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【结 构 式】 
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【药物名称】NSC-706995, MS-275, MS-27-275 【化学名称】N-[4-[N-(2-Aminophenyl)carbamoyl]benzyl]carbamic acid 3-pyridylmethyl ester 【CA登记号】209783-80-2, 209784-80-5 (monoHCl) 【 分 子 式 】C21H20N4O3 【 分 子 量 】376.41855 |
【开发单位】Mitsui Pharmaceuticals (Originator), Schering AG (Originator) 【药理作用】Colorectal Cancer Therapy, Lung Cancer Therapy, Oncolytic Drugs, Prostate Cancer Therapy, Antimitotic Drugs, Apoptosis Inducers, Histone Deacetylase (HDAC) Inhibitors |
合成路线1
The acylation of 4-(aminomethyl)benzoic acid (I) with trifluoroacetic anhydride gives the corresponding trifluoroacetamide (II), which is condensed with the monoprotected ortho-phenylenediamine (III) by means of oxalyl chloride in dichloromethane/DMF yielding the benzamide (IV). Elimination of the trifluoacetyl group of (V) by means of K2CO3 in methanol/water affords the 4-(aminomethyl)-derivative (V), which is condensed with 3-(hydroxymethyl)pyridine (VI) and carbonyldiimidazole (CDI) in THF providing the Boc-protected intermediate (VII). Finally, this compound is deprotected by a treatment with 4N HCl in dioxane/water.
| 【1】 Suzuki, T.; Ando, T.; Tsuchiya, K.; Nakanishi, O.; Saito, A.; Yamashita, T.; Shiraishi, Y.; Tanaka, E. (Mitsui Chemicals, Inc.); Benzamide derivs., useful as cell differentiation inducers. EP 0847992 . |
| 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) | 27823 | 4-(aminomethyl)benzoic acid | 56-91-7 | C8H9NO2 | 详情 | 详情 |
| (II) | 27824 | 4-[[(2,2,2-trifluoroacetyl)amino]methyl]benzoic acid | C10H8F3NO3 | 详情 | 详情 | |
| (III) | 27825 | tert-butyl 2-aminophenylcarbamate | C11H16N2O2 | 详情 | 详情 | |
| (IV) | 27826 | tert-butyl 2-[(4-[[(2,2,2-trifluoroacetyl)amino]methyl]benzoyl)amino]phenylcarbamate | C21H22F3N3O4 | 详情 | 详情 | |
| (V) | 27827 | tert-butyl 2-[[4-(aminomethyl)benzoyl]amino]phenylcarbamate | C19H23N3O3 | 详情 | 详情 | |
| (VI) | 15798 | 3-Pyridinemethanol; 3-pyridinylmethanol | 100-55-0 | C6H7NO | 详情 | 详情 |
| (VII) | 27828 | 3-pyridinylmethyl 4-([2-[(tert-butoxycarbonyl)amino]anilino]carbonyl)benzylcarbamate | C26H28N4O5 | 详情 | 详情 |
合成路线2
The reaction of 4-(aminomethyl)benzoic acid (I) with 3-pyridinylmethanol (II) and CDI by means of DBU and TEA in THF gives the carbamate (III), which is treated with oxalyl chloride in toluene to yield the corresponding acyl chloride (IV). Finally, the condensation of (IV) with 1,2-phenylenediamine (V) by means of imidazole in THF affords the target compound. Alternatively, the condensation of acyl chloride (IV) with 2-nitroaniline (VI) by means of pyridine gives the corresponding amide (VII), which is finally reduced with SnCl2 and ammonium acetate in methanol.
| 【1】 Suzuki, T.; Fukazawa, N.; Ando, T.; Tsuchiya, K.; Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives. J Med Chem 1999, 42, 15, 3001. |
| 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) | 27823 | 4-(aminomethyl)benzoic acid | 56-91-7 | C8H9NO2 | 详情 | 详情 |
| (II) | 15798 | 3-Pyridinemethanol; 3-pyridinylmethanol | 100-55-0 | C6H7NO | 详情 | 详情 |
| (III) | 36524 | 4-([[(3-pyridinylmethoxy)carbonyl]amino]methyl)benzoic acid | C15H14N2O4 | 详情 | 详情 | |
| (IV) | 36525 | 3-pyridinylmethyl 4-(chlorocarbonyl)benzylcarbamate | C15H13ClN2O3 | 详情 | 详情 | |
| (V) | 12824 | 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine | 95-54-5 | C6H8N2 | 详情 | 详情 |
| (VI) | 11608 | o-Nitroaniline; 2-Nitroaniline; 2-Nitrophenylamine | 88-74-4 | C6H6N2O2 | 详情 | 详情 |
| (VII) | 36526 | 3-pyridinylmethyl 4-[(2-nitroanilino)carbonyl]benzylcarbamate | C21H18N4O5 | 详情 | 详情 |