CA2142708A1 - Cationic-2-heteroarylphenyl-carbapenem antibacterial agents - Google Patents

Abstract

2142708 9405669 PCTABS00030 Carbapenems of formula (I) are useful antibacterial agents.

Description

\~'0~4/~ 669 PCT/~'S93/0783~ ~
, , ,:.. `. 1

2 i ~

.

. .

--1 .
1o TITLE OF T~E INVENTION --`
CATIONIC-2-~ETEROARYLPHENYL-CARBAPENEM ANTIBACTERIAL
AGENTS

BACKGR0UND QF T~E INVENTIQN
The present invention relates to ~:~ antibacterial agents of the carbapenem class, in which the 2-position sidechain is characterized by a heteroarylphenyl moiety, substituted by various cationic and neutral substituents~ as described in more detail below.

:~ ;' ~ 30 ~
:

- . ' : ~ -: ~

.

wos~/~;669 PCT/~593/07830 2 l ~ 2 -Thienamyci~ was an early carbapenem antibacterial agent having a broad spectrum; it has the following formula: ,`

HO
H H

o~N~ ~ 2 C~
I

Later, N-formimidoyl thienamycin was discovered; it has the ~ormula:
,~ -, ~ ~
'~
: HO

~ H H

1 . H
OH

Thelclationic 2-heteroarylphenyl-carbapenems of.the, , . j~
present invention are not characterized by a broad : .' :30 antibaeterlal spe~ctrum such as~that of thienamy~in or ~ ~;
N-formimidoyl thienamycin. Rather, their spectrum of ` ~
a~:tivity is la~igely;limited to gram positive : - ~7 microorganisms, esp~ecially methicillin resistant :~ :
t~phylococ~us ~ ~ I(MRSA), methici:Llin 1 `;-`
/0~669 PCT/~S93/07830 2 :~ ~ 2 7 3 ~ !

resistant S~hvlococcus ~ ermidis ~MRSE), and methicillin resistant coagulase negative StaphvlQcoçci (MRCNS). The antibacterial compounds o~ the present invention thus comprise an important contribution to therapy of these difficult to control pathogens. Moreover, there is an increasing need for agents effective against such pathogens (MRSA/MRCNS) which are at the same time safe, i.e., ~ree from undesirable toxic side effects. No ~-lactam antibacterial has yet been found which meets these requirements. And, the current agent of choice, vancomycin, a glycopeptide antibacterial, is e~periencing an ever increasing amount of resistance in the MRSA/MRCNS pathogens.
More recently, carbapenem antibacterial agents have been described which have a 2-substituent which is an aryl moiet~ optionally substituted by, e.g., aminomethyl and substituted aminomethyl. These agents are described in U.S. Patent Nos. 4,543,257 and 4,260,627 and have the formula:

E~2 H or CH~
R~ H NH
CQOH
~ 30 However, there is no description or : suggestion of a cationic heteroarylphenyl ~, ~.
~ .

; :

! ~
WO 9~/~)5fi69 PC~/~,'S93/07830 ~2 ~ '3 ~ 4 -2-substituent such as characterizes the compounds of ~ `
the present invention, nor is there any suggestion of 1:.
the surprisingly be~ter anti-MRSA/MRCNS ac~ivity of the compounds of the present invention.

U.S.P. 4,978,659 describes a particular class of compounds of the formula: i : :
R2 H R Ra R1 ~ -N 3 R (1_ : 15 y ~b ~ ' : but this limited teaching in no way suggests the totally different compounds of the present invention, ` nor their surprisingly hetter anti-MRSA/MRCNS
: 20 actlvity ~ S~M~ARY OF INV~NTIO~
:~ Thc presen~ in~ention provides novel ;`~ carbapenem compounds of the formula: :
~; 25 ~ :

R2 ~ H ~ R ~- R2 , i-R~ L' `~ C03M Ra~

,~

~ 94/0,6~'~ PCT/~'S93/07830 ,.,~. I`` 2 7 a ~
. 5 wherein:
R is H or C~3;

Rl and R2 are independently H, C~3-, CH3CH2-, (CH3)2CH-, HOC~2-, CH3C~(OH~-, (CH3)2C(OH)-, FC~2C~(OH)-, F2C~CH(O~)-, F3CC~(OH)-, CX3C~(F)-, CH3CF2-, or (CH3)2C(F)-;

is a 5- or 9-membered mono or bicyclic ~ heteroaryl ring system wherein 1 atom is O
or S, or an 8-membered bicyclic heteroaryl ring system wherein 2 atoms are O and/or S;

Ra is each independently selected from the group lS consisting of hydrogen and the radicals set out below,~provided that one and only one Ra is selected from Type I
substituents:
I.
a) c~

-- Ap- N~;
~ere -~
A is (CH2)m Q-(CH2)n, where m is 0 to 6 and n is 1 to 6 and Q is a covalent bond, O, S, SO, S2 NH~ -S02N~ S02-~ -CUN~ CO
-SO2N~Cl-C4 alkyl)-, -N(Cl-C4 alkyl)SO2-' .
:

~;~

~:

~: .
...... ...... . . ..

~'O9~/0~669 PCT/~S93/07830 .

2 1 1~ ~3 - 6 --CON(C~-C4 alkyl)-, -N(Cl-C4 alkyl)CO-, -C~=CH-, -CO-, -OC(O)-, -C~O)O- or N(Cl-C
alkyl) and (CH2)m is attached to the phenyl aromatic moiety;

is a 5- or 6-membered monocyclic heterocycle or an 8-, 9- or 10-membered bicyclic heterocycle, the heterocycle containing a first nitrogen in an aromatic 5- or 6-membered first ring, with attachment of the heterocycle to A by way of said first nitrogen and said first nitrogen is quaternary by virtue of the attachment and ring bon~s, with the first ring containing 0 or 1 of either O or S, with the first ring containi~g 0 to 3 additional nitrogen atoms, with the first ring optionally fused to a 3- or 4 membered moiety to form the ~:~ optional second ring, with the moiety containing at least one carbon atom, with the moiety containing 0 or 1 of either O or S, with the moiety containing 0 to 2 nitrogen atoms, and with the moiety being saturated or unsaturated and the second ring aromati~ or non-aromatic;

c is Ra as defined under II belows hydrogen, or .
: -NRYRz ~where RY and RZ are defined in lI
below), but independently selected from Ra and from each other-if more than one Rc is prese~t, and is attached to a carbon ring atom or a nitrogen heteroatom the valency of which is not satisfied by the r~ing bonds;

~,~, wo9~J~)~h6s PC~/~S93/n7~30 ~j ~.. , l' ' 2 1 ~.~ 2 ~ ~ VJ 1~

` 1 p is O or l;
b) .j ,.

~<R ~ 0 - 2 -A' ~ N~R~
,/ (o-~ ) ~ere 10 ~ ~ is a 5- or 6-membered monocyclic heterocycle or an 8--, 9- or 10-membered bicyclic heterocycle, the heterocycle containing a first nitrogen in an aromatic 5- or 6-membered first ring, with said first nitrogen quaternary by virtue of a substituent Rd in addition to the ring bonds thereto, with said first nitrogen neutral in the absence o~ a substituent Rd, with ~;~ attachment of the heterocycle to A' by way of ~ a carbon atom of a xing, with the first ring containing O or 1 of either O or S, with the fir~ ring containing O to 2 additional nitrogen atoms, with the first ring : optionally fused to a 3 or 4-membered ~oiety to form the optional seeond ring, with the moiety containing at least one carbon atom, with the moiety containing O or 1 of either O
or S,; with,the moiety containing O to 2 nitroge~ atoms,-and with the moiety being saturated or unsaturated and the second ring ~-.
aromatic or non-aromatic;

,.

~, : ~ :

,~ ~
1,, ~ .

~v~st/0~669 PCT/~S93/07830 21~`%7`~

Rc is defined above;

~d is hydrogen, NH2, 0~ or Cl-C4 alkyl (where the alkyl group is optionally mono-substituted with Rq as defined under IIc below~;

A' is (CH2)m-Q-(CH2)n, where m is 0 to 6 and n is 0 to 6 and Q is defined above;
C) -Ap-N+RY(P~w)o-l(Rz)~ where RY and RZ are as defined under II below, RY and RZ may further be together a C2-C4 alkylidene radical to form a ring (optionally mono-substituted with R~ as defined below) ;nterrupted by N(O)Re or N~(Re)2 (where Re is ~ hydrogen, Cl-C4 alkyl, or C~ C4 alkyl ;~ mono-substituted with Rq as defined below), Rw is hydrogen, Cl_4 alkyl, 0~, Na2, or absent in which case the N+ is neutrals RW, RY and RZ may ~urther together form a C5-C10 tertiary alkylidene radical which with N~
~: forms a bicyclic ring, where the terti~xy alkylidene radical is optional~y :
mono-substituted wi~h Rq as defined below and where the tertiary carbon of the tertiary ~.
alkylidene radical is optionall~ replaced with nitrogen, N+Re (where Re is defined above),:or N+-0 p is 0 or 1, and A is as defined a~ove;
, . :
. ~ :

'`' ~ ~ :
' :`~:

~ O~ 669 l~c~/~ss3/o7B3o t^ `
~`. . 1-2 i '~ 2 ~
. _ 9 _ I

d ~

S -A' p ~d ~ere is a 5- or 6-membered monocyclic heterocycle ~N~ or an 8-, 9- or 10-membered bicyclic heterocycle, the heterocycle containing a ~irst nitrogen in a first ring, with the first ring saturated or unsaturated and non-aromatic, with the f.irst nitrogen quaternary by vi.rtue of one or two ; substituents Rd in addition to the ring bonds ~: thereto, with the first nitrogen alternatively neutral by virtue of zero or one substituents Rd in : addition to the ring bonds thereto with attachment~ 25 of the heterocycle to Al by way of a carbon atom or non-quaternary nitrogen atom of a ring, with the first ring eontaining in addition to carbon and the , flirFt~ nitrogen 0 to 1 of a memb;er selected ~rom the group consisting~of the non-quaternary nitrogen of: 30 attachment, O, S, S(0), S(0)2 and NRe where Re is defined above, with the ~irst ring optionally fused ~:
to a 2-, 3~ or 4-membered moiety:to form the ~ .

. ~ :
:
.~. .

' ~09~/0~66~ PCT/~IS93/07830 Z i 42 l O ~
.. -- 10 --optional second ring, with the moiety optionally containing in addition to carbon I the non-quaternary nitrogen of attachment, I and with the moiety saturated or unsaturated S and the second ring non-aromatic;
Rd is defined above and where more than one Rd is present on a nitrogen, at least one Rd is hydrogen or Cl-C~ alkyl;
A is defined above; and p is defined abo~e;
R~ is defined below;

II.
a) a trifluoromethyl group: -CF3;
:~ 15 b) a halogen atom: -Br, -Cl~ -F, or -I;
c) Cl-C4 alkoxy radical: -OCl_4 alkyl, wherein the alkyl is optionally -: mono-substituted by Rq, where ~r.'~
20 Rq is a member selected from the group consisting ; -~
~ of -0~ t -OCH3, -CN, -C(O)NH2, -OC(O)MH~, CH0, --"`~ -OC(O)N(c~3)~, -S02MH2.. -S02N(CE3)2, -SOCH3, `~ -S02C~3, -F, ~CF3, -COOMa ~where Ma is : hydrogen, alkali metal, methyl or phenyl), ~: 25 tetrazolyl (where the point of attac~ment is the carbon atom of the tetrazole ring and one :
of the~nitrogen atoms is mono-substituted by ~ Ma as~ defined above) an~ -SO3Mb (where Mb is :~; hydrogen or an alkali metal);
d) a hydroxy group: -OH;
e) a carbonyloæy radical: -O(C=O)Rg, where , , ~

~'O9~/0~669 Pcr/~ss3/o783o ,~
.;, ~ :, .J. ~ i 2 1 4;~

~.
Rs is Cl-C~ alkyl or phenyl, each of which is optionally mono-substituted by Rq as defined above or tri-suhstituted with -~; 5 ~) a carbamoyloxy radical:
-O~C=O)N(RY)Rz~ where RY and RZ are independently H, Cl_4 alkyl (optionally mono-substituted by Rq as defined above), together a 3- to 5-membered alkylidene radical to form a ring (optionally substituted with R~ as defined above) ~r together a 2- to 4-membered alkylidene radical 9 interrupted by -0-, -S-, -S(0)-, -S(0)2- or -NRe-, to form a ring (where Re is : lS hydrogen, Cl-C4 alkyl, and Cl-C4 alkyl mono-substituted with Rq and the ring is optionally mono~substituted with Rq as defined above);
: g) a sulfur radical:
` 20 -S(O)n-RS where n - 0-2, and RS is defined above;
h) a sulamoyl group:
-S02N(RY~RZ where RY and Ræ are as defined above;
~ 25 i) azido: N3 : i) a formamido group: -N(Rt3-C(0)~, where .

t I ~ or Cl-C4 alkyl, and the alkyl thereof is optionally mono-substituted by Rq as defined ~ abo~e; : J
:~ , .

.

~ 9~/~)s~69 PCT/~Ss3/07~30 ,. . .-~1~2~ 0 ~

., k) a (Cl-C4 alkyl)carbonylamino radical:
-N(Rt)-C(O)Cl-C4 alkyl, where Rt is as defined above, and the alkyl group is also optionally mono-substituted by Rq as defined abo~e;
~ 1) a ~Cl-C4 alkoxy) carbonylamino

3 radical: -N(Rt)-C(O)OCl-C4 alkyl, where Rt is as defined above, and the alkyl group is also optionally mono-substituted by R~ as defined above;
m) a ureido group:
-N(Rt)-C(O)N(RY)Rz where Rt, RY and RZ
are as defined above;
. n) a sul~onamido group: -N(Rt)S02RS, where Rs and Rt are as defined above;
o) a cyano group: -CN;
p) a formyl or acetalized formyl radica~:
_c(O)H or -C(0cH3)2~;
q) (Cl-C4 alkyl)carbonyl radical wherein the carbonyl is aceta:Lized:
-C(OC~3)2C~-C4 alkyl, where the alkyl is optionally mono-substituted by Rq as defined aboYe;
r) carbonyl radical: ~C(O)RS, where Rs is as defined above;
s) a hydroximinomethyl radical in which the oxygen or carbon atom is optionally substitutcd by a Cl-C4 alkyl ~roup:
-C(RY)=NORæ where RY and R2 are as defined above, except they may not be I joined to~ether to form a ring;
~ "
:.

' ~vo~/n~66s PC~/~S93/07X30 , 2 i ~ 3 t) a (Cl-C4 alkoxy)carbonyl radical:
-C(O)OCl_4 alkyl, where the alkyl is optionally mono-substituted by Rq as defined above;
5 u) a carbamoyl radical:
-C(0)N(RY)RZ where RY and RZ are as defined above;
v) an N-hydroxycarbamoyl or N(Cl-C4 alkoxy)carbamoyl radical in which the nitrogen atom may be additionally substituted by a Cl-C4 alkyl group:
~(C=O)-N(ORY)RZ where RY and Ræ are as defined above, except they may not be joined together to form a ring;
w) a thiocarbamoyl group: -C~S)N(RY)(Rz) where RY and RZ are as defined above;
x) carboxyl: -COOMb, where Mb is as defined above;
y) thiocyanate: -SCN;
z3 trifluoromethylthio: -SCF3;
: aa) tetrazolyl, where the point of attachment is the carbon atom of the tetrazole ring and one of the nitrogen atoms is mono-substituted by hydrogen, ~ 25 an alkali metal or a Cl-C4 alkyl :~; optionally substituted by Rq as defined above;
ab~ a~ ani~onic function selected ~rom the group consisting of:

~ : f:
'~'` ` ' ,`: :
~:

::

~VO 'J~/~)5669 PCI/I 59~/0 830 21~2708 phosphono [P=O(OMb)2}; alkylphosphono {P=O~OMb)-[O(Cl-C4 alkyl)~}; alkylphos-phinyl [P=O(OMb)-(Cl-C4 alkyl)];
phosphoramido CP=O(OMb)M(RY~RZ and S P=O(OMb)NHRX]; sulfino (SO2Mb); sulfo (SO3Mb); acylsulfonamides selected from the structures CONMbSO2RX, CONMbSO2N(RY)R~, SO2NMbCON(RY~RZ; and S02NMbCN, where lo Rx is phenyl or heteroaryl, where heteroaryl is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atomsj in which a carbon atom is the point of attachment, in which one of the carbon atoms has been replaced by a nitrogen atom, in which one additional carbon atom is optionally replaced by a heteroatom selected from 0 or S in the case of a 5-membered ring, ; and in which from 1 to 2 additional carbon atoms are optionally replaced by a nitrogen heteroatom, and where the phenyl and heteroaryl are optionally mono-substituted by Rq, as de~ined above; ~b is as defined above; and RY and RZ are as defined ab~ve;
~ ac) C5-C7 cycloalkyl group in which one of : 25 the carbon atoms in the ring is replaced by a heteroatom selected from Q, Sl N~ or N(Cl~C4 alkyl) and in which , ; l one additional carbon atom may:~e replaced by NH or N(Cl-C4 alkyl), and ~ in which at least one carbon atom ~:;
ad~acent to each nitrogen heteroatom ~: .

' ~ ~09~/05669 PC~ S93/07830 "` 21-~2738 ` ~,`
... ~ . .
,,.~

has both of its attached h~drogen atoms replaced by one o~ygen thus fo.rming a carbonyl moiety and there are one or two carbonyl moieties present in the ring;
ad) C2-C4 alkenyl radical, optionally mono-~,~ substituted by one of the substituents a) to ac) above and phenyl which is optionally substituted by Rq as defined ~ 10 above;
i~ ae) C2-C4 alkynyl radical, optionally mono-,`3 substituted by one of the substituents a) to ac) above;
af) Cl-C4 alkyl radical;
ag) Cl-C4 alkyl mono-substituted by one of the substituents a) - ac) above;
ah) a 2-oxazolidinonyl moiety in which the point of attachment is the nitrogen atom of the oxazolidinone ring, the ring ~ oxygen atom is optionally replaced by a heteroatom ~elected from -S- and NRt (where Rt is as defined above) and one of khe saturated carbon atoms of the oxa~olidinone ring is optionally mono-substituted by one of the substituents a) to ag) abo~e; and ~ , M lisjselected from: i~ hydrogen~
ii) a pharmaceutically acceptable estcrifying group or removable ~.
carboæyl protecting group;

' :

~VO ~t/O~fi69 PCI/I.'S93/07830 2 1 ~ 2 rl 0 8 ~ iii) an alkali metal or other ¦ pharmaceutically acceptable cation; or iv) a negative charge which is balanced by a positively ¦ charged group.
I

¦ The present invention also pro~ides novel carbapenem intermediates of the formula:

~ O , ~_ ~?a // N

COOM Ra y wherein:
; R is H or CH3;
Ra is defined above, with the proviso that R~
additionally includes OP' where P' is defined below, that Ma and Mb of Rq both include M and that the Type d) hydroxy substituent additionally may be protected hydroxy, Opl;
P' is a rsmovable protecting group for hydroxy;
M is a remo~able protecting group for carboxy; and the Type I, Ra substituent is counterbalanced with ~`
the anionic form of Z where : Z is methanesulfonyloxy, trifluoromethanesulfonyl- ri .

';

t ~ 669 PCT/~iS93/07~30 ` 21 Ll: 2 ~ ~ 3 ~ .
oxy, fluorosulfonyloxy, p-toluenesul-fonyloxy, 2,4,6-triisopropylbenzene-sulfonyloxy, p-bromobenzenesulfonyloxy, p-nitrobenzenesulfonyloxy, bromo, or iodo.
Preferred intermediates have the formu~a:

r ~ `z COOM Ra lS
wherein:
R is ~ or CH3;
P' is a removable protecting group for hydroxy;
M is a removable protecting group for carboæy;
Ra is selected ~rom the group consisting of H, OP', `~--Cl, Br, I, SC~3, CN, ~0, SOCH3, SO2CH3, :`
C02M , C~20P' or COM~2; and with the proviso that the -C~2Z substituent is in the 2- or 3-position of the heteroaromatic ring, X is O or S; and ;~ Z is as defined above.

ETAILED D~SCRIPTIQN OF T~E INVENTION
The manufacture of compounds of Formula I
3 may be carried out in a three-stage synthetic scheme ~`:
~:: followed by deprotection. The ob:jeetive of the first synthetic s~age is to produee a base heteroarylphenyl t~''`
(hereinafter HAP) compound which mày be converted to ,~

09~/~669 PCT/~S93/07830 2`14`2708 - 18 ~

be the two-position substituent of the carbapenem of Formula I. The objective of the second synthetic stage is to attach the base HAP to the carbapenem.
Finally, the objective of the third synthetic stage S is to substitute the HAP with the desired Ra. This third synthetic stage may either be performed after the first synthetic stage or after the second ~ synthetic stage according to the nature of the ¦ desired Ra.
Flow Sheet A demonstrates a suggested first stage synthesis. Flow Sheets Bl and B~ demonstra~e a second stage synthesis. The third stage synthesis varies according to the selec~ed Ra.

