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【结 构 式】 
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【分子编号】18174 【品名】[[bis(methylsulfanyl)methylene]amino](nitrilo)methane 【CA登记号】10191-60-3 |
【 分 子 式 】C4H6N2S2 【 分 子 量 】146.23712 【元素组成】C 32.85% H 4.14% N 19.16% S 43.85% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of propargylamine (II) with dimethyl cyanoiminodithiocarbonate (III) in refluxing acetonitrile gives N-cyano-N'-propargyl-S-methylisothiourea (IV), which is then condensed with 2-[(5-methyl-4-imidazolyl)methylthio]ethylamine (V) in refluxing methanol.
| 【1】 Crenshaw, R.R.; Luke, G.M. (Bristol-Myers Squibb Co.); Imidazolylmethylthioethyl alkynyl guanidines. US 4112234 . |
| 【2】 Serradell, M.N.; Blancafort, P.; Castaner, J.; Etintidine hydrochloride. Drugs Fut 1982, 7, 10, 732. |
| 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) | 18174 | [[bis(methylsulfanyl)methylene]amino](nitrilo)methane | 10191-60-3 | C4H6N2S2 | 详情 | 详情 |
| (II) | 21408 | 2-propyn-1-amine; 2-propynylamine; 2-propylamine | 2450-71-7 | C3H5N | 详情 | 详情 |
| (III) | 37101 | 3-[[(cyanoimino)(methylsulfanyl)methyl]amino]-1-propyne | C6H7N3S | 详情 | 详情 | |
| (IV) | 34071 | 2-[[(5-methyl-1H-imidazol-4-yl)methyl]sulfanyl]-1-ethanamine; 2-[[(5-methyl-1H-imidazol-4-yl)methyl]sulfanyl]ethylamine | C7H13N3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(C)1) By refluxing N-cyano-N',S-dimethylisoithiourea (B) and 5-methyl-4-[(2-aminoethyl)thiomethyl imidazol (III) in acetonitrile. The latter is prepared by reacting cysteamine (A) and 5-methyl-4-(hydroxymethyl)imidazol (II) (from 5-methylimidazol (I) and formalin) in acetic acid, in hydrochloric acid or in hydrobromic acid. 2) By reaction of 5-methyl-4-[(2-aminoethyl)thiomethyl]imidazol (III) with cyanodithioimido carbonic (C) acid dimethyl ester to give the isothiourea (IV), followed by reaction with methylamine. 3) By refluxing 1-methyl-3-[2-[[(5-methylimidazol-4-yl)-methyl]thio]ethyl]-2-thiourea (metiamide) (V) and lead cyanamide. The first is prepared by reaction of 5-methyl-4-[(2-aminoethyl)thiomethyl]imidazol (III) with methyl isocyanate (D).
| 【1】 Durant, G.J.; et al.; Pharmacologically active guanidine compounds. DE 2211454; DE 2265369; FR 2128505; GB 1338169; US 3950333 . |
| 【2】 Erlenmeyer, H.; et al.; Helv Chim Acta 1948, 31, 32. |
| 【3】 Durant, G.J.; et al.; Certain N-cyanoguanidines. DE 2344779; FR 2199467; GB 1397436; JP 49075574; US 3876647 . |
| 【4】 Castaner, J.; Cimetidine. Drugs Fut 1976, 1, 1, 13. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (D) | 12092 | Methyl isothiocyanate; MITC; (Methylimino)(thioxo)methane | 556-61-6 | C2H3NS | 详情 | 详情 |
| (A) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (B) | 34072 | [[(E)-(methylamino)(methylsulfanyl)methylidene]amino](nitrilo)methane | C4H7N3S | 详情 | 详情 | |
| (I) | 34070 | 5-methyl-1H-imidazole | 822-36-6 | C4H6N2 | 详情 | 详情 |
| (II) | 14216 | (5-Methyl-1H-imidazol-4-yl)methanol | 29636-87-1 | C5H8N2O | 详情 | 详情 |
| (III) | 34071 | 2-[[(5-methyl-1H-imidazol-4-yl)methyl]sulfanyl]-1-ethanamine; 2-[[(5-methyl-1H-imidazol-4-yl)methyl]sulfanyl]ethylamine | C7H13N3S | 详情 | 详情 | |
| (IV) | 34073 | 4-[[(2-[[(cyanoimino)(methylsulfanyl)methyl]amino]ethyl)sulfanyl]methyl]-5-methyl-1H-imidazole | C10H15N5S2 | 详情 | 详情 | |
| (V) | 34074 | N-methyl-N'-(2-[[(5-methyl-1H-imidazol-4-yl)methyl]sulfanyl]ethyl)thiourea | C9H16N4S2 | 详情 | 详情 | |
| (C) | 18174 | [[bis(methylsulfanyl)methylene]amino](nitrilo)methane | 10191-60-3 | C4H6N2S2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)OPB-2045 can be obtained by several related ways: 1) The addition of 3,4-dichlorobenzylamine hydrochloride (I) to sodium dicyanamide (II) in refluxing acetonitrile gives 1-(3,4-dichlorobenzyl)-3-cyanoguanidine (III), which is then condensed with octylamine hydrochloride (IV) in refluxing mesitylene. 2) The treatment of S,S'-dimethyl(cyanoimino)dithiocarbonate (V) with aqueous ammonia and further reaction with 3,4-dichlorobenzylamine hydrochloride (I) yields intermediate (III), which is then condensed with (IV) as before. 3) By condensation of 3,4-dichlorobenzylamine hydrochloride (I) with 1-cyano-3-octylguanidine (VI) in refluxing mesitylene.
