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【结 构 式】 
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【分子编号】19113 【品名】(2S)-1-[(benzyloxy)carbonyl]-2-pyrrolidinecarboxylic acid 【CA登记号】1148-11-4 |
【 分 子 式 】C13H15NO4 【 分 子 量 】249.26644 【元素组成】C 62.64% H 6.07% N 5.62% O 25.67% |
合成路线1
该中间体在本合成路线中的序号：(VIII)Nitrophenoxyacetate (III) (prepared from 2-nitrophenol (I) and tert-butyl bromoacetate), was reduced with H2 in the presence of Pd/C to give aniline (IV). This was condensed with Z-D-Phe (V) using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (EDC) and 1-hydroxybenzotriazole (HOBt) to yield amide (VI), which was deprotected to amine (VII) by hydrogenolysis in the presence of Pd/C. Subsequent coupling with Z-Pro (VIII), followed by hydrogenolytic deprotection produced (IX). This was coupled with methyl oxalyl chloride (X) to afford (XI). Then, treatment with trifluoroacetic acid in CH2Cl2 gave acid (XII). Finally, dipeptide (XV) (obtained by coupling of protected 3-amino-2-hydroxy-4-phenylbutyric acid (XIII) with tert-butyl prolinamide (XIV)), was condensed with acid (XII) to produce the title compound.
| 【1】 Asagarasu, A.; et al.; Synthesis of dipeptide-type human immunodeficiency virus (HIV) protease inhibitors with a binding unit to GP120. Chem Pharm Bull 1998, 46, 5, 867. |
| 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) | 19106 | 2-nitrophenol | 88-75-5 | C6H5NO3 | 详情 | 详情 |
| (II) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (III) | 19108 | tert-butyl 2-(2-nitrophenoxy)acetate | C12H15NO5 | 详情 | 详情 | |
| (IV) | 19109 | tert-butyl 2-(2-aminophenoxy)acetate | C12H17NO3 | 详情 | 详情 | |
| (V) | 19110 | (2R)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropionic acid | C17H17NO4 | 详情 | 详情 | |
| (VI) | 19111 | tert-butyl 2-[2-[((2R)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropanoyl)amino]phenoxy]acetate | C29H32N2O6 | 详情 | 详情 | |
| (VII) | 19112 | tert-butyl 2-(2-[[(2R)-2-amino-3-phenylpropanoyl]amino]phenoxy)acetate | C21H26N2O4 | 详情 | 详情 | |
| (VIII) | 19113 | (2S)-1-[(benzyloxy)carbonyl]-2-pyrrolidinecarboxylic acid | 1148-11-4 | C13H15NO4 | 详情 | 详情 |
| (IX) | 19114 | tert-butyl 2-[2-[((2R)-3-phenyl-2-[[(2S)pyrrolidinylcarbonyl]amino]propanoyl)amino]phenoxy]acetate | C26H33N3O5 | 详情 | 详情 | |
| (X) | 19115 | [(chlorocarbonyl)oxy](methoxy)methane | C3H5ClO3 | 详情 | 详情 | |
| (XI) | 19116 | methyl 2-((2S)-2-[[((1R)-1-benzyl-2-[2-[2-(tert-butoxy)-2-oxoethoxy]anilino]-2-oxoethyl)amino]carbonyl]pyrrolidinyl)-2-oxoacetate | C29H35N3O8 | 详情 | 详情 | |
| (XII) | 19117 | 2-(2-[[(2R)-2-([[(2S)-1-(2-methoxy-2-oxoacetyl)pyrrolidinyl]carbonyl]amino)-3-phenylpropanoyl]amino]phenoxy)acetic acid | C25H27N3O8 | 详情 | 详情 | |
| (XIII) | 19118 | (2S,3S)-3-[[(benzyloxy)carbonyl]amino]-2-hydroxy-4-phenylbutyric acid | C18H19NO5 | 详情 | 详情 | |
| (XIV) | 19119 | (2S)-N-(tert-butyl)-2-pyrrolidinecarboxamide | C9H18N2O | 详情 | 详情 | |
| (XV) | 19120 | (2S)-1-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutanoyl]-N-(tert-butyl)-2-pyrrolidinecarboxamide | C19H29N3O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)This compound has been obtained by two related ways: 1) The reaction of 1-(tert-butoxycarbonylamino)cyclopentane-1-carboxylic acid (I) with ammonia, EDC and HOBT gives the amide (II), which is deprotected with 4N HCl and condensed with N-(tert-butoxycarbonyl)-D-methionine (III) by means of EDC and HOBT yielding the dipeptide (IV). The cyclization of (IV) with methyl iodide and NaH affords the pyrrolidinone (V), which is deprotected with HCl and condensed with 1-(benzyloxycarbonyl)-L-proline (VI) by means of EDC and HOBT giving the protected seudopeptide (VII). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C. 2) The deprotection of (V) with HCl and its condensation with 1-(tert-butoxycarbonyl)-L-proline (VIII) by means of EDC and HOBT gives the protected seudopeptide (IX), which is finally deprotected with 4N HCl.
