Note: Descriptions are shown in the official language in which they were submitted.
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PROCESS OF PREPARITfG ESTERS OF
PENICILLANIC ACID SULFOXIDE
Field of the Invention
The present invention relates to the field of
organic chemistry. More specifically it relates to the
fields of medicinal and pharmaceutical chemistry.
Background of the Invention
The discovery and mass prodt;iction of penicillin in
the 1940's revolutionized the treatment of human disease.
These early antibiotics saved countless lives by
providing the first non-invasive treatment for bacterial
infections. Unfortunately, the widespread use of
antibiotics has not been free from costs. Numerous
strains of drug resistant bacterial pathogens have
emerged over the years, challenging the medicinal
chemist's ability to redesign and/or engineer new
antibiotics.
.An important class of building blocks often utilized
in the design of antibiotics and j3-lactamase inhibitors
are the esters of penicillanic acrid sulfoxide. Examples
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of antibiotics and (3-lactamase inhibitors include
cefaclor and cefuroxime. Esters of penicillanic acid
sulfoxide are represented by compounds of formula (T).
O
ll
S
(I)
N
O .'
C021
The reported syntheses of this class of molecules is
accomplished by segregated syntheses and purifications,
which often entail laborious chromatographic separations
(see Beels, C. M. D, et al., J. Chem. Soc. Common. 665,
2979, Kemp, J. E. G, et al., Tet.x~ahedron Letters, 3785,
1979, Micetich, R. G., et al., ~Teterocycles, 23, 325,
(1985), and. Johnson, G.; et a~., Spec. Publ.- R. Soc.
Chem. 38, 170), (1980)). Low overall yields have been
reported, due in part, to the sensitive nature of the
lactam to ring opening events and losses in the multiple
work-up process. The present invention provides a simple
and efficient procedure for the synthesis of this
important class of compounds.
Summary of the Invention
The present invention is a one-pot (one reaction zone,
typically one-vessel) process for the preparation of a
compound of the formula (I):
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_3_
O
//
S
~I)
N '
o ~=
C02~:
wherein R is a carboxy protecting group;
comprising, conducting the following steps A, B, C, D, E
and F in a single reaction zone:
A) diazotizing 6-APA with nitrous acid to form a
compound of the formula (II);
N2 ..
..
1
' ~.,~ ( T I
0
CO~'.F-i
B) reacting a compound of formula (II) with bromide
or other halide anion to form a compound of the formula
(III) ;
Br.,, S
(TII)
''~.
N '
O
C02Ii
C) alkylating a compound of formula (III) with an
alkylating agent of the formula RX, where R is a
monovalent radical and X is a leaving group comprising
halide, hydroxy and the like to form a compound of the
formula ( IV) ;
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Br .,,. S .
'~~.,~ ( IV )
o ':
C 02:R
D) reducing a compound of formula (IV} to form a
compound of the formula (V);
S
(V)
~~~s
N
O ~%
C021
E) oxidizing a compound of formula (V) to form a
compound of the formula (I}; and
F) optionally, isolating the: compound of formula
(I) .
The compounds of formula (I) are valuable
intermediates useful in the preparation of antibiotic
compounds of the formula (IA) and the ~3-lactamase
inhibitors of formula (IB).
O
II
Ov i O
,,v
N /~---SR or ~'
N .",~/
N~R
O . O .. O ~ ':
( I ) COZR ( IA } ~ C02H ( IB ) COZH
Prior reported syntheses of the compounds of formula
(I) have been unsatisfactory in that they require
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multiple steps and report low overall yields of the
desired compounds. In addition, the reported syntheses
require multiple isolation steps and accordingly the use
of large volumes of solvents. The time required to
perform these multiple isolations and handle the waste
stream produced is a severe detriment to a commercial
manufacture of these materials.
The present invention overcomes many of the failings
of the prior art. The novel single-pot synthetic process
avoids numerous isolation steps that require large
volumes of solvents. In addition., the present invention
is robust, does not require extreme temperatures,
utilizes cost effective reagents and solvents, and
produces greatly reduced waste.
As industrial production of antibiotics increases
around the world, the advantages of the present process
become increasingly valuable. This expedient, cost
effective, environmentally conscious process allows
cheaper and easier production of important antibacterial
medicines.
Detailed Description of the Invention
The term "&-APA as used herein refers to the
compound 6-aminopenicillanic acid.
The term "carboxy protecting group" as used in the
specification refers to one of the ester derivatives of
the carboxylic acid group commonly employed to block or
protect the carboxylic acid group while reactions are
carried out on other functional groups on the compound.
