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【结 构 式】 
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【分子编号】32805 【品名】2-vinyloxirane 【CA登记号】930-22-3 |
【 分 子 式 】C4H6O 【 分 子 量 】70.09104 【元素组成】C 68.55% H 8.63% O 22.83% |
合成路线1
该中间体在本合成路线中的序号：(II)The enantiocontrolled addition of phthalimide (I) to 1,3-butadiene monoepoxide (II) with a chiral palladium catalyst and Na2CO3 in dichloromethane gives N-(2-hydroxy-1(S)-vinylethyl)phthalimide (III), which is treated with triflic anhydride and TEA in dichloromethane to yield the triflate (IV). The condensation of (IV) with dimethyl malonate (V) by means of NaH in THF affords the alkylated malonate (VI), which is finally decarboxylated and deprotected by a treatment with aqueous refluxing HCl. Note that the synthesis of the biologically active (S)-enantiomer simply requires a change in the chirality of the Pd catalyst used in the first step of the synthesis.
| 【1】 Trost, B.M.; et al.; Dynamic kinetic asymetric transformation of diene monoepoxides: A practical asymmetric synthesis of vinylglycinol, vigabatrin, and ethambutol. J Am Chem Soc 2000, 122, 25, 5968. |
| 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) | 12376 | Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione | 85-41-6 | C8H5NO2 | 详情 | 详情 |
| (II) | 32805 | 2-vinyloxirane | 930-22-3 | C4H6O | 详情 | 详情 |
| (III) | 38039 | 2-[(1S)-1-(hydroxymethyl)-2-propenyl]-1H-isoindole-1,3(2H)-dione | C12H11NO3 | 详情 | 详情 | |
| (IV) | 38040 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-butenyl trifluoromethanesulfonate | C13H10F3NO5S | 详情 | 详情 | |
| (V) | 19373 | dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester | 108-59-8 | C5H8O4 | 详情 | 详情 |
| (VI) | 38041 | dimethyl 2-[(2R)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-butenyl]malonate | C17H17NO6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)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3
该中间体在本合成路线中的序号：(I)The Grignard reaction of vinyloxirane (I) with phenylmagnesium bromide and CuCN in THF gives 4-phenyl-2-buten-1-ol (II), which is submitted to a Sharpless epoxidation with t-BuOOH and Ti(Oi-Pr)4 in dichloromethane in the presence of (-)-diethyl tartrate [(-)-DET] yielding the chiral epoxide (III). The reaction of (III) with Ti(Oi-Pr)2(N3)2 in refluxing benzene affords the 3(S)-azido-4-phenylbutane-1,2(S)-diol (IV), which is epoxidized with 2-acetoxy-2-methylpropionyl chloride (A) and NaOMe in THF to give the chiral azidoepoxide (V). The reaction of (V) with isobutylamine (VI) in hot isopropanol yields the secondary amine (VII), which is condensed with 4-methoxyphenylsulfonyl chloride (VIII) in pyridine affording the sulfonamide (IX). The reduction of the azido group of (IX) with H2 over Pd/C in methanol provides (X) with a primary amino group that is finally condensed with the succinimidinyl carbonate (XI) by means of triethylamine in acetonitrile.
| 【1】 Ghosh, A.K.; Kincaid, J.F.; Cho, W.; Walters, D.E.; Krishnan, K.; Hussain, K.A.; Koo, Y.; Cho, H.; Rudall, C.; Holland, L.; Buthod, J.; Potent HIV protease inhibitors incorporating high-affinity P2-ligands and (R)-(hydroxyethylamino)sulfonamide isostere. Bioorg Med Chem Lett 1998, 8, 6, 687. |
| 【2】 Hussain, K.A.; Gulnik, S.V.; Ghosh, A.K.; Erickson, J.W. (University of Illinois; US Department of Health & Human Services); Multi-drug resistant retroviral protease inhibitors and associated methods. WO 9967254 . |
| 【3】 Ghosh, A.K.; et al.; Potent HIV protease inhibitors: The development of tetrahydrofuranylglycines as novel P2-ligands and pyrazine amides as P3-ligands. J Med Chem 1993, 36, 16, 2300. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 17616 | bromo(phenyl)magnesium; Phenyl Magnesium Bromide | 100-58-3 | C6H5BrMg | 详情 | 详情 | |
| (A) | 32808 | 2-chloro-1,1-dimethyl-2-oxoethyl acetate | 40635-66-3 | C6H9ClO3 | 详情 | 详情 |
