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【结 构 式】 
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【分子编号】42170 【品名】2-[[(benzyloxy)carbonyl]amino]ethyl 4-methylbenzenesulfonate 【CA登记号】 |
【 分 子 式 】C17H19NO5S 【 分 子 量 】349.4076 【元素组成】C 58.44% H 5.48% N 4.01% O 22.9% S 9.18% |
合成路线1
该中间体在本合成路线中的序号：(II)Reductive cleavage of L-homocystine (I) with sodium in liquid ammonia produced homocysteine, which was subsequently alkylated with 2-(N-benzyloxycarbonyl-amino)ethyl tosylate (II) to afford thioether (III). The benzyloxycarbonyl protecting group of (III) was cleaved with HBr to give diamine (IV). Finally, condensation with ethyl acetimidate (V) furnished the target amidine.
| 【1】 Young, R.J.; et al.; Inhibition of inducible nitric oxide synthase by acetamidine derivatives of hetero-substituted lysine and homolysine. Bioorg Med Chem Lett 2000, 10, 6, 597. |
| 【2】 Beams, R.M.; Frend, A.J.; Drysdale, M.J.; Franzman, K.W.; Hodson, H.F.; Rees, D.D.; Knowles, R.G.; Sawyer, D.A. (Glaxo Wellcome plc); Nitric oxide synthase inhibitors. EP 0958277; JP 2000504041; WO 9830537 . |
| 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) | 42169 | (2S)-2-amino-4-[[(3S)-3-amino-3-carboxypropyl]disulfanyl]butyric acid | C8H16N2O4S2 | 详情 | 详情 | |
| (II) | 42170 | 2-[[(benzyloxy)carbonyl]amino]ethyl 4-methylbenzenesulfonate | C17H19NO5S | 详情 | 详情 | |
| (III) | 42171 | (2S)-2-amino-4-[(2-[[(benzyloxy)carbonyl]amino]ethyl)sulfanyl]butyric acid | C14H20N2O4S | 详情 | 详情 | |
| (IV) | 42172 | (2S)-2-amino-4-[(2-aminoethyl)sulfanyl]butyric acid | C6H14N2O2S | 详情 | 详情 | |
| (V) | 12831 | ethyl ethanimidoate | 1000-84-6 | C4H9NO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)In a further procedure, N-Boc-L-homocysteine tert-butyl ester (XI) was prepared by reduction of N-Boc-homocystine tert-butyl ester (X) with dithiothreitol (DTT). Alkylation of thiol (XI) with tosylate (II) afforded thioether (XII). An alternative synthetic access to (XII) consisted in the esterification of carboxylic acid (VI), prepared as above, by means of either N,N-dimethylformamide di-O-t-butyl acetal or O-t-butyl 1,1,1-trichloroacetimidate. Transfer hydrogenolysis of (XII) using ammonium formate and palladium hydroxide on carbon removed the benzyloxycarbonyl group to furnish (XIII). This was converted to amidine (XIV) by treatment with S-(1-naphthylmethyl)thioacetimidate hydrochloride (VIII). Finally, deprotection of the Boc group and the tert-butyl ester of (XIV) by means of HCl in dioxan afforded the title compound.
| 【1】 Young, R.J.; et al.; Inhibition of inducible nitric oxide synthase by acetamidine derivatives of hetero-substituted lysine and homolysine. Bioorg Med Chem Lett 2000, 10, 6, 597. |
| 【2】 Beams, R.M.; Frend, A.J.; Drysdale, M.J.; Franzman, K.W.; Hodson, H.F.; Rees, D.D.; Knowles, R.G.; Sawyer, D.A. (Glaxo Wellcome plc); Nitric oxide synthase inhibitors. EP 0958277; JP 2000504041; WO 9830537 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 42170 | 2-[[(benzyloxy)carbonyl]amino]ethyl 4-methylbenzenesulfonate | C17H19NO5S | 详情 | 详情 | |
| (VI) | 42173 | (2S)-4-[(2-[[(benzyloxy)carbonyl]amino]ethyl)sulfanyl]-2-[(tert-butoxycarbonyl)amino]butyric acid | C19H28N2O6S | 详情 | 详情 | |
| (VIII) | 42175 | 1-naphthylmethyl ethanimidothioate | C13H13NS | 详情 | 详情 | |
| (X) | 42177 | di(tert-butyl) (6S,13S)-2,2,17,17-tetramethyl-4,15-dioxo-3,16-dioxa-9,10-dithia-5,14-diazaoctadecane-6,13-dicarboxylate | C26H48N2O8S2 | 详情 | 详情 | |
| (XI) | 42178 | tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-sulfanylbutanoate | C13H25NO4S | 详情 | 详情 | |
| (XII) | 42179 | tert-butyl (2S)-4-[(2-[[(benzyloxy)carbonyl]amino]ethyl)sulfanyl]-2-[(tert-butoxycarbonyl)amino]butanoate | C23H36N2O6S | 详情 | 详情 | |
| (XIII) | 42180 | tert-butyl (2S)-4-[(2-aminoethyl)sulfanyl]-2-[(tert-butoxycarbonyl)amino]butanoate | C15H30N2O4S | 详情 | 详情 | |
| (XIV) | 42181 | tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-[[2-(ethanimidoylamino)ethyl]sulfanyl]butanoate | C17H33N3O4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)Ethanolamine (I) was protected as the N-benzyloxycarbonyl derivative (II) and subsequently converted to tosylate (III). Alkylation of N,N,N'-trimethylethylenediamine (IV) with tosylate (III) produced triamine (V). The benzyloxycarbonyl protecting group was then removed by transfer hydrogenolysis with ammonium formate and Pd/C to yield triamine (VI).