~0 .

, ' .

~-- O ~ f/~): 66~ PC~/~ S93/07830 21~ 7û~ lf f FLOW S~IEET A ~ 1 Br ~13(0H)z + Br- ~-Rz Ra A1 A2 .

Pd( PPh3 ) 4 Br aqueous ~[3- ~2 Na2CO3, T,a To l ue ne, ~ A3 EtOH

Alt ernat ively, : Eir ~X +E~t2B--~3-Rz Ra :~ ~ A4 A5 , Pd~ PPh3) 4 3 0 n- Bu4NBr ~ ~: KOH t ; ~ T~ : ~:
~-~ ~ere X=Br, I s :: ~ ; :

9 ~o s~/ns66s PC r/~ ss3/n7x30 1;``~

21~?~7~ 20-Flow Sheet A
Substituted bromophenylboronic acids Al ar~d substituted heteroaryldiethylboranes A5 may be prepared by conventional methods. Exposure of ei~her of these boron compounds to aryl halides in the presence of a catalytic amount o~ palladium catalyst yields the desired synthons A3.
Some of these desired synthons A3 may be prepared by the general synthetic routes published in the literature.

Flow Sheet Bl The second stage synthesis is to attach the base HAP to the 2-position of the carbapenem. With compatible Ra or suitable precursor substituents therefor, HAP ~ may be added to azetidin 2-one Bl in a Grignard reaction as shown in Flow Sheet B. ~1 is subgeneric to the more general Bl*. Replacing Bl by * (where M is as de~ined above under ii) produces a ~ hroader class of compounds analogous to B2, B3, and B4.) The Grignard reaction requires that ~ be converted to a Grignard reagent by reaction with magnesium and 1,2-dibromoethane in THF from 20C to ~S 60~C and subsequently contacting A3 as a Grignard reagent with ~1 in T~F at from -70C to about 20C to produce azetidin-2-one B2. Alternati~ely, A3 may be ! 1 rea~ted with t-butyllithium, n-butyllithium, or the like in Et20 or THF at from ~78 to -50~C followed by t~e addition of magnesium bromide to produce the same Grignard reagent. Ri of Bl is in practice pyridin-2-yl but may clearly be a variety of substituents including aromatic and hetéroaromatic substituents.

~'Q94/0~669 PCT/~S93/078~0 2 1 -1 2 7 ~
, - 2~ ~
!
Further, Rl might be, for example, phenyl, pyrimidinyl or thiazolyl.
Azetidin-Z-one B2 is an intermediate that may be ring closed to a carbapenem. It is on this intermediate that Ra or precursor substituent such as t-butyldimethylsilyloxy-methyl group should be modified where such modification is incompatible with the carbapenem nucleus. For example, a convenien~
reaction to remove the t-butyldimethylsilyl group from a hydroxymethyl substituent of the HAP on compound B2 is to expose compound B2 to a dilute solution of sulfuric acid or hydrochloric acid in methanol at 0C. If the t-butyldimethylsilyl group were removed from carbapenem B3 under the same conditions, a substantial portion of carbapenem would be degraded and lost. Thus, modification of the ~ -precursor substituent in this instance and replacement with another precursor substituent or even Ra is best performed hefore closing the carbapenem. Of course it is possible to remove the t-butyldimethylsilyl group from carbapenem ~ in reduced yield by e~posin~ B3 to tetra-n-butylammonium fluoride and acetic acid in T~F.
;~ Compound ~ may be ring closed to carbapenem ;~ 25 ~ by refluxing in xylene with p-hydroquinone for about 1 to 2 hours. It is on this intermediate that final elaboration of Ra from a precursor substituent, e.~i hydro~ymethyl, may be accomplishçd. Removal of the protecting groups then provides the final compound Formula I. Such final elaboration and deprotection is described in further detail be~ow.

~ t"' '`` ;:
~"

0 9~ fi69 PC[/~S9~/07~33() , , ~ .
`2'~`0'~`

FL~:)W SEEET B 1 C02allyl A3 ~ 2 R li 1 o N~PPh3 ~ o ~PPh3 CO2allyl \ CO2M / _ C02allyl O N~PPh3 R
CO2allyl ~32 B2 CO2allyl ' ~3R2 C02allyl Pd( PPh3 ) ,~{j-R

~` 3 0 \~-- o R~
COOH CO(~tM

C~l~C~ ' E~20 O ~/0:~669 PCr/~ S93/0~1~30 . ~ r `
21~2~0~

~_ow Sheet B2 Flow Sheet B2 shows an alternative second j,~
stage synthesis, i.e. attachment of the base ~AP such as iB5 to the 2-position of the carbapenem. This synthesis involves a palladium catalyzed cro~s-coupling reaction between a carbapenem triflate and a suitably su~stituted arylstannane, a process which is described in U.S. Ser. No. 650,111 filed February 4, 1991. In order to apply thîs synthesis, it is first necessary to modify B5 to the trimethylstannylhetero-arylphenyl B6. This is accomplished by reacting B5 with t-butyllithium in T~F at from -78 to -50C
followed by the addition of trimethyltin chloride.
Alternatively, iB6 may be prepared by simply heating B5 with hexamethylditin in the preisence of tetrakistriphenylphosphine palladium in toluene solution. At this intermediate stage, it may be desirable to remove certain protecting groups if employed on a precursor substituent Ra. For instance, a protecting group such as t-butyldimethyl-silyl on a hydroxymethyl substituent may be removed by exposure to tetra n-butylammonium fluoride in T~F
yielding a particular B6. If the t-butyldimethylsilyl group were removed from carbapenem B7 under the same conditions, a substantial portion of the carbapenem would be degraded and lost. Thus, modi~ication of the prccursor substituent in this instance and r~pllacement~with another precursor substit~ent or even an Ra is best performed before attachment to the ~ ;~
30 carbapenem. ~ ;

..'"
~, :

: ~ ` :

. .

~'O 9~ 6fi'~ PCI/~ S9~s~078~0 ~.~

2 1 ~ 2 7 0 ~3 The steps for preparing the 2-oxocarbapenam intermediate B8 are well known in the art and are ' r. . ' explained in ample detail by D.G. Melillo et al., ' ~i-Tetrahedron Letters, 21 , 2783 (1980), T. Salzmann S ~ . J Am. Chem. Soc., 102, 6161 (1980), and L.M. :~
Fuentes, I. Shinkai, and T.N. Salzmann, J. Am. C~
~, 108, h675 (1986). The syntheses are also disclosed in U.S. Patents 4,269,772; 4,350,631;

4,383,946; and 4,414,155 all incorporated herein ~y lo reference Referring again to Flow Sheet B2, the 2-oxocarbapenam, B8, is reacted at -78OC to -50C
with a suitable trifluoromethanesulfonyl source, such as trifluoromethanesulfonic anhydride, trifluoro- ~:
methanesulfonyl chloride and the like, in the presence of an organic nitrogen base, such as triethylamine, diisopropylamine and the like, in a polar aprotic solvent, such as tetrahydrofuran or ;~
methylene chloride. Optio~ally, an organic nitrogen base, such as triethylamine and the like, is then added to the reaction solution ~ollowed immediately by a silylati~g agent, such as trimethylsilyl trifluoromethanesulfonate to provide intermediate B9. An aprotic polar coordinating solvent, such as DME, l-methyl 2-pyrrolidinone and the like, is optionally added. This is followed by the addition of a palladium compound, such as tris(dibenzylidene-. ; ace~one)dipalladium-chloroform (Pdz(DBA)3~CHCl palladium acetate and t~e like, optionally, a 30 suitably substituted phenylphosphine, such as ~.;
tris(4-methoxyphenyl)phosphine9 tris(2,4,6-trimethoxy .

9~ 669 pcT/~s9~/o7~3n ~.

~27~`3 phenyl)phosphine and the like, and thè stannane ~6.
A halide source such as lithium chloride, zinc chloride or ammonium chloride and the like, is added t and the reaction solution is allowed to warm and is stirred at a suitable temperature, such as 0 to 50C
for from a few minutes to 48 hours. The carbapenem B7 is obtained by conventional isolation/purification methodology known in the art.
Generally spea~ing, the milder conditions of 10 the synthesis shown in Flow Sheet B2 allow for a wider range of functional group Ra to be present than the synthesis illustrated in Flow Sheet Bl ~owever, in certain cases, it is ad~antageous for the Ra substituent(s~ of the stannane B6 to be introduced in 15 a protected or precursory form. Final e}aboration of Ra from a precursor substituent, e.g. hydroxymethyl, : may be accomplished on earbapenem intermediate B7. . `
Removal of hydroxyl and ester protecting groups then provides the final compound, C5 of Formula I. Such f.inal elaboration and deprotection is described in detail below.

,.

3 73v.

~; :
~ ' ' ' .".

~'O 9~/0~66~ P~r/~ss3/o7~o !~

21'1~0g FkOW S~IEET B2 ~
1. `
HO H H R

H ,g I ~) Br ~ 3~ R2 H CO2- p- NI3 E3~ 1 ~ B5 F;' ~33S~ ~33Sn~3-Rz E~9 CO2 - p- NE + R~ ~6 ~3SiO H H R ~3-R2a B7 ¦ CO2- p~

~ R3 C5( I~ . COOM
~ere p-NE3 = -CH3 ~NO~ , -:

~'O 9 ~/05fi69 PCr/~S93/07~30 .: .,....................................................................... ,`,., 21~270~ ~-~1Q~_Sheet C
Azetidin-2-ones Bl and Bl* ~Flow Sheet Bl), pyridyl-thioesters, are well known compounds in the production of carbapenems. Di~erse synthetic schemes useIul to make Bl and Bl* may be imagîned by the ski.lled artisan. Particularly useful to ~he instant inventors is a synthetic scheme set out further in Flow Sheet C below in which the symbol R is.as defined above. The steps for preparing intermediate and Bl* are analogous to the procedures described, for example, in U.S. Pat. Nos. 4,260,627 and :~-4,543,257; L.D. Cama et al. Tetraked_Qn 39, 2531 :;
(1983); R.N. Guthikonda et al. J. Me~. Chem., 30, 871 ~1987) hereby incorporated by reference, as discussed below.
'~

r :~ 5 f "~'j, " ` : :

~VO'~ 6~i9 PCT/-S93/n7~30 ~,,' i . ~
; ` " ' '; `

2~ 42r7 0 ~ ~ 28 -FLQW ~HEET C ~ , ~ . . .

t - E~uMe S iO R

C2 Me a~ NaOH/M~OH ~;
o I b. carbonyl ~, a diirr~Ldazole/
t - ~3uMe2SiO R TM~
I H H I ~

/~)\ CCz H c. 1 OHCCO
,~NH ii. SOC12 iii. Ph~P
.
t - BuMe2SiO R d. 6N HCl~M~30H
I H H
2 0 ~ ~TMS
H~NH

O I . i:

t-~3uMQ2SiO R ~
I H H ~

/~\C2 /\~TMS
H ~N
3 0 0// \~ PPh~ 3 ; 2 \~'~\
: ~ :
d ; ~

.
~:

~0 4~/0;664 - P~/~ S93/07~30 i`~
`:, ` :
2 ~ 2 7 ~ ~

FLOW SHEET C ( CONT ' D
~ ,.

HO R
S ~ TMS

~NyP

C2 ~ _.. ,, ; ~

O2CO R ~
¦ H H ~
~ f\~TMS

1 S ~ ~ ~ PPh3 ~ ;

e ClCOz ~ /DMAP

~--2C R F. nE3u4NF
g. Pyr-SS-Pyr, / Ph3P

i ~j ~2CO ~ ` :R ~

~VO 9J./~fi9 PCr/~iS93/07830 (' :, .' 2 1 4 2 7 0 ~ !

, The general synthesis description depicted above in the Flow Sheets shows a protected l-hydro~yethy~ substitution on the 6-position of the carbapenem. After final deprotection, a l-hydroxyethyl substituent is obtalned, which is preferred in most cases. ~owever, i~ has been found that with certain 2-side-chain selections, the ultimate balance of favorable properties in the overall molecule may be enhanced hy selection of the ;
6-(1-fluoroethyl) moiety instead. Preparation of 6-fluoroalkyl compounds within the scope of the present invention is carried out in a straightforward manner using techniques well known in the art of preparing carbapenem antibac~erial compounds See, ;~
lS e.g., J. G. deVries et al., ~erocvçles, ~ , 1915 (1985); BE 900 718 A (Sandoz) and Japanese Patent Pub. No. 6-0163-882-A (Sanruku Ocean).
In the compounds of the present invention, one of the Ra substituents must be of Typie I. As a general matter, it is conjectured that anti-MRSA/MRCNS
activity results from the configuration of the overal:l ;
molecule uniquely conferred by the HAP nucleus. The Type I substituent proYides still greater anti~
MRSA/MRCNS activity to the molecule. `
~ The Type II Ra substituents are distin-guishable from Type I substituents chemically and with respect to the biological properties which they confer. In related compounds, it has been ~oun~ that !` t~e Type II substituted compounds afford greater 30 water solubility and reduced potential for CNS s.ide ~.;
ef~ects. Substituents which tend to confer improved ?
''' ';
'~

~; :

~vo~/0~669 ~CT/-S93/~7830 ;; 21~2~0 3 i ~

~ - 31 - I

water solubility on the overall compound have been ~ ¦
found useful, since they are contemplated to thereby improve the transport o~ the compound involved.
Although a substantial number and range of Type II
substituents have been described herein, all of these are contemplated to be a part of the present invention based on the biologic.al performance o~
substituents related iIl terms of their medicinal chemistry.
Since it is possible to combine, in the compounds of the present invention, the required Type .
I substituents with the optional Type II
substituents, there can be obtained a combination of desired attributes in the final overall molecule not lS attainable with a single substituent, i.e., i~proved ~ anti-MRSAlMRCNS activity together with enhanced water ~.
: solubility.
Type X substituents employed in the compounds of the present invention may have .
quaternary nitrogen groups, and these include both cyclic and acyclic types, as is described under Type I. As already pointed out above, it is required that one, but no more than one, of the substituents Ra ~: must be a member selected from the group consisting ~25 of the definitions under Type I. It is optional that one, or at most two, of the remaining substituents ~. .
may be a member selected ~rom the group consisting of ~ I
; definitions under T~ype II. For example, Ra;attached to the phenyl group may-be Type I and Ra at a 3Q position on~the EAR moiety may be OL` Type II, while ~ .
the rema`ini~g~substituent~ are hydrogen.

~ ~ , ~'09~ 66~ l~CT/~S93/078~0 ~.

.. . . ~ .
~ , ~ i, j.
21~27~8 In preferred compounds of ~ormula I, Rl is hydrogen. More preferably, Rl is hydrogen and R2 is (R)-CH3CH(OH)- or (R)-CE3CH(F)-. In the most preferred case, Rl is hydrogen and R' is (R)-CH3CH(O~)-. While R = H is usually preferred, there are instances in which R = C~3 may provide .improved chemical stability, water solubility, or pharmacokinetic behavior. The substituent R = CH3 may be of either configuration, i.e., the ~ or r3-stereoisomer. Additionally, in preferred compounds, at least one Ra is other than hydrogen. ~
In the most preferred compounds, in total, up to two :
Ra substituents are other than hydrogen;

. :'~
. . .

~5 ::

1' ~ ; .
~- ~
. ..

'~.

:

W(~ 9~ 669 P~/I~S93/07830 21 4 ~ 7 ~

Preferred Type I. a) substituents include:

~N ~ 0-2; ~N ~ R 0-2 ;

"

1 0 . -~ ~

A + ~ N R 0-2 ; + ~ , Y 0-2 : ' `
: 15 -A-N 0 t R 0-2 + ~N~RC

~ier~ t he ring ~ere t he ring ~ -. . . ,~j.
cont ains t hree cont ains t ~
carbon atoms; carbon~ atoms;

~G ~ 2 ;

s ~ i ~

66() PC r/~ S93~078~
. ~-....... . .
2~42708 X ~, ,.
\\~ C - A- N~
N 0-2 ; N 0-2 '.

.

A N/ ~N N~X~RC
~J ; ~A
+
RC

< ~RCo~ RCO-~ ;

: 2 5 A `
~ / :

1` ~ ' ' " I ` , ., .
:~ , ; ~ ` `

~:0 9~/0~669 PCT/I 'S93/07~30 21~2~0~

- 35 - ~ :

R o_1 X A N/ \N
N~ ' ~N ' :~`
/ + RCo_l :
l o A

N--I + ~X~

RCo 1 A_ `~

R O-1 ~X ~ N/ \ ~ `

X 5 N N )--N i~
RCo, ,. .. -` .

.
.

' \~0 9-i/()~669 PCT/I~S93/07830 21~L27~ -R 0-2 ~R 0-2 ~ ; X~3R o_~
~Co Z

:~ 20 A
Rc : ~ -: : , where X = 0, S ~ or NRC . For structures of Type I . :~
~, , a) ,~ Iwhere Rc is shown to have an inde~inite position, it may be attached to any carbon of the ring.

~ -.

~n 9~ 69 PCT/~S93/07~30 ~

2 1 L~ 2 7 '~ g ` I ~ .

. - 37 Preferred Type I.b) substituents include~

-A~ --~3-RCo-2 -A~ ~Rc0-2 Rd Rd ~

, -A~ ~\~RC0 2 -A _~ 3RCO ~ ~

Rd Rd ~ :

-+hd -A _~-R 0-2;

where t he ring cont ains t hree ~s ..
carbon atoms;

..
-A~ RC0-2 ; G ~' ~.1 ~, "~

\-O 9~ 669 PCr/~S9~/0783n 214~708 ` 38 -s --A ~N~

Rd 1 s --A ~RCo l; ,A '~ ?N + d ;~

~ 0-1 ~

., 2. 5 '~, ; ' ~
o ' `~ ~

', ;~

: .

~O 9-1/(1:.669 PCT/I S9~07~?10 t ~
;;, . ~ ~
~ 1 4 ,~ D &

.~ -- 39 --R o ~X~ R

N--N ; Rd ~`N
R~ --A

2.0 A' ~X' N~N ' ~) N
; + ~d _ A~ ~ R

A --~ ~N Rd N ~ , N- Rd N N ; ~N

';
: ..
~: :

~VO 9~1/():`66() PCl /~ S93/07830 . ~ ~ . . . .
21~270~

Rd -A' ~ ~ - RCo z; -A ~ RC

Rd \ RCo z and A ~ R 0-2 0-2 Rd -where X = O, S, or NRC and X' = O or S. For 2S structures of Type I. b), where Rc and/or A' are : shown to have inde~inite positions, they are independently attached to any carbon atom of the ring. ', ~;

3 0 : ~
~. ~
., ~ ''~'.

`.

--, .

\~'09~ 566') PCT/~S93/07830 ~
~ 2 ~ 7 ~ ~ ~

Preferred Type I. c) substituents include~
1~ . `
-Ap-+N(CH3)3. ~Ap-+N(C~2cH3)3 -Ap-+N(CH3)2CH2Rq, -Ap--+N(CH2cH3)2cH2cH2R ~ .

10~AF~RqO, C/H~Rq Rqo - ~ -N O-l -Ap N ~ ~ -Ap-N ~
CH2CH2Rq CH~ ~qo-t Rqo 1 ;
. ...

.
+ ~ N o~
-Ap-N ~ -Ap-N ~
Rqo-l R O-l ;

'.
, .

where W is O, S, NRe, N(O)Re, SO, S02 or N+(Re)2 an~
.W' is M~Re or NO.~ For structures of Type I.c), where ~ .
30 R~ is shown to have an indefinite position, it may be ';
attached to ~ny carbon atom of the r ing .

'.' :., ' :~

! ~

~-'09~ 669 PCT/~S9~/07X~0 2 1 ~27 0`~ i i ` ` ``

Preferred Type I. d) substituents include:

d ~ N ~ ;
Rd Rqo Rd ` ::
N
-A~ p ~
Rqo /d Rqo 2 0 ~d --A' --N N a nd P \_~,/ \Rd ~q L~ O_ 1 Rd : - A' p ~
For structures of~ Type I.d), where Rq and/or A'p is 30 shown to have an ind~efinite position, it may be s attached to any carbon atom of the ring.

~ , . .

