Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~æ~s3~
-
1. Field of the In~ention
.
The chem~cal proce~se~ of the pre~ent ~nv~ntion
provide novel ~ntibacterlal agents o~ the ~lactam type
conta~ning a hitherto unknown nucleu~ ~nd u~e~ul inter-
~¢diate~ ~or the synthe~ls of ~aid ~ntibacterlal agent~.
2. De~cription of the Prior Art
Penicillin~ ~nd cephalosporin~ compri~e a group
of ~ell-known antibacterial agent~ commonly grouped ko-
gether as a class called ~-lactam antibiotic5. Most of
the work in this field h~s been done, broadly speaking~
with 6_aminopenicillanic acld, 7-aminocephalo~por&nic
acld ~nd deriv~ti~es thereof produced by fermen~ation or
chemlcal transformatlon of the natural products. De~pite
the exten~ive progre~s made in preparlng active derivatives
of 6-amlnopenicillanic ~cld and 7-aminocephalo~por~nlc
acld, there i9 a continuing ~earch ~or synthetic s~d semi_
synthetic routes to new families o~ ,B_lactam antibiotics
which may po~sess more advantageous properties than
those derived from the krlown penicillin and cephalo~porin
nuclel .
~ terature publications relating to other more
non;conYentiollal ~-lactam-contalning antiblotics include
the ~ollowing: ~ :
-2 :
1~ 2 ~ ~ 3~
aO Belgi~n P~tent 846~933 di~clo~e~ the compound o~ the
formula
C ~ OH
Ll 'd
O N COOH
whlch has been i~olated from fermen~ation of
~ Yi~ This compound, named cla~ulinic acld,
possesses a low order o~ antibact~rial acti~ity but
inhiblts the action of certain ~Llactam~s2s and
reportedly enhances the in vitro and in vivo acti~i~y
o~ ~ome penicillins and cephalo~porins.
b. U.K. Patent 1,~67,413 dl~closes the fermentatlon
product having the formula
O
CH~ ~
~ S-C~=CH-NH-COG~3
~03S-O l ll
~ N I COOH
whlch is reported to posses5 some ~ntibacterial
actlvity and to be a ~-lactamase inh-lbitor.
c. ~rown, et al. in J.C.S. Chem. Comm. 3 359_~60 (1977)
disclose preparation of the compound of the formula
~ o~H~
, ~ ~ L~ C02CH2C6H5
There i~ no indlcation from th~ publication that
the co~pound posse~ses any antlbacteria~ activity.
_~,
~3LZ~531
d. IJ.S. Patent 3,950,357 describes a ~ermentation process
for producing thie~amycin, the co~poun.d of the formula
C~3CH(OH)~ ~-C~I2C}~2NH2
O N COOH
Thienamycin ls reported to be a highly poterlt broad-
spectrum antlbiotic.
e. Belgiarl Patent 849,118 (equivalent U.S. Patent is 4,070,477)
digcloses a 6eries of 6-amino-2-penem-~-carboxylic acid deri-
vatives of the formula
Ra E H
Rb~
where Rl ls hydrogen or a~n M-protect~ng group, Rl ~s
hydrogen or acyl (or Rl and Rl taken together are
a divalent N-protecting group),-CO-R2 is carboxyl or
a protected carboxyl group and R3 is hydrogen or a
C bonded organic group. The compounds and thelr
salt~ are said to possess antlbacterial actiYlty.
No compounds are disclosed in the publication which
do not contain the amino or acylamido moiety at the
6-position o~ the ~-lactam rlng.
2~3s3~L :
~ .
The pre~ent ~nvention provides a novel
lactam compound havin~ the formula
. ,_ S
C~ OC ~ C ~ OCH3
C90~
, .
or ~ pharmaceukically acceptable 8alt or ea~lly clea~able
eRter thereo~. The ~bove compounds, including especlally
the dextrorotatory optical i~omers thereof, are potent
~ntibacterial agent-~ or are intermediates useful in pre-
parlng said an~ibacterial agents.
Also included in this invention are ~arious
novel intermediates use~ul in preparing the active ~-
l~ctam derivatives de~cribed abo~e and proces~es for th~
production o~ the ~ntermediates ~nd active compound~.
Detailed Description
The compound~ represented by formula I for~
a new ~-lactam r~g æystem, The nomenclature to be
u~ed ~or th~ compounds could be the followlng:
6 ~ ~S
O~N--~C~OCH2CH20C~3
COOH
3-~2-methoxyethoxymethyl)-7-oxo-4-'thia-1
azabicyclo[3,2,0~hept-2-ene-2-carboxylic acid.
-5-
112~S3~!L
Alternati~ely, the compounds can be c~n~iclered a8 penem
deri~atives and ~amed a9 follows:
~~ S~2
7L~ ~CH20CH2CH20C~ ..
~0~
2-(2-methoxyethoxymethyl)penem-3-carboxylic
acid.
The Btereoconfiguration o~ the 2~penem compo~nds
o~ the present ~n~ention ~y be represented as follows:
'
H ~ S
~ /~ C ~ OC ~ C~ OCH3
O ~
C~O~
S~nce an asymmetrlc carbon atom is present (carbon 5 o~
the penem ring), the compounds o~ ~ormula I ~y exist
either in the form of racemic mixtures or as the in-
di~riduE~1 dextrorotatory and le~orotatory optical i~omers.
