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【结 构 式】 
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【分子编号】26697 【品名】benzyl (2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoylcarbamate 【CA登记号】 |
【 分 子 式 】C18H26N2O5S 【 分 子 量 】382.48092 【元素组成】C 56.53% H 6.85% N 7.32% O 20.92% S 8.38% |
合成路线1
该中间体在本合成路线中的序号：(IV)The reaction of D-methionine (I) with tert-butoxycarbonyl anhydride and NaOH in water gives the N-protected compound (II), which is treated with more tert-butoxycarbonyl anhydride and ammonium bicarbonate in pyridine/DMF yielding The N-protected methioninamide (III). The protection of the amide group of (III) with benzyloxycarbonyl chloride and BuLi in THF affords the fully protected methioninamidde (IV), which by reaction with methyl iodide in acetone or acetonitrile gives the dimethylsulfonium iodide (V). The cyclization of (V) by means of DOWEX 2X8-400 (hydroxide form) yields the protected 3-aminopyrrolidinone (VI), which by selective deprotection with HCl followed by acylation with methyl trifluoroacetate and NaHCO3 affords N-[1-(benzyloxycarbonyl)-2-oxopyrrolidin-3(R)-yl]trifluoroacetamide (VII). The reduction of the carbonyl group of (VII) with LiBH4 in THF provides the pyrrolidinol (VIII), which is treated with ethanol and conc. H2SO4 giving the ethyl ether (IX). The condensation of (IX) with the triisopropylsilyl derivative of ethyl 3-methylbutyrate (X) by means of BF3 ethearate in dichloromethane yields the 2-pyrrolidinylbutyrate (XI) as predominant isomer, which is destrifluoroacetylated with K2CO3 in refluxing ethanol/water affording aminopyrrolidine (XII). The cyclization of (XII) by means of tert-butylmagnesium chloride in THF gives a mixture of bicyclic pyrrolidones, from which the chiral isomer (XIII) was separated by crystallization. The mesylation of (XIII) with methanesulfonyl chloride and lithium hexamethyldisylazane in THF affords the sulfonamide (XIV), which is deprotected by hydrogenation with H2 over Pd(OH)2 in ethyl acetate/dioxane giving the bicyclic pyrrolidone (XV), which is finally acylated with 4-(1-piperidinyl)-2(E)-butenoic acid (XVI) by means of HOBT and triethylamine in acetonitrile or oxlayl chloride in dichloromethane.
| 【1】 Macdonald, S.J.F.; et al.; A flexible, practical, and stereoselective synthesis of enantiomerically pure trans-5-oxohexahydropyrrolo[3,2-b]pyrroles (pyrrolidine-trans-lactams), a new class of serine protease inhibitors, using acyliminium methodology. J Org Chem 1999, 64, 14, 5166. |
| 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) | 26695 | D-methionine | 348-67-4 | C5H11NO2S | 详情 | 详情 |
| (II) | 26710 | (2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butyric acid | 5241-66-7 | C10H19NO4S | 详情 | 详情 |
| (III) | 26696 | tert-butyl (1R)-1-(aminocarbonyl)-3-(methylsulfanyl)propylcarbamate | C10H20N2O3S | 详情 | 详情 | |
| (IV) | 26697 | benzyl (2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoylcarbamate | C18H26N2O5S | 详情 | 详情 | |
| (V) | 26698 | [(3R)-4-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]-4-oxobutyl](dimethyl)sulfonium iodide | C19H29IN2O5S | 详情 | 详情 | |
| (VI) | 26699 | benzyl (3R)-3-[(tert-butoxycarbonyl)amino]-2-oxo-1-pyrrolidinecarboxylate | C17H22N2O5 | 详情 | 详情 | |
| (VII) | 26700 | benzyl (3R)-2-oxo-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate | C14H13F3N2O4 | 详情 | 详情 | |
| (VIII) | 26701 | benzyl (3R)-2-hydroxy-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate | C14H15F3N2O4 | 详情 | 详情 | |
| (IX) | 26702 | benzyl (3R)-2-ethoxy-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate | C16H19F3N2O4 | 详情 | 详情 | |
| (X) | 26703 | 1-Ethoxy-3-methyl-1-(triisopropylsilyloxy)-1-butene | C7H13O2Pr3Si | 详情 | 详情 | |
| (XI) | 26704 | benzyl (2S,3R)-2-[(1S)-1-(ethoxycarbonyl)-2-methylpropyl]-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate | C21H27F3N2O5 | 详情 | 详情 | |
| (XII) | 26705 | benzyl (2S,3R)-3-amino-2-[(1S)-1-(ethoxycarbonyl)-2-methylpropyl]-1-pyrrolidinecarboxylate | C19H28N2O4 | 详情 | 详情 | |
| (XIII) | 26706 | benzyl (3aR,6S)-6-isopropyl-5-oxohexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate | C17H22N2O3 | 详情 | 详情 | |
| (XIV) | 26707 | benzyl (3aR,6S,6aS)-6-isopropyl-4-(methylsulfonyl)-5-oxohexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate | C18H24N2O5S | 详情 | 详情 | |
| (XV) | 26708 | (3S,3aS,6aR)-3-isopropyl-1-(methylsulfonyl)hexahydropyrrolo[3,2-b]pyrrol-2(1H)-one | C10H18N2O3S | 详情 | 详情 | |
| (XVI) | 26709 | (E)-4-(1-piperidinyl)-2-butenoic acid；(E)-4-(piperidin-1-yl)but-2-enoic acid | C9H15NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXIV)Alternative synthesis of intermediate (XVII) of Scheme 25142902b: In a further procedure, (R)-methionine (XXI), was protected as the Boc derivative (XXII). Subsequent treatment of (XXII) with Boc2O and then with ammonium bicarbonate yielded amide (XXIII), which was condensed with benzyl chloroformate to produce imide (XXIV). The S-alkylation with CH3I yielded sulfonium salt (XXV), which was then cyclized to pyrrolidinone (XXVI) in the presence of Dowex 2x8-400 resin. Acid deprotection of the Boc group of (XXVI), followed by condensation with methyl trifluoroacetate furnished intermediate (XVII) already described in Scheme 25142902b.