~ 669 PCT/~S93/07X30 :,',~'. ~;., 2 ~ ll 2 ~

~' ' The Rc substituents herein are intended to ~ ' represent suitable further substituents on the Type {
I. a) or b) substituents for ~AP~ As seen above, these Type I. a) or b) substituents are monocyclic or bicyclic aromatic groups containing heteroatoms.
Given this class of primary sub~tituent, further suitable substituents may be readily discovered in the penem and carbapenem art. For example, suitable ;
substituents for Type I. a) or b) substituents are generally taught in U.S.Patent No. 4,729,993 assigned to Merck and Co. or in U.S.Patent 4,746,736 assigned to ~ristol-Myers Co. These patents are hereby .:' incorporated by reference.
Broadly, Rc may be the same or different and 15 may be selected on an independent basis from the group as defined above. While a single such substitution is preferred, there is occasion to use up to two such substituen~s on an Ra, e.g., where it is desired to enhance the effect of a particula~
20 substituent group by employing multiple substituents. The particular choice of Rc will depend upon the situation. For instance, a specific may le~d particular stability to a nitrogen cation At other times it may be desired to employ a - ;
25 substituent knoFwn to enhance antibacterial activity of the overall molecule against a particular bacterium, for example, while also employing a substituent known to improve some other property such as water solubility or the duration of action of the 30 overall molecule.
The scope of Rc herein includes tFwo specific s Types of further substi~uent attached to the Type I.
', ~ 0 9~ h69 PCr/~'S93/0783~) i ~,.
;,. .`

21~~

a) or b) substituent. A first Type of Rc are those attached to a ring carbon and a second Type of Rc are those attached to a neutral ring nitrogen. Persons skilled in the art will readily recognize that a wide range of organic substituents are suitably used as RC. Persons skilled in the art will also recognize that some substituents including the -NRYRZ
substituents, useful for one purpose of RC, i.e.
carbon substitution, are not equally useful in the other, i.e. nitrogen substitution.
Preferred Rc attached to ring carbon atoms are -NH2, -SCH3, -soc~3, -C~20~, -(CH2)2OH, -OC~3, -COOMb, -CH2COOMb, -CH2CH2COOMb, -CH2SOCH3, -C~2SC~3, CM, -SG3Mb, -C~2S03Mb, -C~2C~2SO3Mb, -Br, -Cl, -F, ~ CH3, CR2CH3, CH2CON~2 and CH2CON(Cl-C4 alkyl) where Mb is defined above. Preferred~RC attached to neutral ring nitrogen atoms are -CH20H, -(C~2)20~, -C~2COOMb, -C~2CH2COOMb, -CE2SOC~3, -CE2SC~3, CN, _CH2SO3Mb, -C~2CH2SO3Mb, -~3~ C~2C~3~ C~CON~2 a C~2CON(Cl-C4alkyl) where Mb is defined above.
It is preferred that each Type I. a) or b~
substituent have no more than two Rc substituents which are other than hydrogen. Thus, the formula shown above for Type I. a) substituents has up to two Rc substituents with the remainder of course being hydrogen. Further, the formula for the Type I.-b) substituent also allows up to two Rc In accordance with these $ormulae, the previously listed more ! !~
specific structures should be interpreted to ha~e no more than two Rc for each monocyclic or bicyclic group. Similarly for Type I. c) or d) subs~ituents i~
it is preferred that any monocylic or bicyclic group have no more than a single R~ substituent.

~0 91/1)~669 PCT/~rS93/07830 2 i ~2705~ i :
~ 45 The scope of Rd includes a single type of further substituent attached as a Type I. b3 or d) subst.ituent. The Rd substituents are attached to a < :;
cationic nitrogen which may or may not be aromatic. :
Preferred Rd attached to cationic nitrogen atoms are hydrogen, -CH3, CH2CH3, -CH2CH2C~3~ -C~2cOoM --C~2S03Mb, -~I2 and a(-), where Mb is defined above.
The formulas depicting Type Ib, Ic, and Id substituents show positively charged states for those substituents. It is understood that certain of those substituents, which are cationic by virtue of having a protonating hydrogen atom attached to the nitrogen, may also exist or be produced under certain conditions as a neutral substituent by ~irtue of the absence of such a hydrogen atom (i.e., in Type Ib, when the~e is no Rd; in Type Ic, when there is no RW; :;
and in Type Id, when there is zero to one Rd, depending on Type of heterocycle). Whether such a Type Ib, Ic, or Id substituent will be predominately cationic or neutral in a given physical state will be governed by principles of acid-base chemist~y, which are well ~nown to those skilled in the art. ~or example, the particular ratio of neutral form to cationic form will depend upon the basicity of the amine and acidity of a solution. When such a substituent is in a prot~nated quaternized stat~, the compound exists as a zwitterion which is internally balanced as to charge or as an ammoni~m salt which is externally balanced. In illustration, if there is no 30 Rd on a Type Ib substituent, it is understood that ~. `
such a substituent is neutral (there is DO positive \~09~t~669 PCT/~:S93/07830 tr ` .,,: !`: .

2 1 ~ 2 ~ 0 '~ - 46 - `

charge on the nitrogen). A compound containing such a substituent is typically produced in this form as a salt, wherein M is an alkali metal, and may exist in solution in its neutral form. However, depending upon conditions, a compound containing a neutral Type Ib substituent may be in equilibrium with, and may also be represented by a formula showing, the corresponding compound containing the quat~rnized protonated substituent where Rd is present and is a hydrogen atom. Furthermore the same compound may exist with the Type Ib substituent in a completely protonated quaternized form, for instance in an aqueous solution in the presence of a stoichiometric amount of a strong mineral acid. It is intended herein that both the protonated (cationic) and the unprotonated (neutral) forms of Type Ib, Ic and Id substituents of the type just described are within the scope of the present invention.
Suitable A spacer moieties include ~CH2-, C~2CE~2~ H2C~E2CH2- ~ -cH2c~2c~2c~2- ~ -0CH2CH2--SOCH2-, -S02C~2-, -SC~I2(:~H2,-, -SOCH2C~I2-, -SOZC~2c~2-. -N~CH2C~2-, -N(C~3)C~2c~2 , -C~2N(CH3)CH2C~2-, -COM~C~2C~2-, -S02N~C~2C~2 ~
-COCH2-, -C~=CHCH2- and -CH?OCH~CH2-. Preferably, where Q is 0, S, N~ or N(Cl_4alkyl), then n is 2-6.
Suitable A' are listed for A above. Further A' may suitably be -0-, -S-, -NH-, -S02-, -S02N~-, -C,ONH- ~ -CH=CH-, -CH2S-, -CH2NH-, -CON~CH2- or ~ ~
S02N~C~2- . ~ .
; 30 '.`,.
''. ;' ' ~, ,,~", :, ;-~ o~ 669 rcr/~ss3/o,s30 2 i~2~
- 47 ~ I

The Type I. cationic substituents are generally added to ~AP following attachment of HA* to the carbapenem. Conveniently, the ~AP side-chain should be synthesized with a precursor substituent which may be elaborated into the desired cationic substituent. The identity of the precursor substituent will vary according to thè particular Ra desired. For example, one such precursor substituent is -A-OH, such as hydroxymethyl.
The hydroxymethyl precursor substitue~t may be elaborated into cationic substituents of Type I.a) by converting the hydroxyl into an active leaving group such as an iodide (giving -A-I~ followed by reaction with a desired nitrogen containing aromatic compound. More particularly, two alternative procedures may be utilized to produce a leaving group on the moiety -A- and subsequently to replace such a leaving group with cationic substituents of the type just described.
For a first procedure, the hydrox~l group of -A-OH may be con~erted to a methanesulfonate group by treating with methanesulfonyl chloride in the presence of triethylamine. A suitable solvent , e.g., dichloromethane, is employed and the reaction is carried out at reduced temperatures. In turn, the methanesulfonate intermediate may be converted to the reacti~e iodide derivative by treatment with sodium iodide in a suitable solvent, e.g., acetone, at reduced or ambient temperatures. Alternatively, the 30 hydroxyl group may be directly converted into the ~.
iodide group by common methods known to the art. For ...
:`' ~-094/1)~669 pcTt~ss3/o7~3n .

. - 48 -example, treatment of the hydroxyl group with methyl tripheno~yphosphonium iodide in a suitable solvent, .
such as dimethylformamide, at reduced or ambient temperatures, directly provides the desired iodide.
S Once the iodide has been formed, the introduction of the cationic substituent is accomplished simply by treating the iodide with the desired nitrogen containing compound, e.g. a heteroaromatic compound such as pyridine. The reaction wil~ proceed in a suitable solvent, such as acetonitrile, at or about room temperature. This displacement reaction may also be facilitated by the.addition of excess silver trifluoromethanesulfonate to the reaction mixture, in which case reduced temperatures are often desirable.
For a second procedure, the hydroxyl group of -A-O~ may be converted into the reactive trifluoromethanesulfonate (triflate) group. ~owever, such an activating group cannot be isolated by . ~
conventional techniques but may be for~ed and used in ~.
20 ~, Thus, treatment of the hydroxyl group with ~.
trifluoromethanesulfonic (triflic) anhydride in the presence of a hindered, non-nucleophilic base such as 2,6-lutidine, 2,4,6-collidine, or 2,6-di-tert-butyl-4-methylpyridine in a suitable :~
solvent, such as dichloromethane, at reduced temperatures provides for the generation of the triflate activating group. Introduction of the ~, cationic group is then accomplished by reacting the above triflate in .situ with the desired nitrogen containing compound at reduced temperature. In ~: certain cases it is possible and desirable to use the .

,:
. ~ :

~-~9~ 66'~ P~T/~IS93/07~30 21~08 , :

., j .

reacting nitrogen containing compound as the base for ~ I .
the formation of the triflate activating group. In this case treatment of the hydroxyl group with triflic anhydride in the presence of at least two e~uivalents of the reacting nitrogen compound under the conditions described above provides the cationic substituent. . .
The above are representative of suitable ::
leaving groups: alkylsulfonyloxy, substituted alkylsulfonyloxy, arylsulfonyloxy, substituted arylsulfonyloxy, fluorosulfonyloxy and halogen. The cGmmon sulfonate leaving groups are:
methanesulfonylo~y, trifluoromethanesulfonyloxy, .;
fluorosulfonyloxy~ p-toluenesulfonyloxy, 2,4,6-tri-isopropylbenzenesulfonyloxy, p-bromo-benzenesulfonyloxy and p-nitrobenzenesulfonyloxy.
The preferred halo leaving groups are bromo and iodo. These alkyl and arylsulfonate leaving groups may be prepared using an analogous route to the one ~.
described above using the sulfonyl chloride or the sulfonic anhydride.
Where the cationic substitution has a substituent RC, the most ~acile method of providing such a substituent is to employ as the reactant in the preparation methods described above a nitrogen containing compound which already has the desired substituent. Such substituted compounds are readily available starting materia~s or may be prepared in a d;
.,:

'`

, ~

~v094/0~669 PCT/~S93/07830 ~'. . , '-' 2 1 ~'10 ~ - 50 -straight-forward manner using known literature methods.
The Type I.b) cationic substituents are prepared by quaternization of an aromatic ring nitrogen of a neutral precursor substituent on either of the HAP rings. Examples of neutral precursor substituents are -CONHC~2~ pyridyl), -CONHC~2-(4-pyridyl) or -S02CH2-(4-pyridyl).
Quaternization is accomplished by reacting the nitrogen compound in an inert organic solvent (e.g.CH2C12) at about 0C to room ~emperature with an alkylating agent Rd-Y where Rd is given above and Y
is a leaving group such as iodide, bromide, mesylate (methanesulfionate), tosylate (p-toluenesulfonate) or triflate. Alternati~ely, the aromatic ring nitrogen may be quaternized by reaction with an oxidizing agent such as 3-chloroperbenzoic acid (giving the N-oxide~ or an aminating reagent such as 0-(2,4,6-triisopropylbenzenesulfonyl)hydro~ylamine (giving the N-amino derivative) in a suitable solYent (e.g. dichloromethane or CH3CN) at about room temperature. In addition, the neutral precursor substituent may be rendered cationic through protonation of the basic aromatic ring nitrogen.
This may be accomplished by treatment of the neutral precursor with a suitable inorganic or organic acid, e.g. hydrochloric acid, phosphoric acid, hydrobromic acid, acetic acid or benzoic acid. Protonation may !' I fu~lther be açcomplished by a carboxylic acid function elsewhere in the molecule, including the C-3 carboxyl on the carbapenem. The neutral precursor substituent may be already attached to HAP at the time of its . .

: ,:

\V~94/05~6~ PCT/~'S93/07830 ;~ 2l~2~a~

- 51 - , I .
connection to the carbapenem, or it may be elaborated from a simpler precursor after connection to the carbapenem. An example of a precursor substituent for elaboration is -A'-0~ such as hydroxymethyl. In one suggested synthesis, the hydroxyl may be converted to a reactive leaving group such as iodo as described above. The iodide is then reacted in a nucleophilic displacement reaction with a nitrogen containing aromatic compound which has a nucleophilic side-chain substituent such as CH~SH or C~2NH2. In this displacement reaction, it is the side-cnain substituent that is the reacting nucleophile and not the aromatic ring nitrogen. Suitable substrates for this reaction include 2-(mercaptomethyl~pyridine, 2-amlnopyridine, 2-(aminomethyl)pyridine or 4-(mercaptomethyl)pyridine. The reaction is carried-out in an inert organic solvent, e.g.
methylene chloride, at from about 0C to room temperature in the presence of a non-nucleophilic base such as triethylamine or diisopropylethylamine.
Quaternization or protonation of the aromatic ring ;-nitrogen as described above then gives the Type X.b~
cationic substituent. A second suggested synthe~is of a Type I.b) cationic substituent starting from a precursor ~A'-O~ (e.g. hydroxymethyl) consists of oxidation of the alcohol functionallity to an aldeh~de follow~d by Wittig-type olefination with an appropriate nitrogen-containing aromatic substituted reagent, and finally quaternization. The oxidation may be co~veniently accomplished by a Swern oxidation employing oxalyl chloride-dimethylsulfoxide followed ,-by triethylamine. The reaction is conducted in ~` -.1 . .

`: ' ' ' .' ~'09~ 6S9 PCT/~S43/07830 ` 2 1~

methylene chloride as a solvent at from -70C to 0C. The Wittig reaction is carried-out by reacting the aldehyde with the desired Wittig reagent in a -~
polar solvent such as acetonitrile or dimethyl-sulfoxide at about room temperature. Suitable Wittig reagents include: pyridylmethylene-triphenylphosphorane, quinolylmethylenetriphenyl-phosphorane, and thiaæolylmethylenetriphenyl- ~;
phosphorane. Quaternization or protonation as described above then completes the synthesis of the Type I.b) cationic substituent. Depending on the ~.
particular Ra of Type I.b) that is desired, many other synthesis schemes may be employed, as would be apparent to an organic chemist skilled in the art.
The Type I.c) cationic substituents may be prepared in an analogous manner to that described for I.a) substituents except that the nitrogen containing compound employed in the displacement reaction ls an `.
aliphatic amine (i.e. NRYRZRw). However, in cases where the amino group is directly bonded to HAP (i.e.
ApN+RYRZRw where p-~), the amine is most -.
conveniently attached to ~AP prior to its incorporation into the carbapenem system. If such an amine is primary or secondary, it may require pxotection with a suitable amine protecting group during the steps employed~to attach ~AP to the ;
carbapenem. Tertiary ami~es require no pro~ection and may be quaternized or protonated as described for $he!Type I.b~, catibnic substituents. ~ I /
The Type I.d)~~cationic substituents are ;
` 3 prepared by quaternizàtion or protonation of a non-aromatic ring nitrogen of an appropriate neutral :;

YO ~ 66') ~ S93/~)7P.30 ~ 2l~27a~ ~ -1`'' precursor substituent on HAP. Quaternization or protonation is accomplished as described above for the Type I.b) substituents. As with the Type I.b) substituents, the neutral precursor may already be ~-attached to HAP at the time of its connection to the carbapenem, or the neutral precursor may be elaborated from a simpler precursor substituent on ~AP after its connection to the carbapenem. Examples of neutral precursor substituents are -CONH(3-quinuclidinyl), -CONH[4-(N-methylpiperidinyl)], -SO~CH2CH2t2-(N-methylpyrrolidinyl)], -S02N~ (4-methylpiperazinyl)] and -C~2~1-(4-methylpiperazinyl)J. Elaboration of -the neutral precursor substit.uent from a simpler substituent such as hydroxymethyl may be accomplished in an analogous manner to that described previously for the Type I.b) substituents by employing appropriate reagents to introduce the Type I.d) non-aromatic ring nitrogen moiety which is subsequently to be quaternized or pro~onated.
It should be clear that for any of the Type I.a) to I.d) substituents, the substituent may be suitably ~ormed on ~AP prior to addition to the carbapcnem. Thus, the substituent may be formed on a~d reacted with B9 to ~orm the protected carbapenem B7. For e~ample, 2-hydro~ymethyl-5-(3'- J
trimethylstannylphenyl)thiophene, i.e. B6, may be substituted by reaction with triflic anhydride and N-methylimidazole in a suitable solvent, such as, ~.
dichloromethane under nitrogen at -78C to room temperature to form a Type I.a) substituted HAP, i.e.
i .
.

~'O9~ 5669 PCT/US93/~7830 - 1`' . . : .;: ; ~ .
..... '' ~
` 21~`10~ - 54 -B6. This substituted HAP may be reacted with B9 employing conditions otherwise described herein and specifically using an ammonium chloride source. 1`~"
In the compounds of the present invention, the Ra substituents can be selected based on the `~
biological properties which they confer. In related ::
compounds, it has been found that the neutral or ~`
anionic substituted compounds afford greater water solubility and reduced potential for CNS side effects. Substituents which tend to confer improved water solubility on the overall compound have been :
found useful, since they are contemplated to thereby :
improve the transport of the compound involved.
Although a substantial number and range of ;

5 substituents have been:described herein, all of these ~ 1-are contemplated to be a part of the present invention based on the biological performance of ~
substituents related in terms of their medicinal ~ -.
chemistry. 1`

: ~ is a 5-, 8-j or 9-membered mono- or bicyclic aromatic ring system wherein ~ -up to two carbon atoms are replaced by 0 or S.
HAR can be represented by 25` :
(where X is~ o or s)~ or or ~

30~ ~ (Whete ~ i3 phrnyl~ne or a bivalent : ~ }`~
: 5-nen~er2d aronatlc ring wher~in ~
~ Feplacrd by o o- s~

w094/0~669 PCl/~S93/07830 ':
Thus, this aryl structure may be the radical of a S-membered furan or thiophene, of an 8-membered ~urofuran, thieno.furan, or thienothiophene, or of a 9-membered benzofuran or benzothiophene. The carbon atom at the point of attachment, however, cannot be replaced by a heteroatom.
The Ra ~ubstituents are on the carbon atoms of the aryl ring system but not on the one at the point of attachment. It is preferred that Ra =
when it is a to the point of attachment.
In preferred compounds of Formula I, R~ is hydrogen. More prefera~ly, Rl is hydrogen and R2 is (R)-CH3CH(OH)- or (R)-CH3C~(F)-. In the most preferred case, Rl is H and R2 is (R)-CE3CE(OH).
While R = H is usually preferred, there are instances lS in which R = C~3 may provide improved chemical stability, water solubility, or pharmacokinetic behavior. The substituent R = CH3 may be of either con~iguration, i.e., the ~ or ~-stereoisomer.
Additionally, in preferred compounds, at least one Ra in the meta-position of the HAP moiety from the point of attachment to the other aromatic ring is other than hydrogen. In the most pre~erred compounds, in total, up to two Ra substituents are other than hydrogen.
Among preferred Ra substituents are Cl-C
alkyl mono-substituted with hydroxy, such as, hydroxymethyl; formyl; carbamoyl, such as, -CONE2;
hiydroxyiminomethyl, ~uch as, -C~=NOH; cyano; or halogen such as chloro, bromo, and iodo.
~

-.
:: "
.
, ~094/()~669 PCT/~S93/1)7830 ~;i 2 1i~27 0 8 - 56 -- :

Flow Sheet D
In regard to this preferred substitution, the hydroxymethyl group may be obtained in the Ra position of the phenyl portion of EAP as shown in Flow Sheet D, in which A3 is obtained as given in Flow Sheet A. Selective metallation of A3 and formylation with N,N-dimethylformamide provides synthon Dl . Reduction of ~l with sodium borohydride in methanol yields the preferred substituent which is protected as its silylether in the next step to give D~i. The latter reagent is then incorporated into -Flow Sheet Bl as A3. The preferred hydroxymethyl group may also be obtained in the appropriate Ra positions of the heteroaryI portion of HAP. Thus, by a judicious choice of starting materials as exhibited `;
in Flo~- Sheet A, the desired substitution pattern is ~`
rea~ily available.
: ,.:.

;~ ..
: 20 1' '.' . ,-' ,.
~: : 25 ::
:.
~ .:
: ~ :

i" ' :~ 30 , ~ . ~ : ,, .
, . ~, WO ~ 669 PCr/~S93/07830 ~``;.
2 1 ~ 3 FLOW S~EET D

Br Br Ra 1 ) BuL~ Ra ~/ 2 ) DMF ~=/ 2 Br O~C
A3 ( phenyl R~= Br ) D1 Br NaSH" ~-R2 33CSi(1~22)Cl~
HO

Br ~-~2 ~3CSiO

'.

