Note: Descriptions are shown in the official language in which they were submitted.
115Z~382
This invention relates to a new chemical process, and to
new chemical compounds useful as intermediates in said process.
More particularly, it relates to a new chemical process for the
prepaxation of penicillanic acid l,l-dioxide and esters thereof
readily hydrolyzable in vivo. Said new chemical process comprises
oxidation of a 6-halo derivative of penicillanic acid, or ester
thereof readily hydrolyzable in vivo, to the corresponding l,l-
dioxide, followed by dehalogenation. Said new chemical compounds
useful as intermediates are 6-halo derivatives of penicillanic
acid l,l-dioxides and esters thereof readily hydrolyzable ln vivo.
Penicillanic acid l,l-dioxide and esters thereof readily
hydrolyzable in vlvo are useful as beta-lactamase inhibitors and
as agents which enhance the effectiveness of certain beta-lactam
antibiotics when the latter are used to treat bacterial infections
in mammals, particularly humans. Previously, penicillanic acid
1,1-dioxide and esters thereof readily hydrolyzable in vlvo have
been prepared from 6-bromopenicillanic acid, or ester thereof
readily hydrolyzable in vivo, by debromination to give
penicillanic acid, or ester thereof readily hydrolyzable ln vivo,
followed by oxidation to the l,l-dioxide. Although the process
of the present invention starts with a 6-halopenicillanic acid,
or ester thereof readily hydrolyzable in vivo, and involves the
steps of dehalogenation and oxidation, surprisingl~ it is found
that, if the oxidation step is performed before the dehalogenation
step, a better yield of product is obtained. See Belgian Patent
No. 867,859, granted December 6, 1978; and West German Offenlegungs-
schrift No. 2,824,535 for details of methods of preparing penicil-
lanic acid l,l-dioxide and esters thereof readily hydrolyzable
in vivo.
~`1 -1-
~ .
,
9 Sz~ ~ Z
~2-
6-Halopenicillanic acid~ h~ve be.en disclosed ~y
Cignarella et al~, ournal af Qx~anic Chemistry~ 27~
2668 (1~6:2~ and in United $tates; Patent No. 3,2Q6~6~;
hydrogenolysis of 6-halopenicIllani:c acids to penicillanic
acid is disclosed in British Patent Specification No.
1,Q72,lQ8.
Harrison et al., ournal of the Chemical Society
(London), Perkin I, 1772 ~76L disclose; ~a2 the
oxidation o~ 6,6-d;~romopenicillanic acid with 3-
chloroperbenzoic acid, to give a mixture o$ the corres-
ponding alpha- and beta-sulfoxides; o~I oxidation of
methyl 6,6-dibromopenicillanate with 3-chloroper~enzoic
acid to give a methyl 6,6-dibromopenicillanate 1,1-
dioxide; (cl oxidation of methyl 6-alpha-chloropenicil-
lanate with 3-chloroperbenzoic acid, to give a mixture
of the corresponding alpha- and beta-sulfoxides; and
(d) oxidation of methyl 6-bromopenicillanate with 3-
chloroperbenzoic acid, to give a mixture of the corres-
ponding alpha- and.beta-sulfoxides.
Clayton, Journal of the Chemical Society (London~,
(C), 2123, (1969), discloses: (a) the preparation of
6,6-dibromo- and 6,6-diiodopenicillanic acid; C~2 oxida-
tion of 6,6-dibromopenicillanic acid with sodium periodate,
to give a mixture of the corresponding sulfoxides; (c2
25 hydrogenolysis of methyl 6,6-dibromopenicillanate to give
methyl 6~alpha-bromopenicillanate; (d2 hydrogenolysis
of 6,6-dibromopenicillan;c acid, and its methyl ester,
to giye penicillanic ac;~d and its methyl ester,
respectively; and (el hydxQgenolysi$. of a ~;~xture.of
30 methyl 6,6-dIiodopenLcillanate and methyl 6-alpha~
odopenicillanate to give pure me.thyl 6-alp~a-
iodopenIcillanate..~
~ ThIs ~nvention relates to a process ~or the
;: - prepar~tion of a compound of tn~ formula
H Q"~ ~CH3
~CN~"~ 3 1 ~ ~ -(I)
. .
... .
.
-
" . ' ' ' ' '
: . ,
.. ~ .
115Z982
or a pharmaceutically-acceptable base salt thereof, wherein Rl is
select:ed from the group consisting of hydrogen and ester-forming
residues readily hydrolyzable in vivo, which comprises the steps of:
(a) contacting a compound of the formula
Y H
X", ` cH33 ---(II)
COOR
or a base salt thereof with a reagent selected from the group
consisting of alkali metal permanganates, alkaline earth metal
permanganates and organic peroxycarboxylic acids, to give a
compound of the formula
~N ~ ~, 3
COOR ---(III)
or a base salt thereof, wherein X and Y are each selected from the
group consisting of hydrogen, chloro, bromo and iodo, with the
proviso that either X or Y, but not both, must be hydrogen; and
(b) dehalogenating the compound of formula III.
A preferred way of carrying out step (b) comprises
contacting the product of step (a) with hydrogen, in an inert
solvent, at a pressure in the range from about 1 to about 100
kg/cm2, at a temperature in the range from about 0 to about 60C., .
and at a pH in the range from about 4 to about 9, and in the
-3-
' ' ' :
'~
115~9~Z
presence of a hydrogenolysis catalyst. The hydrogenolysis catalyst
is usually present in an amount from about 0.01 to about 2.5
weight-percent, and preferably from about 0.1 to about 1.0
weight--percent, based on the compound of formula III.
The preferred value for X and Y is bromo, and the
preferred reagents for carrying out step (a) are potassium
permanganate and 3-chloroperbenzoic acid.
This invention relates to the preparation of compounds
of the formula I, and to several intermediates therefor.
Throughout this specification, these compounds are named as
derivatives of penicillanic acid, which is represented by the
following structural formula:
H CH
3 ---(IV)
N
COOH
In derivatives of penicillanic acid, broken line attachment of a
a substituent to the bicyclic nucleus indicates that the
substituent is below the plane of the nucleus. Such a substituent
is said to be in the alpha-configuration. Conversely, solid line
attachment of a substituent to the bicyclic nucleus indicates
that the substituent is above the plane of the nucleus. This
latter configuration is referred to as the beta-configuration.
Thus, the group X has the alpha-configuration and the group Y has
the beta-configuration in formula II.
~ .
~ " . ' '' : ':'. :. ,
'1~529~3Z
--5--
In this, speci~ica,tion,,when Rl is. an estex-
forming residue readi,ly hydrolyza~le In v~Yo~ it is a
grouping which.is notionally de~,ived from an alcohol
of the formula Rl-OH, such.that the moiety COORl in
such.a compound o~ form,ula I represents an es.ter
grouping. Moreover, Rl is of s,uch.a nature that the
grouping COORl is readily cleaved in vivo to li~erate
a free car~oxy group t:COOH~. T~at is to say, Rl is a
group of the type that when a compound of formula I,
wherein Rl is an ester-forming residue readily
hydrolyzed in vivo, is exposed to mammalian ~lood or
tissue, the. compound of ~ormula I~ w.herein Rl is
hydrogen, is read~ly produced. The. groups Rl are
well known in t~e penicillin art. In most instances,
they improve the absorption characteristics of the
penicillin compound. Additionally, Rl should ~e of
such a nature that it imparts pharmaceutically-
acceptable properties to a compound of formula I,
and it liberates pharmaceutically-acceptable fragments
when cleaved in vivo. The groups Rl are well known
and are readily identi$ied by those skilled in the
penicillin art. See, for example, ~est German
Offenlegungsschri~t No. 2,517,31~. Speci~ic examples
of groups for Rl are 3-phthal;dyl, 4-crotonolactonyl,
gamma-buty~olacton-4-yl and groups o~ the formula
: R O R2 O
: ,C-o-c-R4 and ~C-o~c~O~R4
~3 R3
V VI`
wherein R2 and R3 are each.se?ected from th~ group
consIsting of hydrogen and alkyl~having from 1 to 2
carbon atoms, and R4 is alkyl h~ ng from 1 to 5
carbon atoms. Howe~er, preferred groups for Rl are
5 ` "Jl
~ ..
~1 ~ZgBZ
~6~
alkanoyloxymethyl having fro~ 3 to 7 carbon atcms,
l-(alkanoyloxylethyl ha~in~ from 4 t~ 8 carbon
atoms, l~methyl-l-(alkanQyloxy~ethyl having fr~m 5
to 9 carbon atoms, alkjoxycarbonyloxymethyl having
S from 3 to 6 carbon atoms, l~lkoxycarbonyloxy~ethyl
having from 4 to~7 car~on atoms, l-methyl-l-alkoxy-
carbonyloxy)ethyl having $rom 5 to 8 carbon atoms,
3-phthalidyl, 4-crotonolactonyl and gamma~buty-
rolacton-4-yl.
3-Phthalidyl, 4-crotonolactonyl and gamma-
butyrolacton-4-yl refer to structures VII, ~III and
IX. The wavy~lines are intended to denote either of
the two epimers or a m~.xture thereo~.
0~ ~o~ 0~
O O O
VII VIII IX
Step (a) of the process of this invention
involves o~idation of the sulfide grouping in a
compound of the formula II to a sulfone grouping,
thereby prod~cing a compound of the formula III. A
wide variety of oxidants known in the art for the
oxidation of sulfides to sulfones can be used for
this process. However, particularly convenient
reagents are alkali metal permanganates such as
sodium and potassium permanganate; alkaline earth
metal permanganates, such as calcium and barium
~: 25 perman.ganates; and organic perox~carboxyltc ac~ds,
~uch ~s perac~iD acld ard 3-chloroperDeDzolc ac~d.
:
~529~Z
--7--
When a compound of the formula II, wh.erein X, Y
and Rl are as defined preyiou~ly, is oxi~diz.ed to th.e
correspondipg compouna of the formula III, using a
metal permanganate, the react;on is usually carried
out ~y treating t~e compound of the ~ormula II w~th
from about 0.5 to about ten molar e~uivalents, and
preferably from about one to about four molar equivalents,
of the permanganate in an appropriate, reaction-inert
solvent system. An appropriate, reaction-inert solvent
system is one that does not adversel~ interact
with either t~e starting materials ox the product,
and water is commonly used. I~f des~red, a co-
solvent which is misc~.ble w.Xth ~ater ~ut ~ill n~t
interact with.the permanganate, such as tetrah.ydro-
furan, can be added. T~e reaction can be carr~edout at a temperature in the. range from about -30 to
about 50C., and it is preferably carried out from a~out
-10 to about 10C. At about 0C. the react;on is normally
substantially complete within a short period, e.g.
within one hour. Although.the reaction can be
carried out under neutral, basic or acid conditions,
it is preferable to operate at a pH ~n the range from
about 4 to about 9, perferably 6-8. Ho~ever, it is essen-
tial to choose cond;tions which avoid decomposition of
the beta-lactam ring system of the compound of the
ormulae II or III, Indeed, it is often advantageous
to buffer the pH of the reaction medium in the
vicinity of neutrallty. T~e.product is recovered by
conventional techniques. Any excess permanganate is
usually decomposed using sodium bisul~ite, and then
~ if the product is out o~ solution, it ~5 xecovered
: ~y~filtration. It is separated from m.an~anese
~ dioxide ~y extracting it into an organic solvent and
~5Z~Z
-8~
removing the solvent by evapoXation. Alternatively,
if the product is not out Q~ solution at th~ end of
the reaction, it is isolated by the usual procedure
of sol~ent extraction.
When a compound of the formula II wherein X, Y
and Rl are as previously defined, is oxidized to the
corresponding compound o~ the formula III usin~ a
peroxycarboxylic acid, the reaction is usually
carried out by treating the compound of the ~ormula
II with from about 1 to a~out 6 molar equivalents,
and preferably about 2.2 molar e~uivalents of the oxidant
in a reaction-inert organic solvent. Typical solvents
are chlorinated hydrocar~ons, such as dichloromethane,
chloroform and 1,2-dichloroethane; and ethers, such
as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane.
The reaction is normally~ carried out at a temperature
of from about -30 to about 50C,, and preferably from
about 15 to about 3QC. At about 25C., reaction times
of about 2 to about 16 hours are commonly used. T~e
product is normally isolated by removal of the solvent
by evaporation ln vacuo. The reaction product can be
purified by conventional methods, well known in the
art. Alternatively, it can be used directly in step
(b) without further puri~ication.