| 【1】 Evans, M.C.; et al.; Synthesis and dopamine receptor modulating activity of novel peptidomimetics of L-prolyl-L-leucyl-glycinamide featuring alpha,alpha-disubstituted amino acids. J Med Chem 1999, 42, 8, 1441. |
| 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) | 30890 | 1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid | C11H19NO4 | 详情 | 详情 | |
| (II) | 30891 | tert-butyl 1-(aminocarbonyl)cyclopentylcarbamate | C11H20N2O3 | 详情 | 详情 | |
| (III) | 26710 | (2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butyric acid | 5241-66-7 | C10H19NO4S | 详情 | 详情 |
| (IV) | 30892 | tert-butyl (1R)-1-([[1-(aminocarbonyl)cyclopentyl]amino]carbonyl)-3-(methylsulfanyl)propylcarbamate | C16H29N3O4S | 详情 | 详情 | |
| (V) | 30893 | tert-butyl (3R)-1-[1-(aminocarbonyl)cyclopentyl]-2-oxopyrrolidinylcarbamate | C15H25N3O4 | 详情 | 详情 | |
| (VI) | 19113 | (2S)-1-[(benzyloxy)carbonyl]-2-pyrrolidinecarboxylic acid | 1148-11-4 | C13H15NO4 | 详情 | 详情 |
| (VII) | 30894 | benzyl (2S)-2-[([(3R)-1-[1-(aminocarbonyl)cyclopentyl]-2-oxopyrrolidinyl]amino)carbonyl]-1-pyrrolidinecarboxylate | C23H30N4O5 | 详情 | 详情 | |
| (VIII) | 16734 | (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid | C10H17NO4 | 详情 | 详情 | |
| (IX) | 30895 | tert-butyl (2S)-2-[([(3R)-1-[1-(aminocarbonyl)cyclopentyl]-2-oxopyrrolidinyl]amino)carbonyl]-1-pyrrolidinecarboxylate | C20H32N4O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Coupling of PhCH2OOC-Pro-OH (I) with diphenyl (1-amino-2-phenylethyl)phosphonate (II) by means of DCC in THF affords derivative (III), which is then subjected to hydrogenation followed by coupling with PhCH2OOC -Val-OH (IV) by means of DCC to provide peptide derivative (V). Finally, reaction of (V) with succinic anhydride in EtOAc under an atmosphere of H2 in the presence of Pd/C provides the target compound.
| 【1】 Oleksyszym, J.; Powers, J.C.; Irreversible inhibition of serine proteases by peptide derivatives of (alpha-aminoalkyl)phosphonate diphenyl esters. Biochemistry 1991, 30, 2, 485. |
| 【2】 Powers, J.C.; Ni, L.; Jackson, D.S. (Georgia Technology Research Corp.); Basic alpha-aminoalkylphosphonate derivs.. US 5952307 . |
| 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) | 19113 | (2S)-1-[(benzyloxy)carbonyl]-2-pyrrolidinecarboxylic acid | 1148-11-4 | C13H15NO4 | 详情 | 详情 |
| (II) | 44216 | diphenyl (1R)-1-amino-2-phenylethylphosphonate | C20H20NO3P | 详情 | 详情 | |
| (III) | 44217 | benzyl (2S)-2-([[(1R)-1-(diphenoxyphosphoryl)-2-phenylethyl]amino]carbonyl)-1-pyrrolidinecarboxylate | C33H33N2O6P | 详情 | 详情 | |
| (IV) | 18092 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid | C13H17NO4 | 详情 | 详情 | |
| (V) | 44218 | diphenyl (1R)-1-([[(2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)pyrrolidinyl]carbonyl]amino)-2-phenylethylphosphonate | C38H42N3O7P | 详情 | 详情 | |
| (VI) | 11291 | Dihydro-2,5-furandione; Succinic anhydride | 108-30-5 | C4H4O3 | 详情 | 详情 |