~-~ ' , \~0~ 669 PCT/~S93/07830 : ^~

21~2:~'3 58 -The preferred formyl substitution on the HAP
moiety may be obtained from the hydroxymethyl substitution of B3 or isomeric B3~'~ described in Flow i-Sheet Bl by a Swern oxidation. For example, isomeric ~* is oxidized in methylene chloride at from -70C
to room temperature employing oxalyl chloride-dlmethyl sulfoxide as the active agent.
Obviously, the position of the resultant formyl substitution will depend upon the position o~ the hydroxymethyl substitution in isomeric B3*.
The preferred -C~=NOH substitution on the HAP moiety may be conveniently obtained ~rom the formyl substitution just described. This is accomplished simply by exposing the formyl substituted compound to hydroxylamine in an appropriate sol~ent at room temperature.
The preferred cyano substitution on the HAP
moiety may be obtained from the -C~=MO~ substitution JUSt described. The -C~=NO~ substituted compou~d is dehydrated with triflic anhydride and triethylamine in a solvent at -70~C.
.
The preferred carbamoyl substitution, CONH2, may be obtained from B2 or 'iisomeric" ~* by oxidizing hydroxymethyl with Jones reagent to the corresponding carboxylic~acid substitution as (, described above. This carboxylic acid is converted t`o -CONH2 by seque~tially contacting with l-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hyd~rochloride; l-hyldroxy-bènzotriazole, and a~monia in~an organic solvent at~room temperature.
Substituted amides may of course be obtained by replac~ing ammoni~a with the correspondlng substituted , ~v~9.l~5669 PCT/~S93/07830 t ~' _ 59 _ 21~270~ `

amine. In contrast to the carbo~ylic acid substitution, this carbamoyl substituent requires no protection from the conditions of carbapenem cyclizatlon. Deprotection following cyclization is carried out with palladium catalyzed deallylation in a solution containing potassium or sodium 2-ethyl-hexanoate as described in McCombie and Jeffrey, 1- -Q~g. Chçm., 47, 2505 ~1~83). Deprotection in such a solution yields the desired potassium or sodium salt.
In addition to or including the above, 1 suitable Ra of Type II include: ~:
-oc~3 -OCH2CH20~ ocH2co2c~3, -Br -Cl . :.
-OH -I
-OCON~2 -OCOCH3 -SC~[2CEr20H S02CE3 -S2N~2 -SOC~2C~2OE
-N~C~O -SO2N(C~3)2 -NRCO~CH3 -N~COC~3 -.
-CN -NHS02C~3 -CH=NOH -COCH2OE
-CH=NOCH~CO2CH3 -CH=NOCH3 -S2CH2CH2~I -CH=NOCMe2CON~2 ,, , -CH=NOCMe2C02Me -C2cH2c~2H
CONH2 -CO~C~3 -CoN(~3)2 -C:ON:E~C~2CN i,.
-CON~CH2COMg2 -CONECH2CO~CH3 ~:
-CON~OH -CON~C~3 .-.

'~
.

\-09~/()s6~9 PCT/~IS93/07830 ~ ~

2i427~

, . .
-tetrazolyl -C02CH3 ;
-SCF3 -CON~S02NH2 -CONHS02N~2 -S02NHCN
-S02CF3 -CH=CHCN

-502NHCON~2 -cH=c:EIco2cH3 -CH=CHCON~2 -C_C-CN
-C-C-CONH2 -C~2N3 and -CH20~I -C~2I

-C~2c02cH3 ~.

. . ..

In the preparatlon methods described above, the carboxyl group at the 3-position and the hydroxyl group at the 8-position of the carbapenem remain blocked by protecting groups until the final product is prepared. Suitable hydroxyl protecting groups, P', are silyl groups s~ch as trialkylsilyl, : `

aryl(alkyl)alkoxysilyl, alkoxydiarylsilyl and :: ~ r;

diarylalkylsilyl and carbonate groups such as alkyloxycarbonyl, substituted alkyloxycarbonyl, benzyloxycarbonyl, substituted ben2yloxycarbonyl, allyloxycarbonyl and substi~uted allyloæycasbonyl.

The p~referred protecting groups, in addition to or including those shown in the schemes, are ~-butylmethoæyphenylsiIyl, t-butoxydiphenylsilyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl t benzyloxycarbonyl, t-butyloxycarbonyl, 2,2,2 trichloroethyloxycarbonyl and allyloxycarbonyl. , Suitable carbo~yl protecting groups, M, in addition i ~ I`` ~ `

to or including those shown in the schemes are : i ;

described herein below. ; ` ~ ~

; ~: ' ~, r' ~ ~ : '' '`

:: ~ : : :

: : .

:, U~9~ 669 pcT/us93/n7~3o 2~ a~

Deblocking may be carried out in a conventional manner, with care being taken to avoid a -procedure which is so harsh as to disrupt other portions o~ the final product molecule. For compounds prepared according to Flow Sheet Bl, deprotection may be carried out in a palladium catalyzed reaction in a solution containing potassium 2-ethylhexanoate and 2-ethylhexanoic acid or, alternatively, another suitable nucleophile such as pyrrolidine. Alternatively, for those prepared via Flow Sheet B2, deprotection is conducted sequentially. Thus, compound B7 is exposed initially to aqueous acidic conditions, acetic acid or dilute HCl or the like, in an organic solvent such as tetrahydrofuran at 0C to ambient temperature for from a few minutes to several hours. The resulting desilylated carbapenem may be isolated by conventional techniques, but is more conveniently taken into the final deprotection process. Thus, addition of an inorganic base such as NaHC03 or K~C03 ; and a catalyst, such as, 10% Pd/C or 5a~ Rh/A1~03 ~ollowed by hydrogenation provides for the removal of the p-nitroben2yl protecting group and the formation o~ the final compound of For~ula I.
The overall molecule must be electronically balanced. Since a quaternary nitrogen is present in the compounds of the pr~sent invention, a balancing anion must also, in that case, be present. This is usua~ly accomplished~by allowing COOM to be COO~.
~owever 9 where M is, e.g., a pharmaceutically 3~ accopeable ester, a counterlon (anion) Z~ must be i~

~ , ~

;~

~09-~/05669 PCT/~S93/07830 2 ~ ~ 2 r~ 0 8 - 62 - ~

provided, or alternatively, an anionic substituent might be utilized. A counterion must also be provided or additional anionic substituent utilized -where there is more than one quaternary nitrogen.
Further, it is within the scope of this invention to utilize an anionlc substituent where the quaternary nitrogen is already balanced by COOM i~ C00~. In that case, it will be understood that it is necessary to provide a counterion (cation) for the anionie substituent. However, it is well within the skill of a medicinal chemist, to whom there .is available many suitable anionic and cationic counterions, to make such choices.
With reference to the above definitions, "alkyl" means a straight or branched chain aliphatic hydrocarbon radical.
The term "guaternary nitrogen" as used `;
herein refers to a tetravalent cationic nitrogen atom ,``;
including the cationic nitrogen atom in a -tetra-alkylammonium group (e.g., tetramethylammonium, N-methylpyridinium), the cationic nitrogen atom in a ~ i`
protonated ammonium species (e.g., trimethyl-hydroammonium, N hydropyridinium), the cationic nitrogen atom in an amine N-oxide ~e.g., N-methylmorpholine-N-oxide, pyridine-N-oxide), and the cationic nitrogen atom in an N-amino-ammonium group (e.g., N-aminopyridinium).
The term "heteroatom" means N, S, or 0, ~-selected on an independent basis.
.
~
, .

, ,~

, ~ 94/()~669 PCT/~S93/07830 ~:
:~` 1``
2~2~0~ ` ' j - 63 ~ i The term "heteroaryl" has been defined herein, in relation to the ~ group~ to have a specific and limited meaning t being only monocyclic.
It is required that the monocyclic heteroaryl have at least one nitrogen atom, and optionally at most only S one additional oxygen or sul~ur heteroatom may be present. Heteroaryl~ of this t~pe are pyrrole and pyridine (1 N); and oxazole, thiazole or oxazine ~1 N
~ 1 0 or 1 S). While additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giving, e.g., a thiadiazole (2N's lS), the preferred heteroaryls are those where only nitrogen heteroatoms are present when there is more than one. Typical of these are pyrazole, imidazole, pyrimidine and pyrazine (2 N's) and triazine (3 N's).
lS The heteroaryl group of Rx is always optionally mono-substituted by Rq, defined above, and substitution can be on one of the carbon atoms or one of the heteroatoms, although in the latter case certain substitutent choices may not be appropriate.
Listed in Table I are specific compounds of the instant invention. In the table, R2 substituents containing a chiral center (i.e., -CH(F)CH3 and -C~(O~)C~3) have the (R) configuration, and the Ra :
column refers to the substituent on the phenyl ring.

, . i . ~
's.
, .
` : .

~VO ~i05669 PC~/US43/07830 2142 1 ~ - 64 - ' TABLE I ~¦

COO~ Ra ','`.

I
1 o -~ , .

HAR_Ra ! . ,'~
No. R R2 Ra 2 ~
. ., ~: 1 S 1 H - CH( OH) CH~ H _~, N~NCH3 2 o - CH( OEI) CH3 Cl ~ N~ ~NCE~3 , . .
3 H -CH(OH~CH3 3r ~3 N~NCH3 : :
: ~ 4 H -CH(OH)CH3 I ~ N~ CH3 :

H -CH(OH)CH3 S~3 ~ 'N;~NCH3 1, "

~VO 91/()~669 PCr/~!S93/07830 j~
2 ~ ~ 2 ~

- 6 5 -TABLE I (C0NT~ ) , HAR- R~
No. R R2 Ra 2 6 H - CH~ OH~ CH3 S~ O) ~ ~N~NCH3 S

7 H -CH(O~CH3 S2~ ~N~NCH3 `

lS B H -CH(O~CH3 F ~N~NCH3 ~ ~ N~"NCH3 9 H - CH( OEI) C~3 H S
~0 ;' ~N~"NCH3 H -CH(OH)CH3 H S
:
:~5 ' ~ '' _~\N~NCH3 . 7 ' 11 H -CH(OH)CH3 F S

1' ' I ' , : ~ ! , ~ ' 1 2 H - CH( OH~ CH, F ~ ~,N~;~NCH~

' :~

,, ,, ,. ,,, " . .......... . . , ~- . -~ 1 ) 9 ~ 6 6 9 I C~ / ~ S 9 3 / 0 7 8 3 0 S~. ~

. 2 1 0 ~ - 6 6 TABL~ I (CONT. ) No. R R2 R~ R- R2 ~ ~.
13 H - C~¢ OH~ CH3 ~ N~,NCH3 1 0 14 H - CH~ OH) CH3 13r ~N~NCH3 1 5 15 H - CH( OH) C~I3 I ~N~NCH3 1 6 H - CH( OH) CH3 I ~,N~NCH3 17 H - CH~ OH~ CH3 Cl ~NCH3 13 H -CHtOH~CH3 Cl ~ ;~H3 .. . .
, 1 9 H -C~(OH)CH3 CH2-N~NCH3 ~3 \~'O 9~ 66'~ PCI/~S93/0783() ~.
2~2~0~ ~
-- 6 7 -- . 1 ' i TABLE I (CONT. ) ~.

No. R R2 R~H~- R2 .. . .. ~
2 O H - CE1( OH) C H3 - C Hz- N~NCH3 ~3 Z1 H -CH~ OH~CH3 -CH2-N~NCH3 ~--CHO

CHO
22 H -CH(OEl~CH3 -CH2-N~,NCH3 23 H -CH(OH)CH3 -CH!-N~,NCH3 ~HO

2 0 Z 4 H - Cl~ OH) CH3 - CHO ~NCH3 ', ~ICH3 2 5 2 5 H - CE~( OH) CH3 - CN

2 6 H - CE~( OH) CH3 -ICINH2 ~CH3 `
1 I i O
: ~

1/05669 PCl /~'S93/Q7830 2~ 0S - 68 -TABLE I (CONT. ) No. R R2 Rn H~- R2 27 H -CH~OH)CH3 ~HO ~ ,NCH3 28 H -CH~OH)CH3 -CN 1~NCH3 29 H -CH~OH)CH3 - IClNHz , 5~NCH3 H -CH~OH)CH3 11 --~--~N~lz 31 H - CH( OH) CH3 H ,~ ~,+N~

32 H -CH~OH)CH3 H l~N~SCH3 I , i , `: .
33 H -CH~OH)CH3 -SCH3 ~NCH3 w 0 94/05669 PC-r/US93/07830 2 ~ ~ ~ rl ~ ~3 .:

1 .:
TABLE I (CONT.) . .
t; .

No. R R2 Ra H~- R2 - - _ 34 H -CH(OH)CH3 -SCH3 ~\~

H -CH(OH)CH3 -SCH3 ~ilCH3 36 H -CH~OH)CH3 -SCH3 ~\~\NCH

~7 H -CH(OH)C~3 -SCH3 ~/=\ : :

20~ ,;
o :
38 H -CH(OH)CH3 -SCH3 ~,~ H ` ~
~:, .
~H2 39 H -CH~OH)CH3 H

' ! : " i: :

~ ~ 40 H -CH(OH)CH3 F ~, ~`.~? ' ;~;

`- :`~ ' : ;

, . ~ .: `

~'O 9~ 669 PCI/~'S93/()7~0 :` ` `' l ~ .,`
21~2 10 8 70 ~ ~

TAB?LE 1 ( CONT ~

No. R _ R Ra HAR- R ? ` ` "

41 H -CH~OH)CH3 Cl NH2 . .

42 H --CH~OH)CH3 ~3r /~ ~?

43 H -CH~OH)CH3 I
S NHz . ~ I

44 H - CH( OH) C~13 - S CH3 Q ~ `
1~/ NH2 H -CH~OH)CH3 -S~CH3 ~
M~2 46 H -CH(OH~CH3 -ScH3 47 CH3 -C~(OH)CH3 ~ ~NCH3 : :~

`:

~'0 ~ Sfih9 rc~ s~3/n~830 ```` 2~12~8 1 T BLE l (CONT.) No. R ~? Ra H~R- R ~, 48 H -CH(FjCH3 H ~N~NCH3 ,~\ ~H3 ;
lS 49 H - CH~ F) CH3 H S :

H -CH(F)CH3 H\~5~ ~/ 3 ~ /~\ ' `
51 CH3 - CHC OH) CH3 H~ N~NCH3 ~ `

52 CH3 -CH(OH)CH3 H ~N~NCH3 3 j ~
~30 ~

,' '-' ,''~`,.
''' ,.' :

~-'O 9~ .66~ PCr/~S93/07~30 4~1~ - 72 -TA~3I.E I ~CONT.

No. R R2 ~a H~R-Ra - _ 2 5 3 H - C H( OH) C H~ C N ,~N~N( C H2 ) 2 OH

,~ ( CH2) 20 54 H-CH(OH~CH3 CN S `
: , ., 1/ ~ ~'NCH2CN
H-CH{O.H)CH3 CN S \=/ ;

!
56 H-CH(OH)CH3 CN ~tJ

57 HCH~OH)CH3 CN ~5~` N~N--CONH

';",', s~

~`
\~'O 9~ 669 PCr/~!S93/0783() ```` 2~ 7a~i !``~`

TABLE I ( CON~2.

~ ``
!

;
No. R R~ R~ HAR- R~ .

58 H CH( OH)CH3 CN ~~li jN--~H

,.

59 H CH(OH)CH3 CN --~N~CONHz ~N~N--OH `
H CH( OH~CH3 CN --~S~
~ `~

61 H CH( OH) CH3 CN --~F ~ON~2 S ` ~ ;` ' 62 H CH(OH)CH3 CN ~ ~ Z

-.`,.

j.~ . . ~

' ~ ' '`"'~

66(~ PCr/~'Ss3/07s3n r~ O I ~ 7 4 The carbapenem compounds of the present invention are useful per se and in their pharmaceutically acceptable salt and ester forms in . ~
the treatment of bacterial infections in animal and ~ ~`
human subjects. The term "pharmaceutically acceptable ester or salt" refers to those salt and ester forms of the compounds of the present invention which would be apparent to the pharmaceutical ~`~
chemist, i.e~, those which are non-toxic and which ~
would favorably affect the pharmacokinetic properties ~ ;
of said compounds, their palatability, absorption, :~
distribution, metabolism and e~cretion. Other factoræ, more practical in nature, which are also important in the selection, are cost of the raw materials, ease o~ crystallization, yield, stability, ~-hygroscopicity, and flowability of the resulting bulk drug. Conveniently, pharmaceutical compositions may ;:.
be prepared from the active ingredients in combination with pharmaceutically acceptable carriers. Thus, the present invention is also concerned with pharmaceutical compositions and methods of treating bacterial infections utilizing as ~;
an active ingredient the novel carbapenem compound~ ~-of the present invention.
The pharmaceutically acceptable salts ~`
referred to above may take the form -COOM. The M may be an alkali metal cation such as sodium or potassium. Other pharmaceutically acceptable cation~
~orl M may be calcium, magnesium, ~inc, ammonium, or alkylammonium catio~s such as tetramethylammonium, 3 tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanolhydroammonium, etc.

:`, ~iO')~/056611 P(~/~S93/07830 ~i `` 21~270~

... .
The pharmaceutically acceptable salts ~, referred to abo~e may also include non-toxic acid addition salts. Thus, the Formula I compounds can be used in the form of salts ~erived ~rom inorganic or organic acids. Inc~uded among such salts are the S following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentaIlepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalene-sulfonate, nicotinate, oxalate, pamoate, pectinate, pcrsul~ate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.
The pharmaceutical acceptable esters of the novel carbapenem compounds of the present i~vention 20 are such as would be readily apparent to a medicinal :`
chemist, and include, for example, those describe~ in detail in U.S. Pat. No. 4,309,438, Column 9, line 61 to Column 12, line 51, which is incorporated here:in by reference~ Included within such pharmaceutically acceptable esteræ are tho3e which are hydrolyzed under physiological conditions, such as pi~aloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and,methoxymejthy~, and those described in detail in I :~
U.S. Pat. No. 4,479,947, which is incorporated herein by reference.

. - .
:
' .,, . . .~ .

E; ~`` ``
~v~ /0~66s PCT/~S93/07830 ~ ~

2 1 ~ 2 7 ~ ~
- 76 - I :

The novel carbapenem compoun~s of the ~`
present invention may take the form COOM, where M is a readily removable carboxyl protecting group. Such ` :
conventional blocking groups consist of known ester ;;
groups which are used to protectively block the ;~
carboxyl group during the synthesis procedures described above. These conventional blocking groups are readily removable, i.e., they can be removed, if ~:
desired, by procedures which will not cause cleavage or other disruption of the remaining portions of the molecule. SUCh procedures include chemical and enzymatic hydrolysis, treatment with chemical reducing or oxidizing agents under mild conditions, treatment with a transition metal catalyst and a nucleophile, and catalytic hydrogenation. Broadly, such ester protecting groups include alkyl, substituted alkyl, benzyl, substituted benzyl, aryl, :~
substituted aryl, allyl, substituted allyl and triorganosilyl. Examples of speciic such ester ~
protecting groups include benzhydryl, p-nitrobenzyl, ~:
2-naphthylmethyl, allyl, 2-chloroallyl, benzyl, t-butyl, 2,2,2-trichloroethyl, t-butyldimethylsilyl, `
t-butyldiphenylsilyl, trimethylsilyl, 2-~tri.methyl)silylethyl, phenacyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl and 4-pyridylmethyl. `~
The compounds of the present inventîon are valuable antibacterial agents active against various Gram-positive and to a lesser extent Gram-negative bacteria and accordingly find utility/in human and veterinary medicine. The antibacterials o~ the invention are not limited to utility as medicaments;

.,:
., ': ' `

~V~} 9~ .fi69 PCT/~'S93/n7830 ~
" 2~27û~

they may be used in all manner of industry, for example: additives to animal feed, preservation of food, disinfectants, and in other industxial systems ,~
where cont.rol of bacterial growth is desired~ For example, they may be employed in aqueous compositions in concentrations ranging ~rom 0.1 to 100 parts of antibiotic per million parts of solution in order to destroy or inhibit the growth of harmful bacteria on medical and dental equipment and as bactericides in industrial applications, for example in waterbased paints and in the white water of paper mills to inhibit the growth of harmful bacteria.
The compounds of this invention may be used in any o~ a variety of pharmaceutical preparations. -They may be employed in capsule, powder form, in liquid solution, or in suspension. They may be administered by a variety of means; those of principal interest include: topically or parenterally by injection (intravenously or intramuscularly).
Compositions for injection, a preferred route of deli~ery, may be prepared in unit dosage ;`~
form in ampules, or in multidose containers. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, ~`~
S and may contain ormulatory a,gents. Alternatively, the active ingredient may be in powder form for ~ .
reconstitution, at the time of delivery, with a 3uiitable vehicle,~such as sterile water. Topical applications may be formulated in hydrophobic or `~
hydrophilic bases as ointments, creams, lotions, i paints, or powders~
' .
i .,:

: : , ., -, .