Step (b) of the present process is a dehalogena-
tion reaction. One con~enient method of carrying out
this transformation is to stir or shake a solution of
a compound of the ~ormula III under an atmosphere of
hydrogen, or hydrogen mixed with an inert diluent
such as nitrogen or axgon, ~n the PXesence o~ a
hydrogenolysis catalyst. Suita~le sol~ents ~or th~s
~y~rogenol~is ~eactio~ a~e t~ose whic~ su~tantl~all~
:
.
'
~lSZ982
g
dissolve th.e starting comp~und Qf the fQxmula III hut
which do not thems~lves suf~er hydrogenatian QX
hydrogenoly~is. Example.s Q~ such s~l~ents include
ethers such as diethyl et~er, tetra~ydrofuran,
dioxan and 1,2-dimethoxyethane; 1Q~ molecular we;ght
e.sters such as ethyl acetate. and butyl acetate;
tertiary amides suc~ as NrN~dimethylformamIde~ N,N=
dimethylacetamide and N-methylpyrrolidone; water; and
mixtures thereof. Additionally, it 's usual to buffer
the reaction mi~ture so as to 4perate at a pH ~n the
range from about 4 to 9, and preferably from a~out 6 to 8.
Borate and phosphate ~uffers axe commonly used. Intro-
duction of the hydrogen gas into the reaction medium is
usually accomplished by carrying out th.e reaction in a
sealed vessel, containing the compound of formula III~
the solvent, the catalyst and the hydrogen. T~e
pressure inside the reaction vessel can vary from
about 1 to about 100 kg/cm2, The preferred pressure
range, when the atmosphere ins;de the reaction
vessel is substantially pure hydrogen, is ~rom about
2 to about 5 kg/cm . The hydrogenolysis is generally
run at a temperature of from a~out Q to a~out
60C., and preferably from about 25 to a~out 50C.
Utilizing the preferred temperature and pressure
values, hydrogenolysis generally takes place in a few
hours, e.g., from ahout 2 hDurs to about 2Q hours.
The. catalysts used in this hydrogenolysis reaction
are the type of agents known in th~ art ~or this
-~ kind of transformation, and typical examples are the
3:Q no~le metaLs, suc~ as nick.el, palladium, platinum
~: and rhodium. T~e catalyst is usually present ~n an
amount from a~out Q.~l to abo.ut 2.5 ~e~ght-percent,
l~SZ9132
and preferably from about 0.1 to about 1.0 weight-percent, based on
the compound of formula III. It is often convenient to suspend the
catalyst on an inert support; a particularly convenient catalyst
is palladium suspended on an inert support such as carbon.
Other methods can be used for reductive removal of the
halogen from a compound of formula III, i.e. step (b). For
example, X and Y can be removed using a dissolving metal reducing
system, such as zinc dust in acetic acid, formic acid or a
phosphate buffer, according to well-known procedures. Alter-
natively, step (b) can be carried out using a tin hydride, forexample a trialkyltin hydride such as tri-_-butyltin hydride.
As will be appreciated by one skilled in the art, when
it is desired to prepare a compound of the formula I, wherein Rl
is hydrogen, a compound of the formula II, wherein Rl is hydrogen,
can be subjected to steps (a) and (b) of the process disclosed
herein. In other words, the process comprises oxidation, followed
by dehalogenation, of a 6-halo derivative of penicillanic acid
with a free carboxy group at the 3-position. However, in a
further aspect of this invention, it is possible to begin either
of steps (a) and (b) with the carboxy group at the 3-position
blocked by a conventional penic~llin carboxy protecting group.
The protecting group can be removed during or after step (a) or
step (b), with regeneration of the free carboxy group. In this
regard, a variety of protecting groups conventionally used in the
penicillin art to protect the 3-carboxy group can be
--10--
.,; ....
.
.
,
~1529~32
employed. The major re~uLrementS ~or the p~tecting
group are that it must ~e. attac~a~le.to t~e parti.cular
compound of ~ormula II~or ~ and xe~o~le ~rom the
part~culax compound o~ ~or~ula I~or I~2~ usin~ conditions
under wh~:ch th~ ~eta-lactam rin~ s.yste~ remai~ns su~stan-
tially intact. For each o~ steps ~L and ~, typical
examples are the tetra~ydropyranyl group, trial~ylsilyl
groups, the benzyl group, substituted benzyl groups
(e.g. 4-nitrobenzyll~ the ~enzhydryl group, the 2,2,2-
10. tri-chloroethyl group, the t~utyl group and the phenacyl
group. ~lthough all protecting groups are not opera~le
in all situations a particular group w~ch.can be used
in a part;cular situatton ~ill ~.e.readily selected by
one skilled in the art. See ~urther: United States
Patents 3,632,850 and 3,197,466; British Patent No. 1,041,985,
Woodward et at, Journal of the American Chemical Society,
_
88, 852 (1966); Chauvette, Journal of Organic Chemistry,
36, 1259 (1971~: Sheehan et al. Journal of Organic
Chemistry, 23, 2006 (1964); and "Cephalosporin and
Penicillins, Chemistry and Biology~, edited-by
H. E. Flynn, Academic Press, Inc., 1972. The penicillin
carboxy protecting group is removed in con~entional
manner, ha.ving due regard $or the lability o~ t~e
beta-lactam ring system.
The compounds of formula I, II and III, wherein Rl is
hydrogen, are acidic and Will ~orm salts with ~asic agents.
These salts can ~e prepared ~y standard techniques, such as
contacting t~e ac~dic and ~aai.c components, us~ally in
a stoàchiometr~'c ratio, in an a~ueous, non-aqueous or
: 30 part~ally a~ueous medau~, as appxQpri~te. Th y axe
then recovered ~ lt~at~on, ~y precip~tation ~ith a
non-solvent followed ~y f~ltration, ~y evapo~at-~on of
.
,
.
.
.
~52~}2
~12~
the solvent, or in the case ~f a;~ueous solutiQns, by
lyophilization, as appropXiate. Basic a~ents ~ich are
suitably em.ployed In s.alt formation b.elong to ~oth.the
organic and inorganic types, and they include.ammonia,
organic amines, alk.ali metal hydroxides, carbonates,
b~carbonates, hydrides and alkoxides, as well as alkaline
earth metal hydroxides, carbonates, hydrides and alkoxides.
Representattve. examples of such.bases are primary
amines, such as _-propylamine, n-butyla~Ine, aniline,
cyclohexylamine, benzylamine and octylamine; secondary
amines, such as diethylamine, morpholine, pyrrolidine
and piperidlne; tert~ary amines, such as triethylamine,
N-ethylpiperidine, N~methylmorpholine and 1,5-dia-
zabicyclo~4.3.0]non-5-ene; hydroxides, such as sodium
hydroxide, potassium hydrox;~de, ammoniu~ hydroxide and
barium hydroxide.; alkoxides, such as sodium ethoxide
and potassium ethoxide; hydrides, such as calcium
hydride and sodium hydride; carbonates, such as potas-
sium carbonate and sodium carbonate; bicarbonates, such
as sodium bicarbonate and potassium bicarbonate; and
alkali metal salts o~ long-chain fatty acids, such as
sodium 2-ethylhexanoate. Preferred salts of the com-
pound of the formula I are the sodium, potassium and
triet.hylamine salts~ -
The compound o~ ~ormula I, wherein Rl is hydrogen,
and the salts thereof is active as an antibacterial
agent of medium potency ~oth.in vItro and in vivo, and
the compounds of formula I~ w~erein Rl ;~s an ester-
~orming residue readily hydr~l~za~le ln o F are active
as antibacter~al agents of medium ~Qtency ~n VIVq~
~inimum inhi~i:tory concentrations (~IC~s~ o~ penicillanic
acld l,l-dioxide against several microqrga.nI.sms are
s~own in Ta~le I.
..
.
:.... . . - . - ' :
,. . . . , :
.
.
llSZ9~32
-13~
TABLE I
In ~Itro Antibacterial Activ~ty
of ~en~ci-llan~c Acid l,l-Di~x~;dè
MicroorganismMIC (mcg.~ml~
5 Staphylococcus aureus lQa
Streptococcus faecal~s20.Q
Streptococcus pyogeneslOQ
Escherichia coli 5a
Pseudomonas aeruginosa2QQ
lO Klebsiella pneumoniae 5Q
Proteus mirabilis lO0
Proteus morganl lOa
Salmonella typhimurium50
Pasteurella multocida 50
15 Serratia marcescens lOQ
Enterobacter aerogenes25
Enterobacter clocae laO
Citrobacter fre.undii50
: : ~ Providencia lQQ
; 20 Staphylococcus epidermIs2QQ
~ Pse.udomonas putida 2QQ
: Hemophilus influenzae5Q
~; ~; Ne~se ~a gonorr~oeaeQ,312
,.......... . - . . :
. .
: ' ' , ' ',
:
~ ~5~Z982
-14-
The ln yitro anti~acte~ial actiy~ty of the
compound of the formula ~! w~he~ein Rl I~ fiydro~en, and
its salts, makes th~m useful as industrial an=
timicrobials, for example in water treatment, slime
control, paint preservation ~nd wood preservatron, as
well as for topical application as disinfectants. In
the case of use of t~ese compounds for topical appli-
cation, it is often convenient to adm;~x the active
ingredient wIth a non-toxic carrier, such as vegeta~le
I0 or mineral oil or an emollient cream. S~milarly, it
can be dissolved or dispersed in liquid diluents or
solvents such as water, alkanols, glycols or mixtures
thereof In most instances it is appropriate to
employ concentrations o~ the active ingredient of
from about 0.1 percent to a~out 10 percent by weight,
based on total composition.
The in v;`vo activity of the compounds o~ formula
I wherein Rl is hydrogen or an ester-forming residue
readily hydrolyzable in vivo, and the salts thereof,
makes them suitable for the control of hacterial
infections in mammals, including man, by both the
oral and parenteral modes of administration. The
compounds will find use in the control of infections
caused by susceptible bacteria in human subjects,
e.g. infections caused by strains of Neisseria gonorrhoeae.
When considering therapeutic use of a compound
of the formula I, or a salt t~ereof, in a mammal,
particularly man, the compound can be adm;nistered
alone, or it can be mixed ~ith pharmaceutically
3Q acceptable caxr~ers or diluents. ~t can fie adm~nistered
orall~ or parenterally, ~.e. intra~us:cularly, suB-
cut~ne~usly or intraperitoneally~ Tfie caxrier or
diluent is cho~en on the bas~s of the ;~ntended
.
, - . .:
-.
1~5298Z
~15-
mode of a&inistration. Por example, ~hen consider-
ing the. oral mode of adminIstration, t~ compound can
be used in the. ~orm of tablets, caps.ules, lozenges,
troche.s, po~ders, syrups, el~xirs, aqueous solutions
and suspensions, and the lik.e, in accordance with.
standard pharmaceutical practice. The proport~onal
ratio of active ~ngredient to carrier ~ill depend on
the chemical nature., solubi.lity and sta~ility of the
active ingredient, as well as the dosage contem-
plated. However, pharmaceutical compositions con-
taining an antibacterial agent of the formula I ~ill
likely contain ~rom about 20% to a~aut ~5% of active
ingredient. In the case o~ ta~lets for oral use,
carriers which are commonly used include lactose,
sodium citrate and salts of phosphoric acid. ~arious
disintegrants such as starch., and lubricating agents,
such as magnesium stearate, sodium lauryl sulfate and
. talc, are commonly used in tablets. For oral admin-
istration in capsule form, useful diluents are lactose
and high molecular weight polyethylene glycols. When
aqueous suspens.ions are required for oral use, the
active ingredient can fie combined with emulsi~ying
and suspending agents. If desired, certain sweeten-
ing and/or ~lavoring agents can ~e added. For
parenteral admi~istration, which includes intramus-
cular, intraperitoneal, su~cutaneous and intravenous
use, sterile solutions of the actiVe ingred~ent are
usuall~ prepared, and the. pH of the solut~ons are
suitably adjuste.d and ~uffexed~ ~or intra~enous use,
30.:~ the total concentration af solutes s:hould ~e con-
trolled to render th~ prepa~at~.~n ~Sotonic.
Th~ p~escr~in~ p~s~cian wXll ulti~ately deter-
mine. the appropriate dose o~ a compound of ~or~ula I
for a giYen human su~ject, and th~s can fie expected
: 35 to vary according to the age, weig~t, and rasponse of
the individual patient, as well as the nature and the
.
. ' ~ . . ,
~lSZ~82
~16-
severity o~ the patientls s~m,ptoms, The compound
will normally be used orally at dQs,ages- ~n t~e xange
from about 10 to aBout 2QQ m~. per k;~,logram ~ bQdy
weight per day, and parente~all~ at dosages ~r~m
about lQ to a~out 4QQ mg. per ~logra~ o~ body weig~t
per day. These figures are illustrati,~e only, ~owever,
and in some cases it may ~e necessaxy to use dosages
outside these l~mits.
