【结 构 式】 |
【分子编号】28227 【品名】(Z)-1-ethoxy-3-methyl-1-butenyl triisopropylsilyl ether 【CA登记号】 |
【 分 子 式 】C16H34O2Si 【 分 子 量 】286.53026 【元素组成】C 67.07% H 11.96% O 11.17% Si 9.8% |
合成路线1
该中间体在本合成路线中的序号:(VIII)Synthesis of intermediate (XI) of Scheme 25142902e: Racemic 2,4-diaminobutyric acid (I) was esterified in MeOH in the presence of SOCl2. The resulting methyl ester (II) was cyclized using Dowex 2x8-400 resin to give 3-amino-2-pyrrolidinone (III), which was converted to the trifluoroacetamide (IV) using methyl trifluoroacetate in MeOH. The lactam nitrogen of (IV) was then protected with benzyl chloroformate and lithium hexamethyldisilazide yielding (V). Reduction of (V) with NaBH4, followed by treatment with ethanolic H2SO4 provided ethoxypyrrolidine (VI). Ethyl isovalerate (VII) was converted to the silyl enolate (VIII) employing lithium hexamethyldisilazide and silyl triflate. Coupling of (VIII) with ethoxypyrrolidine (VI) in the presence of BF3-Et2O provided (IX). After hydrolysis of the trifluoroacetamide group of (IX) with K2CO3 yielding (X), its cyclization by means of tert-butylmagnesium chloride yielded the pyrrolopyrrolone system. Separation of the required (3aS, 6aR)-isomer (XI) was achieved by chiral HPLC.
【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 |
---|---|---|---|---|---|---|
(I) | 28222 | 2,4-diaminobutyric acid | 1883-09-6 | C4H10N2O2 | 详情 | 详情 |
(II) | 28223 | methyl 2,4-diaminobutanoate | C5H12N2O2 | 详情 | 详情 | |
(III) | 28224 | 3-amino-2-pyrrolidinone | C4H8N2O | 详情 | 详情 | |
(IV) | 28225 | 2,2,2-trifluoro-N-(2-oxo-3-pyrrolidinyl)acetamide | C6H7F3N2O2 | 详情 | 详情 | |
(V) | 28229 | benzyl 2-oxo-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate | C14H13F3N2O4 | 详情 | 详情 | |
(VI) | 28230 | benzyl 2-ethoxy-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate | C16H19F3N2O4 | 详情 | 详情 | |
(VII) | 28226 | ethyl 3-methylbutanoate | 108-64-5 | C7H14O2 | 详情 | 详情 |
(VIII) | 28227 | (Z)-1-ethoxy-3-methyl-1-butenyl triisopropylsilyl ether | C16H34O2Si | 详情 | 详情 | |
(IX) | 28231 | benzyl 2-[1-(ethoxycarbonyl)-2-methylpropyl]-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate | C21H27F3N2O5 | 详情 | 详情 | |
(X) | 28232 | benzyl 3-amino-2-[1-(ethoxycarbonyl)-2-methylpropyl]-1-pyrrolidinecarboxylate | C19H28N2O4 | 详情 | 详情 | |
(XI) | 28228 | benzyl (3aR,6S,6aS)-6-isopropyl-5-oxohexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate | C17H22N2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(VIII)Alternative synthesis of intermediate (XI) of Scheme 25142902e: In an alternative procedure, (R)-asparagine (XII) was protected as the trifluoroacetamide (XIII) and then esterified by means of AcCl in MeOH yielding (XIV). Dehydration of the amide function of (XIV) employing tosyl chloride and pyridine produced nitrile (XV). The catalytic hydrogenation of (XV) with concomitant cyclization of the intermediate amine generated the chiral pyrrolidinone (XVI), which was protected with benzyl chloroformate and n-BuLi to give (XVII). This was converted to the intermediate (XI) by means of a sequence analogous to that for the racemic pyrrolidinone (IV).
【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 |
---|---|---|---|---|---|---|
(VIII) | 28227 | (Z)-1-ethoxy-3-methyl-1-butenyl triisopropylsilyl ether | C16H34O2Si | 详情 | 详情 | |
(XI) | 28228 | benzyl (3aR,6S,6aS)-6-isopropyl-5-oxohexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate | C17H22N2O3 | 详情 | 详情 | |
(XII) | 28237 | R-(-)-Asparagine; S-(-)-2-Aminosuccinamic acid; D-asparagine | 5794-13-8 | C4H8N2O3 | 详情 | 详情 |
(XIII) | 28233 | (2R)-4-amino-4-oxo-2-[(2,2,2-trifluoroacetyl)amino]butyric acid | C6H7F3N2O4 | 详情 | 详情 | |
(XIV) | 28234 | methyl (2R)-4-amino-4-oxo-2-[(2,2,2-trifluoroacetyl)amino]butanoate | C7H9F3N2O4 | 详情 | 详情 | |
(XV) | 28235 | methyl (2R)-3-cyano-2-[(2,2,2-trifluoroacetyl)amino]propanoate | C7H7F3N2O3 | 详情 | 详情 | |
(XVI) | 28236 | 2,2,2-trifluoro-N-[(3R)-2-oxopyrrolidinyl]acetamide | C6H7F3N2O2 | 详情 | 详情 | |
(XVII) | 26700 | benzyl (3R)-2-oxo-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate | C14H13F3N2O4 | 详情 | 详情 | |
(XVIII) | 26702 | benzyl (3R)-2-ethoxy-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate | C16H19F3N2O4 | 详情 | 详情 | |
(XIX) | 26704 | benzyl (2S,3R)-2-[(1S)-1-(ethoxycarbonyl)-2-methylpropyl]-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate | C21H27F3N2O5 | 详情 | 详情 | |
(XX) | 28238 | benzyl (2S,3R)-3-amino-2-[(1S)-1-(ethoxycarbonyl)-2-methylpropyl]-1-pyrrolidinecarboxylate | C19H28N2O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(XIII)Synthesis of silyl enol ether intermediate (XIII): The reaction of ethyl isovalerate (XII) with triisopropylsilyl trifluoromethanesulfonate and 1,3-dimethylperhydropyrimidin-2-one by means of LiHMDS in THF gives the target silyl enol ether (XIII).
【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 . |
合成路线4
该中间体在本合成路线中的序号:(XIII)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 |