~09J/()566~ PCI/~593/(17830 `` ' `` .

. . .
~ l ~f~7 ~ 78 - ;~
The dosage to be administered depends to a ~ -large extent upon the condition and size of the subject being treated as welI as the route and , ~:
frequency of administration, the parenteral route by injection being preferred for generalized in~ectiors. Such matters, however, are left to the routine discretion of the therapist according to principles of treatment well known in the anti-bacterial art. Another factor influencing the precise dosage regimen, apart from the nature of the infection and peculiar identity of the individual being treated, is the molecular weight of the chosen species of this invention.
The compositions for hu~nan delivery per unit dosage, whether liquid or solid, may contain from 0.1% to 99% of active material, the preferred range being from about 10-60%. The composition will ;
generally contain from about 15 mg to about 1500 mg of the active ingredient; however, in general, it is preferable to employ a dosage amount in the range of 2 from about 250 mg to 1000 mg. In parenteral ;~ administration, the unit dosage is usually the pure compound I in sterile water solu~ion or in the form of a soluble powder intended for solution. ~;;
The pre~erred method of administration of the Formula I antibacterial compounds is parenteral by i.~. infusion, i.v. bolus, or i.m. injection. t .
For adults, 5-50 mg of Formula I , an~ibacterial compounds per kg of bod~y weight given 2, 3, or 4 times per day is preferred. Preferred 3 dosage is 250 mg to ~000 mg of the Formula I ~; ;
antibacterial given two (b.i.d.) three ~t.i.d.) or `~

~. .

\VO~ 66') rcTl~ss3/o7s3o ~ ~
2 ~ ~ 2 ~ ~ o - 79 - `;

four (q.i.d.) times per day. More specifically, for mild infections a dose of 250 mg t.i.d. or q.i.d. is ~ !
recommended. For moderate infections against highly ~;
susceptible gra~ positive organisms a dose of 500 mg t.i.d. or q.i.d. is recommended. For severe, life-threatening infections against organisms at the upper limits of sensitivity to the antibiotic, a dose of 1000 mg t.i.d. or q.i.d. is recommended.
For children, a dose of 5-25 mg/kg of body weight given 2, 3, or 4 times per day is preferred; a a dose of lO mg/kg t.i.d. or q.i.d. is usually recommended.
Antibacterial compounds of Formula I are of the broad class known as carbapenems or l-carbade-thiapenems. Naturally occuring carbapenems are susceptible to attack by a renal enzyme known as :~
dehydropeptidase (D~P). This attack or degradation `~
may reduce the efficacy o~ the carbapenem antibacterial agent. The compounds of the present in~ention, on the other hand, are significantly less 2 subject to such attack, and therefore may not require the use of a DRP inhibitor. However, such use is optional and contemplated to be part of the present invention. Inhibitoss of D~P and their use with carbapenem antibacterial agents are disclosed in the ~5 prior art ~see European Patent Applications No.
79102616.4 filed July 24, 1979 (Patent No. ~ 007 ' .
614); and No. 82107174.3, filed Au~,ust ~, 1982 (Publication No. 0 072 014)].
The compounds of the present in~cntion may, 30 whese DHP inhibition is desired or necessary, be ~ -combined or used with the appropriate DHP inhibitor ~

. .. .
. ~ .

. .~
; .. ' , .
,,, ~-09~Jn;S6') pcT/~s~3/n7s æ ~ 'i~) - 80 -as described in the aforesaid patents and published application. Thus, to the extent that the cited ~ , :
European patent applications 1.) define the procedure for determining DHP susceptibility of the present carbapenems and 2.) disclose suitable inhibitors, combination compositions and methods of treatment, they are incorporated herein by reference. A
preferred weight ratio of Formula I compound: D~P
inhibitor in the combination compositions is about 1:1. A preferred DHP inhibitor is 7-(L-2-amino-2- ::
carbo~yethylthio)-2-(2,2-dimethylcyclopropaneearbox-amide)-2-heptenoic acid or a useful salt thereof.
The invention is further de~ined by ~-;
reference to the following examples, which are intended to be illustrative and not limiting.
All temperatureæ are in degrees Celsius.

~ARI'ING MAT~RI~L SYNT~ESES

Br ~(OH)~ ~

~-BROMOF~ENXLBO~QNIC ACID:
N-Butyllithium (2.5M; 44 mL; 0.11 M~ was added dropwise over 15 mins. to a vigorously stirred soIution of m-dibromobenzene (25g; 0.106 M) in 500 mL ~:
30 of anhydrous ether at -78 under nitrogen. After ~ ~

~-'.

'~,', '.': `' ~94/(~669 ` PCT/~S93/0783 2 i Ll ~ l O

,~ I
stirring 10 mins. more, a solution of triisopropylborate (25.3 mL; O.llM) in anhydrous ~ I
ether (200 mL) was added over 20 mins. The coolin~ ~
bath was then removed, and the stirring solution was i `;
allowed to warm to R.T. over ~2 hrs. A small amount of solid separated. After stirring 15 mins. more at R.T., 150 mL o~ ice cold 8% aqueous hydrochloric acid was cautiously added, and the stirring was continued ~or 15 mins. The organic phase was separated, washed with 2 x 100 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. Solvent removal gave ~~OG of crude product as a semi-solid, which was shaken well with 150 mL of `~
hexane. The solid was filtered and washed with 2 x 25 m~ of hexane. The resulting silky solid (mp 178-9C after softening at ~160C) (6.5 g) was used as 3-bromophenylboronic acid with a small amount of contamination. The hexa~e filtrate was concentrated ~;~
and the residue was stirred well with 150 mL of ;~
petroleum ether (30-60). The resulting solid was ~iltered and washed with 2 x 25 mL of petroleum ether. This resulting solid (4.4 g) melting at 178.3-179C was the desired 3-bromophenylboronic acid.
NMR: 7.38-7.46; 7.70-7.80; 8.1-8.18; 8.31 (aromatic ~I ' s ) ..
''.

, -, .
. ~ , I , ~. ...

`~ --~ ~,...
i. -. .
`~ ., : .

........
"

~ ~, \~0 '~ fi69 PCI`/I_'S93/07830 ~`
I f``
21~270~') 82~
!
.
Br ~ I
s (\~
2-(3 1-BRQ~QP~E~YL)THIOP~EN~
To a stirred solution of m-bromoaniline (34.4 g;
0.2M) in thiophene (200 mL) was added isoamylnitrite (46.86 g; 0.4 M) dropwise over a period of 30 mins. at ~;
0C. The resulting mi~ture was cautiously warmed to R.T. and heated to reflux for 16 hours. The reaction `
mixture was cooled, diluted with 400 mL of ether, washed with 3 x 100 mL of satd. sodium chloride ; `
soluti~n, and dried over anhydrous magne~ium sulfate.
Sol~ent and e~cess thiophene were~removed. A solution of the residue in 200 mL of ether was filtered through 50 G silica gel bed. Solvent was removed, and the ~
residue was distilled to give 34% of 2-(3' bromo- :
phenyl) thiophene as a yellow liquid boiling at ~:
130-2/~0.2 mm. This liquid solidified on standing in the refrigerator.
MMR: 7.06-7.78 .~
.

2~ 4'-BRO~OP~ENYL)THIOPHENE:
Similarly, 2-(4'bromophenyl)thiophene was prepared ~rom 4-bromo aniline in 29% yield as a :

W09~/0~669 P~ S93/07830 -~ 2lA2~0~i yel.Low oil boiling at 146-8/-0.5 mm.
NMR: (C6D6): 6.68-6.92(thiophene H's~ 7.03-7.20 ~ .
(p-phe~yl H's).

2-P~ENYLTEIQ~HENE:
The above method was used to prepare 2-phenylthiophene from aniline in 11% yield as colorless liquid boiling at 110~113/~3 mm. . :-''''. ~

Br ;-;

S ~.
,,.
- :, ~3'-B~OMOP~ENYL)T~IOPHE~E~
2 The thiophene was prepared according to G.
Martelli Q~ . Chem. Soc (B)., 901, (1968).
, .j , ~

~ ;30 ~VOs~ 66s ` PcT/~ss3/o783o - 84 ~
, ~ ;

E~r ~`

Br 2-(3'~5'-DIBROMO~EENYL~T~I~PHENE:
3,5-dibromoaniline was treated as described in the procedure for 2-(3~-bromophenyl)thiophene to give 2-~3',5'-dibromophenyl)thiophene in 55% yield as a yellow oil, which solidified as a glassy solid.
MMR: 7.04-7.68 (aromatic ~'s) ;;

E3r C HO

2-FQRM~L-5-(3'-BROMOP~ENYL)TEIOPHENE:
Phosphorus oxychloride (1.15 mL; 15.4 mM) was added slowly to stirring dimethylformamide (0.95 mL; 12.2 mM) at -10 under nitrogen. The resulting mixture was stirred for 1~ mlns. ~ romOrhe~ly}~
thiophene (2.12 g; 9 mM) was then added. The reaction mixture was then warmed slowIy to 110 over a period ~;
o~ 1 hr. cooled and poured into ice, and cautiously neutralized with sodium carbonate. Extraction~with j :
~` ethyl acetate and drying the or~ganic phase with anhydrous magnesium sulfate provided upon conccntration 2.16 g of the desired aldehyde as an oily solid.
NMR: 7.26-7.84 ~aromatic ~s~; 9.92(-C(O)E; S) , ~ , .
.
' ~ ,:

\V09~/0~669 PCT/~S93/07830 214~
, `; . , .

i ~;

Br ; . :

S

2-(HYDROXYMETHYL)-~-3l-BROMOPHENYL)THIGPHENE:
Sodium borohydride (400 mg; 10 mM) was added portionwise over 5 min. to a stirred suspension of :~
the above crude aldeh~de (2.16 gj in 100 mL of ,~
methanol at 0C. The resulting clear solution was stirred 30 mins. Solvent was then removed in ~S~Q
at R.T. The residue was taken up in 50 mL of ethyl acetate, washed with 3 x 20 mL of sat'd. sodium 1 ~;
:~ chloride solution, and dried over anhyd. magnesium ~: sul~te. Solvent removal followed b~ silica gel chromatography with methylene chloride gave 1.355 g .;
of desired alcohol as an amorphous solid.
~: NMR: 1.83 (OH; t; J-6~3); 4.82~CH2; d; J-6~3);
6.96-7.75 (aromatic H's) / ~ \ ~ OSi : 2-(t~ TYLDIMET~YLSXLYLO~M~T~YL)-5-(3~-BROMOP~NYL)-IOPHENE i~
~30 ~ To a stirred ~olution~of 2-~hydroxymethyl)-5~
: (3'-bromophenyl)thiophene (1.08 G; 4 mM) and :~ t t~-~tb ~ U i~ ~ ml ~ t~ e ~O~ 669 l~CT/~93/078~0 2 1 ~ 2 7 0 ~ - 86 - 1~
chloride at R.T. was added t-butyldimethylchloro-silane (1.5 g; 10 mM). This mixture was stirred ~ ~
overnight, diluted with 30 ml of ethyl acetate, '~ :
washed with 2 x 15 ml of sat'd. sodium chloride ~.
solution, and dried over anhyd. magnesium sulfate. ~:
Solvent was removed to give a residue, which was puri~ied on silica gel with ether:petroleum ether (1:20) as solvent mixture. Eluate was distilled to :~
give 0.9~ g of 2-(t-butyldimethylsilylo~ymethyl)-5-(3'bromophenyl~thiophene as colorless liquid boiling at 167-170/~0.2 mm.
~R: 0.17 & O 95 (silyl methyls); 4.88 (s, C~2);
6.88-7.75 (aromatic ~1s) Br ~S

2-r3'-~ROMO-5'-M~TH~LT~IO~P~ENYLlT~IOP~ENE:
2,5M n-Butyllithium (1.5 mL; 3.75 mM) was added dropwise to a solution of 2-(3',5'-dibromo-pheny~)thiophene (1.06 g; 3.33 mM) in anhydrous tetrahydrofuran (7 mL) at -78 under nitrogen. The reaction mixture was then stirred 10 min. a~d a solution of dimethyldisulfide(0.9 mL; 10 mM) in 3 mL
of;anhydrous tetr:ahydrofuran was added. ~he re~ulting mixture was stirred overnight at R.T. after which 5 mL o~ sat'd. ammonium chloride and 20 mL of '.
'.

, .. .........................

wo s4/n~6~s Pcr/uss3/07~30 ~ , 21~270~ , i ethyl acetate were added. The organic phase was separated, washed with 2 x 10 mL of sat'd. sodiu~
ch~or.ide solution, and dried over anhyd. magnesium ~.
sulfate. Solvent removal, and purification on silica t ;~
gel using hexane as solvent gave a liquid, which was distilled to give 52r/o of ~-~(3 '-bromo)-(5'-methyl-thio)]phenylthiophene as a colorless oil boiling at ~150-152/~ 0~2 mm. (oil bath temp. 180) NMR 1~52(SCH3; s); 7~00~7~50 (aromatic ~'s) ,. . .
Br ;

Br 2-BROMO-5- r 3'-BROMOPHENYLlTHIOPHENE:
A solution of bromine (8 g; 50 mM) in ~0 mL
o~ glacial acetic acid was added dropwise to a vigorously stirred solution of 2-(3'-bromophenyl)-thiophene (12 g; 50 mM) in 80 mL of glacial acetic acid. The resulting mixture was heated to reflu~ 5 1~
hrs, cooled and poured onto ice. A solid separated ~`
which was filtered and washed with ice water, and puri~ied on silica gel using heæane as solvent to give 68~/o of 2-bromo-5-r3'-bromophenyl]thiophene as an ~ ;
amorphous solid.
!' I ' N~R 7.00-7.68;(aromatic H's) ; I I .

, , ~ ~
s . ..

. .

: ~ , WO 94/05669 PCr/US93/07830 1 `"
21~'.1 0'~

.
3 - ( 3 1 -BROMOP~ENYL ) - 5 -BROMOTHI OPHENE:

Br Br S \~

~r To a,solution of 3-(3'-bromophenyl)thiophene, (G. Martelli e~ al., J. Chem. Soc., (B), 901, 1968) (712 mg, 3 mmol) in acetic acid (6.2 ml) with ' stirring under N2, a solution of Br2 (154 ~1, 3 mmol) ' in acetic acid (4.8 ml) was added dropwise. The 15 resultant orange-red solution was heated for 5 hours `, at 100C. After cooling, the reaction mi~ture was ' ~:
poured into ice water with stirring. A non-~ilterable milky precipitate was extracted 2X with Et20. The combined Et20 layers were carefully extracted 3X with Na~C03 solution a~d then 2X with brine. Ater drying (MgS04), ~iltering and concentrating, the residue was chromatographed on a ,' column of Bakers Si Gel (60-200 mesh) packed, applied and eluted with hexane. Those fractions containing the slightly less polar product were combined and concentrated in ~cuo ~763 mg). Preparative TLC of 663 mg of this material on 7-1000 ~ Si Gel GF plates (eluting with hexane and extracting with CE~C12) ~'' provided a purer sample o~ the desired 5~bromo isomer (416 mg~ (i.e., les~ of the uniesired Z-bromo iso=er .

W094~05669 PCT~US93/07830 2 ~ ~ i2 7 ~

,. : :
was present). Approximately 162 mg of this material was further purified by preparative TLC on 4-1000~ ~ ¦
Si Gel GF (elutin~ and extracting as above) to give 3-(3'-bromophenyl)-5-bromothiophene pure enough for t further reaction (196 mg).
MS: m/z 316/318/320 (MI).
lH NMR (300 MHz, CDC13)): ~ 7.01 (d, J-6~z, ~4 of `~.
2-Br compound~; 7.23-7.70 ~series of m's, phenyl and thiophene protons of the minor 2-Br and the desired 5-Br isomers). ...
, ;, 13r ~3r \ E3r 1 .

~ ~ ~3 ,:

, .
,.: ....

3-(3'-BROMOP~ENYL2-5-T~IOPHENE CARBOXALDE~XD~:. .~`
;l ,.
To a solution of the brominated thiophene ~:` (mainly the correct 5-bromo isomer; 196 mg, 0.62 - .` ~:
mmol) in ether (2.7 ml) at -78C under N2, 1.6M BuLi .`
in hexane (388 ~1, 0.62 mmol) was added dropwise.
~5 A~ter 15 mln. at -78, DME (63 ~1, 0.81 mmol) was :~: added, and the reaction mixture was stirred overnight ~ j"'!"., at ambient tempera~ur.e. The reaction was partitioned i .
between EA and brine. After phase separation, the :~l orgànie layer was agai~ extracted with brine, dried, ~-~iltered and conce~trated to provide crude formylated .-~ ;: ~ .' w09~/0~669 PCT/US93/07830 ~' ~.~
J 1 O g ~ 90 ~ .
.
product ~151 mg). Preparative TLC on 3-lOOO ~ Si Gel GF plates (eluting with 20% Et20/he~ane and e~tracting with CH2C12) provided a major band containing a mixture (80 mg) of the desired 5-formyl isomer contaminated with a small amount of the ~-formyl isomer.
MS: m/z 266/268 (MI.) IR(CH2Cl2): 1670 (formyl) cm~l ~H NMR (300 MHz, CDC13): ~ 7.22 (low amplitude d, J=S~z, H4 o~ minor amount of 2-formyl); 7.29-8.00 (series of m's phenyl & thiophene protons); 9.88 (d, J=lHz, long range splitting minor amount of 2-formyl); 9.98 (d, J=l~z, C~O of S-formyl, allylic splitting).

Br :

~ \ 3 4 ~

3- r (3'-BRO~OPEENYL)- ~-HYpROXYMETKYL)lT~IOPHENE:

To a solution of the formylated thiophene (79 mg, 0.3 mmol) stirred in MeOH ~3 ml) at 0, NaBH4 s (13.6 mg, 0.34 mmol) was added, and stirring was ~ r continued for 40 min. Upon concentration to an oil 30 under a N2 stream, the residue was partitioned .

W09~/0~669 PCT/~IS93/07830 ~,. .
2 i~2~0~ ~ `

between EA and brine, the organic lay~r was again ~ashed with brine, dried, filtered and concentrated in vacuo to give the crude product ~77 mg).
Preparative TLC on 2-lOOO ~ Si Gel GF plates (eluting with C~2C12 and extracting the major W band with 10%
MeOH/CH2Cl2) provided the purified 5-hydroxymethyl ~:
compound (70 mg, 88% yield). A small amount of faster running material (5 mg, 6% yield) proved to be the undesired 2-hydroxymethylthiophene compound havi.ng the widely split H4-doublet (J=4.5 Hz). The desired 1 product contained none of this impurity.
MS: m/z 268/250(MI) ;
~(C~C12) 3600(0H) cm~l lH NMR (300M~z, C~C13): i~ 1.84 (t, J=6Hz, OE); `;
4.85(dd, J=O.S (allylic coupling to ~4) and 6Hz; ;~
C~20~); 7.24, 7.42, 750 and 7.70 (4 sets of m1s;
phenyl and thiophene H's).
NMR data for the less polar 2-hydroxymethylthiophene l~
(5 mg above): i;
1~ ~MR (300 mHz, CDCl3): ~ 1.81 (t, J=6 Hz, OH); 4.82 (d, J=6Hz, C~20H); 4.86 (br d, J=6 Hz, C~20H of small l`
amount of 5-isomer); 7.08 (d, J=5 Hz, ~4); 7.25~7.71 :`
(series of multiplets, phenyl and thiophene protons).

,,.

t ., .

3~ ; .
? ~
~, . .

~ ' :, , = .

,, ~vos4/0~66~ PCT/US93tO7830 Br ~ ..