The compounds of the formula, I~ ~herein Rl is
hydrogen or an ester-forming residue readily hydro-
lyzable _ ~ivo, or a salt thePeaf, enhance the anti-
bacterial effectiveness of beta-lactam antibiotics in
vivo. They lo~er the amount o~ the antibiot;~c which
is needed to protect mice aga;nst an otherwise
lethal inoculum of certain beta-lactamase,producing
bacteria. This ability makes them valuable for co-
administration with beta-lactam antibiotics in the
treatment of bacterial infections in mammals, parti-
cularly man. In the treatment of a bacterial in-
fection, said compound of the formula I can be com-
ingled with the beta-lactam antibiotic, and the two
agents thereby administered simultaneously. Alterna-
tively, said compound o~ the formula I can be admin-
istered as a separate agent during a course of
treatment with a beta-lactam antibiotic. In some
instances it is advantageous to pre-dose the subject
with the compound of the formula ~ b,efore initiating
treatment with a ~eta-lactam antib;otIc,
When using pen~cillanic acid l,l-d~o~de, a salt
or~an ester th~reaf read~ly hydxolyzable i~n ~ivo to
enhance the effectiveness Q~ beta-la,cta,m antibiotic,
it,is admin~stered preferabl~ in ~ormulatiQn w~t~
standard p~armaceutical car~i~ers Q~ diluents~ The
methods o~ ~ormulat~on d~scuss~ed earlier for use of
penicillanic ac;~d 1,1-di~xide or an ester t~ereo~
readily ~ydrol~z~le in V~VO 55 a 5ingle-entity
' ~
~` , '
:
llS2~1~2
antibacterial agent can he u~ed when c~-adminIstration
with another beta~lactam antib~otic ~5 intended. A
pharmaceutical composition co~pris;in~ a pharmaceutically-
acceptable carrier, a beta~lactam anti~iot;~c and
penicillanic acid l,l-dioxide or a readil~ hydrolyzable
ester thereof will normally contain from a~out 5 to
about 80 percent of the pharmaceutically accepta~le
carrier by weight.
When using penicillanic acid l,l~dioxide or an
ester thereof read~ly hydrolyzable in vivo in com~ina-
tion with another beta-lactam antibiotic, t~e sulfone
can be adm;~n;stered orally or parenterally, I. e.
intramuscularly, subcutaneou~ly or intraper-~toneally.
Although the prescribing physician will ultimately
decide the dosage to be used in a human suBject, the
ratio of t~e daily dosages of the penicillanic acid
l,l-dioxide or salt or ester thereof and the beta-
lactam antibiotic will normally be in the range from
about 1:3 to 3:1. Additionally, when using penicil-
lanic acid l,l-dioxide or salt or ester thereof
readily hydrolyzable in vivo in combination with
another Beta-lactam antibiotlc, the daily oral dosage
of each component will normally be in the range from
about lQ to about 200 mg. per kilogram of body weight
and the daily parenteral dosage of each component
will normally ~e a~out lQ to a~out 4~0 mg. per
kilosram of bod~ weight. These figures are illus-
trative only, howe~er, and in some cases it may ~e
neces$ar~ to use dosages~ outside t~ese lim~ts.
3Q Typlcal heta-lactam anti~iotics~ ~it~ w~ic~
peni~c~ nic acid l,l-d~oxide and itS estexs read~ly
hydrolyzafile ~n ~IyO can Be co~administered are;
2-phenylacetam~dQlpenicillani~c acid,
6-(P-2-am~no-2-phen~lacetamidoLpenicillan~c
acid,
,~
115;29E3Z
-18-
6-(2-carboxy~2-phenylaceta~dQLpenicillanic
acid, and
7-(2-Il-tetrazolyl]acetamidoI~3-(2~I5-methyl-
1,3,4-thIadiazolyl]thiomethyl~-3-desacetoxymethyl-
cephalosporan;c acid.
Typical microorganisms a.gainst whic~.t~e anti-
~acterial activity o~ the abo~e beta-lactam anti~iotics
is enhanced are:
Sta.phylococcus aureus~
Haemophilus influenzae
r
Klebsiella pneumoniae and
Bactero~des fragilis
As will be apprec~ated ~y one sk~lled in t~e
art, some beta-lactam compounds are ef~ective ~hen
administered orally or parenterally, while ot~ers are
effective only when administered by t~e parenteral
route. When penicillanic acid l,l-dioxide, a salt or
an ester thereof readily hydrolyzable ln vivo, is to
be used simultaneously ~i.e. co-mingledl with a beta-
lactam antibiotic which is effective only on parenteraladministration, a combination formulation suitable
for parenteral use will be required. When the penicil-
lanic acid l,l-dioxide or ester thereof is to be used
simultaneously (co-mingledl with a beta-lactam
~ 25 antibiotic which.is effect~ve orally or parenterally,
: ~ combinations suitable for either oral or parenteral
: administration can be. prepared. Addit;~onally, it is
~: possible to admin~ster preparat~.ons o~ the penIcillanic
acid l,l~diox~de or .salt ox estex thexeo~ oxally,
3Q while at the same:ti~e admin~ste~ng a ~urt~er beta-
: lactam ant~fiiotic parenterally; and ~t is also
: possible to adm~nl~.tex prepaxati~ns Q tA~ penicIllanic
acid l,l-dLoxide or salt or estex thereo~ parenterally,
.
~ ,~
,, . . ' .
. ' '` ' .
~ 5~2
while at the same time administering the further beta-lactam antibiotic orally.
Further details concerning the use and synthesis of compounds of
the formula I are disclosed in West German Offenlegungsschrift No. 2,824,535.
6-alpha-Chloropenicillanic acid and 6-alpha-bromopenicillanic acid
are prepared by diazotization of 6-aminopenicillanic acid in the presence of
hydrochloric acid and hydrobromic acid, respectively (Journal of Organic
Chemistry, 27, 2668 [1962]). 6-alpha-Iodopenicillanic acid is prepared by
diazotization of 6-aminopenicillanic acid in the presence of iodine, followed
by hydrogenolysis (Clayton, Journal of the Chemical Society~C), 2123 [1969]).
6-beta-Chloropenicillanic acid, 6-beta-bromopenicillanic acid and 6-iodo-
penicillanic acid are prepared by reduction of 6-chloro-6-iodopenicillanic
acid, 6,6-dibromopenicillanic acid and 6,6-diiodopenicillanic acid, respective-
ly, with tri-n-butyltin hydride. 6-Chloro-6-iodopenicillanic acid is prepared
by diazotization of 6-aminopenicillanic acid in the presence of iodine
chloride; 6,6-dibromopenicillanic acid is prepared by the method of Clayton,
Journal of the Chemical Society (London) (C) 2123 ~1969); and 6,6-diiodo-
pencillanic acid is prepared by diazotization of 6-aminopenicillanic acid in
the presence of iodine,
The following examples and preparations are provided solely for the
purpose of further illustration. Infrared (IR) spectra were measured as
potassium bromide discs (KBr discs), and diagnostic absorption bands are
reported in wave numbers (cm ). Nuclear magnetic resonance spectra (NMR)
were measured at 60 M~lz for solutions in deuterochloroform ~CDC13), perdeutero
acetone (CD3COCD3), perdeutero dimethyl sulfoxide ~DMSO-d6) or deuterium oxide
(D20), and peak positions are expressed in parts per million (ppm) downfield
from tetramethylsilane or sodium 2,2-dimethyl-2-silapentane-5-sulfonate. The
following abbreviations for peak shapes are used: s, singlet; d, doublet;
t, triplet; q, quartet; m, multiplet.
. ,~
. . -- 19 --
,
11~2~2
~20~
ExAMRLE 1
6-al~ha-Bromopenicillanic Acid l,l~-~Dioxide
To a st~red mi~xture of 560 ml o~ water, 3QQ ml o~
dichloromethane and 56.0 ~ o~ 6-alpha-~romopenic~llanic
S acid was added 4N sod~u~ h~ydxoxide solution until a
stable pH of 7.2 was achieved. This required 55 ml o~
sodium hydrox~de. The mixtuxe was stirred at pH 7.2 for
10 m~nutes and then it was filtered. The layers were
separated and the organic phase was d~scarded. Tne
aqueous phase was then poured rapidl~, w~th stirring,
;nto an oxidizing mixture ~hich had been pxepared as
follows.
In a 3 l~ter flask was mixed 63.2 g o~ potassium
permanganate, 1,000 ml of water and 48.Q g of acetic
acid. This mixture was stirred ~or 15 minutes at 20 C.
and then it was cooled to 0 C.
After the 6-alpha-bromopenicillanic acid solution
had been added to the oxidizing mixture, a cooling bath
at -15 C. was maintained around the reaction mixture.
The internal temperature rose to 15 C. and then fell to
5 C. over a 20 minute period. At this point, 30.0 g of
sodium metabisulfite was added with stirring over a
10 minute period at about lQ C. After a ~urther 15
minutes, the mixture was filtered, and the pH of the
filtrate was lowered to 1.2 by the addition of 170 ml of
6N hydrochloric acid. The aqueous p~ase was extracted
with chloroform, and then ~ith ethyl acetate. Both the
chloroform extracts and the ethyl acetate extracts were
- dried using an~ydrous ~agnesiu~ sulfate and then they
a were e~aporated in ~acuo. T~e chlo~orm solut-~on afforded
'
:
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.
,
.
1~2~Z
-21-
10.0 g. (16% y~eld) o~ the title compound, T~e ethyl
acetate solution afford~d 57 g. o$ an oil, wh~ch was
triturated under hexane. A whIte salid appeared~ It
was filtered o~, g;~ving 41.5 ~ 66~ yieldl o~ the title
compound, mp 134~ C, (dec.~
Analysis:-Calcd. ~or C8~1Q~r~Q5S: C~ 3n.78; H,
3.23; Br, 25.60; Nt 4.4~; S! 10.27~, Found; C, 31.05;
H, 3.24; Br, 25.54; N, 4~66; S, 10.21%~
EXAMPLE 2
Oxidation of 6-alpha-chloropenicillanic acid and 6-
alpha-iodopen;cillanic acid with potass;~um permanganate,
according to the procedure of Example 1, affords 6-
alpha-chloropenic;llanic acid l,l-diox~de and 6-alpha-
iodopenicillanic ac;~d l,l-d;oxide, respecti~ely.
EXANPLE 3
6~beta-Chloropenicillanic Acid l,l-Dioxide
An oxidizing solution was prepared from 185 mg. of
potassium permanganate, Q.063 ml. of 85% phosphoric acid
and 5 ml. of water. This oxidizing solution was added
dropwise to a solution of 150 mg. of sodium 6-beta-
chloropenicillanate in 5 ml. of water at 0-5 C., until the
purple color of the potassium permanganate persisted.
Approximately half of the oxid;zing solution was required.
At this point, the potassium permanganate color was
discharged by the addition of solid sod~um bisulfite,
and then the reaction mixture ~as filtered. Ethyl
acetate was added to the filtrate and the pH was adjust-
ed to 1.8. The layers were separated and the aqueous
layer was furt~er extracted w~th ethy~l acet te. The
com~ined ethyl acetate laye~s ~e~e ~ashed w~t~ water,
dried and e~aporated ~n ~acuo to giVe 118 mg. o~ the
title compound~ Tfie NMR spectxum (ln CD3C~CD3L s~owed
", :
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'
i~%~82
-22-
absorption at 5. 82 (d~ 1~). ! 5. 24 (~ 4~ 53 (~t~ lH)
1. 62 (s ~ 3H~ and l. 5Q (5~ 3E~ p~.
The a~,ove product wa$ dissolved In tetrahydrofuran
and an e~ual volume Qf water was added. Th,e pH was
5 adjusted to 6. 8 usIng dilute sod~um hydroxi,de, t~e
tetrahydro~uran was remo~ed b~ evaporatton In vacuo r and
the residual aqueous solutiQn was ~reeze dried. T~is
afforded the sod~um salt o~ the title compound.
