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【结 构 式】 
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【分子编号】26709 【品名】(E)-4-(1-piperidinyl)-2-butenoic acid；(E)-4-(piperidin-1-yl)but-2-enoic acid 【CA登记号】 |
【 分 子 式 】C9H15NO2 【 分 子 量 】169.22364 【元素组成】C 63.88% H 8.93% N 8.28% O 18.91% |
合成路线1
该中间体在本合成路线中的序号：(XVI)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：(XXX)Synthesis of intermediate (XXX) of Scheme 25142902e: Alkylation of piperidine (XXVII) with ethyl 4-bromocrotonate (XXVIII) afforded tertiary amine (XXIX). Acid hydrolysis of the ethyl ester of (XXIX) then provided carboxylic acid (XXX).
| 【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 |
|---|---|---|---|---|---|---|
| (XXVII) | 10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 |
| (XXVIII) | 28239 | ethyl (E)-4-bromo-2-butenoate | 37746-78-4 | C6H9BrO2 | 详情 | 详情 |
| (XXIX) | 28240 | ethyl (E)-4-(1-piperidinyl)-2-butenoate | C11H19NO2 | 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 |
合成路线3
该中间体在本合成路线中的序号：(XXX)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4
该中间体在本合成路线中的序号：(XXVII)Compound (XIII) can be obtained by reductocondensation of 3-chloro-4-fluoroaniline (XIX) with 3,4-dimethoxybenzaldehyde (XXI) using NaCNBH3 or NaBH(OAc)3 in AcOH/i-PrOH to yield the benzylaniline derivative (XXII), which by condensation with 4-chloro-7-fluoro-6-nitroquinazoline (XVIII) in i-PrOH gives the tertiary amine (XXIII) . Substitution of fluoroquinazoline (XXIII) with NaOMe in refluxing MeOH affords the 7-methoxyquinazoline derivative (XXIV), which is reduced to the quinazoline-4,6-diamine (XXV) by means of H2 over Raney Ni in THF. Finally, compound (XXV) is coupled with 4-(piperidin-1-yl)-2-butenoyl chloride (IV) in DMA .
4-(Piperidin-1-yl)-2-butenoyl chloride (IV) can be prepared by condensation of methyl 4-bromocrotonate (XI) with piperidine (X) to yield methyl 4-(piperidin-1-yl)-2-butenoate (XXVI), which is then hydrolyzed with HCl to give 4-(piperidin-1-yl)-2-butenoic acid (XXVII). Finally, acid (XXVII) is reacted with (COCl)2 in the presence of DMF in CH2Cl2 .
| 【1】 Fakhoury, S.A., Lee, H.T., Reed, J.E., Schlosser, K.M., Sexton, K.E., Tecle, H., Winters, R.T. (Pfizer, Inc.). 4-Phenylamino-quinazolin-6-yl-amides. EP 1746999, JP 200753668, JP 2009007363, US 2005250761, US 7772243, WO 2005107758. |
| 【2】 Bridges, A.J., Horne, N.M., Jacks, T.E. et al. (Pfizer, Inc.). Preparation of substituted quinazolines. JP 2006517959, US 2004158065, WO 2004069791. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| （XXVI) | 68482 | (E)-methyl 4-(piperidin-1-yl)but-2-enoate | C10H17NO2 | 详情 | 详情 | |
| (IV) | 68473 | 4-(piperidin-1-yl)-2-butenoyl chloride；(E)-4-(piperidin-1-yl)but-2-enoyl chloride | C9H14ClNO | 详情 | 详情 | |
| (X) | 10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 |
| (XI) | 26358 | methyl (E)-4-bromo-2-butenoate | 1117-71-1 | C5H7BrO2 | 详情 | 详情 |
| (XIII) | 68477 | (E)-N-(4-((3-chloro-4-fluorophenyl)(3,4-dimethoxybenzyl)amino)-7-methoxyquinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide | C33H35ClFN5O4 | 详情 | 详情 | |
| (XVIII) | 19142 | 4-chloro-7-fluoro-6-nitroquinazoline | C8H3ClFN3O2 | 详情 | 详情 | |
| (XIX) | 18688 | 3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline | 367-21-5 | C6H5ClFN | 详情 | 详情 |
| (XXI) | 18304 | 3,4-Dimethoxybenzaldehyde; Veratraldehyde | 120-14-9 | C9H10O3 | 详情 | 详情 |
| (XXII) | 68478 | 3-chloro-N-(3,4-dimethoxybenzyl)-4-fluoroaniline | C15NClFO2 | 详情 | 详情 | |
| (XXIII) | 68479 | N-(3-chloro-4-fluorophenyl)-N-(3,4-dimethoxybenzyl)-6-fluoro-7-nitroquinazolin-4-amine | C23H17ClF2N4O4 | 详情 | 详情 | |
| (XXIV) | 68480 | N-(3-chloro-4-fluorophenyl)-N-(3,4-dimethoxybenzyl)-6-methoxy-7-nitroquinazolin-4-amine | C24H20ClFN4O5 | 详情 | 详情 | |
| (XXV) | 68481 | N4-(3-chloro-4-fluorophenyl)-N4-(3,4-dimethoxybenzyl)-6-methoxyquinazoline-4,7-diamine | C24H22ClFN4O3 | 详情 | 详情 | |
| (XXVII) | 26709 | (E)-4-(1-piperidinyl)-2-butenoic acid；(E)-4-(piperidin-1-yl)but-2-enoic acid | C9H15NO2 | 详情 | 详情 |