Note: Descriptions are shown in the official language in which they were submitted.
1339~20
The present invention, which is divided out of
Application Serial No. 431,361, relates to the use of ~-bromodi-
ethylcarbonate in the preparation of the l-ethoxycarbonyloxyethyl
ester of penicillin-G.
Bacampicillin, or the l-ethoxycarbonyloxyethyl ester
of the 6-(D-(-)-~-phenylacetamido)penicillanic acid of formula
CH - CO - NH - CH - CH C
CH3 (I)
NH2 CO - N CH3
is an amplicillin ester which is extremely important from the thera-
peutic point of view since it is well absorbed when administered
orally and gives much higher blood levels than ampicillin.
This ester is isolated in the form of a hydrochloride.
On the basis of previous known processes (cf. Belgian
patent No. 772723), bacampicillin hydrochloride can be synthesized
by the two following methods.
A) Reaction of potassium benzylpenicillin with ~-
chlorodiethylcarbonate in an aqueous solution of 70% dioxane in
the presence of sodium bicarbonate. The l-ethoxycarbonyloxyethyl
ester of benzylpenicillin which is obtained is subjected to the
reaction of removing the phenylacetic chain, via the iminochloride-
iminoether, in order to obtain the l-ethoxycarbonyloxyethyl ester
of the 6-aminopenicillanic acid, which is isolated as the hydro-
chloride.
By subsequent condensation of the latter intermediate
-- 1 -- *
-- 1339~20
with D-(-)-~-phenylglycine, the compound according to formula I
is obtained.
B) Esterification reaction of the 6-(D-(-)-~azido-
~-phenylacetamido) penicillanic acid with ~-chlorodiethylcarbonate
in a polar solvent.
Subsequently, by catalytic hydrogenation of the 1-
ethoxycarbonyloxyethyl ester of the 6-(D-(-)-~-azido-~-phenyl-
acetamido) penicillanic acid the compound according to formula I
is obtained.
As one can see, these methods are rather complex since
they involve the use of numerous raw materials and lengthy
processing times.
The invention
An object of this invention is to provide a method of
preparing the active substance concerned which is easier to carry
out and industrially more advantageous.
The invention of Parent Patent Application 431,361
provides the novel compound ~-bromodiethylcarbonate. The invention
of the present divisional application provides for the use of ~-
bromodiethylcarbonate in the preparation of the ethoxycarbonyloxy-
ethyl ester of penicillin-G.
~ -Bromodiethylcarbonate is used with great advantage
as a reactant in these esterification processes. The use of ~-
bromodiethylcarbonate leads to particularly high yield and high
purity of the final products such as bacampicillin.
Application Serial No. 431,361 is concerned with
133~621~
improvements in and relating to the preparation of ~-bromodiethyl-
carbonate of the formula:
CH3 - 1H.O.CO.O.C2H5 (II)
This compound is sometimes referred to by the alter-
native name ethyl-o~bromoethylcarbonate. The alpha-bromo-diethyl-
carbonate of the formula (II) may be used in the preparation of
the ethoxycarbonyloxyethyl ester of penicillin-G.
Application Serial No. 431,361 discloses two novel
and inventive processes, herebelow denoted process A and process
B, for the preparation of alpha-bromodiethylcarbonate of the
formula II.
A. The first of these processes, process A, comprises
the steps of :
(a) reacting an aldehyde of the formula
CH3CHO (III)
with carbonyl bromide
COBr2 (IV)
to give an alpha-bromoethyl-bromoformate of the formula:
Br
CH3 CH.O.CO.Br (V)
and;
(b) reacting the alpha-bromoethyl-bromoformate of
formula V with an alcohol of the formula C2H5-OH to yield the
desired alpha-bromo-diethylcarbonate of the formula II.
Thus, the process A may be summarised by the reaction
scheme:
1~39~20
Br +C2H5OH Br
CH3CHO + COBr~ CH3- CH.O.CO.Br ' CH3 _ CH.O.CO.OC2H5 + HBr
The alpha-bromoethyl-bromoformate of the formula V
is in itself a new compound.
The reaction between the aldehyde, CH3CHO, and car-
bonyl-bromide is most suitably carried out in the presence of a
catalyst which may be, for example, a tertiary amine (for example
a tertiary aliphatic amine, a tertiary mixed alkyl/aryl amine or
a tertiary aromatic amine), tertiary phosphine, amide, substituted
urea or thiourea, phosphoric acid amide, tertiary oxonium or sul-
phonium salt, or a quaternary ammonium or phosphonium salt.
