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【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%

与该中间体有关的原料药合成路线共 4 条

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
Extended Information