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【结 构 式】 
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【分子编号】46599 【品名】[[(3R,4S)-4-azidotetrahydro-3-furanyl]oxy](trimethyl)silane; (3R,4S)-4-azidotetrahydro-3-furanyl trimethylsilyl ether 【CA登记号】 |
【 分 子 式 】C7H15N3O2Si 【 分 子 量 】201.30062 【元素组成】C 41.77% H 7.51% N 20.87% O 15.9% Si 13.95% |
合成路线1
该中间体在本合成路线中的序号：(II)A new concise synthesis of nelfinavir has been reported: The asymmetric desymmetrization of the meso-epoxide (I) by means of azidotrimethylsilane and a chiral (R,R)-(salen)chromium(III) complex as catalyst gives the chiral 3-(trimethylsilyloxy)-4-azidotetrahydrofuran (II), which is deprotected with TFA in methanol yielding the chiral 4-azidotetrahydrofuran-3-ol (III). Hydrogenation of (III) with H2 over PtO2 affords the chiral 4-aminotetrahydrofuran-3-ol (IV), which is condensed with 3-acetoxy-2-methylbenzoyl chloride (V) by means of NaHCO3 in dichloromethane to provide amide (VI). The mesylation of the OH group of (VI) with Ms-Cl gives mesylate (VII), which is isomerized with Ac2O and H2SO4 to yield oxazoline (VIII). Condensation of compound (VIII) with the perhydroisoquinoline-3-carboxamide derivative (IX) by means of K2CO3 in methanol affords the oxazoline-adduct (X). Finally, the oxazoline-ring opening of compound (X) is performed with thiophenol (XI) and KHCO3.
| 【1】 Inaba, T.; Cho, H.; Yamada, Y.; Sagawa, S.; Abe, H.; (1S)-1-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethylammonium benzoate, a versatile building block for chiral 2-aminoalkanols: Concise synthesis and application to nelfinavir, a potent HIV-protease inhibitor. J Org Chem 2000, 65, 6, 1623. |
| 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) | 46598 | 3,6-dioxabicyclo[3.1.0]hexane | C4H6O2 | 详情 | 详情 | |
| (II) | 46599 | [[(3R,4S)-4-azidotetrahydro-3-furanyl]oxy](trimethyl)silane; (3R,4S)-4-azidotetrahydro-3-furanyl trimethylsilyl ether | C7H15N3O2Si | 详情 | 详情 | |
| (III) | 46600 | (3R,4S)-4-azidotetrahydro-3-furanol | C4H7N3O2 | 详情 | 详情 | |
| (IV) | 46601 | (3R,4S)-4-aminotetrahydro-3-furanol | C4H9NO2 | 详情 | 详情 | |
| (V) | 46596 | 3-(chlorocarbonyl)-2-methylphenyl acetate | C10H9ClO3 | 详情 | 详情 | |
| (VI) | 46602 | 3-([[(3S,4R)-4-hydroxytetrahydro-3-furanyl]amino]carbonyl)-2-methylphenyl acetate | C14H17NO5 | 详情 | 详情 | |
| (VII) | 46603 | 2-methyl-3-[([(3S,4R)-4-[(methylsulfonyl)oxy]tetrahydro-3-furanyl]amino)carbonyl]phenyl acetate | C15H19NO7S | 详情 | 详情 | |
| (VIII) | 46604 | (2R)-2-[(4S)-2-[3-(acetoxy)-2-methylphenyl]-4,5-dihydro-1,3-oxazol-4-yl]-2-[(methylsulfonyl)oxy]ethyl acetate | C17H21NO8S | 详情 | 详情 | |
| (IX) | 13955 | (3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide | C14H26N2O | 详情 | 详情 | |
| (X) | 46605 | (3S,4aS,8aS)-N-(tert-butyl)-2-[(2R)-2-hydroxy-2-[(4S)-2-(3-hydroxy-2-methylphenyl)-4,5-dihydro-1,3-oxazol-4-yl]ethyl]decahydro-3-isoquinolinecarboxamide | C26H39N3O4 | 详情 | 详情 | |
| (XI) | 12951 | Benzenethiol; Phenylmercaptan; Phenylhydrosulfide | 108-98-5 | C6H6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Asymmetric opening of epoxide (I) with trimethylsilyl azide in the presence of (R,R)-N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamino-chromium as the chiral catalyst (Salen catalyst) provided the (3S,4R)-azido silyl alcohol (II). Removal of the silyl group with camphorsulfonic acid in MeOH and subsequent reduction of the azido moiety of (II) with hydrogen in the presence of Pd/C afforded the amino alcohol (III). Coupling of (III) with the mixed anhydride prepared from N-Cbz-leucine (IV) and isobutyric acid gave amide (V). The N-carbobenzoxy group of (V) was then removed by hydrogenolysis, yielding amine (VI), which was coupled with benzothiophene-2-carbonyl chloride (VII) to furnish the diamide (VIII). The secondary alcohol of (VIII) was finally oxidized to the target ketone using the Dess-Martin reagent in CH2Cl2.
| 【1】 Fenwick, A.E.; Ife, R.J.; Gribble, A.D.; Witherington, J.; Stevens, N.; Diastereoselective synthesis, activity and chiral stability of cyclic alkoxyketone inhibitors of cathepsin K. Bioorg Med Chem Lett 2001, 11, 2, 199. |
| 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) | 46598 | 3,6-dioxabicyclo[3.1.0]hexane | C4H6O2 | 详情 | 详情 | |
| (II) | 46599 | [[(3R,4S)-4-azidotetrahydro-3-furanyl]oxy](trimethyl)silane; (3R,4S)-4-azidotetrahydro-3-furanyl trimethylsilyl ether | C7H15N3O2Si | 详情 | 详情 | |
| (III) | 46601 | (3R,4S)-4-aminotetrahydro-3-furanol | C4H9NO2 | 详情 | 详情 | |
| (IV) | 22839 | tert-butyl 3-[((2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoyl)amino]-4-hydroxy-1-pyrrolidinecarboxylate | C23H35N3O6 | 详情 | 详情 | |
| (V) | 47941 | benzyl (1S)-1-([[(3S,4R)-4-hydroxytetrahydro-3-furanyl]amino]carbonyl)-3-methylbutylcarbamate | C18H26N2O5 | 详情 | 详情 | |
| (VI) | 47942 | (2S)-2-amino-N-[(3S,4R)-4-hydroxytetrahydro-3-furanyl]-4-methylpentanamide | C10H20N2O3 | 详情 | 详情 | |
| (VII) | 47943 | 1-benzothiophene-2-carbonyl chloride | 39827-11-7 | C9H5ClOS | 详情 | 详情 |
| (VIII) | 47944 | N-[(1S)-1-([[(3S,4R)-4-hydroxytetrahydro-3-furanyl]amino]carbonyl)-3-methylbutyl]-1-benzothiophene-2-carboxamide | C19H24N2O4S | 详情 | 详情 |