Wh~le the present in~ention ~ncludes both the racemic
mixtures and re~ol~ed opkical isomer~g the pre~erred com- ~-
po~nds are the dextrorotatory optic~l lsomers (S~
configuration) since these have been ~ound to possess
~ub~tantlally all o~ the antibacterial activity attrl_
buted to the racem~c ~ixtur~s.
Th~ pharmaceutically ~ccep~able s~lt~ re~erred
to a~o~e include nontoxic m~tallic s~lts such a~ sodium~
potassium, calcium and alum~num, the ~mmon~um ~alts ~nd
~alt~ w~th nontoxic ~m~n~s ~uc~ as tri~lkylamines (e.g.
_6_ :
;3~L
triethyl&mine ), procaine ~ dibe~ylamine , ~-benæyl-
~ph~ethylamine, l-ephel1amine, ~IJ~'-dibenzylethylenediamine,
N-alk~rlp~per~ dine (e .g. N ethylpiperid~e), cc-met~ylbenzyl-
aniine~ c~ ethylberlzylamine, and other ~ e~ which ha~re
been ~ed to ~orm ~alts of` penicillir~ and cephalosporins.
E~s~y cle~Yable esters of the :free arid co~-
pounds of formula I include conventional e~ter gro~ps
whlch haYe been u~ed in the penlcillin and cephalosporin . .
art to block carboxyl group~, i.e. ester grou~ ~rhich are
removable by method3 which do not result in any appreciable
destruction o~ the remalning portion of the molecule.
For use a~ an intermediate, the preferred ea~ily clea~able
ester i~ the p-nitrobenzyl ester which may be removed by
hydrogenolysis, e.g. catalytic hydrogenation ~ith a noble
metal catalyst. For u5e as biologically acti~e compounds~
physiologlcally ~leavable esters are employed. Phyæio~
loglcally cleavable e~ters of the ~ree acid compounds of
~ormula I include those e3ters known in the penic~llin
and cephalosporin art to be east~y cleaved with~n the
body to the parent acid. Examples o~ ~uch eæters in-
clude ~ndanyl~ phthalidyl, methoxymethylg glycyloxyme~hyl,
phenylglycyloxymethyl, thienylglycyloxym~thyl or acyloxy-
methyl of the ~ormula
O
C Y
in ~hich Y ls Cl-C4 alkyl or phenyl~ Particularly pre-
~erred biologica}ly ~ctive esters ~re ~ethoxymethyl~
~cetoxymethyl, pivaloyloxymethyl, phthalidyl and indanyl.
It will be appreciated that the com? ound~ o~
formula X may exist in ~ar~ous states of ~ol~ation ~Qnd
~7--
112B53~
the anhydrous as well ~5 ~olvated ~orm~ ~re ~ntended to
be ~ithin the ~cope of the in~ention~
~ he present invention further provides ~riou~
novel intermed~ates useful in the s ~ thes~ of the com-
pounds o~ formula I.
; A preferred embodiment of the present ~nvention
i5 a noYel lntermediate o~ the ~or~ula
S-C-C ~ OC~ C ~ OCH~
O ~ ~ P(Z)3
COO-C~No2
II
wherein Z i~ phenyl or Cl~C6 ~lkyl (e.g. n-butyl). The
most preferred compound of formula II is that in ~hich
Z is phenyl.
Another preferred embodiment of the present
i~rention is a novel intermedlate o~ the formula
O
S~C-C~ OC ~ C~ OCH~
~ ~.
~OH '
coo0cx2~3NO2
III
wherein the w~ry line indlcates that compound III exist~
~s a mix~ure of epimers.
Ano~her pre~erred em~odiment of the, present
i~Yentian i~ a no~el intermediate o~ the ~ormul~
2l3~ii3
S~ CH20CH2CH20C~3 :
o~ Cl
CoC-c~l2~3l~o2
~hieh exist~ as a mixture of epimers.
rhe 2-penem compounds o~ formula I ~nay be pre~
pared by the process ~omprislng the steps of`
(1) thermally cyclizlng in an inert orga~ic
~olvent a phosphor~ne intermediate of the formula
S-C ~ CH~ OCH2 CH2 OCH3
Or~P(Z)3
II COO-C~ 102
wherein Z represent~ phenyl or Cl-C6 alk~rl but pre~erably
phenyl to produce a compound of the formula
CH2 OCH2 CH2 OCH3
COO-C~2~NO~ ; -
(2 ) ~ub~ectlng the e~ter o~ ~ormula Ia~ to
~talyti~ ~ydrogenation employing a noble metal catalyst;
in a no~-reducible inert aqueous csr non-aqueous solvent ir
the pr~sence or ~b~ence o~ a b~se to produce the racemic
acid of the formula
..9_
35i3~
o~N - ~ C~20C~2c~20c~3
coo~ :
or a carboxylic acld ~alt thereo~ and, if desired, performing
one or more o~ the further steps selected from (al resolving
the s~-produced racem~c compound into its dextrorotator~ :
and levorotatory optical isomers thereof and recovering
the dextrorotatory isomer; and (b) convert~ng the racemic
~rse acid or salt o~ ~ormul~ ~ or the dextrorotatory isomer
thereo~ to a physiologically hydrolyzed eæter thereof or
a pharmaceutically acceptable carbox;ylic acid salt th~reo~
The cyclization reaction mQy be carrled out ~n
an inert organic solvent or mixture of solvent~ such as
allphatlc, cycloaliphatic or ar~m~tic hydrocarbons (e.g.
