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【结 构 式】 
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【分子编号】17525 【品名】(2S)-6-amino-2-[[(benzyloxy)carbonyl]amino]hexanoic acid 【CA登记号】 |
【 分 子 式 】C14H20N2O4 【 分 子 量 】280.32388 【元素组成】C 59.99% H 7.19% N 9.99% O 22.83% |
合成路线1
该中间体在本合成路线中的序号：(I)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
该中间体在本合成路线中的序号：(XVII)Synthesis of the final product: The cyclization of L-lysine (XVII) according to Miller et al. gives cyclic hydroxamate (XVIII), which is deprotected by hydrogenation with H2 over Pd/C in MeOH yielding 3-amino-1-(tert-butyldiphenylsilyloxy)perhydroazepin-2-one (XIX). The condensation of (XIX) with acid intermediate (V) by means of DEPC and TEA in DMF affords the corresponding amide (XX), which is esterified at its free OH group with acid intermediate (XVI) by means of DCC and DMAP in toluene to provide the ester (XXI). The deprotection of (XXI) with H2 over Pd/C in MeOH gives the amine (XXII), which is acylated with acid intermediate (XII) by means of EDC in CH2Cl2 to furnish the corresponding amide (XXIII). Finally this compound is deprotected with trifluoroacetic acid in CH2Cl2 to give the title product.
| 【1】 Miller, M.J.; Hu, J.; Total synthesis of a mycobactin S, a siderophore and growth promoter of Mycobacterium smegmatis, and determination of its growth inhibitory activity against Mycobacterium tuberculosis. J Am Chem Soc 1997, 119, 15, 3462. |
| 【2】 Yokokawa, F.; et al.; Total synthesis of amamistatin A, an antiproliferative linear peptide from an actinomycete. Tetrahedron 2000, 56, 19, 3027. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 42019 | (3S)-3-hydroxy-2,2-dimethyldecanoic acid | C12H24O3 | 详情 | 详情 | |
| (XII) | 42025 | 2-(2-hydroxy-5-methoxyphenyl)-5-methyl-1,3-oxazole-4-carboxylic acid | C12H11NO5 | 详情 | 详情 | |
| (XVI) | 42030 | (12R)-12-[[(benzyloxy)carbonyl]amino]-8-formyl-2,2-dimethyl-5,7-dioxa-8-aza-2-silatridecan-13-oic acid | C20H32N2O7Si | 详情 | 详情 | |
| (XVII) | 17525 | (2S)-6-amino-2-[[(benzyloxy)carbonyl]amino]hexanoic acid | C14H20N2O4 | 详情 | 详情 | |
| (XVIII) | 42031 | benzyl (3S)-1-[[tert-butyl(diphenyl)silyl]oxy]-2-oxoazepanylcarbamate | C30H36N2O4Si | 详情 | 详情 | |
| (XIX) | 42032 | (3S)-3-amino-1-[[tert-butyl(diphenyl)silyl]oxy]-2-azepanone | C22H30N2O2Si | 详情 | 详情 | |
| (XX) | 42033 | (3S)-N-((3S)-1-[[tert-butyl(diphenyl)silyl]oxy]-2-oxoazepanyl)-3-hydroxy-2,2-dimethyldecanamide | C34H52N2O4Si | 详情 | 详情 | |
| (XXI) | 42034 | (1S)-1-[2-[((3S)-1-[[tert-butyl(diphenyl)silyl]oxy]-2-oxoazepanyl)amino]-1,1-dimethyl-2-oxoethyl]octyl (12R)-12-[[(benzyloxy)carbonyl]amino]-8-formyl-2,2-dimethyl-5,7-dioxa-8-aza-2-silatridecan-13-oate | C54H82N4O10Si2 | 详情 | 详情 | |
| (XXII) | 42035 | (1S)-1-[2-[((3S)-1-[[tert-butyl(diphenyl)silyl]oxy]-2-oxoazepanyl)amino]-1,1-dimethyl-2-oxoethyl]octyl (12R)-12-amino-8-formyl-2,2-dimethyl-5,7-dioxa-8-aza-2-silatridecan-13-oate | C46H76N4O8Si2 | 详情 | 详情 | |
| (XXIII) | 42036 | (1S)-1-[2-[((3S)-1-[[tert-butyl(diphenyl)silyl]oxy]-2-oxoazepanyl)amino]-1,1-dimethyl-2-oxoethyl]octyl (12R)-8-formyl-12-([[2-(2-hydroxy-5-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]carbonyl]amino)-2,2-dimethyl-5,7-dioxa-8-aza-2-silatridecan-13-oate | C58H85N5O12Si2 | 详情 | 详情 |