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【结 构 式】 
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【药物名称】(-)-Bupivacaine hydrochloride, Levobupivacaine hydrochloride, Chirocaine 【化学名称】(-)-(S)-1-Butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide hydrochloride 【CA登记号】27262-47-1 (free base) 【 分 子 式 】C18H29ClN2O 【 分 子 量 】324.89763 |
【开发单位】Celltech (Originator), Abbott (Licensee), Maruishi Pharmaceutical (Licensee), Purdue Pharma (Licensee) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Anesthetic Drugs, Local Anesthetics, K(V)1.5 Channel Blockers |
合成路线1
Levobupivacaine has been obtained by two different ways: 1) The deamination of N-benzoyloxycarbonyl-L-lysine (I) with NaNO2/acetic acid gives 6-acetoxy-2(S)-(benzyl-oxycarbonylamino)hexanoic acid (II), which is amidated with 2,6-dimethylaniline (III) and dicyclohexylcarbodiimide (DCC) to the expected amide (IV). The deacetylation of (IV) with K2CO3 in methanol affords compound (V), which is tosylated as usual with tosyl chloride giving intermediate (VI), which is stereospecifically cyclized by means of K2CO3 in ethanol yielding N-(2,6-dimethyl-phenyl)piperidine-2 (S)-carboxamide (VII). Finally, this compound is alkylated with butyl bromide and K2CO3 or by reductoalkylation with butyraldehyde. 2) The amidation of piperidine-2-carboxylic acid (VIII) with 2,6-dimethylaniline (III) by means of SOCl2 in toluene gives the corresponding amide (IX), which is alkylated with butyl bromide as before yielding racemic bupivacaine (X) (3). This compound is then submitted to optical resolution by treatment with (S,S)-()-tartaric acid followed by crystallization of the resulting tartrate and acidification with HCl in isopropanol.
| 【1】 Dyer, U.; Hutton, G.; Adger, B.; Woods, M.; Stereospecific synthesis of the anaesthetic levobupivacaine. Tetrahedron Lett 1996, 37, 35, 6399-402. |
| 【2】 Skead, B.M.; Langston, M. (Celltech Chiroscience plc); Crystallization of levobupicavaine and analogues thereof. WO 9612699 . |
| 【3】 Hutton, G.E. (Celltech Chiroscience plc); The manufacture of levo-bupivacaine and analogues thereof from L-lysine. WO 9611181 . |
| 【4】 Frampton, G.A.C.; Zavareh, H.S. (Celltech Chiroscience plc); Progress for preparing levobupivacaine and analogues thereof. WO 9612700 . |
| 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) | 17525 | (2S)-6-amino-2-[[(benzyloxy)carbonyl]amino]hexanoic acid | C14H20N2O4 | 详情 | 详情 | |
| (II) | 17526 | (2S)-6-(acetoxy)-2-[[(benzyloxy)carbonyl]amino]hexanoic acid | C16H21NO6 | 详情 | 详情 | |
| (III) | 17527 | 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine | 87-62-7 | C8H11N | 详情 | 详情 |
| (IV) | 17528 | (5S)-5-[[(benzyloxy)carbonyl]amino]-6-(2,6-dimethylanilino)-6-oxohexyl acetate | C24H30N2O5 | 详情 | 详情 | |
| (V) | 17529 | benzyl (1S)-1-[(2,6-dimethylanilino)carbonyl]-5-hydroxypentylcarbamate | C22H28N2O4 | 详情 | 详情 | |
| (VI) | 17530 | (5S)-5-[[(benzyloxy)carbonyl]amino]-6-(2,6-dimethylanilino)-6-oxohexyl 4-methylbenzenesulfonate | C29H34N2O6S | 详情 | 详情 | |
| (VII) | 17531 | (2S)-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide | C14H20N2O | 详情 | 详情 | |
| (VIII) | 17532 | 2-piperidinecarboxylic acid; pipecolic acid | 535-75-1 | C6H11NO2 | 详情 | 详情 |
| (IX) | 17533 | N-(2,6-dimethylphenyl)-2-piperidinecarboxamide | C14H20N2O | 详情 | 详情 | |
| (X) | 17534 | 1-butyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide | 2180-92-9 | C18H28N2O | 详情 | 详情 |
合成路线2
Improved yield in the synthesis of levobupivacaine. An improved yield in the synthesis of levobupivacaine can be obtained by recovering the unwanted (R)-enantiomer side product in the optical resolution of the racemic bupivacaine. The treatment of (R)-(I) with refluxing propionic acid causes its racemization, yielding racemic-(I) (bupivacaine), which is then submitted to a new optical resolution process using dibenzoyl-L-tartaric acid.
| 【1】 Zavareh, H.S.; Dyer, U.C.; Woods, M.; Hutton, G.; Langston, M.; Skead, B.M.; Frampton, G.A.C.; Lock, C.J.; Racemisation of R-bupivacaine: A key factor in the integrated and economic process for the production of levobupivacaine. Org Process Res Dev 2000, 4, 6, 530. |