Preferred examples of catalysts for use in the process A according
to the invention include pyridine, dimethylformamide, tetra-n-
butyl urea, hexamethyl-phosphoric-tri-amide and benzyltrimethyl
ammonium bromide.
The catalyst is suitably used in an amount of from
0.05 to 0.5, preferably from 0.05 to 0.15, moles of catalyst per
mole of aldehyde.
The reaction between the aldehyde and the carbonyl
bromide is suitably carried out in the presence of a solvent which
may be,for example, an aromatic hydrocarbon such as toluene or
a halogenated hydrocarbon such as dichloromethane, carbon tetra-
chloride or chlorobenzene. The reaction between the aldehyde and
the carbonyl bromide is suitably carried at a temperature of from
-40 to 120~C, preferably 0 - 40~C. The carbonyl bromide will
usually be used in molar excess with respect to the aldehyde,
133~620
suitably in a molar excess of from 10 to 100%, preferably from 20
to 50~-
The intermediate alpha-bromoethyl-bromoformate of
formula V produced in step (a) of the process A need not be iso-
lated prior to reaction with the alcohol C2H5OH and, indeed,
it is generally preferred not to do so. Thus, in accordance with
a preferred embodiment, the reaction mixture obtained from step
(a) is freed of excess carbonyl bromide, for example by warming
under reduced pressure or by purging with nitrogen. The crude
alpha-bromoethyl-bromoformate-containing reaction mixture is then
reacted with an excess of the alcohol. The reaction may conven-
iently be effected by heating the mixture under reflux until the
evolution of hydrogen bromide ceases or by adding a tertiary base
to the mixture and, if necessary, warming it. Any residual
catalyst from step (a) or its complex with carbonyl bromide does
not appear to interfere with the subsequent reaction and, in some
cases, appears beneficial.
The resultant crude alpha-bromocarbonate may con-
veniently be isolated from the reaction mixture by fractional
distillation under reduced pressure.
Process A is illustrated in Examples 1 and 2 r which
are given by way of illustration only.
B. The second process, process B, for the prepara-
tion of ~-bromodiethylcarbonate will now be described. Method B
is exemplified in Example 3, which is given by way of illustration
only.
l~C.~62a,
Process B is concerned with improvements in and
relating to the preparation of ~bromodiethylcarbonate by a
modification of the Finkelstein reaction, that is by reaction
of an alkyl chloride or arylalkyl chloride (or a compound contain-
ing such a group) with an alkali metal bromide or alkali metal
iodide to replace the chloride substituent by a bromine or iodine
substituent respectively; or by the reaction of an alkyl bromide
or arylalkyl bromide (or a compound containing such a group) with
an alkali metal iodide to replace the bromine substituent by an
iodine substituent.
The Finkelstein reaction is useful since the result-
ing iodides are generally more reactive than the bromides which
in turn are more reactive than the chlorides. In some cases only
catalytic amounts of the alkali metal bromide or iodide are
necessary and the resulting more reactive species is allowed to
react with the desired substrate regenerating the alkali metal bro-
mide or iodide, thus continuing the reaction.
Not all optionally substituted alkyl chlorides or
arylalkyl chlorides undergo the reaction and, in particular, it has
been found difficult to carry out the reaction with alpha-chloro
esters and alpha-chlorocarbonates, that is compounds in which the
chlorine atom is attached to a carbon atom which is, in turn,
attached to either end of a group -C(0)-0-. An example of such an
alpha-chloro-carbonate is ~-chlorodiethylcarbonate, which is a known
intermediate in the preparation of ethoxycarbonyloxyethyl esters
of 6-aminopenicillanic acid and of penicillins as described above.
133g~20
It has now been found that this problem may be
overcome by carrying out the reaction using a two-phase solvent
system, one phase of which is water and the other is a water-
immiscible organic solvent, in the presence of a phase transfer
catalyst.
According to process B therefore, there is provided
a process for the preparation of ~-bromodiethylcarbonate by
reaction of ~-chlorodiethylcarbonate with an alkali metal bromide,
which process is characterized in that the reaction is carried
out in a two-phase solvent system comprising water and a water-
immiscible organic solvent in the presence of a phase transfer
catalyst.
Suitable water-immiscible organic solvents include
halogenated hydrocarbons, for example halogenated paraffins such
as dichloromethane; and aromatic hydrocarbons such as toluene.
