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【结 构 式】 
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【分子编号】14547 【品名】(1S)-1-[(2S)oxiranyl]-2-phenylethyl azide; (2S)-2-[(1S)-1-azido-2-phenylethyl]oxirane 【CA登记号】 |
【 分 子 式 】C10H11N3O 【 分 子 量 】189.21696 【元素组成】C 63.48% H 5.86% N 22.21% O 8.46% |
合成路线1
该中间体在本合成路线中的序号：(XXXII)4) The selective esterification of 3(S)-azido-4-phenylbutane-1,2(S)-diol (XXIX) with 2,4,6-triiosopropylbenzenesulfonyl chloride (XXX) gives the sulfonate ester (XXXI), which by treatment with KOH is converted to the azido epoxide (XXXII). The condensation of (XXXII) with decahydroisoquinoline (XI) affords the azido condensation product (XXXIII), which is finally hydrogenated with H2 over Pd/C to the amino condensation product (XIII), already obtained in scheme 16810301a. 5) The reaction of (XXIX) with SOCl2 and RuCl3 gives the dioxathiole dioxide (XXXIV), which is condensed with decahydroisoquinoline (XI) to afford the azido condensation product (XXXIII), already obtained.
| 【1】 Parkes, K.E.B.; Bushnell, D.J.; Crackett, P.H.; et al.; Studies toward the large-scale synthesis of the HIV proteinase inhibitor Ro 31-8959. J Org Chem 1994, 59, 13, 3656. |
| 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) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 | |
| (XIII) | 14528 | (3S,4aS,8aS)-2-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(tert-butyl)decahydro-3-isoquinolinecarboxamide | C24H39N3O2 | 详情 | 详情 | |
| (XXIX) | 14544 | (2S,3S)-3-azido-4-phenyl-1,2-butanediol | C10H13N3O2 | 详情 | 详情 | |
| (XXX) | 14545 | 2,4,6-triisopropylbenzenesulfonyl chloride | 6553-96-4 | C15H23ClO2S | 详情 | 详情 |
| (XXXI) | 14546 | (2S,3S)-3-azido-2-hydroxy-4-phenylbutyl 2,4,6-triisopropylbenzenesulfonate | C25H35N3O4S | 详情 | 详情 | |
| (XXXII) | 14547 | (1S)-1-[(2S)oxiranyl]-2-phenylethyl azide; (2S)-2-[(1S)-1-azido-2-phenylethyl]oxirane | C10H11N3O | 详情 | 详情 | |
| (XXXIII) | 14548 | (3S,4aS,8aS)-2-[(2R,3S)-3-(1-azanylhydrazino)-2-hydroxy-4-phenylbutyl]-N-(tert-butyl)decahydro-3-isoquinolinecarboxamide | C24H41N5O2 | 详情 | 详情 | |
| (XXXIV) | 14549 | (4S)-4-[(1S)-1-azido-2-phenylethyl]-1,3,2lambda(6)-dioxathiolane-2,2-dione | C10H11N3O4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)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3
该中间体在本合成路线中的序号：(XVI)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 |