| 【1】 Kikuchi, M.; Ishikawa, H.; Yasumura, K.; Ohguro, K.; Tsubouchi, H.; Synthesis and structure-activity relationships of novel antiseptics. Bioorg Med Chem Lett 1997, 7, 13, 1721. |
| 【2】 Yasumura, K.; Kikuchi, M.; Ishikawa, H.; Ohguro, K.; Tsubouchi, H.; Synthesis and structure-activity relationships of new disinfectants. Symp Med Chem 1996, Abst 2-P-3. |
| 【3】 Sorbera, L.A.; Castañer, J.; OPB-2045. Drugs Fut 1999, 24, 2, 151. |
| 【4】 Ishikawa, H.; Yasumura, K.; Tsubouchi, H.; Higuchi, Y.; Tamaoka, H. (Otsuka Pharmaceutical Co., Ltd.); Biguanide derivs., manufacturing method thereof, and disinfectants containing the derivs.. EP 0507317 . |
| 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) | 21140 | (3,4-dichlorophenyl)methanamine hydrochloride | C7H8Cl3N | 详情 | 详情 | |
| (II) | 21141 | sodium dicyanimide | C2N3Na | 详情 | 详情 | |
| (III) | 21142 | N-cyano-N'-(3,4-dichlorobenzyl)guanidine | C9H8Cl2N4 | 详情 | 详情 | |
| (IV) | 21143 | 1-octanamine hydrochloride | 142-95-0 | C8H20ClN | 详情 | 详情 |
| (V) | 18174 | [[bis(methylsulfanyl)methylene]amino](nitrilo)methane | 10191-60-3 | C4H6N2S2 | 详情 | 详情 |
| (VI) | 21145 | N-cyano-N'-octylguanidine | C10H20N4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Reaction of dimethyl N-cyanodithioiminocarbonate (I) with cyclohexylamine (II) in ethanol afforded isothiourea (III). Then, the title compound was prepared by condensation between an excess of isothiourea (III) and the sodium salt of sulfonamide IV, generated in the presence of NaOH in DMF-dioxane.
| 【1】 Masereel, B.; et al.; Synthesis and biological evaluation of sulfonylcyanoguanidines and sulfonamidonitroethylenes as bioisosteres of hypoglycemic sulfonylureas. Eur J Med Chem 1997, 32, 5, 453-456. |
| 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) | 18174 | [[bis(methylsulfanyl)methylene]amino](nitrilo)methane | 10191-60-3 | C4H6N2S2 | 详情 | 详情 |
| (III) | 18176 | 1-[[(cyanoimino)(methylsulfanyl)methyl]amino]cyclohexane | C9H15N3S | 详情 | 详情 | |
| (IV) | 18177 | 4-(5-Chloro-2-methoxybenzamido ethyl)benzenesulfonamide; 5-Chloro-2-methoxy-n-(2-(4-sulfamoylphenyl)ethyl)benzamide; N-[4-(aminosulfonyl)phenethyl]-5-chloro-2-methoxybenzamide | 16673-34-0 | C16H17ClN2O4S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The condensation of pyridin-4-ylamine (I) with the iminodithiocarbonate (II) by means of NaH in DMF gives the isothiourea (III), which is finally condensed with 6-(4-chlorophenoxy)hexylamine (IV) by means of TEA in pyridine. Alternatively, the target guanidine can also be obtained by condensation of N-[6-(4-chlorophenoxy)hexyl]-N'-(4-pyridyl)thiourea (V) with cyanamide by means of DCC and TEA in acetonitrile.
| 【1】 Schou, C.; et al.; Novel cyanoguanidines with potent oral antitumor activity. Bioorg Med Chem Lett 1997, 7, 24, 3095. |
| 【2】 Bramm, E.; Petersen, H.H.J. (Leo Pharmaceutical Products Ltd. A/S); N-Cyano-N'-pyridylguanidines as serotonin antagonists. EP 0660823; JP 1996501539; US 5563160; US 5696140; WO 9406770 . |
| 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) | 25661 | 4-pyridinamine; 4-aminopyridine | 5044-74-5 | C5H6N2 | 详情 | 详情 |
| (II) | 18174 | [[bis(methylsulfanyl)methylene]amino](nitrilo)methane | 10191-60-3 | C4H6N2S2 | 详情 | 详情 |
| (III) | 54403 | 4-{[(cyanoimino)(methylsulfanyl)methyl]amino}pyridine | C8H8N4S | 详情 | 详情 | |
| (IV) | 54404 | 6-(4-chlorophenoxy)-1-hexanamine; 6-(4-chlorophenoxy)hexylamine | C12H18ClNO | 详情 | 详情 | |
| (V) | 54405 | N-[6-(4-chlorophenoxy)hexyl]-N'-(4-pyridinyl)thiourea | C18H22ClN3OS | 详情 | 详情 |