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【结 构 式】 
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【分子编号】41013 【品名】(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 【CA登记号】 |
【 分 子 式 】C26H23N3O4 【 分 子 量 】441.48644 【元素组成】C 70.74% H 5.25% N 9.52% O 14.5% |
合成路线1
该中间体在本合成路线中的序号：(XXV)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 |
合成路线2
该中间体在本合成路线中的序号：(XV)Protection of (R)-glycidol (I) with trityl chloride (II) and TEA in dichloromethane gives the trityl ether (III), which is condensed with vinylmagnesium bromide (IV) in THF to yield the pentenol (V). The alkylation of (V) with allyl bromide (VI) by means of NaH in THF affords the allyl ether (VII), which is oxidized with O3 in methanol/dichloromethane, giving dialdehyde (VIII). Reduction of (VIII) with NaBH4 in ethanol provides diol (IX), which is treated with mesyl chloride and TEA in dichloromethane to afford the fully protected alcohol (X). Cyclization of (X) with 3,4-bis(3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione (XI) by means of Cs2CO3 in DMF yields the hexacyclic compound (XII), which is N-demethylated by reaction with KOH in refluxing ethanol to give the hexacyclic furan derivative (XIII), which is then treated with hexamethyldisilazane (HMDS) in hot methanol to afford the hexacyclic demethylated pyrrole (XIV). Elimination of the trityl protecting group of (XIV) with HCl in dichloromethane gives the methanol derivative (XV), which is treated with Br2, pyridine and triphenyl phosphite in dichloromethane to yield the bromomethyl derivative (XVI). Finally, this compound is treated with dimethylamine in DMF to provide LY-333531. Alternatively, compound (XV) is treated with methanesulfonic anhydride and pyridine in THF, giving the mesylate (XVII), which is then treated with dimethylamine as before.
| 【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】 Sorbera, L.A.; Rabasseda, X.; Silvestre, J.S.; Castañer, J.; LY-333531 Mesylate Hydrate. Drugs Fut 2000, 25, 10, 1017-1026. |
| 【3】 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 . |
| 【4】 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 . |
| 【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. 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) | 16260 | (R)-(+)-Glycidol; (2R)-Oxiranemethanol; (2R)oxiranylmethanol | 57044-25-4 | C3H6O2 | 详情 | 详情 |
| (II) | 28630 | Triphenylchloromethane; 1-[Chloro(diphenyl)methyl]benzene; Trityl chloride | 76-83-5 | C19H15Cl | 详情 | 详情 |
| (III) | 41006 | (2S)-oxiranylmethyl trityl ether; (2S)-2-[(trityloxy)methyl]oxirane | C22H20O2 | 详情 | 详情 | |
| (IV) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (V) | 41007 | (2S)-1-(trityloxy)-4-penten-2-ol | C24H24O2 | 详情 | 详情 | |
| (VI) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (VII) | 41008 | 1-[[[(2S)-2-(allyloxy)-4-pentenyl]oxy](diphenyl)methyl]benzene; allyl (1S)-1-[(trityloxy)methyl]-3-butenyl ether | C27H28O2 | 详情 | 详情 | |
| (VIII) | 41009 | (3S)-3-(2-oxoethoxy)-4-(trityloxy)butanal | C25H24O4 | 详情 | 详情 | |
| (IX) | 41010 | (3S)-3-(2-hydroxyethoxy)-4-(trityloxy)-1-butanol | C25H28O4 | 详情 | 详情 | |
| (X) | 41011 | (3S)-3-[2-[(methylsulfonyl)oxy]ethoxy]-4-(trityloxy)butyl methanesulfonate | C27H32O8S2 | 详情 | 详情 | |
| (XI) | 41012 | 3,4-di(1H-indol-3-yl)-1-methyl-1H-pyrrole-2,5-dione | 113963-68-1 | C21H15N3O2 | 详情 | 详情 |
| (XII) | 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 | |
| (XIII) | 41017 | (18S)-18-[(trityloxy)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 | |
| (XIV) | 41014 | (18S)-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 | |
| (XV) | 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 | |
| (XVI) | 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 | |
| (XVII) | 41015 | [(18S)-3,5-dioxo-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-nonaen-18-yl]methyl methanesulfonate | C27H25N3O6S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XV)The carbinol intermediate (XV) has also been obtained as follows: Alkylation of 4-(tert-butyldiphenylsilyloxy)-3(S)-hydroxybutyric acid methyl ester (XVIII) with allyl trichloroacetylimidate (XIX) and trifluoromethanesulfonic acid gives the allyl ether (XX), which is reduced with DIBAL in toluene to afford the alcohol (XXI). Ozonolysis of (XXI) with O3 in methanol provides the hydroxyaldehyde (XXII), which is reduced with NaBH4 in methanol, giving diol (XXIII). Reaction of (XXIII) with MsCl and TEA in ether yields the dimesylate (XXIV), which is treated with NaI in hot acetone to provide the diiodide (XXV). Cyclization of (XXV) with 3,4-bis(3-indolyl)-1-methyl-2,5-dihydro-1H-pyrrole-2,5-dione (XI) by means of Cs2CO3 in DMF gives the hexacyclic compound (XXVI), which is demethylated as before by reaction with KOH in refluxing ethanol to the hexacyclic furan derivative (XXVII) and then treated with HMDS in hot methanol to give the demethylated pyrrole derivative (XXVIII). Finally, this compound is desilylated with HCl to the carbinol (XV).
