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【结 构 式】 
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【分子编号】22839 【品名】tert-butyl 3-[((2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoyl)amino]-4-hydroxy-1-pyrrolidinecarboxylate 【CA登记号】 |
【 分 子 式 】C23H35N3O6 【 分 子 量 】449.54752 【元素组成】C 61.45% H 7.85% N 9.35% O 21.35% |
合成路线1
该中间体在本合成路线中的序号：(VII)3-Pyrroline (I) was protected with di-tert-buyl dicarbonate to give N-Boc-pyrroline (II), which was then epoxidized with meta-chloroperbenzoic acid. The resulting epoxide (III) was opened with sodium azide in aqueous MeOH to yield trans-azidoalcohol (IV). Subsequent reduction of the azide (IV) to aminoalcohol (V) was effected by hydrogenation over Pd/C (1). Condensation of the racemic trans-aminoalcohol (V) with N-Cbz-L-leucine (VI) in the presence of EDC and HOBt provided amide (VII) as a diastereomeric mixture. The N-Boc group of (VII) was then deprotected with HCl in EtOAc, and the resulting amine (VIII) was coupled with another N-Cbz-L-leucine (VI) unit to give (IX). Oxidation of the alcohol group of (IX) to the target ketone was accomplished with Jones reagent in acetone. The diastereomeric mixture was separated by reverse phase-HPLC, however the diastereomers were not configurationally stable and reequilibrated spontaneusly to the original mixture.
| 【1】 Marquis, R.W.; Yamashita, D.S.; Ru, Y.; LoCastro, S.M.; Oh, H.J.; Erhard, K.F.; DesJarlais, R.L.; Head, M.S.; Smith, W.W.; Zhao, B.; Janson, C.A.; Abdel-Meguid, S.S.; Tomaszek, T.A.; Levy, M.A.; Veber, D.F.; Conformationally constrained 1,3-diamino ketones: a series of potent inhibitors of the cysteine protease cathepsin K. J Med Chem 1998, 41, 19, 3563. |
| 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) | 22833 | 2,5-dihydro-1H-pyrrole;3-Pyrroline | 109-96-6 | C4H7N | 详情 | 详情 |
| (II) | 22834 | 2,5-Dihydro-1H-pyrrole-1-carboxylic acid 1,1-d;2,5-Dihydropyrrole-1-carboxylic acid tert-butyl ester;tert-Butyl 2H-pyrrole-1(5H)-carboxylate;1-tert-Butoxycarbonylpyrroline;tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate | 73286-70-1 | C9H15NO2 | 详情 | 详情 |
| (III) | 22835 | tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate | C9H15NO3 | 详情 | 详情 | |
| (IV) | 22836 | tert-butyl (3R,4S)-3-azido-4-hydroxy-1-pyrrolidinecarboxylate | 143700-05-4 | C9H16N4O3 | 详情 | 详情 |
| (V) | 22837 | tert-butyl (3S,4S)-3-amino-4-hydroxy-1-pyrrolidinecarboxylate | 190792-74-6 | C9H18N2O3 | 详情 | 详情 |
| (VI) | 22838 | (2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoic acid | C14H19NO4 | 详情 | 详情 | |
| (VII) | 22839 | tert-butyl 3-[((2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoyl)amino]-4-hydroxy-1-pyrrolidinecarboxylate | C23H35N3O6 | 详情 | 详情 | |
| (VIII) | 22840 | benzyl (1S)-1-[[(4-hydroxy-3-pyrrolidinyl)amino]carbonyl]-3-methylbutylcarbamate | C18H27N3O4 | 详情 | 详情 | |
| (IX) | 22841 | benzyl (1S)-1-([3-[((2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoyl)amino]-4-hydroxy-1-pyrrolidinyl]carbonyl)-3-methylbutylcarbamate | C32H44N4O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)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 |