n-hexane, cyclohex~ne, benzene or toluene), halogenat~d
hydrocarbons (e.g. mekhylen2 chlorlde, chloroform, carbon -
tetrachloride)~ ethers (e.g. diethyl ether, dioxane or
tetr~hydrofuran)~ c~rboxylic acid amldes (e~g. dimethy~-
~ormamide)g di Cl-C6 alkylsul~oxides (e.g. dimethyl-
~ ~oxlde) or a Cl-C6 alk~nol (e.g. ~ethanol, ethanol, t-
butanol). E~e~ated temperatures are used, ~or exampl~,
temperatures rang~ng grom above room temperature to the
re~lux temperature o~ the solvent systemO Good results
are obtained at temperatures o~ from ~bout 50 100e.
~ he prnitrobenzyl est~r Ia is then cleaved ~y
hydroge~olysiR ~n a conYentional m~nner to give the
correæpon~ing ~ree ~cid or a ~alt thereo~. Ca~alytlc
1~-
,:
~L~2Ei 53~
hydro~nation may be employed with a noble metal catalyst
such as palladium or rhodium3 lncluding der~vatl~s thereof
~uch as oxides, hydroxides or halide~ sa:Ld catalyst
being optionally supported on a conventio~al carrler such
as carbon or diatomaceou~ earth. A non-re~ducl~le a~ueou~
or non-aqueous inert solvent such ~s w~ter, meth~nol,
ethanol, ethyl acetate, tetrahydrofuran, diethyl ether
or dioxane is used ~or th~ hydrogenolysls reactlon. The
reactlon is pre~erably conducted at atmospheric or slightly
olevated pressure at room temperature and ~or a period of
~'rom about 1 to 5 hours depending on the solvent and
catalyst used. I~ an equivalent weight of a ba~e such
as an alkali m~tal or alkaline earth hydroxide or an
amine is employed during the hydrogenolysi~, the product
may be r~covered in the form of a carboxylic ~cid ~alt.
Alternatively, i~ no base is used, the free acid product
i8 ob~ain~d.
Compound I is reco~ered from the hydroge~olysis
step as a racemic mixture of the dextrorotatory a~d leYo-
rotatory optical iso~ers of the free acid or salt thereo~.
While ~he racemic mixture possesses potent antibacterial
acti~ity and may be employed in that ~orm as an ant~biotic
Rgent, 1~ has been found upon re~olution of the ra~em~te
th~t ~ub~tantially all o~ the antib~cterial activlty iB
~n the dex~rorotatory optical i~omer. A~cordingly, it
is pre~erred to re~olve the racemlc compound I into i~s
optlcal i~omers by a conventional resolution procedure~
e.g. by re~cting the race~ic acid ~ith an optlcally
actiYe am~ne ~uch a~ ~-methylbenzyl~m~ne to form
di~ster~oisomeric ~ltsg s~p~rating the salt~ and co~v~rting
,~
2~3
~hem into the dextrorotary ~nd le~orotato:ry optlcal
i~omers of ~ree acid I. By thi~ procedurle the dextro;
rotatory isomer may be recovered in a form subst~ntially
free of the les~ active levoro~atory isomer.
A racemic or resolved co~pound of formula I
may then be con~erted to a pharmaceutically acceptable
B~lt thereo~ or ~ p~ysiologically cleavable ester thereo~.
Phar~aceutically acceptable salts m~y be formed by reactlon
o~ the acid o~ formula I ~ith a su~table non~toxlc base
ln an inert sol~ent and reco~er~ng the de~ired salt as
by precipitation or lyophillzation. Phy~iologlcally
cleavab~e esters may be prepared from the racemic or re-
solved ~ree acids or salts in ~n an~logous manner to
prep~ration of such e~ters of penicillins and ceph~lo-
~porins.
Acyloxymethyl esters in which th~ 3-position
of the 2-penem has the formula
-COO-CE12-0-C-Y
ln which Y is phenyl or Cl-C4 alkyl ~y be prepared by
reactlng an alkali metal salt of the ~ree acid I (~n the
~orm o~ the racemic mixture or resolved dextrorotatory
i omer), for ex~mple~ the lithium, sodium or pot~s~iwm
salt~ with an acyloxy~ethyl halide o~ the formuIa
o
L-CH2-O-C-Y
in which L ~s chloro or bromo and Y is Cl~C4 alkyl or
pheny~0 Acyloxymethyl halide~ which may be ~mplsyed in-
clude chloromet~yl ace~at~ bromomethyl acetate, bromo~
methyl propion~te~ rhloromethyl pi~aloate, chloromethy:L
ben20ate, and the like. The alkali metal salt of compound I
~12-
~2&53~
i5 r~acted ~n ~n ~nert ~olvent ~e,g. tetr~h~dro~uran,dioxane, dimethyl~ormamide or methylene chlorlde~ with
at lea~t a molar equivalent of the acyloxymethyl hal~de
at room temperature or at slightly elevated temper~ture,
e.g. up to ~40-45C.
me methoxymethyl ester o~ compound I (racemic
mixture or dextrorotatory isomer) ~herein the ~-positiQn
ifi -COO-C~OC~ may be prepared by sub~titutlng for tAe
acyloxymethyl halide in the abo~e procedure chloromethyl
methyl ether.
