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【结 构 式】 
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【药物名称】Betrixaban；PRT-054021；MK-4448；PRT-021 【化学名称】N-(5-Chloropyridin-2-yl)-2-[4-(N,N-dimethylamidino)benzamido]-5-methoxybenzamide 【CA登记号】330942-05-7；936539-80-9 (maleate salt (1:1)) 【 分 子 式 】C23H22ClN5O3 【 分 子 量 】451.905 |
【开发单位】Portola Pharmaceuticals, Inc. (U.S.) 【药理作用】Coagulation Factor FXa Inhibitor;Treatment of Venous Thromboembolism |
合成路线1
Coupling of 5-methoxy-2-nitrobenzoic acid (I) with 2-amino-5-chloropyridine (II) by means of POCl3 and pyridine , optionally in acetonitrile solution , yields the corresponding amide (III) , which is then subjected to nitro group reduction to give amine (IV) by either treatment with SnCl2·H2O in refluxing EtOAc or catalytic hydrogenation over sulfided Pt/C in EtOAc or CH2Cl2 . Acylation of aniline (IV) with 4-cyanobenzoyl chloride (V) in the presence of pyridine in CH2Cl2 or THF affords diamide (VI). Finally, nitrile (VI) is converted to amidine by either Pinner reaction with MeOH and HCl in EtOAc and subsequent treatment of the intermediate imino ether with Me2NH in refluxing MeOH , or direct addition of lithium dimethylamide (generated from Me2NH and HexLi) to the cyano group in cold THF .
In an altenative procedure, betrixaban is obtained by coupling of aniline (IV) with the 4-amidinobenzoic acid (VII) in the presence of EDC and a catalytic amount of HCl in DMF or DMA .
| 【1】 Zhu, B.-Y., Wang, L., Goldman, E. et al. (Millennium Pharmaceuticals, Inc.). Benzamides and related inhibitors of factor Xa. EP 1259485, US 6376515, WO 200106442, WO 2001064643. |
| 【2】 Zhang, P., Huang, W., Wang, L. et al. Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl) benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor. Bioorg Med Chem Lett 2009, 19(8):2179-85. |
| 【3】 Kanter, J.P., Sujino, K., Zuberi, S.S. (Millennium Pharmaceuticals, Inc.).WO 2008057972. |
| 【4】 Pandey, A., Leitao, E.P.T., Rato, J., Song, Z.J. (Millennium Pharmaceuticals, Inc.; Merck & Co., Inc.). Methods of synthesizing factor Xa inhibitors. EP 2513058, US 201131927, WO 201108419. |
| 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) | 68321 | 5-methoxy-2-nitrobenzoic acid;2-Nitro-5-methoxybenzoic acid | C8H7NO5 | 详情 | 详情 | |
| (II) | 18559 | 5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine | 1072-98-6 | C5H5ClN2 | 详情 | 详情 |
| (III) | 68322 | N-(5-chloropyridin-2-yl)-5-methoxy-2-nitrobenzamide | C13H10ClN3O4 | 详情 | 详情 | |
| (IV) | 68323 | 2-amino-N-(5-chloropyridin-2-yl)-5-methoxybenzamide | C13H12ClN3O2 | 详情 | 详情 | |
| (V) | 19280 | 4-cyanobenzoyl chloride | 6068-72-0 | C8H4ClNO | 详情 | 详情 |
| (VI) | 68324 | N-(5-chloropyridin-2-yl)-2-(4-cyanobenzamido)-5-methoxybenzamide | C21H15ClN4O3 | 详情 | 详情 | |
| (VII) | 68325 | 4-(N,N-dimethylcarbamimidoyl)benzoic acid hydrochloride | C10H12N2O2.HCl | 详情 | 详情 |
合成路线2
The 4-amidinobenzoic acid intermediate (VII) is prepared by esterification of 4-cyanobenzoic acid (VIII) with MeOH in the presence of H2SO4 at reflux to give methyl 4-cyanobenzoate (IXa), which is then subjected to Pinner reaction with EtOH in the presence of HCl to yield methyl 4-[ethoxy(imino)methyl]benzoate (X). Without isolation, imidate (X) reacts with dimethylamine hydrochloride in refluxing EtOH to provide methyl 4-[(dimethylamino)(imino)methyl]benzoate (XIa). The analogous ethyl ester (XIb) can be alternatively prepared by reaction of ethyl 4-cyanobenzoate (IXb) with Me2NLi (generated from Me2NH and HexLi) in THF. Finally, either methyl (XIa) or ethyl (XIb) esters are hydrolyzed with LiOH in H2O/THF, and then acidified with HCl .
| 【1】 Pandey, A., Leitao, E.P.T., Rato, J., Song, Z.J. (Millennium Pharmaceuticals, Inc.; Merck & Co., Inc.). Methods of synthesizing factor Xa inhibitors. EP 2513058, US 201131927, WO 201108419. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IXa) | 10169 | methyl 4-cyanobenzoate；4-Cyanobenzoic acid methyl ester | 1129-35-7 | C9H7NO2 | 详情 | 详情 |
| (IXb) | 68326 | ethyl 4-cyanobenzoate | C10H9NO2 | 详情 | 详情 | |
| (XIa) | 68328 | methyl 4-[(dimethylamino)(imino)methyl]benzoate;methyl 4-(N,N-dimethylcarbamimidoyl)benzoate | C11H14N2O2 | 详情 | 详情 | |
| (XIb) | 68329 | ethyl 4-(N,N-dimethylcarbamimidoyl)benzoate | C12H16N2O2 | 详情 | 详情 | |
| (VII) | 68325 | 4-(N,N-dimethylcarbamimidoyl)benzoic acid hydrochloride | C10H12N2O2.HCl | 详情 | 详情 | |
| (VIII) | 36897 | 4-cyanobenzoic acid；4-Carboxybenzonitrile;p-Carboxybenzonitrile | 619-65-8 | C8H5NO2 | 详情 | 详情 |
| (X) | 68327 | methyl 4-[ethoxy(imino)methyl]benzoate | C11H13NO3 | 详情 | 详情 |