EXAMPLE 4
6-beta-Bromopenicillanic Acid l,l-Dîoxide
To a solution of 255 mg, of sadium 6-~eta-~romo-
penicillanate ;n 5 ml. of water, at Q to 5a C. ~ was added a
solution prepared from 14Q m~ of potassium permanganate,
0.11 ml. of 85% phosphoric acid and 5 ml. of water, at Q
15 to 5 C. The pH was maintained ~etween 6'.~ and 6.4
during the add~tion. The reaction mIxture was stirred
at pH 6.3 for 15 minutes, and then the purple solution
was covered with ethyl acetate. The pH was adjusted to
1.7 and 330 mg. of sodium bisulfite was added. After
5 minutes, the layers were separated and the aqueous
layer was further extracted with ethyl acetate. The
combined ethyl acetate solutions were washed with brine,
dried (MgSO41 and evaporated in vacuo. This afforded
216 mg. of the title compound as white crysta,ls. The NMR
spectrum Cin D20~ showed absoxptions at S.78 Cd, lH,
J = 4HzJ, 5.25 (-d, 1~ 4~Z~f 4.2a (s, lH)~ 1.65 Cs,
3H) and 1.46 (~s, 3~ ppm~
EX~MPLE 5
6-~eta-Iodopenic~,llan~c Ac~d l,l~Diox;de
3Q Oxidation o~ 6'-~eta-iodo~enic~llani~c ac~d ~th
potass~um perman~anate, acco~d~n~ tQ tHe p~ocedure of
Example 4, af~ords 6-~eta-i~odopenicillanic acid, 1,1
di~xide~
.--
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1152982
~23-
EXAMPLE 6
Pi~aloyloxymethyl 6-alpha-E^~om4penic~ nate l,l-D~oxide
To a $olut~n o~ 3~4 m~. o~ pival~loxymethyl 6-
alpha-~romopenicillanate ~n lQ ~1. of dichloromethane is
added 400 mg. of 3-chIoroper~enzQic acid a~ Q to 5 C.
The reaction mlxture ~s stirred at a to 5 a C. ~or 1 hour
and then at 25 C~ ~or 24 ~ours. The ~ltered reaction
mixture is e~aporated to dryness ln vacuo to gIve the
title compound.
EXAMPLE 7
The procedure of Example 6 ~s repeated, except that
the pivaloyloxymet~lyl 6-beta-brQmopenicillanate acid is
replaced by:
3-phthalidyl 6-alpha-chloropenIcillanate,
4-crotonolactonyl 6-beta-chloropenicillanate,
gamma-butyrolacton-4-yl 6-alpha-bromopenic~llanate,
acetoxymethyl 6-beta-bromopenicillanate,
pivaloyloxymethyl 6-beta-bromopenicillanate,
hexanoyloxymethyl 6-alpha-iodopenicillanate,
l-(acetoxy)ethyl 6-beta-iodopenicillanate, -
l-(isobutyryloxy)ethyl 6-alpha-chloropenicillanate,
l-methyl-l-(acetoxyJethyl 6-beta-~hloropenicillanate,
l-methyl-l-(hexanoyloxy)ethyl 6-alpha-bromopenicillanate,
methoxycarbonyloxymethyl 6-alph~-bromopenicillanate,
propoxycarbonyloxymethyl 6-beta-bromopenicillanate,
l-(ethoxycarbonyloxy~ethyl 6.alpha-bromopenicillanate,
utoxycarbonyloxyleth~l 6-alpha-iodopen cillanate,
l-methyl-l-methoxycaxbonyloxyL~tRyl 6-~eta-Iodopenicil-
lanate and
l-methyl-l-r~sop~opoxyc~ony~l~xy~et~l 6-a~lpha-c~loro-
penici}lanate,
respecti~ely, Th~s~af~o~ds;
.. .
:
:
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~L52~
-24-
3-phthalidyl 6-alpha-chloropenicillanate l,l~dioxide,
4-crotonolactonyl 6-~eta-chIoropenicillanate l,l-diQx~de,
gamma~(utyrolacton-4-yl 6:-alp~ xomopenIc~llana,te 1,1
dioxide,
acetoxymet~yl 6-beta-~xomopenici~llanate 1,l-d~oxIde,
pivaloyloxymethyl 6-~et~-brqmopenic~llanate l,l-d;~oxide,
hexanoyloxymethyl 6-alpha-iodopenIcillanate l,l-d;~oxide,
l-(acetoxy)ethyl 6-~eta-Iodopen~cillanate l,l-dioxide,
l-(isobutyryloxylethyl 6-alpha-chloropenic;llanate 1,1-
dioxide.,l-methyl-l-Cacetoxylethyl 6-beta-chloropenicillanate
l,l-dioxide,
l-methyl-l-(hexanoyloxylethyl 6-alpha-bromopenicillanate
l,l-dioxide,
methoxycarbonyloxymethyl 6-alpha-bromopenicillanate 1,1-
dioxide,
propoxycarbonyloxymethyl 6-beta-bromopenicillanate 1,1-
dioxide,
l-(ethoxycar~onyloxylethyl 6-alpha-bromopenicillanate
l,1-dioxide, -
1-(butoxycarbonyloxylethyl 6-alpha-iodopenicillanate
l,l-dioxide,
l-methyl-l-(methoxycar~onyloxy~ethyl 6-beta-iodopenicil-
lanate l,l-dioxide and
l-methyl-l-(isopropoxycar~onyloxyLethyl 6 alpha-chloropen-
icillanate l,l-dioxide,
respectively,
EXAMPLE 8
Pen~c~llanic Ac~d l,l-Dio~de
lQQ. ml. of ~ater ~as~ added ~,4 g. of 6~alpha-
hrQmQpen~cillan~ic ~cid, l,l~dio~i~de, at 22Q C,, followed
: ~y su~f~cient 4N sQd~um ~ydroxide. 5qlutiQn to achieve a
sta~le p~ ~f 7.3. To t~e resulting solut;~on ~as added
2~25 g, of 5% pallad~um-on-car~on follo~ed ~y ~ g. of
:dipotacsium phoYp~ate tri~ydrete~ This mixture was then
lJ~Z~
~25
shaken under an atmos~here of h~drogen at a ~ressure
varying from 3.5 to 1.8 kg~cm . ~hen hydxo~en uptake
ceased, the. solids were ~e~oved by ~iltration, and the
aque.ous solution was covered w;~.th lQ~ ~1. o~ e.th~l acetate.
The pH was slo~ly lowered from 5.0 to 1,5 wIth 6N hydro-
chloric acld. The layers were separated, and the
aqueous phase was extracted w~ith.furt~er ethyl acetate.
The combined ethyl acetate layer~ were w.ashed with
brine, dried us;ng anh~dxous magnesium sulfate and
evaporated in vacuo. The residue wa$ triturated under
ether and then the soltd mater;al w~s collected ~y
filtration. This a~forded 4.5 g. (65% yield) of the
title compound.
Analysis:-Calcd. for C8HllNO5S: C, 41.2Q; H, 4.75;
N, 6.00; S, 13.75%. Found: C, 41.16, Hr 4.81; N, 6.11;
S, 13.51%.
EXAMPLE 9
Penicillanic Acid l!l-Dioxide
Hydrogenolysis of each of;
6-alpha-chloropenic.illanic acid l,l-dioxide,
6-alpha-iodopenicillanic acid l,l-d;.oxide,
6-beta-chloropenicillanic acid l,l-dioxide~
6-beta-bromopenicillanic acid l,l-dioxide and
6-beta-iodopenicillanic acid l,l-dioxide, ~:
according to the procedure of Example 8, affords pen-
icillanic acid l,l-d;oxide.
EXAMPLE lQ
Piv~loylox~meth~l Penicillanate l,l-D~oxide
To a solution of 1.0 g. o~ piyal~yl~xy~et~l 6-
3a alp~a-~romopeniclllanate ~n lQ ml. o~ met~anol is added
3 ml. of lM sod;~um bicaxbonat~ and 2Q~ mg. Q~ la% palladium
on car~on. T~e. re~ction m~xture ~s s~aken ~igorously
under. an ~tmosp~br~ ~ ~ydxQgen, at a pre~sure o~ a~out
- : :
~S29i8~
-26~
5 kg/cm2, until hydro~en uptake ceas~s.~ T~ m~xture is
then filtered and th~ ~ulk of th~ metnanol IS` remo~ed ~y
evaporatian in vacuo~ ~ater and eth~l acetate ~re added
to the res~due and the pH i.s. adjusted to 8.5. T~e
layers: are ~eparated and the or~anic layer IS washed
with water, dried (~a2S04~ and evaporated ~n vacuo.
This affords the title compound.
EX~MPLE 11
Hydrogenolysis of the appropriate 6-halopenicil-
lanic acid ester l,l-dioxide fro~ Ex~mple 7, according
to the procedure o~ Example lO, af~ords the following
compounds;
3-phthalidyl penicillanate l,l-dioxide,
4-crotonolactonyl penicillanate l,l-dioxide,
gamma-butyrolacton-4-yl penicillanate 1,l-d~ox~de,
acetoxymethyl penic~llanate l,l-dioxide,
pivaloyloxymethyl penicillanate l,l-dioxide,
hexanoyloxymethyl penicillanate l,l-dioxide,
l-(acetoxy~ethyl penicillanate l,l-dioxide,
l-(isobutyryloxy).ethyl penicillanate l,l-di~xide,
l-methyl-l-(acetoxylethyl penicillanate l,l-dioxide,
l-methyl-l-~hexanoyloxy~ethyl penicillanates l,l-dioxide,
methoxycar~onyloxymethyl penicillanate l,l-dioxide,
propoxycarbonyloxymethyl penicillanate l,l-dioxide,
l-(~ethoxycarbonyloxy~ethyl penicillanate l,l-dioxide
l-nputoxycarbonyl)ethyl penicillanate ~ dioxide,
methyl-l-(methoxycar~onyloxylethyl penicillanate 1,1-
dioxide and
~ l-methyl-l- ~sopropoxyc~bonylox~Lethyl pen~c~llanate ~ 30 l,l-dioxide,
respecti~ely.
:
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982
~27-
EXAM~LE 12
.
Pivaloyloxymethyl 6~A ~ QmQpeni~cillanate l!l~D~oxide
An oxidIzing solution ~as: prepaxed ~y com~in~n~
4.26 g~ o$ potassium permanganate, 2.6:5 gt Q~ 85~ phos~
phoric acid and 40 ml. of water, The ~ixture was stirred
for one houx, and then it was added slowly, during 2
minutes, at 5 to 10~ C~, to a stirred solution o~
5.32 g. o~ p~valoyloxymethyl 6~alpha~romopenicillanate
~n 70 ml. of acetone and lQ ml~ o~ water. The mixture
was stirred at 5 C, ~or 3Q minutes, and lQQ ml. of
ethyl acetate was added. After a $urther 3Q m~nutes,
a solution o~ 3.12 g. o~ sodium ~isul~ite in 3Q ml. o~
water was added during 15 m~nutes at a~out la C,
Stirring was continued for anot~er 3Q m~nutes at 5 C.,
and then the mixture was ~ltered. The organic phase
was separated and washed ~ith saturated sodium chloride
solution. The dried organic layer was evaporated to
give 5.4 g. of the title compound as an oil, which
slowly crystallized. The NMR spectrum (in CDC1
showed absorptions at 5.80 (q, 2H], 5.15 Cd. lH~,
4.75 (d, lH), 4~50 rS~ lHl~ 1.60 ~sr 3Hl, 1.40 Cs, 3H)
and 1.20 (s, 9~ ppm.
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1152~8Z
~28r~
E~LE 13
Pi~aloyloxymethy~l Pen~cilla,nate l,l~ ~ide
A solut~n of 4..4 g. of pi.~,loy~loxymet~l 6-alpha~
bromopenic~llanate l,l-d,i~o:~Ide In 6Q ml. o~ tetra~
5 hydrofuran wa,s added to Q~,84 ~. o~ sodium bicarBonate
in 12 ml. of ~ater. T~e solution ~as shaken under an
atmosphere of hydrogen in the presence of 2.Q g. of
5% palladium on carbon at 47 to 51 psig. Th~ reaction
mixture was then ~iltered and t~e ~e.s~due was washed
10 ~ith. lQ0 ml. of eth~l acetate and 25 ml. of water.
The combined filtrate and washes were separated. The
organic layer wa~s washed. with. ~saturated sodium chloride,
and dried (MgS04~,, and evapoxated affordi.ng the title
compound as an oil. Thi:s oil was di:ssolved ~n ethyl
15 acetate (,20 ml.),, To the solution wa~s added hexane
(100 ml.) slowly, and the prec;pitate was f~.ltered off.
Yield: 2.4 g. The NMR spectrum ~i;n DMSO-d6~ showed
absorptions at 5.75 (q, 2H), 5.05 r~, lH), 4.40 (~s, lH~,
3.95 - 2.95 (m, 2H), 1.40 ~s, 3H), 1.25 Cs, 3HI and
20 1.10(s, 9HI ppm.
