Note: Descriptions are shown in the official language in which they were submitted.
~ 3
28, 538
IMPROVED PROCESS FOR. P~EPARING 6-[D(-)-alpha-(4-Cl-C4-
ALKYL-2,3-DIOXO-l-PIPERAZINOCARBONYLAMINO)PHENYL-
ACETAMIDO]PENICILLANIC ACIDS
BACKGROUND OF THE INVENTION
Field of Invention
The present invention relates to a novel improved
process for ~he preparation of 6-substituted penicillanic
acids. More particularly 9 it relates ~o an improved
process for the preparation of 6-~D(-)-alpha-(4-alkyl-
2,3-dioxo-1-piperazinocarboxylamino)phenylacetamido]penicil-
lanic acids o Formula (I)
,~ e ~ ~S ~ ~ H3
R-N JN-C-N-I-C-N CH3 (I)
~ O H
wherein R represents Cl-C4 alkyl. These compounds are
useful as antibiotics for the treatment of pneumonia,
peritonitis, and blood system infections.
Description of Prior Art
Saikawa et al disclose in U.S. Patent 4,112,090
a process Eor preparing 6-substituted penicillanic acids
of formula (I) by reacting a 4-Cl-C4 alkyl-2,3-dioxo-1-
piperazinocarbonyl chloride of Formula II
o
R- ~ ~ ~-Cl (II)
0~\~0
~ ~ ~(3
-- 2 --
wherein R is Cl-C4 alkyl, with 6-[D(-)-alpha-amino-phen-
ylacetamido]penicillanic acid trihydrate, represented by
Formula (III).
H 0 H H
S ~ CH3
~ ~ ~C02H (III)
The anhydrous form of (III) is hereafter referred
to as ampicillin. In ExamplP 23 of this reference, a
suspension of (III) in a mixture of 10 par~s water and 4.5
parts by weight of ethyl acetate per part by weight of
1 compound III is cooled to 2C, admixed with 2 molar equiva-
lents of potassium carbonate at 2-3C for several minutes,
admixed with 1 molar proportion of a compound of formula
(II) wherein~R is methyl at 2-3C over a period af 10
minutes, and further reacted at said temperature for 15
minutesO The reaction mixture is clarified to remove
some insolubles and the mother liquor is mixed with an
add;tional 18 parts by weight of ethyl acetate per part
by weight of compound III originally charged. The re~
sulting mixture is then acidified with 1 mslar equivalen~
o~ 2N HCl at 20 22C o~er a period of 5 minutes, and
stirred at 20-22C for S hours. The crystals which preci-
pitate are collected, washed successively wîth water and
isopropanol, and dried to obtain a dihydrate of 6-[D(-)-
alpha-(4-methyl-2,3-dioxo-1-piperazinocarbonylimino)phen-
ylacetamido~penicillanic acid in a yield o 75.4%. In a
similar example, a monohydrate of 6-~D(-)-alpha-(4-ethyl-
-2,3-dioxo-1-piperazinocarbonylamino)phenylace~amido]pen-
icillanic acid is obtained in a yield of 84.8% with the
compound of Formula (II) wherein R = ethyl~
There is a need for an improved process which
significantly increases the yield obtai~ed. The presen~
invention provides such a process, with a final yield of
-; about 95%.
