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【结 构 式】 
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【药物名称】 【化学名称】N-[2-(4-Aminophenyl)-1(S)-[4-(2-fluoroethyl)piperidin-1-ylcarbonyl]ethyl]-4-[1(S)-benzyl-2-(4-morpholinyl)ethyl]pyridine-3-sulfonamide 【CA登记号】200270-65-1 【 分 子 式 】C34H45FN6O4S 【 分 子 量 】652.83795 |
【开发单位】Novartis (Originator) 【药理作用】Anticoagulants, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Thrombin Inhibitors |
合成路线1
Coupling of N-Boc-p-nitrophenylalanine (I) with 4-(2-fluoroethyl)piperidine (II) by means of 2-benzotriazolyl-1,1,3,3-tetramethyluronium tetrafluoborate (TBTU) gave amide (III) which, after acidic deprotection provided aminoamide (IV). 4-Chloropyridine-3-sulfonyl chloride (VI), generated from 4-hydroxy pyridine-3-sulfonic acid (V) by chlorination with PCl5/POCl3, was coupled with amine (IV) to afford sulfonamide (VII). Further condensation of (VII) with L-phenylalaninol (VIII) produced aminopyridine (IX). Conversion of the alcohol group of (IX) to the corresponding mesylate, followed by displacement with morpholine furnished the N-substituted morpholine (X). The nitro group of (X) was finally reduced to the target aniline by hydrogenation over Pd/C.
| 【1】 Ambler, J.; Baker E; Brown, L.; Butler, P.; Farr, D.; Dunnet, K.; Le Grand, D.; Janus, D.; Jones, D.; Menear, K.; Mercer, M.; Smith, G.; Talbot, M.; Tweed, M.; The discovery of orally available thrombin inhibitors: Studies towards the optimisation of CGH1668. Bioorg Med Chem Lett 1998, 8, 24, 3583. |
| 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) | 28516 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-nitrophenyl)propionic acid | C14H18N2O6 | 详情 | 详情 | |
| (II) | 28517 | 4-(2-fluoroethyl)piperidine | C7H14FN | 详情 | 详情 | |
| (III) | 28518 | tert-butyl (1S)-2-[4-(2-fluoroethyl)-1-piperidinyl]-1-(4-nitrobenzyl)-2-oxoethylcarbamate | C21H30FN3O5 | 详情 | 详情 | |
| (IV) | 28519 | (2S)-2-amino-1-[4-(2-fluoroethyl)-1-piperidinyl]-3-(4-nitrophenyl)-1-propanone | C16H22FN3O3 | 详情 | 详情 | |
| (V) | 28520 | 4-hydroxy-3-pyridinesulfonic acid | C5H5NO4S | 详情 | 详情 | |
| (VI) | 28521 | 4-chloro-3-pyridinesulfonyl chloride | C5H3Cl2NO2S | 详情 | 详情 | |
| (VII) | 28522 | 4-chloro-N-[(1S)-2-[4-(2-fluoroethyl)-1-piperidinyl]-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide | C21H24ClFN4O5S | 详情 | 详情 | |
| (VIII) | 28523 | (2S)-2-amino-3-phenyl-1-propanol; L-phenylalanilol; (S)-2-amino-3-phenyl-1-propanol | 5267-64-1 | C9H13NO | 详情 | 详情 |
| (IX) | 28524 | 4-[[(1S)-1-benzyl-2-hydroxyethyl]amino]-N-[(1S)-2-[4-(2-fluoroethyl)-1-piperidinyl]-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide | C30H36FN5O6S | 详情 | 详情 | |
| (X) | 28525 | 4-[[(1S)-1-benzyl-2-(4-morpholinyl)ethyl]amino]-N-[(1S)-2-[4-(2-fluoroethyl)-1-piperidinyl]-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide | C34H43FN6O6S | 详情 | 详情 |