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【结 构 式】 
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【分子编号】13579 【品名】2-Methoxy-1,3-propanediol 【CA登记号】 |
【 分 子 式 】C4H10O3 【 分 子 量 】106.1216 【元素组成】C 45.27% H 9.5% O 45.23% |
合成路线1
该中间体在本合成路线中的序号：(III)Two different routes have been described for the preparation of Et-18-OCH3: 1) The methylation of 1,3-benzylideneglycerol (I) with methyl iodide and KOH gives 1,3-benzytidene-2-O-methylglycerol (II), which is hydrolyzed with HCl to 2-O-methylglycerol (III). The condensation of (III) with octadecyl bromide (IV) and KOH in DMSO/THF yields 1-O-octadecyl-2-O-methyl-(rac)-glycerol (V), which by reaction with phosphorodichloric acid 2-bromoethyl ester (VI) and pyridine is converted to 3-octadecyloxy-2-methoxypropyl bromoethyl phosphate (VII). Finally, this compound is converted to Et-18-OCH3 with trimethylamine (VIII) in toluene and treated with silver carbonate to remove traces of bromide. 2) The reaction of 1,2-isopropylidene-sn-glycerol (IX) with benzyl bromide (X) and NaNH2 in benzene gives 1,2-isopropylidene-3-O-benzyl-sn-glycerol (XI), which is hydrolyzed with acetic acid to 3-O-benzyl-sn-glycerol (XII). The etherification of (XII) with (IV) as before or with NaNH2 gives 1-O-octadecyl-3-O-benzyl-sn-glycerol (XIII), which is methylated with methyl iodide and NaNH2 in dioxane to give 1-O-octadecyl-2-O-methyl-3-O-benzyl-sn-glycerol (XIV). Finally, this compound is debenzytaled by hydrogenolysis with H2 over Pd/C in petroleum ether to form (V), an intermediate previously described above.
| 【1】 Tsutsumi, H.; Kamata, T.; Nakajima, K.; Katagi, M.; Tsuchihashi, H.; Nishioka, H.; Nishikawa, M.; Miki, A.; Tatsuno, M.; Chem Phys Lipids 1982, 30, 9, 389-392. |
| 【2】 Fast, L.D.; et al.; Chem Pharm Bull 1982, 30, 9, 3260-3270. |
| 【3】 Castaner, R.M.; Castaner, J.; Serradell, M.N.; ET-18-OCH3. Drugs Fut 1987, 12, 4, 341. |
| 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) | 28795 | 2-phenyl-1,3-dioxan-5-ol | 1708-40-3 | C10H12O3 | 详情 | 详情 |
| (II) | 28796 | 5-methoxy-2-phenyl-1,3-dioxane | C11H14O3 | 详情 | 详情 | |
| (III) | 13579 | 2-Methoxy-1,3-propanediol | C4H10O3 | 详情 | 详情 | |
| (IV) | 28797 | 1-bromooctadecane | 112-89-0 | C18H37Br | 详情 | 详情 |
| (V) | 28798 | 2-methoxy-3-(octadecyloxy)-1-propanol | C22H46O3 | 详情 | 详情 | |
| (VI) | 13033 | Dichlorophosphoric acid 2-bromoethyl ester | C2H4BrCl2O2P | 详情 | 详情 | |
| (VII) | 28799 | 2-bromoethyl 2-methoxy-3-(octadecyloxy)propyl hydrogen phosphate | C24H50BrO6P | 详情 | 详情 | |
| (IX) | 16476 | 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane; (2,2-dimethyl-1,3-dioxolan-4-yl)methanol; 2,3-o-Isopropylideneglycerol | 100-79-8 | C6H12O3 | 详情 | 详情 |
| (X) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (XI) | 28800 | benzyl 2,2-dimethyl-1,3-dioxolan-4-yl ether | C12H16O3 | 详情 | 详情 | |
| (XII) | 28801 | 1-(benzyloxy)-1,2-ethanediol | C9H12O3 | 详情 | 详情 | |
| (XIII) | 28802 | 1-(benzyloxy)-2-(octadecyloxy)-1-ethanol | C27H48O3 | 详情 | 详情 | |
| (XIV) | 28803 | 1-[[1-methoxy-2-(octadecyloxy)ethoxy]methyl]benzene | C28H50O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The condensation of 2-methoxypropane-1,3-diol (I) with octadecylisocyanate (II) in pyridine gives 3-(N-octadecylcarbamoyloxy)-2-methylpropanol (III), which is esterified with 2-bromoethyl phosphorodichloridate (IV) by means of pyridine in benzene and treated with water to afford 3-(N octadecyicarbamoyloxy)-2-methoxypropyl2-bromoethyl acid phosphate (V). Finally, this compound is treated with thiazole (VI) and Ag2CO3 in hot toluene.
