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【结 构 式】 
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【分子编号】23403 【品名】Methyl p-toluenesulfonate; Methyl 4-methylbenzenesulfonate; Methyl 4-toluenesulfonate 【CA登记号】80-48-8 |
【 分 子 式 】C8H10O3S 【 分 子 量 】186.2316 【元素组成】C 51.6% H 5.41% O 25.77% S 17.22% |
合成路线1
该中间体在本合成路线中的序号：(A)The reaction of 1,4-dihydro-4-phenylcinnoline (I) with methyl p-toluenesulfonate (A) and acetic acid by means of KOH in refluxing toluene gives 1-(N-methyl-N-acetylamino)-3-phenylindole (II), which is hydrolyzed by treatment with refluxing concentrated HCl to afford 1-methylamino-3-phenylindole (III). Finally, this compound is condensed with 2-dimethylaminoethyl chloride (IV) by means of sodium amide in refluxing toluene.
| 【1】 Schatz, F.; et al.; Amino-3-phenylindoles with antidepressant activity. Binodaline hydrochloride and relatd compounds. Arzneim-Forsch Drug Res 1980, 30, 6, 919-923. |
| 【2】 Schatz, F.; et al. (Siegfried AG); N-Amino indole derivatives having pharmacological activity. US 4204998 . |
| 【3】 Hillier, K.; Castaner, J.; Blancafort, P.; Serradell, M.N.; Binodaline. Drugs Fut 1981, 6, 4, 212. |
| 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) | 23403 | Methyl p-toluenesulfonate; Methyl 4-methylbenzenesulfonate; Methyl 4-toluenesulfonate | 80-48-8 | C8H10O3S | 详情 | 详情 |
| (I) | 37421 | 4-phenyl-1,4-dihydrocinnoline | C14H12N2 | 详情 | 详情 | |
| (II) | 37422 | N-methyl-N-(3-phenyl-1H-indol-1-yl)acetamide | C17H16N2O | 详情 | 详情 | |
| (III) | 37423 | N-methyl-N-(3-phenyl-1H-indol-1-yl)amine; N-methyl-3-phenyl-1H-indol-1-amine | C15H14N2 | 详情 | 详情 | |
| (IV) | 11907 | Dimethylaminoethyl chloride; 2-Dimethylaminoethyl chloride; 2-Chloro-N,N-dimethyl-1-ethanamine; N-(2-Chloroethyl)-N,N-dimethylamine | 107-99-3 | C4H10ClN | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)A slightly modified method of Houlihan et al. is used in making the intermediate 1-amino-3-hydroxyguanidine tosylate. Thiosemicarbazide (I) (0.5 mol) and methyl p-toluenesulfonate (II) (0.5 mol) are refluxed with stirring for 18 h. The reaction mixture is then evaporated to about 250 ml in vacua, and 500 ml of ether is added. The white precipitate formed is filtered and washed with ether. The resultant S-methylisothiosemicarbazide tosylate (III) (135g) gives a melting point of 144-6 C. Cold methanolic KOH solution (0.5 mol in 250 mI) is added to a cold hydroxyamine hydrochloride solution 10.5 mol). The mixture is stirred for 1 h in a salt-ice bath. The KCl precipitate formed is removed by filtration. S-Methyl-isothiosemicarbazide tosylate (III) (0.4 mol) is added to the filtrate. The reaction mixture is stirred at room temperature for 48 h, then evaporated to dryness in vacua at 40 C. The residue is dissolved in hot ethanol (800 mI) and cooled to room temperature. A small amount of insoluble precipitate is filtered off, then the filtrate is concentrated to about 200 ml in vacuo. Ether (400 ml) is added and mixed thoroughly to precipitate out the desired intermediate. This is filtered and washed with a mixture of ether and ethanol (2:1). White crystalline product of 1-amino-3-hydroxyguanidine tosylate (IV) (50 g) is obtained with an m.p. of 136-7 C, and it decomposes at 150-5 C. To prepare title compound 0.04 mol of freshly distilled 2-formylpyridine (V) is added dropwise to a solution of 0.04 mol of 1-amino-3-hydroxyguanidine tosylate (IV) in 25 ml methanol. The reaction mixture is stirred overnight at room temperature. The solvent is evaporated in vacuo. The final resultant Schiff's base is recrystallized with a mixture of ethanol-ether (1:1). The yield of the final product is 6.48 g (46.1%).
| 【1】 Tai, A.W.; Moore, E.C.; Chun, Y.; Lien, E.J.; Roberts, J.D.; Studies of N-hydroxy-N'-aminoguanidine derivatives by nitrogen-15 nuclear magnetic resonance spectroscopy and as ribonucleotide reductase inhibitors. J Med Chem 1983, 26, 9, 1326-1329. |
| 【2】 Houlihan, W.J.; Manning, R.E. (Novartis AG); Improvements in or relating to benzylideneamino guanidine derivatives. BE 0727146; DE 1902449; ES 362712; ES 374472; ES 374475; FR 2000512; FR 2059987; FR 2061583; GB 1253548; GB 1253549 . |
| 【3】 Lien, E.J.; LT-1. Drugs Fut 1985, 10, 1, 26. |
| 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) | 29023 | 1-hydrazinecarbimidothioic acid | CH5N3S | 详情 | 详情 | |
| (II) | 23403 | Methyl p-toluenesulfonate; Methyl 4-methylbenzenesulfonate; Methyl 4-toluenesulfonate | 80-48-8 | C8H10O3S | 详情 | 详情 |
| (III) | 29025 | methyl 1-hydrazinecarbimidothioate | C2H7N3S | 详情 | 详情 | |
| (IV) | 29026 | N-hydroxy-1-hydrazinecarboximidamide | CH6N4O | 详情 | 详情 | |
| (V) | 25173 | 2-pyridinecarbaldehyde | 1121-60-4 | C6H5NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(A)1) By methylation of gentamicin C1a (I) with methyl p-toluenesulfonate (A) in acetonitrile. 2) By methylation of gentamicin C1a (I) with methyl bromide (B) in methanol. 3) The reaction of gentamicin C1a (I) with CS2 in ethanol gives the 6'-N-dithiocarbamylgentamicin (II), C1a which is reduced with LiAlH4 in refluxing THF.
