CA1218663A - Antibacterial penum derivatives - Google Patents

Abstract

ANTIBACTERIAL PENEM DERIVATIVES

Abstract The invention relates to compounds of the formula II

Description

~ 2 This application is a divlsional of Canadian Patent ~ 3 Appllcation Ser~al number 406,827, Eiled July 7, 19~2 ~ hi~ ~e~t~o~ relate~ to per~em de:ri~a~es, to a prclces~ ~or their preparat~on~ to pharmaceu~ic~l prepa~a tiona cQmpri~i~g thela9 alld to inte:e~aediat~ ~o~ ~e jn t}Le preparat~s~ o~ ~bstarlea ~ b cterial ~ct~ y arldfor ~-lactamaae ~hlbito2y and/or ~act~ating act~ityO
The term Npan~ is ~sed ~Ler~ o derLote the ~llo~-ing struct~r~

7~,r~~2 ~ 3 . . . .
,~, . . . ...

~he pres~rLt imre~ion pro~i.de~ a compolmd of the ge:~eral RormulP I

~ ~2 ~ ~ 0 -- . _ in ~ch R represents a h~droge~ .ato~ or a carbo~
e~terii~ ro~p~
p~l repre~e~ts a phe~yl" 3:laphth~17 th~, ~rid~?
qu~ol~l o~ l~oq~nol~ group ~ d at a r~g carbo~ atom 'tD the o~ge~ ato~ attached to th@
~-positio~ of the pe~e~ r~ struct;~, a ~llp Rl bei~ unsubstitu*ed or ~iubstit~ted by one, ~o o~ t~ee substituen-ts~
~hich may be the san~e or different~ ~elected from halogen atDms

2~ NO29 - CIY~ N37 R3-~ R30--9 1~.3S~
R3--S02--, R3--Co-9 R3O--GO-, R~--C~ 2N--CO--9 .3 ~ a.3

3~N ~ N-CO~~ 3~N-COa-9 ~,~CO-N~-~N-CO~~ N~ N-CO~ / N-CO-O-~

R~--CO~N~--, ~2--C(~N~ 3--S02~N33 r, NE~2--SO ~1 . H2N--S02--, ~3~" R3 ~ ~3~
N-S02~ 39~ N-S02 NE[ ~ 3~/ N S02-, ~2~ ~ R3R3'N R3R3\ R3~
~ ~ ~ N- C ~ 3~,~ C = ~ S02~, -CF~ SCF39 -SQCF3, -SO~C~3 a~d H0-C0- grOllp~37 in ~rhich ~39 ~ a:nd li~ each repr~eDts an alkyl gro~p h~i~
~ro~ 1 to 4 ~a~bon ato~ns, R3, ~3 ~d ~13 b~s; ihe ssme or different~ d R repr~e~ a ~droge~ tom~ or a ~ox~ ap ~hi~h m~ be prote~t~d ~ a ~;ydro:~l p~otec~;~g ~o !I!he ~7e~tiOIl alzo pro~ide~ 8alt~3 0:~ a c~mp~nd o~
1~ fo~mula Is~ ~p~3c:iall~ ph;yRiolQgi~ t~lerable ~ r~-0~., -..
~ he stereochemist~ at po~itio~ 5, 6 repre~ent~ a hydro~;yl gr~p,at p~t~on 8, ca~L be ~ r ~
~depe~de~tl~y (R a~d ~3 ~eing a~ d~i~ed by t~e ~I~gold- -20 ~?rel~ ~7~t~m- of rl~me~clat~e)~ Ths pre~er2~d ~tere~
chem:~st~y a~ positi~II 5~:~ EL, .Whe~ a h~r~yl or protected h~drox~l graup~ ~he ~ter~che~ t~ i8 preferably at po8it~0~ 6 and :E~ at po~itio~ ~.

..... . . . . .. . . . .. . . .... _ .. . _ _ .. , . . . , . . . _ . . . .

~ he is:lverL tio~ f~Lrthe2 provide~ a proce~s ~r the production Or ~ compo~nd of the general formula I or a ~alt thereof " ~ h ompri~e~
react~ a compo~ o~ the general form~la II

~4 E~2 ~ CQR5 II
a--a~
~o~ ~o~
in which ~ ar~ a~ def~ea abo~Je ~ repre~e~ts a chlorir~e or bromi~e atom" and ~5 repre~erlt~ a~ a~l grD~Lp ~a~r~g Irom 1 ~o 4 carbon aton~3, or ~ phenyl group, w~h a bas e and9 ~ des~red, ~a:rry~ng o~t. ary one or more o~ the fo~lowirlg ~tep~ i~L ~ desired orderO
a) co~erting ~ ester o~ iorm~la I ~o the c~rre~pond ~ Iree acia"
b~ co~v~rt~g a îree acid oX fo~la I i~t~ arL e~ter thereoi, c) transe~terify~g a compourld o~ formula l;
d~ co~erti~g a ~ree acid or ~ ester o~ formula I i~to a 6al~ ~ or a ~alt i~to t~e free acid~ an e~ter" or a~other ~alt, e) remo~ing any pr~tective groups pre~ent other than an esterifyi~Lg ~DIlp ~9 _ 5 ~ 6~3 f~ convert~ a sub~tituent of ~ grouE ~1 n~o an~t~er substitue~ 0~ ~1,..
:Eroteetive gro~p~ for :hydro~ roup are well 1~19 a~d the~s ~d other ~rotectl~e g:rocLp~ are descri~ea bel~.
The ~erm Sllower'9 a~ ed herein denote~ a rnolec~leg group or rad~ca:L ha~g ~p to 4 c:~r~o:n atom~ le~
~ta~ed o~he~:Lse; hal~geIl ~to~3 ar~ ~luor~ep 6~ ne, brom~e 2~d iodi:~le atDm~9 ~e te2~ "kn~ mez~ i:CL
act~ e i~ the a:~ o~ aesc:r:Lbed ~:L ~he li~e:~e 10 the art .
represent~ ~or ~æmple~ bs~ ihe~;y group or a phe~gl group ~u~ ed by a chlorine~ ~l~e9 tr:inuorl~methyl, meth~ ae~ho:~7 ~t~o" c~ano, meth~lthio7 me~h~lsulph~l9 meths~ al~o~gl, D:ethyl--amino group. The pre~erred substituents are hydroxy, cyano, acetox~, methyl sulphinyl and ~ethyl sulphonyl~ Rl may also represent a phenyl group sub-o ~ro~p. ~ m~y ~l~o repre~e~ a phe2~
~itu~ed by more ~han one g:ro~p~ ~or e:~ampleJ ~ ~ or ~bree ~nethy~ or ~netho::~ group ~. ~ he~erocyclic g:r~p 1~
m~Ly al~o ca~ ~ap ~o ~hree~ sti~en1~s~ ior ~e~ o:z~e 20 Dr ~o methyl g~OUp89 pre~erably a~ r~g ca:rbQD a~
~ ~ill be apprec:iated tha~ the choice o~ su~titu~ts ior ~ ma;sr be ~ubjeo~ to con~ide:~atio~ o~ ~3terevche~
~d also ~ possible i~e:racti~:~ be~7elo~ 9;he ~ubsll;i~nt~
them~el~e~ d othe~ pa~ts o~ a ~olec le in ~-hi~
preaent, ~or ex~nple9 R~ ay h~e 1.,. ~ o~-3. su~sti~Le~t~y b~
~ot more ~han one s~ould be selected i~rom a) 0~ a~d ~ group~
a~d :!lot more than one should be selected iE~m b) --C~ 29 ~3_co~, R30~o~ SO-- a~d :~i--S02 grou~s~
; i (Other substitue~ts may9 o:3~ couse, be ~resent o.~ iti~
~. ~o a group selected ~rom a) and/or a group sele ~ea ~:~o:m b).3 ~ e expert ~ril 1 be aware OI any restrictinn~ o~ the choice o~ ~ubsti~ue~ts, as sueh re~trictions are :known irl the a~
A:~L esteri~ied carbo$yl ~oup~O~ i~; for e~ ple~
5 n e~ter formed with a~ ubs~ uted or sub~ti~atea ali~
phatic 7 ~ycloaliphatic, cycloalip~ic~p~tie; æ~yl, a~aliph2tic9 heter~c~lic or~he~ero~yclic-aliphztic alcohol ~a~ng up ~o 20 carbo~ atom~ or is~ :~or e~ ple, a ~ r ~tan~l ester.
~ alip~atic ~up ~ , Yor ~æ~ple a ~t~ght, or braDc~ed cha~ ~u~stituted or un~ubs~it~ted al~l, ~s:e~
~r al~yl group ha~i:~ ~p to 18 c~rbo~ atoms~ p~e~er~Lbl;y ap to 8 car~o~ a~omsp a~d e~pecially up to 4 carbon ato3n~
. . iQ::r e~ample, a m~th;~1, eth;yl1 n prop;srl, i80--pr~ blat~l, ec~but~ obutyl~ ter~b~tyl, g-pent~ he~yl, all~l, or ~ yl group.
Asl aliphatic group ~" e~pec~l~ a meth~l ,group" masr be s~b~tituted by a c~clo l.kyl9 a~l or hetero~yclic ~¢O~p5 ~or e:~ample, a pyrid~rlmethyl ~ Lps, or ~L mæy it~e~ repre 20 ~ent a cycloalkrl~ l or ~eterocyclic ~ro~;Lp.
A cycloaliphatic group R m~ ~e up to 18 cæ~bo:~l atoms and ~5~ ~or e;:ample, a ~clope~tgl7 cycloheæyl o~ adam~l group. ArL aryl g~oup ~ ~e up to 12 ca:rbo zto~ a~d ~ may have two or more iuaed r~gs. B~ up ~ o~
~5 e~ample, a~ u~substitu~ed or ~ub~tuted phes:yl group, arLd a~ un~ub~t~tuted ~r sub~tituted ~ra~l group i~ Ior e2:a~ple, ~ 7 --a benzyl, ~:nitrobenzyl or benzhyd~l ~roUpQ
~ heterocyclio g~Otlp ~ may have one or more, pre-ferabl~ o~e to three~ heteroatoms, w~:Lich may be the s2me or di~ferellt7 ~3elected ~roxn oæ~gen~ ~troge~ d ~ L~ry 5 a~d up to 14 ato~8 i~ totalO ~ heterocy lic group i8, ~or ex~mple~ a~ 0:2~ygen-co~ta:i~rLg het~rocyGl:ic ~3rsup~ for e:~amp~e~ a ~et~ah3rdrop~ran~1 o~ phthal~d~l ~ollpc A ~t~yl group ~ ~y ha~e ~p to 24 carbo~ ~to~, ~or ~xamplet :E~ may repre~t a ~t~;yl g:ro~Lp hæ~ t~ee 10 ~ubYtitue~ts, which m~y be the 3~e or di:EIere~; 3elected ~rom al~rl, al*er~rl, c~cloalk~ 9 a~O;Ey a7ld aralko~y groups, Ior e:cample, al~l gro~p~ g ~p ~

4 carbo:c~ atom~9 ~or e:~ample~ but~yl groups, phe~l a:nd be~ l grO~lpBg~ especially three bu~yl grD~p~
1~ ~ 8ilyl ,~ro~p ~ three Rub~titue~s o~ ths ~ co~
a~m a~d pre~erabl~ ~p ~o 24 carborL aiiom~ i~ total~ !l~e three substitue~ mR;sr be the same oa~ aifferentp ~~ ~elec ted ~rom al~l" alkeny~7 cycloa3kyl~ a~l s~d a~l groTIp8 pre~erabl~ ~elected ~rom alkyl group~ ha~ up to 4 ~bo~
2Q atoms a~d phenyl grOUp99 e~pec all~ selected ~rom me~
t. butyl and phen~ ~ps. PreIerred 8i~ grOUpl3 a~ ~tri~
meth~ls~ diphe~,~butylsi~srl, arld di~e~hyl ~b~t~l Bllyl ~roup3 .
1~ group ~ that i~ capable o~ ~ubstit~tio~ ~2;y be 25 sub~tit~tedO ~xa~nples oi ~ub~tit~ ts are ~l~ge:c~ ato~;
B.30- ~.3~ R3~ 3~ , R3W~o_o, ~.3 ~ 7 ~_CO~ 2~- C~ O, R
~-CO~ f ~ C~ N-C~0~, B.3 ~3 1 3,~N-CO~ 2~ ~CN, N3~ R~-CO~ 3 CO-N~' R~
9 ~- 9 ~r ~r ~r ~3 so-, R3~so~

~3 SO~ 9 ~ ~O--f, ArO0C~ 0-7 ~-COovO~

5 ~r-CO-S-~ Ar~O_CO~ 9 ~-~38 CO~, Ar~ C~O~
.3_co~ R,3t)_J .l~.r-R3S~9 ~ b~hlrh ~3 a~d ~L are a3 defil~ed abo~e9 and Ar d note~ a~ aryl gr~up, e~peclally a phe~yl groupp aromat~C g~d a~ aromatic heterocyclic group~ 9 :For e~:ample, 10 ~a~ng one or more hetero~toms~ for ~s:ampl8, up to 3 heteroa~oms, which S~Ly be the ~e or differe~t~ 3elected -from ~itrogen; o;~ger~ a~d aulph~ atoms, a~d prefera~l~
up to 14 ~tom~ ~ total~ and the corre~ponding hetero~
cycl~co~y gro~ps a~d heterocyclicthio group~O When 15 represent~ other thaxl a~ aliphatic group~ a ~rthe~
po~ible sub~tituen~ i8 a lo~er al~yl group.
~he group R may be remo~a~le by h;sraroly~is, by ph~to~
, by reacLction or b~ en~yme actiosl to g~e ~he ire~
acid, or two or more methods may be llsed~ for e:cam~le, 20 reductioD Io:Llowed b~ hydrolsr~ , A gIDUp B. th~t ~Ly be remoYed read~l~ without sub t~tial degradatiorl oY the re~t OI the molecule i~ par~icularly osefu:L as a carbo~l protecting grOUp1 :13xamples o:~ e8teI'9 that are readil~ plit ~ 9~ 3 by reductio~ are a~lmethyl e~ters~ Ior e~ample,, b~zyl, ~trobenzyl, bPn~.hydryl ~nd tri~l e~ter~. ~eh~c~io~
o~ an e~ter~ for e;c~ple~ arL ~y~ethyl ester7 ma~ be - car:ried out u~i~g h;ydr~en arLd a metal cP1;alyst, .ILOT
5 e~;ample~ a r~obl~ met21~ for example9 plati~ pa~i~m ~r rhodi~ hich catal~st ~ be ~upported,, Ior e~a~e on ~harc~al or kieselg~hr.
Alte2~ati~vel~ a ~trobe~z;rl e~ter may b~ c~n~erted to the ~re~ ac~d ~r a ~ ~tep metho~g with ~ iDi~
10 reductio~ o~ the ~tro gro~ap" :~oll~ed b;y hydroly~ e ~'cr~ group ma~ be reduced b~ ~o~le ~tal catalysed h~drogenatio~q for ex~ple, ~sing platiRum~or palladiam o~ ca:~bon, .or by.2 me~l redu~in~ aEeat9 for example9~~ c lL~ acetic acid, ~ther me~al reduci~g agen~s are~ ior eaple, 15 alus~ amalgam~ ror~ ~Ld ammo~ium c~l ori`ae, see~
~or e:cample9 Br~t~h Paten~ ~pec~icatic~ 35o. 1~ 60.
Reductio~ ~f the nitro ~r~Up i8 iollowed b~ drol~i~
which msy occur _n t-a duri~g reduc~ion o~ the ~,r~
gro~p or wh~ch ~a~ be c~rried ou~ subsequen~ly by treæt-20 me~ ~ith an acid or a b~ n o-nitrobe~zyl e3ter ~as~
be c~n~er~Pd to the Iree acid by photol;~
A sta~yl ester, for e:g:ample, a tri-n-butgl ~1 ester, ma~ be split readil~ b~ hydroly~16, îor e~ple, b~ ~l~ol~ or example? ~ aterf ~ alc~hol~
2~ phenol or a carbo~lic acid? for e:~ample~ cetic acid~, Certa~ este~ group~ ~y be aplit o~f b;sr base hydro~
ly~is, ior example, acet~lmethyl a~à aceto2~gme "h~l es ,,er 8~

group~ ~, ~ here may be ~ ed an e~teri~y~ng gro~p that i~
remo~able under phy~iologic~l co~lditio~ ~ that i~ to the e~teri~ylng gr~llp 1~ Rplit OI~ ~ vi~o to gi~e the free acid or the ca~bo:~ylate, fo~ e:~ample~ an acylo~met~yl e#ter, ~O~ an aceto~methyl or pi~aloylo~meth~l ester, oalka~oyloæ~ethyl ester~ for e~camplet ~ I~g~ycyl~
~:~ymethyl~ ~alylo~methyl ~or l--l~cylo~methyl ester9 or a phth lidyl ester9 or an optio~ ~b~tit~d 2~o-10 ~thyl e~ter, ~or e~ample; a 2~dieth;ylamLno~th;yl or 2-(l-morpholi~o) eth;yl eRter., Preferred e~t~r~ are the ~ rob ~;~1, phthaliay~
pi~a:Loglsxyme4~;yl, acet;ylmeth;~ d aceto~ neth~l es~e~.
~ es~er of formula I~ or oi a~ other :~re~ ~ci~
15 deacrib~d herei~ may be prepared by reactio~ R:Lth a~
alcohol~ phe~ol or ~tan~ol~or a reacti~e deri~atiTe tnereofO ~he reaction ~ prefer~l;y ca~Tied o~t ~der ~n~ld ~o~ditions i~ order to pre~e~t a~ptu:re of the ~ ~r ri~ ~ystem, ~or e~;ample, ~nder ne~ral or mild acid~c or 20 basic co~dit~on~ d ~t ternperat~res with~ the range of ~rom-70 to ~5C.
A~ alkyl" Plkw;yalkyl or ~1 e~te~ may be pre~
pared b~ reactio~ o~ aci~d of ~o~ula I or an;y othe~ ~ree acid ~i~h the apprDpr~.ate diazoalkane o~ di~zoar~l~e for 25 e:cample ? diazometh~ne or diphe:llyldi~zorr~eth~e. ~he reac tion i~ prefera~l~y carr~ed ou~ an ethe~ e~ter or h~l~
ge~h;ydrocarbon a~ ~olve~t, ~ or e~ample, i~ die~hgl e .,her"

8~i~3 ethyl acetate or dichlorometsl~e ~ ID generPl, tempe~atu~es below room temperatLre are prefe~Tedg for ~ample 9 from -~ 5 to ~15~C.
~ e~te~ deri~ed Ir~m ~L alcchcl m~y al~o be ~roduced 5 b~ react~ 021 o~ a reacti:ve deri~ati~e oi the ~lcohsl" for e:~:ample, a halide, ior e:~ample a chloride9 ~rom~de or iodtde7 or a hydrocarbon~ulphon;yl deri~at~e~ for example~ a me~y or tosyl eBter~ with a ~a:lt o~ ~ acid~ o~ iorr~ I or a~other ~ree acid de~cribed h re~ or e:~amplel, a~L a~i lt3 or alkaline earth metal ~ lt~ for ezaslple~ a ~th~
svdi~m~ pota3si~mS caloium or baria~ ~alt or an ami~ t9 ~or e:~:~ple, a triethylanmorL~ lt~ re2ctio~ iB pre;
~erabl~ c~ie~ out ~ a ~ub~tit~ed ~ulpho~ide or ~ide sol~ent ior e:~a~plet ir~ dimeth~ lpho~de, di~ethy~or~a 15 mide or he~amethglphosphoram~de or, alte~ati~e~y9 a~ e~te~
may be prepared by react~on o~ the acid ~ith the ~lcohol i~
the prese~ce of a co~den~ g ~Lgent" for ex mple~ aic~cl~
he:~1carbodiimide .
A ~tanr~l ester may be for~ed by reaotion o~
20 bo:~y1ic E~cid of ~orm~la I or ~nother ~ree~.id descr~b~L
here~r~, or a salt thereo~ with a react~re tetra~a:!erLt ti~
comp~lmd~ e~pecis11~ a trialky1 ~ L o~:ide~
~ he pre~e~t invention al~o pro~ide~ the ~3al~,B OI
tho~e co~pou~ds o~ ~02mula I that ha~e ~lt formi~g group~5 25 eEpec:l a11y the sPl t~ o~ iree 2cid~ OI I orm~la I ~d the acid addition ~al th o:E com~o~ds oi form~la i havi~ a ~asic group. The ~alts are e~peciall~ ph;y~iolo~icall;y to1erab1e ~ 12~ 6~

s21t89 for example7 alkali s~etRl ~rLd alkali~e eærth met~:L
8al-t8~ fo~ eæ~mple, sodi~m, potassium, lithium, c21ci~
and magneei~m sal-t~9 ammonium sPlt~ and ~alt~ with organic am~e; al~o pn3~iologicall~ tolerable acid ac~
5 tiorl ~8~t8~ ~he~e may be formed7 wi~h ~uitable ixLor~;~c and organic acid~3 7 ~or examp:Le, h~chloric acidg E;U3 phu~lc acid" organic c~bo~lic P~d org~niC ~ulpho:~Lic a~iQs ,~
~or esample, tri~l~oroacet~c acid ~ ~tol~ e~ lphonic acidO ~ome compou~d~ of ~orm~l~ I ~ch co~tai~ a bR~3ic 10 centre ma~ e~ t a~ Z~tteri~ Lch salt~ are ~ so pæ~
oi ~,.his ~entio;EI.
~ salt o~ a ~ree acid of ~o~sula I may be prod~ed by reac~i~g the i~r~e a.cid with the approp~iate ~ase ~n sol~entl preferabl~ under conditio~ der ~hich the aa 15 precipitateB. A pre~erred base is p~tass-i~m eth~l hesa~l~a~e.
- ; ., t may be produced directlg ~om a~:L ester by ~plitti~g oif the ester gro~p ~Lder suitable reaction con-ditio~s, for e::ample~ catal rtic red~ction o~ a~ ester, ~or e:~ample t ~ ~nitrobenz;yl ester~ aq~eous/org~c ~o ~ol~e~t, ~or e~ample, compri~ing ~ater arLd ethyl aceta.,e, diosa~e, ~r tetrahydrof~ran, i~ the pre~e~ce of a met~l salt, e6pecial1y a ~icarbo~ate, ~or es:~mpleg i~ a;l ea~a-1 erLt arllou~t or ~ a ~light e:ceess, yield~ 2 salt di:~ec~ 7 Cc~ pou~ds of the general ~o:rm~la I may be ~r~àuced, 25 for eatample, a8 show~ i~ the rea^tio~ ~cher~e bel~.

