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【结 构 式】 
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【分子编号】16476 【品名】2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane; (2,2-dimethyl-1,3-dioxolan-4-yl)methanol; 2,3-o-Isopropylideneglycerol 【CA登记号】100-79-8 |
【 分 子 式 】C6H12O3 【 分 子 量 】132.15948 【元素组成】C 54.53% H 9.15% O 36.32% |
合成路线1
该中间体在本合成路线中的序号：(IX)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：(X)The reaction of 2,2-dimethyl-1,3-dioxolane-4-methanol (X) with ethyl 4-chloroacetoacetate (II) gives the adduct (XI), which is cyclized with 2-chlorobenzaldehyde (IV) and methyl 3-aminocrotonate (V) in refluxing ethanol to yield the dihydropyridine (XII). The cleavage of the dioxolane ring of (XII) by means of Ts-OH in methanol affords the vicinal diol (XIII), which is cleaved by means of NaIO4 in methanol to provide the already reported acetaldehyde derivative (VIII).
| 【1】 Karimian, K.; Leung-Toung, R.C.S.H.; Tam, T.F. (Apotex Inc.); 1,4-Dihydropyridines, N-substd. bicyclic 4-hydropyridines, and bicyclic N-substd. 4,5-dihydropyridines. US 5723618 . |
| 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) | 23541 | ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloro-3-oxobutanoate；Ethyl 4-chloroacetoacetate | 638-07-3 | C6H9ClO3 | 详情 | 详情 |
| (IV) | 24114 | 2-chlorobenzaldehyde | 89-98-5 | C7H5ClO | 详情 | 详情 |
| (V) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (VIII) | 48280 | 5-ethyl 3-methyl 4-(2-chlorophenyl)-2-methyl-6-[(2-oxoethoxy)methyl]-1,4-dihydro-3,5-pyridinedicarboxylate | C20H22ClNO6 | 详情 | 详情 | |
| (IX) | 48258 | 3-ethyl 5-methyl 4-(2-chlorophenyl)-2-[[2-(hydroxyimino)ethoxy]methyl]-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C20H23ClN2O6 | 详情 | 详情 | |
| (X) | 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 |
| (XI) | 48281 | ethyl 4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-3-oxobutanoate | C12H20O6 | 详情 | 详情 | |
| (XII) | 48282 | 3-ethyl 5-methyl 4-(2-chlorophenyl)-2-[[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]methyl]-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C24H30ClNO7 | 详情 | 详情 | |
| (XIII) | 48283 | 3-ethyl 5-methyl 4-(2-chlorophenyl)-2-[(2,3-dihydroxypropoxy)methyl]-6-methyl-1,4-dihydro-3,5-pyridinedicarboxylate | C21H26ClNO7 | 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 compound S 16961-1 was synthesized in three steps from solketal (I) by acylation with nicotinoyl chloride (II), deprotection of the isopropylidene ketal (III) by heating in dilute aqueous acetic acid and acylation of this key intermediate (IV) with a slight excess of palmitoyl chloride (V) in the presence of triethylamine and 4-dimethylaminopyridine (DMAP) as catalyst. The enantiomers of S 16961-1 were obtained independently in one step from the commercially available (d)- and (l)-1,2-dipalmitoyl glycerols by acylation with nicotinoyl chloride in the presence of triethylamine. The enantiomers were found equiactive and therefore were not pursued individually.