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The species of carboxy-protecting group employed is not
critical so long as the derivati::ed carboxylic acid is
stable to the condition of subsequent reactions) and can
be removed at the appropriate point without disrupting
the remainder of the molecule. :>uitable protecting
groups are well known to chemist:> and chemical
engineering practitioners of the art and are further set
out in standard references such <~s T.W. Greene and P.
Wuts, Protective Groups in Organic Synthesis, John Wiley
and Sons, New York, N.Y., 1991, Chapter 5. See also E.
Haslam, Protective Groups in Organic Chemistry, J.G.W.
McOmie, Ed., Plenum Press, New York, N.Y., 1973.
Examples of carboxy protecting groups include for
example, p-nitrobenzyl group, al~_ylic groups, benzyl,
butyl, and trichloroethyl groups,. In general suitable
carboxy protecting groups are groups that result in
formation of readily hydrolyzable esters. A related term
is "protected carboxy," which refers to a carboxy-
protecting group. .
The term "solvent" means a liquid reaction medium in
which the selected reactants) has a solubility of at
least 1% by weight.
The terms "one-pot," "singlE~-pot," "one reaction
zone" or "one-vessel" as used herein are synonymous and
mean a chemical synthesis in which the entire reaction
sequence is performed in one reacaion.zone (typically in
one reaction vessel without product removal or separation
or purification until all essential reaction steps are
completed).
The term "leaving group" as used herein defines the
part of a substrate molecule that: is cleaved in a
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reaction and comprises the groups halides, hydroxy,
alkoxy sulfonate esters, triflates, phosphonates and the
like.
The term "diazotization" refers to the formation of
a RN2+ radical either by the treatment of a primary amine
with nitrous acid or other nitrite source or the
protonation of diazo compounds. Diazotization is well
known to artisans in the field and may be found in
general reference texts including for example J. March,
Advanced Organic chemistry, John Wiley and Sons, New
York, N.Y., 1985.
General Process t~onditions
The reaction is carried out in a single reaction
zone, typically a reaction vessel, having an input and an
output means, an agitation means (electric stirrer),
heating and cooling means (heat exchange coils), and is
constructed of materials which are non-reactive with the
reactants and products of the reaction (e. g. glass lined
vessel ) .
The process may be conducted as a batch, semi-batch
2S or continuous process, but batch operation is preferred.
The process may be conducted at ;superatmospheric or
subatmospheric pressure but ambient atmospheric pressure
is preferred for convenience (e.g. about 101.3KPa).
A preferred reaction medium is one or two phases
where each phase is a solvent or mixture of solvents for
the reactants and the reaction products at each step of
the process. Solvents useful fo:r the purpose of this
invention include methylene chloride, water, lower (C1-C2)
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_g.
alcohols , chloroform, acetonitrile and the like.
Particularly preferred solvents =include methylene
chloride and water.
Scheme 7:
Scheme I describes an effic_Lent and practical one-
pot synthesis of the compounds of formula (T).
H 2 N''' S 2 ~''. S
Diazotization
N ~'~'~ ,--~. N ''
Nitrous acid
O : O
co2H step A
(6-APA) Co2H
(II)
Br~ Br~~ S
'~ S '
Bromide Alkylation
displacemen ' N ~~~'' St:ep C~ N
Step B 0 - 0
COzR
(III) (~)
O
Reduction S Oxidatio S'
-1- ,~ ._
Step D N ''~ Step S N ~''y
O ~' Isolation O
C02R atep F C02R
(V) (I)
The starting material useful for the purpose of this
invention is 6-aminopenicillanic acid , chemically known
in the art as 6-amino-3,3-dimethyl-7-oxo-4-thia-1-
azabicyclo[3.2.0]heptane-2-carbo~.~ylic acid (6-APA). 6-
APA is an item of commerce and is obtained from cultures
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of Penicillium Chrysogenum in the: absence of side chain
precursors: Batchelor et al., Nature 183, 257 (1959).
Synthetic methods for the preparation of 6-APA have been
disclosed by Sheehan et al., J. ~~m. Chem. Soc. 81, 5838
(1959), ibid. 84, 2983 (1962). Nfethods of preparation of
6-APA have also been disclosed in U.S. Patent Nos.
3,028,379; 2,934,540; and 2,941,995, the entire
disclosures of which are incorporated by reference. 6-
APA is also readily commercially available from the
various chemical supply sources available to
practitioners of the art.
Step A: The diazotization of 6-aminopenicillanic
acid (6-APA) can be performed by methods well known in
I5 the art including but not limited to treatment with
nitrous acid in a suitable solvent such as ethanol.