Y ~1 ~sR }~ ~R6 C~l ~ Q!3~ CR3~

COOR
VI . V n 1~ B SR6 C~ - CB ~ ~ - CB +~/
R _~; SC0R~
f SC0~ ~-rh~n 2R O ~ \ ,f C --C ~ C --C
I OR~ onl coo~
%I I Ill CH3 - ~n4 ~ 4 o ~ ~ c = c C =C
COOR ûRI Il '00?. 7~ OR
XII

C~l - C~ OR~

000~

~n ~hich ~ 2,R4 ~nd ~15 are a~ d&fi~ed abo~re;
repre~e:~lts a hydro:~yl protect.~g grc~..p, ~6 i~ de~i~ed belo~r~
and ~ repre~z~t~ a group that is capa~le o~ being re placed by a ~ucleophili~ group and i~ e~pecially a:s acrl 5 ox~ grou~3" a ~ulph~ l ~oup, or a halogen atom., acg-loxy group ~ e~p~oially a lo~er alkyl~rbo~ rlo~y gro~ap~ parti~lar ~ aceto:~ group. ~ haloge~ ato~ 1 e~p~cially a chlori~e a~om~ ~ ~alpho~ raup is a group _so2R7 ~ ~hich R7 represe~t~ an alkyl groap 10 har~ iroD~ 1 to 4 carbo~ at~ or a~ ~1 groap, peclall~ a ph~n~l group., A compound of formula VI in which R represents a hydrogen atom, or a modified hydroxyl yroup may be prepared in known manner.
A compound of formula VI may be converted into a com-pound of formula V by reaction with a compound of formula VII

R8 _ S - R~

~ hich R~ r~pre~ent~ a~ al3~ roup ha~ ~r~ 1 ~ 8, pre~erably ~03~ 1 t~ 4 ca:rbo~ at~ms, a~ al~e~l g3~
havi~ 3 - ~ - carbo~ atbms9 or a phe~yl ~OUp9 a~ ~3 5 repre~ent~ a hydroge~ ato~ or ~ ~:ali EEetal ato~
e~p~cial~y a aodi~m or potas~i~ ato~ 6 preieraDl~
repre~nt~ ~ allyl gr~uE or a ~traigh~ cha~n,, lo a~l grs~p~ e~pecially a~ ethyl group~
~he reacti~ gener~ ca:rrlèd out ix~ a ~ol~ t;9 10 pre$`erably a protic ~ e~t" for esa~ple9 ~ater or alcohol, or a l~o~-protic, ~ater-~iRcible ~ol~ent i~ich i~
preferably p~l rr for e~asaple, dis~eth~ ~de" ai~
sQlphoside, tetrah~droiura~ or dio~ e reacti~ te~
perat~re :~S9 :Eor e~a~ple~ iro~ -20 to ~5û~ prefe~ ro 10 ~o ~2~C~
~ o ~btai~ a c~olp~u~d o~ o~ul~ IY~ a co~apo~a ~3~
~o~ula V may be reacted, i~ ths pre~e:nce 9I a ba~e, ~ith a compou~d o~ ~ormul~ VIII

~ ~2CO~

20 ir~ ~hich ~ i~ a~ de~ined abo~e a~d ~ 1 repre~e~t~ a ~:roup that i~ capable OI bei~ lac~d by a nucleophilic gr~up a~d is, ~or e:~ple7 æ
haloge~ atom, preferabl~ a b:rom~ or iodi~ at~
or a Jnodi~ied h;ydro~ group~ preferabl;s a ~1~Le~1 o~ group o~ the Io~m~a in which R represents a lower alkyl or -CF3 group, or a phenyl group which is unsubstituted or is sub-stituted by a p-nitro, p-bromo or p-methyl group.
yl preferably represen-ts a bromine or iodine atom or a methylsulphonate, trifluoromethylsulphona-te, tolylsulph-onate or benzenesulphonate group.
The base may be inorganic, organic or organometal-lic, for example, an alkali metal or alkaline earth metal hy-10 droxide, oxide, carbonate, bicarbonate or hydride, for exam-ple, sodium hydroxide, magnesium oxide, potassium carbonate, potassium bicarbonate or sodium hydride; a tertiary amine, for example, a trialkylamine, for example, triethylamine, DABCO (diazabicyclo(2,2,2)octane), pyridine, or an alkyl-sub-15 stituted or amino-substituted or dialkylamino-substituted py-ridine, for example, N,N-dimethylaminopyridine, or collidine;
a guanldine, for example, tetramethylguanidine; DBN (diazabi-cyclo[4,3,0]non-5-ene) or DBU (diazabicyclo[5,4,0]undec-7-ene); a polymeric base i.e. a base attached -to an inert poly-20 meric support e.g. Hunig's base (diisopropylethylamine a-t-tached to e.g. polystyrene); a metallated amine, for example, a metallated alkyl or arylamine, for example, li-thium diiso-propylamide (LDA), lithium hexamethyldisilazide, lithium pip-eridide, lithium 2,2,6,6-tetrame-thylpiperidide, or a Grignard 25 reagent, for example, methylmagnesium bromide. Preferred 7 ~

bæse~ are~ ior exzmple~ pota~itam caIbo~te9 8c~di~
hydride, lithium dii~oprop~lamide a~d triet,~l2min ~!
The reactio:c 1B gener211y ~ rried out i:~ ~ a~ro~c ~ol~ent ~r dillle~t~ ~or ~ample, ~ tertia~ ~de9 lo~
5 e~ample~ d:Lme~h;yl~o~amide~ dimetnylaceJGPm;.de or heza~
meth;ylpho~phor~de; a h~drocarborL9 ~or e2:Prr!ple ~ ber~e~e or toluene or an ether, ~or ~::ample, diet~l sthe~, tetr~;ydro~ura~ or-dio~:a~e; ~ a eh:Lori ated h;ydro~o~
~o~ eæample, met~le~e chlor1de or chlorofo~ or ace~
10 rLitr; ~1 e, di~eth;yl ~ulph~xide ~ or ~ulphol~ne. D~me~
f`onna~ide a~d dimethylaceta~de are pref`e~e~. ~ ~æ~e Ol tws or more ~ol~ent~ nd/or dilue~t~ m~Ly be ~edi, ~ he reactio~ e ca2ried oat at a ~mpe~ enerally with~L the ra~ge oi from ~30C to +~O~C prelerabl;y -40 to ~3occ9 a~d e~peciall;y ~rom-20 to ~20~
Prorll 1 to 1.5 mol~ of compo~d ~III are p~efer~l~
tlsed per mole o~ compo~n~ V, -eRpe~ially :Ero~ 1 to l~l moles of VIII per mole o~ ~0 ~e base i~ nsed iiL ~L ~ mt . -~or e:~ample, ~rom 1 to 4 mole~ of b~e per mole o~ com 20 pou~d V~
~ he reactio~ i~ pre~era~ly ca~ried out, b~ d{s~o~g compo~d V i~ a solvent, ad~antageo~sl~ :Ln di~:neth;y~D
Iormamide~with ~3tirri~1g9 addi~g the base, aadi~g the compo~nd o~ ~ormt?l P ~II ~na reac ,ing at the desire~
2~ temperat~Lre. ~he re~ in~ oompo~d o~ ~o~ulæ IY ~v be worked up and isolated in the u6ual maD~er~ ~cr e~le, usin~; chrDmatographic andJor cr;y8tallis2tio~ te h~e .

. ~ 18 --or the ~ubseque~t reaction may be cz2ried out directl~
o~ ~he re~ ~g reactio~ mixtu~e after re;~oYPl ol a~y solverLt that i not compatible with the ~ubseouent rezc,ion~, II R ~ f ormu:La IY repre~e~t~ a carbo~l es~eri~ cLg 5 grollp, this group may be co~Ye:~ted iIlto another ester~-~;yi~g ~ up 3~? for ~:~amPle~ ~D i~ uce group ~ ~h i~ more easily ~emovable ~de~ de~ired ~orldi~iorL~
tra~ee~teri~ catio~ i~ ge~es~ ¢~ied o~ a~ ~ollc>~:
the ester o~ form~la IV i~ hydrol~se~ ~ krlo~ m~er 10 u~iDgD ~r e:~amp7 e, acid or alkali:~e h;ydrDly~ preferabl~
us~g an alkali metal h~dro:~ide9 e~peci 11~ ~9dium or p~-tas~ m h;ydro~cideO ~he e~ter of ~o~ La IY, ~or e~ample, a m~hyl e~ter9 i pre:ferablg hydr~ed tl8~ ~ ~li metPl hydro~cide e~peclall~ one mol~ ~hereof per s~ole o 15 the eR~er o~ form~la IV ~ a eol~ent,~ ~or e~ample-etha:~lg methanol or water, o~ a~ aqueou~-orga:~lic Rolve~t, ~or e~ Lple,, tetra~ydru~ur~/w ter~ et~olJwatert or ace~o~
rile~ater.
~he reacti~n m~ture may the~ b~ acidi~ied to gi~e a ~ 80~ t~0n oî p~ 1 ~G 5, pre~erab:4r 2 tg 49 2~d the ~ree acid ma~ the~ be i~olated andt ii desire~, the ~ree acid i~ thell esteri~ied with ~r~ e~teri~yi:~lg ag~t capable of introduci~g -~ a dif~e~ent esterif~ g group ~ ~or e:~:ample ~ith ZIl ~lc~
hol RO~ i~ the presence of an acid or ~nother acti~t~
25 agerlt, ~or es:~rnple/ dicyclohe:~glcarb~diimide, or ~i..h 21~1æting age~t B~ irL which ~ as deDi~ed aboveO
~lte~Lat~vely, a salt ma;y be ~solsted and e~ ~eri~. ed dire~tl~, 6g~3 ~ 19 E~terifica~ioR methods are de~c~bed above ~ L relæ~,io~
to the co~pound o~ Iormula I, ~ ran~e~tel i,icatio~ may be carried o~t o:E~ com~ou~Ld IV
as de~cribed abov~, or oll any vther i~termed~te o- o~
5 the ~inal product of iorm~a Io A compou~d o~ fo:rmula IV ma;y be co~erted irL-.o a com~
psur~d o~ fo~ la III by reaction, iD the pre~e~ce o~ a base~ with a compour:Ld oi ~o~mQla I~

a~

10 ~ which ~1 ia a~ deIi~ed ~bo~e, followed b;y reac~io~ Rith an acti~ted carbo~glic acia deri~tive ~ich cosc~ses the group R, ior e ample9 a compow:ld o~ ~o~
O ~ .
;~5 i~ whi.~ R~ ~8 as d~ ed abo~e, Some comp~d~ o~ form~la I~ are k~own a~d som~ a~ . .
ne~. ~ew compo~d~ be prepared b~ proceæses analogou~
to those ~or the prepara~io~ of ~,he ~o~ ~ompo~d~. c~ ., ~l~er t3: Schalch, :E~elvO C hem. Acta, ~ol 6, 1923, p.6~$~ a~d ~ich & Nart:~:L, Cherll :Berichte~ ~1 98~ 1965 p~2û6~.
~he reaction between compo~and I~ a~d compotmd IV i~
carr~ed out ln the prese~ce of a b2se~ pre~erably h~ing a p~a ~209 pre~erabl~ a metal~ated ami~e? ~d ex~m~le~ o~
preferred ~a~e~ are lithium ali~opropylamide~ hi~
he~amethyldisilazideg lithium 6,~j2~2-te~rameth~l~iperidide, f ~ 3 20 ~

lithium cycluhe~ opropylzmide ~ d sod~d~, ~ he reactio~ i~ ge~erally carried ou~ .sro.,ic ~ol~entD for e:cample, an o:~:ygen~,ed h;5~dr~car~on9 pre~
ferably an ether~ for e::~ample, die.,h~l ether, te..r~
5 fura~, dio:~ane, ,glyme o~ diglyme. ~he ~eactio~ tempe~2~e i~ for example, ~rom -120 to ~50~C9 pre~rably from -~l8 to 20C.
~ he amou~G oi base ~d i~ or e:~ample~ lro~ 1 to 3 mole~9 calc~alat~d per mole o~ compo~d IV, preierably from 10 1.5 to 2~ moles of` ~a~eO ~he compnurld o~ for~
preIerably u~ed i~ an amoun~ o~ ~rom 1 to 1.5 mole~ per mole vf compo~Ld I~9 preferabl;y from 1 t~ 1"1 molD~ o5' compo~d I~.
~he r~actio~ i~ p~eferabl~ carried o~; as iollo-~:
1~ ~o a s~ ed s~lutio~ o~ comp~na IV ~de~ ner~ a~
- mosphere i~ added the ba~ ~d ~ub~eq~e~tly a ~ol~-,io~ o~
compourld IX in ~he ~ame or a di~ere:~t 901~eD'to !~he aotivated acid derivati~e, pre~erably of LO C~
pre~erably adde~ to the ~t~e ~esult~ ~rom ~h~
20 r~a~tion o~ compounds IV ar~d X~ e~pecially i~ ~ amo~ o~
~rom 1 to 2 moles calc 1 a~ed o~ co~pou~d I~ he re~c~ ~ orL
i~ pre~erably carried out at a ~emperature ol ~rom ~0 to ~40Cs addi~,g the comp~ d 05~ ~o:~nla ~ to the reac~,io~
miæture at the temperat~re at ~ich the reactiorL be~ee:n 25 compou~ds IV and I~ tcok pl~Lce, ~n~ 'chen wPrmi~g~ or ~7 ~ o~--ing the mi:~ture to ~arm~to ro~m t~mperatureS i~ d~sired, h~ating the misture to a temperature of ~p to 40C.

- 21~

q~he -SCoR5 gr~up i~ the re~3ulti~lg compou~d oi foD~ala III may be ,~ or tran~ to the -COOiR gro~p~ The iæ~
~ay be separated for the ~;Lbsequent reactio~, but ~i~; i8 ot g~llerall;~ ece~ary ~ and t~e i~o~eric ~ILi~e i~3 ger~erally u8ed3 It iB pre~erable to protect a ~ree hydro~ ~p ~
b . iore the ~o~mation OI compou~d I:l:I, to preve~t the $a~e hydro~sy group from reacti~ng with the co~npou~Ld o~ f~ula I~ and~or with the acti~rated carbo~ylic acid deri~a~
e protective ~roup ~y be i~ltr~duced i~;o co~p~o~xLa :~
before ~t~ co~er3io~ i~to compou~d III~ or it ~y ~ in-troduced at a~ earlier ~tage irL ~he reactio~ ~eg~eD~ç eg~.
i~ co~p~u~d Y or VI"
~ compQund OI ~or~ula II may be produced fro~ a 15 compo~d oi for~aula III directl;sr by haloge~atio~L~
The ~alogeIlatio~ i~ carried out 7~ith n ageIl~ ca~le of E~plitti~Lg a carbor~-~ulphur bo~d a:~d i:~trod~c~g a halogen atom~ ~3Rch agents are well known ~ ~.he ar~
i~clude, ~or ~ple~ IDole~ular ~ chlorine, mole~ br~
20 ~ine, ~ulphury~ chloride, ~lp~r;yl brom~de, ~b~
ch:Lorite a~d c~a~ogen chloride.
T~e reactio~ i8 generally ca~i~a 25 out at a-temperature within the range of ~rom 40 ~3 ~20Co ~he reaction i~ generally carried out i~L a 8c~
~ent or dilue~:Lt, tha~ i6 rLor~-pr~tic a~d i~ ~er1i am~ ~e : .

.

- 21a -reaction conditions, for example, an ether, a hydrocarbon or a halogénated hydrocarbon, for examplel dioxane, benzene, chloroform or methylene chloride. A mixture of two or more solven-ts may be used. Examples of halogenating systems are:
chlorine in chloroform and, especially, chlorine in benzene and t-butylhypochlorite in benzene. In the latter two cases, the temperature is preferably from 5 to 20, and especially from 5 to 10Co Generally 1 to 2 moles of chlorine, bromine or cyanogen bromide are used per mole of compound III. (cf.
S. Kukolja J. Amer.Chem~ Soc. (1971) 93 6267, and P.C.Cherry, C~E. Newall and N.S. Watson, J.C.S. Chem. Comm. 1979 p. 663).
Before halogenation, however, it is preferable -to remove the protective group R2a from a hydroxy group R2 in compound III, in order to obtain the most desirable stereo-chemistry in the final product. The protective group may beremoved in any conventional manner (see below) to give comp-ound XI. Preferred hydroxy-protecting groups R2a are those which are compatible with the synthesis of! the compound of formula III and which may be removed under reaction condit-ions in which the resulting compound XI is stable. CompoundXI has been found to be stable in the presence of a proton source, for example, hydrogen chloride, aqueous hydrochloric acid or aqueous hydrofluoric acid. Accordingly, one type of preferred hydroxy protecting groups Ra are those which may be removed under acidic conditionsO Such groups are well known in the art ~ 21b and are, f or e:~ample, tetrs~ydropy~yl a~d tetrah~dro~ur a~yl group3; acetal and ketal ~oup~ ~ ~or e~ample, o~

f o~mula ~ -~7 ./ \

in which :B8 and R9) which ~nay be the ~arne or di~ferent, each repreee~ a h;ydrogen ato~a or a lo~er al~ ~up~
preferably a ~nethyl grOUp9 or R8 an~ ~9 t~gether ~ith the carbo:~ atom to ~hich they are attached, represent a cyc~o-al~l ri~g ka~i~g ~rsm 4 to 7 carbo~ atosn~9 or a tetr~
10 h~drop~ yl ri~:Lg" and ;~ represe~ts a l~er alkyl gro~p, pref erably æ meth~l or et~l gro~p; al~o Bilyl e~ters 7 ior e~cample~ a~ described abo~e i relation ~o :E~" for ~ OR~ 2 gr~up~ in which Rl R a~d ~ 7 ~hic3:
ma,;sr he the ~ame or dif~ere~." eac~ represe:~s a lol;er 15 alk~l group or an ~1 group, for e:~ample$ tTieth~rl~il~rl, t b~yldimeth~lsil~l and meth~ldiphe:~;ylsily:l gro~p~; and ~ta~myl ~ro~ps, ~or e~{ample, a~ d~cribed above in relation S~L3.B.14.~.15 ~oup i~ ~hich ~ 3, :~

~d EL15, wh~ch may be the ~ame or different, eac~ repre~e:cLt~
20 a lower alkyl group~ Ior e~ sLpïe, a tri~ butyl~t~n~l group~ Pre~erred :E~a groups ~e tetrahydropy:rarLyl, 2~
methoæypro-2-yl~ trimeth~l~ilyl9, ~,riethyl~ilyl and, e~-peciall~S t-b~tyld~methyl~ilyl group~O
Such group2 sla~ be removed by acid hydroly~ o~
25 e:~ample, u~ing moderatel~ conce~trated h~d~rochloric aci e~3. 6M ~ICl, eg. i~ tetrahydro*~ (c~ Belgian Patent 21c --~pec~Iicatio~ 39c. 881 012); t~ !? in an acidic ~edi~a e,g. in acetic acid (cf~. ~elgian Pate~t ~pecifica~ion ~.
882 764): or aqueou~ droge3~ nuor~de, eg. :L~ the pre~e~ce o~ aceto~itrile (c~. J. Che~ ~ocO Pe~:ki~ 1~ 19819 20 ~he halo~se~atin~L oî co~po~d ~I t~ gi~e co~p~
be ca~ d 2crt ~;ub~ta~tia~ a~ de~cribed albo~, ~e ~aloge~ating s~gent i~ generally ~3ed ~ a~ a~o~L~ o:t ~ro~n 1 to 2 ~ole eq~i~alent~, calc~lated o~ the eo~
o~ ~or~la ~I~
t 10 . It ~ bee~ Iound, svrpr~y7 that balogeDat~on o~ a compo~d o~ I o~D~ I that ~ tereochem~
give~ predomi~antl;s~ the corresporLd~ 4~ co~np~u~d e~
fo~ula ~ rhereaa haloge~atio~ ~i the corre~po~ing compnund of formula III having a prote~ted hydro~ group R g~vr~
predominantly the les~ deYired 4R halogenated-compo~nd.
h compound of formula ~ i8 produced ~rom a compo~nd o~ form~la II or gII by reacti~n ~ith a base, The base must be - capable of ~plitt- g the thviQcarb~ bond i:~ a c~a~a o~ ~on~ula II or for~La :~II ~d oi bri~ g abo~t :ring Clo8ure:. ~he ba~e 2ay be ~orga~:ic or organio, ~or e:E-alQple, a~aonia9 or an alkali ~etal~ especiall;r a ~ma 2~ or pot~s~iam, carbo~ate~ blcarbonate~ or h~drG:~ide; 2 pr:Lma~ amine, ~or e:cample, meth y~a~e 9 ethylami~e5 ~ili~e or be~z;ylamir,e; a~ alkali ~aetal alkozide ~n the corresponding alcohol9 ~or exa~n~le, ~dium metho~ide ill metha~ol; ~r a heteroc;yclic bas~ for 0~ample, 25 a PEa ~ithi~ the ra~ge o~ ~rom 5 to 9, ~o~ e::ample~
ida~ole or pyridi~e or a ~ub~tituted p;~ridi~e, ~or e~mple~ aD alkyl, amirLo, or alk~l~r,iDo-~ub~tit~ted '.`~

- 21d -p~idine, ~or ~ampl~, 4 ~aeth;yl-~ or 4-dlmethglami pyridi~e,, Imidazole i~ pa~tictala~l;y prefe:rred.
The reaetio~ i~ gen~rall;y carried o~t , n a solTG~t or dil~ent, the choice o* ~hick i~ ~ide, prc~ide~
inert ~a~der the reaction coIlditio~ amples 9i ~ol~en~s a~d diluent~ are o~yg~ted h;ydrocarb3~, ior e~bleD
alcohol~, xor e:ca~ple" havirlg up to 4 carbon ato~aa9 for escample, metha:Z~ol and ethanol; eth~r~" ior e:~ample up to 4 carbo:a, atosn~, Ior e~ple, diethyl ~th~r~
10 tetr~dro~ararL a:cld dis3:cane; keto~es, ~or e~ple, ha~ng up to 4 carbo~ ato~s~ ~or e~ample, aceto~ l e~
ketone; ester~, ~or e:~mple, meth~rl ace 4 . te ~d e~l acetat~, and ~ides, ~or e~a~ple 7 dimeth;srl:eo:r~Lide ~d dimeth~laGet~ide; al80 ehlori~ated hydrocarboru3, ~or 15 e~ 9 chlsroform, meth~rle:~e chloride 3~d car~o~ ~e~a chloride; aro~atic h~rdrocarbon~, Ior e~:~mple " ~e~2;~e and toluene; and other ~o~ventFs Ior P~cample g aceto~itr~e a~d 2~itrometha~e~ ture of a~ two or more ~ol~er?ts ~L~ ~e ~sed, and svlve:~ts are preferabl~ ed in ad3;Lirt~re ~n~h 20 water, preferably a ~ter~ cible eol~erLt i~ ad~
with ~ to 2~ (v/v3 water9, ~he reactio~ i~ ge~er~ ll;y carried out a~ a tem~rat~re with~ the range of ~rom 0 to 40~C, preferably ~rOF O ~
~oa~
It i~ prefer~ble to e~teri~ an;y free ear~o~
pre~ent in a compo~d of form~la II or form~ II prior to co~version to a co~npo~d of for~la Io ~ltho~ ~

8~i3 ester group may be introduced immediately prior to thi~
co~ver~ion, it i~ pre~erable to esteri~y the carbo~yl gro~p at an earlier stage in the pre~erred reaction ~equence, ~or e2ample, to ~steri~y a ~ree carboxyl group in a com-pound o~ ~ormula III, IV or XII to ensure that the car-bo~yl gro~p d~es ~ot tRke part i~ ~ny o~ the suhseque~
reactio~s. ~ e~teri~ing group ~a~ be tran~esteri~ied to another ester group h~ g more de~irable properties ~or a particular ~tage o~ the reactio~ s0que~ceO
Purther~ore, it is advisable to protect any reacti~e ~oiety pre~e~t in either R or ~ co that ~uch a ~oiety does no~ react with any of the reage~te used in a~y su~-~eq~ent reac~lo~. ~ample~ o~ mo~eties ~hi~h may req ~ e protection are hydro~y, carbo~y and amine moietie~ ~hich h5 m~y, ~or e~mple react ~ith the reagen~ ed to co~Yert a compo~nd IV to a co~pou~d IIlo Gro~p~ ~uitable for protecting such re~oti~e moiet~e~ are well kno~, a~
are methods for their removal. (c~. Protecti~e Group~ in Orga~ic Chemi~try, editor J~F.W. ~cOmie, Plenw~ Pre~s~
197~). (The speclal consideratio~ ~ith regard to a ~ree hydro~ gro~p R2 are gi~e~ a~ove~) E~droxy_protecti~g group are exempli~ied abo~e.
~ arbo~-protectlng group~ ~re, ~or e~æmple, a~ de~-cribed above for ~ ~mi~o protecti~g group8 are, for 2~ e~mple, t-butyloxycarbonyl~ be~z~lo~ycarbo~yl, l~nitr~-ben~ylo~ycarbonyl~ ~nitrobe~zen~ulphe~gl a~d trityl gruup~.
Reacti~e mol~tie~ ma~ be pro~ected at any appropr~ate poi~t ~n t}le reaction sequ0nce,, a~d the protecti~e g~
are pre~erably remov2d a~ter the fo~atio:~ o~ the c~tmd o~ forsltala I, for e~ple, i~ ;~ o~ la I represe~t~ an e~teriIying group, this may be remo~ed ~ the u~al ~er;
deperLding o~ the ~ re o~ the e~ter group, for e:~ple~
by h;ydrolyei~, reduction, or enzymaticall~, to ~elf! ~
~ree acid~ ee acid or a~ e~ter may be co:D~erted ~o a ~altg e~peciall~ a ph;y~iologicall;y tole le sal~, or a ~t n~ay be con~erted irlto a~other salt or ~he iree ac~d or arl ester. ~n e t~r ma;sr be tra~ st~riiiedJ or a :~ree acid co~verted into arl e~ter, ~or e:~ample, to gilire a:c~
ester capable o~ removal unaer phy~ ological co~di~io:~.
:E~cample~ of ~uch procedures are giYen abo~eO
Ii ~2 ir~ a compou~d o~ Io~la I represent~ a p:rotec=
ted hydro~y group, the protecting group ~a~ be re~
~o~ver~ely, i~ ~2 repre~e~t~ a iree hydro~ gro~p, l~is may be cor~verted into a protected h;srdro:~y ~ pg e~pec~ly one ~ whioh ~he pro~ecting gr~up i~ phg3iologi all~

movable, for example, a group of the formula R10Co_ or R11_ in which R10 represents a hydrogen atom or a straight or branched chain alkyl yroup having from 1 to 4 carbon atoms, especially a methyl, ethyl or t-butyl group, or represents a phenyl group or a phenoxyalkyl group in which the alkyl mo~ty is straight-chained or branched and has up to 4 carbon atoms, and is especi~lly a methyl groupi and R11 represents an alkanoyloxymethyl group in which the alkane moiety is a straight or branched chain alkyl group having up to 4 carbon - 23a atom~, and is especially a methyl or t-butyl group. Preferred physiologlcally removable protecting groups for a hydroxy group R are acetyl, propionyl, pivaloyl, benzoyl, phenoxy-methylcarbonyl, pivaloyloxymethyl and acetoxymethyl groups.
In a compound of formula I, a hydroxy protecting group that is not removable under physiological conditions may be con~er,ed into one that is remo~able under such conditions.
An advantage of physiologically removable protecting groups is that they appear to increase the oral absorbabitity of the compounds of ~ormula I.