S H2 QS i ~

3-(3'-~ROMOPHENYL)-5~ BUTYLDIMET~YLSILYLOXYMET~YL) THIOPHENE: _ , ~
To a solution of the 5~hydroxymethyl thiophene (62 mg, 0.23 mmo~) in C~2C12 (1.1 ml) at `
0C with stirring under N2, TB~SiCl (183 mg, 0.55 mmol) and Et3N (80 ~1, 0.59 mmol) were added. The cooling bath was remove~, and the reaction mixture was stirred overnight at ambient temperature.
Wor~-up of an aliquot showed incomplete conversion.
Therefore, D~F (20 ~1) in CH2C12 (l ml) was added, and stirring was resumed for a few hours*. ~rine containing 1 M K2EP04 (1 ml) and additional CH2Cl2 wexe added to the reaction mixture with stirring.
Af~er phase separation, the aquPous layer was again extracted with C~2Cl2, and the combined organic layers were washed with brine, dried, filtered and concentra~ed ~a vacuo to give the crude product (97 mg). Preparative TLC on 2-1000 ~ Si Gel GF plates (eluting with 20% Et20/hexane and extracting with . .;
C~2C12) provided the purified 5-si~yloxymethyl , ,~
thiophene (79 mg, 90Z yield).
*In later runs, the DMF was introduced initially ~i.e., starting material (~20 mg~; C~2C12 (10.5 ml);

' .'"'~
: : ~ ' `', ;
` ~., ; ~ ~, . 1' - 93 _ 21~?,7~

TBDMSiCl (820 mg); Et3N (788 ~1); DMF (830 ~1)] and o~ernight reaction provided complete silylation.
MS: m/z 325/327 (MI - t-butyl); 251/253 (MI - ¦ ~
OTBDMSi). ' ~:
H NMR ~300M~z, CDC13): ~ 0.13 (s, Si(C~3~); 0.94 ;
(s, t-butyl-Si); 4.8g (s, CH2OTBDMSi); 7.16-7.70 (series of m's, phenyl and thienyl ~'s). .-Br ~3 2-(3~-BROMOPHENYL)FURAN:
BP: 98-105/0.1 mm . ~;~
Reference: E. L. Plummer, J. Agric. Food Chem., ~1. 718-721 (1983).
. .
~ o+i/

2~ BUTYL~lMET~YLSILYL~XYMETHYL)FURAN: ::
To a stirring mi~ture of 2-furan methanol (33 g, ~0.335M) and triethylamine (47 mL, ~0.335 M) in anhydrous methylene chloride (200 mL) under l `;
nitrogen was;added t-butyldimethylchlorosilane portionwise at room temperature. 20 mL of :.
t .. . .

`.:
. :, w094/05669 PCT/~S93/07830 i~i~

2l~ ~ ~
~ 94 -N,N-dimethylformamide was added. The resulting mixt~re was stirred 3 hrs. After dilution with 400 mL of ekher, the reaction mi.xture was washed with 3 x . ~
100 mL of ice-water, 100 mL of saturated sodium -:
chloride solution, and dried o~er anhydxous magnesium S sulfate. Solvent removal gave a crude product, which was distilled to afford 39.8 g of the desired silyl ether as a colorless liquid boiling at 76-7/~0.5 mm.

Br ~ o+i~

2-(3'-BROMOPHENYL)-5-(~-BUTY~__METHYLSILYLOXYMET~YL)-1 F~
To a stirred solution of m-bromoaniline ~6.88 g; 0.04 M) in 42.2 g (0.2M) of 2-(t-butyl-dimethylsilyloxymethyl)furan at 0 was added isoamylnitrite (10.75 mL: 0.08M) dropwise over a period of 0.5 hr. The resulting mixture was then heated 16 hours at 50C. The reaction mixture was - :
cooled and diluted with 150 mL of ether and washed with 2 x 100 mL of ice cold water. The organic phase ;
was dried over anhydrous magnesium sulfate, and the residue was distilled after filtering through 50G of silica gel bed, to give 26% of the desired 2-(3'-bromophenyl)-5-(t-butyldimethylsilyloxymethyl)-! I ~furan as a colorless liquid boiling at 163-7/~0.5 mm.

'' ~
'`.
' :' W~9~JOSfi69 PCT/~S93~07830 k-~
. ;,. . ,, ' .

_ 95 _ 2i~2'7~ ~

STEP Al: GENERAL SYNT~ESI~__F ARYLKETONES:
, `
O O ., .:'.
~CO ~ ~CO R
// ~ H H I ~ Ar-~r ~ ' ~ N ~ M~ ~ N

O ~ Ph3 0/ ~ Ph3 Icoo = Icoo = ''i, ,~
MET~OD l:
. Aryl bromide (l mM) was added to a stirred ~:
suspension of magnesium chips (1.25 mM) in 2mL of anhydrous tetrahydrofuran under nitrogen at R.T. 8 ~L
f 1,2-dibromoethane was then added. The resulting : mixture was stirred 3 hours, when most of the metal was digested. The resulting dark yellow solution was :
used as 0.5 M solution of the aryl Grignard reagent. l'~
This Grignard reagent solution was added 20 dropwise to a stirred solution of (3S, 4R)~
~(allyloxy)carbonyl~(triphenylphosphoranylidene~-methyl}-3~ (allyloxy)carbonyloxy]ethyl]-4-~2'-pyrid~lthio)carbonyl]methyl]azetidin-2-one, (~0.5 mM) in 2 mL of anhydrous tetrahydrofuran at 0 : ~;
25 under nitrogen. The reaction mixture was stirred 15 mins at 0. Satd ammonium chloride solution (5mL? and 10 mL of ethyl acetate were added~ The organic layer :
was separated, and washed with 2 x 5 mL of satd;
sodium chl orî~de ;solution and dried over anhyd 30 magnesium sulfate. Solvent removal followed by ~.
silica gel chromatography using mixtures (1:1 to 2~ c of ethyl acetate:hexane as eluant ga~e the desired ylid arylketone as a pale yellow fQam.

.
, ~
, .
~.
. .
. - . .

:, ....

WO g4/056~9 ~Cr/US93/07830 ~
2l~C~rln~ ' ; ',' ~r~-oD 2:

Ar - Br n- BULi r ~ E~r 2 [
ETHER THF
O O

[ ~r~ ~o o / `FPPh 3 o / `FPPh3 1 0 Icoo = CQO

To a stirred solution of 3 mM aryl bromide in anhydrous ether (12 mL) at -78 under nitrogen was added n-butyllithium (2.5 molar solution; 1.32 mL;
3.3 mM) dropwise. The resulting mixture was stirred O.S hr. A solution of magnesium bromide, freshly prepared by stirring 6.6 mM of magnesium ~urnings in ~4 mL of anhydrous tetrahydrofuran with 6 mM of 1,2-dibro~oeth~ne for about 1 hr under nitrogen at ambient :~-temperature, was then added dropwise to the above stirring lithium salt at -78. The resulting mixture `
was stirred 15 mins at -78, and 30 mins at 0. The thus obtained turbid solution was used as a 0.0833 molar~solution of ~he required aryl magnesium bromide.
30`

', ;' , :' 1;
w094/0~669 PCT/US93/07830 2 ~ 7 ~

:.

This solution of the Grignard reagent was ~ ;
added slowly to a stirred solution of 1.4 mM of (3S, 4R)-l-[[allyloxy)carbonyl](triphenylphosphoranyli-dene)methyl]-3-~(lR)-l-~(allyloxy)carbonyloxy]ethyl]-2-~[~21-pyridylthio)carbonyl]methyl]azetidin-2-one, in 5 mL of anhydrous tetrahydrofuran at 0 under nitrogen. The reaction mixture was stirred l5 mins.
at 0, and satd. ammonium chloride (l5 mL) and 30 mL -`
of ethyl acetate were added. The organic layer was se.parated, washed with 2 x 15 mL of sat'd. sodium `~
chloride solution, and dried over anhydrous magnesium .`~
sulfate. Solvent removal and purification on silica ;`
gel using a (l:l to 2:l) mixture of ethyl acetate:hexane gave the desired aryl ketone, as a light yellow foam. `~`
.~ .
STEP A~: DESILYLATION OF T~E YLIDE SILYLET~ER KETONE
TO YLI~ ALCO~OL KF.TON~:

A solution of the arylketone (from Step Al) (~20 mg) was dissolved in 3.5 mL of an ice-cold .
mixture of 2% H~S04 in methanol. After stirring the mixture 75 mins at 0, it was diluted with 5 mL of ethyl acetate and washed with 3x 5 mL of 10% sodium bicarbonate solution followed by 5 mL of saturated sodium chloride solution and dried over anhyd.
magnesium sulfate. Sol~ent removal afforded l63 mg ~;
of almost pure alcohol as white foam. ~`
"~
~ ~

~.~ ,. .

,.

WO 94/1~56~9 P~/US93/~)7830 2~ 98-';
STE.P Bl: GENERAL PROCEDURE FQR CYCLIZATION :

O O
Il 11 rOCO R r) -S /~

CO~

A solution of the ylid ketone (0.~5 mM) in 2 mL of p-xylene containing a tiny crystal of hydroquinone was heated 45 mins. to 3 hours (depending on the nature of R) at 130C under nitrogen. The solution was cooled, applied in a suitable solvent to a silica gel column packed with he~ane and then eluted first with hexane and then with 4:1 to 2:3 mixtures of hexane:ethyl acetate to give the desired carbapenem analogs.

STEP B2: GENERAL PROCEDURE FOR QUATERNIZATION:
,1',' To a solution of 120 mg (0,2 mm~ of the carbapenem carbinol from Step B2 in 3 mL of methylene chloride at 0 under nitrogen were added 0.5 mm of amine, and O.25 ~m o~ trifluoromethane sulfonic anhydride. After stirring 15 mins at 0, the reaction mixture was diluted with 10 ~L of methylene ch~oride and washed with 5 mL of ice water. The organic phase was dried over anhydrous magnesium sulfate. Solvent remo~al afforded 118 mg of the desired quaternary salt as yellow foOEm. ~ :

: ~ .

W094/05~69 PCT/~JS93/07830 ~: 2 ~ ~ i~ 7 0 ~ `

STEP C: GE.NE,RAL PROCED~RE FOR DEALLYLATION:

O
rOCO HO :
/~

o~ O / ~
COO - COOM x ~0 ;~'`'`
To a stirred solution of the carbapenem (0.2 ~`
mM) in 3 mL o~ a 1:1 mixture of methylene chloride:
ether in a centrifuge tube at 0~ under nitrogen were `
added 2-ethylhexanoic acid (0.2 mM~, triphenyl-phosphine (0.05 m~), tetra~is-(triphenylphosphine)-palladium (0.04 mM), and O.2 mM of sodium or potassium ;~
2-ethylhexanoate. This mixture was stirred 2 hrs when a solid precipitated out. After diluting with 10 mL
of ether, the mixture was centrifuged and the super-natant liguid was decanted. The remaining solid was stirred with 2 mL of ethyl acetate and centrifuged.
The resulting solid was dissolved in 1 mL, of water and applied to a 1000 ~ reverse phase silica gel plate.
Elution with mixtures of acetonitrile:water or EtO~:
water gave an ultra~iolet active area, which was scraped and stirred with 5 mL of 4:1 acetonitrile:water mixture. The solid was filtered ~ ;
andlwashed with 3~ 2 mL of a 4:1 acetonitrile:w~ter mixture. The f iltrate was washed with 4x 10 mL of ~ ;~
hexane, concentrated to 1 mL in v~cuo at R.T. and lyophiliæed to give the sodium or potassi~m salt of the carbapenem as a white to cream~, fluf~y mass.
~., .

wo94~ 6~s PCT/~S93/0,830 ~;~
;. . ~.:

?,~411~ - lol~ -In the following examples: -the IR data are in cm~l;
the UV data are in nanometers for ~.a~
water; and `
the NMR spectra are measured in CDCl3 solvent unless otherwise specified.

EXAMPLEI , ' STEP A
STEP AI: PREP~RATION OF YLIDE KETONE
STEP A2: DESILYLATION OF SILYL ET~E~ ;
':
STEP Al: I
: .
sr ~r-~r=

~Si~
` i:`
Conditions: l) MgjT~F; 3 hr./R.T. ~:
2) 0; 15 min; THF; pyridylthioester ~ield: 67% .

.STE~ A2 Conditions: C~30H/H2S04; 0; 1.25 hrs i~
Yield: 81% ~:
' I ~
S~EP B . ~ :
STEP ~1: CYCLIZATION OF YLIDE KETONE TO CARBAPENEM
STEP ~2: QUATERNIZATION OF CARBINOL

, W094/~5669 PCT/US93/07~30 ~
.'`,: , i - 101- ?,~

Conditions ~ i :
Bl: Xylene; 130; 1.5 hrs.
Yield: 83~L . ~;

~2:
~N\>

~ NC H3; :

triflic anhydride; CH2C12; 0; 15 min. -Spectra:
IR: 1775; 1745; 1720 NMR: ~6. 3.42-3.50; dd, J = 3 ~ 8 Hz H5: 4.24-4.36; ddd; J - 3, 9 & 10 Hz `~
NC~3: 3.96 (s); M+CH2: 5.62 (s);
N+-CHN: 9.44 (s) s~æ_~: DEALLYLATION

Conditions: ~Ph3; Pd(PPh3)4 \ ~ , CO2K ~,~

.

CO2H ~ i ~.:
C~2C12; 0; 4 hrs Yield: 67% . ~`
, .

Wo~4/os66s PCT/US91/07830 `21~270~
- lQ2 -Spectr~:
W : 2~2 E ext 5074 `

EX~MPLE 3 H ~ -CH~

co- Br i.

~RTING.nATERI~h SYNT~ESIS

Br 9 ~, :H~osi t ~ ~

Br :~:
25 2-~t-~UTYLDIiMETHYLSILYLOXYMET~YL)-5-(3',5'-DIBROMO- ~;~

E~E~, ; ' `' Conditions: l) POCl3, DiMF; 0C; l0 min 3~ 2) 2-(3',5'-dibromophenyl)thiophene; :
ll0-120; l.5 hours ~ ' ' ~: '' ;';

,'`,.
.

~ .

w094/05669 PCT/VS93/0783~ ~ `
;~` 2~ 7~
`:

. - 103 Yield: 40% -Spectra:
IR: 1670(CHO) cm~~
1~ NMR (300 M~z, CDC13); ~ 7.4-7.76 ~phenyl & ::
thiophene H~s); 9.92 (C~O). -R~DUCTIQN
Conditions: 1) NaBH~/MeO~ ~-2) 0; 1 hour o Yield: 99%
Spectra:
MS m/z: 346, 348, 350 (MI). `:
1~ NMR (300 M~z, CDC13): ~ 1.82 (t, 0~); 4.84 (d, ~:
C~20~); 6.88 & 7.18 ~thiophene protons); 7.55-7.64 (phenyl protons) ~ .
~IkyLATIQN
Conditions: 1) TBDMSiCl; Et3N; DME/CH2C12 ;
2) R.T.; few hours; 10; o.n. :~
Yield: 95~L :~
Spectxa:
MS m/z: 460, 462, 464 (MI); 403, 405, 407 (MI-t-butyl) ;;.
1~ NMR (300 M~z, CDC13); ~ 0.12 (s, Si(C~3)2); 0.94 ~:
(s, t-butyl); 4.86 (s, CX20); 6.87-7.62 (phenyl & j-`.
thi.ophene protons) ~A~BINOL PREPARATIO~ ~
. i i . ~.

3 ~~ 02 ~ H

. WO 94~05669 PCr/~JS93/07i~30 .`, . ~:
I
2 1 llt~
. - 104 -STEP Al: PREPARATION OF YLIDE KETONE

STEP A2: DESILYLATION OF SI~YL ETEER TO CARBINOL

Br Ar-Br = ~ Si' ~

~r :
Conditions:
Al: 1) Mg/THF; 3 hrs.; R.T.
2) 0; 15 min; pyridylthioester Yield: 23% of ylide ketone Spectra;
IR: 1740; 1690; 1645; 1620 A2: CH30~; H2S4 Yield: 72% of carbinol Spectra: :~
IR: 3100(0~); 1740; 1685; 1620 ~0 . . .:
. .,`~;
Conditions: Xylene; 130; 3 hrs.
~ield 81%
Spectra:
IR: 3500(0~); 1740; 1720 :~
NMR: 0~ 6-2.06; t; J = 6 C~20: ~.80-4.86; d; J = 6 ~æ
~6: 3.40-3.49; dd; J =~3 ~ 8 ~z 5: 4.24-4.38; ddd; J = 3, 8.5 & 9.5 ~z ~; ~

:: . '' '.

, ~

w~94/osc69 P~T/US93/07830 ;~

~ 7 ~3 Q~ATERNIZATION OF CARBINOL
C~nditions: 1) 2.5 eq. l-methylimidazole/C~2C12 2) 1.1 eq tri1ic anhydride 3) 0~; 45 min.
Yield: 85% ::
Spectra:
lH NMR (300 MHz, CDCl3): ~ 1.48 (d~ CH3); 3.49 (dd, E6); 3.96 (s, N-CH3); 5.58 (thiophene-C~-); 9.26 (s~ ;:
N=CH-N).
DEALLYLATION
Conditions: PPH3; Pd(Ph3) CO2K CO2H i"'~:' CH2C12/EtOAc; 2 hours :-:
Yield: 31%
Spectra: -W(H20): ~max = 295 m~
1~ NMR (300 MEz, D20):(no inte~nal standard - DOH at :::4.80); ~ 1. 24 ~d, C~3C~OE-); 3.37 (dd, ~6); 3.80 (s, N-C~3); 5.50 (s, thiophene-CH2-); 8.78 (s, N=CH-N).
t ~,.
3 HO ~ ~ ~ N ~ N-CH3 ~:

O - N
~2 ~

.
~.~

W09~1JnS669 PCr/US93/07830 ~

21~ ~0~

5~RIAL SYNTHESI S

s ~ -H2 I t ~

2-(t-BUT~LDIMET~IYLSIL~LOX~MET~YL)-5-(3 ', S ' -DIIODO-10 P~EN~L ) THI OPHENE _ _ I

~ NO~
':
I

13.8 g (0.2M) of sodium nitr;te was added p~rtionwise slowly to 96 mL of conc. sulfuric acid at 0C. The resulting thick mixture was stirred at 0C
~or 10 minutes. A suspension of 68.25 g (0.175M) of finely powdered 4-nitro-2)6-diiodoaniline in 175 mL
of glacial acetic acid was added cautiously portionwise to the above mixture at 0C. After the i addition, the mi~ture was stirred 30 mins. The~
~esulti~g slurry was then added slowly to a ~igorously stirred suspension of 4 g of cuprous oxide ~:
in 420 mL of absolute ethanol over a pèriod of 25 mins. Vigorous effe:vescence was observed~during ~ 3 '''` ,';

,''' '.

w094/056~9 PCT/US93/07~3U
2 ~ a ~

this addition. The resulting mixture was stirred 20 ~ :~
mins. at room temperature and then heated to reflux for 30 minutes. After cooling, this reaction mixture was poured onto a large amount of ice. The solid S which separated was filtered, and washed with water.
This solid was dissolved in a minimum amount of .
chloroform, dried over anhyd. magnesium sulfate, and the solvent was removed to give 62 g of 3~5-diiodnitrobenzene as a yellow solid.
,~

~ ~ 2 ~

I
3.5-DIIO~OANILINE:

A mixture of 61.5 g (Q.164M~ of 3,5-diiodonitrobenzene and 111.1 g (0.4924M) of stannous chloride in 900 mL of ethanol was heated to re1ux l.S hrs under nitrogen. The reaction mixture was cooled and most of the solvent was removed va~uo The residue was partitioned between ethyl acetate and excess ice-cold 5N sodium hydroxlde and ice. The organic phase was separated, washed with : --sat'd sodium chloride solution, and dried o~er anhyd. magnesium sul~ate. Solvent remoYal afforded ;
a crude oil which was purified on silica gel using '

8:1:1 mixture of hexane:methylene chloride ethyl acetate to gi~e 35 g of 3,5~diiodoaniline as a light tan colored solid.

W~:) 94/05669 PCI /US93/07830 ,: - . .`

~ ~ 4 2 1 0 ~
- 1 0 8 ~ .