EX~PLE 14
2,2,2-Trichloroeth~l 6-a,lpha-
Bromopenicillanate l,l-Dioxide
2,2.,2-Trichloroet~l 6-alpha-bromopenicillanate
25 was oxidized with potassium permanganate substantially
according to,the procedure o~ Example 12 to gi~re the
title compound in 7~% y~ield. The N~R spectrum of the
product (:~n CDC131 sl~owed a,~so;r:ptions at 5~3Q to
4.70 ~n, 4HI, 4.60 (s, lE[l, 1.7Q (~, 3H~! and 1. sa
30 ('s, 3Hl ppm.
,
::
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: ~ .
1152~32
~22-
EXAM,¢,LE 14A
Penicillan;c Aci,d l,l--Dio~de
To a st~,rred slurry~of ~.S g. of, zinc powder xn
lOQ ml. of a 7Q:3Q gla,ci,al acet~c acid - tetrahydr~uran
mixture, was added, port~,on~se duxing 5 minutes, 4. a g.
of 2,2,2-trichloroeth~l 6~alp~a~romopenicillanate 1,1-
dioxide. The mtxture wa,s stirred at am~;ent temperature
for 3 hours, and then it was f~ltered. Th~ filtrate
was concentrated to a, volume of lQ ml. and the tan
solution was mixed ~ith 50 ml~ o~ water and 100 ml. of
ethyl acetate. The pH was adiusted to 1~3 and the layers
were separated. The organic phase was washed w~t~
satura,ted sodium chloride solution, dr-ed using
magnesium sulfate, and then concentrated to dryness
_ vacuo. The residue was triturated under et~er for
20 minutes. This af~orded 553 mg. of the title compound
- as a solid. The NMR spectrum ~n CDC13~DMSO-d61 showed
absorptions at 11.2 ('~road s, lHl, 4.65 ~, lH~, 4.30
t3, lH), 3.4Q (m, 2H), 1.65 (S, 3H~ and 1.50 Cs, 3H~ ppm.
EXAMPT.~ 15 ,,
Benzyl 6-alpha-Bromopenicillanate l,l-Dioxide
Benzyl 6-alpha-bromopenicillanate was oxidized with
potassium permanganate substantially according to the
procedure of Example 12, to give the title compound in
~5 ~4% yield. The NMR spectrum Cin CDC13), showed
absorptions at 7.35 (s, 5H), 5.10 ~n, 3Hl, 4.85 ~n, lHl,
4.40 ('s, 1~1, l.5Q ~,,3Xl and 1.25 C~, 3H) ppm.
.
~ ~.
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~15;2~Z
~30~
EXAMRLE 16
Pen~cilla,nic ~c~d l,l-D~Qxide
A solution o~ 4~Q g. o~ benzyl ~-alpha-br~mo~
penicillanate l,l-dioxide ~n 5~ ml. o~ tetra~ydro~uxan
was com~ined ~,~th a, solut~on o~ g. o~ sQdIum
bicar~onate In 50 ml. o~ watex. To t~e mixture was
added 2.Q g. o~ a 5Q% suspension of 5% palladium-on-
carbon in w,ater, then th~s mixture was sha~en under an
atmosphere of hydrogen, at a pressure o~ 46.5 to 5Q psig.
for 20 minutes. The catalyst wa5 remo~ed ~y filtration,
and then 30 ml. o~ tetrahydrofura,n and 3.Q g. of a
5Q% suspension of 5~ palladium-on-carbon were added.
The resultIng m~xture was shaXen under an atmosphere
of hydrogen, at pressure o$ from 42 to 45 psIg., for
65 minutes. The reaction mixture was then filtered and
the tetrahydrofuran was removed ~y evaporation. Ethyl
acetate was added to the aqueous residue and the pH
was adjusted to 7.1. The ethyl a,cetate layer was remo~ed,
and fresh ethyl acetate was added to the remaining
aqueous phase. The pH was lowered to 1.5,'and the layers
were separated. The aqueous phase was further extracted
with ethyl acetate, and the combined ethyl acetate
solutions were washed with saturated sodium c~loride
solution and dried ~MgS04~ Evaporation in ~acuo gave
a gum which was tr~turated under ether. This afforded
31 mg. o~ penicillanic actd l,l-diox~de as a yellow
solid. The NNR spectru~ ~n CDC13~D~SO~d6~ ,s~owed
absorpt~on at ~.45 (~road s, 1~1, 4.6Q ~t, lH~ 4.25
; C~, lH~, 3.4Q ('d, 2~I r 1. 65 (~ 3~ and 1.3Q G~, 3Hl ppm.
. :
., :
. ~,
~- - .
~z~z
-31~
EXA~LE 17
6,6~Dibromopenicillani,c Acid l,l-~D~xide
To the dichIoromethane solut~Qn o~ 6,6~
dibromopenicillanic acid fxom Preparation K was added
300 ml o~ w,ater, ~ollowed b~ the dropw~se addition
over a period o~ 30 minutes o~ lQ5 ml o~ ~N sod~um
hy'drox~de. The p~ ~ta~ zed at 7.Q. The aqueous
layer was remo~ed and the or~anic layer ,was extracted
with water ('2 x lOQ mll, To tAe combined aqueous
solutions was added, at -5qC r a premixed solution
prepared from 5~.25g o~ potassium pexmanganate, 18 ml
of concentrated phosphoric acid and ~OQ ml of water,
until the pink color of the permanganate persisted.
The addition took 50 minutes and 550 ml of oxidant
were required. At t~is point 500 ml o~ ethyl acetate
was added and then the pH was lowered to 1.23 by the
addition of 105 ml of 6N hydrochloric acid. Then 250
ml of lM sodium bisulfite was added during lQ-15
minutes at ca, 10C. During the addition of the
sodium bisulfite solution the pH was mainta-ined at
1.25-1.35 using 6N hydrochloric acid. The aqueous ,
phase was saturated with sodium chloride and the two
phases were separated. The aqueous solution was
extracted with additional ethyl acetate C2 x 150 mll
and the combined ethyl a,cetate solutions were washed
with brine and dried Q~gS~4 L. Th~s a~orded an ethyl
acetate solut~,on o~ 6,6-dibromopenicillanic ac~d 1,1-
dioxide.
T~e 6r6-di~romopencillan~c ac~d l,l-dioxide
3Q can b~ isolated b~ removal o~ the s~l~ent ~n vacuo.
A ~a,mple s~ ~sol~ted fxo~ an analQgous preparat~on
had a melt~n~ po~nt of 2~1C (dec.~. T~e NMR
:
,.
.:
'.
S2~Z
~32~
spectrum (CDC13~ DMSO-d6) shswed absorption~ ~t 2.35
(s,lH~, 5.3Q (s,lHJ, 4.42 ~,lH~, 1.63` (~-,3~ and
1.5Q (~,3Hlppm, The ~R spectru~ r di~c~ s~owed
absorptions at 3846-250Q, 1818, 1754, 1342 and 125a-
1110 cm~l.
EXAMRLE 18
6-Chloro-6-iodopenicillan;~c ~cid l,l-Dioxide
To a solution o$ 4.2g of 6-chloro-6-
iodopencillanic acid tn 50 ml o~ d~chloromethane was
added 50 ml of water and then the pH was raised to
7.2 us~ng 3N sodium h~drox;de. The layers were
separated and the a~ueous layer was cooled to 5C. To
this solution was then added, dropw~se, o~er a 20
minute period, a prem;xed solut~on prepared from
15 2.61g of potassium permanganate, 1.75 ml of con-
centrated phosphoric acid and 50 ml of water. The pH
was maintained at 6, and the temperature was maintained
below 10C, during the addition. At this point, 100
ml o~ ethyl acetate was added and the pH was adjusted
20 to 1.5. To the mixture was then added 50 ml of 10%
sodium bisulfite, keeping the temperature bel~ 10C
and the pH at ca 1.5 by the addition of 6N hydro-
chloric acid. The pH was lowered to 1.25 and the
layers were separated. The aqueous layer was saturated
with sodium chloride and extracted with ethyl acetate.
The combined organic solutions were ~ashed with
brine, dr~ed (MgS~4~ and e~aporated In vacuo bo give
4.2g of the t~tle compound, mp 143-145C~ The NMR
spectrum ~DC13~ s~o~ed a~soxption$ at 4~86 ~,lH~
30 4,38 C~!lHJ, 1.60 (~,3~ and 1.43 ~,3H~ppm. Tfi~ ~R
spectrum ~KB~ d~scl showed a~sorpt~ons at 18~0, 1740
and 1250~1110 c~
:
:~
~15~9~2
EXAMPLE 1~
6-Bromo-6-i:odo~eni,c~lla,n,ic AC~'d l,l~D,i~axide
TQ a solution o~ 6.Q ~ 6,~ro~6~
iodopen~cillanic acid in SQ ml o~ dichIoro~eth~ne
5 was added S0 ml of water. T~e pE was ra~sed to 7.3
using 3N sod~um hydroxide and the a~ueous la~er ~as
removed. T~e orsan~c layer w~s extracted with lQ ml
o$ water. The comb~ned aqueous phases wexe cooled
to 5C, and a premixed solut~on of 284g of potassium
permanganate in 2 ml of concentrated phosphorIc
acid and 5Q ml of wa,ter ~-as added d~op~se, ~etween
5 and lOQC. The add~tion took 2Q minutes. At this
point, 50 ml of ethyl acetate was added and the pH
of the mixture was lo~ered to 1.5 using 6N hydrochloric
acid, To this two-phase system ~as added, dropwise,
50 ml of 10~ sodium b~sulfite, ma~ntaining the pH
at about 1.5 by the additlon of 6N hydrochloric
acid. An additional 50 ml o~ ethyl acetate was
added, and then the pH ~as lowered to 1.23. The
layers were separated and the aqueaus layer was
saturated with sodium chloride. The saturated
solution was extracted with ethyl aceta,te C3 x 5Q
ml) and the com~ined ethyl acetate layers were
washed with brine, dried (,NgS041 and evaporated in
vacuo. The residue was dried under high vacuum,
leaving 4~2g of the tltle compou~d, mp 145-147.
The N~R spectru~ ~CDC13~ sho~ed abso~pt~ons at 4~ 3a
(s,lH~ 4.30, ts~,lH~, 1.60 C~3H~ and 1~42 ~,3HIppm.
The IR spectxum (~Br d~sc~ sh~ed a~sorpt~ons at
3~ 18QQ,,174Q, 13~3~ and 125Q-lllQ c~ ~
.. - ~ ~' ~'' ': ': ' '
- . .
.. .
- l~S~2
~34r
EX~LE 2 ~
6-Chlo~o-6~romopen~cii1an~c Ac~d l,l~Qx~de
~ xidati~n o~ 6l~c~10xo-6~iro~r~Qpeni~c~iianic
aci,d ~ith potassium pe~ma,nganate, accoxding to the
procedure of Example l~, affords ~chloro-6~romopen~-
cillanic acid l,l-d~oxide.
EXAMPLE 21
P'enic~llanic Acid l,l-Diox~de
The ethyl acetate solution of 6,6-di~romo-
penicillanic ac~d l,l-di,oxide from Example 17 ~as
com~ined with 7Q5 ml of saturated sodium ~icar~onate
solution and 8.88g of 5% palladium-on-cax~on cat-
alyst. The mixture was s-haken under an atmosphere of
hydrogen, at a pressure of a~out 5 kg~cm2for a~out l
hour. The catalyst was removed by filtration, and
the pH of the aqueous phase of t~e f~ltrate was
adjusted to 1.2 with 6N hydrochloric-acid. The
aqueous phase was saturated with sodium chloride.
The layers were separated and the aqueous phase was
extracted with further ethyl acetate L3 x 200 ml~.
The combined ethyl acetate solutions were dried
(MgSO4) and evaporated in vacuo to afford 33.5g C58%
yield from 6-aminopenicillanic acidL of penicillanic
acid 1,l-dioxide. This product was dissolved in 600
ml of ethyl acetate, the solution was decolorized
using activated carbon and the sclvent was removed ~y
evaporation in vacuo. The product was washed with
hexane~ T~is affoxded 31.ag o~ puxe px~duct.
...
.
,. ' .
1~1 SZ~3~2
-35~
EXAMRLE 22
Eydrogenolys~s of eac~ o~ h~chloxo~6
iodopenicillan~c acid l,l-d~oxide, ~ omQ~
~odopenicillanic acid and 6~c~ o~6~romopen~-
cillanlc ac~dt respect~vel~, accoxd~ng to the proce-
dure of Example 21, a$~ords, ~n each case, penicillanic
acid l,l-dioxide.
EXAM~LE 23
Pen;cillan~c Acid l,l-DiQxide
To a stirred suspension of 786 mg of 6~
chloro-6~iodopenicillanic acid l,l~d~ox~de in lQ ml
of ~enzene was added 0.3 ml of triethylamine folla~ed
by a. 25 ml of trimet~yls;~lyl c~l~ride, at ca QC~
Stirr;ng was continued for 5 mtnutes at-ca ~C and
then at the reflux temperature of the solvent for 30
minutes. The reaction mixture ~as cooled to 25C and
the precipitated material was removed by filtration.