| 【1】 Ritchie, T.J.; Hallett, A.; Dziadulewicz, E.K.; et al.; 1-(2-Nitrophenyl)thiosemicarbazides: A novel class of potent, orally active non-peptide antagonist for the bradykinin B2 receptor. J Med Chem 2000, 43, 5, 769. |
| 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) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (II) | 32497 | benzyl 2-hydroxyethylcarbamate | 77987-49-6 | C10H13NO3 | 详情 | 详情 |
| (III) | 42170 | 2-[[(benzyloxy)carbonyl]amino]ethyl 4-methylbenzenesulfonate | C17H19NO5S | 详情 | 详情 | |
| (IV) | 15778 | N-[2-(dimethylamino)ethyl]-N-methylamine; N,N,N'-trimethyl-1,2-ethanediamine; N(1),N(1),N(2)-trimethyl-1,2-ethanediamine | 142-25-6 | C5H14N2 | 详情 | 详情 |
| (V) | 42316 | benzyl 2-[[2-(dimethylamino)ethyl](methyl)amino]ethylcarbamate | C15H25N3O2 | 详情 | 详情 | |
| (VI) | 42317 | N-(2-aminoethyl)-N-[2-(dimethylamino)ethyl]-N-methylamine; N(1)-(2-aminoethyl)-N(1),N(2),N(2)-trimethyl-1,2-ethanediamine | C7H19N3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Reductive cleavage of L-cystine (I) with sodium in liquid ammonia produced cysteine, which was subsequently alkylated with 2-(N-benzyloxycarbonylamino)ethyl tosylate (II) to afford thioether (III). After protection of (III) as the N-Boc derivative (IV), sulfur oxidation by means of Oxone(R) produced sulfone (V). The benzyloxycarbonyl protecting group of (V) was then cleaved by transfer hydrogenolysis employing formic acid and palladium catalyst, and the resulting amine (VI) was converted to amidine (VIII) by reaction thioacetimidate (VII). The Boc protecting group of (VIII) was finally removed by acidic treatment.
| 【1】 Young, R.J.; et al.; Inhibition of inducible nitric oxide synthase by acetamidine derivatives of hetero-substituted lysine and homolysine. Bioorg Med Chem Lett 2000, 10, 6, 597. |
| 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) | 42188 | (2R)-2-amino-3-[[(2R)-2-amino-2-carboxyethyl]disulfanyl]propionic acid | C6H12N2O4S2 | 详情 | 详情 | |
| (II) | 42170 | 2-[[(benzyloxy)carbonyl]amino]ethyl 4-methylbenzenesulfonate | C17H19NO5S | 详情 | 详情 | |
| (III) | 42189 | (2R)-2-amino-3-[(2-[[(benzyloxy)carbonyl]amino]ethyl)sulfanyl]propionic acid | C13H18N2O4S | 详情 | 详情 | |
| (IV) | 42190 | (2R)-3-[(2-[[(benzyloxy)carbonyl]amino]ethyl)sulfanyl]-2-[(tert-butoxycarbonyl)amino]propionic acid | C18H26N2O6S | 详情 | 详情 | |
| (V) | 42191 | (2R)-3-[(2-[[(benzyloxy)carbonyl]amino]ethyl)sulfonyl]-2-[(tert-butoxycarbonyl)amino]propionic acid | C18H26N2O8S | 详情 | 详情 | |
| (VI) | 42192 | (2R)-3-[(2-aminoethyl)sulfonyl]-2-[(tert-butoxycarbonyl)amino]propionic acid | C10H20N2O6S | 详情 | 详情 | |
| (VII) | 42175 | 1-naphthylmethyl ethanimidothioate | C13H13NS | 详情 | 详情 | |
| (VIII) | 42193 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-[[2-(ethanimidoylamino)ethyl]sulfonyl]propionic acid | C12H23N3O6S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)In a related procedure, N-Boc-L-cysteine tert-butyl ester (X) was prepared by reduction of N-Boc-cystine tert-butyl ester (IX) with dithiothreitol (DTT). Alkylation of thiol (X) with tosylate (II) afforded thioether (XI). After oxidation of (XI) to sulfone (XII), transfer hydrogenolysis using ammonium formate and palladium hydroxide on carbon removed the benzyloxycarbonyl group to furnish amine (XIII). This was converted to amidine (XIV) by treatment with thioacetimidate (VII). Finally, deprotection of the Boc group and the tert-butyl ester of (XIV) by means of HCl in dioxan afforded the title compound.