| 【1】 Brown, G.; Albers, J.J.; Fisher, L.D.; Schaeffer, S.; Lin, J.; Kaplan, C.; Zhao, X.; Bisson, B.; Fitzpatrick, V.; Dodge, H.; Regression of coronary artery disease as a result of intensive lipid lowering therapy in men with high level of apolipoprotein B. New Engl J Med 1990, 323, 19, 1289-98. |
| 【2】 Cordi, A.A.; Duhault, J.; Laudignon, N.; Castagne, I.; S 16961-1. Drugs Fut 1996, 21, 5, 490. |
| 【3】 Cordi, A.; Lacoste, J.-M.; Duhault, J.; Espinal, J.; Boulanger, M. (ADIR et Cie.); Diacylglycerol nicotinates. EP 0574312; JP 1994056786; US 5385920 . |
| 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) | 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 |
| (II) | 10753 | Nicotinoyl chloride | C6H4ClNO | 详情 | 详情 | |
| (III) | 16478 | (2,2-dimethyl-1,3-dioxolan-4-yl)methyl nicotinate | C12H15NO4 | 详情 | 详情 | |
| (IV) | 16479 | 2,3-dihydroxypropyl nicotinate | C9H11NO4 | 详情 | 详情 | |
| (V) | 16480 | Palmitoyl Chloride; hexadecanoyl chloride | 112-67-4 | C16H31ClO | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(B)1) Condensation of 2-trifluoromethylaniline (I) with ethyl ethoxymethylenemalonate (II) at 125 C to give ethyl-alpha-carbethoxy-beta-(2-trifluoromethylanilino)acrylate (III), m.p. 94 C; this product is cyclized by refluxing with diphenyl ether affording 3-carbethoxy-4-hydroxy-8-trifluoromethylquinoline (IV), m.p. 216 C, which in turn, is hydrolyzed with refluxing aqueous NaOH to the corresponding acid (V), m.p. 290-2 C; this acid is decarboxylated by refluxing in diphenyl ether to 4-hydroxy-8-trifluoromethylquinoline (VI), m.p. 180 C; this product by refluxing with POCl3 is converted into chloro-8-trifluoromethylquinoline (VII), m.p. 78 C; the condensation of quinoline (VII) with methyl anthranilate (A) by means of aqueous 2N HCl affords 4-(2-methoxycarbonylphenylamino)-8-trifluoromethylquinoline (VIII), m.p. 176 C (1,2). The transesterification of methyl ester (VIII) with glycerol affords the final product. (1) 2) Transesterification of methylester (VIII) with 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane (B) to give the acetoneketal of floctafenine (IX), mp 108 C which is finally hydrolized with HCl. (2) 3) Condensation of the chloroquinoline (VII) with the 2,2-dimethyl-4-hydroxymethyl-2,3-dioxolane ester of anthranilic acid by means aqueous HCl to give the already obtained acetoneketal (IX), which is finally hydrolized as before. (2)
| 【1】 (Roussel-Uclaf.); DE 1815467 . |
| 【2】 Castaner, J.; Arrigoni, Martelli, E.; Floctafenine. Drugs Fut 1976, 1, 2, 59. |
| 【3】 Allais, A.; et al.; NMR structure of tissue inhibitor of metalloproteinases-1 implicates localized induced fit in recognition of matrix metalloproteinases. Chim Ther 1973, 8, 2, 154. |
| 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) | 11161 | methyl 2-aminobenzoate; Methyl anthranilate | 134-20-3 | C8H9NO2 | 详情 | 详情 |
| (B) | 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 |
| (I) | 25812 | 2-(trifluoromethyl)phenylamine; 2-(trifluoromethyl)aniline | 88-17-5 | C7H6F3N | 详情 | 详情 |
| (II) | 14088 | Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate | 87-13-8 | C10H16O5 | 详情 | 详情 |
| (III) | 60720 | diethyl 2-{[2-(trifluoromethyl)anilino]methylene}malonate | C15H16F3NO4 | 详情 | 详情 | |
| (IV) | 60721 | ethyl 4-hydroxy-8-(trifluoromethyl)-3-quinolinecarboxylate | C13H10F3NO3 | 详情 | 详情 | |
| (V) | 60722 | 4-hydroxy-8-(trifluoromethyl)-3-quinolinecarboxylic acid | C11H6F3NO3 | 详情 | 详情 | |
| (VI) | 60723 | 8-(trifluoromethyl)-4-quinolinol | C10H6F3NO | 详情 | 详情 | |
| (VII) | 60724 | 4-chloro-8-(trifluoromethyl)quinoline | C10H5ClF3N | 详情 | 详情 | |
| (VIII) | 60727 | methyl 2-{[8-(trifluoromethyl)-4-quinolinyl]amino}benzoate | C18H13F3N2O2 | 详情 | 详情 | |
| (IX) | 60726 | (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 2-{[8-(trifluoromethyl)-4-quinolinyl]amino}benzoate | C23H21F3N2O4 | 详情 | 详情 | |
| (C) | 60725 | (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 2-aminobenzoate | C13H17NO4 | 详情 | 详情 |