| 【1】 Castaner, J.; Sweetman, A.J.; Serradell, M.N.; Blancafort, P.; Sagamicin. Drugs Fut 1979, 4, 5, 360. |
| 【2】 Matsushima, H.; et al.; JP 75123640 . |
| 【3】 Matsushima, H.; et al.; JP 75129531 . |
| 【4】 Matsushima, H.; et al.; JP 75126639 . |
| 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) | 23403 | Methyl p-toluenesulfonate; Methyl 4-methylbenzenesulfonate; Methyl 4-toluenesulfonate | 80-48-8 | C8H10O3S | 详情 | 详情 |
| (I) | 39511 | (2R,3R,4R,5R)-2-[((1S,2R,3R,4S,6R)-4,6-diamino-3-[[(2R,3R,6S)-3-amino-6-(aminomethyl)tetrahydro-2H-pyran-2-yl]oxy]-2-hydroxycyclohexyl)oxy]-5-methyl-4-(methylamino)tetrahydro-2H-pyran-3,5-diol | C19H39N5O7 | 详情 | 详情 | |
| (II) | 39512 | [(2S,5R,6R)-5-amino-6-[((1R,2R,3S,4R,6S)-4,6-diamino-3-[[(2R,3R,4R,5R)-3,5-dihydroxy-5-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl]oxy]-2-hydroxycyclohexyl)oxy]tetrahydro-2H-pyran-2-yl]methylcarbamodithioic acid | C20H39N5O7S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)The condensation of 3-(methylmercapto)propionyl chloride (I) with 4-(3-ethoxy-2 hydroxypropoxy) aniline (II) by means of triethylamine in DMF gives the corresponding amide (III), which is then treated with methyl p-toluenesulfonate (IV) in dichloromethane.
| 【1】 Hori, M.; Matsuura, N.; Ueda, S.; Yamawaki, I.; Yasumoto, M.; Tada, Y.; Koda, A. (Taiho Pharmaceutical Co., Ltd.); Sulfonium cpds., processes for preparing the cpds. and pharmacological compsns. containing the same. CH 659066; DE 3408708; FR 2542312; GB 2137986; JP 1984167564; JP 1984170062; JP 1985152459; US 4556737 . |
| 【2】 Prous, J.; Castaner, J.; IPD-1151T. Drugs Fut 1988, 13, 11, 952. |
| 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) | 23400 | 3-(methylsulfanyl)propanoyl chloride | 7031-23-4 | C4H7ClOS | 详情 | 详情 |
| (II) | 23401 | 1-(4-aminophenoxy)-3-ethoxy-2-propanol | C11H17NO3 | 详情 | 详情 | |
| (III) | 23402 | N-[4-(3-ethoxy-2-hydroxypropoxy)phenyl]-3-(methylsulfanyl)propanamide | C15H23NO4S | 详情 | 详情 | |
| (IV) | 23403 | Methyl p-toluenesulfonate; Methyl 4-methylbenzenesulfonate; Methyl 4-toluenesulfonate | 80-48-8 | C8H10O3S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(A)Perifosine was synthesized via a two-step process. In the first step, phosphorus oxytrichloride (I) was reacted with 4-hydroxy-1-methylpiperidine hydrochloride (II) in dichloromethane at room temperature using pyridine as auxiliary base. The resulting intermediate, without isolation, was reacted with octadecanol (III) to yield desmethyl perifosine (IV). Desmethyl perifosine was purified by recrystallization prior to methylation. The second step consisted of the methylation of desmethyl perifosine (IV), which was carried out with p-toluenesulfonic acid methyl ester in boiling ethanol using potassium carbonate as base. The crude perifosine solution that was obtained after filtration of the cooled reaction mixture was treated with ion exchange resin in order to remove remaining salts and ionic by-products. Pure perifosine was obtained after evaporation and crystallization.
| 【1】 Eibl, H.; Engel, J.; Synthesis of hexadecylphosphocholine (miltefosine). Alkylphophocholines: New drugs in cancer therapy. Prog Exp Tumor Res 1992, 34, 1-5. |
| 【2】 Engel, J.; Hilgard, P.; Nossner, G.; Voss, V.; Traiser, M.; Klenner, T.; Kutscher, B.; Perifosine. Drugs Fut 2000, 25, 12, 1257. |
| 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) | 23403 | Methyl p-toluenesulfonate; Methyl 4-methylbenzenesulfonate; Methyl 4-toluenesulfonate | 80-48-8 | C8H10O3S | 详情 | 详情 |
| (I) | 42493 | Phosphoryl chloride; Phosphorus Oxychloride; Phosphorus (V) trichloride oxide | 10025-87-3 | Cl3OP | 详情 | 详情 |
| (II) | 42494 | 4-hydroxy-1-methylpiperidinium chloride | C6H14ClNO | 详情 | 详情 | |
| (III) | 21494 | 1-octadecanol | 112-92-5 | C18H38O | 详情 | 详情 |
| (IV) | 42495 | 4-[[chloro(octadecyloxy)phosphoryl]oxy]-1-methylpiperidinium chloride | C24H50Cl2NO3P | 详情 | 详情 |