| 【1】 Sorbera, L.A.; Rabasseda, X.; Silvestre, J.S.; Castañer, J.; LY-333531 Mesylate Hydrate. Drugs Fut 2000, 25, 10, 1017-1026. |
| 【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. |
| 【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 . |
| 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 |
| (XV) | 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 | |
| (XVIII) | 41019 | methyl (3S)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-hydroxybutanoate | C21H28O4Si | 详情 | 详情 | |
| (XIX) | 22755 | allyl 2,2,2-trichloroethanimidoate | 51479-73-3 | C5H6Cl3NO | 详情 | 详情 |
| (XX) | 41020 | methyl (3S)-3-(allyloxy)-4-[[tert-butyl(diphenyl)silyl]oxy]butanoate | C24H32O4Si | 详情 | 详情 | |
| (XXI) | 41021 | (3S)-3-(allyloxy)-4-[[tert-butyl(diphenyl)silyl]oxy]-1-butanol | C23H32O3Si | 详情 | 详情 | |
| (XXII) | 41022 | 2-[[(1S)-1-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3-hydroxypropyl]oxy]acetaldehyde | C22H30O4Si | 详情 | 详情 | |
| (XXIII) | 41023 | (3S)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-(2-hydroxyethoxy)-1-butanol | C22H32O4Si | 详情 | 详情 | |
| (XXIV) | 41024 | (3S)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-[2-[(methylsulfonyl)oxy]ethoxy]butyl methanesulfonate | C24H36O8S2Si | 详情 | 详情 | |
| (XXV) | 41025 | tert-butyl(diphenyl)silyl (2S)-4-iodo-2-(2-iodoethoxy)butyl ether; tert-butyl[[(2S)-4-iodo-2-(2-iodoethoxy)butyl]oxy]diphenylsilane | C22H30I2O2Si | 详情 | 详情 | |
| (XXVI) | 41026 | (18S)-18-([[tert-butyl(diphenyl)silyl]oxy]methyl)-4-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 | C43H43N3O4Si | 详情 | 详情 | |
| (XXVII) | 41027 | (18S)-18-([[tert-butyl(diphenyl)silyl]oxy]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 | C42H40N2O5Si | 详情 | 详情 | |
| (XXVIII) | 41028 | (18S)-18-([[tert-butyl(diphenyl)silyl]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 | C42H41N3O4Si | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XI)A new synthesis of (9S)-9-(hydroxymethyl)-6,7,10,11- tetrahydro-9H,18H-5,21:12,17-dimethenodibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecine-18,20-dione (XI), a key intermediate in the synthesis of LY-333531, has been reported: Enantiocontrolled condensation of 2-bromoethanol (I) with epoxide (II) by means of a chiral Pd catalyst, triethylborane and DMAP in dichloromethane gives the chiral allyl ether (III), which is protected with TIPS-OTf yielding the silyl ether (IV). Hydroboration of ether (IV) with 9-BBN followed by oxidation with H2O2 provides the primary alcohol (V), which is mesylated with MsCl to afford the mesylate (VI). Mesylate (VI) is cyclized with the bisindolylmaleimide (VII) by means of Cs2CO3 in DMF at 100 C resulting in the macrocyclic compound (VIII). Hydrolysis of (VIII) with KOH, followed by acidic workup yields the anhydride (IX), which by treatment with HMDS in methanolic DMF provides the maleimide (X). Finally, this compound is desilyl-ated with TBAF to afford the target intermediate (XI).
| 【1】 Trost, B.M.; Tang, W.; An enantioselective strategy to macrocyclic bisinsolylmaleimides, an efficient formal synthesis of LY 333531. Org Lett 2001, 3, 21, 3409. |
| 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) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
| (II) | 32805 | 2-vinyloxirane | 930-22-3 | C4H6O | 详情 | 详情 |
| (III) | 53241 | (2S)-2-(2-bromoethoxy)-3-buten-1-ol | n/a | C6H11BrO2 | 详情 | 详情 |
| (IV) | 53242 | {[(2S)-2-(2-bromoethoxy)-3-butenyl]oxy}(triisopropyl)silane; (2S)-2-(2-bromoethoxy)-3-butenyl triisopropylsilyl ether | n/a | C15H31BrO2Si | 详情 | 详情 |
| (V) | 53243 | (3S)-3-(2-bromoethoxy)-4-[(triisopropylsilyl)oxy]-1-butanol | n/a | C15H33BrO3Si | 详情 | 详情 |
| (VI) | 53244 | (3S)-3-(2-bromoethoxy)-4-[(triisopropylsilyl)oxy]butyl methanesulfonate | n/a | C16H35BrO5SSi | 详情 | 详情 |
| (VII) | 53245 | 1-benzyl-3,4-di(1H-indol-3-yl)-1H-pyrrole-2,5-dione | n/a | C27H19N3O2 | 详情 | 详情 |
| (VIII) | 53246 | (18S)-4-benzyl-18-{[(triisopropylsilyl)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 | n/a | C42H49N3O4Si | 详情 | 详情 |
| (IX) | 53247 | (18S)-18-{[(triisopropylsilyl)oxy]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 | n/a | C35H42N2O5Si | 详情 | 详情 |
| (X) | 53248 | (18S)-18-{[(triisopropylsilyl)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 | n/a | C35H43N3O4Si | 详情 | 详情 |
| (XI) | 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 |