Suitable phase transfer catalysts include quaternary ammonium salts,
for example tetraalkyl ammonium salts such as cetyltrimethyl
ammonium bromide and tetra-n-butyl ammonium hydrogen sulphate.
The alkali metal bromide may, for example, be sodium, potassium,
or lithium bromide, lithium bromide being preferred.
Thus, in process B, ~-chlorodiethylcarbonate of the
formula:
Cl O
..
CH3 - CH - O - C - O - C2H5 (VI)
is reacted in a two-phase solvent system, one phase of which is
water and the other is a water-immiscible organic solvent, with
an alkali metal bromide of the formula
1333~20
R-Br (VII)
in which formula R is an alkali metal such as Na, K and Li, to the
formation of the compound of the formula:
Br O
..
CH - CH - O - C ~ ~ C2 5 (VIII)
As noted above, the preferred alkali metal R is Li
so that LiBr is a preferred reagent of the formula VII.
In connection with process B it has been found that
lithium bromide may be used with advantage in a conventional
Finkelstein reaction (i.e. one employing a single phase organic
solvent system), for example to halogenate an alpha-chloro-
carbonate. This method is exemplified in Example 4.
Accordingly, Application Serial No. 431,361 discloses,
in accordance with a further embodiment thereof, a process for the
preparation of ~-bromodiethylcarbonate which comprises reacting
~-chlorodiethylcarbonate with lithium bromide.
Suitable solvents for such a process include lower
aliphatic alcohols, lower aliphatic ketones, lower aliphatic ethers
and lower aliphatic amides of formic acid.
The invention of this relates to the use of the
novel compound ~-bromodiethylcarbonate in the preparation of the
ethoxycarbonyloxyethyl ester of penicillin-G.
Accordingly, the present invention provides a process
for the preparation of an ethoxycarbonyloxyethyl ester of
penicillin-G which comprises reacting penicillin-G or a salt
thereof with a ~-bromodiethylcarbonate compound of the formula
9 620
Br\
~ CH-O-CO-O-C2H5
CH3
and recovering the desired product.
The reaction is carried out in the presence of a
quaternary ammonium compound as catalyst. Suitably the said
quaternary ammonium compound is present in an amount of 1-25,
preferably 1-10% of the equimolar amount with respect to the
amount of penicillin-G.
The ethoxycarbonyloxyethyl ester of penicillin-G is used
as is known in the art in the preparation of any desired such
semisynthetic penicillin ester by acylating the 6-NH2 group after
removing the side chain in e.g. the penicillin-G ester obtained.
This aspect of the invention is concerned with
improvements in and relating to the preparation of esters by the
reaction of salts of carboxylic acids with a-bromodiethyl-
carbonate.
The reaction of metal salts of carboxylic acids with
alkyl halides of arylalkyl halides to form esters is well known.
However, yields are not particularly high and the reaction
generally requires forcing conditions such as high temperatures
and/or extended reaction times. These forcing conditions limit
the synthetic utility of the reaction and its commercial applica-
bility to heat sensitive and labile substances such as
pyrethroids, prostaglandins, peptides, penicillins and
cephalosporins.
The British Patent Specification 1443738 discloses
A'
n
the use of a quaternary ammonium salt of penicillins and cefalo-
sporins in place of a metal salt thereof in the preparation of
esters of penicillins and cefalosporins.
The preparation of the quaternary ammonium salt of
the acid may be time-consuming and expensive. However, as is also
disclosed in the British patent specification 1443738, it is not
necessary to first prepare the quaternary ammonium salt of a
penicillin or cefalosporin, but the reaction may be carried out
by reacting a metal salt of the carboxylic acid, that is the 6-apa,
penicillin or cefalosporin with the alkyl or arylalkyl halide in
the presence of a quaternary ammonium salt, other than the salt of
the carboxylic acid.
It has now been found, according to the present inven-
tion, that it is not necessary to employ the said quaternary
ammonium salt in a stoichiometric amount with respect to the car-
boxylic acid, that is the penicillin-G but that a less than
stoichiometric amount with respect to the carboxylic acid
penicillin-G will be sufficient.
According to the invention, therefore, there is
provided a process for the preparation of an ethoxycarbonyloxy-
ethyl ester of penicillin-G by reaction of a metal salt of the
penicillin-G or cefalosporin with ~-bromodiethylcarbonate in
the presence of a quaternary ammonium salt (other than a salt of
the said carboxylic acid) whereby the quaternary ammonium compound
is present in a less than stoichiometric amount with respect to
the penicillin-G.
