U.S. patent application number 09/740152 was filed with the patent office on 2001-04-26 for racemisation process for use in the manufacture of levobupivacaine and related piperidinecarboxanilide anaesthetic agents.
Invention is credited to Dyer, Ulrich Conrad, Langston, Marianne, Woods, Martin.
Application Number | 20010000522 09/740152 |
Document ID | / |
Family ID | 27267553 |
Filed Date | 2001-04-26 |
United States Patent
Application |
20010000522 |
Kind Code |
A1 |
Dyer, Ulrich Conrad ; et
al. |
April 26, 2001 |
Racemisation process for use in the manufacture of levobupivacaine
and related piperidinecarboxanilide anaesthetic agents
Abstract
An optically-enriched piperidine-2-carboxanlidecompound, in
which the piperidine is optionally N-alkylated, is racemised by
heating the compound in an aqueous medium, provided that the medium
includes an organic co-solvent if the compound is N-alkylated. This
process is particularly valuable, in conjunction with a resolution
process, for the manufacture of levobupivacaine.
Inventors: |
Dyer, Ulrich Conrad;
(Cambridge, GB) ; Langston, Marianne; (Cambridge,
GB) ; Woods, Martin; (Cambridge, GB) |
Correspondence
Address: |
SALIWANCHIK LLOYD & SALIWANCHIK
A PROFESSIONAL ASSOCIATION
2421 N.W. 41ST STREET
SUITE A-1
GAINESVILLE
FL
326066669
|
Family ID: |
27267553 |
Appl. No.: |
09/740152 |
Filed: |
December 18, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09740152 |
Dec 18, 2000 |
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09396628 |
Sep 15, 1999 |
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09396628 |
Sep 15, 1999 |
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08875636 |
Jul 16, 1997 |
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Current U.S.
Class: |
546/225 |
Current CPC
Class: |
C07D 211/60
20130101 |
Class at
Publication: |
546/225 ;
546 |
International
Class: |
C07D 211/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 18, 1995 |
GB |
9501071.6 |
Claims
We claim:
1. A process for the racemisation of an optically-enriched compound
2wherein R.sup.1 is C.sub.1-6 alkyl, the compound being in free
base form, which comprises heating the compound in an aqueous
medium which includes an organic cosolvent, and recovering the
product that is precipitated, on cooling.
2. The process according to claim 1, wherein said compound is
enriched in the (R)-enantiomer.
3. The process according to claim 1, wherein the cosolvent is an
alcohol or polyol.
4. The process according to claim 3, wherein the cosolvent is an
ethylene glycol.
5. The process according to claim 1, wherein the concentration of
the compound in the medium is at least 100 mg/ml.
6. The process according to claim 1, wherein R.sup.1 is n-butyl,
for preparing bupivacaine of diminished optical purity.
7. The process according to claim 1, wherein R.sup.1 is
n-propyl.
8. A process for preparing (S)-bupivacaine, which comprises
resolving a mixture of enantiomers of bupivacaine, separating
(S)-bupivacaine, and racemising residual (R)-bupivacaine, prior to
further resolution; wherein said racemisation of residual
(R)-bupivacaine comprises heating the compound in an aqueous medium
which includes an organic cosolvent, and recovering the product
that is precipitated, on cooling.
Description
FIELD OF THE INVENTION
1. This invention relates to the racemisation of optically-enriched
piperidine-2-carboxanilides. In particular, the process is suitable
for use in the manufacture of levobupivacaine and related
piperidinecarboxanilide anaesthetic agents.
BACKGROUND OF THE INVENTION
2. Compounds of formula 1 1
3. wherein R.sup.2 is 2,6-dimethylphenyl and R.sup.1 is methyl
(mepivacaine), n-propyl (ropivacaine as S-enantiomer) or n-butyl
(bupivacaine) are widely used as local anaesthetics. The
corresponding compound when R.sup.1 is H is a useful
intermediate.
4. Biological studies have shown that the (S)-enantiomers of such
N-alkyl-piperidine-2-carboxanilides 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. For this purpose, conventional resolution approaches
invariably afford up to 50% of the unwanted enantiomer. To improve
atom utilisation in such processes, it is desirable to recycle the
unwanted enantiomer by effecting its racemisation in order to
provide material suitable for subsequent resolution.
5. Friberger et al, Acta. Pharm. Suec. (1971) 8:361-364, report a
study of the solubility and partition coefficients of the racemates
and enantiomers of mepivacaine and bupivacaine. It is reported that
racemic bupivacaine is more soluble than the isomers at a pH above
6. All of the compounds tested have solubilities decreasing to low
levels, especially for bupivacaine, at pH values approaching
neutrality.