~ he ~n~e~tio~ also pro~ida~ a modi~ica~io~ o~ t~e proce~æ described above9 ~herei~ in a compo~d o~ lorm~l~
I" II, III, :~I:I or XII or i~ more t~ one o~ these co~
pounA~, a sub6tituent o~ a group E~l iæ con~erted ag a:n appropri~te po~t ~L the x eactio~ ~eque~ce ~Lto aD~;her ~ub~tit~nt 0~ u~stitlaent o~ i~ compu~ III9 ~or e~ample, ma~ be co~verted ~to another ~ubs~l~Lt of R~ before t~e ~loge~atio~ reactio:~ to gi~e cosnpo~ II9 or the initia.î sub~tituent OI }~1 3aay ~e reta~ed d~zr~g the hal~genatio~ rea~tio~? be~g collverted :~to a~o~h~r ~ub~titue~t of Rl be~ore the reactio~ of co~po~d II to give compou~d I~, The ~llowing ~re e:~amples o~ ~t~rcO~erBion~ n~
~ub~titRe~ts o~
to R3 ~3S- or R3So~ to E~3~30 :E~O~-- to l~ , ~hi~h ~a~ tbe3~ be alkylated or acylated"
to C~2-, -- ditts N3 to 1~ ditto Ht)- may be alk~lated or a~ylated R3~o-o~ to ~, ~hich m~;r then be ~ylæted or acylate~,, The m~hod~ ~or carry~g ou~ such reactio~s are ~LOW~
irL the ~rt~, fo~ example9 a~ a~ylthio group ma~ be o:gidised, ~r~ferably with a ca~bo~srlic peracid, especially ~chloro~
perbenzoi~ acid, to gi~e the corre~pond~ a~ls~ll phin~l 20 or al~lsulpho~l group; a nitro group may be red~ced to o ~3roup b~ noble metal cata~ ysed hydrogenatio~7 ~or e~ample, USirlg platl~m~ or lC)~ palladiam on carbon~ cofs M. Preirelder, Catal~ic :EIydroge~atio~ i~ Or~ic 5~hesi~, Wille~r I31te:r'8Ciel~C99 1978, page 26, a~d P.:~, Rylax~er, Catalsrtic Hydroge~ation over Pla~ um Metals, ~cadeE~:Lc Press, 1967~ Chapter 11; an a~no grvup may be a~lated ~i.,h a conve~tion~ ~l~lat~g age~t, ~or e~ ple~ a lo~e~

~yl halide, ~or e:zample, methyl iodide, or acylat~ ~th~
Ior e~ple, a~ acid chlorid~ or ac~d a~hydride;, lor e:~ample, ace~yl chloride or ace l;~c a~h~dri de, ~ c~o group may be con~erted ~n~o a~:L amino group by red~c~ L9 5 ior e:~ample, U~ g a me..al hydride; arL azide grolip ~y be con~erted i~to a:~ amino gr~up by reductioIl, for e~ple, u~i~g h;ydroge~ ~ulphide or catslsrtic reductio~
hydro~y gronp may be alk~l~ted or ac~lated a3 d~cr:L~ed abo~e ~
~he~e modi~icatio~ o~ the prc~ces~ o~ the ~iO2:1 are part~cularly u~ef`~l Ior ~he prod~ction o~ a cosap~L
o:e iorm~la I h~vi~g a group ~1 bear.~ 17 2 or ~ c~
stitllents9 an~ o~e or more o~ whic~ i~ pote~ti~ly Im-~table or illcompatible ~uri~g an;y o~e or more OL ~he 15 stage~ o~ the reactio~ ~eque~c~ de~cribed above. ~Le ~n ~ersion ~tep ig, accordi~gl;y, carried out a~ter the step in which the ~bstitue~t is pote~tially u~gtable o~ n-compatible .
It will be app:reciated that although the~e moAifi~
tio:ns are particularl~ use~ or ~he production OI C31e~
poullds of ~ormula I having æubstituent~ on ~1 that are potential ly u~s1;able in the production proce~R, it ~ Lot limited to 6uch groups, and i~ a Iurthe~ modiIi~atio~ oi the process OI the i~ention, a s~bstltuent o~
25 prod~ced by co~versio~ oî aDother ~ubstitue~t ~hat dc>e~
~ot it~el~ fall within the defi~ition of a s~b~tit~Lt OI
~1, for e~:ample9 a~ wlsubstitated or subsuituted, pJ~Dena'lO?J~J

~ 26 E~-rLitrosllb~tituted~ be~zylo~c~:rbon~lam~o ,~roup may be con~erted i to a ~ree a~ino group, for e:~:ample, by noble metal cataly~ed h;ydroge~atisn~ cO~., N" ~rei~elder; loc,a ~it~, page 111~ P.15r, Rylanderg loc~ cito, page 455, and C~ :~erae et al~ J0 OrgO ~he~0 2~ 805~ 1957al ~ each stage o:~ the pr~ed reaction ~e~ue~ce, the d~ir~d comp4~d ~ay b~ i801~1ted ~rom the reactio~
~:~t~Lre and, i~ de~ d, puri~ied b~ appropriats tec~
~iq~ea ge~erally ~ed ~or the p~r~icatlo~l o~ or~c 10 comp~d~ ~or ~æample~ chromatogra~r or C~Bta~ ;2tiOll..
~ indicated abo~re, Yariou~ ~termediate~ 3~ay be pro-duced i~ the ~o~L OI miæture of i~omers of various ki3Lds ~uch a mix-,~re may be ~eparated or re~ol~red at a~;y ~tage7 or the isomeric mi:~ture ma~ be ~sed ~;E ae ~or a~bseq~Le:nt 15 reactioDH~ (I~ the ca~e ~here a protecti~e grollp ~2 ha been removed beIore ~loge~Latiol:L9 a re~ lng compo~ oi formula ~ preferabl~ separa~ed i~to the ~ a~d 4S
i~omer~ ~ ~ee below)~
~Ll o~ the compound~ that are pr~ided by the ~ven~
2U tion ma~ e~ in ~ iRomeric Iorm~ as di~c~aed above9 either as a pure i~omer or a~ a ~i:~tlLre o~ two or more i~omersO
1~ compourLd of ~orm~ala I m~y :t~ve the ~- or S-~er~
chemi~ ndepella~ ;sr at po~itio:~ 5 s~d 6; and al~o at 25 po~ io~ 8 whe~ R2 repre~e~ts a h~dro~ or protected hy-dro~ group. ~?urther ~someric ~o:~ns will occ~r ~hen a~
sub~ti~uent con~ain~ . ch~ral carbon atom~ ~y .mi:~e - 26a ~ 3 OI two or more isomeric forms m~y be reæ~lved i:e desi~ed, or a compo~d o~ ~o~la I carL be u~3ed :in the *or~a of the i~omeric D~i~tureO ~he pre~erred stereochemist~y at pusi tion 5 i n compouIld I iB ,ge~erall 5~ :~, correspon~ing to 5 that ~ :~aturally occ~illg peDicill~ns arld ceph~o~pori~sg a~ po~itio~ 6 i~ S, and at po~ition 8 i~
I~ a co~po~d o~ ~or2n~1a III in ~bich ~ repre~ent~
a prs:~teoted h;srdro~y ~oup i~ co~verted ~to a compound :~I
before ~aloge~ation, ie. ~ ~he protecti~g gro~p ~
1~ mo~ed be~ore ~ELlogenation7 it ha~ bee~ i~d that the re~ulti~g compo~nd OI Ior~ula I iB predo~tly ~e de~ired 5~ omer,. ~he ~ollowi~; reactiorL ~che~e il~
trate~ the stereochemi try, ~ -R R~ ~4 ~ d :E~.5 be:Lx~g de~i~ed 1~ as abo~e.

~2 OH

C~ H SCE~2a~3 aE~ ~ H SCE~2~E3 /,L~ ~OR ~ ~

aooR ~soo~5 COCXB ~sco~5 III $~

26b -~ 0~
7 ~ 4 H C~ C- H ;;, E~
o~l ~ ~ o~
0~ ~ f COOR COt~ B.5 ~alogenation o~ the 4~ co~po~d o~ IO~IllR ~ e8 predom~n~tly ~he 4~ co~pota~d oi ~o~m~la ~ Io The p~
po:r~ion 4S:4R co po~d :5~II depend~ o~ the haloge~ati~
5 agent u~e~ a~d the r~action co~ditiion~3 9 but i~ g~neral ~aries ~rom 3:1 to amou~t~ as high a~ 9~1o ~he 4~ a~d 4~
i~omer~ c n be separated readily~ ior e:~:ample, by chr~a~-tograph;~ compou~d of form~:La ~ o ha~ ~Z i80-meri~m at the dolible bond7 ~o the ~ a~d 4S i~omer~ ~y 10 be f~rther separal;ed i~to the indi~ridual :E a~d Z i~oD~r~9 ~his i~ llot ge~erally ~ece~sary, b~ ~he 4R an~ 4S i~Q~er~
are pref erabl~ ~eparat0d be~ore co~7er~io~ to a compo~d o~ ~o~ la I. ~8 c~ be ~een ~rom the reactio:rl scheme7 a 4S co~Lpoulld ~ co~erted by reactio~ with a ba~e irL~o 5 a 5R compou~d Ir ï~ howeverp a compou~d of formula III
hydro~y 2 ha~ing a protectedigroup R i8 halogenated directly, the resulting compou~d II i~ d the re~ulti~g comvo~ I
i~ 55. ~8 the pre~erred ~tereochemi~t~ a,t positisn :~, it will be appreciated that lt ie pre~erable to 20 deprotect befor~ halogenatiDn, -- 26c --The compou~à~ of ~o~ul I aDd salts thereof are lactama~e inhibltor~ 7 arld the compound~ are ge ~table to ths actio~ o~ ~ lactamase~ produced b~
po3itive organi~ms9 Ior e~ample, b~
5 aRreus arld gram rle~ative orgarLi~ms, f or ~ample ~gg~e. ?hey al80 pos~e66 a~tibacte~
propertie~ them~el~e~ ~d may be u~ed i~ huma~ a~
other a~ or e~cample, to treat bacterial in~oc~io~
cau~ed by gr~-positiv~ and gram-~egati~re bacteria, :E or ' 10 e:2cample, ~a~Q~,~3~ ~E~a~

~ g3~, ~ome strai:~s of ~hich are pe~cil~n--re~ista~.
~he in~e~tio~ accordingl~r pro~rides a pha~ace~tical 15 preparation which co~pri~e~ a compo~d o~ fo~31~, or a ph;~siologically tolerable SP~t thereof, or a mi~e o~ two or ~ore such sub~aDce~ as acti~ :~redie~
admi~ture or conjunction with a phar~acelltically s~itable carrier. The preparation may al80 comprise o~e or 20 more other pha~maceutica~ ac~ive sub~ta~ces, for e:~ample, a~other antibacterial ~ubsta~ce, e ~peciall~r one which ha~ a ~-lactam ring. ~he preparations ~;y be i~ a ~orm s~itable ~or entera L or p~renteral admi~is-tratio~9 for e:~:ample~ :Eor oral, intra~ellou~g or intra~
2~ ular admi~i~tratio~ ~or e:~ample, as tablets, ca~le~, 8~UpE;, or ~terile injectable or i~ible aoluti~O

.. ...

~he preparatio:~ls are advantageou~ly ~ unit do~a,ge Io~
~d preferably compri~e ~rom 10 to 2000 mg o~ the a~ti~e i~gredie~tO ~he daiîy do~age o~ the ao~i~e ~redie~t i~ geRerally from 20 to 8000 mg9 in di~ided à~e~, 5 general~r ~ap to 4 do~e~"
~ he in~ention al~o pro~de~ the ~se o~ a~ acti~e i~gredie~t as de~i~ed a~oYe a~ a ~-lac~ e :~ibitur a~d/or a~ an a~ibacteri&l agentl>
~ he i~vention ~urther pro~ e~ a p~a:rmace~tical 10 preparatio~ ~hich compri~es all acti~e i~sredient as de~ ed abo~e9 in u~it do~age forms, ~he i~re~ti o~ o pro~ride~ a pharmaoeu~ical pre-paration which comprise~ active i~gredie~t as de~ed al )OY8 9 or a phy~iologically tolera~le salt thereoI os a mi:cture o~ t~o or more such ~ub~ta~:LceE7 a:~ o~e or more *la~thsr pharmaceuticall~ ac~i~e ~ub~tances ~ for e~cample, as de~cribed abo~e and, ior e:g:ample ~ mit dosaæe Porm.
ITnit do~age~ are preferably a~ de~cribed above., ~he f~llowing Table provid~ e~amples of compou~
o~ the i~re~tion.

`- 2~
T~Iæ

~ ~2~o~l CO~

~1 al ~Cl E ~ . ~

~ 0~ ..

....

E~ ~1 p"2 ~, ~0~ ~[ ' ~ 0~

~N02 ~ ' ~2 ~H

ac~
~ E~
~~3 ' ~ ' OC~

...
E3 0~
o~3 . . ., . :
--11 o~
~jC

H ~ :~

~ .

--~3C ~

.

~ 3~ --R Bl /=~ I~CO~

C0~3 -~2 -~,9 0~

~ 8C~3 E

~ ~3 0~ __ - ' ,.._. o ~' . ' ... .

~ _ 32 .' ~ ~ .~ C O C~
~) X ~0~3 ~S02- C~;

H ~3-S02~

~ CO~ 3 o~ ..

.
. . ~S~-C~3 .

- _ ~3 ` ~ 8~3 ~1 SO~

H -phenyl-hydroxy H
H -phenyl-hydroxy OH
H -phenyl-acetoxy H
H -phenyl-acetoxy OH
OOC~3 ,' ~c~o~ a~

- .

hlter~atlvely, ~or each o~ ~,he abo~e compo~
m~y repre~e~t ~a~ or a pi~:Lo~loxy~ethyl o~
pht~Llidyl gr~O
~ he ~tereochemi~t~ a~ po~ition ~ i~ pre~erab~ ~.
Whell R2 represex~s a free or pr~tec4ed ~drO3yl gro~p ~hestere~chem~s~ at ponitior~ 6 1B pre~erably S, at p~8i~io~ 8 i8 pref~rably ~.
Furthermore, in each of the above compounds (salts and esters), in which R2 represents a hydroxy group, this group may be protected by an acetyl, propionyl, benzoyl, phenoxymethyl-carbonyl, pivaloyloxymethyl or acetoxymethyl group.

~ 34 ; ~

q:he prese~t î~Yentioxl al~o ~roYide~ comDou:nàg oD .,ne gen-eral formulae II7 I~ IV, V~ ~I & ~I~?and mo~e espec~y provide~ the comp~u~ds ~pecifically d~8cribe~ in .,h~
~able, and ~ the E~:ample~ gi~en herein~terO
~he iollowing ~ ample~ ill~strate the ~:~en"io In them, temperature~ Pre ~pre~sed i~ d~gree8 ~el~3,.
and ~den~ tes th~ layer ~hromatograph;~O

_ ,_=_==
To a stirred ~olution OI 3.2 g c~ SOai2lm hydro:~i~ie ~ 40 31 of ~ater urldPr a~ argo3:l atmo~phere ~3 added 8 ml o~
5 ~about 85,~ pure), A~t,er 20 minutes o~ î~t~er stirri~9 a sol~tion of 12.5 g o~ ~acet~sy-~e~hyl~ etidin~ e in 2û ~1 o:f ~s~ ~s added and the D~xt~re ~as ~tirred :~or a ~urther 15 ~ir~es9 ~1 ~e~
estracted i~to dichlor~meth~e, T~ne org~ic extr~ct~ ~ere ~3~a ~ith ~at~r~, ~ere dried o~er ~gS0~ nd e~poratea ~ qa~o :~ ~i~O
lû Chromatography over ~ilica gel~ elllti~g ~rith ~ hyl a~;e m~x~ures, aîforded the title ço~po~d a~ ~ yello~ o~ (3.2 ,;~ m~-Cl)Cl~;) 176~ (~lactun) c~ 1 - 7420 ~ c~
.
~ (~DC13~ J 7~Z~ ~3) 1.73 1~9 S~ $E~3~[~) 2.95 - :~.35 1~9 2D~ SC~2 ~a 3-H) 4,4~ dt J 2~
~, O _ 5,~ (~, m, CE12~) 5.6 - 6,~ , ~=C)

6.77 ~lH9 broad, N~l) ~.'' , .

~o a ~ig~rously sti~red ~ol~tion o~ 2.34 ~ ~ 4 alls~lt}li~
3--~ylazetidi~-2-oa~e i~ 20 ~1 oî dimethylfcr~amide ~as ad~L~d 1.37 ~al o~ ~ethyl bromoacetate ~:nd 4.16 ~ oi~ fiaely gro~d p~t~ssi~
carb~ate. After 18 hoor~9 the mi~t~e ~L~ p~ed ia~ 7~ ~Dl oiE
;r~ter~ ~8 e~:tr~cted i~to eth~ cetate (~20 ml) a~ld ~he eo~:~ed org~c e~stract~ ~rere ~a~hed ~ith ~r~ter ~6sl~ ried ~er 1~;0 ~d ~raporated i~ ~ao~o t~ dryne~3e, C'hro~2Ltograp~y ~ ~3il~ca 1~ gel, ~l~ti~g~ith hex~e-ethyl ~ce~ate lsli:~e89 a:t:forded ~he ~;itl~
compolmd a~ a yello r oil ( 5 g)~, (CDCl~j~ 17~9 (ester) e~
1763 (~laet~L) csn DC~7) lgO5 (3~ J 7~Z- ~2 1.E32 (~
3,,æ ~H, ~, s~2 ~d 3~) .
3~--4~3 (~[~ 8 s~d A:E ~tter~, t~ a~ C~2t:~) 4~8 (l~ a, J ZEIz9 J~
40~ ~ 5.~5 (~f, m; ~12~c) 5,5~ 6.2 (l~ C) .

.

-- ~ 7 --~ 3 To a stirred s31utio~ o ~ g of ~ethyl 2-(~allyl~o-~ethylaz~tidi~ ? o~-l yl)acetate a~ 1 o~ absol~te e~ha~ol ~dded dropwifie ~ solutio~ o~ 0.9 g of po*E~ssi~2 ~ydro:ride i~ r mixt~re of 12 ~1 oî ethaa21 and 1 ~1 OI qrater, Afte3 ~ ~i~tes, ~e ture ~as poured i~lt~ a mi:~ts~e o~ lû snl of ~ichlornme~h~2e 20 ~1 of ~rater, Aftes acidificatio~ ;h 13 ~1 ~ Gl9 ~2e mixt~re ~Iras ertract~d ~ith ~nr~her dichloromethasle;. t~e ai~l~r~e~a~e 10 estr~ct~ ~ere e~racted ~ at~rated 80di~ bic~bonæte ~Dl~ica:L.
The~e aque~s extr~cts ~ere ~cidified ~ ~ h 5X HFl a~ the~
extrfL~te~ ~ith dichlorometha~e, ~e~e org~nic e~ract~ ~ere ~a~rated to d~g~e s t~ ~Iîord the title c~p~nd as a ~rhite c~s~ ~lid . (2.~6 g~

lS ~ Dc13) 1.~2 ~, t, J 7~
1, 78 ~ m~ C~3~--23 .3~ g S~2 as~d 3--H~
.5~ B patter~, NCH2) .6û (lH9 d~ J 2~Iz9 ~E~) ~20? m~ Cff2'C) 5,~- 6.~ (lEl~ D~, CE[~C) 1 0 . ~ 3 1 ~ ) ~T.~ 6~

4-Nlt~=~ ~_~

A mixtl~re ~ 2,5 g of 2-(~allylthio~e*b~ etiG~2 anh~dro~
acetic ~cid7. ~3 ~1 o~ di~eth~lacetamide a~d 636 r:lg o:~qodi~
~i carbo~ate ~a3 stirred under arE~o~ ~or 20 D~te59 aDd ~heD 2,~
o~ 4--nitrobe~zyl broi:~ide ~ere added~, .Aiter 30 ~ tes :IE~he~
~tirri~ the sl~ixture ~ partiti~ned be~lqeen ethyl 2~etæte ~d ~a~er. The orgasLic 18~5~e~ was sep~ar~*ed a~ ;hed ~it;h ~a~r-.

a*ed ~cdiu~ bicsr~ona*e~ ~ith ~ater, ~ri~h bri~e, ~as dried a~r ~;0~, 10 ~d was e~aporated i~ q~o to d~g~e88, C:hromato~p~ ~ 5i'1;~a g~l, elutisg ~ith he~a:ne-e.t~ ~cetate ~ares~ rdea ~e ti~le co~np~und a a pale ~ello~ oil. (3,0 g~

3x (CDCl~) 17~1 (es*er3 c~s~ 1 1755 (~o~lder, ~ eta~ c~ 1 CDCl~) 1.û6 (~I, ~,9 3 7~

- 3.20 (~[~ m~ S~2 a~d 3-E) 3, ~ o (2~ t*e~ N~2) 4,5B (l~I, dt J 2.5~z, ~) 4, 9 _ 5~ t C~2~c) 5,3~. ~,5, ~3 ~,5 _ 6.3 (lE~

7.~ - 8.4~ ~N2 ) . _ - 4 ~ltr~be~yl 2~(4~allylt~:Lio-3~Pthyl~a2et~ai~ 2~

~o a ~t~ea olut~on o~ 1 g o~ 4 nitr~be~z~l 2- (4-5 allylthi~ thyl-azetidi~ acet~e iD e at ~78 ande~ argon ~a~ added a 80~utio~ oi a 1~5 ml o~ hesamet~ldis~Laza~ .2 mmol o~
l~um ~ a~ ~?~, ~ ~:~r~ ~a~ ~ed ~or ~ mi~, as~d a 8011CLtiO~ e 006~5 g O~ lo~ph~yl c~l~tbi~
10 *~:rmat9 i~ ~ 0~ LB aa~
wsr~ed So 40C, a~d ~t~ ~iO ~utes Wa8 't;tleD C~OLea~0 --78, a~d a solu~io~ ~i 0,,5~ ~il o~ p~oyl ~l~
ada~aP ~he D~ ~o~
a~d ~ 0 ~u~e~, 15aceti~ acid wa~ added., ~he Iri~e e~ap~rated ~o d~ esul~;~g o~ ~ pa~

betuee~ eth;yl acet~e a~ld ~a~er~ ~h~ or~c 3~ eparated9 aq~e~as d ~ith ~rRter~ withlc~tric ~cia~ ~h sa~Tæ~
bic~b~r~at~, ~lth b~ec ~d wa~ ~he~ drie~ ~ve~ ~ a~a 20 ~vap~:ratea t~ ~e~ hrom~t~graph~ o~er ~a g~
eluti~ ~rith he~s:ne Ov ~th71 ~ceta~e xsLi~ dea the title comp~ d ~1~3 g, 76~ a8 a yello~ c~ilo (CDC1~53 17~5 cm~

13) 0.>85 ~ 1~30 (12~, ~aQ (C~)3~ ~33 1-~0- 202û (~I, D19 ~2~'~
3.00- 3.75 l~. m, ~ 27 ~39 4 80- 5~ E, m~ C~2~2, . 6 ~8 -- ~103 ~, m~ lt~ .