The ~ndanyl e~ter of compound I wherein the
3_position ha~ the ~ormula
-COO~
~ay be prepared by reacting 5-indanol ~n ~n lnert ~ol~ent
such as dioxane or tetrahydro~uran with the free acid form
o~ compound I (racemic mixture or dextrorotatory isom2r)
in the presence Or a condensing agent ~uch as N,N'-
dicyclohexylcarbodiimlde .
Phthalidyl ester compound~ o~ ~ormula I where
the 3-po~ition has the formul~
COO
o
may be prepared by reacti~g bromophthalide ha~lng the
~ormuls.
.
353~
o~
wi~h a 8alt o~ ~he free acid I (rac~mic mi~ture or dextro-
rot~tory isomer). m e e~teri~icat~on ca~ be carried out
~n an lnert solvent ~uch as dimethylform~mid~ d~ox~n~ ;
or tetr~hydro~uran by warm~ng equimolar amounts o~ the
salt of ~ormula I, for example, the sodium or pota~s~um ~; -
salt, and bromophthalide.
The phosphorane intermedlate o~ ~ormula II may
be prep~red from 4-acetoxy~2-azetidinone, a known
compound, by the ~ollowing pro~edur~:
(a) react~ng 4-acetoxy-2-azetidinone of
the formula
~ O-C-CH3
O H
with 2-metho~yethoxythioacetic acid in an inert solvent and
in the presence o~ a base to produce the intermediate of
the ~ormula
5-C-C ~ OC~ C~ O~H3
N ~
ol4 - .
353~ ~
(b) reacting the above-produced intermediate w1th :
a glyoxylic acid ester of the formula ::
CH(OH~2 ~ ~,
C02C~ ~ NOz
or a reactive oxo-derivative thereof such as a hydrate in an
inert organic solvent, preferably at an elevated temperature,
to produce a mixture o~ epimers h~ving the formula
L ~ ~ N
COO-CN2- ~ 2
III ;
(c) converting the so-produced hydroxy intermediate
III to the corresponding chloro epimer~c mixture of the
formula
li .
~:-C-CH20CH2CH20C~
N ~ Cl
COO-CN2 ~ N2
IV '
by treatment with a chlorinating agent in an~inert organic
solvent in the presence or absence of a base; and
:
(d) reacting the chloro intermediate IV with
a phosphine co~pound of the formula
Ib
wherein Ra~ Rb and Rc are phenyl or Cl-C6 alkyl, preferably
phenyl~ in an inert organic solvent in the presence of a
base to produce the desired phosphorane intermediate II.
The nucleophilic displacement of the acetoxy group
in step (a) may be conducted according to the general pro-
cedure of Clauss et al. in Liebigs Ann. Chem. 1974~ 539-560.
The 4-acetoxy-2-azetidinone is reacted with approximately an
equimolar amount of the 2-methoxyethoxythioacetic acid in an
inert solvent (e.g. water, methanol, ethanol) in the presence
of a base such as an alkali metal hydroxide or alkoxide. Good
results are obta~ned when the reactants are added under ice-
bath conditions and the stirred reactiorl mixture is then
allowed to warm to room temperature.
Reaction step (b) is carried out -Ln a suitable inert
organic solvent ~uch as benzene or toluene with p-nitrobenzyl
glyoxylate or a reactive oxo-derivative thereof such as p
nitrobenzyl glyoxylate hydrate. The reaction is pre~erably
carried out at elevated temperatures (e.g. 50-150C.), most
preferably under reflux conditions. When a hydrate of the
ester is used 3 resulting water may be removed azeotropically
or with molecular sieves. The hydroxy ester product III is
fQrmed as a mixture of epimers which may be optional:Ly
purified by chromatography or used directly in the next step.
16
~ S3~
The chloro ester intermediate IV is next formed
by reacting intermediate III in an inert organic solvent
(e.g. tetrahydrofuran, dioxane, or a mixture ther~of~ in
the presence or absence of a base, preferably an organic
base such as an aliphatic tertiary amine (e.g. triethylamine)
or a heterocyclic tertiary amine (e.g. py:ridine or collidine~,
with a chlorinating agent capable of conv~rting a hydroxy
group to a chloro group such as SOC12, POC13 or PC15. Pre-
ferred temperatures for this step are room temperature for
the case when a base is not employed to about 0 to -10C.
when a base is present. Where the chlorinating agent used
is it~elP an inert solvent under the reaction conditlons of
step (c), e.g. SOC~ , the reaction may be carried out without
the use of a separate sol~ent. Product IV is obtained as a
mixture of epimers which may opt~onally be purified by
chromatography be~ore use in step (d).
