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【结 构 式】 
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【药物名称】GW-475151A(hydrochloride), GW-475151 【化学名称】(3S,3aS,6aR)-3-Isopropyl-1-(methylsulfonyl)-4-[2-(1-pyrrolidinylmethyl)oxazol-4-ylcarbonyl]perhydropyrrolo[3,2-b]pyrrol-2-one 【CA登记号】221323-42-8, 221323-43-9 (diastereomer), 221321-77-3 (monohydrochloride) 【 分 子 式 】C19H28N4O5S 【 分 子 量 】424.52281 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Chronic Obstructive Pulmonary Diseases (COPD), Treatment of, Cystic Fibrosis, Treatment of , Respiratory Distress Syndrome, Agents for, RESPIRATORY DRUGS, Leukocyte Elastase Inhibitors |
合成路线1
Synthesis of oxazole intermediate (IX): The reaction of 2,2-dichloroacetonitrile (I) with sodium methoxide in methanol gives methyl 2,2-dichloroethanimidoate (II), which is cyclized with DL-serine methyl ester (III) in methanol to yield oxazoline (IV). The reaction of (IV) with sodium methoxide in methanol affords 2-(chloromethyl)-4-methoxy-4,5-dihydrooxazole-4-carboxylic acid methyl ester (V), which is treated with Ts-OH in refluxing toluene to provide the chloromethyloxazole (VI). The reaction of (VI) with pyrrolidine (VII) in toluene gives the 2-(1-pyrrolidinylmethyl)oxazole-4-carboxylic acid methyl ester (VIII), which is hydrolyzed with K2CO3 to yield the target oxazole (IX). Alternatively, the reaction of 2-(bromomethyl)oxazole-4-carboxylic acid ethyl ester (X) with pyrrolidine (VII) gives the precursor (XI), which is hydrolyzed with K2CO3 as before to afford the target oxazole intermediate (IX).
| 【1】 Hermitage, S.A.; et al.; An efficient, practical approach to the synthesis of 2,4-disubstituted thiazoles and oxazoles: Application to the synthesis of GW475151. Org Process Res Dev 2001, 5, 1, 37. |
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 47789 | 2,2-dichloroacetonitrile; Dichloroacetonitrile | 3018-12-0 | C2HCl2N | 详情 | 详情 |
| (II) | 47790 | methyl 2,2-dichloroethanimidoate | C3H5Cl2NO | 详情 | 详情 | |
| (III) | 14224 | Serine, methyl ester; methyl 2-amino-3-hydroxypropanoate | 2104-89-4 | C4H9NO3 | 详情 | 详情 |
| (IV) | 47791 | methyl 2-(dichloromethyl)-4,5-dihydro-1,3-oxazole-4-carboxylate | C6H7Cl2NO3 | 详情 | 详情 | |
| (V) | 47792 | methyl 2-(chloromethyl)-4-methoxy-4,5-dihydro-1,3-oxazole-4-carboxylate | C7H10ClNO4 | 详情 | 详情 | |
| (VI) | 47793 | methyl 2-(chloromethyl)-1,3-oxazole-4-carboxylate | C6H6ClNO3 | 详情 | 详情 | |
| (VII) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (VIII) | 47794 | methyl 2-(1-pyrrolidinylmethyl)-1,3-oxazole-4-carboxylate | C10H14N2O3 | 详情 | 详情 | |
| (IX) | 47795 | potassium 2-(1-pyrrolidinylmethyl)-1,3-oxazole-4-carboxylate | C9H11KN2O3 | 详情 | 详情 | |
| (X) | 47796 | ethyl 2-(bromomethyl)-1,3-oxazole-4-carboxylate | C7H8BrNO3 | 详情 | 详情 | |
| (XI) | 47797 | ethyl 2-(1-pyrrolidinylmethyl)-1,3-oxazole-4-carboxylate | C11H16N2O3 | 详情 | 详情 |
合成路线2
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3
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 |
合成路线4
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 |