-1~0 266;3 EXA}~E 6 ___._ . 4-~trobe~z~l 2-(4-chlor~ eth~l~azetid~2 _~C

To a 801ut:~o~ o:t 1.~5 g oi 4-n$hroberL~1 2-(4~ælly1 thi~3~thyl ~ azet~d~2~ 3~3~(4~ hlorop~
~r~ ac~ p~ e ~ hlDr~ a~ ~O 9 add~d ~ ~olu~io~ oi 4~.2 ~nmo~ o~ ~lo:~e ~- c2r~
~e~rach~orideO ~er ~ ~te~ the D~ ~ ~ed to ~o~ temperature, -e~pora~d l~i7acuo1 æ~ the ~sia~al lo oil wa8 ehro~atog~Lphed o~er B~liCa gelO 3~ka~ 0~
he~e -- et~1 acetat~ m~æture~ ~orded 1.~ g o~ ~e title co~po~nd a ~ p~ yello~ oi~ ~9~ ~ o:~ the t~e~
tical ~eld~

~a~;io Ci8:~18 = 1:20~i b~ ~

~ C SaDC13) 1785 c~-l (CDC13~ 0~0 ~ :L030 (12~, ~L,, C~t~,)~j7 C~3~"
1.50 ~ ~, m~
3~0 - 3~B5 ~ m? 3~) 9 ~.,2 (~ 7 C02~2)~
20 ~,~o, ~.0~ d~ Jc~ 8 4~[Z9 Jtra~ 1.5~1 4~
6.80- ~20 (8~ mq ~1~ ~02~r 4--l~itr~e~z~ (4--chlorophe~o~ hyl~7 ~4 ~

.
~o a ~stirred ~ol~tlo~ o~ 161 g Of 4~:~trobe~:1. 2-in - -(4~2hlor~3~eth;~1 azeti~ on-l~yl~ (4 cl:~:Loro~a:~3-~
tr~ethyla~etylt~ prope~e ~g d:Lo~ ~ er (9 ~ v~
a~ Wa8 added 260 ~g o~ ~niaaz~l~. ~ter ~ ~lm~
~~ t~e ~l~ as wa~ea t~ room tempera~ ~ t~
pa~i~oned between el;hyl ace~te a~ld ~ater4, ~e 10 layer-~a~ ~epQ~at~d, ~ ra~hed ~i~ er, ~ith aqneo~ ci~is acid~
~rith ~ater~ ~rith ~at~rated sodi~ bicarbs~rLate~ aDd ~it~L ~e~, ~d the;cL ~ie~ o~er ~gS04~ ~d ~apora.,~d $~n ~ao~~ v ~o~ato~aph;y orer ~ ca ~81 ~ el~at~o~ L e*~l ac~tats he~e ~ re~ a~forded 720 ~ o~
1~ . co~pot2rLd ~82 %)~-.as a 3~ell~-oi~, ~ati~ 2~
.

1795 ~1 cS (aDC13) 0.8t) s, 1040 ~7~ m;
.70~ 2.~ E9 ~
. 2~) 3.~0 4~,10 (~, ~,, 6~)9 .2~ 9 C02C~2~ 9 .30, 5.65 (3~9 2d, J~iB ~ ~ 1.~2;~

.80-- 8~ 0 (~ 9 ;~, '' , - 1 - 42~ 36~3 ~ '

8~dium 3-(4-chl~rophe~ox;y)-6~ethgl~7 o~ thia~1 re o~ a ~ tiorL O:e 2~ ~g o~ 4 ~tr~
5 ~-(4-chlorophe~o:~y3--6~thyl 7 ~ o~t~ l~b~clo~
~2~0~eFt-2--e~e~2-carbo:5~1at~ ~ dios~ mg o~ d~ bi~Lr~on~ er9 ~a ~ laai~cha:e~
coal ~aa h~droge~ed at ~0 p~ a~ 2~ ~r ~0 ~i~e~..
~ he ~e ~as ~ er~
10 through Ce~te, and the2:~ l;yoph~ o yield 83 mg o~
the t~le c~po~d as a p~e yellow c~st~liDe 801:~
(~3 4~ 6~3 ~ . I
4-Nitroben~l 2~(4~allylthi~3-ethylaz~tidi - 2 on~1 yl3~-.
!~o ~ ~t~red ~ol~ n Q~ 20C) ~5 oi 4-~it:roben~yl 2--(4-allylthic~3 et~l~zetid~-2-o~-13.. ac~tate ~ ~ ~ æ~ ~78 u~d~r a~gD'rl wa~ adaed a 801~iorL o~ ~ ~e o~ 20~ ~ CJ~
l~thiU~ hess~cne~hy~disilaza~ hç
8ti:r:red :~r ~ e~ o~ 9i ~ ; O:r p~:L
c ~o~ Lo~o~o~ata i~ 10 ml o~ d~ ~ wa~ ~Lded. ~
~ armea to ~40~ d ~ter 30 ~i~mtes ~ ff~rL
ooolea t~ -78~ d a ~ol~on oi 1~.97 ml o:~ ~e~e~l chloride ~a8 adde~0 ~he ~ ~med~
- t~re ~d afte~ 1~ mi~ute~
- . the ~f~ s~apora~a ~ va~ t~ a~O
1~ ~trhe resul~g o~ ps~tio~ed 'bet~een e~l aee~t~ a~a~,~7 the orgs~c l~yer ia~ ~epar~ted, ~a~ ~ashed ~nth t~ater7 Yri~l a~eo~2s ~itri~
acid, ~*th s~turæ~ed aodiu~ bicarborlate~ th bri~e7 d~ied o~er I~S04 a~d e~apora~ied ~o dr~es~ Chro~nP~og~
over ~ a ,gel~ el~ting ~th he~ e - e~ l acet~
ture~ orded the ~$tle co~po~d (2~,58 g9 ~3 a.s a oil.

~4 --36~3 C~3~ = 1764 ~m~l O o ~1 .30 (~ 9 ~9 C(~,~3~ 7 C~2 2.15 (2~ ~2 'V'E~
3~0~ 3-~3 ~ ' ~29 ~ 3 -~i 4.82, 4,9~ d, Jl ~B 33~

4 q 9~ i9 (4~9 ~la9 t~ O~ t 5.4~ ~3 9 6.78~ 8 (93~ 2~

. 10 ~a/e ba~e peak ~7~0708; C~) 5, - ~5~ ~ i3 ~LE 10 4-~itrobe~æyl ~-(4 ch~oro 3-e~ aze~idin 2~n~

~ o a ~ol~tl~ o~ 2~47 g 4~ be~zyl 2~
~e~h~l~zetidin;2 ~n 1~ 3 pheno~ 3 trime~;yl ace~ylthi~propel~ate :~ ~ichlor~me~ e at ~0. ~g ~Lea a ~oln~L of 8~4 ~ol oi clilor~e ~ ~bo~ at~d~O
~er ~o 7~te~ th~ m~ture wa~ ~a~med t~ :rc;o~ æ~rre9 e~aporated ~ ~Cll~, arLd th~ 2~e ia~ a~ ~hrQma~
10 ~;raphed o~er ~iliea ~el,, :31utio~ ~$th he~ Qe ~ e~r;y?
aceta~e ~t;-Qre~ æiorded 1.7B2 g o~ th~ ;le co~d a~ a pale yell~w ~ l3% o~ the theoretical ;yie~

13) ~ 1784 ~1 0.80- 11,42 (~ 9 3~1J C~
~956 - ~.15 ~ 2~)9 ~5000 -- ~80 ~3~[? ~9 3 3 ~ g~
~.71, 6.17 (1~ 2d~ J~8 ~Z9 4--~ ) 7 2~ 6~86 - 8937 ~9H, m, - ~6--~ ~ ~ 8 6 ~ 3 a~
4-~itr~be~zyl 6-ethyl-7-o~-3-phe~x~-4~ia-l-a2abi~
or 2 Olhe t-2~ene~2~arbo lPte ~ a ~ti~ed ~olutio~ o~ 00416 g o~ 4~:~tro~enzyl 2-(4-~hloroD3~th~axa~id ~2 ~ 13~3~phenus~3 ~eth~lacet~lthi~prope~ate i~ dioæan ~ ~ater ~9 at 5 ~a~ added 104 ~g o~ ~mida~oleO ~t~r 30 m~Dm~e~
5~ t~e misture wa8 war~ea ~0 ~om temperat~x~9 ~n~ ~h~ -pas~tio~ed be~wse~ eth~l acetate ~ ~ater~ ~e o~ ic lavcr `~ 10 '1~8 separated,~as ~ashed ~ith ~ate~, ~ith ~qseo~ ric acid~ ~ ~L*e ~th ~aturated ~di~ bicar~o~a~e~ ~d ~*~h bri~e~ ~a~
~ æried oYer Ng~04, ~nd the~ evap4ratsd ~ Ya~ t~ ~r~e~
~hr~stography ~Yer ~lica gel End el~tion ~i~h e~hyl ~c~ate - hes~ mi~ures ar~orded Z16 m~ o~ ~he tl~l~
co~p~u~ ~67~) aB a yell~w ~oa~ -1790 em 1, 1800 (~h) c~ ~
(~DCl~ ? (3~, ~9 ~ 9 6~ ~a20 (2~ m~

3u53 ~ 4~05 ~ 6 5~35 (2~; q~ C0 5-369 5O75 ~ 2d~ Jtr3D~ 5~9 J~
4B,z, ~ ~) 9 7O0~ ~ 8~9 (9~ 2~

~odiu~ 6~eth;yl-3~phen~ 7~o~ 1 aza~icsrc~

m~ure o~ a 8~1~'cio~ ~ 3Q6 mg o~ ~nitT~E~;yl 6~e~ phe:5ao~ o;E~othia~ 3~2~o~-e~s~2 ca~boæy:Late ~ Llo~ an~ 6Q mg oI BOa~ bisa~ ;e .~ ~n ~at~r~ ~ 1~ pa~ladiu~ oa:l ~as ~;yd:r~g~

~jO p~i at 2~ ~r 60 ~i~te~. The ~nis~r~ ~as ~he~ ~3;1~ered Celite~ and l~ophili~ed *o yiela 216 ~ o~ the ti~le c~a as ~c pale .yello~ crystalliI~e ~olid ~96~ of the theos~etical ~ela30 , , ; '. . ' .

3(S) ~ Dimethyl(2 methylprop-~-yl)~ilylo~yethyl~
ethylthioazetidin-2 one To a stirrea 801ution of 2,03 g of sodium hydro~ide in 70 ml oi water at 0C u~der an argon atm~sphere was added ~94 g o~ ethane thiol. A~ter 30 minutes ~tirring9 a ~olution of 12.6 ~ of 3(~ l(R)-dimethyl(2-methylprop~2-713sil~lo~-ethyl~-4-aceto~yaæetidi~-2-o~e in 200 ml oi methAnol ~a~
added. ~he mi~ture wa~ warmed to room temperature a~d, after 90 mi~ute~, wa~ partitio~ed between ethyl acetate and water~ The aqueous layer was ~ur~her wa~hed with ethyl acetate. The combined organic layers ~ere back-wa~hed with brine, dried ove~ ~odium Qulphate, and e~a-porat~d to drynes~. 609 g of the title product were obtained. Yield: 54 ~ma~ (CDC13) 1765 cm~~
(CDC13) 0.10 (6H,a) 0-90 (9~t9) 1~26 (3H, d, J - 6 ~z~
1.33 (3~, ~, J = 7 ~) 2~68 (2~, q, J _ 7 H2) 3016 (l~.,m) 4.1~4.3 (lH, m) 4.85 (lH, d, J ~ 2 ~z) 6.78 (lH, broad e3.

- ~9 -EXI~LE 1 Methyl~ (S)~ dimethyl(2 methylprop-2-yl~ loxyeth~
4(R)_e~hylthio~azetidin 2~on~ y~ acetate To 2 stirred ~olution of 6~ g of 3(S3O~1(R)-dimeth~1(2~
methylprop-2-yl)silyloxyethyl~-4(~) ethylthioazetidin-2-one in 150 ml of dry dimethyl~ormamide was added 13.15 g o~ ~inely ground anhydrous potas~ium carbo~ate and 2.~2 ml o~ methyl bromoacetate, A~ter 24 hour~, the mi2ture ~as filtered and then partitio~ed between ethyl acetate and water. The aqueous layer wa~ adju~ted to pH2 by dr~p~is~
addition o~ dilute hydrochloric acid9 and then bac~ es-tracted with ethyl acetate. The combi~ed organic ~yer~
~ere washed with wa~er, dried over sodium sulphate9 and eva~orated in acuo to give an orange oil, ~hi~h was chromatographed over æilica gel, ~lution with eth~l acetate/he~an~ tures afforded 6.~7 g of the title compo~nd a~ a pale yellow oil. Yi~ld: 72~.

ma~ (CDC13) 1749 (eæter3 and 1760 (~-lact~m) cm~~
S ~CDC13) 0.06 (6 , 8) 0.86 (9H, 8) 1~3 (6~
2~58 (2~I~ q) J = 6 ~Iz) 3~12 (I~ ~d, ~ _ 2 ~z and 4 3.7 (3~, 9) 3a93 (2H, dd, J gem - 17 Ez) 4.3 ~1~, m) ~.92 (lH, d, J = 2 Hz).

_ 50 ~ 3 4-Nitrobenzyl 2 [~(S)-~l(R3-dimethyl-(2-methylprop~2-yl) ~ilylo~yethyl~-4(R)-ethylthioazetidi~-2-on-l-yl]-acet2te ~o a solutio~ o~ 6037 g o~ methyl~ l(R)~dimeth~1(2~
methy~prop 2-yl)silylo~ethyl~-4(R)-ethylthio-azet~din-2-o~-l y~ acetate in 25 ml of 95~ ethanol ~a~ added a ~olu-tion of 1~16 g of pota~eium hydro~ide in 25 ml of 9~
ethanol. ~fter 15 minute~, the mi~ture wa~ e~aporated in ~acuo to dryne~. The product ~as dis~olved immediately in 25 ml of dimethylacetamidel and 4.24 g of solid 4 ~itro-benzyl bromide were added with vigorous stirri~g. ~ter 60 minu~es, the m~ture wa9 partitio~ed between ethyl acetate Pnd water. ~he ~eparated aqueous layer was washed with ~urther ethyl acetate; the combined org~nic layer~
were backwashed with ~ater, t~en -~ith brine, and were the~
dried over 90dium sulphate a~d evaporated in vacuo to zfford an orange oil. Chrom~tography over ailica gel~ eluting ~ith ethyl acetate/he~ane-mi~ture~ a~orded the title compo~nd z3 a pale yello~, vi~cou~ oil. Yield: 6.18 g, 80~.

20 ~ max (CDCl~) 1765 (~lactam) and 1755 ~e~ter)cm~
(CDC13) 0.05 (3~
0008 (3~ B) 0.88 (9~, s) 1.25 (3H, t~ J = 7 H~
2~ 1.28 ~E~ d, J = 6 ~z) 2058 (2~, q~ J - 7 ~) 3.18 (lH, d~, J - 2 Ez ~nd 4 ~z) 36~3 4. 05 ~ 2~, dd, Jgem = 18 :~z ) 4~1-4.3 (lE~ m) 4.93 (11~ dt J = 2Hz) EX~MPLE 16 4-Nitrobenzyl 2-[3(S)-~l(R)-dimethyl-(2-methlyprop-2-yl)-sil-yloxyethyl3-4(R)-ethylthio-aze-tidin-2-on-1-yl]-3-(4-methyl thiophenoxy)-3-trimethylacetylthio-propena-te To a stirred solution of 2.0g of 4-nitrobenzyl 2-[3(S) {-l(R)-dimethyl-(2-methylprop-2-yl)silyloxyethy~-4(~)-ethylthio-azetidin-2-on-1-yl]-acetate and 1.123g of 4-[(me-thylthio)phenyl)phenoxy]chlorothionoformate in dry tetrahyd-rofuran at -100C under argon was added a solu-tion of a mix-10 ture of 2.35ml of hexamethyldisilazine and 6.64ml of a 1.55 molar hexane solution of butyllithium in dry tetrahydrofuran.
The mixture was stirred at -100 for 30 minutes and at -40 for 30 minutes, and 1.05ml of trimethylacetyl chloride was added. The mixture was allowed to warm to room temperature 15 and was stirred for 2 hours. Acetic acid was then added and the mixture was partitioned be-tween ethyl acetate and wa-ter.
The organic layer was washed with citric acid, with water, with sodium bicarbonate, with brine, and was then dried over magnesium sulphate and evaporated to dryness. Chroma-tography 20 over silica gel, eluting with hexane/ethyl ace-tate mixtures, afforded 2.06g of the title compound as a yellow oil. Yield:
65%
max (CHCL3) = 1764 cm 1 ~ (CDCL3) 0.06 (6H, s) 0.80, 0.87 (9~l, 2s) 1.0, 1.09 (9H, 2s) 1.23 (3H, t, J = 7 Hz) ;`

53~ 3 1.26 (3~[, d, J = 6 Hæ) 2q~ [7 S) ~o64 ~;2~I9 q9 J = 7 :~Izj 3.20 (l~I, dd, J = 2 ~ a~d 4 4~00 - 4.40 ~ m) 5.30 (3H~ b~) 6.73 - 7031 (4~, m) 7.35 ~- 8.28 (d,E, m) 4 Nitr~benzyl ~-~4(R)~ethylthio 3(S)~l(R)-hydro~yet~yll-azetidin-200n-l yl~3-(4-methylthiophe~o~y)-3-tr1meth~1-acetylthio~propenate To a stirred ~olution o~ 2~06 g o~ 4-nitrobenzyl 2-r3(S)-~l(R)-dimethyl (2 me~hylprop 2~yl)sil~10~yethyl~4(~-ethylthio-az~tidin-2-on 1 yl 3-~ (4~methylthiophe~o~y) 3-trimethylacetylthlo-propenate in tetrahydro~uran at roo~
temperature wa6 added 2 ml of water and 22 mmol of concen-trated hydrochloric acid. The mixture was ~tirred ~or 28h~ara until T.~.C. analysi~ showed the reactio~ to be com-plete. The mixture wa~ partitio~ed between ethyl acet~t~
and ~ater, the organic layer was ~shed with sodi~m bi-carbonate and brine, dried over MgS04 and e~a~orated to dryne~s. Chromatography over silica gel and elutio~ ~ith he~an~-ethyl acetate mixture& a~forded the title compo~nd (1.21 g, 70~) as a ~ellow foam.
~he product i~ isolatea as a mi~ture of ~ and Z i~o~rsJ
ob~erved as double peaks in the nmr spectrum.

~ ~ max (C~C133 = 1762 cm~l (CDC13) 1.02, 1~13 (9~, 2~) 02~ (3~, t9 J = 7 ~) 1.30 (3H, d, ~ = 6~z) 2.44 (~H, 8) 2.76 (2H, q9 J = 7 ~3 3024 (1~, dd 9 J = 2 Hz and 4 ~z) ~8~3 3.90 - 4.38 (IEI, m) 5, 2~ d, J = 2 ~Iz ) 5 . 26 ( 2~
6 O74 - 7 . 20 (4H, m) 7.27 - 8.~ " m~.

~ 3 EXAMPLE~8 ___ 4-~itr~be~zyl 2-~4(R)~chloro~(S)- ~R)-h~dro~yeth~13~
a~etid m~2-cn~1-yl~-3-(4-met~ylthiopheno~y)-3-trimethvl-acetylthio-prope~te.

To a stirred solutio~ o~ 1 g of 4-~itrobenzyl 2-[4~
ethylthio~3(S)-~l(R3-hydro~yeth~13-a~etidin~2-on~ 3-(4-meth~lthiophenox~ trimethylacetylthio-propenate i~
dichlorometha~e at -40~ was added a solutio~ of 1.6 mmol of chlcri~e in carbon tetrachloride. Afte~ 30 mi~utes the reactic~ was warmed to room temp rature and evaporated to dryness. Chromatography over silica gel and elutio~ with h~a~e ethyl acetate mi~tures afforded the title c~pound a~ a pale yellow foam (0.66 g, ~%).

~ ma~ = 1783 cm 1 ~ (CDCl~) 1.06, 1.09 (9H, 23) 1.40 (3H~ d, J = 6Hz) 2.44 (3H; s) ~52 (IH~ dd, J = 4Hæ and 9Hz) 3.98 - 4~58 (1~9 m) 5~3~ (2~, s) 6.03~ 6.17 (lH, 2d, J = 4 6.72 7.33 (4~ m) 7"38 -- 8.32 (4~, m) and Z isomers are ~eparable b~ chromatography.

~X~MP~ 9 4-~itrGben~yl 5(R), 6(S) ~l(R3-hydro~ethyl~-3~
methylthiophe~o~y)-7-o~o-4-thia-1-a~abicyclo~3,2,0]-hept~2-e~-2--carbo~late To a ~tirred ~oluti~ of 0~42 g of 4;nitroben~1 2~t4(~) chloro-~(S~ R3 hydro~yethy~ -a~etidia~2~n l;yl~-3-(4-methylthiopheno~ trimethylacetylthio-propenate i~
dioxa~ - water ~9,1 v/v) at ~5 ~as added 1012 mmol o~
imidazol~ ter 30 minutes at +5 the reaction ~iæture was warmed to room temperature and partitioned be~ee~
ethyl acetate and wate~. ~he organic layer ~as ~a~hed with citric acid1 with water, with saturated ~odi~m bi~
carbonate a~d with brine, was dried over Mg~04 a~d ~as then evaporated in Yacu~ to dryness, ChromatogrPph~ over silicP
gel and elution with he~ne-eth~l acetate mi~t~re~ af~orded the title compound (0.1~ g9 49%) as a pale yello~ ~osm.

~ma~ (C~ ) = 17867 1790 (sh), 1797 (sh) cm 1 (C~ 0 (~, d, J = 6Hz) 2~46 (3 2V 3~68 (lH9 dd, J = 1.5~z ~nd 6Hz~
3~88 - 4.33 (lHr m) 5c29 (2E9 q) 5.56 (1~9 d, J = 1.5~2) 6.90 - 7.29 (4E7 m~

7.31 - 8.20 (4 EX~Mælæ 20 ___ 4-~itroben~.yl 5(R)~ 6(S)-(l(R)-hydrosyethyl)-3-(4-methyl~ulphinylphenoxy)-7-o~o 4-thia-l~azabicyclo-[3 7 2,0~hept~2 ene-~-carbo~ylate To a ~ti~red ~olution o~ 0.28 g of 4 nitrobe~z~1 5(~
- 6(~ ydro~ethyl~ (4-methylthiophe~o~y)-7~o~o-4 thia~ azabicyclo~3,2~0~hept-2 e~-2-carbo~ylate in ethyl acetate at -78 was added a ~olution of 0.57 mmol og m-chloropero~be~zoic acid in ethyl acetate. APter 30 ~inute~ the reaction miæture ~a~ ~ar~ed to room tempera-tur~ ~na ~aQhed with ~at~rated sodium bicarbo~ate, ~ith brine~ dried o~er MgS04? and the~ e~aporated ~o dryne~æ~
Chromato~raphy o~er silica ~el and elutio~ with he~a~e-ethyl acetate mi~tures afforded the title compou~d (0.19 g, 66~ a~ a white ~oam.

