Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-06-09
1999-07-27
Kumar, Shailendra
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
514330, 564194, C07D21102, C07D21130
Patent
active
059292423
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to a cost-effective process for the conversion, via diazotisation methodology, of L-lysine to a carboxanilide precursor of levobupivacaine and related compounds.
BACKGROUND OF THE INVENTION
Compounds of formula 1 wherein R is a methyl, n-propyl or n-butyl group are widely used as local anaesthetics. Biological studies have shown that the (S)-enantiomers of such compounds (e.g. levobupivacaine wherein R is n-butyl) display lower cardiotoxicity than the corresponding racemates whilst maintaining the same anaesthetic potency, and are therefore more beneficial for clinical uses. Thus there is a requirement for efficient processes to manufacture compounds of formula 1 in the form of single enantiomers. The process embodied by the present invention employs a chirality pool approach to levobupivacaine, commencing from L-lysine, an inexpensive starting material which is readily available in bulk.
Although L-lysine has been converted through to optically enriched L-pipecolic acid and esters thereof by diazotisation and cyclisation reactions, cyclisation of an intermediate to form a piperidine-2-carboxanilide directly has hitherto not been reported. Furthermore, in the context of the present invention, these existing methods are hampered by an excessive number of steps required for manipulation of protecting groups in order to obviate Walden inversion at the carboxyl-bearing centre, which leads to the formation of D-pipecolic acid.
An additional benefit of the invention is the provision of unnatural amino acids of formula 2 with (S) configuration, which are important as pharmaceutical intermediates, e.g. for incorporation into physiologically active synthetic peptides. Compound 2a is commonly prepared by a multistep synthesis of the racemate commencing from dihydropyran followed by enzymatic resolution of an ester derivative (e.g. p-nitrobenzyl). This process in inefficient with respect to the number of steps required and by the fact that resolution produces up to 50% of an unwanted enantiomer. Diazotisation of L-lysine and derivatives thereof has been identified as an alternative strategy for the preparation of 2-amino-6-hydroxyhexanoic acid and derivatives thereof. However, such an approach has hitherto only been applied to the synthesis of compound 2c, but this process, employing sodium nitroprusside, is low yielding (28%).
Copper complexation of lysine and similar amino-acids has been extensively used as a technique for temporary protection of the .alpha.-amino acid moiety, as disclosed by Ledger et al, Anstr. J. Chem. 18:933-5 (1965). This procedure facilitates selective transformation of the second amino group present in the side-chain, e.g. the attachment of a covalently-bonded amino-protecting group.
SUMMARY OF THE INVENTION
This invention provdes a cost-effective process for preparing compounds of formula 1, wherein R is H or alkyl, from the inexpensive starting material L-lysine, using a chirality pool approach, and involving scission of the terminal C--N bond of L-lysine. In particular, the present invention provides a practical and economical process for the manufacture of levobupivacaine from L-lysine, which is exemplified in Scheme 1. This process involves the preparation of novel compounds of formula (X) as defined in claim 1; either R' is a protecting group, in which case R is H in the product, which can then be alkylated as desired, or R' is alkyl and corresponds to R as alkyl.
DESCRIPTION OF THE INVENTION
Formula (X), and other formulae used herein, refer to compounds that have at least predominantly the given stereochemistry. They are at least substantially free of their optical antipode, e.g. in at least 50%, more preferably at least 70% or 99%, enantiomeric excess.
According to the particular reactions shown in Scheme 1, the .alpha.-N-benzyloxycarbonyl derivative of L-lysine is initially (a) subjected to diazotisation in the presence of acetic acid to afford (S)-2-(benzyloxycarbonylamino)-6-acetoxyhexanoic acid (2b). Alternatively, Z may be
REFERENCES:
Kisfaludy et al, Synthesis, p. 163, 1982.
Kedger et al, Australina Journal of Chemistry, vol. 18, pp. 933-935, 1965.
Darwin Discovery Limited
Kumar Shailendra
LandOfFree
Manufacture of levobupivacaine and analogues thereof from L-lysi does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Manufacture of levobupivacaine and analogues thereof from L-lysi, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Manufacture of levobupivacaine and analogues thereof from L-lysi will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-880063