| (I) | 32805 | 2-vinyloxirane | 930-22-3 | C4H6O | 详情 | 详情 |
| (II) | 32806 | (E)-4-phenyl-2-buten-1-ol | C10H12O | 详情 | 详情 | |
| (III) | 32807 | [(2R,3S)-3-benzyloxiranyl]methanol | 116949-62-3 | C10H12O2 | 详情 | 详情 |
| (IV) | 14544 | (2S,3S)-3-azido-4-phenyl-1,2-butanediol | C10H13N3O2 | 详情 | 详情 | |
| (V) | 14547 | (1S)-1-[(2S)oxiranyl]-2-phenylethyl azide; (2S)-2-[(1S)-1-azido-2-phenylethyl]oxirane | C10H11N3O | 详情 | 详情 | |
| (VI) | 13306 | 2-Methyl-1-propanamine; Isobutylamine | 78-81-9 | C4H11N | 详情 | 详情 |
| (VII) | 32809 | (2R,3S)-3-azido-1-(isobutylamino)-4-phenyl-2-butanol | C14H22N4O | 详情 | 详情 | |
| (VIII) | 15719 | 4-methoxybenzenesulfonyl chloride | 98-68-0 | C7H7ClO3S | 详情 | 详情 |
| (IX) | 32810 | N-[(2R,3S)-3-azido-2-hydroxy-4-phenylbutyl]-N-isobutyl-4-methoxybenzenesulfonamide | C21H28N4O4S | 详情 | 详情 | |
| (X) | 32811 | N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutyl-4-methoxybenzenesulfonamide | C21H30N2O4S | 详情 | 详情 | |
| (XI) | 32812 | 1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione | C11H13NO7 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XI)The reaction of butadiene monooxide (XI) with phenylmagnesium bromide (XII) and CuCN in THF gives trans-4-phenyl-2-buten-1-ol (XIII), which is enantioselectively epoxidated with Ti(O-iPr)4, diethyl D-tartrate and tBu-OOH to yield the (2R,3R)-epoxide (XIV). The reaction of (XIV) with Ti(O-iPr)4 and N3-SiMe3 in refluxing benzene affords the chiral azidodiol (XV), which is epoxidated by means of 2-acetoxyisobutyryl chloride (AcBCl) and NaOMe in THF to provide the chiral azidoepoxide (XVI) (1). Opening of the epoxide ring of (XVI) with isobutylamine (XVII) in hot isopropanol gives the secondary amine (XVIII), which is acylated with 4-aminophenylsulfonyl chloride (XIX) and pyridine in dichloromethane to yield the corresponding sulfonamide (XX). The reduction of the azido group of (XX) with H2 over Pd/C in THF/methanol/HOAc affords the expected primary amine (XXI), which is finally condensed with the already reported intermediate (X) in dichloromethane to provide the target carbamate.
| 【1】 Ghosh, A.K.; Kincaid, J.F.; Cho, W.; Walters, D.E.; Krishnan, K.; Hussain, K.A.; Koo, Y.; Cho, H.; Rudall, C.; Holland, L.; Buthod, J.; Potent HIV protease inhibitors incorporating high-affinity P2-ligands and (R)-(hydroxyethylamino)sulfonamide isostere. Bioorg Med Chem Lett 1998, 8, 6, 687. |
| 【2】 Hussain, K.A.; Gulnik, S.V.; Ghosh, A.K.; Erickson, J.W. (University of Illinois; US Department of Health & Human Services); Multi-drug resistant retroviral protease inhibitors and associated methods. WO 9967254 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 32812 | 1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione | C11H13NO7 | 详情 | 详情 | |
| (XI) | 32805 | 2-vinyloxirane | 930-22-3 | C4H6O | 详情 | 详情 |
| (XII) | 17616 | bromo(phenyl)magnesium; Phenyl Magnesium Bromide | 100-58-3 | C6H5BrMg | 详情 | 详情 |
| (XIII) | 32806 | (E)-4-phenyl-2-buten-1-ol | C10H12O | 详情 | 详情 | |
| (XIV) | 53549 | [(2R,3R)-3-benzyloxiranyl]methanol | n/a | C10H12O2 | 详情 | 详情 |
| (XV) | 14544 | (2S,3S)-3-azido-4-phenyl-1,2-butanediol | C10H13N3O2 | 详情 | 详情 | |
| (XVI) | 14547 | (1S)-1-[(2S)oxiranyl]-2-phenylethyl azide; (2S)-2-[(1S)-1-azido-2-phenylethyl]oxirane | C10H11N3O | 详情 | 详情 | |
| (XVII) | 13306 | 2-Methyl-1-propanamine; Isobutylamine | 78-81-9 | C4H11N | 详情 | 详情 |
| (XVIII) | 32809 | (2R,3S)-3-azido-1-(isobutylamino)-4-phenyl-2-butanol | C14H22N4O | 详情 | 详情 | |
| (XIX) | 53550 | 4-aminobenzenesulfonyl chloride | 98-62-4 | C6H6ClNO2S | 详情 | 详情 |
| (XX) | 53551 | 4-amino-N-[(2R,3S)-3-azido-2-hydroxy-4-phenylbutyl]-N-isobutylbenzenesulfonamide | n/a | C20H27N5O3S | 详情 | 详情 |
| (XXI) | 45533 | 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutylbenzenesulfonamide | C20H29N3O3S | 详情 | 详情 |