PROCEDE POUR LA PREPARATION DE SELS DE SODIUM ET DE POTASSIUM DE L'ACIDE CLAVULANIQUE

PROCESS FOR THE PREPARATION OF SODIUM AND POTASSIUM SALTS OF CLAVULANIC ACID

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
A process is disclosed for the preparation of a substantially pure
solid sodium or potassium salt of clavulanic acid which comprises the
hydrolysis of an ester of clavulanic acid in an aqueous medium containing
a sodium or potassium base and thereafter isolating the sodium or potassium
salt in the form of a substantially pure solid.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a substantially pure
solid sodium or potassium salt of clavulanic acid which process
comprises the hydrolysis of an ester of clavulanic acid,
formula (II):
(II)
<IMG>
wherein R is alkyl, alkenyl, aralkyl or aryl of up to 16
carbon atoms; or the alkyl, alkenyl, aralkyl or aryl substituted
with one or more lower alkoxy groups; bromobenzyl, pivaloyloxy-
methyl, a-pivaloyloxyethyl, acetoxymethyl, phthalidyl, acetoyl-
methyl or benzoymethyl;
in an aqueous medium containing a sodium or potassium base
and thereafter isolating the sodium or potassium salt in the
form of a substantially pure solid.
2. A process according to Claim 1 wherein R is an alkyl
or aralkyl group of 2 to 12 carbon atoms.
3. A process according to Claim 1 wherein R is an
ethyl, benzyl, methoxybenzyl, bromobenzyl, pivaloyloxymethyl,
a-pivaloyloxyethy, acetoxymethyl, phthalidyl, acetoylmethyl,
or benzoylmethyl group.

4. A process according to Claim 1 wherein from 0.9 to
1.05 equivalents of base are employed.
5. A process according to Claim 1, 3 or 4 wherein the
base is added at a rate which maintains the pH of the mixture
at from 8.5 to 9.5.

Description

~ t~3
The present invention relates to a process for the prepara-
tion of the sodium and potassium salts of clavulanic acid.
Belgian Patent No. 827926 (corresponding to Canadian appli-
cation S.N. 224,970 and divisionals) disclosed inter alia that
clavulanic acid, which has the formula (I~:
H CH20H
(I)
0/~\ .'
C02H-
and its salts may be prepared in good yields from its benzyl or like
ester by means of catalytic hydrogenation. It has now been discov-
ered that the sodium or potassium salts of clavulanic acid may be
prepared from its esters by hydrolysis. This process is frequently
more convenient than catalytic hydrogenation and avoids the use of
expensive catalysts.
Accordingly, the present invention provides a process for
the preparation of a solid sodium or potassium salt of clavulanic
acid which process comprises the hydrolysis of an ester of clavulanic
; acid in an a~ueous medium containing a sodium or potassium base and
thereafter isolating the sodium or potassium salt of clavulanic acid
in the form of a substantially pure solid.
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When used herein the term "substantially pure" means at
least 60% pure9 more suitably at leas-t 80% and preferably at
least 90%.
Suitable aqueous media include water and mixtures of water
with one or more inert water miscible organic solvents in which
the ester to undergo hydrolysis is soluble. Suitable organic
sol~ents ~or use in such mixed solvent systems include methanol,
ethanol, tetrahydro~uran, dimethylsulphoxide and the like. Such
solvents should not normally account for more than about 50% of
the total volume of the solvent system, usually not more than
20% and preferably not more than 10% of that volume.
Normally from 0.8 to 1.2 and more usually 0.9 to 1.05
e~uivalents vf base will be prese~t for every equivalent of
hydrolysable ester present.
The base employed in the hydrolysis may be NaOH, KOH,
NaHC03, Na2C03, KHC03, K2C03 or any chemically equivalent agent.
The base used in the hydrolysis is pre~erably added
gradually in small quantities so that no large excess o~ base
is present at any time. Most suitably the base is added at a
rate such that the p~ o~ the medium is maintained between 7 and
11 and preferably from 8.5 to 9.5, for example at about 9.
The hydrolysis ma~ be carried out at any non-extreme
temperature, for example at a depressed, ambient or slightly
elevated temperature such as -5C to +30C, more suitably from
about 0C to about 25C, ~or example ~rom about 5C to about 20C.
An~ convenient ester disclosed in the aforesaid~selgium
- Patent ~ ~ may be used in this process but most suitably the
ester is not one notionally derived from a highly lipophilic
alcohol because it is desirable that the ester is soluble in
.
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the aqueous solvent systems hereinbe~ore described.
Particularly suitable esters ~or use in the process o~
this invention include those o~ the formula (II):
H
CH20H (II)
N
C0 - 0 - R
wherein R is an inert, stable, organic group of up to 16 carbon
atoms.
The compound of the formula (II) is most suitably solid
at ambient temperature.
Suitable groups R include alkyl, alkenyl, aralkyl, aryl
and like groups optionally subs-tituted by one or more inert
substituents such as lower alkoxy groups or the like groups~
Certain ~avoured groups R include alkyl and aralkyl groups
o~ 2 to 12 carbon atoms optionally substituted by inert groups
; such as alkoxyl groups o~ 1 to 4 carbon atoms or the like.
Particuarly suitable groups R include ethyl, benzyl,
methoxybenzyl, bromobenzyl, pivaloyloxymethyl, ~-pivaloyloxyethyl,
acetoxymethyl, phthalidyl, acetoylmethyl, benzoylmethyl and the
like.
The hydrolysis reactions of this invention are normally
substantially complete in under one hour if carried out at
2~ 12 - 20C. If the group P, is particuarly labile, ~or example,
as in the case of the acetoxymethyl, pivaloyloxymethyl or
phthalidyl groups, then reaction can be substantially complete
in as little as 10 minutes. Hydrolysis of these highly reac-tive
moieties can occur in acceptably short tlme i~ the alkalinity
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is maintained at a level even as low as pH 7 but in general
other ester groups require a higher pH for hydrolysis to
proceed in an acceptably short time.
The desired sodium or potassium salt when formed can
be obtained ~rom the solution by the general methods
disclosed in Belgian Patent Mo. 827926, for example, by
evaporation of the solvent under reduced pressure and
preferably at a depressed temperature
The ~ollowing Examples illustrate the inven-tion:
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Clavulanic ~cid ethyl ester (200 mg) in water (100 ml)
was treated dropwise with one equivalent of a solution of
sodium hydroxide (O.lN) in water at a rate such that the
pH of the medium was maintained at 9 + O.2. The solutions
were maintained at 25 + 2C. The addition of the alkaline
solution took place over 30 minutes. When addition was
complete the solution was evaporated in vacuo to yield the
sodium salt of clavulanic acid.
Example Z
Clavulanic acid pivaloyloxymethyl ester (250 mg) in
tetrahydrofuran (3 ml) was added to water (100 ml). Sodium
hydroxide solution (O.lN) was added dropwise over 5 minutes
until the pH stabilised at about 7. The solution was
concentrated to 1/3 ~olume under vacuum and ~reeze dried
to yield a 1:1 mixture o~ the sodium salts of clavulanic and
pivaloic acids. Separation of these salts by chromatography
yielded the desired pure sodium clavulanate which was
obtained as a solid by freeze drying.
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