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【结 构 式】 
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【分子编号】42295 【品名】(2R)-N-methyl-2-(methylamino)-3-(2-naphthyl)-N-[(1R)-2-oxo-1-(2-thienylmethyl)-2-(1,2,2-trimethylhydrazino)ethyl]propanamide 【CA登记号】 |
【 分 子 式 】C25H32N4O2S 【 分 子 量 】452.62084 【元素组成】C 66.34% H 7.13% N 12.38% O 7.07% S 7.08% |
合成路线1
该中间体在本合成路线中的序号：(V)Conversion of amino acid (I) into its methyl ester derivative (II) by means of SOCl2 in MeOH, followed by coupling with ethyl isocyanatoacetate (III) and Et3N in CH2Cl2/THF yields derivative (IV). Cyclization of (IV) by means of H2O/HCl affords hydantoin (V), which reacts with 2-methylthio-2-imidazoline (VI) in an aqueous NaOH solution to provide cyclic guanidine derivative (VII). Treatment of amino acid (VIII) with isobutylene (IX) and H2SO4 in dioxane affords t-Bu ester (X), which then couples with (VII) by means of HOBt and DCC in DMF to furnish derivative (XI). Finally, tert-butyl ester is hydrolyzed by treatment with TFA in the presence of 1,2-dimercaptoethane.
| 【1】 Knolle, J.; Peyman, A.; Wehner, V.; et al.; RGD mimetics containing a central hydantoin scaffold: alphavbeta3 vs alphaIIbbeta3 selective requirements. Bioorg Med Chem Lett 2000, 10, 2, 179. |
| 【2】 Wehner, V.; Knolle, J.; Stilz, H.U.; Carniato, D.; Gourvest, J.-F.; Gadek, T.; McDowell, R. (Aventis SA); Inhibitors of bone resorption and vitronectin receptor antagonists. DE 19626701; DE 19635522; EP 0796855 . |
| 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) | 30898 | (2S)-2-amino-5-[[(benzyloxy)carbonyl]amino]pentanoic acid | C13H18N2O4 | 详情 | 详情 | |
| (II) | 42993 | methyl (2S)-2-amino-5-[[(benzyloxy)carbonyl]amino]pentanoate | C14H20N2O4 | 详情 | 详情 | |
| (III) | 18312 | ETHYL ISOCYANATOACETATE; ethyl 2-isocyanatoacetate | 2949-22-6 | C5H7NO3 | 详情 | 详情 |
| (IV) | 42994 | 12-ethyl 8-methyl (8S)-3,10-dioxo-1-phenyl-2-oxa-4,9,11-triazadodecane-8,12-dicarboxylate | C19H27N3O7 | 详情 | 详情 | |
| (V) | 42295 | (2R)-N-methyl-2-(methylamino)-3-(2-naphthyl)-N-[(1R)-2-oxo-1-(2-thienylmethyl)-2-(1,2,2-trimethylhydrazino)ethyl]propanamide | C25H32N4O2S | 详情 | 详情 | |
| (VI) | 42996 | 4,5-dihydro-1H-imidazol-2-yl methyl sulfide; 2-(methylsulfanyl)-4,5-dihydro-1H-imidazole | 5464-11-9 | C4H8N2S | 详情 | 详情 |
| (VII) | 42997 | 2-[(4S)-4-[3-(4,5-dihydro-1H-imidazol-2-ylamino)propyl]-2,5-dioxoimidazolidinyl]acetic acid | C11H17N5O4 | 详情 | 详情 | |
| (VIII) | 18008 | (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propionic acid; N(alpha)-Z-L-2,3-diaminopropionic acid | 35761-26-3 | C11H14N2O4 | 详情 | 详情 |
| (IX) | 15926 | 2-methyl-1-propene; isobutylene | 115-11-7 | C4H8 | 详情 | 详情 |
| (X) | 18009 | tert-butyl (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propanoate | C15H22N2O4 | 详情 | 详情 | |
| (XI) | 42998 | tert-butyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(2-[(4S)-4-[3-(4,5-dihydro-1H-imidazol-2-ylamino)propyl]-2,5-dioxoimidazolidinyl]acetyl)amino]propanoate | C26H37N7O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)The title compound was prepared by stepwise peptide synthesis starting from N-Fmoc-N-methyl-D-thienylalanine (I), which was condensed with trimethyl hydrazine (II) to give hydrazide (III). Removal of the Fmoc protecting group with piperidine in DMF provided amine (IV), which was subsequently coupled with N-methyl-D-naphthylalanine (V) in the presence of EDC and HOAt to furnish the dipeptide hydrazide (VI). After removal of the Fmoc group of (VI) with piperidine, the resulting amine (VII) was coupled with N-Boc-5-amino-5-methylhex-2-enoic acid (VIII), yielding amide (IX). Final deprotection of the Boc group of (IX) using trifluoroacetic acid afforded the title compound.
| 【1】 Hansen, B.S.; Ankersen, M.; Nielsen, K.K.; Hansen, T.K.; Raun, K.; Growth hormone secretagogues derived from NN703 with hydrazides as c-terminal. Eur J Med Chem 2000, 35, 5, 487. |
| 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) | 42289 | (2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino]-3-(2-thienyl)propionic acid | C23H21NO4S | 详情 | 详情 | |
| (II) | 42290 | 1,1,2-trimethylhydrazine | C3H10N2 | 详情 | 详情 | |
| (III) | 42291 | 9H-fluoren-9-ylmethyl methyl[(1R)-2-oxo-1-(2-thienylmethyl)-2-(1,2,2-trimethylhydrazino)ethyl]carbamate | C26H29N3O3S | 详情 | 详情 | |
| (IV) | 42292 | (2R)-N,N',N'-trimethyl-2-(methylamino)-3-(2-thienyl)propanohydrazide | C11H19N3OS | 详情 | 详情 | |
| (V) | 42293 | (2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl](methyl)amino]-3-(2-naphthyl)propionic acid | C29H25NO4 | 详情 | 详情 | |
| (VI) | 42294 | 9H-fluoren-9-ylmethyl methyl[(1R)-2-[methyl[(1R)-2-oxo-1-(2-thienylmethyl)-2-(1,2,2-trimethylhydrazino)ethyl]amino]-1-(2-naphthylmethyl)-2-oxoethyl]carbamate | C40H42N4O4S | 详情 | 详情 | |
| (VII) | 42295 | (2R)-N-methyl-2-(methylamino)-3-(2-naphthyl)-N-[(1R)-2-oxo-1-(2-thienylmethyl)-2-(1,2,2-trimethylhydrazino)ethyl]propanamide | C25H32N4O2S | 详情 | 详情 | |
| (VIII) | 22191 | (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoic acid | C12H21NO4 | 详情 | 详情 | |
| (IX) | 42296 | tert-butyl (E)-1,1-dimethyl-5-[methyl[(1R)-2-[methyl[(1R)-2-oxo-1-(2-thienylmethyl)-2-(1,2,2-trimethylhydrazino)ethyl]amino]-1-(2-naphthylmethyl)-2-oxoethyl]amino]-5-oxo-3-pentenylcarbamate | C37H51N5O5S | 详情 | 详情 |