| 【1】 Inada, Y.; Terashita, Z.; Yoshioka, Y.; Tsushima, S.; Nishikawa, K.; Nomura, H.; CV-3988 - A specific antagonist of platelet activa. Life Sci 1983, 32, 1975. |
| 【2】 Nomura, H.; Hozumi, M.; Yoshioka, Y. (Takeda Chemical Industries, Ltd.); Carbamic acid esters, their production and use. EP 0035375 . |
| 【3】 Castaner, J.; Prous, J.; CV-3988. Drugs Fut 1987, 12, 1, 12. |
| 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) | 13579 | 2-Methoxy-1,3-propanediol | C4H10O3 | 详情 | 详情 | |
| (II) | 13586 | 1-Isocyanatooctadecane; octadecyl isocyanate | 112-96-9 | C19H37NO | 详情 | 详情 |
| (III) | 22997 | 3-hydroxy-2-methoxypropyl octadecylcarbamate | C23H47NO4 | 详情 | 详情 | |
| (IV) | 13033 | Dichlorophosphoric acid 2-bromoethyl ester | C2H4BrCl2O2P | 详情 | 详情 | |
| (V) | 22999 | 3-[[(2-bromoethoxy)(hydroxy)phosphoryl]oxy]-2-methoxypropyl octadecylcarbamate | C25H51BrNO7P | 详情 | 详情 | |
| (VI) | 23000 | 1,3-thiazole | 288-47-1 | C3H3NS | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The racemic form of E-5880 is prepared as follows: The esterification of 2-methoxy-1,3-propanediol (I) with phenyl chlorocarbonate (II) in pyridine gives the diester (III), which is treated with 2-(aminomethyl)pyridine (IV) in refluxing chloroform, yielding the carbamate (V). The reaction of (V) with 4-hydroxypiperidine (VI) in refluxing chloroform affords the dicarbamate (VII), which by treatment with octadecyl isocyanate (VIII) gives the tricarbamate (X). Alternatively, (X) can be obtained by treatment of (VIII) with carbonate (II), yielding the intermediate (IX), which by treatment with octadecylamine (XI) at 100 C affords (X). The acylation of (X) with 2-methoxybenzoyl chloride (XII) in pyridine gives the precursor (XIII), which is finally treated with ethyl iodide in excess at reflux temperature and submitted to an ion exchange resin (Amberlite IRA-410 Cl- type). The optically active (R)-enantiomer is synthesized starting from L-mannitol.
| 【1】 Okano, K.; Asano, O.; Shimomura, N.; Kawahara, T.; Abe, S.; Miyazawa, S.; Miyamoto, M.; Yoshimura, H.; Harada, K.; Nagaoka, J.; Kawata, T.; Yoshimura, T.; Suzuki, H.; Souda, S.; Machida, Y.; Katayama, K.; Yamatsu, I. (Eisai Co., Ltd.); Glycerin deriv. and its pharmacological use. AU 8937213; EP 0353474; JP 1990131467; JP 1996231508; US 5037827; US 5273985; US 5476863; US 5476864 . |
| 【2】 Okano, K.; Shimomura, N.; Asano, O.; et al.; Okano, K., Asano, O., Shimomura, N. et al. Structure-activity relationships of platelet activating factor (PAF) antagonists. 198th ACS Natl Meet (Sept 10-15, Miami Beach) 1989, Abst MEDI 55. |
| 【3】 Prous, J.; Castaner, J.; E-5880. Drugs Fut 1992, 17, 12, 1082. |
| 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) | 13579 | 2-Methoxy-1,3-propanediol | C4H10O3 | 详情 | 详情 | |
| (II) | 13580 | 1-[(Chlorocarbonyl)oxy]benzene; phenyl chloroformate | 1885-14-9 | C7H5ClO2 | 详情 | 详情 |
| (III) | 13581 | 2-methoxy-3-[(phenoxycarbonyl)oxy]propyl phenyl carbonate | C18H18O7 | 详情 | 详情 | |
| (IV) | 13582 | 2-Pyridinylmethanamine; 2-Pyridinylmethylamine; 2-(Aminomethyl)pyridine | 3731-51-9 | C6H8N2 | 详情 | 详情 |
| (V) | 13583 | (5-oxo-6-phenyl-1,4-dioxan-2-yl)methyl 2-pyridinylmethylcarbamate | C18H18N2O5 | 详情 | 详情 | |
| (VI) | 12076 | 4-Piperidinol; 4-Hydroxypiperidine | 5382-16-1 | C5H11NO | 详情 | 详情 |
| (VII) | 13585 | 2-methoxy-3-([[(2-pyridinylmethyl)amino]carbonyl]oxy)propyl 4-hydroxy-1-piperidinecarboxylate | C17H25N3O6 | 详情 | 详情 | |
| (VIII) | 13586 | 1-Isocyanatooctadecane; octadecyl isocyanate | 112-96-9 | C19H37NO | 详情 | 详情 |
| (IX) | 13587 | 2-methoxy-3-([[(2-pyridinylmethyl)amino]carbonyl]oxy)propyl 4-[(phenoxycarbonyl)oxy]-1-piperidinecarboxylate | C24H29N3O8 | 详情 | 详情 | |
| (X) | 13588 | 2-methoxy-3-([[(2-pyridinylmethyl)amino]carbonyl]oxy)propyl 4-[[(octadecylamino)carbonyl]oxy]-1-piperidinecarboxylate | C36H62N4O7 | 详情 | 详情 | |
| (XI) | 13589 | 1-Aminooctadecane; Octadecylamine; 1-Octadecanamine | 124-30-1 | C18H39N | 详情 | 详情 |
| (XII) | 13590 | 2-Methoxybenzoyl chloride; o-Anisoyl chloride; 2-Anisoyl chloride | 21615-34-9 | C8H7ClO2 | 详情 | 详情 |
| (XIII) | 13591 | 2-methoxy-3-([[(2-methoxybenzoyl)(2-pyridinylmethyl)amino]carbonyl]oxy)propyl 4-[[(octadecylamino)carbonyl]oxy]-1-piperidinecarboxylate | C44H68N4O9 | 详情 | 详情 |