-- 10 --
133~9620
In accordance with a preferred embodiment of the
invention, between 1~ and 25% of an equivalent of the quaternary
ammonium salt is used for each equivalent of the metal salt of
the carboxylic acid, and more preferably between 1% and 10% of an
equivalent of the quaternary ammonium salt is used.
The quaternary ammonium salt of the carboxylic acid
is suitably prepared by reaction of a metal salt of the carboxylic
acid with a quaternary ammonium salt of an acid other than said
carboxylic acid, typically a mineral acid such as hydrochloric,
hydrobromic or sulphuric acid.
Suitable metal salts of carboxylic acids for use in
accordance with the present aspect of the invention (either as
precursors for the carboxylic acid quaternary ammonium salt or as
such) are alkali metal or alkaline earth salts such as sodium,
potassium, lithium, magnesium and calcium salts. Suitable quater-
nary ammonium salts of acids other than the carboxylic acid (for
use either as precursors for the carboxylic acids quaternary ammon-
ium salts or as such) include for example tetra-alkyl ammonium
salts such as tetra-n-butyl ammonium bromide and cetyltrimethyl
ammonium bromide and quaternary pyridinium salts such as cetyl-
pyridinium bromide. Suitable halides include fluorides, chlorides,
bromides and iodides, preferably activated fluorides or activated
chlorides or bromides or iodides.
The esterification reaction in accordance with this
aspect of the invention may be carried out in the presence or
absence of a solvent. Suitable solvents include lower aliphatic
9 6 2 1~
alcohols, lower aliphatic ketones, lower aliphatic amides of
formic acid and dimethylsulphoxide. Alternatively, when no
solvent is used, an excess of the ester forming halide may be
used, particularly if this is a liquid at the temperature of
the reaction.
In the previously described aspect of the inven-
tion which relates to the use of ~-bromodiethylcarbonate in the
preparation of the ethoxycarbonyloxyethyl ester of penicillin-
G, the use of catalyst is optional. Approximately equimolar
amounts of the quaternary ammonium salt of the carboxylic acid
and the ester forming halide may be used in the reaction.
Preferably between 5% and 100% excess of the ester forming
halide is used for each equivalent of the salt of the carboxy-
lic acid used and more preferably an excess of between 20%
and 60% of the ester forming halide is used.
The improvements in the esterification processes
of the invention are particularly suitable for the preparation
of the ester of penicillin-G and thus, in accordance with the
invention penicillin-G of the formula:
~ CH2CO-NH CH3 XI
/~N
~ CO2H
- 12 -
- 1339623
or a salt thereof, is reacted with a compound of the formula
Br
CHO-CO-O-C2H5
CH3
in the presence of a catalyst.
In accordance with a preferred embodiment of the
lnvention the catalyst is a quaternary ammonium salt, preferably
tetra-n-butylammonium bromide.
In order that the invention may be well understood
the following examples are given by way of illustration.~-Examples
1 to 5 illustrate the preparation of the novel compound ethyl ~-
bromoethylcarbonate by methods disclosed in Application Serial No.
431,361.
Example 1
A mixture of acetaldehyde (44 g, 1 mole), carbon
tetrachloride (300 ml) and freshly distilled carbonyl bromide
(235 g, 1.25 mole) was cooled to 0~C and maintained at this tempera-
ture by external cooling during the addition over a period of 1
hour of pyridine (11.9 g, 0.15 mole).
The mixture was allowed to warm up to ambient tempera-
ture and then heated to 50~C and maintained at this temperature
for a period of 3 hours during which time a precipitate formed.
Evaporation of the reaction mixture under reduced
pressure at 50~C gave a semi solid oily mass which readily dissolv-
ed in ethanol (92 g, 2 mole) on warming and heating under reflux.
After heating under reflux for a further 2 hours, excess ethanol
1~39~;20
was removed in vacuo and the residue triturated with water (100 ml)
and methylene dichloride (200 ml~.
Separation of the organic layer and fractional dis-
tillation afforded pure ethyl alpha-bromo-ethyl-carbonate (130 g,
66~ yield) having a boiling point of 90-92~C at 45 mms of mercury
pressure and identical in all respects with an authentic specimen.