~ma~ (C~ = 1790, 1797 cml (~DC13) 1~5 (3~ d, J = 6~z) 2.73 (3~ 9) 3~81 (~, dd, J = 1~5~z a~d 6 3090 4 D 37 ( 1~7 m) 5.31 (2~, q) 5,74 (lH, d, J = 1.5~) 7.15 - 7D52 (4H, m) 7.55 - 8u27 (4H, m) ~ 5 ~MP~æ 21 Sodium 5(~)~ 6(S3-(l(P.)~h~dro~yeth~ 3-(4~meth~1 ~ulphinylpheno:~y ) -7-o~o-4~thia -l-azabicyclo ~ 3, 2, O ]-hept-2~en~2-ca~bo~late ~, ~_ ~ mi~ture of a ~olutio~ of 65 mg o~ 4-~itrobeDzyl 5 6(S~-(l(R)-hydro~ethyl3-3-(4 methyl~ulphinylp~enoxy3~7 oxo-4-thia-1-azabicyclo~3 7 2,0]hept-2~e~-2~e~rbo3ylate i~ dio~a~7 a~d 11 mg sodium bicarbo~ate ia ~ater, a~d 1 palladium~charcoal wa~ h~drogenated at ~0 p.~.i. un~il ~.~.C. analy~i~ indicated complete reactlon.
The mixture was ~iltered ~hrough ~ellts ~Tra~e ~ar~) ~nd l~ophili~ed to yield 42 mg oi the title compound (830 a~
a cr~talline ~oltd~

~ 60 ~ 3 EIam~le 22 4 ~itr~be~æyl ~(R), 6(S)-~l(R~ hydroxyethyl~-3-(4-me~hyl~ulphon~lpheno~y)-7-o~o~4-~hia-1-azabic~clo-[3t2~01hept-2-ene-2-carbo~ylate 20 mg of ~he above compou~d ~ere obtained b~ a procedure anal~gou~ to that described in ~ample 20 ~s;~g 125 mg o~ 4 nitrob~ l 5(R) 9 6(S) ~l(R~ hydro~y~thyl) 3-(4-methylsulphin~lphe~o~y~-7~oxo-4 ~hia-1~=a~.abicgclo~3~2~01-h~pt-2-e~e~2-carbo~ te and 0O25 ~mol m-chloropero~benzoi~
acidd 6(aDC13) 1039 (3H~ d, J = 6Ez3 2.97 (1~, bs) 3009 (~, s~
3.86 (IH, dd, J = 1.5Hz and 6Hz) 4.00 - 4.51 (lH, m) 5030 (2H, q) 507~ d9 J ~ ld5~Z) 7.13 - ~.32 (8Et m) _ 61 ~ 3 Sodium 5(~), 6(S)~ hydro~ethyl~-3-(4;~eth~ ilphonyl phe~o~yj-7-o_~4~thia-l~a~abicyclo[3~2~0]hept-2~ene-2-carbo~ylate ~8 mg of the bove compound were obtained f~om 20 ~g of the c~rre~po~ding 4-~itrobe~71 comp~und (~ee ~mpl8 22) by a procedure analogou~ to that deacribed ~n ~ample 21, u~ing ~.2 mg o~ ~odium bicarb~ate.

62 ~ 3 4-~itrobe~zyl 2-[3(S) ~ d ~ethyl (2~methylpr~p-2-yl) 8il~10~y~ethy~ -4~R~-et~ylthioaz~tldin 2-on-l~yl~3;
phe~o~y~-tr~methylacetylthio propenoateO
400 ~g o~ the above compound ~ere obtained)as a ~ello~
o~l, by a procedur~ analogou~ to that descr~bed in ~ample 16; U5 i~g 500 mg oP the azetidl~one ~tarti~g materi~l de~ined in E~amp~e 16, 200 mg o~ phenyl chlorothio~oformate 9 700 of hexamethyldi~ilazane a~d 2 ml o~ ~-butyllithiu~, a~d 260 ~1 of trimethylacetyl chlorid~.

~(CDC13) OoOl (6~
0.809 0.90 (9~I, 28) 1.0, 1006 (9~I, 2B) 1.25 (6~, m) 2~7 (2~, q ~ = 7~z) 3.20 (I~, dd~
4,0 ~ 4O40 (1~, m) 5~30 (3~, bm) 6.8 - 7.5 ~5~? m~
7~5 - 8.4 ~4E, m) ~L~
4-~litrobe~zyl 2~3(S) ~ hydro:~yethyl}-4(~3~ eth~l~o~
azelidin-2-on01-yl ]-3 pheno~y-~trimethylacetglt~i~
propenoate 0~19 g of the ab~ve ~omp~u~d ~ere obtained fr~ 0 g o~ the corre~pondi~g ~ di~ethyl (2 methylpro~2 silyloxyeth~ compound (~ee ~ ample 24) b~ a proce~
analo~ou~ to that de~crîbed ~L Esample 17~ ~ing 0~4 ~1 oi wa~er and 0 . 4 m:L OI conce~rated h;~d:rochloric acid O

~ DC1~) 1.05, 1.10 (~9 2~) 1 . 35 ( 5 2~70 (2~19 q, 7 = 7~z~
2.8 (~, broad) 3 ~ 30 ( 1~, dd J -- 2~z + J = 5Hz ) 4.03 - 4.46 (lH, m) 50~ ~ m) 6.94 7.50 ~5H, m~
705~ - 8.~0 (~

~ 6~ 8~3 E:caml~le 26 4-Nit:r obenzyl 2 .- ~ 3 ( S ) - ~1 ( R) ~h~rdro:~yet ;y1}-4 ( ~) -ch l or~
a~etidi2:l~2~o~ gl]-~-phe~o~y-~wtrimethylacetyl thi~~
prope~oato ~o a stirred sslution oi O,114 g OI the 1 (R) oh~O~-eth;ylaz~tiàino~e derivative de~i~Led i~ ampl~ 25 ia CDC13 at -~0C wa~ added a ~olutio~ OI ~-.2mmol oî ch:Lor~e i~ carbon tetrachloride a~d the 801utioll was ~ti~æed ~o~
. 1 hour. ~he reaction m~tur~ ~7a~ med to room tempera-tlLre and evaporated t~ d~e3~ ~he product ~as ~ed urlp~ ied in the follo~ g ~t~p~

~S(CDt~13~ loO~iy 1~06 (9E, 2~) 1~40 (~ m) 2,,8 (lH, bro d) 1~ 3,50 (lH, dd) 4.06 - 4060 (L~I, m~
5.30 (2H, ~;~
6~13 (l~t d, J = 4:Ez) 6.90 ;; 7.4~ (5E[, ~) 7.40 8.35 (4:E~, m) 4-~itrobe~Lz;yl 5 ( R ) ~ 6 ( S ) - ~L (R ) -h~rd ro:~yeth~ 3 ~ pherloa~yD
7-o~-4-thia; l-azabicyclo ~ 3 ~ 2 ~ O ~hept 2-e~-2 carbo~ te 0.044 g of the above compound were obtai:r~ed b;y a 5 procedure a:rlalogou~ to t~at desc~ibed in ~ uaple 19, ~i the urlp~riIied product of :13xample 26 and 0 . 22 mmol o~
imidaz31e .

S(CDC1 S3 1~30, 1.40 (3H, d9 J ~ 6~Z) 2.,0 (lE" broad) ~ . 76 ( l~I, dd J = 10 5:EIz a~d S~ ) 3~,96 - 4.43 (lH, m) 5.35 ~2H, q) ~,.6~ (lI[, d, .J - 1,5Hz) 7.10 7,.40 ~5H9 m) 7.50 - 8.30 (4~, m3 6~

Sodi~ 5(R~, 6($)~&(R)-h;ydro;cyeth~ 3-pheno~ 7-o~o~4-thia l~azabicyclo [ 3 9 2 ~,0 ]hept 2-en~2-carbo~cyla~

0~02~7 g of the abo~e ¢ompo~d ~er~ obtained Irom 5 O. 031 g o~ 1;he corre3pondirlg 4~nil;robe~z~r1 carbo3:ylate (see ~ ample 27) by a proc~dure analogou~ to that describiod i~ E~ample 21, UBi~ 0"0061 g of ~odi~m blcarbona~2O

~ ~7 ~
. ~
4-~itrobenzyl 2[3(S~ dimethyl~ meth~lpro~2 ~ilylo~:;rethyl~-4(~ eth;rlthioazetidi~2-on-1-yl]-3--( 4 Iluorophe~o~ 3-tr~meth~lac~t~lthio propenoate 0,592 g OI the above ~ompoulld ~ere obtained ~ a proced~e a~alogou~ to th~t de~ribed in :~mple lÇ
0~ 5 g of the aæetidirlo~e ~tartillg material deiined ~L
ample 16, 171 ~1 of ,;E2~1uorophenyl chlorothiono~o~ate, 0.67 ml of hea~amethyldis~lazi:lle a;~d lu99 ml o~ n~
li~hi~n, and 261 ~1 o:E tri~eth;srlacet~l chlorid~.
Yma~ (CDC13) 1763 cm l ~(CDC13) 0.06 (6~
0.7~, 0.80 (9~[, 2~) 1.00, 1.06 (9~9 2~
1.22 (~p t, ~ = 7:EIz) 10~5 (3X~ t~J = ~) 2.70 (2~ J = 7:E~z) 3 ~ 20 ( l~I, dd, J = 2H~ and 4~z ) 4.~0 ~ ~40 (L~I, ~n) 5.25 (3H, bs) 6.8 ~ 8.2 ~81~, m) 6~

4~trobe~z;yl 2~3(S) {1~ hydro:~ethyl~4(~ ethylthio-azetidin-2 o~-l yl J-3- ( 4~f'1uor~pheno:~y ) 3-tr~eth~ylacet~l-thi~ -p~pe~oate 3B0 mg o~ the above compo~a~d were s: btairled ~rom 59~g ~ the correæpo~ding ~ dimethyl-(2 meth;ylprop-2-;srl)~ilylo~
eth~l~ compo~d ~3ee ~ample 29~ by a procsss a~Llogous ~o that describ~d in E~ pl~ 17, u~ing 1 ml o~ water a~d 1 inl of concentra'Ged ~ICl.

~ 3 ~ 1761 cm~
(CDC13) 1.02, lolO (9~I~ 2a~
1.20 ~ 1.3~ (6:~, m) 2.70 (2H9 q~ J = 71~z3 2 . 8 ( lE 5 br~ad ~
3 . 28 ( lH7 dd 9 J - 2~z and 4EEz ) 3.90 ~ 4.30 (l:EI" m3 5 . 22 (~H~ b~
6.85 ~ 8.,20 (8H, m) ~ 69 4-~itrobenzyl 2 [3~S)~l(R) h~dro~e~hyl~-4(S)-chaoro~
zetidi~-2-on-1-yl 3 -~ (4-~luorophe~oæy~ ~-trimetQyl-acetylthio-propenoate ~ h~ ab~ve compound was Qbtain~d by a proced~re ~Dalo.
g~U8 to that de~cribed in Example 26, ~ing 378 ~g of the l(R)~hydroxye~hylazetidi~one der~a~i~e dsiined la ~ample 30~ and ~ ~olution o~ 0.45 mmol o~ chlorine in 116~ ~1 of carbo~ tetrachloride. The product ~a~ ~9~d i~ t~e ~bse~
que~t reactio~ ~itho~t puri*ication~

13) 1.10, (9~, 2~) 1.30 (3~, t) 2.5 ~l:H, broad) ~.5 (I~, dd J = 4~ and 9H~) 4.00 (1~, m) 5~30 (2a~ B) 6.10 (lHy m~
6.80 ~ 8.30 (8~, m) 70 ~

4 ~ obe~z~1 ~(R)9 6(S)~ h~ro~ye~h~ (4~1uorv-pheno~ 7-o~-4-thia-1 azabicyel~332~0~hept-2~en-2 carbo~ylate .
. . ~
67mg of the ~bo~e oompound were ~btai~d by a prooedure ~nalogo~
to that described in Example 19 u~ing 0,622 mmol of the u~p~ri~ied - product of Example 31 a~d 42,3mg of imid~ole~

.. ... . . _ , ~J ma~ ( CDC13 ) 17~6, 1790 ( ~ ) ~ ~CDC13) 1.~2 (3~1, d, J = 6~Iz) 2.0 (lH, broad) .70 (l~I9 dd J - 1.,5~Iz s~d 6:EIz) ~,,,00 - 4,,30 (~9 5.30 (2~, q) 5~56 (l~I, d5 J = 1.5~Iz) 6.90~ 0 (8~I, ~a) ~2~86~3 -- 71 ~

Sodium 5(~), 6(S) ~l(X)~hydro~yethyl~3~(4--~luorophe o~y)-7~oxo-4-thi~ azabic~clo~3~2~03hept 2~en-2~cPrbo~ylate 460~ mg o~ the above comp~u~d were ob~ained ~r~ 67 mg of the corre~ponding 4-~itrobenzyl ~arbo~lat~ ~ee ~3aEpl~
32) b~ a proc~dure a~alogou~ to that describsd i~ ple 21 ~Ri~g 12.2 mg o~ sodium bicarbo~at~.

72 ~ 3 ~a~
4r-~itr~benzyl 2-[~(3)~ 3~dimethyl~ methylprop~2~13-loxyethyl~ 4(R)-ethylthioaz~tidin-2 on~ 1]i3 (4-chlorophenox~ trlmethylacet~ hio prope~oate 600 m~ of the above compou~d wer~ obtai~ed by a pr~~
ced~re analogou~ to that de~cribed in ~2ample 16, u~lng 500 ~g o~ the azetidino~e ~tart ~ material de~ined i~
Example 16~ 0~25 ~1 o~ ~-chlorophe~yl chlorothiono~or~at~9 0.67 ~1 of hexamethyldisilazane and 1099 ~1 Di n butyl-lithium, and 0.195 ml ~ trichloroacet~l chloride.

~maX 1760 cm~l ~(~DC13) Q.06 (6E9 ~) 0.8, 0.87, ~9H" 2 1--05, 1D10~ ( 9~, 2&~
1.20 - 1040 (6H~ m) 3 . 60 ( 2~ 9 q.~ J=7EI~ ) .?0. ( LEI9 dd~J = 2~1z a~d 4Hz) 4000 ~ 4050 (~1~ m~
5.20 (3~7 b~) ~0 ~.70 - 8.30 (8E, m) - 73 ~

~a~
4-~itrobenz~l 2 [~(S)~ hydro~yethyl~-4(R3 ethyl~hi~
azetidi~-2-o~ yl]~ 4-chloroph~o~y)-~-tr ~thylacet~l~
thio-propeno2te 290 mg o~ the above compo~d wer~ obtai~ed ~ro~
600 mg oi the corre~po~di~g ~l(R)-di~ethyl (2-m~thylprop-2~ sllylo~yethyl} compou~d (see ~æample 34) by a pr~-cedure analogous to that ~e~eribed in ~ample 17 u~g 1 m~
o~ water and 1 ml of concentrated HCl.

~ 1765 cm 1 DC13~ lqO5~ lolO (g~I, 2B) 1.27 (6E, m) 2.70 (~ q, J = 73z) 2 0 8 ( I~, broad) 3.20 (lH 9 dd~ J = 2Hz and 4~) 3.90 ~ 4~40 (1~, m) 5.25 (3~ bs~
6.80 ~ 8.20 (8H, m) -- 7 Jr 4-~itroberLzyl 2- ~(S)~l(R3~hydrox;yeth~ 4~S)-chloro-azetidirl-2-o~ yl ~ ( 4~chloropheno:; :y 3 ~tri~ethyl~ cetyl-thio propenoate The aboYe coDIpou~d ~a~ obtai~ed by . a pr~ce~s a~logolls to that de~cr~bed i~ cample 26 U~ g 290 mg o~ the 1(~-h~dro:~rethylazetidi~one derivatl~e deii~ed is~ campl~ 35 a~d a solution of 0.~5 mmol of chl~ri~e ~n 1 ml of carbor tetrachloride~ ~he product wa~ used ~L the ne:rt reactio~
10 ~ithoc~t pllriiication~.

~DC13~ 1.05, le~10 (9~, 2~
1~,40 (3H, d, 3 = 6~z) 2 ~, 5 ( l~I~ broad ) 3 . 50 (lE~ m) 4O0~4~50 (~I" m) 5~22 (2~[9 8) 6.039 6,15 (lEg 2d, J = 4EIz~
6.80 ~ 8.30 (8~I9 m) 75 ~

~:Z
4~Nitrobe~yl ~(R~, 6(S)~ 3-hydro~yethy~ -3-(4-~hloro~
pheno~y)-7-o~ 4-thia l~azabic~cloL3~2~0]hept-2-e~-2-carbo~ylate ~7 ~g ~ the above co~pound were obtained by a ~-csdure a~alogou~ to that de~cribed in ~ample 19~ ~ing 00458 mm~l o~ the unpuri~ied product of ~ample 369 ~n~
32 mg o~ imidazoleO

~ma~ 1787, 17gO (Bhj cm~
10 ~CDC13) 1.30 (3H, d, J = 6Ez~
2 D O (lH., broad?
3060 (IH, dd, J = 1.5H~ a~d 6~z~
3.90 - 4~40 (I~9 m) 5.22 (2H, q) 5~55 (I~, d, J = 105Ez) 6~0 - 8~20 (8~, m) ~ r~ ~ 3 ; 76 ~odium 5 (:~, 6 ( S ) ~l (R) ~hsrdroxyethyl~ ( 4~chlorophe~o~
7-o3:o-4 -thia l-az bi c~clo ~ 3 ,j 2 ~,0 ~hept- 2 en-2 -carbo~ylate 43 mg o~ the above compound ~ere obtai~ed ~rom 57 mg 5 o:e the oorre~poslding 4-~ltrobenzyl earboa:yla~e (see :E~cample 37) by a procedure analogoas to th~t described i~ E~mple 217 ~ g 10 mg of ~odium bicarbonate~, ,77 ~ 3 4w~it.robe~z~l 2~ [ 3 ( S ) ~ dimethyl- ( 2-methylprop~2-;y13 -silylox;yethyl}4(~)~@thylthioazetidi~-2~on~ (4~
~, c~anopheno~ 3-trimeth~lacet~lthio propenJate J' _ ~ ~
11.12 g of the above compo~nd were obtai~ed by ~ pr~
ced~lre ~nalogou~ to that de~cribed i~ E:~:ample 16 ~3ing 1 ~ o~ the a~etidinone startirLg material def`ined i~L
ample 16, 0063 g of ,pcysrlophenyl chlorothionoforEa~.e~
1.34 m~ oi he~ameth;yldisi~azlne and 3098 ml o~ n-bu~
10 lithium, a~ld 0. 52 ml OI trimethylacetyl chloride.

a~ 1768 cm~ 1 N~ ~(CDC13) 0.06 (6H~ Z3) 0.E~0, 0087 (9EIt 2 )-l.C5, ~L.10 (9E, 2~3) 1.20 (6~, m~
2~,70 (2:EI9 q,3J = 7~z) 3.22 ~l~I, dd, J = 2~z and 4Hz) 3 . 90 ~ 4.4Q (lH, m) 5~30 (3X, bs) ?0 6.i88 - 8.30 (8~1, n~) 4-Nitrobenzyl 2~3(S)~l(R)-hydro~yethyl3-4(R)-ethylthio-azetidin-2-on 1-~1]-3-(4-cyanopheno~y)-~-trimethylacetyl-thiopropenoate 185 mg of the ~b~ve compound were obtained ~rom 325 mg o~ the correspondi~g ~l(R~dimethyl ~2-methylprop~2-yl)-~ lo~yethyl3 compou~d (~ee ~ample 39) b~ a procedure a~alogous to that de3~ribed in E~ample 17, u~i~g 0,5~ ml of water and 0.55 ml of concentrat~d hydrochloric acid~

10 ~max 1765 cm 1 (CDC13) 1.05, 1.10 (9~ ~B~
1~30 (6~, m) 2.6~ , q, J = 7~Z) 2.8 (1~, broad) 3.16 (1~ 9 da ~ J = 2Hz and 4Hz~
~5o 91 ~ 4~ 50 (lH~ m) 5.30 (3~, b9) 6~90 - 8~3 ~8~, m~.

:~æ~

' ~e3~a 4-~itrobenz~l 2-~3(S)-~l(R) h~dro~7etky~ _~(s)-ch a~etidin~2-one 1-yl~-3~(4-cyanophe~o~y) 3~trimethyl~cetyl~
thlo-prope~o~te The above compound was obtained by a process ~nalogo~s to that described i~ ~ample 26 usi~g 340 mg of th~
hydroxyethylaz~tidinon~ deriv~ti~e de~ined i~ ~ample 40 and a ~olution of 0.676 mmol o~ chlorine in 0.81 ml o~
carbon tetrachlorideO ~he product ~a~ u~ed i~ the ~xt reactio~ without puri~ication.

'Jm~ 1785 cm 1 (CDC13) 1.06, 1~09 (9~, 2~) 10~5 (3~, d, J = 6E~) 2.5 (1~, broad~
3.50 (IH, dd~J = 4~z and 9Hz) 3.95 ~ 4.40 ~IH, ~) 5.~5 (2~
6~03~ 6717, (lH, 2d~ J = 4Hz) 6.90 ~ 8.4 (8~, m).

- 80 ~ 6 a~
4-~itrobe~zyl 5(R), 6(S) ~1(R) hydro:cyethyl} ~-(4-o3~ano--phenoacy) 7-o~-4-thia~l-azabic~clo[3~2jO~hept~2-en-2-carbo~yl~t0 89 mg o~ t;he above compo~d :were obtairled by a proced~re aalOgOU9 to ~hat described in Es:ample 19" ~ing 350 mg o~
the unpu:rified product o~ ample 41 and 45 mg of imid~zole.

c~ (CDC13) 1~30 (3~ d)J = 6~z) 2.55 (~EI" broad) 3 ,, 8 ( 1 Fl 9 dd ~ J = 1. 5~ and 6Hz ) 4~ 23 (~s s~
5.25 ~2~7 q~
5,.70 (lE:7d~J = 105Hz) 7.15 - 8.20 (8H~ m~.

81 ~

~a~
Potas~ 5(R), 6~S)~ hydroxye~hy~ (4-cyanopheno~y)-7-o~o-4-t~ia -l-azab icyclo [ 3 ~ 2 ~, O ] hept~2-en 2-carbo~y~t e 67 lag of the above compou~d were obtained Xrom lOOmg ~f tne corre~po~din~ 4 nitroben~yl carbo3ylate (3ee ~ample 42) by a proc~dure ~nælogo~s to that de~cribed in ~a~ple 219 u~ing 21 mg o~ potas~ium bicarbo~ate.

~(D20) 2DOO (~ d, J = 6~z) 4060 (1~9 dd>J = 1.5~z a~d 6~z) 4081 (lH, m) 5~40 ~2 (~rom D20~
6038 (IH~ d7.J = 1,5H~) 7~8 - 804 (4E, m).

6~3 ~c~le 44 4-~itrobe~z;yl 2~ 3 ( S ) ~ R~ -dimethyl- ( 2 methylpro~2 ~ilylo:~rethy~ 4(R~-ethylthioazetidi -2-on-1-yl~-3 ~4 tolylo~ 3 -trime ,,hylacetylthio-p:roper 2.0 g of the ~ve compou~d ~er~ obtai~ed by ~ pr~
cedure ~a~ogou~ to that described in ~ampl~ 1~9 u~ing 2~0 g of 4-nitrobenz~l 2-~(S~ dimethyl-(2-methyl-- prop-2~ ilylo~yethy~ -4(~-eth~l~hio-azetidin-2 on l~yl~
acetate, ~.35 ml o~ he~amethyldisil~ane, 0~73 g of 4~
tolyloxychlorothionoformate, 10~63 mmol o~ n butyllithi~m, a~d 0.78 ml of trimethylacetyl chloride.

