【结 构 式】 |
【分子编号】30890 【品名】1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid 【CA登记号】 |
【 分 子 式 】C11H19NO4 【 分 子 量 】229.2762 【元素组成】C 57.63% H 8.35% N 6.11% O 27.91% |
合成路线1
该中间体在本合成路线中的序号:(II)The N-protection of 1-aminocyclopentane-1-carboxylic acid (I) with Boc2O and NaOH in dioxane gives the carbamate (II), which is condensed with 4-O-methyl-L-tyrosine ethyl ester (III) by means of DCC and HOBt yielding the protected dipeptide (IV). The reaction of (IV) with HCl in dichloromethane affords the free dipeptide (V), which is finally condensed with 2(S)-(acetylsulfanyl)-3-methylbutyric acid (VI) by means of DCC, N-hydroxy-7-azabenzotriazole (HOAt) and triethylamine in dichloromethane.
【1】 Fink, C.A.; et al.; Mercaptoacyl dipeptides as orally active dual inhibitors of angiotensin-converting enzyme and neutral endopeptidase. J Med Chem 1996, 39, 16, 3158. |
【2】 Johnson, E.P.; et al.; Efficient large scale preparation of neutral endopeptidase/angiotensin-converting enzyme dual inhibitor CGS30440. Org Process Res Dev 1998, 2, 4, 238. |
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) | 33149 | 1-aminocyclopentanecarboxylic acid | 52-52-8 | C6H11NO2 | 详情 | 详情 |
(II) | 30890 | 1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid | C11H19NO4 | 详情 | 详情 | |
(III) | 33150 | ethyl (2S)-2-amino-3-(4-methoxyphenyl)propanoate | C12H17NO3 | 详情 | 详情 | |
(IV) | 33151 | ethyl (2S)-2-[([1-[(tert-butoxycarbonyl)amino]cyclopentyl]carbonyl)amino]-3-(4-methoxyphenyl)propanoate | C23H34N2O6 | 详情 | 详情 | |
(V) | 33152 | ethyl (2S)-2-[[(1-aminocyclopentyl)carbonyl]amino]-3-(4-methoxyphenyl)propanoate | C18H26N2O4 | 详情 | 详情 | |
(VI) | 33153 | (2S)-2-(acetylsulfanyl)-3-methylbutyric acid | C7H12O3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(I)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:(IV)Cycloleucine (I) is esterified with HCl/MeOH, and the resultant amino ester (II) is further protected as the tert-butyl carbamate (III) employing Boc2O and Et3N in CH2Cl2. Then, hydrolysis of the methyl ester group of (III) with LiOH furnishes N-Boc-cycloleucine (IV). N-Boc-L-Biphenylalanine (V) is simultaneously deprotected and esterified with HCl/MeOH to yield amino ester (VI). Coupling between N-Boc-cycloleucine (IV) and L-biphenylalanine methyl ester (VI) in the presence of EDC/HOAt gives rise to the protected dipeptide (VII). Subsequent removal of the N-Boc group of (VII) under acidic conditions yields the dipeptide methyl ester (VIII).
【1】 Fink, C.A.; De Lombaert, S.; Hoyer, D.W.; Jeng, A.Y.; Firoozina, F. (Novartis AG; Novartis Pharma GmbH); Certain thiol inhibitors of endothelin-converting enzyme. WO 9955726 . |
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) | 33149 | 1-aminocyclopentanecarboxylic acid | 52-52-8 | C6H11NO2 | 详情 | 详情 |
(II) | 10444 | methyl 1-aminocyclopentanecarboxylate | C7H13NO2 | 详情 | 详情 | |
(III) | 62819 | methyl 1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylate | C12H21NO4 | 详情 | 详情 | |
(IV) | 30890 | 1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid | C11H19NO4 | 详情 | 详情 | |
(V) | 62820 | (2S)-3-[1,1'-biphenyl]-4-yl-2-[(tert-butoxycarbonyl)amino]propanoic acid | C20H23NO4 | 详情 | 详情 | |
(VI) | 62821 | methyl (2S)-2-amino-3-[1,1'-biphenyl]-4-ylpropanoate | C16H17NO2 | 详情 | 详情 | |
(VII) | 62822 | methyl (2S)-3-[1,1'-biphenyl]-4-yl-2-[({1-[(tert-butoxycarbonyl)amino]cyclopentyl}carbonyl)amino]propanoate | C27H34N2O5 | 详情 | 详情 | |
(VIII) | 62823 | methyl (2S)-2-{[(1-aminocyclopentyl)carbonyl]amino}-3-[1,1'-biphenyl]-4-ylpropanoate | C22H26N2O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(V)The protected 4-pyrimidinylphenylalanine (III) was prepared by palladium-catalyzed coupling of the boronophenylalanine (I) with the 5-halopyrimidine (II). After acidic cleavage of the N-Boc protecting group of (III), the resultant amino ester (IV) was coupled with N-Boc-cycloleucine (V) to provide dipeptide (VI). Further acidic treatment of (VI) removed the N-Boc group to yield amine (VII). The chiral bromo acid (IX) was obtained by diazotization of D-valine (VIII) in the presence of HBr and KBr. Acylation of the racemic amine (VII) with bromo acid (IX) furnished the corresponding amide (X) as an epimeric mixture. The bromo group of (X) was finally displaced with potassium thioacetate to give the title thioacetate ester.
【1】 Gude, C.; Chan, K.; Firooznia, F.; et al.; Synthesis and biological activity of novel potent endothelin-converting enzyme-1 inhibitors. Bioorg Med Chem Lett 2001, 11, 3, 375. |
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) | 47701 | methyl 2-[(tert-butoxycarbonyl)amino]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate | C21H32BNO6 | 详情 | 详情 | |
(II) | 38987 | 5-bromopyrimidine | 4595-59-9 | C4H3BrN2 | 详情 | 详情 |
(III) | 47702 | methyl 2-[(tert-butoxycarbonyl)amino]-3-[4-(5-pyrimidinyl)phenyl]propanoate | C19H23N3O4 | 详情 | 详情 | |
(IV) | 47703 | methyl 2-amino-3-[4-(5-pyrimidinyl)phenyl]propanoate | C14H15N3O2 | 详情 | 详情 | |
(V) | 30890 | 1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid | C11H19NO4 | 详情 | 详情 | |
(VI) | 47704 | methyl 2-[([1-[(tert-butoxycarbonyl)amino]cyclopentyl]carbonyl)amino]-3-[4-(5-pyrimidinyl)phenyl]propanoate | C25H32N4O5 | 详情 | 详情 | |
(VII) | 47705 | methyl 2-[[(1-aminocyclopentyl)carbonyl]amino]-3-[4-(5-pyrimidinyl)phenyl]propanoate | C20H24N4O3 | 详情 | 详情 | |
(VIII) | 21056 | (R)-(-)-Valine; D-Valine; (R)-alpha-Aminoisovaleric acid | 640-68-6 | C5H11NO2 | 详情 | 详情 |
(IX) | 33158 | (2R)-2-bromo-3-methylbutyric acid | 565-74-2 | C5H9BrO2 | 详情 | 详情 |
(X) | 47706 | methyl 2-[[(1-[[(2R)-2-bromo-3-methylbutanoyl]amino]cyclopentyl)carbonyl]amino]-3-[4-(5-pyrimidinyl)phenyl]propanoate | C25H31BrN4O4 | 详情 | 详情 |