Example 2
A mixture of acetaldehyde (44 g, 1 mole), dichloro-
methane (300 ml) and hexamethylphosphoric-tri-amide (17.9 g, 0.1
mole) was cooled to -10~C and freshly distilled carbonyl bromide
(207 g, 1.1 mole) was gradually added over a period of 4 hours
during which time the temperature was allowed to rise to 10~C.
The mixture was then heated under gentle reflux
(ca. 40~C) for 4 hours. While still under reflux, ethanol (69 g,
1.5 mole) was carefully added over a period of 1 hour and heating
under reflux continued for a further 1 hour.
Fractional distillation of the resulting mixture
afforded pure ethyl alpha-bromoethyl-carbonate directly (114 g,
58% yield).
The authenticity of the ethyl alpha-bromoethyl-
carbonate formed was confirmed by analysis and independent synthe-
sis as follows.
Diethylcarbonate (118 g, 1.0 mole) was stirred and
heated to between 110~C and 120~C and illuminated by a 150 watt
tungsten filament lamp. Bromine (96 g, 0.6 mole) was added drop-
wise over a period of 3 to 4 hours and at such a rate that the
~- 1339~20
mixture did not deepen beyond a pale orange colour.
After addition of bromine was complete, the mixture
was cooled to ambient temperature and sodium bicarbonate (20 g)
added.
Distillation and fractionation of the resulting
mixture gave authentic ethyl alpha-bromoethyl carbonate (84.2 g,
70% yield) having a boiling point of 87-88~C at 40 mms of mercury
pressure.
Example 3
A mixture of lithium bromide (43 g, 0.5 m), ethyl
alphachloroethylcarbonate (15.3 g, 0.1 m); water (100 ml),
dichloromethane (100 ml) and cetyl trimethyl ammonium bromide
(1.5 g) was stirred at ambient temperature for 24 hours. The
aqueous layer was removed and replaced by a fresh solution of
lithium bromide (26 g, 0.3 m) in water (40 ml) containing cetyl
trimethyl ammonium bromide (1 g). After stirring for a further
24 hours during which time the temperature was raised to 35~C,
the organic layer was separated, dried and vacuum distilled to
afford after repeated fractionation the new compound, ethyl alpha-
bromoethylcarbonate (15.0 g, 76% yield) having a boiling point of
90-92~C at 35 mms of mercury pressure.
Found: C 30.7 H 4.8 Br 40.1%
Calculated: C 30.5 H 4.6 Br 40.6
The NMR spectrum exhibited peaks as follows:-
- 15 -
1339~20
1.2 - 1.6 (3H, triplet) CH2.CH3
2.0 - 2.2 (3H, doublet) -CH.CH3
4.1 - 4.5 (2H, Quartet) CH2.CH3
6.5 - 6.8 (lH, Quartet) -CH.CH3
Example 4
Lithium bromide (17.4 g, 0.2 m) was dissolved in di-
methyl formamide (150 ml) and the mixture cooled to ambient tem-
perature. Ethyl alpha-chloroethyl carbonate (30.5 g, 0.2 m) was
added and the mixture stirred at ambient temperature for 24 hours.
The precipitated lithium chloride was filtered off and the filtrate
vacuum distilled to afford after careful re-fractionation, ethyl
alpha-bromoetpyl carbonate in 76~ yield based upon recovered ethyl
alpha-chloroethyl carbonate.
Example 5
The authenticity of the foregoing new compound ethyl
alpha-bromoethyl carbonate was confirmed by independent synthesis
as follows:-
A mixture of diethyl carbonate (35 g, 0.3 m) in
carbon tetrachloride (50 ml) and alpha-azo-isobutyronitrile (AIBN)
(0.1 g) was heated to gentle reflux and dibromodimethyl hydantoin
(28.6 g, 0.1 m) was added in small aliquots over a period of 8 hours
together with further additions of AIBN (8xO.05 g): care being
taken to ensure that free bromine did not accumulate in the re-
action mixture. At the end of the reaction the mixture was subjec-
ted to vacuum fractional distillation to afford pure ethyl alpha-
bromoethyl carbonate (32.3 g, 82% yield) identical in all respects
-- 1~ --
13.~9~20
with the product of Examples 3 and 4.