C~(~DC13) 0~07 (6H, 8~
0.80, 0087 (9H, 2s) .0, 1.10 (9H~ 2B) 1~24 (3H, t, J _ 7~) 1.28 ~3~t d, J = ~z) 1~33 (3H; æ) 2.7~ (2~, q, J = 7~z) 3.20 (IH, ~d, J = 2~ and 4~) 2Q 3.90 - 4.36 (lH, m~
5.2~ ~3~, ~s) 6.60 7014 (4~, m) 7~34 8~27 (4H, ~).

E~ le_~
4 ~ltrobe~zyl 2 ~ 3 ( S ) - ~,1 ( R ) ~ h~dro~yethy;3 -4 ( ~) ethy~ ia azet idin-2 on~ l 3 -~- ( 4-t ol~l~xy ) -3-trimethylace~y ~hi~
propen ate 258 mg of the ~o~e coD~pou:lld were obtzined fro;~ 502 mg o~ the corresponding 1~ dimethyl~(2~methylprop-2 ~ilylo~ethyl3 compound (~ nple 44~ b~ a proce~
~logous to that de~cribed in :æ2cample 17 u8ing 5.5 Esaol~s of 6 ~ HCl .

:5 (CDCl~ )lq 1.,09 (9~1, 2 1.~0 (31~, t~ J - 7Ez~
1.~3 (~,El d, J ~ 6:1~z) 2.3~ (3H~ 8~
2~64 (2H, q, J = 7Hz) 3022 (I~l, dd, J = 2~Iz and 4~) 4.00 - 41~40 (lH, m~
5.22 (1~1, d~ J = 2H~) 5.26 (2H, ~) 6.73 - 7.18 (4~, m) 7.~2 - 8.20 ~4~ m).

-- ~4 ~

4-liitrobenzyl 2 ~ [3 ( S )- ~lP~hydro:~:yethyl~ - 4 (S ) -chloro -azetidin-2-on-l~;yl ~-3~ ( 4-tol;ylo~y )-3-tr~aeth~ acetylthic>-proper -a-~e ~he above ::ompound was obtained by a proces~ ~Lalogous to that de~cribed i2~ ample 26 usi~g 00213 g o~ the 1(~
hydro:~yethylazetidi~or e deri~ati~ defi~ed i ~ample 45 arld a ~ol~t~o~ of 0.365 mmol chlori~e in carborl tetrachlorlde.
!ehe product wa8 used in the neact rea~tion without ptlrifica tio~.

(C~13) 1.06; 1.10 (9F~, 2~) la38 (3~I, d, J = 6H~) 2.33 (3E~ B) 2.81 (lH, b~) 3.60 (lH, dd, J ~ 4~Iz, 9Hz) 4.02 - 4.47 (lH; m) 5.~3 (2 6"119 6,.24 (1:~, 2d, J
6.72 - 81130 (8H, m ).

~5 ~a~
4-~Nitrobenzyl 5(R~, 6(S)~ hydro~yeth~ -3-(4 tDlylo~y) 7 o~-4-thia~ a~abic~clo~33230~hept-2 e~-2-carbo~ate 89 mg o~ the above comp~und were obtained ~y a pr~
5 cedure anal~gous to that described in E~ample 19 u~i~g 3 mmol of the unpuri~ied product o~ E~ample 46 and 43 m~
o~ im~dazole, ma~ (C~c13) = 1788 cm c~ ~CDCl~) 1,31 (3~ d, J - 6~Z) 2~36 (~Hg ~) 2,60 (lH, b~) 3.68 (lH, dd~ J = 1.5Ez, ~nd ~Ez) 4.00 - 4.43 ( IE? m) 5.33 (2~
5.57 (1~, d, J = 1.5Ez) 7.12 (4H~ 8) 7.36 - 8.29 (4H, m).

~6 --Sodium 5(R~, 6(S)~ R)-h~dro:~:;yethy~ (4-tolylo~)-7--o~4-thia~l~azabicyclo ~ 3 s2 ~, O ~hept-2~en~2 carbo:~late 69 mg o~ the above compoQnd were ob~ained i~rom 150 m~;
o~ the correspond~Lg 4-nitrobenz~l carboac~rlat~ (see :E~&mple 47) by a procedure a~logou~ to that de~cribed ~ :@zample 21, us~ng 0.,33 mmol of sodlum bic~rbo~te..

~ 3 4(R)~llylthio-3~S)~[l(R)-~dimethyl-(2-meth~lprop~
sil~lo~y~eth~ azetidin~ one To a stirred solution of 1914 ml of allyl mercPpta~
~7~ and 0.4 g o~ sodi~m h~droxide in 25 ml o~ ~ater u~der ~n argon atmosphere Nas added a ~olu~ion ~f 2.~7 g o~ 4~acetosy-3(S)~ dimethyl ~ ~meth~lprop-2-yl~
~ilylo~y~ethy ~ a~etidi~-2 one i~ 10 ml of methanol~ ~ter 30 mi~u~es, the mixt~r~ wa~ partitio~ed betwee~ dichlor~-meth~ne and water. The separ~t~d organic l~er ~as ~ash~dwith water, dried over ~gS04, evaporated to dry~ess~ zn~
then chromatographed on ~ilica gelO Elution Rith e~h~l acetate - he~ane mixture6 a~f~rded 1.8 g o~ ~he title co~pouad as ~hite cryst~l~.

~ ma~ (~DC13) 3420, 1767 cm 1 d~ ~CDCl~ (6 0~88 (9~, 8~
1.20 (3E, djJ 6 9~) 2.9 ~ 3.2 (3H, m~

3D9 - 4-~5 (lH, m!
4.84 (I~ d~J~ ~ 2 Hz) 4.95 - 6.3 ~3H9 m) 7~28 (1~, broad 8j.

- 8~ -Me~hY1 2-(4(R)-a11Y1thi~ 3(S)~ R)~imethY1-~methY1PrO
2~i)8i1Y10æ~eth~1] a~etid1~2~0n~1-Y1) aCetate ~0 a ~tirred aO1UtiOn Of 1D76 g 0~ 4(~ 11Y1~hi~-~(S)-[~ imeth~ `~ethylprOp-2-y~ Bi1Y10~Y~e~hY1~
azetidin-2~one ~ 60 ml dr;y D~F ~as added ~"52 g of *inely ground ~::2C03 and 0.6 ml OI methyl bromoacetate. ~ter 18 hswr~, the mi:~:t-lre wa~ filtered a~d then Part1~iOned be-tween ethyl acetate and water~, ~he separated organlc layer 10 was washed with water and dr~ed o~er MgS04O ~3vaporation in Yacuo a~îorded a crude product ~hich wa~ c~romato--graphed on s;lica gel. Elutio~ h sthyl acetate - he~ e miacture~ a~forded 1~56 g OI the title compou~d a~ a pale yells~w oil"

~fma~CDC13 17539 a~d 1768 cm 1 5) O~06 (61I, ~) 0.86 (9~, 8) 1.23 (~Ht d J 6~5 3y2 (~E; ~) 3.70 (3E, ~) 3,6 - 4.3 (3H, m) 4 ~ 87 ( ~E~ d J^~ 2 ~Iz ) 4.9 - 6.3 (3H, m).

~9 ~a 4-:~itroben~yl 2- ( 4 5 ~ ) ~allylthi~ 3 ( S ) ~ [ 15~ ) ~!imeth;srl~-meth~lprop-2 ~y~ lo;~:~ethyl ~ azetidiri~2 on-l-yl) acetate ~o a ~tirrad solutio~ o~ 3.Q4 g o~ 855~ p~re 80 ml o~ 95S~ ethanol ~a~ added a ool~tio~ o~ 16 g ~e~
2--(4(~)--allylthio 3(S~ dimet~l~--meth~lprop--2 yl) rlo~ et~ azetidir~ on l-yl) aoetate. ~fter 10 minutes the mi:cture ~a~ evaporated to abo~t one ~ h oi - 10 its ~olume; 100 m:L o~ dimethyl cetam~de w~ added~
:~ollo~ed by a ~olution of 9, 25 g of 4-nitrobe~z~ mide 1r~ 50 ml dimethylacetamia~ ~ter 1 hour, the mirt~
wa~ partitioned bet~een O~,OlM HCl a~d eth;srl acetate.
The ssparated organic layers were ~ashed ~ith O.O~
15 ~ith water, wlth cold saturated ~a~EC0~ Ld with ~ e9 were dried aDd e~aporated~ The crude produc~ ~a~ chr~
matographed over silica gel, elutio~ with eth~l ac~i~e - he:~a~e mi:~tures a~fordeà 19.5 g o~ the title compo~d.

`Jma~ (CDCl~) 1755 and 1769 cm 1 20~S (CDC13) 0.07 ar~d 0.09 (6~, two ~inglets) o,,P~3 (9~I, s) 1.25 (3~I, d J 6 :E~z) 3. 2 (~E~ m) 3 . 7 - 4 / 5 (~H" m) 4.95 (1~" d J 2 ~Ez~

-- 90 ~`

4.9 - 60~ (5H9 m) 7v5 ~ 8~ ~7 (4H, m~ .

4-Nitrobenzyl 2-[2(S)-~l(R)-dimethyl-(2-methylprop-2-yl)sily-loxyethyl3-4(R)-allylthioazetidin-2-on-1-yl]-3-(4-chlorophen-oxy-3-trimethylacetylthio-propenoate 670mg of the above compound were obtained by a procedure analogous to that described in Example 16, using lg of 4-nitrobenzyl 2-[3(S)-~l(R)-dimethyl-(2-methylprop-2- yl)-silyloxyethyl]-4(R)-allylthioazetidin-2-on-1-yl] acetate, 0.32ml of 4-chlorophenyl chlorothionoformate, 0.95 ml of hex-amethyldisilazane and 2.28ml of 1.6M n-butyllithium, and 0.4 ml of pivaloyl chloride; and l.Oml of glacial acetic acid.
max (CDC13) 1733 and 1759 cm (CDC13) 0.04 (6H, s) 0.83 (9H, s) 1.03 and 1.06 (9H, two singlets) 1.23 (3H, d J 7 Hz) 3.0 - 3.4 (3H, m) 4.0 - 4.3 (lH, m) 4.9 - 6.0 (6H, m) 6.8 - 8.4 (8H, m) - 92~ 6~3 4 -~it:robenzyl 2~ [ 3 ( S ) ~ P~ ) ~dimethyl ( 2-methylprop~2-yl ) -~ilylo:~yethyl~ -4 ( R ) chloroa~e .,idin~2-on lo;yl ~ ( 4-c~l oro pheno~y)-3-trimethylacetylth~o-propenoate ~he above compound ~a6 obtained b~ a process a~alogo~s to that de~cribed in ~xample 26 ~ing 73 mg o~ the corre~
po~ding 4(R3-allylt~ioazetidi~ons derivatlve ~see ~ample 51) and a ~olutio~ o~ 1~24 mmol o~ chlori~e in 0~12 ml oi carbo~ tetrachl sride, ~ maC 1788 cm 1 ~(CD~13~ 0.05 (6~
0~90, 0.91 ~9~, 2g) 1~05, 1910 (9:EI, 28) 1.40 (3H9 d~ J = 6 H~;) 3J40 (lH, dd 1~.5~Iz and 8Hz3 4 . 00 - 4 . 40 (l~ m) 5.40 (2H, B) 6 .1 ( l~I d J = 1~ 5Hz ) 6.8 ~ 8.5 (8H9 m).

- ~3~ 3 4-Nitrobenz~1 5(S~, 6(S)- ~(R) dimethyl-(2 meth~lpro~-2-yl3silylo~yethyl~-3-(4 chloropheno~y)-7-o~o-4-thia ~-azabicyclo~270~hep~-2-2n 2~carboxylate 108 mg of the abo~e compou~d were obtained b~ ~ ~rOD
cedure analogou~ to that de3cribed in ~ample 19, ~ng ~00 mg of ~he unpuri~ied product of ~xample 53 and 24~ ~g o~ imidazole.

~ma~ 1792, 1800 (~) 6 (C~ ) 0.06 (6~
0~9~, 0~929 t9~, 28) 1.38 (3~, d, J = 7H~.) 80 ~ 4aB (~ m) 5.22 (2H, q) 5.65 (l~t d~ J _ 4E~
6.90 - 8.50 (8H9 m).

.- 9~ -~a~
4-Nitrobe~zyl 5(S) 3;(4-chlorophenoxy)~6~S)-~l(R)-h~dro~yethyl~-7~o~o~4~thia-1-aza~bicyclo[3~2~0~hept-2 ene-2~carbo~1ate - 5 To a 901utio~ of 108 mg ~f 4 iitrobe~zyl 5(S)-3_ (4~chloropheno~y)-6(S)~ imethyl ~-methylprop~2~yl) silylo~y3ethyl~-7-o~-4 thia-1-azabicyclo~3,2,0]~ept~2 e~e-2 carbo~late i~ 54.9 ~1 acetic acid at room tempera-ture wa~ added 54 ~1 of a 1 molar ~Y ~olution of tetra~
butylammonium fluoride. ~fter the mi~ture had been ~ti~red for 16 hour~j it ~as partitioned bet~ee~ ethyl acetate and - water; the ~rganic layer was ~eparat~dt ~a~ washed ~i~h wa~er, with saturated ~a~C03 301ution~-~th brine, a~ ~a3 then dried over MgS0~ and e~aporated i vaouoO Chro~Pto-graphy over ~ilica gel and elution ~ith ethyl acetate -he~ane mi~tures a~ord~d 33 ~g o~ the title compow~d~

`Jma~ (CDC13) 179C and 1~00 cm 1 C~ (CD~13) 1.40 (3H9 d, J = 7 ~) 2, 25 ( lFI, broad) 20 3, 86 ( lH ~ dd J = 4~ a~d 1 OHz ) ~4 (1~ m~
5~30 ~2~, AB, J= 14Hz) 5. 70 (1~, d, J = 4Hz) 6,8 - 8,5 (8H, m) - 95 ~
~8~ 3 ~odium 5R-3-(4-methylthiopheno~y)-6S-(lR-hydrogyeth~13-7-o~o-4-thia-1-azabic~clo r~, 2 t O~hept-2-ene 2-carboæ~ e 63 mg of above compound ~ere obtained by a proc~
an~logou~ to that described in ~ample 217 u~ing 84 ~ O~
the corresponding 4-nitrobenzgl carbo~ylate (~ee ~ ple 1~) and 13 mg o~ so diu~ bicarbonate.

- 96 ~ 3 4-~itrob~nzyl 2-~3(S) ~l(R~-dimethyl (2-me~hylprop-2-yl)-s lylogyv~thyl}--4(R)-ethylthio azetidin~2~on 1-yll-3 ~2-fluoropheno~y)-3-trimethylacetylthio-propenate 840 mg of the above compound were obtained by a pr~cedure analogous to that described in ~ample 16, u~ing 1 g of the azetidi~one ~tarting material, 486 mg o~ 2 fluoropheno~ chlorothionoformat~ 18 mls o~ he~amethyl~
silaz~ne and5.32 mm~l of n-butyllithium? nd 0.525 ml of trichloroacetyl chlorideO

~?ma~ 1764 cm~l C13) 0.06 (6~, B~
0~81, 0~87 (9H, 2s) 0.97, 1.05 (9~, 2~
i5 1~15 - 1,33 (6~, m) 2.67 (2H, q, J = 7 ~Iz) 3 . 22 ( 1'~ 9 dd ~ J = 2 Hz and 4 :E~z ) 4.02 ~ 4040 (1~, m) 5~30 (2H, ~3) 5.39 (lH, dt J = 2 Hz) 6.90 - 8.27 (8H, m~

~ 97 _ ~2 ~
..

4-~itrobenzyl 2-~4(R)-ethylthio~(S)-~l(R)-hydroxye~h~l~
azetidin-2~on-l-yl]-~ (2~fluorophenox~)-3-trimethyl2cetYl-thio-propenate 434 mg of the abo~e compound were obtained fr~ 830 mg of the corres~onding ~l(R)~dimethyl (2~meth~1prop-2 silylo~yethy~ compound (~ee Example 57j by a pro~ed~r~
analogou~ to that deecribed i~ Ex~mpl~ 179 u~ing 0~85 ml o~ water and 0.85 ml of concentrated hydrochloric acid.

~ ma~ 1760 cm 1 S (CDC13) 1.01, 1.09 (9~`28) 1.2~ 48 (6E, m) 2~65 (1~, b~
2.68 (2~, q, J = 7 ~z) 3~23 (1~9 ddg J = 2 Hz and 4 Ez) 4.02 - 4~40 (lH, m) 5,30 ~3H, b~) 6~95 - 8.26 (8~, m) ~a~
4-~itrobenzyl 2-~4(S)-chloro~3(S)-~l(R)-hydro~-eth~l~ azetidin 2~on-l-yl~-3 (2-fluorophens~y~-3-trimethgl-acetylthio-propenate 23~ mg of the above comp~und was prepared b~ a procedure analogous to that described in Example 26 using 434 mg o~
the l(~)-hydrox~ethyl aze~idinone derivative de~ined in E~ample 58 and 0.78 mmol of chlorlne ~ 01 ml8 carbo~
tetrachloride.

~ 17B0 cm 1 (CD~13) 1.0, 1.04 (9~9 28) 1020 ~ 1.55 (6H~ m~
2.52 (lH, b~
3.51 (1~, dd, J = 4 Hz and 9 Hz) 3~95 - 4.48 (1~, m) 5.21 (2H~ 8~
5.98~ 6.10 (lE, 2d, J _ 4 Ez) 6.87 - 8015 (8H, m) -~ 99 -~8~3 ~xam~le 60 ~_, 4;Ni~robenzyl 5(R)~-(2-fluoropheno~y~-6(S)~
hydroxyethy~ -7 oxo~4 thi~ l~azabic~clo[3~2,0~hept~2-ene-2-carboxylate 58 mg o~ the ab~ve compound were obta~ed ~y a ~r~-cedure a~logou~ to that de~cribed in ~ample lg ~izg 273 mg of the product of ~ample 59 and 54 mg o~ im~dæ~oleO

max 1790~ 1795 (ah) cm 1 ~ (CDCl~ 37 (3~, d, J = 6 ~) 2.22 (1~, b~) 3.75 (1~, ddj J = 1.5 Hz and 6 ~z) 4.05 ~ 4050 (lH, m) 5.34 ~2~9 q) 5.62 (I~) d~ J = 1~5 ~z) 7O04 - 7.33 (4H9 m) 7 ~ 39 - 8a 2~) ( 41~I, m) - loo ~
8~

E~am~le 61 ___ Potas~ium 5(R)~ fluorophenoxy)-6S~l(R)-hydroxyeth~ ~ -7~o~o-4-thia-1-azabioyclo r ~ ~ 2,0]hept-2-ene-2carbo~yl2te 56 mg of the above compound were obtai~ed by a proced~re - 5 analogous to that dessrib-ed i~ Example 21, using 58 mg of the corresponding 4-nitrobenzyl carboxylate (see E~ample 60) and 13 mg of pota~Si~m bicarbo~ate.

4 Nitrobenzyl 2-[3(S)~,Çl(R)~dimethyl~(2-methylp~op-2 vl)-~ilylo~y~ethyl~ ~(R)-ethylthioazetidin-2 on-l~yl)-3 (3-fluoropheno~y3~3~trimethylac~tylthi~ propenat~

0.974 g of the ab~ve c~mpound were obtai~ed by a pr~cedure analo~ous ~o that described in ~ample 16, ~ng 1~0 g of 4-nitroben~yl 2-[3(S)-~l(R) dimeth~l(2-~e~hyl-prop-2-yl)silylo~yethyl~-4(R)-ethylthioazetidin-2 o~
~1~ acetate, 1~34 ml of hexamethyldisilazane, 0.6 ~ of ~-fluorophenylchlorothionoformate, 6.38 nm3l D~ n~bu~yl-lithium, a~d 0O53 ml of trimethylacetyl chloride.

~max (C~C13) 1763 cm 1 S(CDC13~ 0.06 (6H, ~) 0.75, 0.80 (9~, 2 1.05~ 1.10 (9~, 28) 1.22 (3~, t7 J = 7 ~z~
1.25 (3X, t, J = 6 H
2.71 ~2X, q~
3.22 (~, dd) 4.0 - 4O5 (lH, m) 5.35 (3H, bs) 6.8 ~ 8.2 (8H, m3 102 ~
~ 3 ~a~ .
4-Nitroben~yl 2-[~(S) ~l(R)-hydro~yethy~ -4(R)~ethylthio-azetidin-2-on-1-yl]-3-(3-fluorophe~o~y)-~-trimethylacet~l~
thio~propenate 0.516 g of the abo~e compound were obtained ~rom 0.97 g of the correspo~ding ~l(R~dimethyl-(2-methyl~ro~-2-yl)8ilylo~yethyl3 compound (see E~ample 62) by a pr~ce1ure a~alog~u~ to that de~cribed in ~ample 17 using 2 ml of concentrated hydrochloric acid, 2 ml of water and 20 ml of tetrahydro~ura~.

I~ max (~DC13~ 1762 cm 1 (CDC13) 1.~5, 1~10 (9~, 2~
1.20 ~ 0 (6~9 m) 2~50 (1~9 b) 2~70 (2~
3.24 ~lH, dd) 3091 ~ 4,40 (IH, m) 5.~0 (~H, b~) 6,70 - 8~20 (8H, m) - 103 ~
~ 3 4-~itrobenzyl 2-r3(S)-~l(R) hydro~yethyl~4(S) chlo~o~
azetidin-2~on-1-yl~ (3-fluorophenoxy) 3-trim~thyl-acetylthio propenate 405 mg of the above compound were obtai~ed bv a ~ro~es~
- analogous to that de~cribed in ~ample 26 using 716 ~ o~
the l(R)-hydr~x~ethylazetidinone derivati~ de~ined ~n Example 63 and a solution o~ 0.912 mmol o~ chlori~e i 1.2 ml of carbon tetrachloride. The product ~a~ u~e~ in th~ next reaction without purification.

~ma~ (cDc~ 7~2- cm 1 ~CDC133 1.06, 1.10 ~.H, 2s) 1.35 (3H~ t) 2u5 (lH9 b) 3~5 (1~? dd J = 4 ~z and 9 ~z~
4.05 (lH~ m) 5.~0 (2~ s) 6.10 (lH, d~ J = 4 ~z~
6.80 - 8,30 (8~, m~

_ 104 ~ ~ 3 4-~itrobenz~l 5~R~, 6(S)-~l(R)-hydro~yethy~ -3-(3 fluo~o~
p~eno~y)-7-oxo-4-thia-1-azabicyclo~3~2,0]hept-2~2-carbo~ylate 205 mg o~ the above compound were obtained by a pro-cedure analogou3 to that described in ~ample 19 u~Ing 400 mg o~ ~he unpuri~ied produc' o~ ~xample 64 ~d 56~2 mg o~ imidazole.

~ma~ (CDCl~) 1784 cm 1790 (~h~ cm ~ (CDC13) 1.32 ~3H, d~
1~90 (I~, b~
3~70 (lH, dd J = 1.5 H and 6 H~) 4~00 - 4~30 (IE, m) 5~30 ~2H, q) 5,56 (lX, d, J = 1.5 ~z) 6,90 - 8,30 (8~7 m) - 105 ~ 8 ~ ~

Potassium 5~R), 6(~ l(R~-hydroxyethy~ -3~(3~fluorophe~oxy)-7-oxo-4-thia-1-azabicyclo [ 3, 2, O ] hept-2 -ene-2 carboæylate 160 mg of the above compound were obtai~ed fro~ 200 mg of the correspo~ding 4-nitrobenzyl ~arboxylate (~ee E~ample 65) by a procedure analogous to that described in 2~ample 21, u~ing 43.4 mg of ?otassium bicarbonate~

~ 3 Pivaloylo~ymethyl 3~ luoropheno2y) 6~ R)-hydro~y ethyl~ -7-o~o-4~thia-1-a~abieyclo~3j2~0]hept-2 ene-2-c~r-bo~ late ~o a ~olutio~ of 100 mg o~ pota3sium 3-;(3-~luoro-phenoxy~-6(S)-~l(R)-h~dro~yeth~ 7-o~o-4 thia-l azabi-cyclo~3,2,0Jhept_2-e~e-2~carbo~ylate in 1 ml of dimethyl~
~ormamide wa~ added ~8 ul o* pi~aloylo~ymethyl iod~de and the mix~ure wa~ stirred at room temperature ior 90 mi~U~e~D The mixture was partitioned betw~n eth~l acetate and w~ter, the orga~ic layer ~a3 wa~hsd ~ith water and brine, dried o~er mag~e~ium sulphate and evaporated in acuo to dryne6s. Chromatography over silica ge~ and elution with he~a~e-ethylacetate afforded 50 mg of the title com~
pound as a ~ellow oil~

S(CD~13) 1-20 (9H9 S ) ~
1.34 (3H, d, J = 6~z) 9 2.41 (I~9 ~) 9 3O75 (IH, dd, J = 1.5~z, 6~z~, ?0 4~27 ~lH; m), 5.67 (IH, ~)~
5~86 (2~, q), ~81 - 7,45 (4~, m~.

