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【结 构 式】 
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【分子编号】17283 【品名】N-methylthiourea 【CA登记号】598-52-7 |
【 分 子 式 】C2H6N2S 【 分 子 量 】90.14912 【元素组成】C 26.65% H 6.71% N 31.07% S 35.57% |
合成路线1
该中间体在本合成路线中的序号：(I)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：(XII)The reaction of indole-3-carbaldehyde (I) with benzyl chloroformate and NaH in THF gives the carbamate (II), which is condensed with the chiral oxazepinedione (III) by means of TiCl4 and pyridine in THF to yield a mixture of the cis (IV) and trans (V) adducts, which are easily separated by chromatography. The cis (IV) isomer can be thermally isomerized to the desired trans (V) isomer. The diastereoselective methylation of the double bond of (V) by means of MeMgBr in THF affords the methylated adduct (VI), which is hydrolyzed in acidic medium to afford the chiral indolylbutyric acid (VII). The reaction of (VII) with diazomethane provides the corresponding methyl ester (VIII), which is submitted to alpha hydroxylation by means of LDA, O2 and triethyl phosphite in HMPT/THF to give the chiral 2-hydroxy-3-(3-indolyl)butyric acid (IX). The protection of (IX) by means of dihydropyran (DHP) and Ts-OH yields the tetrahydropyranyl diprotected compound (X), which is hydrolyzed with LiOH in THF/water to afford the carboxylic acid (XI). The condensation of (XI) with N-methyl-thiourea (XII) by means of 2-chloro-3-ethylbenzoxazolium tetrafluoroborate (CEBF) and TEA in HMPT/dichloromethane provides a mixture of the S-acylisothiourea (XIII) and N-acylthiourea (XIV), which are easily separated. The S-acyl isomer (XIII) can be rearranged to the desired N-acyl isomer (XIV) by heating in refluxing dioxane. The N-acyl isomer (XIV) is deprotected by means of Ac-OH in THF/water to give the hydroxy derivative (XV), which is finally cyclized by means of CEBF and TEA in acetonitrile to afford the target indolmycin.
| 【1】 Takeda, T.; Mukaiyama, T.; Asymmetric total synthesis of indolmycin. Chem Lett 1980, 163. |
| 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) | 46797 | Indole-3-aldehyde; 3-Formylindole; 1H-Indole-3-carbaldehyde; Indole-3-carboxaldehyde | 487-89-8 | C9H7NO | 详情 | 详情 |
| (II) | 58319 | benzyl 3-formyl-1H-indole-1-carboxylate | C17H13NO3 | 详情 | 详情 | |
| (III) | 58320 | (2R,3S)-3,4-dimethyl-2-phenyl-1,4-oxazepane-5,7-dione | C13H15NO3 | 详情 | 详情 | |
| (IV) | 58321 | benzyl 3-{[(2R,3S)-3,4-dimethyl-5,7-dioxo-2-phenyl-1,4-oxazepan-6-ylidene]methyl}-1H-indole-1-carboxylate | C30H26N2O5 | 详情 | 详情 | |
| (V) | 58323 | benzyl 3-{[(2R,3S)-3,4-dimethyl-5,7-dioxo-2-phenyl-1,4-oxazepan-6-ylidene]methyl}-1H-indole-1-carboxylate | C30H26N2O5 | 详情 | 详情 | |
| (VI) | 58322 | benzyl 3-{(1S)-1-[(2R,3S)-3,4-dimethyl-5,7-dioxo-2-phenyl-1,4-oxazepan-6-yl]ethyl}-1H-indole-1-carboxylate | C31H30N2O5 | 详情 | 详情 | |
| (VII) | 58324 | (3S)-3-(1H-indol-3-yl)butanoic acid | C12H13NO2 | 详情 | 详情 | |
| (VIII) | 58325 | methyl (3S)-3-(1H-indol-3-yl)butanoate | C13H15NO2 | 详情 | 详情 | |
| (IX) | 58326 | methyl (2S,3R)-2-hydroxy-3-(1H-indol-3-yl)butanoate | C13H15NO3 | 详情 | 详情 | |
| (X) | 58327 | methyl (2S,3R)-3-(1-tetrahydro-2H-pyran-2-yl-1H-indol-3-yl)-2-(tetrahydro-2H-pyran-2-yloxy)butanoate | C23H31NO5 | 详情 | 详情 | |
| (XI) | 58328 | (2S,3R)-3-(1-tetrahydro-2H-pyran-2-yl-1H-indol-3-yl)-2-(tetrahydro-2H-pyran-2-yloxy)butanoic acid | C22H29NO5 | 详情 | 详情 | |
| (XII) | 17283 | N-methylthiourea | 598-52-7 | C2H6N2S | 详情 | 详情 |
| (XIII) | 58329 | S-[imino(methylamino)methyl] (2S,3R)-3-(1-tetrahydro-2H-pyran-2-yl-1H-indol-3-yl)-2-(tetrahydro-2H-pyran-2-yloxy)butanethioate | C24H33N3O4S | 详情 | 详情 | |
| (XIV) | 58330 | N-methyl-N'-[(2S,3R)-3-(1-tetrahydro-2H-pyran-2-yl-1H-indol-3-yl)-2-(tetrahydro-2H-pyran-2-yloxy)butanoyl]thiourea | C24H33N3O4S | 详情 | 详情 | |
| (XV) | 58331 | N-[(2S,3R)-2-hydroxy-3-(1H-indol-3-yl)butanoyl]-N'-methylthiourea | C14H17N3O2S | 详情 | 详情 |