~ 3~ ~ ~
SUMMhRY OF THE INVENTION
The present invention provides an improvement
in a process for preparing a 6-[D(-) alpha-(4-Cl-C4 alkyl-
-2,3-dioxo-1-piperazinocarbonylamino)phenylacetamido]
penicillanic acid of Formula ~I) wherein a 4-Cl-C4 alkyl-
2,3-dioxo-1-piperazinoearbony'L halide is added to a solu-
tion or suspension of ampicil:Lin in a mixture of ethyl
acetate and water in the presence of a base to form a
reaction mixture, the resulting mixture is agitated until
the reaction is completed, the reaction mixture is acidi-
fied, and a crystalline product is recovered therefrom;
said improvement comprising:
~ 1) adding about 1-1.5 molar proportions of a
4 Cl-C4 alkyl-2,3 dioxo-l-piperazinocarbonyl halide to an
agitated suspension of about one molar proportion of
ampicillin and an appropriate amount of a suitable base
in a solvent mixture consisting of about 9 12 parts by
weight of water and about 0.5-8 parts by weight of ethyl
acetate per part by weight of ampicillin, over a period
of at least 30 minutes, at about 10-25C, while maintaining
a pH of about 6-8.3;
(2) further agitating the reaction mixture at
about 10-25C for at least 15 minutes upon completing
tbe addition of the 4-C~-C4 alkyl-2,3-dioxo-1-piperazino-
carbonyl halide in step (1);
(3) adding to the reaction mixture about 0.05-
0.2 part by weight each of an activated carbon and a
filter-aid per part by weigbt of ampicillin charged in
step (1), and agitating the resulting mixture at about
10-25C for at least 10 minutes;
(4) clarifying the resulting mixture, and washing
the insoluble materials with about 0.6-2.5 parts by weight
of water per part by weight o ampicillin charged in step
(l);
(S) combining the mother liquor and wash liquor
obtained in step (4) with about 2~12.5 parts by weight of
ethyl acetate per part by weight of ampicillin charged in
step (1), with the proviso that the total amount of ethyl
-- 4 --
acetate used in steps (1) and (5) is about 10-13 parts by
weight per part by weight of said ampicillin, and warming
the resulting mixture to about 15~25C;
(6) acidifying the mixture obtained in step (5)
to about 15~-25C to a pH of about 2.0-Z.5;
(7) agitating the acidified mixture for at
least one hour at about 15-25C, before collecting the
resulting crystalline product; and
(8) optionally converting the product to a
pharmaceutically acceptable salt.
The process of the present invention results in
about a 95% yield of the product of Formula (I).
DETAILED ~ESCRIPTION OF THE INVENTION
In carrying out the process of ~his invention, a
stirred suspension of ampicillin in a mixture of water and
ethyl acetate is prepared in amounts to provide about 9-12,
preferably about 10-11~ parts by weight of water and about
0.5-8, preferably about 4-6, parts by weight of ethyl ace-
tate per part by weight of ampicillin. Ampicillin is de-
fined as tbe anhydrous form of Compound III.
To this mixture is added an appropriate amount ofa suitable base. In order to insure the hig~ yields of the
present invention, the amount of base must be sufficient to
bring the pH of the initial mixture to about 6-8.3, prefer-
ably about 6.5-8, and tQ maintain the pH rangP during the
subsequent addition of the 4-Cl-C4 alkyl-2,3-dioxo-1-pipera-
~inocarbonyl halide. The preferred method of adding base
is to charge the initial mixture with about 2.4--300, pre-
ferably ab~ut 2.5-2.7, molecular e~uivalents of a base such
as sodium or potassium bicarbonate per mole of ampicillin
charged. With this method the subsequent addition of the
carbonyl halide will not induce a pH change. Alternatively,
a base such as, e.g., potassium or sodium hydroxide or
potassium or sodium carbonate may be used to bring the pH
of the initial mixture to about 6-8.3, prPferably about
6.5~8, but care must be taken thereafter to monitor the pH
and to maintain this pH range during the subsequen~ addi-
3-- 5 --
tion of the carbonyl ~alide. The pH may be monitored by
direct inspection and addition of appropriate acid or base
or the pH may be maintained at the proper range by the
addition to the initial reaction system of an appropriate
non-interfering buffer system, which buffer system is rea-
dily determined by those skilled in the art.
The initial mixture is adjusted to a ternperature
of about 10-25C, preferably about 12 18C, to which is
added about 1 1.5, preferably about 1.05-1.15, molecular
proportions of a 4-Cl~C4alkyl--2,3-dioxo-1-piperazinocar-
bonyl halide of the formula:
R ~N N ~ C -~ (IV)
~ ~ ~
wherein R is Cl-C4 alkyl and X is fluoro, chloro, bromo, or
iodo. The compound of Formula IV is added to the mixture
over a period of at least 30 minutes, preferably over about
40-60 minutes, while maintaining the reaction mixture at
the above-stated temperature and a pH of about 6-8.3, pre-
ferably about 6.5-~. In the preferred process the campound
of Formula IV is 4-Cl-C4 alkyl-2,3-dioxo-1-piperazinocarbon-
yl chloride; 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride
is particularly preferred.