| 【1】 Dowle, M.D.; Harrison, L.A.; Macdonald, S.J.F.; Inglis, G.G.A.; Johnson, M.R.; Shah, P.; Clarke, G.D.E.; The discovery and synthesis of some bicyclic trans-lactams having potent neutrophil elastase inhibitory properties. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.215. |
| 【2】 Dowle, M.D.; Finch, H.; Harrison, L.A.; Inglis, G.G.A.; Johnson, M.R.; Macdonald, S.J.F.; Shah, P.; Smith, R.A. (Glaxo Wellcome plc); Pyrrolopyrrolone derivs. as inhibitors of neutrophil elastase. EP 0891362; JP 2000507950; US 5994344; WO 9736903 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 26700 | benzyl (3R)-2-oxo-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate | C14H13F3N2O4 | 详情 | 详情 | |
| (XXI) | 26695 | D-methionine | 348-67-4 | C5H11NO2S | 详情 | 详情 |
| (XXII) | 26710 | (2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butyric acid | 5241-66-7 | C10H19NO4S | 详情 | 详情 |
| (XXIII) | 26696 | tert-butyl (1R)-1-(aminocarbonyl)-3-(methylsulfanyl)propylcarbamate | C10H20N2O3S | 详情 | 详情 | |
| (XXIV) | 26697 | benzyl (2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoylcarbamate | C18H26N2O5S | 详情 | 详情 | |
| (XXV) | 26698 | [(3R)-4-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]-4-oxobutyl](dimethyl)sulfonium iodide | C19H29IN2O5S | 详情 | 详情 | |
| (XXVI) | 26699 | benzyl (3R)-3-[(tert-butoxycarbonyl)amino]-2-oxo-1-pyrrolidinecarboxylate | C17H22N2O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVIII)The reaction of D-methionine (XIV) with Boc2O in dioxane gives the N-protected methionine (XV), which is treated with Boc2O, pyridine and ammonium bicarbonate to yield the methioninamide (XVI). The reaction of (XVI) with benzyl chloroformate (XVII) by means of BuLi in DMF/pyridine affords the carbamate (XVIII), which is treated with methyl iodide in acetone to provide the sulfonium salt (XIX). The cyclization of (XIX) by means of Dowex 2XB-400 (OH form) in acetonitrile gives the N-protected pyrrolidinone (XX), which is deprotected with HCl in dioxane to yield the amino compound (XXI). Finally, this compound is acylated with methyl trifluoroacetate (XXII) and NMM in dichloromethane to afford the target pyrrolidinone intermediate (XXIII).
| 【1】 Dowle, M.D.; Finch, H.; Harrison, L.A.; Inglis, G.G.A.; Johnson, M.R.; Macdonald, S.J.F.; Shah, P.; Smith, R.A. (Glaxo Wellcome plc); Pyrrolopyrrolone derivs. as inhibitors of neutrophil elastase. EP 0891362; JP 2000507950; US 5994344; WO 9736903 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 26695 | D-methionine | 348-67-4 | C5H11NO2S | 详情 | 详情 |
| (XV) | 26710 | (2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butyric acid | 5241-66-7 | C10H19NO4S | 详情 | 详情 |
| (XVI) | 26696 | tert-butyl (1R)-1-(aminocarbonyl)-3-(methylsulfanyl)propylcarbamate | C10H20N2O3S | 详情 | 详情 | |
| (XVII) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (XVIII) | 26697 | benzyl (2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoylcarbamate | C18H26N2O5S | 详情 | 详情 | |
| (XIX) | 26698 | [(3R)-4-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]-4-oxobutyl](dimethyl)sulfonium iodide | C19H29IN2O5S | 详情 | 详情 | |
| (XX) | 26699 | benzyl (3R)-3-[(tert-butoxycarbonyl)amino]-2-oxo-1-pyrrolidinecarboxylate | C17H22N2O5 | 详情 | 详情 | |
| (XXI) | 47798 | benzyl (3R)-3-amino-2-oxo-1-pyrrolidinecarboxylate | C12H14N2O3 | 详情 | 详情 | |
| (XXII) | 47799 | Methyl trifluoroacetate; Trifluoroacetic acid methyl ester; methyl 2,2,2-trifluoroacetate | 431-47-0 | C3H3F3O2 | 详情 | 详情 |
| (XXIII) | 26700 | benzyl (3R)-2-oxo-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate | C14H13F3N2O4 | 详情 | 详情 |