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【结 构 式】 
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【药物名称】 【化学名称】3-Chloro-N-[4-chloro-2-(5-chloropyridin-2-ylcarbamoyl)-6-methoxyphenyl]-4-[[N-(4,5-dihydro-1,3-oxazol-2-yl)-N-methylamino]methyl]-2-thiophenecarboxamide 【CA登记号】229335-75-5 【 分 子 式 】C23H20Cl3N5O4S 【 分 子 量 】568.86995 |
【开发单位】Berlex (Originator) 【药理作用】Anticoagulants, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Coagulation Factor Xa Inhibitors |
合成路线1
Treatment of 3-methoxy-2-nitrobenzoic acid (I) with oxalyl chloride gave the corresponding acid chloride (II), which was then coupled with 2-amino-5-chloropyridine (III) to yield amide (IV). The reduction of the nitro group of (IV) using sodium hydrosulfite afforded aniline (V). Further chlorination of (V) with N-chlorosuccinimide furnished the 5-chloro derivative (VI).
| 【1】 Cheeseman, S.; Chou, Y.-L.; Ye, B.; et al.; Design, synthesis, and biological activity of novel non-amidine factor Xa inhibitors, 4: Optimization of hydrophilic substituents for potency and oral availability. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 128. |
| 【2】 Snider, R.M.; Liang, A.M.; Wu, S.C.; Arnaiz, D.O.; Sacchi, K.L.; Kochanny, M.J.; Phillips, G.B.; Ye, B.; Zhao, Z.; Morrissey, M.M.; Griedel, B.D.; Lee, W.; Sakata, S.T.; Karanjawala, R.E.; Chou, Y.-L.; Shaw, K.J. (Schering AG); Ortho-anthranilamide derivs. as anticoagulants. EP 1040108; JP 2001526283; US 6140351; WO 9932477 . |
| 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) | 25827 | 3-methoxy-2-nitrobenzoic acid | 4920-80-3 | C8H7NO5 | 详情 | 详情 |
| (II) | 25828 | 3-methoxy-2-nitrobenzoyl chloride | C8H6ClNO4 | 详情 | 详情 | |
| (III) | 18559 | 5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine | 1072-98-6 | C5H5ClN2 | 详情 | 详情 |
| (IV) | 51186 | N-(5-chloro-2-pyridinyl)-3-methoxy-2-nitrobenzamide | C13H10ClN3O4 | 详情 | 详情 | |
| (V) | 51187 | 2-amino-N-(5-chloro-2-pyridinyl)-3-methoxybenzamide | C13H12ClN3O2 | 详情 | 详情 | |
| (VI) | 51188 | C13H11Cl2N3O2 | 详情 | 详情 |
合成路线2
Benzylic bromination of 2-(methoxycarbonyl)-3-chloro-4-methylthiophene (VII) gave rise to dibromide (VIII), which was further hydrolyzed to aldehyde (IX) using sodium acetate and acetic acid. Reduction of aldehyde (IX) with NaBH4 afforded alcohol (X). After basic hydrolysis of the methyl ester group of (X), the resulting hydroxy acid was treated with thionyl chloride to furnish (XI). Condensation of aniline (VI) with acid chloride (XI) gave amide (XII). Subsequent chloride displacement with methylamine yielded amine (XIII). This was then condensed with 2-bromoethyl isocyanate, producing the N-(2-bromoethyl)urea (XIV). Cyclization of bromo urea (XIV) upon treatment with triethylamine (1,2) or with other amines generated the title oxazoline derivative.
| 【1】 Cheeseman, S.; Chou, Y.-L.; Ye, B.; et al.; Design, synthesis, and biological activity of novel non-amidine factor Xa inhibitors, 4: Optimization of hydrophilic substituents for potency and oral availability. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 128. |
| 【2】 Snider, R.M.; Liang, A.M.; Wu, S.C.; Arnaiz, D.O.; Sacchi, K.L.; Kochanny, M.J.; Phillips, G.B.; Ye, B.; Zhao, Z.; Morrissey, M.M.; Griedel, B.D.; Lee, W.; Sakata, S.T.; Karanjawala, R.E.; Chou, Y.-L.; Shaw, K.J. (Schering AG); Ortho-anthranilamide derivs. as anticoagulants. EP 1040108; JP 2001526283; US 6140351; WO 9932477 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 51188 | C13H11Cl2N3O2 | 详情 | 详情 | ||
| (VII) | 51189 | methyl 3-chloro-4-methyl-2-thiophenecarboxylate | C7H7ClO2S | 详情 | 详情 | |
| (VIII) | 51190 | methyl 3-chloro-4-(dibromomethyl)-2-thiophenecarboxylate | C7H5Br2ClO2S | 详情 | 详情 | |
| (IX) | 51191 | methyl 3-chloro-4-formyl-2-thiophenecarboxylate | C7H5ClO3S | 详情 | 详情 | |
| (X) | 51192 | methyl 3-chloro-4-(hydroxymethyl)-2-thiophenecarboxylate | C7H7ClO3S | 详情 | 详情 | |
| (XI) | 51193 | 3-chloro-4-(chloromethyl)-2-thiophenecarbonyl chloride | C6H3Cl3OS | 详情 | 详情 | |
| (XII) | 51194 | 3-chloro-N-(4-chloro-2-[[(5-chloro-2-pyridinyl)amino]carbonyl]-6-methoxyphenyl)-4-(chloromethyl)-2-thiophenecarboxamide | C19H13Cl4N3O3S | 详情 | 详情 | |
| (XIII) | 51195 | 3-chloro-N-(4-chloro-2-[[(5-chloro-2-pyridinyl)amino]carbonyl]-6-methoxyphenyl)-4-[(methylamino)methyl]-2-thiophenecarboxamide | C20H17Cl3N4O3S | 详情 | 详情 | |
| (XIV) | 51196 | 4-[[[[(2-bromoethyl)amino]carbonyl](methyl)amino]methyl]-3-chloro-N-(4-chloro-2-[[(5-chloro-2-pyridinyl)amino]carbonyl]-6-methoxyphenyl)-2-thiophenecarboxamide | C23H21BrCl3N5O4S | 详情 | 详情 |