~ 3 4-~itr~benzyl 2~4(R)~ethyl~hi~ ~(S)-~l(R~ ~i~ethyl-(2~methylprop ~2 yl)_~ilyo~y eth7~ azetid m-2~on-l~yl~
~`~`~
0.56 g o~ the abo~e compound wer~ obtained by a pro~
cedure analogou~ to that d~cribsd in E~ample 16, u~ing 1 g of 4 nitrobe~yl 2-L~ l(R~di~eth~1-(2-methyl-prop~2~ ilylo~y e~hy~ ~4(R) ethylthioazetidin-2 ~n 1 yl~acetate, 1.34 ml of he~meth~ldiailazane~ 0~63 g o~
2-c~anopheny~chlorothionoformate, 6.38 mm~l o~ n-butyl-lithium, and 0~53 ml o~ trime~hylacetyl chlorid~

~S ma~ ~CDC13~ 1765 cm 1 (CD~ 0~07 (6~, 8~
0080g 0~87 (9H, 2~), 1.10, 1~15 (9~I9 28) 1~23 (3EI t J = 7~
1.26 (3H d J - 6Hz), 2.62 ~2~, q~, 3~25 (1~ d,d), 4O0 ~ 4~5 (1~, ~), 5 ~ 40 ( 3~ bs), 7.10 - 8~50 (~H, m).

~2 4-Nitrobenzyl 2 - [ 4 ~R ) -e thylthi o~3 ~ S ~ - ~1 ( R ) hydroxyethy~
aæetidin-2~vn~1~yl ]~3- ( 2 cyanopherlo~y ~ trimeth~
~aD~t~
0. 220 g o~ the above compound were obtained from 0~,560 g o~ the ~orresEo~ding ~l~R)-dimethyl--(2~-methyl~
prop~2~ ilylox~ethyi3 comp~und (Eee :~x mple 68~ b~
a procedure snalogo~s to that de~cribed in ~ mple 17 u~ing 1~5 ml o~ cotlceD.trated hydrochloric acid~ 1~,5 ml of water and 20 ml o~ tetrahgdrofura~e max ( CDCl ~ ) 176~ cm (CDC13) 1~, :)6, 1.10 (9~9 2~), 1.,20 - 1.40 (6~I, m), 2~,50 (l.E9 'b) 1 2"80 (2~, q), 3.24 (l~I, dd), 4.0 - 4040 (l~I, m~, 5.40 (31~, b~), 7.10- 8,,~5 ~81I, m)q ~ 3~ 3 - lOg --~aa~
4-Nitr~benzyl 2[4(S3 chloro~3(S)-~l(R)-hydro~yethyl}
azetidin 2~on-l~yl]-3~(2-cyanopheno~y) ~trimethyla-132 mg o~ ~he above compound were obtalned by a proce~s analogou~ t~ t~at d~cribed ~n ~ample 26 u8ing 190 ~g o~ the l(R)~hydrox~ethylazetidinone deri~ative def~ned in ~ample 69 and a solution oi 0~33 mmol of chlor~ne i~ 0.688 ml o* carbon tetrachloride~ The pro-duct wa~ purified by chromatographg oYer silica gel, eluting with ethyl acetat~/he~a~e mi2tures.

ma~ (CDC13) 1785 (CDC13~ 1.07, 1.13 (9~, 29)9 1.40 (~, m) D
1.5 (I~, b3, 50 (1~ dd,~, 4.06 - 4960 (1~, m) 5.~0 (2~, 8,), 6e25 (IH, d~ ~ = 4~z), 7.00 - 8~5 (8H9 m), - 110 ~

4-Nitrobenzyl 5(R)-3 (2-cyanophenox~)-6~S)-~l(R~
hydrogyet~yl3 7-o~o~4~thia-l azabic~clo ~39230]hept-2 80 mg o~ the above compou~d were obtai~ed by a procedure analogou~ to that d~scribed in ~xample 19 u9ing 130 mg o~ the product o~ ~aOE~le 70 and 18 mg o~
imidazole~

~ max (CH~al3) 1792 cm ~ ~CDC1~) . 1030 (~, d)~
3.71 (lH dd J = 1.5Hz and J = 6Hz), .00 - 4.30 (I~
5.20 (2Ht q), 5.65 ~1~9 dt J - 1.5 Hz~
6.90 - 8~10 (a~, m,), ~- 111 Pota~sium 5(R)-3-(2 cyano~heno~ 6(S~ - ~l(R)~hydro~y-eth~-7-oxo-4 thia-l azabic;yclo ~3,2~0~hept -2- ~e-carbo~: late 62 mg ~ the abo~e compound were obtained irom 80 mg o~ the corre~pondin,g 4-nitroben~;ylcarb~s:ylate (see ~ample 71) by a procedure analogous to that de~cribed in ~ample 21"
u6ing 17.,1 mg of potas3tum bicarborlat~O

8~3 4 Nitr~benzyl 3~(3 -aGeto:~yphe~oxy)-2-¦4(R)z e~hylthio-3 ( S ) ~ (R) -dimethyl ( 2~methylprop~2-yl ) ~ilylox;y''ethyi?~, -1. 05 g of the above compou~d were obtai~ed by R
procedur~ ar~Rlogou~ to that de~cribed in Example 16 using 1 g o~ 4-nitrob~n~yl 2--~3(S) ~l~R) dlmethyl (2~
meth~lprop-2-yl) silylo~cyethyl~ ~4 (R)~ethylthioazetidin-2-on-l yl] acetate, 1.34 ml o~ he;camethyldi~ za~e~ 0098 g c)f 3-aceto~cyphenylchlorathio:~oIormate, 6.~8 mmol of n-butyllithium a~d 0~ 5~ ml o~ trimethyl~cetylchloride .

Y'ma~ (CDC13) 1760 cm 1 (S(~DC13~ 0.06 (6~I, s), 0~,80, 0090 (9H, 2B), 1.059 1.10 (9H~ 2~
1~,22 (3E, t ~ J - 7Hz), - 1 " 25 ( ~E d J - ~H~ ) 2.28 (3~I, s), 2.70(2H9 q), 3030(lH~ dd), 4.104.5 (lE" m) 50~6(3Ht bB) .
6.75 8940 (8~I, m~0 ~ 113 ~ 86~3 4-~itrobe~yl 3-(3~acetoxypheno~y~-2-~4~R3 ethylthio~
~ l(R)-hydro~yethyl~azetidin-2-o~ yl]~-trimethgl-thioprope~ate(I) and 4-~itro~enzyl 2~-~4(R~-eth~lthio~ 3-~lR-hydro~yethyl~ a~etidin-2-on 1~ 3 (3-hydro~yphenox~) 88 mg of compound I abo~e, and 110 mg of compo~nd II
were obtained ~rom 400 g of tha corresponding ~l(Rf~di-methyl-(2-methylprop-2-yl)~ilylo~yeth~ oomp~und (se~
Example 7~) by a proceduxe anal.ogou~ to that de~cribed in ~ample 17 u~ing 1 ml of concentrate~ hydroehloric acid 7 1 ml o~ water and 10 ml oY tetrahydro~ura~. Compou~ds I a~ II ~ere separated by column chroma~ography.on ~llioa gel, eluting with ethyl acetate/he~ane mi~tures, data ~or comPound ~I~
15~ma~ (CD~13) 1767 c~ 1 (C~C13) 1.07, 1.13 (9~, 29)9 1~0 (3H, t J = 7Hz), 1032 (~H9 d J _ 6Hz);
2~25 (lfl b~33 9 20~2 (~H, 8), 2070 (2H, q)~
3.28 (lH, ddf~, 3.90 _ 4.40 (I~, m), - 114 ~ 8 5~30 (3Hp b~) $
6~80 - 8.30 (8~ m~5 ~m~ (CD~ 1755 cm ~
6 (CDC13) 1~05, 1"12 ~9H9, 2~), 1.29 ~H~ 't7 J = 7Hz), ., 32 ( 3H" d ~ J ~ ~i~Iz ), 2072 (2~I9 q) ~
2. 85 (1~ b~3 "
~i o 2E~dd i ~
3,,954.50 (lH, m) ~35 (31~, b8) 7 6"40 - 8.,~0 (8~I9 m).

E~
4 Nitrobenzyl 3=(3 -aceto~;yphe~o:~y) 2~4~S3- chloro 3(S)~
~lR~hydroxyet~yl3~aæetidin-2~on-1-yl~ ~ trim~thylacet~

246 mg OI the above compourla ~ere obtained by a proc~ss analogous ~o t;hat de~cribed i~ ~sample 26 using ~88 mg o~ the ~-(3~acetogypheno~y)l(R3-hydroxyeth~l-azetidinone derivati~e I d~ ed ~ Example 74 and a ' ~olution of 0.?2~ mol o~ chlorl~e in 1~49 ml o~ carbon 10 tetrachloride. The produc~ wa~ purified by colum~ chromato~
graphg. on silica ,~el, elutin~ with ~thyl acetate/31exane ixtures 0 ~m~ (CDC13) 1775 (CD~13) 1.07p lol~i (9H9 2~), 1"35 (~I, d) 9 2.25 (3H, 8), 2055 (,lFJ., bs) ~
3150 (lH, 2.dd), 4000 - 4060 (lH9 m) 503Q (2Hp 8), 6.15 (l~I~ 2d J = 4Rz) 9 6"80 8.30 (8H, m).

- 116 ~

4_Nitrobenzyl 5(R)-3 (3-acetoxyphe~o:2:y)~6(S~-~l(R)-hydroxyethyl~, ~7-oxo-4~thia -l-azabicyclo [3 i 2 9 O]hept ;2-115 mg o~ the above compound wera obtai~ed by a procedure ~alogou~ to that described in J~xample 19 USiI~g 240A~ oi~ the chloroa~etidino~e deri~atl~s de~ined in Example 75 and 31. 6 mg OI irQida~ole .

~ma~ (~DC13) 1782 cm 1 1791 (sh) cm 1 10~5 ( C~13 3 1 . 30 ( 3H , d ), 2~ 25 ~ [9 8 ~ "
2.60 (l:E~, bs), 3~71 (lII9 dd J _ 1.5~z and 6:E~z), 3.90 - 4.40 (lX, m)t 5 ~ ~7 ( 2~I,, ~), 5~,60 (1~17 d J = 105 ~I~.), 6.80 - 8.20 (~, m~., ~ 117 ~

Pota~sium 5(R~-3~(3~acetoxypheno~y)~(S) ~lR)-hydroxy-ethyl~-7 oxo-4-~hia-1-azabicyclo~,2,0]hept 2~ene~2-carbo~ l~te 32 mg of the above compound were obtained ~rom 115 mg of the corresponding 4 nitroben~yl carbo~late (~ee ~sample 76) by a procedur~ ~nalogo~s to that de~cribed ~n ~ample 21~ using 23 mg o~ p~tas~iu~ bicarbonate.

8~3 4-~ltr~benzyl 2-[4(S)~chlor~-3(S)-llR-hydro~yethyl~
azetidin~2~on~1-yl]-3 (3~hydro~yphe~o~y~-3 ~rimethgl~

270 mg of the above compound were obta~ned bg a proces~ analogou~ to that described ;n xample 26 using 400 mg o~ the 3-(3-hydro~ypheno~y~l(R~hydro~yeth~l-~zetidi~one derivative II de~ined i~ Example 74 and ~olution of 0~7~mol of chlorine in 1~6 ~1 of carbon tetrachloride. The produc~ wa~ puri~i~d by chr~mat~-graphy on silica gel9 eluti~g with ~t~yl acetate~he~ane mi~tureæ~

~ma~ (~DC13~ 1778 cm 1 ~(CW l~ 017 1005 (9H~ 2~) 9 1~35 (3H~ d), 2.60 (lH vbs), .50 (1~ d~d)~
4.00 - 4.50 (lE, m), 5~30 (2H~
6.10 (IH, 2d J = 4~2)~
6040 - 8.30 (8~, m)0 ~- 119 --~2 4-Nitrob~nzgl 5~R~; 6(S)- ~ ~ hydrog~ethy~ -3 (3-hydroxyphe~o~y3 7=o~o~4 thla-l azabicyclo~3~2~0~-he t-2-en~2~carbo~ late 150 mg o~ the abov~ compound were obtai~ed by a procedur~ analogo~ ~o that described in ~xampl~ 19 u~i~g 265 mg o~ ~he chloroaz~tidi~one derivatlve defined ~n ~ample 78 and 37.4 mg of imida~ol~D

~tma~ (CDCl~) 1780 cm 1 1790 (Sh) cm 1 10~ ~D~13) 1~32 (3HI d) 9 3.10 (1~ bs~ 9 3.8C (lHt dd, J = 1,.5 Hz, and 6 Hz), 4.00 - 4.40 (lH, m), 5e3t~ (2~I q)g 5070 (lH d J - 1~5 Hz~
6~4~ - 8D20 s8H m)t 8.70 (IH bs).

~ 120 -Potas~ium 5(R)1 6(S)~ R)-hydro~yethy~ -3~(3~hg~roxy-pheno~y)~7-o~o--4~thia-azabic~clo~290~hept;2 e~e~2-55 mg of the above compound were obtained ~rom 98 mg o~ the corre~po~ding 4-~itrobenzyl carbo~late ( ee E~ample 7~) b~ a procedure analogous to that de~cribed in ~ample 21, uslng 21~3 mg o~ psta~iu~ bicarbonate.

~'2 ~ 3 - 121 ~

E:camDle 81 4-Ni~robenzyl ~-(4 dimethylamino~ulphonylphenoxy)~
2~[4(R)-eth~lthio-3S~l(R)-dimethyl~(2--methy~prop-2-yl~ilylo~ethyl3~azetidin 2-on-1-yl]-3-trimethyl~

009~ g of the æbove compound ~erç obtained b~ a proced~re analogous to that descri~ed in ~ample 16, u~ing 103 g o~ ths azetidi~one ~tarting material deiined in E~ampl~ 16, 1.45 ml oi hexam~thyldi~ila~a~e, 1 g of 4 dimethylamino~ulphonylphenylchlorothiono~ormat~ 6,88 mmol o~ ~ but~llithium9 ana O.68 ml of trime~hylacetyl-chloride.
`

0.70 (6H, ~, 008~, 0.90 ~g~ 2s) 7 1~07~ 1~15 (9~, 2B3, 1020 (~H9 t~ J - 7Hz), 1.30 (~H d J = 6Hz)~
` 2.75 (6~ 8)~
3.27 (I~ dd, J= 211z and ~)t 4,3 (111, m), 5,3 ~H, m), 7,2 ~ 8,35 (8TI, m) E~aml~le 82 __ 4 Nitrobe~zyl ~s- ( 4~dimeth~laminosulpho:tlylpheno~y 3 ~2-~4(R)~ethylthio -3(S) -~lR~h;ydroxyethy~ azetidill 2 o~
11 3 trimet ~lacet lthio ro e~at~
0 e 57 g O:f~ the above compound wa~ obtained from 0.930 g o~ th~ corre3ponding ~ d~ethyl~(2~methyl-prop-2-yl)silylo:~yethy~ c~mpou~d ~e~ Example 81) by a procedure a~alogous to that d~cribed in ~ ample 11 u~ing 1,3 ml o~ conoentrated hydrochloric acid, 1~,~5 ml o~ water and .5 ml of tetrahydrofuran 0 m~2 (~DCl~;) 1728,, 1761 cm~l ~CDC13) 1.02, 1,11 (9H~ 23~, 1.20 (3H9 t), 1~,25 (3H, d~ 9 2052 (lH9 bs) 2~68 (6;E~, 3), 2O80 (2H, q3, 3.24 (lH" dd), 4.0 ~ 4.40 (lH, m), 5.30 (3H bs), 7~10 8.30 (8Hm), 4.10 - 4.50 (lH, m), 5.35 (3E3t b~) 7 7.1; 8.,4 (8HJ m~.

~ 2 ~ ~ 6 4~Nitrobenzyl 2~4(S~chloro 3(~ l(R)-hydro~y~th~l~
azetidin-2-on~l-yl]-3-(4~dimethyl~minosulphonylpheno~y) 445 mg o~ the abova compou~a were obtained by a proce~s analogou~ to that de~cribed in ~ample 26 u~ing 560 mg of ! he l(R) hydroxye~h~lazetidinone de~ati~e deiined i~ ~ample 82 and 1 ml o~ a 0.85 molar ~olutio~
of chlor~e i~ carbon tetrachloridec The prod~ct was puri~ied by chromatography over silica gel~ eluting with ethyl acetate/hexan~ mixture~.

ma~ (CDC13) 1783~ 1730 cm 1 ~CDC13~ 1007~ 1012 (9~, 2~), 1.40 (3~
2,50 (1~l, b~), 2075 (6Hg 8) 3060 (lH, ~) 4.05 - ~.50 (1 5.35 (2~, 8), 602 (1~, d, J = 4~z) 7.1 - 8.3 (8~p m).

- 1~4 4--~itrobenzyl 5~R3-3 (4-dimethylaminosulphonylphenoxy3 6 ( ~ 1 (R) -hydro~yethy~ -7 ;o:;Eo~4-thi~l azablc~clo [ 3, 2 ~ O ~ he pt-2 ene-2 carbo:~;ylate ~25 mg oî the above compound ~ere obtained by a pr~-ced~ analogou~ to that de~cribed ir~ :~ample 19 using 445 mg o~ the chloroaze~idinorle derivative definad i~
E~ample 83 a~d 50 mg sf imidazole.

y ma:ic (CDCl 5) 17891 1793 (~h) cm 1 lo h (cDa~ 5 (3H" d7 3 - 6Hz) 2.~0 ~1~, bR), 2 0 l3~S ( 6~
3 . 80 ( lE dd J -- 1 . 5~Iz and J = 6Ez 3, 4~00 4040 (lH9 m) 9 5.30 (2H, q9 2~ AB9 Jge~ 14~1Z)7 5 . 75 ~ l~I ? d 9 ~ - 1 . 5 ~" "To2 ~ 8~3 (8~ m3, - 125 ~ 3 ~,1~
Potassium 5(R)~-3~(4-dimethylami~o~ulphonylpheno~y)-6(S)-~l(R3-hyd~o~ye~hy~ -7~o~ow4-thi~-l azabicyclo [ ~ J 2,0]hep~2-e~e-2-car~o~ylate 70,8 mg o~ th~ above compound were obtained from 112 mg of the corre~ponding 4-nitrobenzyl carbox~late (3ee ~xample 84~ by a procedure analogo~ to tha~
- de~cribed in ~x~mple 21D u~ing 20.4 mg of potasBium bicarbonate.

~ 12 4 ~itrobenæyl ~- [ ~ ( S ~ - ~1 ( R j -dimethyl- ( 2-rnethylprop 2~
yl)8ilyloxyethyl~ ~4~R)-ethylthi oazetidi~-2-on-l~yl~-3-170 mg o~ the aboYe compound wer~s obtained~ as a y8110w oil, by a procedure analogous to that described in E~cample 16, U9:iXlg 2~,0 g o~ ~he azetidinone ~tarl;i~g material de~ined in E~ample 16t 1.3 g of 3 rlltroph~nyl chlorothiono:form~s, 2 a 2 ml 4Y hexam~thyldis~lazan~ and 10 10,1 mmol o~ ~-butyllithium7 and 1.5 ml of trimethyl-ace~yl chloride 7 ((~7~0 3 1765 cm~l ~5 ( CDC13 ) 0 .. G6 ( 6~I ~ s ~ 9 0,,80, G.85 (9H, 2s~
1~,00 (gH~
1~,10 - 1030 (6H~ m), 2064 (2Hp qg J -- 7Hz), 3 0 19 (lH9 m), 4.00 4~45 (lHg m~, 20 5.25 (3H~ bs~ ~
7,00 - 8710 (8Hg m)0 .

- ~.27 ~ 3 4-~itrobenzyl 2 ~ ~ ~ S ) - ~1 ( R ~ ~hydroxye thy~ -4 ( R ~ -e thyl-thioazetidin~-2-on-1-yl]~3~(3~n~trophe~xy)~=3-trimethyl-0.,755 g of the abo~e compou~d were obtained ~rom 1,.7 g OI th~ corre~pondi~g ~l(P.)-dimethyl ~2~methylpro-2 yl)~ilylox~srethyi~ compou~d ~ee ~;zample 86) b;y a pro-cedur~ analogous to that d~crlbed i~ Example 179 u~i~
107 ml of water and 1~7 ml o~ cor~centrated hydrochloric acid .

~max (C3~1 ~)1730 7 1762 cm 1 (CDCl~) 1.06" 1~,16 (9H~ 29), 1 ~ 20 - 1 0 3E3 ( 6H ~ m), 3 . 75 ( 2H, q, J = 7 3.29 (l~I, dd~ J = ~z and 4Hz) 3 ~, g8 - 4 " 40 ~
5v27, 5.30 (3~1, 2 b~), 70~5 8.18 (8H, m) O

- ~28 ~

4-~itrob~nzyl 2~C3(S)-~,l(R)-hydro::~ye~h;yl~-4~S)-chlor~-azetidin 2-on~l~yl~-3-~3-nitropheno~ trimethylacetyl-To a s~irred sol~tion of 00755 g of the l(~
hydro~yet}lylazetidinone deri~ative de~ined in ~3gample 87 in CI)C13 a~ -40C wa~ added a ~ol~tion of 1.,3 mmol ~f chlorine i~ carbo~ etrachlorlde a~d the solutio~ wa3 stirred ~or 1 hour~ The reaction m~;ture wa~ w~rmed to 10 room temperature a~d e~aporated to d~ne~s. Chroma~o-graphy o~er silica gel arld elution with he:ica~e/ethyl acetate mi~ture~ a~forded 0~536 g OI ~he title compourld.

~max(''3~ 72g~ 1784 cm 1 S (CDCl~;) 1.02, 1008 ~9H, 2s), lnl5 (3H7 d9 J = 6Hz), 2.45 (lH7 bs), 3.56 ~l~I9 dd, J _ 4~z and 9Hz), 3090 - 4.57 ~l~I, m), 5.~4 (2E~
6,16 (111~ d, J _ 4F~z)9 7.40 - 8"~3 (8H, m)~

~ 129 ~

~2 .
4-~itrobenæyl 5(R), 6(S)-~l(R) ~hydro~ye~hy~ 3- (3 nitropheno~y ) -7o20-4-thia01~azabicyclo ~ 3, 2 9 0 ~ -0~176 g of the aboYe ~ompound were obtailled by a pro~ed~2re analogo~s to tha~ described in E:~anple 19 u~ing 00299 g o~ the 4~ s~ chloroaz0tidinone of ~xample 88 and 0. 0668 g of imidazole i3 ~max(C3Cl~j3 1712, 1789 cm 1 ~(~D~13) 1.32 (~;~? d., J - 6~z), 2.20 (l~I9 bs), 3,,80 - 3.90 (~, ~D.), 4 olO o 4~40 (lE[~ m3 s 5~33 (2H~ q), 5.72 (l~I, d, J = 1.,5Hz3, 7.48 - 8~25 (8H, m).
( ~ l~o ~

4_Nitroben~yl 5(R~ 9 3~(3 aminopheno~y) 6(S) ~l(R)o hydro~yethy~ -7~ozo-4-thia~l-a~abicyclo [~72~0~hept~

~ mi~tuTe o~ a solutio~ of OD175 g of 4 nitroben~yl 5(R) t 6(S)-~l(R)~hydro~ethyl ~ 3~ nitropheno~y~-;7-o~o 4-thia l~azabicyclo ~2~0]heptD2e~-2-carbo~ylate ~n ethyl acetate and 25 mg sf Adam~ catalyst ~platinum dio~ide) was hydrogenated at 50 p~Soi~ ~or 105 mi~, ~ha mixture was ~iltered through Celite (Trade Ma~k3 and evaporated to dryness. Chromatograph~ over ~ilica gel and elution with he~ane/sthyl acetat~ ml~tur~ afforded 7.5 mg of the title oompou~d, a~ a yellow solid.