6. Fyhr et al, Acta.Pharm.Suec. (1988) 25:121-132, report the
racemisation of optically-enriched ropivacaine hydrochloride in
dilute aqueous solution at pH 1-6 and 80-130.degree. C. HCl or
citric acid was present, in order to establish the pH. The
conclusions of this pre-formulation stability study were that the
racemisation involves hydroxyl ion-catalysed racemisation of the
N-protonated species. This study provides no useful indication as
to how to conduct racemisation as such, and does not suggest any
volume-efficient commercial process.
SUMMARY OF THE INVENTION
7. The present invention is based on the surprising discovery that
piperidine-2-carboxanilides, including compounds of formula 1
wherein R.sup.1 is H, methyl, n-propyl or n-butyl and R.sup.2 is
2,6-dimethylphenyl, undergo rapid racemisation when heated in
aqueous solution, provided that an organic cosolvent is present
when R.sup.1 is not H. The practical nature of this discovery is
evident in that much more concentrated systems can be used than in
the prior art.
8. Whereas, at concentrations of 30 mg/ml, at a pH above 5, the use
of conditions otherwise specified by Fyhr et al lead to complete
inhibition of racemisation of ropivacaine and bupivacaine, the rate
of racemisation can be increased, under the conditions used in this
invention, with increasing pH of the solution. Racemisation occurs
most efficiently at a pH greater than 6, without loss of
solubility, which means that no acid need be added.
DESCRIPTION OF THE INVENTION
9. The reaction can be carried out in water alone, when R.sup.1 is
H. In this case, a preferred embodiment of the invention is the
racemisation of optically-enriched
2',6'-dimethylpiperidine-2-carboxanilide (1: R.sup.1.dbd.H,
R.sup.2.dbd.2,6-dimethylphenyl).
10. Alternatively, for N-alkylpiperidine compounds of formula 1,
the reaction is carried out in the presence of an organic cosolvent
such as an alcohol or polyol, e.g. ethylene glycol thus allowing
solutions of higher concentration to be used, than in the prior
art. A preferred embodiment of this aspect of the invention is the
racemisation of optically-enriched bupivacaine in ethylene glycol
containing 10% v/v water. The presence of salt forms of compounds
of formula 1 does not impede the efficiency of the racemisation
process.
11. The reaction conditions may comprise heating, as desired.
Suitable conditions will depend on the nature of the reactants, but
can be readily chosen by those skilled in the art.
12. In summary, the present invention establishes simple and
economical processes for the racemisation of
piperidine-2-carboxanilides, in either neat aqueous media or
aqueous media combined with inert organic cosolvents. The invention
is particularly suited to the optimum utilisation of unwanted
enantiomer in the preparation of enantiopure therapeutic agents,
and therefore in practice the starting material will usually be
richer in the (R)-enantiomer. When R.sup.1 is H, a compound of
formula 1 is an intermediate en route to anaesthetic agents. When
R.sup.1 is n-butyl, the present invention is of particular utility
for preparing (S)-bupivacaine, in conjunction with a resolution
process, e.g. that described in PCT/GB95/02513 and South African
Application No. 95/8993.
13. The following Examples illustrate the invention.
EXAMPLE 1
14. (S)-2',6'-Dimethylpiperidine-2-carboxanilide (>99% ee, 155
mg, 0.67 mmol) was dissolved in water (14.5 ml). The pH was
measured to be 9.97. The solution was heated under reflux for 19
hours. Aqueous ammonia (28% w/v; 1 ml) was added to the cooled
solution and the mixture extracted with ethyl acetate (2.times.20
ml). The combined organic layers were dried with magnesium sulphate
and the solvent removed under reduced pressure to give a white
crystalline solid (128 mg). Analysis by chiral HPLC showed this to
be racemic 2',6'-dimethylpiperidine-2-carboxanilide.
EXAMPLE 2
15. A mixture of (S)-bupivacaine (>99% ee, 1.5 g mmol), ethylene
glycol (13.5 ml) and water (1.5 ml) was heated at 138.degree. C.
for 9 hours. On cooling to ambient temperature crystallisation of a
solid occurred. The solid was filtered to give a quantitative yield
of bupivacaine which was shown by chiral HPLC analysis to be a
52:48 mixture of (S)-bupivacaine and (R)-bupivacaine.
EXAMPLE 3
16. (S)-Bupivacaine (>99% ee, 0.27 g, 0.94 mmol) and
(S)-bupivacaine (-)-tartrate (2:1 salt, 0.23 g, 0.32 mmol) were
heated at 150.degree. C. in propan-2-ol (2.5 ml) and water (2.5 ml)
in a sealed vessel for 22 hours. A portion of solution was removed,
basified with 28% aqueous ammonia and extracted into heptane. The
organic solution was dried with magnesium sulphate and the solvent
removed under reduced pressure. The residue was shown by chiral
HPLC to be a 63:37 mixture of (S)-bupivacaine and
(R)-bupivacaine.
* * * * *