The resulting mixture is stirred at said tempera-
ture and pH for at least 15 minutes; and preferably for
about 20-30 mi~utes, after completion of the addition of
the compound of Formula IV. The reaction mixture is then
treated wi~h about 0.05-0.2, preferably about 0.08-0.1,
part by weight of an activated carbon such as, e.g., activa-
ted charcoal or Type RB Activated Carbon (Pittsburgh Coke
and Chemical Co.), and about 0.05-0.2, preferably about
0.1-0.15, part by weight of a filter aid such as, e.g.,
Hyflo~ Super-Cel (Johns-Manville Sales Corp.), per part by
weight of arnpicillin originally charged. The resulting
mixture is then stirred at said temperature for at least 10
3'~ ~q~
-- 6 --
minutes, and preferably for about 15-20 minutes.
The insolubles are then separated from the reacti-
on mixture by conventional methods well known to those
skilled in the art. The preferred method of separation is
filtration. The filter cake is washed wi~h about 0.6-
-2.5, preferably about 1.0 1.2, parts by weight of water
per weight of ampicillin originally charged. The wash
liquor is then combined with the mother liquor obtained
from the filtration process and about 2-12.5, preferably
about 6-7, parts by weight of ethyl acetatc per part by
weight o~ ampicillin originally charged is added thereto,
with the proviso that the total amount of ethyl acetate
used, including the ethyl acetate in the original reaction
mixture, is about 10-13, preferably about 11-12, parts by
weight per part by weight of ampicillin originally charged.
The resulting mixture is warmed to about 15-25C,
preferably to about 18-22C, and acidified at said tempera-
ture to a pH of about 2.0-2.5, preferably about 2.2-2.3,
with dilute mineral acid, e.~. 2 5 N hydrochloric or sulfur-
ic acid.
The acidified reaction mixture is then stirred at
said temperature for at least one hour 9 perferably for
about 2-3 hours, and the resulting crystals are collected
by means well known to those skilled in the art, such as,
~, by filtration or centriEugation. The crystals are
then washed with water and dried to obtain the desired
free acid product in a yield of about 94-96%. This free
acid may be hydrated in varying degrees.
The choice of ethyl acetate as a solvent is criti-
cal, as is the relative conce~tration of ethyl acetate
during the crystallization step. Control o the pH during
the reaction and crys~allization stages is also critical.
Variation of the stated ranges o~ these factors will either
decrease the ultimate yield or result in an inferior crys-
tallization structure, possibly even resulting in an amor-
phous mass with no crystalline structure at all, which
-- 7
makes isolation and purification of the final product time-
-consuming and expensive.
The free acid obtained above may be converted to
a phsrmaceutically acceptable salt by procedures well known
to those skilled in the art. Pharmaceutically acceptable
salts include, ~ , alkali metal, alkaline earth metal,
ammonium, N-methylglucamine, etc. The sodium ~alt is pre-
ferred and is preferably obtained by treatment of the
compound of Formula (I) obtained by the above process with
an equivalent amount of sodium bicarbonate in water.
As used hereinabove and below unless expressly
stated to the contrary, all temperatures and temperature
ranges refer to the centigrade sys~em. The term percent or
~%) refers to the weight percent and the terms mole and
moles refer to gram moles. The term equivalent refers to a
quanti~y of reagent equal in moles to the moles of the
preceding or succeeding reactant cited in that particular
preparation or example in terms of moles of finite weight
or volume.