The filtrate was cooled to ca 0C and 1.16g of tri-n-
butyltin hydride and a few milligrams of azobisiso-
butyronitrile were added. T~e reaction mix~ure wasstirred and irradiated with ultraviolet light for 1
hour at ca 0C and then for 3.5 hours at the reflux
temperature o~ the solvent. A further quantity of
tri-n-butyltin hydride ~1,1 ml~ and a catalytic
amount of azobisisobutyronitrile were added and
stirring and irradiation at the reflux temperature
were continued for an additional 1 hour. The re~
action mixture was then poured ~nto 5Q ml o~ cQld 5
sodium bicarbonate and the twa-phase system was
stirred for 3a minutes. Eth~l acetate ~ ml) was
added and t~e p~ ~as adjusted to 1.5 w2th 6N hyd~o-
chloric aaid. Th~ layer~ ~ere separated and the
t.`',~l
,........... ~ , .
'. ' ' ~ . ' ~
'
,
'
1~52~82
-36~
aqueous layex was extracted ~i~th ethyl ~cetate~ The
combined ethyl a,cetate s~lut~ons~were wa~ed ~th
brine, dr~ed (~O4~ and e~apoxated in v~cuO. T~e
res~due was tr~turated unde~ ~exane and then recovered
by- $iltration. ThIs afforded Q~075 mg o~ t~e t~tle
EXA~LE 24
Penicillani:c Acid l,l-Dioxide
To a stirred suspension o~ Q~874g of 6~
bromo-6-iodopen~cillan;c acid l,l-dxoxide in 10 ml
of benzene at ca S~C~ was a,dded Q.3 ~1 of triethyl-
amine followed ~y 0.25 ml of tri~eth~ls~lyl chlor;de.
Stirring was continued at ca 5ac ~or 5 m~nutes and
then for 30 minutes at the re~lux temperature of the
solvent. The reaction mixture was cooled to room
temperature and the solids were removed by filtration.
The filtrate was cooled to ca 5C, and l.QS ml of
tri-n-butyltin hydride and a catalytic amount of
azobisisobutyronitrile were added. The mixture was
irradiated with ultraviolet light for 1 hour at ca
5C, and then it was poured into 30 ml of cold 5%
sodium bicarbonate. The mixture was stirred for 30
minutes and then 50 ml of ethyl acetate were added.
The mixture was acidified to p~ 1.5 and the layers
were separated. The aqueous layer ~as extracted with
ethyl acetate (2 x 25 ml~ and the com~ined ethyl
acetate layers were washed with br;ne, dried ~gSO4l
and evaporated in vacuo~ ~e res~due was dr;~ed under
high vacuum and the 3~ ml o~ hexane w,as addede The
;nsoluble mater~al was reco~e~ed ~ ltx~t~on,
qffording O.Q35g o~ the title co~ound.
~15;29E~Z
~37~
E~AMP~E 25
Pivalo~loxymeth~l 6,6;-D~omQpen~c~lla;n~te l,l-D~oxide
To a solution o$ 4.73g o~ p~alo~oxymeth~l
6,6-dibromopen~cillanate ~n 15 ml o$ dic~loxomethane
is added 3.8Qg o~ 3-chIoroperbenzoic ac~d at 0 to 5C.
The reaction m;xture ~s st~xred at a. to 5C for 1
hour and then at 25~C ~or 24 hours. Th~ filtered
reaction m~xture. is e~aporated to dryness in vacuo and
the residue is partit~oned between eth~l aceta.te and
water. The p~ of the a~UeQuS phase. ~s adjusted to 7,5,
and the layers are separated. ~he ethyl acetate phase
is dried tNa2SO41 and e~a.por~ted ;n ~acuo to give the
title compound.
EXAMPLE 26
Oxidat;~on o$ each o$ the 6,6-dihalopeni-
cillanic acid esters o~ Preparation P using 3-chloro-
perbenzoic acid, according to the procedure o$
Example 25, affords the follo~ing compounds:
3-phthalidyl 6,6-dibromopenicillanate l,l-dioxide,
4-crotonolactonyl 6-chloro-6-iodopenicillanate, 1,1-
dioxide,
y-butyrolactonyl 6-bromo-6-iodopencillanate 1,1-
dioxide,
acetoxymethyl 6-chlorQ-6~hromopen~c~11anate 1,1-
dioxide~
~: pivalo~loxymethyl 6~c~1OrQ-6_~od~penrcl~11anate 1,1-
dioxide,
......... ,
~,
, .
-` 1:152~8Z
~ 38~
hexanoyloxy~ethyl 6,6-d~h~om,~penicill,a,nate l,l~dioxide,
l-(acetoxy)ethy~l 6,6-d~o,m,Q.pen~c~ nate l,l-d~ox~de,
l-Ci,sobutyxyloxylethyl 6~ro~r~6'~odopen~cill~nate
1, l-di ox~de~
l-methyl-l-(acetoxy~ethyl 6,6-di~romopenicillanate
l,l-dioxide,
l-methyl-l-(~exanoyloxy~eth~1 6~c~10ro-6~romo~
penicillanate,
methoxycar~onyloxymethyl 6,6-d~bromopen~c~llanate
l,l-dioxide,
propoxycarbonyloxymethyl 6-c~loro-6~iodopenicillanate
l,l~dioxide,
l-(,ethoxycarbonyloxy)et~yl 6,6-di~romopenicillanate
l,l-dioxide,
l-(butoxycarbonyloxy)ethyl 6~bromo-6~iodopenicillanate
dioxide,
~ methyl-l-~methoxycar~onyloxylethyl 6,6.-d~romo-
: penicillante 1,l-d~ox~de and
methyl~ sopropQxycax~QnylQ~Lethyl 6,6~d~romo-
penicillanate l,l-d~qx~.de, xes~ect.~.Yely~
~'
.
,~
.
1~ ~2~32
~39-
EXAMPLE 27
Pivaloyloxymethyl Penicillan~t:e l!l.-~Qxide
To a solution Q~ le Qg ~ p~valoy~loxymeth~1
6,6-dibromopenicillanate l.,l~diqxide ~n lQ ml of methanol
is added 3 ml of lM sodium bicar~.onate and 2~a mg of la%
palladium on carbon. Th~ reaction m;xture is shaken
vigorously under an atmosp~ere.of hydro~en, at a
pressure of a~out 5 kg/cm2, until hydrogen uptake
ceases. The m~xture. is t~en ~ltered and the ~ulk o~
the methanol is remo~ed ~y e~aporation ~n vacuo~
Water and ethyl acetate are added to the residue and
the pX ;~s ad~usted to 8.5. The layers are separated
and the organic la~er is washed with.water, dr~ed
(Na2S04) and evaporated ~n vacuo. ThtS affords
pivaloyloxymethyl penicillanate 1,l-dioxide.
EXAMPLE 28
Hydrogenolysis of each of the 6,6-dihalo-
penicillanic acid ester l,l-dioxides ~rom Example 26,
according to the procedure of Example 27, affords the
following compounds: -
3-phthalidyl penicillanate l,l-dioxide,
4-crotonolactonyl penicillanate l,l-dioxide,
gamma-butyrolacton-4-yl penicillanate 1,l-dioxide,
: acetoxymethyl penicillanate l,1-dioxide,
pivaloyloxymethyl penicillanate l,l-dioxide,
hexanoyloxymethyl penicillanate l,l-dioxide,
l-(acetoxy~ethyl penicillanate l,l~dioxide,
1-(1sobutyryloxylet~yl penic~llan~te l,l~dicxide,
:
. ,~
~ .
~............ :.-
r,
1.~ 52~12
-40
l-methyl-(~cetoxyleth~l penicill~nate l,l-diQxIde
l-methyl-l-(hexanoyloxy~eth~l peni~c~llan~te 1,1
dioxide,
methoxycar~onyloxy~et~l penicillanate l,l~dioxides,
propoxycar~onyloxymethyl pen~c;~ nate l,l-d~oxIde,
l-(ethoxycarbonyloxy~ethyl pen~cillanate l,l-dioxide,
utoxycarbonyllethyl ~enic~llanate l,l-diox~de,
l-methyl-l-rmethoxycarbonyloxyLethyl penicillanate
l,l-dioxide and
l-methyl~ sopropoxycarfionyloxylethyl penictllanate
l,l-dioxide, respecti~ely.
EX~MPLE 2~
PivaloyloXymethyl 6,-D~bromopenicIllanate ~ Dioxide
A stirred solution of 3.~2g o~ 6,6~dibromo-
penicillanic acid l,l-dioxide in 20 ml o~ NrN~
dimethylformamide was cooled to 0C and then 1.2~g of
diisopropylethylamine was added. This was ~ollowed
by 1.51g of chloromethyl pivalate. This reaction
mixture was stirred at 0C ~or 3 hours, and then at
room temperature for 16 hours. The reacti~n mixture
was then diluted with 25 ml of ethyl acetate and 25
ml of water. The layers were separated and t~e
aqueous layer was extracted with ethyl acetate. The
combined ethyl acetate layers were washed with cold
5% sodium bicarbonate solution, ~ater and firine. The
ethyl acetate solution was then treated with Darco
(an activated charcoalL, dried ~gSQ4L and evaporated
ln vacuo to a brown o~l weighi~ng 2.lg. This o~l was
chrom~togxaphed on 2Qag o~ sil~ca ~el, us~ng dIcbloro-
methane as eluant. T~e ~a~ct~on~ contain~n~ the desixed
: ~ :
.
. :
,
1~52~Z
-41-
product were combined and recbr~mato,gx~ph~d on sil~ca
gel to give Q.025g of tfi tit}e compound. Tfi~ WMR
spectrum ~CDC13I showed absoxpt~on~ at 6.1Q ~, 2~,
5.ao c-s~ lH~, 4.55 (s,lH~, 1.6'Q Cs~3Hlr 1.5a ~s,3H~,
and 1,15 (s,~H~ppm.
EXAMPLE 3Q
Pivaloyloxymet~l Penicillanate l,l-D~oXide
To a st~rred solut~on o~ 6Q ms. of pivaloyloxy-
methyl 6,6-d;bromopen;~,ci,llanate l,l-d~ox~de In 5 ml
of benzene was added 52 ~1 o~ tri-n~utylt~n hydride
followed b~ a catalytic a,mount o~ azo~isiso~utytroni-
trile. The reaction mixture ,was cooled to ca 5C,
and then it was irradiated with ultra~i,olet light for
1 hour. The react;~on ml'xture was poured into 2a ml
Of cold 5% sodium bicarbonate and stirred for 3Q
minutes. Ethyl acetate was added and the pH of the
aqueous phase was adjusted to 7Ø The layers were
separated, and the aqueous phase was further extracted
with ethyl acetate. The combined ethyl acetate solutions
were washed with brine, dried Q~gS04), and evaporated
in vacuo. The residue was dried under high vacuum
for 30 minutes. This afforded 7Q mg of a yellow oil
which was shown by NMR spectroscopy to contain the
title compound, together with som~ impurities contain-
ing n-butyl groups.
~ 5298Z
-42-
EXA~PLE 3I
6,6-Dihromopen;~c~llanic ~c~d l,l-Dl~Qx~de
To a soluti:on o~ 35~ m~ o~ 6,~-d~B~omopen~cillanic
acid in 30 ml o~ d~chloro~ethane ~s added 38a mg o~ 3~
chloroper~enzo~c ac~d at a-s QC, The react~on ml~xture is
stirred at 0-5~C. ~or 30 minutes and then at 25QC ~or 24
hours. The filtered react~on m~xture is evaporated in
vacuo to give t~e title compound.
, : :
, ~ ~' ' '
.: - : :
,
: ::
~, . - :
.
1152~382
-43-
EXAM~LE 32
Benz~l 6,6-D~bromopenicillanate l,l~D Qx~de
A ml~xture of la.~ ~. of 6:,6-dibromopenicillanic
acid l,l-dio~;~de, 2,15 g. of sod~um ~ca~onate, 3.Q6 ml.
of benzyl bromide and l~Q ml~ Q~ N~N~dimethylformamide
was stixred at am~ient temperature o~ernight. Most of
th~ sol~ent was removed ~ evaporatIon ln vacuo and
the re~idue was partitioned between ethyl acetate and
water. The organ;~c layer was removed, washed ~ith lN
~ydrochIoric acid and w~'th saturated sodium chIoride,
and dried (Na2S04~. Evaporation ~n ~acuo a~forded
11.55 g. o~ the title compound. T~ NWR spectrum Cin
CDC13) showed absorptiQns at ?. 4Q (g, 5Hl, 5.3a ~m, 2H~,
4.95 (s, lH), 4.55 ~s, lE , 1.50 (s, 3H~ and 1.2Q
(s, 3H) ppm.
