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【结 构 式】 
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【分子编号】51947 【品名】(18S)-18-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]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 【CA登记号】 |
【 分 子 式 】C29H29N3O4S 【 分 子 量 】515.63308 【元素组成】C 67.55% H 5.67% N 8.15% O 12.41% S 6.22% |
合成路线1
该中间体在本合成路线中的序号：(XXVI)Hydrolysis of macrocycle (XV) with KOH in refluxing EtOH yields anhydride (XXIII), which is then treated with hexamethyldisilazane (HMDS) and MeOH (in DMF at 80 C) to afford compound (XXIV). Detritylation of (XXIV) with either HCl in CH2Cl2 or HCl in refluxing EtOH gives alcohol (XXV), which is treated with methanesulfonic anhydride and pyridine in either refluxing THF to produce mesylate (XXVI). Finally, the desired product is obtained by reaction of (XXVI) with dimethylamine in THF or DMF. Alternatively, the conversion of (XXV) into the target compound can also be performed by following these steps: treatment of (XXV) with bromine, pyridine and triphenyl phosphite followed by reaction with pyrrolodione provides bromo derivative (XXVII), which is finally converted into the target compound by reaction with dimethylamine in DMF.
| 【2】 Jirousek, M.R.; Gillig, J.R.; Gonzalez, C.M.; et al.; (S)-13-[(Dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16,21-dimetheno-1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-dione (LY333531) and related analogues: Isozyme selective inhibitors of protein kinase Cbeta. J Med Chem 1996, 39, 14, 2664. |
| 【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. |
| 【3】 Heath, W.F. Jr.; Jirousek, M.R.; McDonald, J.H. III; Rito, C.J. (Eli Lilly and Company); Protein kinase C inhibitors. CA 2137203; EP 0657458; JP 1995238044; US 5624949 . |
| 【4】 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 . |
| 【5】 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 . |
| 【6】 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 . |
| 【7】 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 |
|---|---|---|---|---|---|---|
| (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 | |
| (XXIII) | 51945 | (18S)-18-[(4-benzhydrylphenoxy)methyl]-4,17-dioxa-14,21-diazahexacyclo[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 | C45H36N2O5 | 详情 | 详情 | |
| (XXIV) | 51946 | (18S)-18-[(4-benzhydrylphenoxy)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 | |
| (XXV) | 41013 | (18S)-18-(hydroxymethyl)-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 | C26H23N3O4 | 详情 | 详情 | |
| (XXVI) | 51947 | (18S)-18-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]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 | C29H29N3O4S | 详情 | 详情 | |
| (XXVII) | 41018 | (18S)-18-(bromomethyl)-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 | C26H22BrN3O3 | 详情 | 详情 |