CA1128531A - Antibacterial agents - Google Patents

Abstract

Abstract of the Disclosure There is described the preparation of novel phosphorane compounds having the formula

Description

~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.

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 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 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 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.

~ 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.

~ ~ 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 ~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.

~ 3 Pr~aration of _ar~ Materlals Preparation 1: 2-Methoxyethoxyacetic acid -~ ~ 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).

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 ~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 ~ 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 C02~a A mixture of p-nitrobenzyl 2-(2-methoxyethox~nethyl)-penem-3-carboxylate (133 mg.; 0.338 mmole) in t;etrahydro~lran ~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.

~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.

:`

353~

`, . , ., ._Il l,}c~ /ml .
d, Q 2- (2 -metho;cy~
ethoxymethyl ~penem-3 -Organism carbo~li_acid _ A~
Str . pneumoniae. 03 . 004 Str. pyogenes .13 .004 Staph . aureus . 5 3 Staph . aureus 8 . o6 ~ ~o% serum A9537 Staph . aureus 16 > 125 Staph. aureus 16 32 Str. faecalis 63 .25 A2o688 E. coli E. çoli ~ 125 ~125 X. pneumoniae 32 125 K. species >125 ~>125 A2 o468 Pr. mirabilis 1 .13 Pr. vulgaris 1 .25 Pr. morganii 2 125 Prov. stuartii 2 16 Ser. marcescens 8 16 Ent. cloacae 8 63 A9659 .
Ent. cloacae 8 125 Ps. aeruginosa ~125 ~125 : A9843A
Ps. aeruginosa ~ 125 > 125 A~1213

Claims (8)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of phosphorane intermediates of the formula II

wherein Z represents phenyl or C1-C6 alkyl, comprising the steps of:
(a) reacting 4-acetoxy-2-azetidinone of the formula with 2-methoxyethoxythioacetic acid in an inert solvent and in the presence of a base to produce the intermediate of the formula ;

(b) reacting the above-produced intermediate with a glyoxylic acid ester of the formula or a reactive oxo-derivative thereof in an inert organic solvent, preferably at an elevated temperature, to produce a mixture of epimers having the formula III ;

(c) converting the so-produced hydroxy intermediate III

to the corresponding chloro epimeric mixture of the formula 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 compound of the formula wherein Z represents phenyl or C1-C6 alkyl, preferably phenyl, in an inert organic solvent in the presence of a base to produce the desired phosphorane intermediate II as above.

2. A process for preparing a phosphorane compound of formula II
II

wherein Z represents phenyl or C1-C6 alkyl, said process comprising the step of reacting the chloro intermediate IV
IV

with a phosphine compound of the formula wherein Z represents phenyl or C1-C6 alkyl in an inert organic solvent in the presence of a base to produce the desired phosphorane intermediate II.

3. A process as in Claim 1 wherein Z is phenyl.

4. A process as in Claim 2 wherein Z is phenyl.

5. The phosphorane compound of the formula wherein Z is phenyl or C1-C6 alkyl, whenever prepared or produced by the process of Claim 1 or by an obvious chemical equivalent thereof.

6. The phosphorane compound of the formula wherein Z is phenyl or C1-C6 alkyl, whenever prepared or produced by the process of Claim 2 or by an obvious chemical equivalent thereof.

7. The phosphorane compound of the formula wherein Z is phenyl, whenever prepared or produced by the process of Claim 3 or by an obvious chemical equivalent thereof.

8. The phosphorane compound of the formula wherein Z is phenyl, whenever prepared or produced by the process of Claim 4 or by an obvious chemical equivalent thereof,