 2-(1H-indol-3-yl)-2-oxoacetate；Methyl indolyl-3-glyoxylate;Indole-3-glyoxylic acid methyl ester | 18372-22-0 | C11H9NO3 | 详情 | 详情 |
| (III) | 68953 | dimethyl 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)maleate | C25H22N2O4 | 详情 | 详情 | |
| (IV) | 68954 | methyl 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-2-oxoacetate | C14H13NO3 | 详情 | 详情 | |
| (V) | 68955 | methyl 3-indolylacetate;b-Indolylacetic acid methyl ester;Methyl b-indoleacetate;Methyl indole-3-acetate;Methylindol-3-ylacetate;Methyl 2-(1H-indol-3-yl)acetate;Methyl 1H-indole-3-acetate;Methyl 1H-indol-3-ylacetate;Indolyl-3-acetic acid methyl ester;IAAmethyl ester;(1H-Indol-3-yl)acetic acid methyl ester | 1912-33-0 | C11H11NO2 | 详情 | 详情 |
| (VI) | 68956 | dimethyl 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)succinate | C25H24N2O4 | 详情 | 详情 | |
| (VII) | 68957 | 1-benzyl-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione | C30H25N3O2 | 详情 | 详情 | |
| (VIII) | 68958 | 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione | C23H19N3O2 | 详情 | 详情 | |
| (IX) | 68959 | (±)-trans-(3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione | C23H19N3O2 | 详情 | 详情 | |
| (X) | 68960 | 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione | C23H17N3O2 | 详情 | 详情 | |
| (XI) | 68961 | (±)-cis-(3S,4S)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-2,5-Pyrrolidinedione | C23H19N3O2 | 详情 | 详情 | |
| (XII) | 68962 | (±)-trans-(3R,4R)-3-(1-allyl-7-bromo-1H-indol-3-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione | C23H18BrN3O2 | 详情 | 详情 | |
| (XIII) | 68963 | 1-benzyl-3,4-dibromopyrrole-2,5-dione;3,4-dibromo-1-(phenylmethyl)-1H-Pyrrole-2,5-dione;N-Benzyl-2,3-dibromomaleimide | 91026-00-5 | C11H7Br2NO2 | 详情 | 详情 |
| (XIV) | 15292 | Indole; 1H-indole | 120-72-9 | C8H7N | 详情 | 详情 |
| (XV) | 68964 | 1-benzyl-3-bromo-4-(3-indolyl)pyrrole-2,5-dione | C19H13BrN2O2 | 详情 | 详情 | |
| (XVI) | 68965 | 5,6-dihydropyrrolo[3,2,1-ij]quinolin-1-ylboronic acid;(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)boronic acid | C11H12BNO2 | 详情 | 详情 | |
| (XVII) | 68966 | 5,6-dihydropyrrolo[3,2,1-ij]quinoline;5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline;1,7-Trimethyleneindol;1,8-Trimethyleneindole | 5840-01-7 | C11H11N | 详情 | 详情 |
| (XVIII) | 68967 | 1-benzyl-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione | C30H23N3O2 | 详情 | 详情 |