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【结 构 式】 
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【分子编号】49487 【品名】[4-(azidomethyl)-2,6-dichlorophenyl](4-chlorophenyl)methanone 【CA登记号】 |
【 分 子 式 】C14H8Cl3N3O 【 分 子 量 】340.59524 【元素组成】C 49.37% H 2.37% Cl 31.23% N 12.34% O 4.7% |
合成路线1
该中间体在本合成路线中的序号：(VIII)Reduction of 3,5-dichlorobenzoyl chloride (I) with NaBH4 in THF in the presence of N-methyl pyrrolidone (NMP) provides benzyl alcohol derivative (II), which is then treated with tert-butyl dimethylsilyl chloride (TBDMSCl) in DMF in the presence of imidazole and DMAP to furnish protected compound (III). Lithiation of (III) with BuLi (occasionally in the presence of tetramethylethylenediamine) in THF followed by reaction with p-chlorobenzoyl chloride (IV) in THF affords benzophenone derivative (V), which is then deprotected by means of concentrated HCl to yield benzyl alcohol derivative (VI). Conversion of alcohol (VI) into chloride (VII) is then performed by reaction with SOCl2. Next, reaction of (VII) with NaN3 and NaI in refluxing ethanol gives benzylazide derivative (VIII), which is finally converted into the desired product by reaction with cyanoacetamide (IX) and K2CO3 in DMSO.
| 【1】 Bochis, R.J.; Chabala, J.C.; Fisher, M.H. (Merck & Co., Inc.); 5-(Amino or substd.amino)-1,2,3-triazoles. EP 0151529; JP 1985188376; US 4590201 . |
| 【2】 Hube, D. (Merck & Co., Inc.); 5-Amino or substd. amino-1,2,3-triazoles useful as anti-metastasis agents. JP 1991056417; US 5045543 . |
| 【3】 Hupe, D.; Azzolina, B.A.; Argenbright, L.; Behrens, N. (Merck & Co., Inc.); 5-Amino or substd. amino 1,2,3-triazoles useful as antiproliferative agents. EP 0304221; JP 1989068321; US 4847257 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 49483 | N,N,N',N'-Tetramehylenediamine; 1,2-Bis(dimethylamino)ethane | C6H16N2 | 详情 | 详情 | ||
| (I) | 27769 | 3,5-dichlorobenzoyl chloride | 2905-62-6 | C7H3Cl3O | 详情 | 详情 |
| (II) | 24168 | (3,5-dichlorophenyl)methanol | 60211-57-6 | C7H6Cl2O | 详情 | 详情 |
| (III) | 49482 | tert-butyl(dimethyl)silyl 3,5-dichlorobenzyl ether; tert-butyl[(3,5-dichlorobenzyl)oxy]dimethylsilane | C13H20Cl2OSi | 详情 | 详情 | |
| (IV) | 10295 | p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride | 122-01-0 | C7H4Cl2O | 详情 | 详情 |
| (V) | 49484 | [4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2,6-dichlorophenyl](4-chlorophenyl)methanone | C20H23Cl3O2Si | 详情 | 详情 | |
| (VI) | 49485 | (4-chlorophenyl)[2,6-dichloro-4-(hydroxymethyl)phenyl]methanone | C14H9Cl3O2 | 详情 | 详情 | |
| (VII) | 49486 | (4-chlorophenyl)[2,6-dichloro-4-(chloromethyl)phenyl]methanone | C14H8Cl4O | 详情 | 详情 | |
| (VIII) | 49487 | [4-(azidomethyl)-2,6-dichlorophenyl](4-chlorophenyl)methanone | C14H8Cl3N3O | 详情 | 详情 | |
| (IX) | 12122 | Cyanoacetamide; 2-Cyanoacetamide | 107-91-5 | C3H4N2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)Alternatively, the target compound can be obtained as follows: Condensation between 2,6-dichloro-4-methylbenzonitrile (X) and 4-chloroiodobenzene (XI) by means of Mg in refluxing ether gives methyleneimine derivative (XII), which is then converted into 4-(4-chlorobenzoyl)-3,5-dichlorotoluene (XIII) by refluxing in dioxane-aqueous phosphate buffer. (Alternatively, compound (XIII) can also be obtained either by condensation of 3,5-dichlorotoluene (XIV) with p-chlorobenzoyl chloride (IV) by means of BuLi in THF or by treatment of 2,6-dichloro-4-methylbenzoic acid (XV) with thionyl chloride (SOCl2) in refluxing DMF to give (XVI), which then reacts with chlorobenzene (XVII) by means of AlCl3 in refluxing CCl4). Bromination of (XIII) is then performed by reaction with N-bromosuccinimide and dibenzoyl peroxide in refluxing benzene to give 4-(4-chlorobenzoyl)-3,5-dichlorobenzyl bromide (XVIII). (Alternatively, (XVIII) can also be synthesized by treatment of the already reported benzophenone derivative (V) with HOAc in THF/H2O followed by reaction with phosphorus tribromide in diethyl ether.) Finally, (XVIII) is converted into the desired compound either by treatment with 5-amino-1,2,3-triazole-4-carboxamide (XIX) by means of NaH in refluxing EtOH or by first reaction of (XVIII) with KN3 in refluxing EtOH to furnish benzyl azide (VIII), followed by reaction with cyanoacetamide (IX) and NaOMe in refluxing EtOH.
| 【1】 Bochis, R.J.; Chabala, J.C.; Fisher, M.H. (Merck & Co., Inc.); 5-(Amino or substd.amino)-1,2,3-triazoles. EP 0151529; JP 1985188376; US 4590201 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 10295 | p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride | 122-01-0 | C7H4Cl2O | 详情 | 详情 |
| (V) | 49484 | [4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2,6-dichlorophenyl](4-chlorophenyl)methanone | C20H23Cl3O2Si | 详情 | 详情 | |
| (VIII) | 49487 | [4-(azidomethyl)-2,6-dichlorophenyl](4-chlorophenyl)methanone | C14H8Cl3N3O | 详情 | 详情 | |
| (IX) | 12122 | Cyanoacetamide; 2-Cyanoacetamide | 107-91-5 | C3H4N2O | 详情 | 详情 |
| (X) | 49488 | 2,6-dichloro-4-methylbenzonitrile | C8H5Cl2N | 详情 | 详情 | |
| (XI) | 19395 | 1-chloro-4-iodobenzene | 637-87-6 | C6H4ClI | 详情 | 详情 |
| (XII) | 49489 | (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanimine | C14H10Cl3N | 详情 | 详情 | |
| (XIII) | 49490 | (4-chlorophenyl)(2,6-dichloro-4-methylphenyl)methanone | C14H9Cl3O | 详情 | 详情 | |
| (XIV) | 49491 | 1,3-dichloro-5-methylbenzene | C7H6Cl2 | 详情 | 详情 | |
| (XV) | 49492 | 2,6-dichloro-4-methylbenzoic acid | C8H6Cl2O2 | 详情 | 详情 | |
| (XVI) | 49493 | 2,6-dichloro-4-methylbenzoyl chloride | C8H5Cl3O | 详情 | 详情 | |
| (XVII) | 10190 | 1-Chlorobenzene | 108-90-7 | C6H5Cl | 详情 | 详情 |
| (XVIII) | 49494 | [4-(bromomethyl)-2,6-dichlorophenyl](4-chlorophenyl)methanone | C14H8BrCl3O | 详情 | 详情 | |
| (XIX) | 49495 | 5-amino-1H-1,2,3-triazole-4-carboxamide | C3H5N5O | 详情 | 详情 |