Intermediate rv is converted to the phosphorane
intermediat~ II by reaction with triphenylphosphine or
a tri(lower)alkylphosphine such as tri-n-butylphosphine
in an organic solvent (e.g. an aliphatic~ cycloaliphatic
or aromatic hydrocarbon such as hexane~ cyclohexane, benzene
or toluene or an ether such as dioxane or tetrahydrofuran,
or a mixture thereof) in the presence o~ a base, preferably
an organic tertiary amine such as trLethylamine, pyridine
or 2,6-lutidine. The reaction may be carried out at
temperat~res from room temperature up to the reflux tempera-
ture of the solvent system. Intermediate II may be optionally
purified by chromatography be~ore being used as the starting
material for preparation of compound I.
-17-
~ ~ Z ~ 5 ~
The free acid compound of ~orm~La I in the
form of the racemlc mixture or resol~ed dextrorotatory
optical lsomer and. pharmaceut~e~lly acceptable ~lt~
~nd physlolog~cally clea~able esters of said acid have
been found to be potent broad-spectrum antlbacterial
agents useful in the treatment o~ ~nfectious diseases in
animals, including m~n, caused by both Gram~positive a~
Gram-negative organisms. The compounds are also of value
as nutritional suppIements in anlmal feeds and as agents
for the treatment of mastitis in cattle. In addition,
the acti~e compounds of' the in~ention pos~ess good ~-
lactamase reslstance and show advantageously high blood
serum le~els upon oral or parenteral admin~stration.
The actlYe compoundS provided by the present
~n~ention may be formulated as pharmaceutical compo~ltions
comprising, in addition to the aetive ingredient, ~ pharma-
ceutlcally acceptable carrier or dlluent. The compounds
may be administered both orally and parenterally. The
pharmaceut~cal preparations may be ln ~olid ~orm 6uch as
c~psules~ t~blets or dragees, or ln liquid for~ ~uch as
solutions~ ~uspensions or emul~ons. In the trea~ment
o~ bacterial infections in man, the actl~e compounds of
thi~ in~ention may be administered orally or parenterally
-18-
~L2~353~
ln an amowlt oP from ~bout 5 to 200 mg./~;g,/d~y ~nd
preferably about 5 to 20 mg.~kg./day ~ diivlded dosage,
e.g. three or four time a d~y. ~hey ar~ tered
in doliage unlt~ coa~tairling, for exa~ple, 1259 250 or
500 mg. of ~c~ive ingredisnt with suit~ble phy~iologically
accep~ble carrlers or d~uents.
~ rhe pre~ent lnvention al80 proYide~ a method
of com~atting bacteri~l infections ln anim~l~, p~rtlculQrly
blooded animals 3 which co~prlse~ adminl8tering an
acld o~ formula I or a phy~iologlcally cleavable eE~ter
~hereof or a pharmaceutically acceptable salt thereo~,
either i~ the ~orm o~ ~ racemic mixture or prefer~bly
dextrorotatory isomer, or a pharmaceutical co~po~ltlon
thereof, to an infected host in an amount su~icient to
combat such ~n~ection.
Illustratlve e~mples of the preparatlon o~ ~'
starting m~terl~ls and compounds o~ the pre~ent ln~entlon
~ollo~. The~e examples are given in lllustratlon of, but
not in limitatlon of, the pre~ent i~ention. All tempera-
tur~ are in degrees Celsius. ~nle~s otherwise indicated3
the products o~ Example3 1- 6 are racemic mi.~rtures.
-19-
~ 3
Pr~aration of _ar~ Materlals
Preparation 1: 2-Methoxyethoxyacetic acid
-
3 HO
~ ~ 0 " " ~' ~CH
2) BrCH2COOK O
Sodium (1.15 g.; 50.0 mmoles) was dissolved in 2-
methoxyethanol (50 ml.; anhydrous) under N2 at room tempera-
ture. The temperature rose to 110 over about a 30 minute
period. The pale yellow mixture was cooled to room tempera-
ture and to this was added powdered potassium bromoace~ate
(8.85 g.; 50.0 mmoles) under vi~orous stirring. The mixture
(suspension) was stirred at room temperature overnight (19
hrs.) under N2. The excess of methoxyethanol ~as removed in
vacuo and the residue diluted with H20 (5 ml. ) and neutralized
with lN HCl (50 ml.). After evaporation of water, the residue was
extracted with CH2C12(75 ml. x 2) and the extracts were evapo-
rated to dryness yielding 5.26 g. of yellowish oil. This o~l
was distilled under reduced pressure, yielding 2-methoxyethoxy-
ac~tic acid (4.72 g.; 35.2 mmo~es; yield 70.5~) as a colorless
oil: b.p. 98c./o.3 mm Hg; nmr (CDC13): ~ppm 3.~5 (3~, s, -OCH~),
3.4-3.9 (4H, m, -OC~ C ~0~ .22 (2H, s~ H02CC~ 0-), 9.74 (lH,
~ 02H); ir (neat) 1750 c~-l ( ~
Preparation 2: 2-Methoxyethoxyacetyl chloride
SOC12 C~--O ~--~C
T~ 2-methoxyethoxyacetic acid (670 mg., 4.00 mmoles)
was added at 0-2 under N2 atmosphere, SOC12 (5 ml.). The
l~'ZBSi3~
mixture was stirred at room temperature under N2 for 2 hours.