Numerous methods of preparing nitrous acid in situ are
known in the art. Alternatively, other nitrite sources
can be employed including but not: limited to
alkylnitrites and the like. Most: commonly a nitrite salt
solution is added to a cooled solution of the amine and a
mineral acid. The transformation can be preferably
carried out by addition of aqueous sodium nitrite to a
turbid ethanol/sulfuric acid solution of 6-APA. A
skilled artisan will appreciate that the production of
diazonium salts is a potentially dangerous operation that
is most commonly performed at temperatures ranging from
0°C to 15°C. This reaction requires from 1 to 3 hours.
Step B: The bromide displacement to form compounds
of formula (III) can be performed by numerous methods
known in the art, Most commonly the transformation is
accomplished by addition of the diazonium solution to a
solution (e.g., aqueous) of a periodic table group I or
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group II bromide salt. Potassium, sodium, or lithium
bromide are preferred bromide anion sources. For the
same reasons as outlined in the diazonium formation, the
bromide addition is most often performed at reduced
temperatures, preferably from 0°C to 15°C. This reaction
step requires from 1 to 3 hours for completion.
Often, and most preferably, the displacement is
performed by having the bromide anion present in the
reaction mixture when the diazonium salt is being formed.
In this way, the highly reactive ~diazonium species is
immediately displaced with bromide prior to degrading.
In addition, this procedure helps prevent the
concentration of diazonium salts from reaching a level
where a spontaneous and violent degradation is more
likely.
Step C: The alkylation of the carboxyl group to
form compounds of the formula (IV), is well known in the
art and can be effected by a wide variety of reagents.
It is most often performed by reacting the carboxylate
with a compound of the formula R-X; wherein, X is a
leaving group including but not limited to halide,
hydroxy, and phosphonate esters. A skilled artisan will
appreciate that a wide variety of solvents and
temperatures can be utilized in this transformation and
that the specific choices will be determined by the
reactivity of the alkylating ageni~, R-X. An especially
preferred method is one wherein X is halide and the
alkylation is carried out under phase-transfer catalysis
conditions. Most preferred conditions include reaction
of p-nitrobenzyl bromide with the compound of formula
(III) in a biphasic reaction mixture of methylene
chloride and water, at approximatE:ly neutral pH, and in
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the presence of a phase-transfer catalyst. Appropriate
phase-transfer catalysts are well known in the art and
include but are not limited to tetralkylammonium salts,
tetralkyl- phosphanium salts, and. the like.
Tetrabutylammonium bromide is one such preferred
catalyst. This reaction step typically requires 2 to 20
hours for completion depending on. the temperature which
is typically from 0°C to 40°C.
Step D: The reductive dehalogenation, to prepare
compounds of formula (V) can be performed by reagents
known in the art including but not limited to
alkylphosphines, alkylphosphites, zinc, A1/Pb, alkyltin
hydrides, hydrogen/Pd, and the like. A skilled artisan
will appreciate that a wide variety of solvents and
temperatures can be utilized in this and other
transformations embodied in this invention and that the
specific choices will be determined by the reactivity of
the reducing agent. Preferred reducing agents are
trialkylphosphines, especially tributylphosphine, which
are added at 0°C to 30°C over a period of 20 to 60
minutes. A preferred solvent mixture is the mixture of
dichloromethane and methanol.
Step E: The sulfide oxidation, to prepare compounds
of formula (I) can be performed by methods known in the
art including but not limited to reacting the sulfide
with peracids such as peracetic acid and m-
chloroperbenzoic acid, OXONE~ br~~nd of potassium
peroxymonosulfate, ozone, sodium periadate, hydrogen
peroxide, and the like. These oxidations are most often
but not always carried out at reduced temperature. The
reaction is typically performed at from 0 to 10°C over a
period of 1 to 4 hours depending on the rate of addition
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of the oxidizing agent. A wide variety of solvent can be
utilized for the oxidizing agents as long as they are
inert to the reaction conditions. Preferred solvents
include lower alcohols, methylene chloride, chloroform,
acetonitrile, water, arid the like. In addition, these
oxidations are often performed in mixtures of solvent s.
Especially preferred solvent mixtures include
water/methanol, water/ethanol, and methylene
chloride/methanol.
Step F: The isolation of the final products of the
formula (I) is optional and not necessary for the
practice of this invention. The product mixture can be
employed in a subsequent transformation without
isolation. The isolation of the products of formula (I)
if desired can be affected by a variety of known methods
including but not limited to extraction, chromatography,
crystallization, and the like. A. skilled artisan would
appreciate that the optimal isolation technique will be
determined by the particular characteristics of the ester
prepared by the present invention.. A particularly
preferred isolation technique is crystallization of the
product. An especially preferred. method is
crystallization from hot methanol.
