|
【结 构 式】 
|
【分子编号】12501 【品名】Isophthaloyl dichloride 【CA登记号】99-63-8 |
【 分 子 式 】C8H4Cl2O2 【 分 子 量 】203.02396 【元素组成】C 47.33% H 1.99% Cl 34.92% O 15.76% |
合成路线1
该中间体在本合成路线中的序号：(IV)By condensation of 3-[3-(chlorocarbonyl)benzoyl]-1-(ethoxymethyl)-5-fluorouracil (I) with 6-benzoyloxy-3-cyano-2-hydroxypyridine (II) by means of triethylamine in refluxing acetonitrile. The starting compounds (I) and (II) are obtained as follows: The reaction of 1-(ethoxymethyl)-5-fluorouracil (III) with isophthaloyl dichloride (IV) by means of triethylamine in refluxing dioxane gives uracil (I). The esterification of 3-cyano-2,6-dihydroxypyridine (V) with benzoyl chloride (VI) by means of triethylamine in dimethylacetamide affords pyridine (II).
| 【1】 Fujii, S. (Otsuka Pharmaceutical Co., Ltd.); 5-Fluorouracil derivs., process for their preparation and their use. DE 3709699; FR 2605006; GB 2192880; JP 1988201127; JP 1988301880 . |
| 【2】 Castaner, J.; Hoshi, A.; Emitefur. Drugs Fut 1993, 18, 5, 418. |
| 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) | 12498 | 3-[[3-(Ethoxymethyl)-5-fluoro-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]carbonyl]benzoyl chloride | C15H12ClFN2O5 | 详情 | 详情 | |
| (II) | 12499 | 5-cyano-6-hydroxy-2-pyridinyl benzoate | C13H8N2O3 | 详情 | 详情 | |
| (III) | 12500 | 1-(Ethoxymethyl)-5-fluoro-2,4(1H,3H)-pyrimidinedione | C7H9FN2O3 | 详情 | 详情 | |
| (IV) | 12501 | Isophthaloyl dichloride | 99-63-8 | C8H4Cl2O2 | 详情 | 详情 |
| (V) | 12502 | 2,6-Dihydroxynicotinonitrile | C6H4N2O2 | 详情 | 详情 | |
| (VI) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Reaction of isophthaloyl dichloride (I) with cycloheptylamine (II) in the presence of triethylamine in dichloromethane gives N,N'-dicycloheptylisophthalimide (III), which is reduced with sodium bis(2-methoxyethoxy)aluminum hydride in toluene to yield 1,3-bis(cycloheptylaminomethyl)benzene (IV). Compound (IV) is treated with p-nitrophenylisocyanate (V) to afford 1,3-bis[1-cycloheptyl-3-(4-nitrophenyl)ureidomethyl]benzene (VI), which is reduced with hydrogen in the presence of palladium over charcoal to give 1,3-bis[1-cycloheptyl-3-(4-aminophenyl)ureidomethyl]benzene (VII). Finally, compound (VII) is treated with aqueous formaldehyde and hydrogen in the presence of platinum oxide in ethanol, followed by addition of hydrochloric acid in ethanol.
