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【结 构 式】 
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【分子编号】16260 【品名】(R)-(+)-Glycidol; (2R)-Oxiranemethanol; (2R)oxiranylmethanol 【CA登记号】57044-25-4 |
【 分 子 式 】C3H6O2 【 分 子 量 】74.07944 【元素组成】C 48.64% H 8.16% O 43.2% |
合成路线1
该中间体在本合成路线中的序号：(XXIII)4) The condensation of the chiral piperazine (VII) with (S)-(+)-glycicyl 3-nitrobenzenesulfonate (XXII) by means of diisopropylethylamine in DMF [or with (S)-glycidol (XXIII), tosyl chloride and NaH] gives the epoxide (XXIV), which is condensed with the propionamide (IV) by means of butyllithium in THF, yielding the protected hydroxyamide (XXV). The deprotection of (XXV) with aqueous HCl affords the dihydroxy-diamide (VIII), already obtained, which is finally alkylated with 3-(chloromethyl)pyridine (IX) as before.
| 【1】 Mealy, N.; Castaner, J.; Indinavir Sulfate. Drugs Fut 1996, 21, 6, 600. |
| 【2】 Askin, D.; Reider, P.; Rossen, K.; Varsolona, R.J.; Wells, K.M. (Merck & Co., Inc.); Process for making HIV protease inhibitors. WO 9502583 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 16241 | 1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-3-phenyl-1-propanone | C21H23NO2 | 详情 | 详情 | |
| (VII) | 16244 | tert-butyl (3S)-3-[(tert-butylamino)carbonyl]tetrahydro-1(2H)-pyrazinecarboxylate | 150323-35-6 | C14H27N3O3 | 详情 | 详情 |
| (VIII) | 16245 | (2S)-1-((2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl)-N-(tert-butyl)-2-piperazinecarboxamide | C30H42N4O4 | 详情 | 详情 | |
| (IX) | 15793 | 3-(Chloromethyl)pyridine | 3099-31-8 | C6H6ClN | 详情 | 详情 |
| (XXII) | 16259 | (2S)oxiranylmethyl 3-nitrobenzenesulfonate; (S)-(+)-Glycidyl nosylate | 115314-14-2 | C9H9NO6S | 详情 | 详情 |
| (XXIII) | 16260 | (R)-(+)-Glycidol; (2R)-Oxiranemethanol; (2R)oxiranylmethanol | 57044-25-4 | C3H6O2 | 详情 | 详情 |
| (XXIV) | 16261 | tert-butyl (3S)-3-[(tert-butylamino)carbonyl]-4-[(2R)oxiranylmethyl]tetrahydro-1(2H)-pyrazinecarboxylate | C17H31N3O4 | 详情 | 详情 | |
| (XXV) | 16262 | tert-butyl (3S)-4-[(2S,4R)-5-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-4-benzyl-2-hydroxy-5-oxopentyl]-3-[(tert-butylamino)carbonyl]-1-piperazinecarboxylate | C38H54N4O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XLVI)The reaction of (R)-glycidol (XLVI) with dihydropyran (DHP) and PPTS in dichloromethane gives the protected glycidol (XLVII), which is treated with the lithium acetylide (XLVIII) and BF3/Et2O in THF to yield the acetylenic alcohol (IL). The protection of the OH group of (IL) with Mem-Cl and DIEA in hot dichloroethane affords compound (L), which is treated with PPTS in methanol to provide the primary alcohol (LI). The oxidation of (LI) with oxalyl chloride in DMSO/dichloromethane gives the corresponding aldehyde (LII), which is treated with Me-MgBr in ethyl ether to yield the secondary alcohol (LIII). The oxidation of (LIII) with TPAP and NMO in dichloromethane affords the methyl ketone (LIV), which is condensed with the phosphine oxide (LV) by means of BuLi in THF, providing the adduct (LVI). The reaction of (LVI) with N-iodosuccinimide (NIS) and Cy2BH in ethyl ether gives the iodovinyl compound (LVII), which is treated with acetic anhydride, yielding the intermediate (IX).