Excess SOC12 was evaporated and the residue was diluted with
dry benzene (15 ml.), evaporated againg and dried over NaOH
(in ~acuo) to yield 2~methoxyethoxyacetyl chloride (705 mg.;
4.62 mmoles; yield 92.5~) as a colorless liquid. nmr (CDCl~):
~ppm 3.40 (3H, s, -OCH3)3 3.4-3.9 (4H, m, -CH2C~ -), 4-56
(2H, s, ClOC~ O ); ir ~neat): 1810 cm 1 ~ c=~' acid chloride).
Preparatlon 3: 2-Methoxyetho~ythioacetic acid
.
H2S/~C2H5)3N HS,~ ~ O
O CH3 C~ C12 o H3
A solution of 2-methoxyethoxyacetyl chloride (700
mg.; 4.59 mmoles) in methylene chloride (10 ml.; dried over
molecular sieves) was added dropwise at 0-5 to a stirred
solution of triethylamine (0.7 ml., 508 mg., 5.04 mmoles)
~n methylene chloride (20 ml.) which had been saturated at
0-5~ with H2S (ca. 30 min.). The light yellow mixture was
stirred at 0-5 for 30 min. and tben at room temperature for
30 min. The mixture was washed with lN ~Cl (10 ml. x 2) and
then brine. The C~ C12 layer was dried (Na2S04) and evaporated
yielding 2-methoxyethoxythioacetic acid (480 mg.; 3.20 mmoles;
yield 69.7%) as a light yellow liquid: nmr (CDCl~ ppm
3.42 (3H, s, -OCH3), 3.4-3.9 (4H, m, -CH2CH2-), 4.10 (2H, s,
-OCC~ 0), 5.0 (lH, br~ -COSX); ir ~neat): 2550 cm 1 (~ S H)~
1770 (~c=~' thio acid).
-21-
Preparation 4: 4-~2-Methoxyethoxyth_oacetoxy)-2-azetidinone
1l
~ ~CH ~ ~ ~ CH~
To a solution of 2-methoxyethoxythioacetic acid
(990 mg.; 6.60 mmoles) ~n lN KOH (6.o ml.) and water (30 ml.)
was added in an ice-bath under nitrogen atmosphere 4-acetoxy-
2-azetidinone (777 mg.; 6.oo mmoles). The reaction mixture
was stirred at room temperature (N2) for 1 hr. and then ex-
tracted with methylene chloride (30 ml. x 3). The ~xtracts
were washed with brine, drled (Na2S04) and evaporated yleldlng
4-(2-methoxyethoxythioacetoxy)-2-azetidinone (1.26 g.; 5.76
mmoles; 96~ yield) as a yellow oil. nmr (CDC13): S ppm 2-8-
3.8 (2H, m, H-3), 3.40 (3H, S7 -OCH3), 3.4-3.9 (4H, m, -C~ C~ -O),
4.25 (2H, s, O=CCH20-), 5-25 (~H, dd~ J3_4 cis= 5 Hz~ J3_4 trans
3 Hz, H-4), 7.3 (lH, br.s, -NH); ir (neat): 3280 cm 1 (~ N H)~
1770 (~ c=o' ~-lactam), 1690 ( ~ c~o' thioester).
EXam
p-Nitrobenzyl 2-(2-Methoxyeth xymethyl)penem-3-carboxylate
20CH2CH~OCH3
CoOCH2~3 N2
-22-
~21~53~
A) Preparation o~ Nitrobenzyl 2~I4-(2-Methox~ethoxyacetylthio~ -
2-oxo-1-azetidinyl]-2-hydroxyacetate
-C-cH2 0CH2 CH2 OC~
N ~ OH
C02CH2~No2
A mixture of 4 (2-methoxyethoxythioacetoxy)-2-
azetidinone (381 mg.; 1.74 mmole) and p-nitrobenzyl glyoxylate
hydrate (500 mg.; 2.20 mmoles) in benzene (30 ml.) was heated
at reflux with a Dean-Stark trap fllled with 4 A molecular
sieves for 18 hours. Evaporation of the sol~ent gave the
title product (820 mg.) as an oil. nmr (CDC13): ~ ppm 2.8-
3.9 (2H, m, H-31, 3.47-3.49 (3H, s, -OCH3), 3.5-3.9 (4H, m,
-OCH2C~ 0-), 4.19-4.24 (2H, s, O-C-C~ 0-), 5.3-5.7 (5H,
mixture of H-4, -CHOH, CH2-Ar), 7.49, 7.65, 8.20, 8.35 (4H~
A2' B2' type, aromatic -H); ir (neat): 3350 cm 1 (~ OH)~
1770 broad, ~ c=o' ~-lactam and ester), 1695 ( ~c=o' thioester),
1525 (~ N0
B) Preparation of
2-oxo-1-a~etidin~l]-?-chloroacetate
S-C-C~ OC~ C ~ OCH3
n
~ ~ C1
O ~
C 0~, C H2 ~ N2
~2~-
5~
To 800 mg . OI p-nitrobenzyl 2 -[ 4 - ~2-methoxyethoxy-
acetylthio)-Z-oxo-l-azetidinylJ-2-hydroxyacetate was added
(all at once) at 0 under N2 atmosphere, thionyl chloride
(3 ml.) and the mixture was stirred at room temperature under
N2 for 1 hour. The excess of thionyl chloride was removed
in vacuo and the residue dissolved in dry benzene (10 ml.)