DESGRIPTION OF THE PREFERRED EMBODIMENT
The present invention also provides ~or a prefer-
red improved process, wherein
(1) about 1.05-1.15 molar proportions of the 4-
Cl-C4 alkyl-2,3-dioxo-l-pipera2inocarbonyl halide of For-
mula IV is added to a suspension containing 2.5-2.7 molar
equivalents of an appropriate base in a solvent mixture
consisting of about 10-11 parts by weight of water and
about 4-6 parts by weight of etbyl acetate per part by
weight of ampicillin, over a period of about 40-60 minutes
at about 12-18C, while maintaining a pH of about 6.5-8;
(2) the reaction mixture is further agitated at
about 12-18C for about 20-30 minutes;
(3) the reaction mixture is treated with about
0.08-0.1 part by weight of an activated carbon and about
0.1-0.15 part by weight of a filter-aid per part by weight
of ampicillin originally charged and the resulting mixture
is agitated at about 12-18C for about 15-20 minutes;
L~Ol3;~
(4) after clarification, the insoluble materials
are washed with about 1.0-1.2 parts by weight o water per
part by weight of ampicillin;
~ 5~ the mother liquor and wash liquor are combined
with about 6-7 parts by weight of ethyl acetate per part by
weight of ampicillin originally charged, and the resulting
mixture is warmed to about 18-22C, with the proviso that
the total amount of ethyl acet:ate used in steps (1) and (5)
is about 11-12 parts by weight: of ampicillin originally
charged;
(6) the reaction mixture is acidified at about
18-22C to a pH of a~out 2.2-2.3;
(7) the acidified reaction mixture is agi~ated at
about 18-22G for about 2-3 hours, before collecting the
crystalline free acid; and
(8) ~he free acid i5 optionally dissolved in
water at a concentration of about 13.125% (weight oE an-
hydrous free acid/volume of water), to which is gradually
added about one molar equivalent of alkali metal bicarbo-
nate; the reaction mixture is stirred for 3-4 hours at
6+4 until the pH drops to at least 6.5, before collecting
the alkali metal salt o the product of Formula (I).
A further understanding of the invention can be
had from the following non-limiting examples. All parts
are by weight unless otherwise indicated.
Example 1
Preparation of 6-~D(-)-alpha-(4- thyl-2,3-dioxo~l-piperazino-
carbonylamino)phenylacetamido~penicillanic Acid Monohydrate
To an agitated slurry of 27.00 grams of ampicillin
trihydrate (equivalent to 22O86 grams (0.0654 mole) o real
anhydrous ampicillin~, 14.50 grams (0.1726 mole) of sodium
bicarbonate, 238 grams of water, and 119 grams of ethyl
acetate, all at 15+2C, is added 14.73 grams (0.0720 mole)
of 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride at a
rate to maintain a pH greater than 6 and a temperature of
15 + 2C. Upon completion of the addition, the reaction
mixture is agitated at 15 + 2OC for 20 minutes, and 2.1
~ (3~
grams of activated carbon (Type RB Activated Carbon; Pitts-
burgh Coke and Chemical Company), and 3.0 grams of a filter-
-aid (Hyflo~ Super-Cel; Johns-Manville Sales Corp.) are
added thereto. The`mixture is stirred for an additional 10
minutes, and the solids are removed by filtration and
wwashed with 26 grams of wa~er. The filtrate and wash li-
quor are combined and then mixed with 142.5 grams of ethyl
acetate. The temperature of the resulting mixture is ad-
justed to 20-22C, and the pH is adjusted to 2.3 by t~e
addition of 2N hydrochloric acid thereto. The acidified
mixture is agita~ed at 20-22C for 2.5 hours and the crys-
talline precipitate is isolated by filtration, washed with
120 grams of water, and dried to obtain 33.49 grams (95.58%
of theoretical) of the desired product~
Example 2
Preparation of 6-[D(-)-alpha-(4-Ethyl-2,3-dioxo-l-pipera
zinocarbonylamino~phenyl acetamido]penicillanic Acid,
Sodium Salt
13.5 g. of the product of Example l (0.025 moles,
equivalent to 13.125 g. of the anhydrous free acid) is dis-
solved in 100 milliliters ~f water, and to the stirred solu-
tion at 6+4C is added 2.06 grams of sodium bicarbonate
(0.025 moles, equivalent to 15.685% w/w of the anhydrous
free acid) in 10 increments of 0.206 grams each. The reac-
tion is allowed to proceed until tbe pH drops to at least6.5, a period of 3-4 hours. The re~ction mixture is steri-
lized by cold filtration, filled into asceptic vials and
lyophilized to produce white or pale yellow crystals of
6-[D(-)-alpha-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)
phenyla~etamido]penicillanic acid, sodium salt.