EXAMPLE 33
Pen;cillanic Ac;d l,l-Dioxide
To a solution of 2. a g. of benzyl 6,6-dibromopeni-
cillanate l,l-dioxide in 50 ml. of tetrahydrofuran was
added a solution of 0.69~ g. of sodium bica-rbonate in
50 ml. of water, followed by 2.0 g. of 5% palladium-on-
carbon. This mixture ~as then shaken under an atmosphere
o~ hydrogen, at about 50 psig., for 70 minutes. The
tetrahydrofuran was removed ~y eyaporation, and t~e
25 ~ residue was part;tioned ~etween ethyl acetate and water
~at pH 7.37. The aqueous layer ~as removed and fresh
ethyl acetate was added. The pE was lowered to 1~17
and the ethyl acetate was xe~oYed and washed with
saturated` sod~um chloride ~olut~on~ Eyapoxation ~n
~vacuo ~a~e 423 m~. o~ th t~tle product.
::
:;
-'
li5Z~82
~44-
EXAM~LE 34
2,2,2-Trichloroeth~1 6,6-D~b~omoTeni~ci~llanate l!l-D~oxide
The t~tle compound was; ~repared fro~ ~6~d;~omQ-
pentcillanic ac~d l,l-diox~de qnd 2,2~2-tr~chloroeth~l
chloroformate, substantIall~ accord~ng to the procedure
o~ Preparation J. The product w~s puri~ied By chroma-
tography on silica gel. The NMR spectrum of t~e product
(in CDC13~ sAowed absorpt~ons at 4.85 ~m, 2H~, 1.65
Cs, 3H) and 1.45 Cs, 3~ ppm.
EXANpLE 35
Penicillanic Acid l,l-Dioxide
2,2,2-Trichloroethyl 6,6-di~romopenicillanate 1,1-
dioxide was reduced ~;th zinc dust in a mixture of
glacial acetic acid and tetrahydrofuran, substantially
according to Example 14A. TAe yield was 27%.
EXAMPLE 36
l-(Ethoxycarbonyloxy~ethyl
6,6-Dibromopeniclllanate l,l-Dioxide
~ mixture of 2.26 g. of 6,6-dibromopenicillanic
acid l,l-dioxide, 1.02 ml. of l-~ethoxycarbonyloxy~-
ethyl chloride, i.32 ml. of diisopropylethylamine and
10 ml. of N,N-dimethylformamide was stirred at room
temperature for 28 hours. The reaction mixture was
diluted with 100 ml. of ethyl acetate, and then it was
washed sequentially with water, dilute hydrochloric
acid, saturated sodium bicarhonate and saturated sodium
chloride. The dried etA~l acetate solut~on was evaporated
in vacuo to give 1.50 ~. o~ an oil ~ich was c~roma-
tographed on s~lica ~el. Th~ a~o~ded 353 mg. of the
3Q title compound contam~nated ~Ith some l~(~thoxycarbQnyl-
oxy~eth~ bxo~openic~llanate.
,, ' ~. . ~
1~ 529B2
-45-
EXAMRLE 37
l-(Ethoxycar~on~loxy~-ethyl ~en~cillan~te l,1 Diox~de
A portIon (:2~0 mg.I o~ the product of Exa~ple 36
was dissolved in lQ ml. of toluene. To t~;~s was added
Q.4 ml. of tri-n-~ut~lt~n h~dr~de, foll~wed ~y Q~164 ~.
of azo~isIso~utyron~trile, and the mIxture was heated
to 70-80 C. for 3.5 hours. The solyent was removed ~y
evaporation in yacuo, and the res~due was dissolved in
25 ml. of acetonitrile. Th~ acetonitrile solution was
washed with hexane several times, and then ;~t was
e~apoxated in Vacuo. T~e residue was dtssolved tn
ether, and the ether solut~on was washed ~ith 5%
potassium fluoride and followed ~y saturated sodium
chloride. The dried (Na2SO41 ether solution was
evaporated in vacuo, and the residue was chroma-
tographed on silica gel, to g;ve O.Q43 g. o~ the title
product. The NMR spectrum (in CDC131 showed absorptions
at 6.75 (m), 4.60 (m), 4.3Q (~), 4.15 (s), 4.00 Cs~,
3.30 (d) and 1.75-1.00 (~ ppm.
,,
;' ;'~ ~ :
:
~ .
:
- 11 5Z9~32
-46-
PRE~ARAT~QN A
6-Ch oro-6-iodopenicillansc ~cid
To 3.38 g, o~ ~odine monoc~lor~de ~n 3a ml~ o~
dichloromethane was added, with st~xr~n~, at a-5Q C.,
11.1 ml. o~ 2.5N sulfuric acid, ~ollowed ~y~1.92 g. of
sodium nitrite. At this point, 3.QQ g. of 6-am~no-
penicillan~c aci~d was added all at once, and stirring
was continued for 30 minutes at Q-5~ C. To the reaction
mixture was then added 22.8 ml. of 1~ sodium sul~te
solution in portions, and the layers were separated.
The aqueous layer was washed with further dichloromethane,
and then all t~e organ~c phases were washed w;th saturated
sodium chloride. The dichloromethane solut~on was dried
CNa2SO41 and evaporated in vacuo ~ivi~ng 3.48 g. of the
title compound.
The above product was dissolved in 30 ml. of tetra-
hydrofuran, and then 30 ml. of water were added. The pH
was adjusted to 6.8 with dilute sodium hydroxide and the
tetrahydrofuran was remo~ed in vacuo. The remaining
aqueous phase was freeze-dried and the residue was
washed with diethyl ether. This afforded 3.67 g. of the
title compound as its sodium salt.
pREPARATION B
6-beta-Chloropenicillanic Acsd
A 2.95-g. sample o~ sodium 6-chloro-6~iodopenicil-
lanic acid was conYerted to the ~ree acid, and t~en it
was d;ssol~ed in 125 ml. o~ ~enzene under n~trogen~ To
the solution w~s added 1.~8 ml. o~ tr~eth~lam~ne, and
the mixture was cooled to ~-5~ C, To the cooled mi~ture
n was then added Q.977 ml. o~ tr~methylsilyl chloride, and
the reaction msxture was stixxed at Q-5q C, for 5 minutes,
at 25 C~ ~or 6Q minutes and at 50 C, ~or 3Q minutes.
The react~on m~xture was cooled to 25~ C, and tAe
'
,
.
115Zg~2
-47~
triethylamine hydxochloride ~a,s ~emoyed by ~iltxation.
To the filtra,te was added 1~ mg. Qf azQfi~s~obutyron~trile,
~ollowed b~ 2.Q2 ml. of tr~-n~butylti~n h~dride. The
mixture was then ~rrad;~ated w~Ith ultrav~olet light for
S 15 minutes w;~th cooling to ma,intain at temperature of
ca. 20 C. The solvent was then rem,o~ed by evaporation
in vacuo, and the res;~due was dissolved In a 1~1 mixture
of tetrahydrofuran-water. The pH was adjusted to 7.0
and the tetrahydrofuxan wa,,s, rem~ved by evaporat~on ~n
vacuo. The aqueous phase ~as ,washed w~th etAer, and
then an equal v~lume of eth~l acetate was added. The pH
was adjusted to 1.8 and t~e ethyl acetate layer was
removed. T~e aqueous phase was extracted ~ith further
ethyl acetate, and then the com~ned ethyl acetate
solutions were dried and evaporated in vacuo. This
afforded 980 mg. of 6-beta-chlorpen;cillanic acid.
The above product was dissolved in tetrahydrofuran,
and an equal volume of water was added. The pH was
adjusted to 6.8, and the tetra~ydrofuran was removed ~y
evaporation in vacuo. The aqueous phase remaining was
freeze-dried to give 850 mg. of sodium 6-beta-chloro-
penicillanate. The NNR spectrum ~P202 showed absorption
at 5.70 (dl lH, ~ = 4Hzl, 5.50 Cd, lH, J = 4~z), 4.36
(s, lH),, 1.60 ('s, 3H2 and 1.53 ~, 3H2 ppm.
PREPARATION C
6-beta-Bromopeni,cillanic Acid
A mixture of 5.0 g, of 6,6-d;bromQpenic~llan~c
acid, 1.54 ml. of trieth~la~ne and lQa ml. o~ b,enzene
~as stirred under nitrogen until a sQluti~n was obta~ned.
3Q The solut~on wa~ cooled to ~-5~ C~, and 1~78 ml. o~
tr;~met~ylsilyl c~loride ~as~ a,dded. Th~ ~eaction mixture
was stirred at a-s~ c. ~r 2-3 minutes, and then at 5ao C,
for 35 m~nutes. T~e cooled reaction mi~xture was filtered
and the filtrate was cooled to a-so C. A small ~uantity
1~L52~32
-48-
of azobisisobutyronitrile was a,dded f,ollo~ed ~y 3.68 ml.
of tri-n-butylti:n hydr~de. ~e react~Qn ,f,la~sk was
irradia,ted w,ith ultra,vi~olet lIght fox 15 m~nutesr and
then the reactIon was st~rred at ca, 25~ C. ~or 1.75 hours.
The reaction mixture was ~rradi,a,ted a,gain ~r 15 minutes
and then stirring was conttnued 2.5 hours. ~t t~is
point a further small quantity o~ azo~isiso~utyronitrile
was added, followed by Q.6 ml. of tri~ utyltIn hydride
(0.6 ml.),, added and th~ m~xtuxe was again irradiated
lQ for 30 minutes. The solvent was then removed by evapora-
tion in vacuo~ and to the res;due was added 5% sodium
bicarbonate solution and d;eth~l ether. The two-ph~se
system was shaken v~gorously for lQ minutes and then the
pH was adjusted to 2Ø The ether layer was removed,
dried and evaporated tn vacuo to give 2.33 g. of an oil.
The oil was converted into a sodium salt by adding water
containing 1 equivalent of sod;um bicarbonate followed
~y freeze drying the solution thus obtained. The afforded
sodium 6-beta-bromopenicillanate, contaminated with a
small amount of the alpha-isomer.
The sodium salt was purified by chromotography on
Sephadex LH-20, combined with some ~urther material of
the same quality and re-chromatographed. The NMR spectrum
~2)- of the product thus obtained showed absorptions at
5.56 (s, 2H~, 4.25 Cs, lH),, 1.60 Cs, 3HI and 1.5Q ~s,
3H) ppm.
~REPARATI~N D
6-beta-~od~penic~llan~c ~c~d
The t;~tle compound i,s~pxepaxed by reduct~'on o~ 6,6-
diiodopenicillanic acid, ~it~ tri-n-butyltin ~ydride,
~ccording to t~e prQc~dure o~ ~epaxat~an ~.
~' , ' ' ~.
:, ' -- .
.
~L52~82
-49~
PREPARATIQN E
Pi,valoyloxymeth~alpha~BxQm~pen~c~ a~nate
To a solut~on of 28Q ~ o~ 6~alp~a~romopeni
lanic acid in 2 ml. of ~N~dimethylfa~mam~de ~s added
260 mg. of d;~sopropylethylamine ~ollowed ~ 155 mg. of
chloromet~yl pl~alate and 15 m~. o~ sod~um iodide. The
react~on mixture Ig st~r~e~ at room temperature for
24 hours, and t~en it ~s d~luted with ethyl acetate and
water. The pH ~s adjusted to 7.5, and then the ethyl
lQ acetate layer is separated and washed three t'~m~s with
water and once with saturated sod~um chlor~de solution.
The ethyl acetate solution ~s then dr~ed us~ng anhydrous
sodium sulfate, and e~aporated in acuo to yive the
title compound.