and evaporated to dryness. There was obtained the title
product (791 mg.) ~s a yellowish oil. nmr (CDC13): ~ppm
2.9-~.9 (2H, m, H-3), 4.10 (3H, s, -OCH3), 3.5-~.9 (4H, m,
-OCH2CH20-), 4.24 (2H, s, O=C-CH20-), 5.35-5.45 (2H, m,
-CH2-Ar), 5.70 (lH, m, H-4), 6.12 (lH, s, -CHC1), 7.52, 7.67,
8.21, 5.39 (4H, A~' B~', àromatic -H); ir (neat): 1780 cm 1
(broad, ~J c-o' ~-lactam and ester), 1695 (~c-o' thioester),
1525 ( ~)NO )
C ) Preparation of p-Nitrobenzyl 2-[4-(2-Methoxyethoxyacetylthio)-
2-oxo-1-azetidinyl ~-2-triphen~phosphoranylideneacetate
O
S-C -CH2 OCH2 CH2 OCH~;
~N ~P ( C6H5 )3
~02-CH~ ~N2
A mixture of p-nitrobenzyl 2-~4-(2-methoxyethoxy-
acetylthio)-2-oxo-1-azetidinyl~-2-chloroacetate (761 mg.),
triphenylphosphine (524 mg.; 2.00 mmoles) and 2,6-lutidine
(0.235 ml.; 214 mg.; 2.00 mrnoles) in tetrahydrofuran (7 ml.)
was stirred under N2 atmosphere at room temperature for 50
hours. After filtration of the precipitate, the filtrate
was evaporated to yield 1.39 g. of a crude oil. This oi.l
-24-
~ Z ~5 3~
was purified by column chromatography (SiO2; 30 g.; eluant-
ethyl acetate) yielding title product (494 mg.; o.736 mmole;
yield 42.3% based on starti~g ester) as a brownish oil.
D) Preparation of p-Nitroben~yl 2-(2-Methoxyethox~methyl)-
penem-3-carboxylate
A solution of the phosphorane product from step C
(494 mg.; o.736 mmole) in toluene (50 ml.) was heated at
reflux for 4 hours and, after cooling, the insoluble material
was removed. Evaporation of the filtrate gave 498 mg. of
oily solid which was puri~ied by column chromatography (SiO2;
15 g.; eluant-diethyl ether:benzene (1:9 v/v)) yieldlng the
title product (1~3 mg.; o.338 mmole; yield 46~) as an oil.
nmr (CDC13) ~ppm 3-39 (3H, s, -OCH3), 3.4-3.8 (4H, m, OCH2C~ 0),
3.86 (lH, AB o~ ABX type, J6-6= 17 Hz~ J5 6 cis 4 Hz~ H )~
4.77 (2H, AB type, J~B= 16 Hz, C3-C~20-), 5.34 (2H, AB type,
JAB- 14 Hz, -OCH~-Ar), 5.69 (lH~ X of ABX type, J5 6 cis= 4 Hz~
J5 6 trans= 2 Hz, H-5), 7.22, 7.70, 8.17, 8.~2 (4H, A2' B2',
aromatic H); ir (neat): 1790 cm 1 ( ~c=o , ~-lactam), 1710 (Jc=o
ester), 1525 (~ NO ); W (C2H5oH) ~ max 2 ~ (
~21 m~ (= 9.8 x 103).
Example 2
Sodium 2-(2-Methoxyethoxymethyl)penem~3-carboxylate
OCH3
C02~a
A mixture of p-nitrobenzyl 2-(2-methoxyethox~nethyl)-
penem-3-carboxylate (133 mg.; 0.338 mmole) in t;etrahydro~lran
-25-
~L2~3~i3~
(12 ml.), diethylether (24 ml.~ and NaHG03 (28.4 mg.; o.3~8
mmole) in ~ O (12 ml.) was shaken on a Parr hydroge~ator for
3.5 hr. at ~0 p.s.i. ~ using 30~ Pd on Celite (diatomaceous
earth, 135 mg.) as catalyst. The catalyst; was removed and
washed with diethyl ether and water. The aqueous layer
after being washed with diethyl ether was lyophilized to
yield the title salt (68 mg.; 0.24 mmole; yield 72~) as yellow
powder. nmr (D20)~ ~.84 ~3H, s, -OCH3), 3.8-4.5 (2H, ~B of
ABX type, H-6), 4-4.3 (4H, m, -OC~ CH20-), ~.17 (2~, AB type,
JAB= 14 Hz, C3-C~ 0-), 6.18 (lH, X of A~X type, J5 6 ci~- 4 Hz,
J5 6 tran5= 2 Hz, H-5); ir (KBr disc): 1765 cm 1 (~c=o ' ~~
lactam); W (H20) Amax 254 m~ (~ = 3.3 x 10~), 305 m~ ( ~= 4.6
x la3)
Substitution of an equivalent weight of KHC03 in
the above procedure for the NaHC03 used therein gives the
corresponding potassium salt.