DIAZOTIZATION & CONDENS.~N
Conditions: l) Dliodoaniline;thiophene as solvent &
reactant 2) isoamylnitrite 3) 600; 2 hours Yield: 237/o Spectra`:
MS m/z: 411.71 (MI) 1~ NM~ (400 MHz, CDC13): ~ 7.06-7.35 (m's; thiophene ~
lo protons~; 7.~8-7.94 (m's, phenyl protons). ~:

FO~MYLATION ;
Conditio~s: l) POC13; DME; oo; 10 min 2) 2-~3',5'-diiodophenyl)thiophene from abo~e; 110; 3 hours Yield: 77Z (used immediately) R~DU~ION
Conditions: l~ NaBH4lMeO~
2) 0; 1.5 hours . :.
Yield: 69%
Spectra:
1~ NMR (400 Mhz, CDCl3): ~ 1.79 (t, OE); 4.8 (d, : C~20H); 6.95 & 7.13 (2d's, thiophene protons);
7.80-7.~4 (phenyl protons) SIL~LATION :
Condition: 1) TBDMSiCl; Et3N; DMF/C~2C12 2) R.T.; few hours; 10; o.n. ! ;.:
30 ~ield: 97/~
: Spectra: ~.
N~R (400 ~z, CDC13): ~ 0.12 (s, 0.12); 0.94 (s, ,, ~butyl~; 4.84 (s, C~20Si); 6.87 & 7.12 (2d's~ ~:
thiophene protons); 7.85-7.91 ~phenyl proto~s). , ~
-,~"
~ . :

WO~ 5~69 PCT/USs3/07$30 - lOg -I
PREPARATION OF YLIDE KETONE

Ar-I= Si t Conditions~ BuLi/T~F; -78 to -20 (5 min) 2) MgBr2/THF; -20; 5 min 3) Pyridylthioester; 0; 4 hours 15 Yield: 25%
Spectra:
MS m/z: 1028 (M~l); 262 (Ph3R).
1~ NMR (400 MHz, CDC13): ~ 0.15 (s, Si(CH3)2); 0.95 (s, ~-butyl); 1.18 (d, CE3~; 4.86 (C~O); 5 8-5.98 20 (m, C~2=C~--CH2-). ;

~SILYATION OF KETONE ~LIDE TO CARBINOL
Conditions: l)aq. ~Cl/MeOH
2)0; 1.25 hours ~:.
~ields: 90%
Spectra: . ' -~
MS m/z: 914 (M~l); 262 (P~3P).
H!NMR (400 M~æ, CDC13): ~ 1.16 (d, CH3); 4.78 (dd, ~ .
~6); 5.8-6.0 (m, CH2-CH-CH2-) ~.
~ :
~Ç~IZATION QF CA~BINOL ~LIDE ~O CARBAP~NEM ~ :~
Conditions: Benzene; 80; o.n.
~ield: 8~C/o ~vos4t~66~ PCT~US93/07830 ! ~ ~

- 110 - ;

Spectra:
MS m/z: 636 (MI+l); 618 (MI-OH) IR: 1787 ~-lactam C=O); 1750 & 1725 (C=O~s) cm~l ` `
lH NMiR (400 MHz, CDC13); ~ 1~50 (d, CH3~; 1.81 (t, 0~); 3 44 (dd, H6); 4.31 (m, H5); 6.98 & 7.16 ~2d's.
thiophene protons); 7.50-7.87 (phenyl protons).

QUATERNI ZATI ON OF CARBINOL
Conditions: l) 2.4 eq. 1-methylimidazole/CH2C12 lo 2) 1.2 eq. triflic anhydride 3) 0; 45 min Yield: 84% (used immediately) :

PEALLYLATION
Conditions: PPh3; Pd(PPh3)4 ,',.:
ca2~

C02H . - ~
1:1 CH2C12:EtOAc; 2 hours 25 ~ield gz Spectra: ' ~;
W (H20): f~max _ 296 m~
1~ NMR ~400 MHz, 2:1 D20:C~3CN) (no lnternal standard - DOH at 4.80); ~ 1.47 (d, C~j3C~OR-) 3.63 (dd, H6); ~`~
4.05 (s, N-CH3); 5.75 (s, thiophene CH2N~
: 7.45 8.05 (thiophene, N-C~=C~-N, & phenyl protons); i` :
8.98 (partially eæchanged N=CH-N).

f :

, -~.

WO9~/05669 PCr/US93/07830 ~
.. -........................................................................... . . .
2 1 ~ 2 7 ~

:`

S ; ~ , S

CO2il n = 0, 1, 2 ()n ~TA~TI~NG ~ ~IATERIAL SYNTHESI S
Br ~ ~
~S CH2o i t S C ~
2~ B~TYLDIMET~YLSILY~O~YMETH~L)-5-(3'-BROMO-5' M~TEyLT~Iop~NyL)THIop~Er~ _ Conditions: l) 2-(~-butyldimethylsilyloxymethyl)~
5-~3',5'-dibromophenyl)thiophene; ~ -1.1 eq. BuLi/THF, -78; 5 min 2) excess (CH3S)2; -78 to r.t. (o.n.) , ;:
~ield: 71/~ '' ,~

...
,, ~., W094/05669 PCT/USg3/07830 ~ ;
- ,: . .

~ 1~2 10 ~ _ 112 -Spectra:
MS m/z: 428, 430(MI); 371, 373~MI-t-butyl); 297, 299(MI-TBDiMSiO) 1~ NMR (200 M~z, CDC13): ~ 0.13 (s, Si(C~3)2); 0.94 (s,t-butyl); 2.50 (s, SCH3); 4.89 (s, CH20);
6.88-7.47 (thiophene ~ phenyl protons).

~PARATION OF YLIDE KETQNE

Br Ar-Br= ~H20 li t :

SCH3 :-Conditions: 1) t-BuLi/T~F; -78 to -20 (5 min) 2) MgBr2/THF; -20; 5 min ~.
3) Pyridylthioester; 0; 5 hours : Yield: 41%
Spectra: :.
MS m/æ: 949(MI~2); 262(Ph3P).
~ NMR (400 MHz, CDC13): ~ 0.14 (s, Si(CH3)2); 0.94 ~:
: (s,~butyl); 1.16 (d, CH3); 2.55 (s, SCH3); 5.76-5.98 ~ ~5 (m~ C~2=C~-CH2-).
: ~ , .
~` DESILXI.ATION TO ~ARBINOL YLIDE KETONE

; Conditions: f 1 ) ! aq. ~Cl/MeO~ ~
2) Oc; lh ~ ;
Yield: 86%
Spectra~
MS m/z: 555(MI-Ph3PO); 262(Ph~P). ~ ;^.
(300 M~z, CDC13): ~ 1.15 (d, C~3); 2.54 (s, SC~3); 5.74-6.0 (m, C~2 - C~-CH2-)-,,

9 PCI /IJS93/07830 ~ ~
;`'`'`~ 1'. ' 2 ~ ~ 2 ~

-- :L13 -- ~
,.

CYCLIZATION TO METHYLT~IIOCAR:BAPENE~I CARBINOL _ ~
1.:
Conditions: Benzene; 800; o.n.
Yield: 83%
S Spectra: ; :
MS m/z: 555(MI); 385 (MI-J3-lactam cleavage).
IR: 1787 (J3-lactam C=O); 1750 & 1725 ~other C=O's) 1~ NMR (300 MHz, CDC13): ~ 1.49 (d, ClI3); 1.80 (t, OH); 2.50 (s, SMe); 3.43 (dd, H6); 4.30 (m, H5);
5.76-6.0 (m, C~2=CH-CH2-); 6.97-7.40 (phenyl & ~ ~
thiophene protons). :

.
OXIDA~It;)N TO SULFOXIDE AND SULFONE
i 15 Conditions: 1) excess ~-ClPBA; aq. Nc~CO3/CH2Cl2 2) oo; 1 hour 3) aq. Na2S203; 0; 2 hrs.
Yield: 52% Sulfoxide 32% Sulfone :;
20 Spectra (for sulfoxide):

l~I NIIR (400 MEIz, CDC13): ~ 1.48 (d, CH3); 1.86 (t, OH); 2.76 (C~I3-S(0)-); 3.45 (dd, E6); 4.32 (m~ ~5);
4.84 (d, C~;20H); 7.0-7.78 (thiophene & phenyl 2.5 protons).

7 '' ;.
Spectra ~for sulfone):
~I N~ (400 ~z, CDC13) ~ 1.49 (d, ÇE3); ~.85 (t, OE); 3.09 (s, C~3-S02-); 3.47 (d, ~I6); 4.34 (m, ~5);
4.85 (d, C~3;20~); 7.01-8.06 (thiophene & phenyl ~ :
protons). ;

:~' w094/05669 PCT/US93/078N ~

Z ~ ~

OUATERNIZATION OF ~ARBINOL

Conditions:* 1) 2.4-2.6 eq. 1-methylimidazole/CH2Cl2 2) 1.2-1.3 eq. triflic anhydride 3) oo; 45 min *identical for C~3S(O)n where n = O, 1, 2 Yield: methylthio ~97%) methylsulfinyl (82%);
methylsulfonyl (84%).
Spectra:

lH NMR (400 MHz, CDC13) of methylthio: ~ 1.48 (d, CH3); 2.50 (s, SCH3); 3.45 (dd, ~6); 3.97 (CE3N);
l~ 6.15-7.35 (thiophene, phenyl and two imidazole ~
~protons); 9.38 (N=CU-N). ~:
Methylsulfinyl & methylsulfonyl qu~ternaries used immediately.

DEALLYLATION OF METHYLTHIO, METHYLSULFINYL, AND
: ~3~ FQNY~ CARBAPE~S _ _ ; , , ~: Conditions: 1) PPh3; Pd(PPh3)4 : ;i . .
~ 25 ;~ .

C C r~ "
v 2 1~ : 2 ., .~
,...

:~ :
:~ :

W09~/05669 PCT/US~3/~783~ ~

2 ~ dc ~ ~'7 ~
- 115 - !
i Solvent TTime Yield methylthio 2:1 CH2C12 ~t2~ 0 2h 16%
methylsulfi~yl 1:1 CH2C12:DMF r.t. 2h 19%
methylsulfonyl 1:1 CH2Cl~:D~ r.t. 2h 26%

Spectra:
H NMR (400 M~z, 2:1 D20:CD3CN) of methylthio: ~ 1.53 (d, C~3CHO-); 2.76 (s, SCH3); 3.67 ~dd, H6); 4.10 ~N-C~3); 5.81 (thiophene -CH2-+N); 7.47-7.78 (thiophene, } phenyl, & two imidazole protons).

H NMR (400 M~z, 2:1 D20: CD3CN) of methylsulfinyl:
1.58 (d, CH3CHOH-); 3.16 (s, SC~3); 3.75 ~dd, E~);
4.16 (s, CE3N); 5.89 (thiophene-CH2-~N); 7-60-8-13 (thiophene, phenyl, and two imidazole protons); 9.10 (s, N=CE-N). :~

1~ NMR (400 M~z, 2:1 D20:CD3CN) of methylsulfonyl:
1.55 (d, C~3CHOH-); 3.51 (s, CH3SO2); 3.73 (dd, H6); ~.
4.14 (s, CH3N); 5.87 (thiophene-CH2-+N); 7.59-8.25 (thiophene, phenyl, & two imidazole protons); 9.08 ` ::
(+N=C~-N). :-~.

E~AMPLE 9 ~-C~3 '~
3 0 _ ~ .
CO2 ' ' ~' L .,',~

WO 94~05669 PC~/US93/07830 ~.-, ,:`'~ ":, 2 1 ~ z rl o ~ ;
" -- 1~6 --.
STARTlN_ATERIA~ SYNTEESI ~ ~ ;
!

S
.

2-(3~-BROMOP~ENYL)-4-(~-BUTLYDIMETHYLSILYLOXYMET~YL) I~IOP~ENE . _ ~ROMINATION , Conditions: 3-thiophenecarboxylic acid (Aldrieh) was selectively brominated to 5-bromo- .`
3-thiophenecarboxylic acid using the method of Campaigne et al., J.A.C.S., 76, ~445 (1954). -~ield: 53%

: 1~ NMR (400 MHz, CDC13): ~ 7.51 (d, J= 1.5 ~z); 8.11 :
: ~dl J- ~.5 ~z).

~EDUCTION TO 2-~R~Mo-4-T~LQ~NEM~rEA~QL ~ :

Conditions: 1) excess BH3-Me~S/T~F ' '`
2) O to r.t.; o.n.
3) MeO~; 0; slow addition then 15 min.
` 30 Yi ld 82%

~ . , ,. !, .f"~

. ~ ' '.`'`:
~ ` '''"' : : !,., W~4/0~669 PCT/US93/07~30 ~ :
~ ~ 2 ',~ ~ 2 ~

: - 117 -Spectra:
MS m/z MI (192, 194).
1~ NMR ~400 MHz, C~C13): ~ 1.68 (t, 0~); 4.61 (br.d, C~2OE); 7.05 (br. d); 7.11(m), when decoupled at ;.
C~OH- 1.67 (s, OH); 7.04 & 7.11 (sh d's, J= 1.5 Hz, thiophene protons).

~ONDENSATIO~ WI~ 3-BRQMOPHENYLBQRQNI~_ACID

Conditions: 1) 2-bromo-4-thiophenemethanol/toluene 2) (Ph3P)4Pd 3) 3-bromophenylboronic acid/EtoH
4) aq. Na2CO3 5) 80; 5-24 hours 15 Yield: 43%
Spectra:
MS m/z: 268, 270 (MI); slight impurity (344, 346 -dicondensat~on product) 1~ N~ (400 M~z, CDC13): ~ 1.67 ~t, 0~); 4.69 (d, 2n C~2OH); 7.20-7.74 (thiophene & phenyl protons).

SIL~ATION

Conditions: 1) TBDMSiCl; Et3N; DME/C~2C12 2) 0 to r.t.; few hours Yield: 82%
Spectra:
MS mlz: 382, 384(MI); 325, 327(MI-t-butyl); 251, 253 (MI- OSiMe2t-butyl).
1~ NMR (400 MHz, CDC13): ~ O.12 (s, Si(C~3)2), 0.96 ~.
(s, ~-butyl); 4.72 (s, CH2O-); 7.13-7.73 (thiophe~e &
., phenyl proto~s).

i~ ' ,, ~i.j , ~ .

wos4/o5~69 P~T/U~93/07830 ~ ~

PREPARATION OF YLIDE KETONE ~ .
.

s ~3r Ar-Br= ~ I t Conditions: 1) Mg; BrCH2CH2Br/T~F; rflx; 2 hours 2) Pyridylthioester; 0; 3 hours Yield: 45%
Spectra:
MS m/z: 908tMI ~ 7(Li)]; 262 (Ph3P).
1~ NMR (400 M~æ, CDC13): ~ 0.13 (s, Si(CE3)2); 0.95 (~, t-butyl); 1.17 (d, CH3); 5.78-6.06 (m, C:~12=C~ C~2- ) D~SXLYLATION OF YLID~ KETONE CARBINOL

Conditions: 1) aq. HCl/MeOH
: 2) 0; 1 hour Yield: 94%
~ 25 Spectra:
:~ MS m/z: 794~MI + 7(Li)]; 262 (Ph3P).
1~ NMR ~400 M~æ, CDC13): ~ 1.16 ~d, CH3); 2.80 (dd, H6); 4.71 ~d, C~208); 5.77-5.89 (m! CE~=C~-CH2~

~ . . .
:~ 30 ~, :
, ~ .

~, ~
: ~ -`~

` W0~4/~669 PCT/US93/07830 2 1 ~ ~ ~ 0 3 ` . ` .

i Qy~ATERNIZATION Q~ CARBINOL

Conditions: 1) 2.5 eq. 1-methylimidazole/C~2C12 2) 1.~6 eq triflic anhydride ;:
3) 0; 45 min i:.
Yield: 86% (crude~; no data; used immediately.

DEALLYLATION

Conditions: PPh3; Pd(PPh3)4 CO2K CO2H ''.
.:
1:1:1 CH2C12:EtOAc:DME; r.t.; 2 hours , 20 Yield 16%
Spectra: :
W (~2): ~ max - 290 m~ `
1~ NMR (400 ~H~, 2:1 D2O:CD3CN): (no internal standard - DOH at 4.80); ~ 1.52 (d, CH3C~O~-); 3.64 (dd, ~6); 4.08 (C~3N); 5.58 (s, thiophene-C~2);
7.55-7.91 (thiophene, phenyl, & two imidazole protons); 8.99 (s, N=CE-N). :~
' ~

~ ~:

:

`

W094/05669 PCr/US93/07830 ~ ~ - ~^` ., 214~7~)~

'-:
~EXAMPLE 1 0 ~EP A~: `

/~2C H H ~=

o~ /= PPh3 ~OS i C2 ~' ., Yield: 53%
Spectra:
MS: m/z 901(MI); 262 ~Ph3P). .
IR(C~2CL2): 1740 ~carbonyls); 1620 ~ylid) cm~
: lH NMR ~300 M~z, C~C13): selected absorbances ~ O.14 (s, Si~C~3)2); 0.94 ~s, t-butyl Si); 1.16 ~d, J=6 ~z, :
CE3C~OSi-); 2.79 (dd, ~6); 4.90 ~s, CH20Si~
5.75-6.00 (m, two -CH2C~C~2); 7.11-~.21 (all aromatic protons,) ;, .......... ................................................................. ....... .. .~.
S~P A2:
~; '~
~, / ~ Z '~

O 1- PPh3 ~ ~ H

: Yl~ld. 8~%

" , , ` "

:: ~ ` : ,.~`

W094/0~6~ PCT/US93/07830 ~", 2: L 4 ~

Spectra: `
MS m/z 787 (MI); 509 (MI-Ph3PO); 262 (Ph3P).
IR 2965 (CH2Cl~): 3600 (OH); 1740 (carhonyls, 1740 cm~
lH NMR (300 MHz, CDC13): ~ selected absorbances 1.15 (d, J=6 Hz, CH3CEO-); 2.78 (dd, J-2 ~ 10 Hz, H6); 4.87 (s, CH2OH); 5.74-6.00 (m two -CH2-CH=CH2).

ST~P B:

Yield: 49%
Spectra: ;
IR(CH2C12): 1780 (~-lactam); 1740 ~ 1715 (carbonate and ester (cm-l). ;1 1~ NMR (300 MHz, CDC13): ~ 1.49 (d, J=6 Hz, CH3CHO-);
1.85 (t, J=6 Hz, OH); 3.13(dd, J=10 and 18 Hz, Hla);
3.32 (dd, J=9 ~ 18 Hz, Hlb); 3.43 (dd, J=3 & 8 Hz, H6); 4.59-4.74 (m's, two CH2CH=CH2); 4.88 (d, J=6 Hz, C~2OH); 5.13-5.40 (m, two CH2CH=C~2); 5.76-6.01 (m, ;~
two CH2C~=CH2); 7.24-7.55 (m's, phenyl and thienyl protons)-`
OH
~ H H

~ N-CH
C~2- W ~P-`~

W~ 94/05669 PCr/US93/07830 ~, . ,~; . i 21~70~

., Yield: 21%
Spectra:
W (~2) ~a~ = 265 m~; ~sh = 303 m~ (N~20 quenchable); ~ - 8,800.
1~ NMR (300 MEz, D20)~ 6 ~d, J=6 ~z, C~3CEO-);
2.98 (dd, J=10 & 18 ~Z. ~la); 3 34 (dd, J=8 & 18 Hz ~lb); 3.42 (dd, J=2.5 & 6 Hz, H6); 3.79 (s, NCE3?;
4.20 (m's, H5 & Hl,); 5.52 (s, thiophene-CH2-N);
7.11-7.60 (phenyl, thiophene and two imidazole

10 protons); 8.72 (s, N=C~-N of imida~ole). -~

. PREPARA2ION OF INTERMEDIATES:
ST~P Q: `~
:~
~, ., I3r Br fi ~ ' ~53~ ~3 I3r CHO (diforrrylation~
1 2 .;~
, -''.

To a solution of l (2.86 g, 9 mmol) in TEF
(30 m}) with stirring at -78 under N2, 1.6 M ~uLi (5.8 ml, 9.3 mmol) was added dropwise ~ia an addition funnel. After a few mins for the addition and 5 min additional stirring, DMF (0.9 ml, 116 mmol);was added, and the reaction was allowed to warm to ambient temperature. Stirring was continued ~or 3 h. The yellow solution was then poured into brine ~: . (200 ml) and Et20 (100 ml), shakeni and separated.
The aqueo~s layer was again e~tracted with Et20, and ~ the combined organic layers were washed with 1 :.`~ brine:1~20 (100 ml), dried (~gS04), filtered and ~ ~: ;
, "~

WO~qJOSfi69 PCT/US93/07830 ~, 2 1 4 2 7 u ~

- 123 - ! `

concentrated in ~3~Q to a yellow liquid with a tan precipitate. ~exane (a few ml) was added, and the ¦.
residue was slurried and filtered. The insoluble portion was washed 2x with hexane (few ml), and the solid dried in ~~Q to give ~ (496 mg, 19% yield).
The he~ane-soluble filtrate was re-concentrated in ~ s vacuo (2.38 g) and chromatographed on 60 g of ~akers Si gel (60-200 M ~z) packed in hexane. The material was applied to the column in 1:2 CH2CI2/hexane and eluted with the same solvent system (300 ml) after which 10~/o Et20 in he~ane was used to elute 2.
Approximately 814 mg of 2 was eluted, but 630 mg of that required further purification on 1000 ~ Si Gel ;
GF plates (eluting and extracted with CH2C12) to provide a total of purified 2 ~713 mg, 30% yield) Data for 2:
MS: m/z 266/268 (MI) lH NMR ~300 ~ ~z, CDCl3): ~ 7.06 (dd, J=4 and 6, H~);
7.32 (dd, J=0.5 and 6 Hz, Ha); 7.33 (dd, J=0.5 and 4 Hz, B~,); 7.82, 7.90 and 7.96 (3 m's, 3 phenyl H's); ~ `
9.9~ (s, C~0) "
. .
Data for 3:
MS: m/æ 294/296 (MI) H NM~ (300 M~z, CDC13): ~ 7.43 & 7.73 (2 d's, J=4 ~æ, ~ ~ E~,): 7.95, 7.97 and 8.01 (3 m's, 3 phenyl ~'s); 9.87 & 9.94 (2s's, 2 C~O's). I :
~ . .
3~ ~ :

~: i wos~/0~669 PCT/US93/07~30 21 ~ 2 rl ~ '~

':

;. .
Br 2 . ~ ~ :

OH

To a solution of 2 (707 mg, 2.7 mmol) in MeO~(26 ml) with stirring at 0O was added Na~H4 (125 mg, 3.3 mmol), and after some initial foaming, ~-stirring was continued at 0 for 35 min. The . -reaction miæture was concentrated to a small ~olume :
of yellow oil under a N2 stream. Et2O (30 ml) and brine ~30 ml) were added, and the rection mixture was ~haken in a separatory funnel~ After phase ;~
separation, the aqueous layer was again extracted with ether~ The combined organic layers were backwashed with brine, dried (MgSQ4), ~lltered and ~.
concentrated in Y~~Q to ~i~e the crude ~lcohol (735 ` ~;
mg~ as an of~-white solid~ Preparative TLC o.f 304 mg of this substance o~ 4-1000 ~ Si Gel GF plates ;- -~:
(eluting with 5% EA/CH2C12 and extracting with 10% .
MeOH/CX2C12) provided purified alcohol 4 (278 mg). ;~

H NMR (30 M Hz, CDC13): ~ 472 (s, C~20H); 7.~6 (m, ~3 4"'- H of thiophene); 7~30 (m, 3"1 ~ 51~ 's of :
thiophene);; 7.42, 7.50 ~ 7.66 (3 br m~s, phenyl ~'s)~

. ' . .

