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【结 构 式】

【分子编号】41009

【品名】(3S)-3-(2-oxoethoxy)-4-(trityloxy)butanal

【CA登记号】

【 分 子 式 】C25H24O4

【 分 子 量 】388.46316

【元素组成】C 77.3% H 6.23% O 16.47%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(VIII)

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
Extended Information