EXample 3
2-(2-Methoxyethox~methyl)penem-3-carboxylate
F~ OCH2CH20C~
OOH
The procedure of Example 2 is repeated except that
the aqueous layer after being washed with diethyl ether is
acidified to pH 2-2.~ with cold 1% HCl and extracted with
ethyl acetate. The organic extract is then washed with
brine and dried over Na2S04 to give the title product.
-26_
~ 3
EXample 4
Resolution o ~ thox~ethyl)penem- ,t
-
3-carboxylate
A. (+~-2-(2-Methoxyethoxymethyl)penem-3-c:arboxylic Acid
To a suspension of crude d,R 2-(2-methoxyethoxy-
methyl)penem-3-carboxylic acid in isopropanol is added with
stirring an equimolar weight o~ d-(+)-~-methyl~enzylamine.
The mixture is allowed to stand at room temperature for
O.5 hrs. The solid is removed by filtration, recrystallized
from methanol and converted to free acid by treatment with
cold lN HCl. Extraction with CHC13 gives the title lsomer.
B. (-)-2-(2-Methoxyethoxymethyl)penem-3-carboxylic Acid
; To a hot solution of crude d,~-2-(2-methoxyethoxy-
methyl)penem-3-carboxylic acid in isopropanol is added a solution
of an equimolar weight of ~ methylbenzylamine in iso-
propanol. The solution is allowed to crystallize at room
temperature. The crystalline solid is separated by filtration,
recrystallized from CH~OH and treated with cold lN HCl. Upon
extraction with CHC13, the levorotatory free acid product is
obtained.
Example 5
(+)-Sodium 2~2-Methoxyethoxymethyl)penem-3-carbo~yla-te
To a solution of (~)-2-~-methoxyethoxymethyl~-
penem-3-carboxylic acid in methanol is added one equivalent
; of sodium eth~lhexanoate. There is produced the title salt.
Substitution of potassium ethylhexanoate in the
above procedure gives (+)-potassium 2-(2-methoxyethoxymethyl)-
penem-3-carboxylate.
-27-
~L2~S3~l
Treatment of (+)-2-(2-methoxyethoxymethyl)penem-
3-carboxylic acid with other pharmaceutically acceptable
bases in a suitable solvent gives the corresponding pharma-
ceutically acceptable carboxylic acid salts.
Example 6
P~valoyloxymethyl 2-(2-Methoxyethoxymethyl ~ enem-3~carboxylate
:
A mixture of (+)-2-(2-methoxyethoxymethyl)penem-3-
carboxylic acid in dimethylformamide i~ treated with one equi-
valent o~ triethylamine and stirred to effect solution. 3romo-
methyl pivalate (1 equivalent) in dimethylformamide is then
added. The resulting solution is stirred at room temperature.
The mixture is then clarified by ~iltration and the filtrate
poured into ice water. The separated solid is filtered,
washed with water and dried to give the title ester.
The respective acetoxymPthyl, methoxymethyl, acetonyl
and phenacyl esters o~ 2-(2-methoxyethoxymethyl)penem-3-
carboxylic acid may be prepared by substituting in the method
abo~e for the bromomethyl pivalate used therein an equimolar
weight of chloromethyl acetate, chloromethyl methyl ether,
chloroacetone and phenacyl bromide, respectively.
Biological Activity Data
The in vitro minimum inhibitory concentrations (MIC)
of d, ~ -2-~2-methoxyethoxymethyl)penem-3-carboxylic acid (as
the sodium salt) were determined ~or a number of microor~anisms
as determined by overnight incubation at 37C. by tube dilution.
Ampicillin was included a5 a comparison compound. MIC data ~or
the compounds are shown in the following tahle.
-28-
:`
353~
`, . , ., ._Il l,}c~ /ml .
d, Q 2- (2 -metho;cy~
ethoxymethyl ~penem-3 -
Organism carbo~li_acid _ A~
Str . pneumoniae. 03 . 004
A9585
Str. pyogenes .13 .004
A9604
Staph . aureus . 5 3
A9537
Staph . aureus 8 . o6
~ ~o% serum A9537
Staph . aureus 16 > 125
A9606
Staph. aureus 16 32
A15097
Str. faecalis 63 .25
A2o688
E. coli
A15119
E. çoli ~ 125 ~125
A20341-1
X. pneumoniae 32 125
A151 50
K. species >125 ~>125
A2 o468
Pr. mirabilis 1 .13
A9900
Pr. vulgaris 1 .25
A9716
Pr. morganii 2 125
A15153
Prov. stuartii 2 16
A21205
Ser. marcescens 8 16
A20019
Ent. cloacae 8 63
A9659 .
Ent. cloacae 8 125
A9656
Ps. aeruginosa ~125 ~125
: A9843A
Ps. aeruginosa ~ 125 > 125
A~1213
-29-