| 【1】 Bertinato, P.; Danishefsky, S.J.; Su, D.-S.; Kamenecka, T.; Meng, D.F.; Sorensen, E.J.; Savin, K.A.; Chou, T.-C.; Balog, A. (Sloan-Kettering Institute); Synthesis of epothilones, intermediates thereto, analogues and uses thereof. JP 2001507716; US 6242469; WO 9901124 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IL) | 46994 | (2S)-1-(tetrahydro-2H-pyran-2-yloxy)-5-(trimethylsilyl)-4-pentyn-2-ol | C13H24O3Si | 详情 | 详情 | |
| (IX) | 44493 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl acetate | C13H16INO2S | 详情 | 详情 | |
| (XLVI) | 16260 | (R)-(+)-Glycidol; (2R)-Oxiranemethanol; (2R)oxiranylmethanol | 57044-25-4 | C3H6O2 | 详情 | 详情 |
| (XLVII) | 46993 | (2S)oxiranylmethyl tetrahydro-2H-pyran-2-yl ether; 2-[(2S)oxiranylmethoxy]tetrahydro-2H-pyran | C8H14O3 | 详情 | 详情 | |
| (XLVIII) | 16299 | Lithium (trimethylsilyl)acetylide; [2-(Trimethylsilyl)ethynyl]lithium | 54655-07-1 | C5H9LiSi | 详情 | 详情 |
| (L) | 46995 | (2S)-2-(methoxymethoxy)-5-(trimethylsilyl)-4-pentynyl tetrahydro-2H-pyran-2-yl ether; [(4S)-4-(methoxymethoxy)-5-(tetrahydro-2H-pyran-2-yloxy)-1-pentynyl](trimethyl)silane | C15H28O4Si | 详情 | 详情 | |
| (LI) | 46996 | (2S)-2-(methoxymethoxy)-5-(trimethylsilyl)-4-pentyn-1-ol | C10H20O3Si | 详情 | 详情 | |
| (LII) | 46997 | (2S)-2-(methoxymethoxy)-5-(trimethylsilyl)-4-pentynal | C10H18O3Si | 详情 | 详情 | |
| (LIII) | 46998 | (3S)-3-(methoxymethoxy)-6-(trimethylsilyl)-5-hexyn-2-ol | C11H22O3Si | 详情 | 详情 | |
| (LIV) | 46999 | (3S)-3-(methoxymethoxy)-6-(trimethylsilyl)-5-hexyn-2-one | C11H20O3Si | 详情 | 详情 | |
| (LV) | 47000 | (2-methyl-1,3-thiazol-4-yl)methyl(diphenyl)phosphine oxide; 4-[(diphenylphosphoryl)methyl]-2-methyl-1,3-thiazole | C17H16NOPS | 详情 | 详情 | |
| (LVI) | 47001 | 4-[(E,3S)-3-(methoxymethoxy)-2-methyl-6-(trimethylsilyl)-1-hexen-5-ynyl]-2-methyl-1,3-thiazole; methoxymethyl (1S)-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4-(trimethylsilyl)-3-butynyl ether | C16H25NO2SSi | 详情 | 详情 | |
| (LVII) | 47002 | (1S,3Z)-4-iodo-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-butenyl methoxymethyl ether; 4-[(1E,3S,5Z)-6-iodo-3-(methoxymethoxy)-2-methyl-1,5-hexadienyl]-2-methyl-1,3-thiazole | C13H18INO2S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)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4
该中间体在本合成路线中的序号：(III)The enantioselective epoxidation of allyl alcohol (I) with 2-phenylisopropyl hydroperoxide (II) and Ti(iPrO)4 in the presence of D-diisopropyl tartrate gives the chiral epoxide (III), which is esterified with pivaloyl chloride to yield the pivalate (IV). The opening of the epoxide ring of (IV) by means of lithium acetylide (V) and BF3/Et2O affords the alkynyl alcohol (VI), which is cyclized by means of Mo(CO)6 and trimethylamine oxide to provide the chiral dihydrofuran (VII). The oxidation of (VII) with OsO4 and 4-methylmorpholine-N-oxide (NMMO) gives the diol (VIII), which is treated with Ac2O to yield the diacetate (IX). The condensation of (IX) with N6-benzoyl-N6,7-bis(trimethylsilyl)adenine (X) by means of Tms-OTf affords the nucleoside (XI). Finally, this compound is deprotected by means of NaOMe in methanol.