Throughout the course of the reaction scheme, it may
be preferable to add, change, or remove solvents. A
skilled artisan would appreciate that the rate and
efficiency of the process, as well as the purity of the
product, can be affected by the choice of solvents. In
addition, the ultimate purification of the compounds of
formula (I) can be simplified if the reaction mixture is
washed with an immiscible solvent, once or more than
once, throughout the course of the process. Accordingly,
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this exchange, addition, or removal of solvents is within
the scope of the present invention.
A further embodiment of the present invention is the
process scheme (I) wherein step (E) precedes step (D).
The oxidation and reduction steps may efficiently be
performed in either order. Accoz:dingly, the present
invention includes such alternative processes.
The reaction temperature of all reaction steps is
within the freezing point and boiling point of the
reaction medium, and preferably i=rom 0°C and 50°C, with
comparable reaction times of 1 minute to I00 hours.
Each reaction step is perfoz-med for a time
sufficient to convert a major portion of the penicillanic
acid precursor, that is at least about 50 mole percent
and preferably at least 95 mole percent.
The reaction at each stage may be monitored by
conventional means such as withdrawal of an aliquot
sample and analyzing for a product and or by-product or
disappearance of a starting material, to determine
completeness of the reaction.
Examples,
Example 1
p-Nitrobenzyl Penicillanate Oxide
Aqueous sulfuric acid (281 ~~nal, 1.25 M, 225 mL) and
168 mL of ethanol were mixed in a 3-necked, 1 liter flask
equipped with a thermometer, mechanical stirrer and an
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addition funnel connected to a gas bubbler. &-Aminopen-
icillanic acid (222 mmol, 48.1 g) was added at 5°C to
give a cloudy solution, which wa:~ vigorously stirred with
54.0 g of KBr (454 mmol). A solution of NaN02 (21.8 g,
316 mmol) in 56 mL of H20 was adf.ed at such a rate so as
to keep the temperature below 13°'C. Nitrogen gas
generated was let out through the bubbler. The addition
took 40 min and the resulting mi~;ture was stirred at ice-
bath temperature for additional 50 min, during which the
pH rose from 0.97 to 1.97. Dichl.oromethane (250 mL) was
added and the resulting mixture was stirred for 15 min.
The top aqueous layer was removed and replaced with 112
mL of water. To this was added ~1.3g (28.8 mmol) of
nBu4NBr, 48.1 g of p-nitrobenzyl. bromide (223 mmol), and
approximately 95 mL of 45o aqueous K3P04 to bring the pH
to 7.3. The resulting mixture was stirred at room
temperature (22 °C) for 17 h, while keeping the pH at
7.0-7.3 using 45~ aqueous K3P0~ and an automatic titrator.
The top aqueous layer was removed by suction and replaced
with 168 mL of MeOH. The CH2C12-:MeOH solution was cooled
to 8°C, treated with dropwise addition of nBu3P (77mL,
310 mmol), stirred at room temperature for 30 min, and
then cooled to 0°C. Peracetic acid (92 mL, 32~ in dilute
acetic acid, 437mmo1) was added over 55 min, maintaining
the temperature below 6°C. The mixture was stirred at
5°C for 20 min, washed sequentially with 100 mL of 5 $
NaHS03 (to give a negative peroxide test), 100 mL of 5 0
NaHC03, and 100 mL of brine; and concentrated to give 152
g of a thick slurry, which was crystallized from 150 mL
of hot MeOH. After cooling down to 0°C, the solid was
filtered, washed with 150 mL of cold MeOH, and dried in
vacuo at 45°C to give 33.8 g (43~c) of the title compound
as a white solid.
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IR (IiBr) : n = 3000, 1791, 1755, 1526, 1348, 1182 cm-1.
1H NMR (d6DMS0) : d = 1. 17 (s, 3H) , 1 .57 (s, 3H) , 3.04 (dd,
1H, J = 16, 2 Hz) , 3.46 (dd, 1H, J = 5, 16 Hz) , 4.42 (s,
1 H) , 5. 34 (dd, 1H, J = 2, 5 Hz) , 5.39 (s, 2H) , 7.72 (d,
2 H, J = 8 Hz) , 8.27 (d, 2 H, J ---- 8 Hz) .
isC NMR (d6DMS0): d = 15.39, 17.78, 35.50, 64.93, 65.83,
70.43, 72.97, 123.62, 124.90, 142.82, 147.31, 167.89,
171.70.
C15H16N2~6S calc. C 51.13H 4.58N, 7.955 9.10
(352.37) found 51.12 4.65 7.8Ei 8.83
The principles, preferred embodiments and modes of
operation of the present invention have been described in
the foregoing specification. The invention which is
intended to be protected herein, however, is not to be
construed as limited to the particular forms disclosed,
since they are to be regarded as illustrative rather than
restrictive. Variations and changes may be made by those
skilled in the art without departing from the spirit of
the invention.