~ ma~ (CDCl~) 1778 cm 1 ~((GD3)~Co3 1.30 (3~, m)~
3.70 - 3.85 (lH, m), 3098 - 4.40 (lH7 m3 5~32 ~2~ q) 5~70 (lH, d~ J = 1.5 6.55 - 7,30 (4H, m), 7~55 - 8~16 (4H, m).

Pota~01um 5(R~ 9 3~(3-aminopheno~cy) 6(S~ ~l(R)-h~dro~y-ethy~ -7 oxo-4-thia~ azabicyclo [3 5 2,0~hept-2-en-2~

59 m g o~ the title compouIld wer~ obtai~d by a pro-cedu~^e analogous to that d0~cribed irl Ezampl0 21 UBi~g 66 mg o~ 4-nitroben~l 5(R3, 3-(3 aminoph2noxy)-6~S~-Cl~ hydro:~ye~hy;i~ -7 oxo-4 ~thia l~; azablc~clo E3,2PO]hePt-en~2-carbo~;ylate and 15 mg pota 8i~am h~droge~ carbc~te and 10~ palladium/charcoal.

- 132 ~
. ~

4-~itro~enzyl 3 ~4-(c~a~methyl)phe~oxy]~2~
dimQthyl~2-me~hylprop-2-yl)silyloxyethy~ -~(R)-ethylthi~-a2etid ~ 2 o~-yl]-3-trimethylacetylthiopropenat~

326 mg o~ the above compound were obtained by a - proc~dure analogous tv th~t d~cribed i~ ~ample 16~ u in~
0.5 g o~ th~ azetidin~ne ~tarting ma~erial de~ined in E~ample 16 ? 1 . 66 ml of n-butyllithium, 0.59 ml o~ hexa-meth~ldi8il~zane~ 00525 ml o~ trimethylacetyl ~hlor~de~ and 0.269 g o~ 4-~c~nomethyl)phe~yl chlorothionofsrmate.

ma~ (CDal3) 1762 cm 1, 2240 cm 1 ~CDC13) o.o5 (6~ æ3, 0.79, 0.85 (9H~ 28), 19039 1007 ~9~9 2~, 1~21 (3~, t, ~ - 7~
1~,25 (3~I, d, J = 6Hz) 9 ~- 2,.60 (2H, q p J = 7Hz), 3~23 (1~? dd, J = 2~z~ 4Hz~, 3 . 7~ ( 2~
3.97 - 4~44 (1~, m), 5~,25 (3H, bs), 6~,85 8.2~ (8~I, m), - ~33 ~ 3 4~itrobe~zyl ~-[4w(cyanomethyl)phenoxy]-2-~4(R~-eth~l-thio- ~S~l(R)-h~droxyethy~ -azetidin-2 o~ 1 yl~

159 mg of the above compound were obtained by a pr~cedur~ analogou~ to ~hat de~cribed ~n E~ampl~ 17 using 348 mg o~ the col~e~pondi~g ~l(R~d~methgl~(2-me~hylprop-2-yl3~{1ylo~yethgl~ compou~d (~ee ~ample 92~, 095 ml o~ concentra~ed hydrDchloric acid, a~d ~.5~1 of ~at~r.

10 ~ ~ax (CDC13~ = 1760, 2240 (~DC13) 1~07, 1il2 (9H, 2~)~
1~2~ (3~, t? J 7~Z) 9 1.35 (3H, dt J = ~H~), 2.~8 (I~, b~)~
2~72 (2H~ q, J = 7~z), , 3.23 CIH~ dd; J = 2Hz ~ 4~z~, 3.71 (2~
3~95 - 4.~0 (lH~ m), 5027 (3H, bs) 9 6.~6 - 8.23 (8 ~ 13~ 3 4-~itrobenzyl 2 [4(~-chloro-3(S)-~l(R)~hydro~eth~ -azetidin-2-on 1-yl~-3-~4-(cyanomethyl)phenoxy~ 3~tri-70 mg o~ the above compou~d were obtained by a process analogou~ to that de~cribed in ~ampl~ 26 using 100 mg oi-the l(R)-hydro~eth~laæetidinone derivati defined in ~ample 93 and 0.21 ml oi a 0~85 molar ~olution of chlorine i~ carbo~ tetrac~loride~ The product ~O was purified by chromatography o~er silica gel 7 eluting with ethyl acetate/he~ane mi~ture~0 ma~ (CDCl~) = 1780 cm~l, 2242 cm~
~(CDC13~ 1.08, 1.14 ~9~, 2~), 11~5 (3~y d, 3 = 6 2040 (1~ b~)~
3.52 (lH, dd, J = 4Hz), ~,74 (2H, ~), 4.05 - 4.55 (l~I, m~, 5~32 (2H, ~j 9 6.17 (IH, d, J = 4~z)9 6~89 - R.28 (8~, m).

_ 135 ~

~a~
4-Nitrobe~z;yl 5(R)~ 4 (cyanomethyl)pheno~y~ 6(S) hydroxye~hy~ -7~o~o-4 thia-l~azabicyclo ~ ~ ~ 2, 0 ~ -61 mg of the abo7e compouIld were obtained bg- 8 pro~edure a~logous to th~t des~rib~d ~n Example 19 using 190 mg c~ the chloroazetidinone ~erivative deIined in Example 94 and 28 mg OI imidazol~3 ;
~)m~C (CDC13~ 1785~ 1795 (sh~ d 2242 cm 1 10~; (CDC13) 10~i8 (3H~ d~ J - 6~Iz)"
2.39 (lH, b~), 3~
4.05 - 4043 (lH, m), 5.34 (2H, q), 5.68 (lH, d, J = 1.5Hz~ 9 7~09 7.~0 (4H~ m) ~
7"4~ 8.31 (4EI~ m).

~ 13~ 3 Pota~sium 5(R~_3D[ 4-(cyarlomethyl)pherLoxy]-6(S) ~1(R)-hydro:~:yethyl~ ~7~oxo-4 thia~l~a~abicyclo ~3 ~ 2 t Q ]hept-2-en ~-13 sllg o:~ t~e abo~e compound were obtained fro~ 60 mg of the corr~ponding 4 ~itrobe~zyl carbo~late (æee Egample 95 ~ by a proc~dure analogou~ to t~t described ~ ~ample 21 u~:L~g 12~, 5 mg of pota~ium b1 carbo~at2.

~2~ 3 EXAMPI,E 97 4-Nitrobenzyl 5(R), 6(S)-{l(R)-acetoxyethyl7 -3-(4-fluorophen-oxy)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-erle-2-carboxylate To a stirred solution of lOOmg of 4-nitrobenzyl 3-(4-fluorophenoxy)-6(S)- {l(R)-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo-[3,2,0]hept-2-ene-2-carboxylate in 3ml of -tetrahy-drofuran at 0C was added a solution of 3mg of dimethylamino-pyridine in 0.5ml of acetic anhydride. After 30 minu-tes, the reaction mixture was warmed to room temperature, partitioned between ethyl acetate and water, the organic layer was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulphate, and evaporated ln vacuo to dryness.
Chromatography over silica gel and elution with ethyl ace-tate-hexane mixtures afforded 74mg of the title compound.
~ (CDC13) 1.40 (3H, d, J=6Hz) 2.01 (3H, s) 3.80 (lH, dd, J=1.5Hz, 6Hz) 4.99 - 5.26 (lEI, m) 5.29 (2H, q) 5~51 (lH, d, J=1.5Hz) 6.87 - 7.23 (4H, m) 7.34 - 8.22 (4H, m) - .13~ -18~3 4-Nitrobenzyl 5(R), 6(S)- ~l(R)-benzoyloxyethyl} -3-(4-cyano-phenoxy)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carbox-ylate 70mg of the above compound were obtained from the corresponding l(R)-hydroxyethyl compound (defined in Example 42) by a procedure analogous to that described in Example 97, using lOOmy of the l(R)-hydroxyethyl compound, lml of tetra-hydrofuran, lmg of dimethylaminopyridine, 33mg of benzoyl chloride and 18mg of pyridine.
S (CDC13) 1.3 (3H, d, J=6Hz) 3.95 (lH, dd, J=1.5 and 6Hz) 5.25 (3H, m) 5.8 (lH, d, J=1.5Hz) 7.0 - 8.2 (13H, m) \\
.

- 139 _ ~f~

4-Nitrobenzyl 5(R), 6(S)-~l(R)-ace-toxyethy~ -3-(4-methylsulphinylphenoxy)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate _ _ _ _ 571mg of the above compound were obtained, as an oil, from lOOmg of the corresponding l(R)-hydroxy compound (defined in Example 20) by a procedure analogous to that des-crihed in Example 97 using 25ul of acetic anhydride, lml of tetrahydrofuran, and 2mg of dimethylaminopyridine.
S(CDC13) 1.38 (3H, d, J=6Hz) 2.02 (3~, s) 2.74 (3H, s) 3.85 (lH, dd, J=1.5 and 6Hz) 5.3 (3H, m) 5.8 (lH, d J=1.5Hz) 7.0 - 8.3 (8H, m) - 141) - ~2~8~

EXAMPLE l O O
4-Nitrobenzyl 5(R), 6(S)- ~l(R)--(phenoxyacetoxy)ethyl} -3-(4-methylsulphinylphenoxy)-7-oxo-4~thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate 53mg of the above compound were obtained from 170mg of the corresponding l(R)-hydroxyethyl compound (see Example 20) by a procedure analogous to tha-t described in Example 97 using 86.2mg of phenoxyacetyl chloride, 40mg of pyridine and lml of tetrahydrofuran ~(CDC13) 1.35 (3H, d J=6Hz) 2.73 (3H, s) 3.96 (lH, dd J=1.5 and 6Hz) 4.4 (2H, m) 5.1 (2H, m) 5.31 (2H, m) 5.78 (lH, d J=1.5Hz) 7.0 - 8.3 (13H, m) Exampl~ 101 __ 4-nitrobenzyl '(R)~3-(2-fluoropheno~y)-6~S)~l(R)-pivaloyloxymethyloxyethyl~-7-ox~-4-thia-1-azabicyclo~3,2,0 hept-2-ene 2 car~oxylate To a stirred ~olution of 50 mg of ~he correspo~ding ltR)-hydroxyethyl ~ompound (~ee Example 60~ and 96 mg of pivaloyloxym~thyl iodide in 1 ml of te~rahydrofuran wa~
added portionwise 125 mg of ~ilver vxid~v The crude product wa ~ilteredt wa~ evapora~ed in va~uo and ~en dhrnmatogra~hed on ~ilica gel. Elution with e~hyl a~eta~e~hexane mixture~
afforded the title ~ompound a~ an oilD
- V max (CDC13) 1795. ~m ~(CDC13) 1~20 (9H, ~) 1~38 (3~ d J- 6H2 ) 3,85 (1~, dd ~ 5 arld 6}~z) 4c5 (1~, ~R) ~"33 (2H, m) 5080 (3H, b~) 7 ~, 15 -- 8 ., 2 ~

~18~3 Potassium 5(R), 6(S)-~l~R)-acetoxyethyl}-3-(4-fluorophenoxy)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate 47mg of the above salt were obtained from 74mg of the corresponding 4-nitrobenzyl carboxylate (see Example 97) by a procedure analogous to that described in Example 21, using 14mg of potassium bicarbonate and lOOmg of 10% Pd on carbon.

Potassium 5(R), 6(S)- {l(R)-ace-toxyethy~ -3-(4-methylsulphin-ylphenoxy)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept2-2ene-2-carbox-y_ate 41mg of the above salt were obtained by a procedure analogous to that described in Example 21 from 55mg of the corresponding 4-nitrobenzyl carboxylate (see Example 99) us-ing lOmg of potassium bicarbonate and 50mg of palladium on ~harcoal.

Potassium 3-(2-fluorophenoxy)--5(R), 6(S)- ~l(R)-pivaloyloxy-methyloxyethyl~-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate _ 13mg of the above salt were obtained as a yellow, oily solid by a procedure analogous to that described in Ex-ample 21, using 15mg of the corresponding 4-nitrobenzyl car-boxylate (see Example 101) 2.6mg of potassium bicarbonate and 20mg of 10~ palladium on charcoal.

- 1~3 - ~ 3 Potassium 5(R), 6(S)- {l(R)-benzoyloxye-thyl~-3-(4-cyanophen-oxy)-7-oxo-4--thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate 43mg of the above salt were obtained from 65mg of S the corresponding 4-nitrobenzyl carboxylate (see Example 98) by a procedure analogous to that described in Example 21, using 11.4mg of potassium bicarbonate.

Potassium 5(R), 6(S)- ~l(R)-(phenoxyacetoxy)ethyl} -3-(4-meth-ylsulphinylphenoxy)-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate 34mg of the above salt were obtained from 40mg of the corresponding 4-nitrobenzyl carboxylate (see Example 100) by a procedure analogous to that described in Example 21 using 6.3mg of potassium bicarbonate.

- 144 ~ j3 ExamplQ 107 __ Methyloxycarbc)nyl 3-thienyl chlorothionof ormate To a vigorou~ly stirred ~olution of 20 g of methyl 3~ydroxythiophene~2-carboxylate and 15 ml of ~hiophosgene i~ alumina~dried chloroform at Ov was added dropwi~e a ~olution of 5~1 g of ~odium h~droxide in 50 ml of water. The mixture wa~ then warmed to room ~emFerature, wa~ .tirred for a further 105 minutes~ and ~hen partitione~ r ~he organi~
layer wa~ ~eparated, wa~ wa~hed with ice-eold water, with brine and t~orougly dried over CaC12. Evaporation m vacuo afforded a yellow-orange oi~ whi~h ~olidified on ~tanding.
M~ 235~ 93Bl and 237.9337 Found C, 35.79, H, 2~20, o, 20~13~ Clt 14040~o S 27,3B %
~(CDC13) 3.85 (3~,s) 6.95 (la,d J-6 ~z) 70055 t~l:Sl ,d J--6 ~lz ) . .

Example 108 4~ robenzyl 2 -[ 3 ~ S ) ~1 (R ) ~limethyl ( 2 -methylpro -2-yl ~ -silyloxyethyl~-4(R)~ethyl~hio--axe~idin~2~on-l~yl~3~
(2-methyloxycarb~nyl 3-thienyloxy)-3~trimethylacetylthio propenate 580 n~ of the above compound were obtained ~y a procedure analogous to that de~cribed in Example 16, u~ing 1 g of ~he azetidinone ~tarting material, 4 . 90 m~ of 2-methyloxyt:ar~nyl-3-thienyl chlorofc3rmate (~e~ Example 107)~ 1~,18 Tnl of hexamethyldisilazane and 5032 mm~.l o n-~utyllithiumt and 00 52 5 ml o~ trichloroa~etyl chl~ride .

max (CDC13 ) 1765 cm 1 (CD~13) 0.06 (fiEI, ~ ) 0.81, 0.87 (9EI~
.~8, 1005 ~gEI, 2 1035 (6~, m) 2,,70 ~H, ~ J=~2 ) 3023 (lH, dd J=21Iz and 4EI
3.85 ~3Rt s ) 4,0_404 (l~I, m) 5.3 (2~, g ~
5 .40 ( LEI, d, J= ~lEI ) 609~8~3 (6~I~ m) Z

- '14 Example 109 __ 4-~itrob~n2yl 2-~4 (~ ~ ~ethylthio-3 (S ) ~ ~1 (R)~ydroxyethyl~~
aze~idin-2~on-1-yl~-3 (2-me~hyloxycarbonyl-3~thienylo~y)-30 trimethylacetylthioprop~nate 290 mg of the above ~ompound wer~ obtained fro~ 570 mg of the corr~por~ing ~1 (R)~lime~hyl (2-~ethylprop-2 yl )-~ilyloxyethyl~
compound ~ee Example 108) by a p~oc~lure analogo~s to that des~ri):~d in Example 17, u~ing 0. 5 ml vf water and 00 5 ml o~
~oncentra~d hydrol::hloric ac:id O
Vn~ax ~CD~13 ) 1760 ~ 1 S (~DC13) loOl~ 1~09 (9EI~ 21B) 1.2--1048 ( 6E~, ~) 2~5 ~l~I, ~) 2.65 (2H, q J~ 6Hz) 3 s 2 5 - ( lH, dd J= 2~1 asld 4EIz 3.. ~5 (3~
4"0~,,4 (lEI, m) 5,~ (3~I, bs) 609-8~,27 ~6H, ~Q~

7~

Exampl~ 110 _ _ 4-Nitro}:enzyl 2 ~ 4 ( S ) ~hloro ~3 ( S ) - ~1 ( R ) -~ydroxye thyl~ -azetidin-2 on~ yl] 3-~2 methyloxycar~nyl-3-thienyloxy)~
3-trilrethylac2tyli:hiop~operlate _____ 14 5 r~ of the abo~e cs:~m~und wer~! prepared by a procedure analo30u~ to that describea in Exampl~ 26 u in~ ~90 mg o~ thQ
4- (R )~ethyl'chio a:~etidinone derivati~ def ined ill Example 109 and 07~g ~nol o~ ::h}orin~ in 1P5 ml carb~sn t~rachlor-ide~ -V ~nax (CDC13 ~ 1780 cm~l (CDC13~ 1.0, 1~ 9~, 2~3 ) 176 (6R, m~
~ . 5 ~ l~I, ~3a ) 3,52 (lH, dd 35 4H and 7Elzj 3~5 (3EI7 . ) 3O95~.5 (l~I, m~
5.20 (2R, ~ ~
99 ~ = 4~) 60.9-8.2 (8H, m) Example 111 4 ;~itro~nzyl 5 (R), 6(S)~ ~l(R) hydroxy~sthyl~r3~
( 2 methyloxycarb~nyl-3-thi~nyl;~xy ) ~7 oxo~thia -l-azabicy~lo [3~2,o~hept 2 ~ne~2 s:ar}~oxylate 68 ~ of th~ above com~und were obtain~d ~y a pro~eduxe analogau~ to that d~c:ribed in EXanQple 19 u~ing 145 mg o~E the product o~ Exa~ple 110 and 16 m~ of imidazole O
~J~ax (CDC13 ) 1793 s~m 1 ~CDC13~ 1~.37 ( ~, d, J~ 6El 202 (liE~, bB
3, 7 (41E~, m ) ~oO1~5 (1~ m) 5~34 (2~ q~
5 . 62 ( 1~, d 9 ~J-- 1. 5~Iz ) 6.9-8,.2 (6~I, m) .

E~campl~ 112 ___ Pota~ium 5(R), 6(S)~l(R) hydro~ethyl~-3 (2 me'chylo~
~axbonyl 3-thienyloxy ) -70~0~thia~-aza}sicyclo~ 3, 2, o hept-2-ene 2-carboxylate 49 mg o:E the above ~:o~apound wer~ obtained by a prsc~dure analogou~ to that d~cribed irl Example 21, u3ing 60 mg c>~ ~he cc~rre~:ponding 4-nitroberlz5~1 ~arboxylate (se~ ~xample 111 ) and 11. 8 sng s:~f pota~ium bicarbcsnatQ ..

Claims (10)

1. A process for the production of a compound of the formula II

II

in which R is hydrogen or a carboxyl esterifying group removable by hydrolysis, by photolysis, by reduction or by enzyme action to give the free acid;
R1 is phenyl, naphthyl, thienyl being unsubstituted or substituted by one, two or three substituents, which may be the same or different, selected from the group consisting of halogen atoms and -OH, -NH2, -NO2, -CN, -N3, R3-, R30-, R3S-, R3-SO-, R3-SO2-, R3-CO- R3-O-CO-R -CO-O-, H2N-CO-, -CF3, -SCF3, - SOCF3, -SO2CF3 and HO-CO- groups, in which R3, R3 and R3' each represents an alkyl group having from 1 to 4 carbon atoms, R3, R3' and R3" being the same or different, but not more than one should be selected from i) -OH and -NH2 groups and not more than one should be selected from ii) -CN, -NO2, R3-CO-, R30-CO-, R3-SO- and R3 -SO2-groups, and R2 represents a hydrogen atom, or a hydroxyl group which may be protected by a hydroxyl protecting group, or a salt thereof, R4 is chlorine, bromine, -S-alkyl. or -S-alkenyl having up to 8 carbon atoms, respectively, and R5 is alkyl of 1 to 4 carbon atoms, or a phenyl group wherein a compound of the formula IV

IV

wherein R6 is alkyl of 1 - 8 C-atoms, alkenyl of 3 - 8 C-atoms or phenyl is reacted with a compound of the formula IX

IX

in the presence of a base and thereafter with a compound of the formula X - and, if desired, the obtained compound of the formula II
in which R4 is -S-lower-alkyl or -S-lower-alkenyl may be hydrolysed and then halogenated to obtain a compound of the formula II in which R4 is chlorine or bromine.

.

2. A process as claimed in claim 1 wherein R2is hydroxyl or protected hydroxyl and the stereochemistry at carbon atom No. 5 is (R).

3, A process as claimed in claim 1 wherein R2 is hydroxyl and the stereochemistry at carbon atom No. 4 is respectively (S), when R4 is chlorine or bromine, and (R) when R4 is -S-alkyl or -S-alkenyl having up to 8 carbon atoms.

4, A process as claimed in claim 1 wherein R2 is hydroxyl or protected hydroxyl and the stereochemistry at carbon atom No. 3 is (S).

5. A process as claimed in claim 1 wherein a compound of the formula II is produced in which the stereochemistry at carbon atom No. 5 is (R), and wherein when R2 is hydroxyl, the stereochemistry at the ring atoms No. 3 and 4 is respectively (S) and (S) when R4 is chlorine or bromine, and (S) and (R) when R4 is -S-alkyl or -S-alkenyl having up to 8 carbon atoms, which comprises reacting a compound of the formula IV.

IV

wherein R6 and R are defined in claim 1, and wherein R2 is hydroxyl or protected hydroxyl and the stereochemistry at carbon atoms Nos. 5, 4 and 3 is (R), (R) and (S) respectively with a compound of the formula IX

IX

wherein R1 is as defined in claim 1 in the presence of a base and thereafter with a compound of the formula X

X

wherein R5 is defined in claim 1, and, if desired, the obtained compound may be hydrolysed, and then halogenated.

6. A compound of the formula II as defined in claim 1, whenever obtained according to a process as claimed in claim 1 or by an obvious chemical equivalent thereof.

7. A compound of the formula II, as defined in claim 1, wherein R2 is hydroxyl or protected hydroxyl and the stereo-chemistry at carbon atom No. 5 is (R), whenever obtained according to a process as claimed in claim 2 or by an obvious chemical equivalent thereof.

8. A compound of the formula II, as defined in claim 1, wherein R2 is hydroxyl and the stereochemistry at carbon atom No. 4 is respectively (S), when R4 is chlorine or bromine, and (R) when R4 is -S-alkyl or -S-alkenyl having up to 8 carbon atoms, whenever obtained according to a process as claimed in claim 3 or by an obvious chemical equivalent thereof.

9. A compound of the formula II, as defined in claim 1, wherein R2 is hydroxyl or protected hydroxyl and the stereo-chemistry at carbon atom No. 3 is (S), whenever obtained according to a process as claimed in claim 4 or by an obvious chemical equivalent thereof.

10. A compound of the formula II, as defined in claim 1, wherein the stereochemistry at carbon atom No. 5 is (R), and wherein when R2 is hydroxyl the stereochemistry at the ring atoms No. 3 and 4 is respectively (S) and (S) when R4 is chlorine or bromine, and (S) and (R) when R4 is -S-alkyl or -S-alkenyl having up to 8 carbon atoms, whenever obtained according to a process as claimed in claim 5 or by an obvious chemical equivalent thereof.