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【结 构 式】 
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【分子编号】34214 【品名】1-chloro-3-methoxy-2-propanol 【CA登记号】4151-97-7 |
【 分 子 式 】C4H9ClO2 【 分 子 量 】124.56696 【元素组成】C 38.57% H 7.28% Cl 28.46% O 25.69% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of p-benzyloxyaniline (I) with 1-chloro-2-hydroxy-3-methoxypropane (II) in ethanol, followed by cyclization ot the resulting amino alcohol (III) with ethyl carbonate (A) in toluene in the presence of CH3ONa and debenzylation affords a phenolic 2-oxazolidinone (V), which is alkylated with m-cyanobenzyl bromide (VI) to give cimoxatone.
| 【1】 Ancher, J.F.; Bourgery, G.; Dostert, P.; Douzon, C.; Guerret, P.; Lacour, A.; Laglois, M.; Nouvelles oxazolidinones, oxazolidinethiones et pyrrilidinones, leur procédé de préparation et leur application en thérapeutique. FR 2428032; JP 55051064; JP 56167666 . |
| 【2】 Ancher, J.F.; Cimoxatone. Drugs Fut 1984, 9, 6, 412. |
| 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) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (I) | 22460 | 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine | C13H13NO | 详情 | 详情 | |
| (II) | 34214 | 1-chloro-3-methoxy-2-propanol | 4151-97-7 | C4H9ClO2 | 详情 | 详情 |
| (III) | 34215 | 1-[4-(benzyloxy)anilino]-3-methoxy-2-propanol | C17H21NO3 | 详情 | 详情 | |
| (IV) | 28690 | (5R)-3-[4-(benzyloxy)phenyl]-5-(methoxymethyl)-1,3-oxazolidin-2-one | C18H19NO4 | 详情 | 详情 | |
| (V) | 28682 | (5R)-3-(4-hydroxyphenyl)-5-(methoxymethyl)-1,3-oxazolidin-2-one | C11H13NO4 | 详情 | 详情 | |
| (VI) | 13244 | alpha-Bromo-m-tolunitrile; 3-(Bromomethyl)benzonitrile | 28188-41-2 | C8H6BrN | 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 shorter synthetic pathway is through the condensation of the above chlorohydrin (II) with m-cyanobenzyloxyaniline (X), prepared by alkylation of p-nitrophenol (VIII) with m-cyanobenzyl bromide (VII) in the presence of KI and further reduction of the nitro group with Fe-NH4Cl, then cyclization with ethyl carbonate. Cimoxatone can also be obtained by opening glycidol (XI) with m-cyanobenzyloxyaniline (X) in ethanol under reflux, and cyclizing with ethyl carbonate (A) to obtain a 5-hydroxymethyl-2-oxazolidinone (XIII), which is methylated by CH3I under phase-transfer catalysis.
| 【1】 Ancher, J.F.; Bourgery, G.; Dostert, P.; Douzon, C.; Guerret, P.; Lacour, A.; Laglois, M.; Nouvelles oxazolidinones, oxazolidinethiones et pyrrilidinones, leur procédé de préparation et leur application en thérapeutique. FR 2428032; JP 55051064; JP 56167666 . |
| 【2】 Ancher, J.F.; Cimoxatone. Drugs Fut 1984, 9, 6, 412. |
| 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) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (II) | 34214 | 1-chloro-3-methoxy-2-propanol | 4151-97-7 | C4H9ClO2 | 详情 | 详情 |
| (VII) | 13244 | alpha-Bromo-m-tolunitrile; 3-(Bromomethyl)benzonitrile | 28188-41-2 | C8H6BrN | 详情 | 详情 |
| (VIII) | 11236 | 4-Nitrophenol; p-Nitrophenol | 100-02-7 | C6H5NO3 | 详情 | 详情 |
| (IX) | 34216 | 3-[(4-nitrophenoxy)methyl]benzonitrile | C14H10N2O3 | 详情 | 详情 | |
| (X) | 34217 | 3-[(4-aminophenoxy)methyl]benzonitrile | C14H12N2O | 详情 | 详情 | |
| (XI) | 29648 | 2-oxiranylmethanol | 556-52-5 | C3H6O2 | 详情 | 详情 |
| (XII) | 34218 | 3-([4-[(2,3-dihydroxypropyl)amino]phenoxy]methyl)benzonitrile | C17H18N2O3 | 详情 | 详情 | |
| (XIII) | 34219 | 3-([4-[5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenoxy]methyl)benzonitrile | C18H16N2O4 | 详情 | 详情 | |
| (XIV) | 34220 | 3-([4-[(2-hydroxy-3-methoxypropyl)amino]phenoxy]methyl)benzonitrile | C18H20N2O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)Acetylation of 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (I) in refluxing acetic anhydride in the presence of p-toluenesulfonic acid affords acetamide (II). The title compound is then obtained by alkylation of acetamide (II) with 1-chloro-3-methoxy-2-propanol (III). The selectivity in the alkylation at the acetamide N has been improved with the addition of several metallic cations, the best results being obtained with calcium ions.
