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【结 构 式】

【分子编号】26708

【品名】(3S,3aS,6aR)-3-isopropyl-1-(methylsulfonyl)hexahydropyrrolo[3,2-b]pyrrol-2(1H)-one

【CA登记号】

【 分 子 式 】C10H18N2O3S

【 分 子 量 】246.3306

【元素组成】C 48.76% H 7.37% N 11.37% O 19.49% S 13.02%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(XV)

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:(XXXII)

The intermediate pyrrolopyrrolone (XI) was converted to the methanesulfonamide (XXXI) upon treatment with mesyl chloride and lithium hexamethyldisilazide. Removal of the benzyloxycarbonyl group of (XXXI) by hydrogenolysis over Pd(OH)2 produced amine (XXXII). This was coupled with piperidinylbutenoic acid (XXX) using EDC and HOBt to yield the target compound, which was finally converted to the hydrochloride salt.

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
(XI) 28228 benzyl (3aR,6S,6aS)-6-isopropyl-5-oxohexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate C17H22N2O3 详情 详情
(XXX) 26709 (E)-4-(1-piperidinyl)-2-butenoic acid;(E)-4-(piperidin-1-yl)but-2-enoic acid C9H15NO2 详情 详情
(XXXI) 26707 benzyl (3aR,6S,6aS)-6-isopropyl-4-(methylsulfonyl)-5-oxohexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate C18H24N2O5S 详情 详情
(XXXII) 26708 (3S,3aS,6aR)-3-isopropyl-1-(methylsulfonyl)hexahydropyrrolo[3,2-b]pyrrol-2(1H)-one C10H18N2O3S 详情 详情

合成路线3

该中间体在本合成路线中的序号:(XXXIV)

The reaction of D-asparagine (XXIV) with methyl trifluoroacetate (XXII) in methanol gives N-(trifluoroacetyl)-D-asparagine (XXV), which is esterified with MeOH and Ac-Cl, yielding the methyl ester (XXVI). The reaction of (XXVI) with TsCl and pyridine in dichloromethane affords the 3-cyanopropionic ester (XXVII), which is cyclized by hydrogenation over a Rh/Al2O3 catalyst in ethanol to provide the pyrrolidinone (XXVIII). Finally, this compound is condensed with benzyl chloroformate and BuLi in THF to furnish the target pyrrolidinone intermediate (XXIII). Assembly of the target compound: The reductive methylation of intermediate pyrrolidinone (XXIII) by means of LiBH4 in THF, followed by treatment with EtOH and conc. H2SO4, gives 2-ethoxy-3(R)-(trifluoroacetamido)pyrrolidine-1-carboxylic acid benzyl ester (XXIX), which is condensed with the intermediate silyl enol ether (XIII) by means of BF3/Et2O in dichloromethane to yield the adduct (XXX). The deprotection of the amino group of (XXX) with K2CO3 in ethanol/water yields the aminopyrrolidine (XXXI), which is cyclized by means of t-butylmagnesium bromide and TMEDA in THF to afford the bicyclic compound (XXXII). The reaction of the free NH group of (XXXII) with methanesulfonyl chloride and LiHMDS in THF provides the cyclic methanesulfonamide (XXXIII), which is decarboxylated by hydrogenation with H2 over Pd/C in dioxane/ethyl acetate to give the bipyrrolidine derivative (XXXIV). Finally, this compound is condensed with the oxazole intermediate (IX) by means of HOBT and DEC in acetonitrile.

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 .
2 Johnson, M.R.; Shah, P.; MacDonald, S.J.F.; Harrison, L.A.; Finch, H.; Smith, R.A.; Inglis, G.G.A.; Clarke, G.D.E.; Dowle, M.D. (Glaxo Group Ltd.); Pyrrolopyrrolone derivs. as inhibitors of neutrophil elastase. WO 9912933 .
3 Hermitage, S.A.; Cardwell, K.S. (Glaxo Group Ltd.); Process for preparing oxazole derivs.. WO 0053589 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 47795 potassium 2-(1-pyrrolidinylmethyl)-1,3-oxazole-4-carboxylate C9H11KN2O3 详情 详情
(XIII) 28227 (Z)-1-ethoxy-3-methyl-1-butenyl triisopropylsilyl ether C16H34O2Si 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
(XXIV) 28237 R-(-)-Asparagine; S-(-)-2-Aminosuccinamic acid; D-asparagine 5794-13-8 C4H8N2O3 详情 详情
(XXV) 28233 (2R)-4-amino-4-oxo-2-[(2,2,2-trifluoroacetyl)amino]butyric acid C6H7F3N2O4 详情 详情
(XXVI) 28234 methyl (2R)-4-amino-4-oxo-2-[(2,2,2-trifluoroacetyl)amino]butanoate C7H9F3N2O4 详情 详情
(XXVII) 28235 methyl (2R)-3-cyano-2-[(2,2,2-trifluoroacetyl)amino]propanoate C7H7F3N2O3 详情 详情
(XXVIII) 28236 2,2,2-trifluoro-N-[(3R)-2-oxopyrrolidinyl]acetamide C6H7F3N2O2 详情 详情
(XXIX) 47800 benzyl (2S,3R)-2-ethoxy-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate C16H19F3N2O4 详情 详情
(XXX) 47801 benzyl (2S,3R)-2-[(1S)-1-(ethoxycarbonyl)-2-methylpropyl]-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate C21H27F3N2O5 详情 详情
(XXXI) 26705 benzyl (2S,3R)-3-amino-2-[(1S)-1-(ethoxycarbonyl)-2-methylpropyl]-1-pyrrolidinecarboxylate C19H28N2O4 详情 详情
(XXXII) 28228 benzyl (3aR,6S,6aS)-6-isopropyl-5-oxohexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate C17H22N2O3 详情 详情
(XXXIII) 26707 benzyl (3aR,6S,6aS)-6-isopropyl-4-(methylsulfonyl)-5-oxohexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate C18H24N2O5S 详情 详情
(XXXIV) 26708 (3S,3aS,6aR)-3-isopropyl-1-(methylsulfonyl)hexahydropyrrolo[3,2-b]pyrrol-2(1H)-one C10H18N2O3S 详情 详情
Extended Information