| 【1】 Gleason, M.M.; McDonald, F.E.; Asymmetric synthesis of nucleosides via molybdenum-catalyzed alkynol cycloisomerization coupled with stereoselective glycosylations of deoxyfuranose glycals and 3-amidofuranose glycals. J Am Chem Soc 1996, 118, 28, 6648. |
| 【2】 Gleason, M.M.; McDonald, F.E.; Asymmetric syntheses of stavudine (d4T) and cordycepin by cycloisomerization of alkynyl alcohols to endocyclic enol ethers. Angew Chem. Int Ed Engl 1995, 34, 3, 350. |
| 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) | 12234 | 2-Propen-1-ol; Allyl alcohol | 107-18-6 | C3H6O | 详情 | 详情 |
| (II) | 49206 | alpha,alpha-Dimethylbenzyl hydroperoxide; Cumyl hydroperoxide; Cumene Hydroperoxide | 80-15-9 | C9H12O2 | 详情 | 详情 |
| (III) | 16260 | (R)-(+)-Glycidol; (2R)-Oxiranemethanol; (2R)oxiranylmethanol | 57044-25-4 | C3H6O2 | 详情 | 详情 |
| (IV) | 12235 | (2S)oxiranylmethyl pivalate | C8H14O3 | 详情 | 详情 | |
| (V) | 17461 | ethynyllithium | C2HLi | 详情 | 详情 | |
| (VI) | 12260 | diethyl 2-(2,4,5-trifluoro-3-methoxybenzoyl)malonate | C15H15F3O6 | 详情 | 详情 | |
| (VII) | 12226 | (2S)-2,3-dihydro-2-furanylmethyl pivalate | C10H16O3 | 详情 | 详情 | |
| (VIII) | 49207 | [(2S,4R,5R)-4,5-dihydroxytetrahydro-2-furanyl]methyl pivalate | C10H18O5 | 详情 | 详情 | |
| (IX) | 49208 | [(2S,4R,5S)-4,5-bis(acetoxy)tetrahydro-2-furanyl]methyl pivalate | C14H22O7 | 详情 | 详情 | |
| (X) | 49209 | N-(trimethylsilyl)-N-[7-(trimethylsilyl)-7H-purin-6-yl]benzamide | C18H25N5OSi2 | 详情 | 详情 | |
| (XI) | 49210 | [(2S,4R,5R)-4-(acetoxy)-5-[6-(benzoylamino)-9H-purin-9-yl]tetrahydro-2-furanyl]methyl pivalate | C24H27N5O6 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)4-Benzyloxyphenol (I) was protected as the silyl ether (II) upon treatment with tert-butyldiphenylsilyl chloride and imidazole. Then, benzyl ether cleavage in (II) by means of transfer hydrogenolysis with cyclohexene and Pd/C furnished the silyloxy phenol (III). Coupling of phenol (III) with (R)-glycidol (IV) under Mitsunobu conditions yielded the intermediate glycidyl ether (V).
| 【1】 Solvibile, W.R.; et al.; Potent, selective agonists of the human beta3-adrenergic receptor. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 35. |
| 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) | 18956 | 4-(Benzyloxy)phenol; 4-Benzyloxyphenol | 103-16-2 | C13H12O2 | 详情 | 详情 |
| (II) | 52062 | [4-(benzyloxy)phenoxy](tert-butyl)diphenylsilane; benzyl 4-[[tert-butyl(diphenyl)silyl]oxy]phenyl ether | C29H30O2Si | 详情 | 详情 | |
| (III) | 52063 | 4-[[tert-butyl(diphenyl)silyl]oxy]phenol | C22H24O2Si | 详情 | 详情 | |
| (IV) | 16260 | (R)-(+)-Glycidol; (2R)-Oxiranemethanol; (2R)oxiranylmethanol | 57044-25-4 | C3H6O2 | 详情 | 详情 |
| (V) | 52064 | tert-butyl[4-[(2S)oxiranylmethoxy]phenoxy]diphenylsilane; tert-butyl(diphenyl)silyl 4-[(2S)oxiranylmethoxy]phenyl ether | C25H28O3Si | 详情 | 详情 |