| 【1】 Bjoersvik, H.-R.; et al.; An observation of cationic influence on the N/O alkylation selectivity in the alkylation of a compound containing several nucleophilic sites. Acta Chem Scand 1994, 48, 7, 582. |
| 【2】 Wille, K. (Amersham plc); X-Ray contrast agents. EP 0105752 . |
| 【3】 Cockbain, J.R.M.; Gulbrandsen, T.; Ingvoldstad, O.E.; Holmaas, L.T. (Amersham plc); Process for the preparation of contrast agents. WO 9808805 . |
| 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) | 59316 | 5-amino-N~1~,N~3~-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide | C14H18I3N3O6 | 详情 | 详情 | |
| (II) | 59311 | 5-(acetylamino)-N~1~,N~3~-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide | C16H20I3N3O7 | 详情 | 详情 | |
| (III) | 34214 | 1-chloro-3-methoxy-2-propanol | 4151-97-7 | C4H9ClO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Alternatively, 5-acetamido-2,4,6-triiodoisophthalic acid (I) is alkylated with 1-chloro-3-methoxy-2-propanol (II) to produce (III). After protection of the alcoholic hydroxyl group as the acetate ester (IV), the carboxyl groups are activated as the corresponding acid chloride (V) with SOCl2. Coupling of (V) with 3-amino-1,2-propanediol (VI) then produces the title amide.
| 【1】 Skjoeld, W.; Berg, A.; Preparative liquid chromatography in the field of X-ray contrast agents. J Chromatogr 1986, 366, 299. |
| 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) | 59317 | 5-(acetylamino)-2,4,6-triiodoisophthalic acid | C10H6I3NO5 | 详情 | 详情 | |
| (II) | 34214 | 1-chloro-3-methoxy-2-propanol | 4151-97-7 | C4H9ClO2 | 详情 | 详情 |
| (III) | 59318 | 5-[acetyl(2-hydroxy-3-methoxypropyl)amino]-2,4,6-triiodoisophthalic acid | C14H14I3NO7 | 详情 | 详情 | |
| (IV) | 59319 | 5-{acetyl[2-(acetyloxy)-3-methoxypropyl]amino}-2,4,6-triiodoisophthalic acid | C16H16I3NO8 | 详情 | 详情 | |
| (V) | 59320 | 2-[acetyl-3,5-bis(chlorocarbonyl)-2,4,6-triiodoanilino]-1-(methoxymethyl)ethyl acetate | C16H14Cl2I3NO6 | 详情 | 详情 | |
| (VI) | 12979 | 3-Amino-1,2-propanediol；3-aminopropane-1,2-diol | 616-30-8 | C3H9NO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(III)In an improved method, the acetamido isophthalamide (I) is treated with boric acid and KOH to form the cyclic diborate tripotassium salt (II). Subsequent alkylation of (II) with 1-chloro-3-methoxy-2-propanol (III) yields regioselectively the N-alkylated acetamide (IV). The borate groups of (IV) are finally removed upon quenching with diluted HCl.
| 【1】 Bjoersvik, H.-R.; et al.; A selective process for N-alkylation in competition with O-alkylation: Boric acid, borax, and metaborate as a cheap and effective protecting group applicable for industrial-scale synthetic processes. Org Process Res Dev 2001, 5, 5, 472. |
| 【2】 Priebe, H. (Amersham plc); An N-alkylation. GB 2331098 . |