PREPAR~TION F
Reaction of the appropriate 6-halopenic~llanic acid
with 3-phthalidyl chloride, 4-crotonolactonyl chloride,
gamma-butyrolacton-4-yl chloride or the requisite
alkanoyloxymethyl chloride, l-(~lkanoyloxy)ethyl chloride,
1-methyl-1-(alkanoyloxylethyl chloride, alkoxycarbonyl-
oxymethyl chloride, l-Calkoxycarbonyloxy)ethyl chloride
or l-methyl-l-(alkoxycarbonyloxy~ethyl chloride, according
to the procedure of Preparation E, a~fords the ~ollowing
compounds;
3-phthalidyl 6-a}pha-chloropenicillanate~
4-crotonolactonyl 6-~ta-chloropenicillanate,
- gamma-~utyxolacton-4-y~l 6~alpha-bxq~openicillanate,
acetoxymethyl 6-beta-bromopenicillanate,
pivaloyloxymeth~l 6-beta~brQmqpen~cillan~te~
0 hexanoyloxymetn~l 6-alp~a-~Qdopen~c~llanate,
('acetoxyJet~Lyl 6-I~eta,-iodopeni;clllanate,
kso~utYrYloxyleth~l 6-alpha-chlor~penic~llanate,
l-met~ l-(acetoxylethyl 6-~eta-chloropen cillanate,
l-methyl~ xanoyloxylethyl ~-alpha-bromopenicillanate,
methoxycar~ony}oxymethyl ~-alpha-~romopenic~llanate,
:
1~52~2
-50
propoxycarbonyloxymethyl 6-het,a,-bxomQpenicill~nate~
l-(ethoxyca,rbon~loxy),~th~l 6~alpha;-~xo~openic~llan~te,
l-butoxycar~onyloxylet~yl 6-alpha-~odopen~cill~nate,
l-methyl-l-(methoxycar~ony~loxyletll~l 6-beta-~odopenicil-
lanate,,andl-methyl-l-(isopropoxycar~onylox~thyl 6~a,1pha-chloro-
penicilla,nat~s,
respectivel~.
PREPARATION G
lQ 6',6'-DiiodQpeniclllanic Acid
A mixture of 15.23 g. of iodine, lQ ml~ of 2.5N
sulfuric acid, 2.76 g. o~ sod~um nitrite and 75 ml. o~
dichloromethane was stirred a,t 5Q C., and 4,32 g. of 6-
aminopenicillanic ac~d were a,dded over a period of
15 minutes. Stirring ~as cont~nued at 5-lQ C. for
45 minutes after the addition was complete, and then
100 ml. of 10% sodium bisulf;te was added dropwise. The
layers were separated, and the aqueous layer was further
extracted with dichloromethane. The combined dichloro-
methane layers were washed with brine, dried ~gSO4~ andevaporated in vacuo~ This afforded 1.4 g. of the title
compound, contaminated with some 6-iodapenicillanic
acid. The product had a melting point of 58-64 C. The
NMR spectrum CCDC131 showed ahsorptions at 5,77 Cs, lH~,
4.60 (s, lH), 1.71 ~r 3Hl and 1.54 Cs, 3H~ ppm.
~ ~ -
l~Z9~2
PREPARATI~N H
Pivaloylo~y~et~l 6~alphs~BrQ~open~c~ nate
To a stirred mIxture o~ 11.2 ~. o~ 6-alpha~
bromopenic;llan~c ac~d, 3.7 g. o~ sod~u~ b~car~anate and
44 ml. o~ N,N~dimeth~l~o~mamide was added 6.16 g. o~
chloromet~yl pivalate, dropwise, dur~ng 5 minutes, at
ambient temperature. StIr~ing ~as continued for 66 hours
and then the reaction mixture was diluted ~it~ laO ml.
of ethyl acetate and lQ0 ml. of ~ater. The la~ers were
separated, and the eth~l acetate layer was was~ed
sequentially with water, saturated sodium chlor~de,
saturated sod~um bicarbonate, water and saturated sodium
chloride. Th~ decolor~zed ethyl acetate salution was
dried (MgSO41 and evaporated to dryness in vacuo. Thi~s
afforded 12.8 g. (8Q% yield2 of the title compound.
PREPARATIQN I
Benzyl 6-alpha-Bromopenicill~nate
The title compound was prepared by esterification
of 6-alpha-bromopenicillanic acid ~ith benzyl ~romide,
substantially according to the procedure of Preparation H
~Yield 83%). The NMR spectrum Cin CDC13) showed absorp-
tions at 7 35 (s, 5H), 5.35 (~, lH), 5.15 ~s, 2H~, 4.7Q
~m, lH2, 4.60 (s, lHI, 1.55 (s, 3H) and 1.35 Cs, 3Hl ppm.
:
.;
'
- ~ ,
:
: .
.
, . . .
.
li52~
-~2~
PREPARAT~N J
.
2,2,2-Tr~chlQ~oethy~l Penicillan~te
To a stirxed solutIon ~ 2 g~ Q~ 6-al~h~
~xomopenIcillanic ac~d in ~Q ml~ o~ tetra~ydrofuran,
at Q C., was added 3.48 ~. o$ p~idIne oyer a one-
minute period. To the hazy solution so ofitained was
added, over a lQ minute pexiod, 8.47 g. of 2,2,2-tri-
chloroeth~l chIoroformate, maintaining the temperature
between 0 and 2~ C, Stirrin~ ~s continued ~or
30 minutes, and t~en the cooling bath ~as removed.
Stirring was continued at ambient temperature overnight.
The reaction mixture ~as then wa~m~d to 35 C. for five
minutes and then it was filtered. Th~ ~iltrate was
evaporated and the residue was dissolyed in lQa ml.
15- Of ethyl acetate. The ethyl acetate solution was
washed sequentially w;th saturated sodium bicarbonate,
water and saturated sodium c~loride. The ethyl acetate
solution was then decolorized, and dried, and then it
was concentrated to small volume. To the resulting
mixture was added 100 ml. of hexane, and the solids were
removed by filtrationj giving 10.5 g. of the title
compound, m.p. 105-110 C. The NMR spectrum Cin CDC1
showed absorptions at 5.50 (:d, lH), 4.~5 ~d, lHl, 4.90
Cs, 2Hl~ 4.65 ~s, lHl~ 1.7Q Cs, 3H) and 1,55 ~, 3H) ppm.
:~ ~
:~ :
, ~
.. . .
, I , ~
3Z
-53~
P~E~ARATIQN K
6,6-Di~ro~openi~cillanic ~crd
To 5QQ ml of dichloromethane coQled tQ 5ac
was added 11~.9~ o~ brom~ne, 20a ml Q~ 2.5N s~lfuric
acid and 34.5g o~ sodium nitrite. To th~s stirred
mixture was then added 54.Qg o~ 6-aminopen~cillanic
acid, portionw;se o~er 3Q m~nutes, with the temperature
maintained from 4 to 10C~ Stirring was continued
for 30 minutes at 53C, and then 41Q ml of a l.~M
solution of sodium ~isulfite wa$ added dropwise at
5 to 10~C during 20 minutes. The layers were separated
and the aqueous layer was extracted tw-ice ~ith 150
ml of dichloromethane. The oxiginal dichloromethane
layer was combined w;th the two extracts to g;~e a
solution o~ 6,6-dibromopenicillanic acid. This
solution was used directly in Example 17.
PREPARATION L
6-Chloro~6-iodopenicillanic Acid
To 100 ml of dichloromethane cooled to 3C
was added 4.87g of iodine chloride, 10 ml of 2.5N
sulfuric acid and 2.76g of sodium nitrite. To this
stirred mixture was then added 4.32g of 6-amino-
penicillanic acid portionwise during a 15 m~nute
period. Stirring was continued for 2~ minutes at 0 -
5C, and then lQQ ml of 10% sodium ~;sul~ite solution
was added drop~ise at ca 4C, ~tirrins was
continued ~or 5 m~nutes and then the layers~ere separated.
O~e aqueous layer w~s extraoted ~ith d~c~lorometblne
::
.
.
` : : , `
.
~2~82
-54~
(2 x 50 ml), ~nd the com,~ined dichl~x~,methan~ soluti~ns
were washed with ~rIne,,drIed (Mqso4I- ,a,nd eyaporated
in Vacuo to g,iye th~ title compound as a, tan s~li~,d,
mp 148-152QC. The NMR sp~ctrum o~ t~e product
('CDC13~ showed absorptions at 5.4Q (~,lH~ 4.56-
(:,lH),,1.67 (s,3~1 and 1,50, (s,3H-)'ppm, T~e IR
spectrum (:KBr discl showed absorptions at 178Q and
1715 cml.
PREPARATION M
lQ 6-Bromo-6-iodopenicillanic Acid
To lQ0 ml o~ dichlorometha,ne, cooled to
5C, was added lQ ml o~ 2.5N sulfurIc ac~d, 6.21g of
iodine bromide and 2.76g of sodium nitrite~ To th~s
mixture was added, with ~;gorous stirring, at a -
5C, over 15 minutes, 4.32g of 6-aminopenic;llanic
acid. Stirring was continued for a further 20
minutes at 0 - 5C, and then lQ0 ml of 10% sodium
bisulfite was added dropwise between 0 and 10C. At
this point, the layers were separated and the aqueous
layer was extracted with dichloromethane C~x 50
ml). The combined dichloromethane layers were washed
with brine, dried nMgso4l and evaporated in vacuo.
The residue was dried under high vacuum for 3Q
minutes to give 6.0g (72~ yieldl of the title compound
mp 144-147C. The NMR spectrum ~DC131 showed
absorptions at 5.50 Cs/lHl! 4.53 ~s,lH), 1.7Q Cs~3H)
and 1.53 (s,3H)ppm. T~e ~R spectrum c~Br di~scl
showed absorptions at 1785 and 171Q cml. The mass
spectrum sn~wed a prominent ,ion at ~e ~ 4Q6.
, ~ :
,
.
. .
,
~ 5Z~8Z
~55--
pREPARAT~;ON N
6-Chloro~ r.o~nQpeni~ci~llanic Ac~d
6~Chloro-6~romo~enic~11a,n,i~ a,c~d i,s,~
prepared ~rom 6-am~,nopenic~llan~c a,c~d v~a di~azot~
zation ~ollowed ~ reaction w~,t~ ~xom~ne c~loride,
according to the procedure o~ Preparation ~.
PREPARAT3~N O
P~valoyloxymethyl 6,6-d~.~xomopen~c~llanate
To a stirred solution o~ 3.5~g o~ ~,6-
di~romopenic~llanic acid in 2Q ml o~ N~N.dimeth~l-
~ormamide i,s added 1,3Qg o~ di,~sopxopylethylamine
~ollo~ed ~y 1.50g o~ chIo~amet~l p~valate at ca
0C. The reaction m;,xture is stirre.d at ca aoc ~or
30 minutes and then at room temperature, for 24
hours. T~e reaction mixture ~s then diluted with
ethyl acetate and water and the pH of the aqueous
phase is adjusted to 7.5. The ethyl acetate layer
is separated and washed three times with water and
once with saturated sodium chloride solution. The
ethyl acetate solution is then dried usi~g anhydrous
sodium sulfate, and evaporated in vacuo to give the
title compound.
1152~2
PREPARAT~ON
React~on of the appxQprIate 6,6-d~alopeni~
cillan~c acid w~th.3~p~t~a1idyl chIor~d~, 4~crotonlac~
tonl~ chloride, gamm~-~utyrolact~on-4-yl c~loride or
the re~uisite alkanoyloxymethyl chlor~de, 1~ Cal~any-
loxylethyl chlor~de, l-met~ (alk:noy~loxy3.ethyl
chloride., alkoxycarbonyloxy~eth~l chlox~de, l-Cal~oxy-
carbonyloxylet~yl chloride or l-met~yl-l~alkony-
carbonyloxy3.ethyl chloride, accord~n~ to the procedure
Of Preparation 0, affords the follo~ing compounds;
3-phthalidyl 6,6-d;bromopenicillanate,
4-crotonolactonyl 6-chloro-6~iodopenicillanate,
y-butyrolactonyl 6-bromo-6~iodopenicillanate,
acetoxymethyl 6-chloro-6-bromopenicillanate,
pivaloyoxymethyl 6-chloro-6-iodopenicillanate~
hexanoyloxymethyL 6,6-di~romopenicillanate,
l-(acetoxy)ethy~ 6,6-dibromopenictllanate,
l-(isobutyryloxy3ethyl 6_bro.mo-6-iodopenicillante,
l-methyl~ acetoxy3eth~1 6,6-dihxo~openic~llanate,
a :l-methyl-l-(~exancylQxyIeth~l 6~chloro-6 bromQpeni~
: cillante,
me~hoxycaxbonylo~ymethyl 6,6-di~romopentcillanate,
~ propoxycar~onyloxymethyl 6-c~10ro-6-Iodopenicillanate,
:~'' ,' ' - . , . ~.
. . . . -
-: .: ~ , ~
- ::
;
~l~Z9~;~
~57~
l-(ethoxycarbonyloxylethyl 6,,6-~ik~omopen~c~ll,a,na,te,
~ utoxycaxbony~loxy~Lethyl 6;~xomo-6~ ,odopen;~c~ nate,
l-met~ rmethoxycarbQn~loxy~eth~l 6,6~d~romo-
penicillanate and
S l-methyl-l-(~isopropoxycar~Qnyloxy~et~l 6,6-d~bromo-
penicillanate.
