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【结 构 式】 
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【分子编号】17284 【品名】(methylamino)(methylsulfanyl)methaniminium iodide 【CA登记号】 |
【 分 子 式 】C3H9IN2S 【 分 子 量 】232.08841 【元素组成】C 15.53% H 3.91% I 54.68% N 12.07% S 13.82% |
合成路线1
该中间体在本合成路线中的序号：(II)546C88 has been obtained by several related ways: 1) The reaction of N-methylthiourea (I) with methyl iodide gives N,S-dimethylisothiouronium iodide (II), which is then condensed with L-ornithine (III) by means of NaOH or copper acetate. 2) The oxidation of N-methylthiourea (I) with peracetic acid in acetic acid gives N-methylamidinosulfonic acid (IV), which is then condensed with L-ornithine (III) by means of K2CO3 in water. 3) The reaction of cyanogen bromide (V) with methylamine (VI) by means of Na2CO3 in THF gives N-methylcyanamide (VII), which is condensed with pyrazole (VIII) by means of HCl in refluxing dioxane to yield N1-methylpyrazole-1-carboxamidine (IX). Finally, this compound is condensed with L-ornithine (III) by means of LiOH in water. 4) The reaction of cellulose (X) with cyanogen bromide (V) by means of K2CO3 in water/DMF gives the corresponding polymeric cyanate ester (XI), which is condensed with methylamine (VI) to yield the polymeric N-methylamidino compound (XII). Finally, this compound is condensed with L-ornithine (III) by means of CuCO3 in water.
| 【1】 Patthy, A.; Bajusz, S.; Patthy, L.; Preparation and characterization of NG-mono-, di- and trimethylated arginines. Acta Biochim Biophys Acad Sci Hung 1977, 12, 3, 191-6. |
| 【2】 Wroblewski, T.; Castañer, J.; Prous, J.R.; 546C88. Drugs Fut 1998, 23, 2, 123. |
| 【3】 Dowd, P.; Zhang, W.; Hershline, R.; A highly efficient preparation of NG-methyl-L-arginine and NG-methyl-D-arginine. Synth Commun 1994, 24, 19, 2789-92. |
| 【4】 Reporter, M.; Corbin, J.L.; A convenient preparation of NG-methylarginine. Anal Biochem 1974, 57, 1, 310-2. |
| 【5】 Pundak, S.; Wilchek, M.; Synthesis of guanidino-N-alkylarginines by the use of polymeric pseudoureas. J Org Chem 1981, 46, 808-9. |
| 【6】 Hodson, H.F. (Glaxo Wellcome plc); NG-Monomethyl-L-arginine hydrochloride derivs. and their use in the treatment of septic shock. EP 0651741; JP 1995509239; US 5767312; WO 9402453 . |
| 【7】 Gillies, I. (Glaxo Wellcome plc); Process for the preparation of NG-monomethyl-L-arginine hydrochloride. WO 9730972 . |
| 【8】 Patel, R.; Mahal, A.S.; Burford, D.L.W. (Glaxo Wellcome plc); Process for preparing NG-monoalkyl-L-arginine and related cpds. WO 9426701 . |
| 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) | 17283 | N-methylthiourea | 598-52-7 | C2H6N2S | 详情 | 详情 |
| (II) | 17284 | (methylamino)(methylsulfanyl)methaniminium iodide | C3H9IN2S | 详情 | 详情 | |
| (III) | 17285 | L-ornithine | 70-26-8 | C5H12N2O2 | 详情 | 详情 |
| (IV) | 17286 | imino(methylamino)methanesulfonic acid | C2H6N2O3S | 详情 | 详情 | |
| (VII) | 17287 | N-methylcyanamide | C2H4N2 | 详情 | 详情 | |
| (VIII) | 17288 | Pyrazole; 1H-pyrazole | 288-13-1 | C3H4N2 | 详情 | 详情 |
| (IX) | 17289 | N-methyl-1H-pyrazole-1-carboximidamide | C5H8N4 | 详情 | 详情 | |
| (XII) | 17290 | [[hydroxy(imino)methyl]amino]methane | C2H6N2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)5) The reaction of L-ornithine (III) with benzaldehyde by means of LiOH gives Ndelta-benzylidene-L-ornitine (XIII), which is treated first with benzyl chloroformate and NaOH and hydrolyzed with HCl to afford Nalpha-(benzyloxycarbonyl)-L-ornithine (XIV). The condensation of (XIV) with N,S-dimethylisothiouronium iodide (II) by means of NaOH gives Nalpha-(benzyloxycarbonyl)-Nomega-methyl-L-arginine (XV), which is finally deprotected by hydrogenation with H2 over Pd/C.
| 【1】 Sala, A.; Ferrario, F.; Trupiano, F.; Levi, S.; Multigram synthesis of NG-methyl-(L-)-arginine and its analytical characterization. Synth Commun 1991, 21, 99-105. |
| 【2】 Wroblewski, T.; Castañer, J.; Prous, J.R.; 546C88. Drugs Fut 1998, 23, 2, 123. |
| 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) | 17284 | (methylamino)(methylsulfanyl)methaniminium iodide | C3H9IN2S | 详情 | 详情 | |
| (III) | 12034 | 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline | 106-47-8 | C6H6ClN | 详情 | 详情 |
| (III) | 17285 | L-ornithine | 70-26-8 | C5H12N2O2 | 详情 | 详情 |
| (XIII) | 17291 | (2S)-2-amino-5-[[(E)-benzylidene]amino]pentanoic acid | C12H16N2O2 | 详情 | 详情 | |
| (XIV) | 17292 | (2S)-5-amino-2-[[(benzyloxy)carbonyl]amino]pentanoic acid | C13H18N2O4 | 详情 | 详情 | |
| (XV) | 17293 | (2S)-2-[[(benzyloxy)carbonyl]amino]-5-[[imino(methylamino)methyl]amino]pentanoic acid | C15H22N4O4 | 详情 | 详情 |