Example 6 Benzylpenicillin ethoxycarbonyloxyethyl ester
A mixture of potassium penicillin-~ (7.4 g, 20
mmole), ethyl alpha-chloroethyl carbonate (4.6 g, 30 mmole), tetra-
n-butyl ammonium bromide (0.8 g, 2.5 mmole) and acetone (80 ml)
were stirred and heated under gentle reflux for 4 hours. Excess
acetone was removed under partial vacuum and the residue triturated
with ice-cold water and methyl isobutylketone. Evaporation of the
dried methyl isobutylketone under vacuum gave a semi-crystalline
oil (3.8 g) which on trituration with ethanol deposited white
crystals (0.9 g) of the alpha-(ethoxycarbonyloxy)-ethyl ester of
penicillin-G having a purity of 98-g9% by HPLC.
Found: C 43.0 H 7.4 N 7.7%
Calculated: C 43.4 H 7.4 N 8.0%
Example 7 Benzylpenicillin ethoxycarbonyloxyethyl ester
The foregoing experiment of Example 11 was repeated
using ethyl alpha-bromoethyl carbonate (5.9 g, 30 mmole) instead
of ethyl alpha-chloroethyl carbonate, whereon there was obtained,
on evaporation of the methyl isobutyl ketone, 6.0 g of a semi-
crystalline oil. Trituration of this oil with warm ethanol and
then cooling afforded white crystals (2.5 g, 35% yield) of the
alpha-(ethoxycarbonyloxy)-ethyl ester of penicillin-G.
Example 8 Benzylpenicillin ethoxycarbonyloxyethyl ester
Potassium benzylpenicillanate (25.08 g, 66.7 mmol)
sodium bicarbonate (0.50 g, 6.0 ~mol), and tetrabutylammonium
bromide (2.15 g, 6.67 mmol) were carefully stirred in methylene
133962~
chloride (41ml) and warmed to 40~C. When this temperature was
reached ~-bromodiethyl carbonate 17.16 g, 86.7 mmol) was added
and the slurry was stirred for 4.0 hours. Water (30 ml~ was added,
followed by a mineral acid to a pH of approx. 5. The mixture was
stirred for approx. 4 hours, during which time sodium hydroxide
(4%) was added in order to maintain pH between 2.5-3Ø Methylene
chloride (50 ml) was then added and the mixture was allowed to
separate for a few minutes. The organic phase was washed with
water (65 ml) and was then evaporated under reduced pressure. The
oily product thus obtained was dissolved in methylene chloride
(100 ml) and was evaporated again. The remaining oil was dissolved
in methylene chloride to a total volume of 100 ml.
HPLC-analysis of the methylene chloride solution
showed a yield of benzylpenicillin ethoxycarbonyloxyethyl ester
of 96-97%.
Example 9 Benzylpenicillin ethoxycarbonyloxyethyl ester
Potassium benzylpenicillinate (5.02 g, 13.3 mmol) and
potassium bicarbonate (2.99 g, 38.3 mmol) in dimethyl sulfoxide
(13.5 ml) were carefully stirred in an ice-bath. ~-Bromodiethyl
carbonate (3.70 g, 18.6 mmol) was added over a period of 30-40 min.
using a syringe pump. Stirring was continued while keeping the
reaction mixture in the ice-bath. HPLC-analyses showed that a
yield of about 70% of the benzylpenicillin ethoxycarbonyloxyethyl
ester was obtained within 5-10 min.
Example 10 Benzylpenicillin ethoxycarbonyloxyethyl ester
Potassium benzylpenicillinate (47.03 g, 125 mmol)
1~39620
sodium bicarbonate (0.94 g, 11 mmol), and tetrabutylammoniu~, bro-
mide (2.01 g, 6.25 mmol) were carefully stirred in acetone ~77 ml)
and warmed to 40~C. When this temperature was reached ~-bromo-
diethyl carbonate (26.06 g, 131 mmol) was added and the slurry was
stirred for 4.5 hours. Water (56 ml) was added, followed by a
mineral acid to a pH of approx. 5. The mixture was stirred for
approx. 3 hours, during which time sodium hydroxide (4%) was added
in order to maintain pH between 4.5-4.8. Butyl acetate (100 ml)
was then added and the mixture was allowed to separate for a few
minutes. The organic phase was washed with water (80 ml) and then
evaporated under reduced pressure. The rem~ining oily product
was dissolved in methylene chloride to a total volume of 250 ml.
HPLC-analysis of the methylene chloride solution
showed a yield of benzylpenicillin ethoxycarbonyloxyethyl ester
of 9~-99%.
19 ~
