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【结 构 式】 
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【药物名称】Ropivacaine hydrochloride, AL-281(anhydrous free base), LEA-103, Naropina, Anapaine, Naropin 【化学名称】(-)-(S)-N-(n-Propyl)piperidine-2-carboxylic acid 2,6-xylidide hydrochloride monohydrate 【CA登记号】84057-95-4 (anhydrous free base) 【 分 子 式 】C17H29ClN2O2 【 分 子 量 】328.88588 |
【开发单位】AstraZeneca (Originator) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Anesthetic Drugs, Local Anesthetics, Sodium Channel Blockers |
合成路线1
1) The optical resolution of pipecolic acid (I) with (+)-tartaric acid in water-ethanol gives L-pipecolic acid (II), which by reaction with Cl5P in acetyl chloride is converted to the acyl chloride (III). The condensation of (III) with 2,6-xylidine (IV) by means of N-methylpyrrolidone (NMP) in acetone affords L-pipecolic acid 2,6-xylidide (V), which is finally alkylated with propyl bromide (VI) and K2CO3 in hot isopropanol.
| 【1】 T. af Ekenstam, B.; Bovin, C. (Astra Lakemedel AB); L-N-n-Propylpipecolic acid 2,6-xylidide. US 4695576 . |
| 【2】 Prous, J.; Castaner, J.; ROPIVACAINE HYDROCHLORIDE < Rec INNM >. Drugs Fut 1989, 14, 8, 767. |
| 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) | 17532 | 2-piperidinecarboxylic acid; pipecolic acid | 535-75-1 | C6H11NO2 | 详情 | 详情 |
| (II) | 17380 | (2S)hexahydro-2-pyridinecarboxylic acid; (S)-pipecolic acid | 3105-95-1 | C6H11NO2 | 详情 | 详情 |
| (III) | 19499 | (2S)-2-piperidinecarbonyl chloride | C6H10ClNO | 详情 | 详情 | |
| (IV) | 17527 | 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine | 87-62-7 | C8H11N | 详情 | 详情 |
| (V) | 17531 | (2S)-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide | C14H20N2O | 详情 | 详情 | |
| (VI) | 19502 | Propyl bromide; 1-Bromopropane | 106-94-5 | C3H7Br | 详情 | 详情 |
合成路线2
2) The protection of L-pipecolic acid (II) with benzyl chloroformate (VII) gives the benzyloxycarbonyl compound (VIII), which is condensed with o-toluidine (IX) by means of SOCl2 and dimethylaminopyridine (DMAP) yielding the amide (X). The methylation of (X) with methyl iodide and palladium diacetate in acetic acid affords the 2,6-xylidide (XI), which is deprotected with HBr in acetic acid to give L-pipecolic acid 2,6-xylidide (V). Finally, this compound is alkylated with propyl iodide and K2CO3 in acetonitrile.
| 【1】 Prous, J.; Castaner, J.; ROPIVACAINE HYDROCHLORIDE < Rec INNM >. Drugs Fut 1989, 14, 8, 767. |
| 【2】 Sahlberg, C.; Synthesis of carbon-14 labelled ropivacaine, a local anaesthetic agent. J Label Compd Radiopharm 1987, 24, 5, 529. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 17380 | (2S)hexahydro-2-pyridinecarboxylic acid; (S)-pipecolic acid | 3105-95-1 | C6H11NO2 | 详情 | 详情 |
| (V) | 17531 | (2S)-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide | C14H20N2O | 详情 | 详情 | |
| (VI) | 19502 | Propyl bromide; 1-Bromopropane | 106-94-5 | C3H7Br | 详情 | 详情 |
| (VII) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (VIII) | 19504 | (2S)-1-[(benzyloxy)carbonyl]-2-piperidinecarboxylic acid | C14H17NO4 | 详情 | 详情 | |
| (IX) | 15511 | o-toluidine; 2-methylphenylamine;2-Methylaniline；2-Aminotoluene;1-Amino-2-methylbenzene;1-Methyl-2-aminobenzene; ortho-Toluidine | 95-53-4 | C7H9N | 详情 | 详情 |
| (X) | 19506 | benzyl (2S)-2-(2-toluidinocarbonyl)-1-piperidinecarboxylate | C21H24N2O3 | 详情 | 详情 | |
| (XI) | 19507 | benzyl (2S)-2-[(2,6-dimethylanilino)carbonyl]-1-piperidinecarboxylate | C22H26N2O3 | 详情 | 详情 |
合成路线3
3) The protection of 1,2,3,6-tetrahydropyridine-2(S)-carboxylic acid (XII) with benzyl chloroformate (VII) gives the benzyloxycarbonyl derivative (XIII), which is condensed with 2,6-xylidine (IV) with SOCl2 and DMAP as before yielding the amide (XIV). Deprotection of (XIV) with iodotrimethylsilane in dichloromethane affords N-(2,6-dimethylphenyl)-1,2,3,6-tetrahydropyridine-2(S)-carboxamide (XV), which is reduced with H2 over Rh/Al2O3 in DMF giving the saturated amide (V). Finally, this compound is alkylated with propyl iodide and K2CO3 as before.
| 【1】 Prous, J.; Castaner, J.; ROPIVACAINE HYDROCHLORIDE < Rec INNM >. Drugs Fut 1989, 14, 8, 767. |
| 【2】 Gawell, L.; Synthesis of tritium labelled ropivacaine - A new potential local anaesthetic. J Label Compd Radiopharm 1987, 24, 5, 521. |
| 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) | 17527 | 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine | 87-62-7 | C8H11N | 详情 | 详情 |
| (V) | 17531 | (2S)-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide | C14H20N2O | 详情 | 详情 | |
| (VI) | 19502 | Propyl bromide; 1-Bromopropane | 106-94-5 | C3H7Br | 详情 | 详情 |
| (VII) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (XII) | 19508 | (2S)-1,2,3,4-tetrahydro-2-pyridinecarboxylic acid | C6H9NO2 | 详情 | 详情 | |
| (XIII) | 19509 | (2S)-1-[(benzyloxy)carbonyl]-1,2,3,4-tetrahydro-2-pyridinecarboxylic acid | C14H15NO4 | 详情 | 详情 | |
| (XIV) | 19510 | benzyl (2S)-2-[(2,6-dimethylanilino)carbonyl]-3,4-dihydro-1(2H)-pyridinecarboxylate | C22H24N2O3 | 详情 | 详情 | |
| (XV) | 19511 | (2S)-N-(2,6-dimethylphenyl)-1,2,3,4-tetrahydro-2-pyridinecarboxamide | C14H18N2O | 详情 | 详情 |