合成路线: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.
参考文献标题:Progress for preparing levobupivacaine and analogues thereof
文献作者:Frampton,G.A.C.; Zavareh,H.S.(Celltech Chiroscience plc)
参考来源:WO 9612700
合成路线: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.
参考文献标题:Crystallization of levobupicavaine and analogues thereof
文献作者:Skead,B.M.; Langston,M.(Celltech Chiroscience plc)
参考来源:WO 9612699
合成路线: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.
参考文献标题:Stereospecific synthesis of the anaesthetic levobupivacaine
文献作者:Dyer,U.; Hutton,G.; Adger,B.; Woods,M.
参考来源:Tetrahedron Lett 1996,37(35),6399-402
合成路线: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.
参考文献标题:Racemisation of R-bupivacaine: A key factor in the integrated and economic process for the production of levobupivacaine
文献作者:Zavareh,H.S.; Dyer,U.C.; Woods,M.; Hutton,G.; Langston,M.; Skead,B.M.; Frampton,G.A.C.; Lock,C.J.
参考来源:Org Process Res Dev 2000,4(6),530
产品链接: CAS No. 27262-47-1››