| 【1】 Ito, N.; Yasunaga, T.; Iizumi, Y.; Araki, T. (Yamanouchi Pharmaceutical Co., Ltd.); Diurea derivatives useful as medicaments and processes for the preparation thereof. AU 8928669; EP 0325397; JP 1990117651; US 5091419; US 5166429; US 5384425 . |
| 【2】 Yasunaga, T.; Araki, T.; Iwaoka, K.; Iizumi, Y.; Ohata, I.; Matsuda, K.; Ito, N.; Synthesis and activity of a novel phenylenediurea derivative with hypolipidemic and antiatherosclerotic activity. 111th Annu Meet Pharmaceut Soc Jpn (March 28-30, Tokyo) 1991, Abst 29V 3-040.. |
| 【3】 Graul, A.; Castaner, J.; Prous, J.; YM17E. Drugs Fut 1993, 18, 9, 813. |
| 【4】 Iizumi, Y.; Ohhata, I.; Iwaoka, K.; Matsuda, K.; Ito, N.; Yasunaga, T.; Araki, T.; Synthesis and hypocholesterolemic activity of phenylene and pyridylene diurea derivatives as ACAT inhibitors. 202nd ACS Natl Meet (Aug 25-30, New York) 1991, Abst MEDI 109. |
| 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) | 12501 | Isophthaloyl dichloride | 99-63-8 | C8H4Cl2O2 | 详情 | 详情 |
| (II) | 11926 | 1-[4-(Chloromethyl)-2-hydroxy-3-propylphenyl]-1-ethanone | C12H15ClO2 | 详情 | 详情 | |
| (III) | 14907 | N(1),N(3)-dicycloheptylisophthalamide | C22H32N2O2 | 详情 | 详情 | |
| (IV) | 14908 | N-cycloheptyl-N-[3-[(cycloheptylamino)methyl]benzyl]amine; N-[3-[(cycloheptylamino)methyl]benzyl]cycloheptanamine | C22H36N2 | 详情 | 详情 | |
| (V) | 14909 | 1-isocyanato-4-nitrobenzene; 4-Nitrophenyl isocyanate | 100-28-7 | C7H4N2O3 | 详情 | 详情 |
| (VI) | 14910 | N-cycloheptyl-N-[3-([cycloheptyl[(4-nitroanilino)carbonyl]amino]methyl)benzyl]-N'-(4-nitrophenyl)urea | C36H44N6O6 | 详情 | 详情 | |
| (VII) | 14911 | N-(3-[[[(4-aminoanilino)carbonyl](cycloheptyl)amino]methyl]benzyl)-N'-(4-aminophenyl)-N-cycloheptylurea | C36H48N6O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)Reaction of 4-(trifluoromethyl)benzyl alcohol (I) with DSC followed by coupling with partially protected lysine (II) affords carbamate (III), which is converted into derivative (V) first by Boc removal with HCl/dioxane in dichloromethane followed by coupling with Boc-Gly-OH (IV) by means of EDCl and DIEA. Boc removal of compound (V) with HCl/dioxane in dichloromethane, followed by condensation with isophthaloyl dichloride (VI) by means of DIEA in DMF, gives compound (VII), which is finally subjected to methyl ester saponification with LiOH in THF/MeOH to provide the desired product.
| 【1】 Boger, D.L.; et al.; Identification of a novel class of small-molecule antiangiogenic agents through the screening of combinatorial libraries which function by inhibiting the binding and localization of proteinase MMP2 to integrin alphavbeta3. J Am Chem Soc 2001, 123, 7, 1280. |
| 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) | 47327 | [4-(trifluoromethyl)phenyl]methanol | 349-95-1 | C8H7F3O | 详情 | 详情 |
| (II) | 47328 | methyl (2S)-2-amino-6-[(tert-butoxycarbonyl)amino]hexanoate | C12H24N2O4 | 详情 | 详情 | |
| (III) | 47329 | methyl (2S)-6-[(tert-butoxycarbonyl)amino]-2-[([[4-(trifluoromethyl)benzyl]oxy]carbonyl)amino]hexanoate | C21H29F3N2O6 | 详情 | 详情 | |
| (IV) | 18066 | N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid | 4530-20-5 | C7H13NO4 | 详情 | 详情 |
| (V) | 47330 | methyl (2S)-6-([2-[(tert-butoxycarbonyl)amino]acetyl]amino)-2-[([[4-(trifluoromethyl)benzyl]oxy]carbonyl)amino]hexanoate | C23H32F3N3O7 | 详情 | 详情 | |
| (VI) | 12501 | Isophthaloyl dichloride | 99-63-8 | C8H4Cl2O2 | 详情 | 详情 |
| (VII) | 47331 | methyl (2S)-6-([2-[(3-[(10S)-10-(methoxycarbonyl)-4,12-dioxo-14-[4-(trifluoromethyl)phenyl]-13-oxa-2,5,11-triazatetradec-1-anoyl]benzoyl)amino]acetyl]amino)-2-[([[4-(trifluoromethyl)benzyl]oxy]carbonyl)amino]hexanoate | C44H50F6N6O12 | 详情 | 详情 |