| 【1】 Young, R.J.; et al.; Inhibition of inducible nitric oxide synthase by acetamidine derivatives of hetero-substituted lysine and homolysine. Bioorg Med Chem Lett 2000, 10, 6, 597. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 42170 | 2-[[(benzyloxy)carbonyl]amino]ethyl 4-methylbenzenesulfonate | C17H19NO5S | 详情 | 详情 | |
| (VII) | 42175 | 1-naphthylmethyl ethanimidothioate | C13H13NS | 详情 | 详情 | |
| (IX) | 42194 | di(tert-butyl) (6R,11R)-2,2,15,15-tetramethyl-4,13-dioxo-3,14-dioxa-8,9-dithia-5,12-diazahexadecane-6,11-dicarboxylate | C24H44N2O8S2 | 详情 | 详情 | |
| (X) | 42195 | tert-butyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-sulfanylpropanoate | C12H23NO4S | 详情 | 详情 | |
| (XI) | 42196 | tert-butyl (2R)-3-[(2-[[(benzyloxy)carbonyl]amino]ethyl)sulfanyl]-2-[(tert-butoxycarbonyl)amino]propanoate | C22H34N2O6S | 详情 | 详情 | |
| (XII) | 42197 | tert-butyl (2R)-3-[(2-[[(benzyloxy)carbonyl]amino]ethyl)sulfonyl]-2-[(tert-butoxycarbonyl)amino]propanoate | C22H34N2O8S | 详情 | 详情 | |
| (XIII) | 42198 | tert-butyl (2R)-3-[(2-aminoethyl)sulfonyl]-2-[(tert-butoxycarbonyl)amino]propanoate | C14H28N2O6S | 详情 | 详情 | |
| (XIV) | 42199 | tert-butyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-[[2-(ethanimidoylamino)ethyl]sulfonyl]propanoate | C16H31N3O6S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(III)The precursor triamine (VI) is prepared as follows. Ethanolamine (I) is protected as the N-Cbz derivative (II) upon treatment with N-(benzyloxycarbonyloxy)succinimide. Subsequent tosylation of (II) to yield (III), followed by displacement of the tosylate of (III) with trimethyl propanediamine (IV) furnishes the protected triamine (V). Then, Cbz group hydrogenolysis in (V) in the presence of Pd/C gives rise to triamine (VI).
| 【1】 Dziadulewicz, E.K.; et al.; Nonpeptide bradykinin B2 receptor antagonists: Conversion of rodent-selective bradyzide analogues into potent, orally-active human bradykinin B2 receptor antagonists. J Med Chem 2002, 45, 11, 2160. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 30663 | N-benzyloxycarbonyloxysuccinimide; 1-[[(Benzyloxy)carbonyl]oxy]-2,5-pyrrolidinedione | 13139-17-8 | C12H11NO5 | 详情 | 详情 |
| (I) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (II) | 32497 | benzyl 2-hydroxyethylcarbamate | 77987-49-6 | C10H13NO3 | 详情 | 详情 |
| (III) | 42170 | 2-[[(benzyloxy)carbonyl]amino]ethyl 4-methylbenzenesulfonate | C17H19NO5S | 详情 | 详情 | |
| (IV) | 28165 | N-[3-(dimethylamino)propyl]-N-methylamine | 4543-96-8 | C6H16N2 | 详情 | 详情 |
| (V) | 61665 | benzyl 2-[[3-(dimethylamino)propyl](methyl)amino]ethylcarbamate | C16H27N3O2 | 详情 | 详情 | |
| (VI) | 61664 | N~1~-(2-aminoethyl)-N~1~,N~3~,N~3~-trimethyl-1,3-propanediamine | C8H21N3 | 详情 | 详情 |