【结 构 式】 |
【药物名称】Ruboxistaurin mesilate hydrate, LY-333531 mesylate hydrate 【化学名称】9(S)-(Dimethylaminomethyl)-6,7,10,11,19,20-hexahydro-9H,18H-5,21:12,17-dimethenodibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecine-18,20-dione monomethanesulfonate monohydrate 【CA登记号】202260-21-7, 192050-59-2 (anhydrous), 169939-94-0 (anhydrous free base), 286453-43-8 (hydrochloride hydrate), 286453-44-9 (hydro 【 分 子 式 】C29H34N4O7S 【 分 子 量 】582.68093 |
【开发单位】Lilly (Originator), Takeda (Licensee) 【药理作用】Diabetic Neuropathy, Agents for, Diabetic Retinopathy, Agents for, ENDOCRINE DRUGS, OCULAR MEDICATIONS, ONCOLYTIC DRUGS, Ophthalmic Drugs, Treatment of Diabetic Complications, Inhibitors of Signal Transduction Pathways, Protein Kinase PKC beta Inhibitors |
合成路线1
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2
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3
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4
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5
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 |
合成路线6
The intermediate (S)-3-(2-mesyloxyethoxy)-4-(triphenylmethoxy)-1-butanol mesylate (VIII) has been obtained as follows: The hetero Diels Alder cyclization of ethyl glyoxylate (I) with butadiene (II) in toluene at 160-70 C gives racemic 3,6-dihydro-2H pyran-2-carboxylic acid ethyl ester (III), which is submitted to enzymatic resolution by means of B.lentus protease, yielding a mixture of the hydrolyzed (R)-acid and unchanged (S)-ester (IV), that is easily separated. The reduction of the (S)-ester (IV) by means of LiAlH4 in THF affords the hydroxymethyl derivative (V), which is treated with Tr-Cl and DMAP in pyridine to provide the trityl ether (VI). Ozonolysis of the dihydropyran ring of (VI) by means of ozone and NaBH4 in dichloromethane/methanol gives (S)-3-(2-hydroxyethoxy)-4-(triphenylmethoxy)-1-butanol (VII). Finally this compound is treated with Ms-Cl and TEA in dichloromethane to yield the target intermediate (S)-3-(2-mesyloxyethoxy)-4-(triphenylmethoxy)-1-butanol mesylate (VIII). (see scheme no. 25239601a, intermediate no. (X).
【1】 Caille, J.C.; Hetero diels-alder-biocatalysis approach for the synthesis of (S)-3-[2-{(methylsulfonyl)oxy}ethoxy]-4- (triphenylmethoxy)-1-butanol sulfonate, a key intermediate for the synthesis of the PKC inhibitor LY333531. Org Process Res Dev 2002, 6, 4, 471. |
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) | 48591 | Ethyl glyoxylate; Ethyl oxoacetate; Glyoxylic acid ethyl ester | 924-44-7 | C4H6O3 | 详情 | 详情 |
(II) | 11579 | 1,3-Butadiene; Butadiene | 106-99-0 | C4H6 | 详情 | 详情 |
(III) | 56904 | ethyl 3,6-dihydro-2H-pyran-2-carboxylate | C8H12O3 | 详情 | 详情 | |
(IV) | 56905 | ethyl (2S)-3,6-dihydro-2H-pyran-2-carboxylate | C8H12O3 | 详情 | 详情 | |
(V) | 56906 | (2S)-3,6-dihydro-2H-pyran-2-ylmethanol | C6H10O2 | 详情 | 详情 | |
(VI) | 56907 | (2S)-2-[(trityloxy)methyl]-3,6-dihydro-2H-pyran; (2S)-3,6-dihydro-2H-pyran-2-ylmethyl trityl ether | C25H24O2 | 详情 | 详情 | |
(VII) | 41010 | (3S)-3-(2-hydroxyethoxy)-4-(trityloxy)-1-butanol | C25H28O4 | 详情 | 详情 | |
(VIII) | 41011 | (3S)-3-[2-[(methylsulfonyl)oxy]ethoxy]-4-(trityloxy)butyl methanesulfonate | C27H32O8S2 | 详情 | 详情 |