. ", . " . .

~'094/0~6$9 PCTt~S93/0783~
.. ~", " .
2 ~

- - 12~ -HO H H ,r3 ~ . ~
s ~,~-S ' ~

CO~ \~N~\N-CH3 1 o , . . .;, SILYLATION OF 2-(3'-BR0~0-5~-HYDROX~METHYL)P~ENYLTeIO- ~ :
P~ENE
Conditions: 1) TBDMSiCl; ~t3N; DMF/C~2C1 2) overnight `
~ield: 80%
Spectra: .~
MS m/z 382, 384 (MI); 325, 327 (MI-t-butyl); 251, 253 :;
~MI-(CH3)2t-BuSiO~
1~ NMR (300 MHz, CDC13): ~ 0.12 (s~ t-butyl); 0.96 (s, Si(C~3)2); 4.73 (s, CH20); 7.06-7.62 (thiophene phenyl protons).

PR~P~RATION QF YLI~E_E~E~ ~`
,, ~,.
~3 1 ~

osi-t 30 Conditions: 1) Mg; BrCH2CH2Br/TEF; rfl~; ~ hours 2,. """ .2) Pyridylthioester; 0; 2 hours ~ ;
: Yiel~: 33% ~ ~

~' ';:'".

:: .
~ .:

~V094/0~669 PCT/US93/07830 ~

21 0 ~
~ - 126 - I :
, Spectra:
lH NMR (300 M~z, CDC13): ~ ~mixture of correct product and diaddition of Grignard) 0.12 & 0.14 (2s, ~-butyls); 0.96 & 0.97 (2s; Si(C~3)2); 1.15 (d, CH3).
~:
DESILYLATION TO GARBINOL YLIDE KETONE :~
Conditions: 1) aq. ~Cl/MeO~
2) 0; 1 hour ~ .;
3) prep. TLC in 1:1 ~tOAC:CH2C12 to `: ;
remove diaddition product Yield: 74% o~ càrbinol Spectra: .
MS m/z: 787 (MIj; 509 (MI-Ph3PO); 262 (Ph3P) 1~ MMR (300 M~z, CDC13): ~ 1.16 (d, CH3); 5~75~6rO1 (m, CH2=C~-C~2~

CXCLIZATION OF YLI~ CARBIN~L TO CAR~APENEM C ~ INOk `l :
Conditions: Benzene; 80; overnight ~` Yield: 83%
:~ 20 ~Spectra:~
MS m/z: 509 (MI); 339 (~-lactam cleavage).
IR: 1780 (~-iactam C=O); 1745 ~ 1720 (C=O's) cm~l . ;;
1~ MMR (300 MHz, CDC13): ~ 1.49 ~d, CH3); 1.84 (t, ~ 0~), 3.42 (dd, ~); 4.30 ~m, ~5); 5.75-6.00 (m, : 25 CE~=C~-CH2-); 7.06-7.56 (thiophene and phenyl ~: protonæ).

. QU~T~RNIZATION OF.CARBINO~
Conditions: 1) 2.5 eq. 1-methylimidazole/CH2C12 : 2) 1.1 eq. triflic anhydri:de 3~ 0-;~30 min Yield: 94%
no data; used immedlately wo94/n~66s PCT/US93/07830 ~
~ I; 2 ~ ~1 2 7 ~
.~ .
- 127 - i ~;

DEALLYLATION
Conditions: PPh3; Pd(PPh3)4 ~i ~ ~ .

~/~ ''` ' , ~", .

1:1 C~2C12:EtOAc; 2 hours Yield: 20%
.
Spectra: ~:
W (H2Q): ~max = 293 m~
lH NMR (300 M~z, 2:1 D20:CD3CN): (no internal standard - DOH at 4.80); ~ 1.55 (d, C~3C~O~-); 4.1 (s, N-CH3); 5.63 (s, thiophene-C~2); 4.03 (s, N=C~-N).

~ EXAMPLE ~0 STEP A :

.Ar-13r=Br ~ /

Conditions:
Al: 1) Mg/THF; 3 hrs./R.T. .
3 Yield: 2) 0"; 15 min; THF; pyridylthioester ,~

';

' ~:

wos4~0s669 PCT/~S93/07830 i , . . .
'~ 1 4 27 (3 5~
~ - 128 -Conditions:
A2: CH30HIH2SO4; 0; 1.25 hrs Yield: 81% ~ -.

: `
ST~
Conditions .- `
Bl: Xylene; 130; 1.5 hrs.
Yield: 83% .
Conditions .
10 B2: Tri~lic anhydride; C~2Cl2; .~ ~
`: ` .

H O .. ..
N - C O ~/; ~
N ~ `

,,'~
B2 0 15 min : 20 ~Q~
IR: 1775; 1740 ..
NMR: H6: 3.43~3.52; dd; J = 3 & 8 ~z ~5: 4.24-4.38; ddd; J = 3, 9 ~ 10 C~2N+: 5.78 (s); Aromatic ~'s: 7.2-9.65 !
:

; ;~

W 0 94/0~669 PC-r/US93/07830 ~ ~ :
2142'~ ù3 ` I
.. . j : - ].29 - I .
~,` `"' '~, .
STEP C
Conditions: PPh3; Pd~PPh3)4 ~ ; .. :
C ~ K :

~ ` . .
C ~ H `~
",.. .

`., .:
CH2C12; 0; 4 hrs ;~;
Yield: 19%
15 W 298 :
ext 2397 EXAMPLE 31 , . .
~ m~ r~ A `~

Ar-Br= Br ~c .
Conditions A: 1) MgtT~ 3 hr./R.T.
2) 0; 15 min T~F pyridylthioester Yield of A: 67% : -~

Conditions A2: C~3~ 2$4 3 09; 1. 25 hr Yield of A2: ~1%

~., ~ . .
; ~ .

WOg~t/()~fi69 PCT/US93/07830 ~ .

2il~æ7~

~P B
Conditions:
B1: Xylene; 130; 1.5 hrs.
Yield ~3% ~ -Conditions:
B2: Triflic anhydride; CH2C12;
:. ,. . ~ :.

H O ~ .
N ~ N - CO

0; 15 min. -~

1 5 ,' " ` "~:',' Conditions: PPh3; Pd(PPh3)4: ~ ,;

~,~ ~

CE12C12; 0 ; , ,~
~ ext 1107 3~
~ '~'';~.` ''`f , ,,, , ~
,. .
~ .

- ....~ ;., : . - ~

~vo~l/0~69 PCT/US93/07830 ,.~ .
2 1 4 ~ 7 0 ~

~ - 131 -~, f : ' ~r - Br = Br : -S ~ ,C~

~P .9 Conditions:
10 Al: 1) Mg/THF; 3 hr.s/R.T.
2) 0~; 15 min; T~F; pyridylthioester Yield: 67%

Conditions:
A2: C~30H/H2S04; 0; 1.25 hrs.
~ield: 81%

~1æ~ ' Conditions:
Bl: Xylene; 130; 1.5 hrs.
Yield: 83% ~
Conditions: ;
B2: Triflic anhydride; CH2C12; :~

~5 ~SMe :~

N~:

0; 15 min.

;
~ ,'`
::
'~

~09~/0~669 PClt'US93/07830 ~^ ~

2 1 9~ ~ r~

Spectra~
IR: 1780; 1745; 1715 ,~ ;
NMR: SCH3: 2.02(s); ;
H6: 3.42-3.52; dd; J - 3 & 8 ~z H5: 4.24-4.40; ddd; J = 3, 9 & 9 Hz SC~2: 3.88 (s);
NCH2: 6.12(s);
Aromatic H's: 7.22-9.02 ~;
, .
1 0 ~P

Conditions: PPh3; Pd(PPh3)4;
!i . ' ~ ,~
` COOK
i..:`.
~; ~.. , COOH
C~2C12 : c`::
Yield: 14%
W : 293 ;~
ext ` 3847 , .

. .
.`,, ; I , - !:`
. i~

.
.

~ir ~ r~ ~ ;

Claims (24)

WHAT IS CLAIMED IS:

1. A compound of the formula:

(I) wherein:
R is H or CH3;

R1 and R2 are independently H, CH3-, CH3CH2-, (CH3)2CH-, HOCH2-, CH3CH(OH)-, (CH3)2C(OH)-FCH2CH(OH)-, F2CHCH(OH)-, F3CCH(OH)-, CH3CH(F)-, CH3CF2-, or (CH3)2C(F)-;

is a 5 or 9-membered mono- or bicyclic heteroaryl ring system wherein 1 atom is O or S, or an 8-membered bicyclic heteroaryl ring system wherein 2 atoms are O
and/or S;

Ra is each independently selected from the group consisting of hydrogen and the radicals set out below, provided that one and only one Ra is selected from Type I
substituents:

I. a) A is (CH2)m-Q-(CH2)n. where m is 0 to 6 and n is 1 to 6 and Q
is a covalent bond. O, S, SO, SO2, NH, -SO2NH-, -NHSO2-, -CONH-, -NHCO-, -SO2N(C1-C4 alkyl)-, -N(C1-C4 alkyl)SO2-, -CON(C1-C4 alkyl)-, -N(C1-C4 alkyl)CO-, -CH=CH-, -CO-, -OC(O)-, -C(O)O- or N-(C1-C4 alkyl) and (CH2)m is attached to the phenyl aromatic moiety;

is a 5- or 6-membered monocyclic heterocycle or an 8-, 9- or 10-membered bicyclic heterocycle, the heterocycle containing a first nitrogen in an aromatic 5- or 6-membered first ring, with attachment of the heterocycle to A by way of said first nitrogen and said first nitrogen is quaternary by virtue of the attachment and ring bonds, with the first ring containing 0 or 1 of either O or S, with the first ring containing 0 to 3 additional nitrogen atoms, with the first ring optionally fused to a 3- or 4-membered moiety to form the optional second ring, said moiety containing at least one carbon atom, said moiety containing 0 or 1 of either O or S, and containing 0 to 2 nitrogen atoms, and said moiety being saturated or unsaturated, and the second ring aromatic or non-aromatic;

Rc is Ra as defined under II below, hydrogen, or -NRyRz (where Ry and Rz are defined in II below), but independently selected from Ra and from each other if more than one Rc is present, and is attached to a carbon ring atom or a nitrogen heteroatom the valency of which is not satisfied by the ring bonds;
p is 0 or 1;
b) where is a 5- or 6-membered monocyclic heterocycle or an 8-, 9- or 10-membered bicyclic heterocycle, the heterocycle: containing a first nitrogen in an aromatic 5- or 6-membered first ring, with said first nitrogen quaternary by virtue of a substituent Rd in addition to the ring bonds thereto, with said first nitrogen neutral in the absence of a substituent Rd, with attachment of the heterocycle to A' by way of a carbon atom of a ring, with the first ring containing 0 or 1 of either O or S, with the first ring containing 0 to 2 additional nitrogen atoms, with the first ring optionally fused to a 3- or 4-membered moiety to form the optional second ring, with the moiety containing at least one carbon atom, with the moiety containing 0 or 1 of either O or S, with the moiety containing 0 to 2 nitrogen atoms, and with the moiety being saturated or unsaturated and the second ring aromatic or non-aromatic;

Rc is defined above;

Rd is hydrogen, NH2, O- or C1-C4 alkyl (where the alkyl group is optionally mono-substituted with Rq as defined under IIc below);

A' is (CH2)m-Q-(CH2)n, where m is 0 to 6 and n is 0 to 6 and is defined above;

c) -Ap-N+Ry(Rw)0-1(Rz), where Ry and Rz are as defined under II below, RY and Rz may further be together a C2-C4 alkylidene radical to form a ring (optionally mono-substituted with Rq as defined below) interrupted by N(O)Re or N+(Re)2 (where Re is hydrogen, C1-C4 alkyl, or C1-C4 alkyl mono-substituted with Rq as defined below), Rw is hydrogen, C1-4 alkyl O-, NH2, or absent in which case the N+ is neutral, Rw, Ry and Rz may further together form a C5-C10 tertiary alkylidene radical which with N+
forms a bicyclic ring, where the tertiary alkylidene radical is optionally mono-substituted with Rq as defined below and where the tertiary carbon of the tertiary alkylidene radical is optionally replaced with nitrogen, N+Re where Re is defined above), or N+-O-, p is 0 or 1, and A is as defined above;
d) where is a 5- or 6-membered monocyclic heterocycle or an 8-, 9- or 10-membered bicyclic heterocycle, the heterocycle containing a first nitrogen in a first ring, with the first ring saturated or unsaturated and non-aromatic, with the first nitrogen quaternary by virtue of one or two substituents Rd in addition to the ring bonds thereto, with the first nitrogen alternatively neutral by virtue of zero or one substituents Rd in addition to the ring bonds thereto with attachment of the heterocycle to A' by way of a carbon atom or non-quaternary nitrogen atom of a ring, with the first ring containing in addition to carbon and the first nitrogen 0 to 1 of a member selected from the group consisting of the non-quaternary nitrogen of attachment, O, S, S(O), S(O)2 and NRe where Re is defined above, with the first ring optionally fused to a 2-, 3- or 4-membered moiety to form the optional second ring, with the moiety optionally containing in addition to carbon the non-quaternary nitrogen of attachment, and with the moiety saturated or unsaturated and the second ring non-aromatic;

Rd is defined above and where more than one Rd is present on a nitrogen, at least one Rd is hydrogen or C1-C4 alkyl;

A' is defined above; and p is defined above;

Rq is defined below;

II.
a) -CF3;
b) a halogen atom selected from the group consisting of: -Br, -Cl, -F, and-I;
c) -OC1-4 alkyl, wherein the alkyl is optionally nono-substituted by Rq, where Rq is a member selected from the group consisting of -OH, -OCH3, -CN, -C(O)NH2, -OC(O)NH2, CHO, -OC(O)N(CH3)2, -SO2NH2, -SO2N(CH3)2, -SOCH3, -SO2CH3, -F, -CF31 -COOMa (where Ma is hydrogen, alkali metal, methyl or phenyl), tetrazolyl (where the point of attachment is the carbon atom of the tetrazole ring and one of the nitrogen atoms is mono-substituted by Ma as defined above) and -SO3Mb (where Mb is hydrogen or an alkali metal);

d) -OH;
e) -O(C=O)Rs, where Rs is C1-C4 alkyl or phenyl, each of which is optionally mono-substituted by Rq as defined above or tri-substituted with -F;
f) -O(C=O)N(RY)RZ, where Ry and Rz are independently H, C1-4 alkyl (optionally mono-substituted by Rq as defined above), together a 3- to 5-membered alkylidene radical to form a ring (optionally substituted with Rq as defined above) or together a 2- to 4-membered alkylidene radical, interrupted by -O-, -S-, -S(O)-, -S(O)2-or NRe, to form a ring (where Re is hydrogen, C1-C4 alkyl, and C1-C4 alkyl mono-substituted with Rq and the ring is optionally mono-substituted with Rq as defined above);
g) -S(O)n-Rs where n = 0-2, and Rs is defined above;
h) -SO2N(Ry)Rz where Ry and Rz are as defined above;
i) -N3 j) -N(Rt)-C(O)H, where Rt is H or C1-C4 alkyl, and the alkyl thereof is optionally mono- substituted by Rq as defined above;
k) -N(Rt)-C(O)C1-C4 alkyl, where Rt is as defined above, and the alkyl group is also optionally mono-substituted by Rq as defined above;
l) -N(Rt)-C(O)OC1-C4 alkyl, where Rt is as defined above, and the alkyl group is also optionally mono-substituted by Rq as defined above;

m) -N(Rt)-C(O)N(Ry)Rz where Rt, Ry and Rz are as defined above;
n) -N(Rt)SO2RS, where Rs and Rt are as defined above;
o) -CN;
p) a formyl or acetalized formyl radical which is:
-C(O)H or-C(OCH3)2H;
q) -C(OCH3)2C1-C4 alkyl, where the alkyl is optionally mono-substituted by R4 as defined above;
r) -C(O)Rs, where Rs is as defined above;
s) -C(Ry)=NORz where Ry and Rz are as defined above;
except they may not be joined together to farm a ring;
t) -C(O)OC1-4 alkyl, where the alkyl is optionally mono-substituted by Rq as defined above;
u) -C(O)N(Ry)Rz where Ry and Rz are as defined above;
v) an N-hydroxycarbamoyl or N(C1-C4 alkoxy)carbamoyl radical in which the nitrogen atom may be additionally substituted by a C1-C4 alkyl group:

-(C=O)-N(ORy)Rz where Ry and Rz are as defined above except they may not be joined together to form a ring;
w) -C(S)N(Ry)(Rz) where Ry and Rz are as defined above;
x) -COOMb, where Mb is as defined above;
y) -SCN;
z) -SCF3;
aa) tetrazolyl, where the point of attachment is the carbon atom of the tetrazole ring and one of the nitrogen atoms is mono-substituted by hydrogen, an alkali metal or a C1-C4 alkyl optionally substituted by Rq as defined above;
ab) an anionic function selected from the group consisting of:
phosphono [P-O(OMb)2]; alkylphosphono {P-O(OMb)-[O(C1-C4 alkyl)]}; alkylphos- phinyl [P=O(OMb)-(C1-C4 alkyl)]; phosphoramido [P=O(OMb)N(Ry)Rz and P=O(OMb)NHRX]; sulfino (SO2Mb); sulfo (SO3Mb);
acylsulfonamides selected from the structures CONMbSO2Rx, CONMbSO2N(Ry)Rz, SO2NMbCON(Ry)Rz; and SO2NMbCN, where Rx is phenyl or heteroaryl, where heteroaryl is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, in which a carbon atom is the point of attachment, in which one of the carbon atoms has been replaced by a nitrogen atom, in which one additional carbon atom is optionally replaced by a heteroatom selected from O or S in the case of a 5-membered ring, and in which from 1 to 2 additional carbon atoms are optionally replaced by a nitrogen heteroatom, and where the phenyl and heteroaryl are optionally mono-substituted by Rq, as defined above; Mb is as defined above; and Ry and Rz are as defined above;
ac) C5-C7 cycloalkyl group in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S, NH or N(C1-C4 alkyl) and in which one additional carbon atom may be replaced by NH or N(C1-C4 alkyl), and in which at least one carbon atom adjacent to each nitrogen heteroatom has both of its attached hydrogen atoms replaced by one oxygen thus forming a carbonyl moiety and there are one or two carbonyl moieties present in the ring;
ad) C2-C4 alkenyl radical, optionally mono-substituted by one of the substituents a) to ac) above and phenyl which is optionally substituted by Rq as defined above;
ae) C2-C4 alkynyl radical, optionally mono-substituted by one of the substituents a) to ac) above;

af) C1-C4 alkyl radical;
ag) C1-C4 alkyl mono-substituted by one of the substituents a) - ac) above;
ah) a 2-oxazolidinonyl moiety in which the point of attachment is the nitrogen atom of the oxazolidinone ring, the ring oxygen atom is optionally replaced by a heteroatom selected from -S- and NRt (where Rt is as defined above) and one of the saturated carbon atoms of the oxazolidinone ring is optionally mono-substituted by one of the substituents a) to ag) above; and M is selected from: i) hydrogen;
ii) a pharmaceutically acceptable esterifying group or removable carboxyl protecting group;
iii) an alkali metal or other pharmaceutically acceptable cation; or iv) a negative charge which is balanced by a positively charged group.

2. A compound of Claim 1 wherein R1 is hydrogen and R2 is (R)-CH3CH(OH)- or (R)-CH3CH(F).

3. A compound of Claim 2 wherein the Type I.a. substituents are selected from the group consisting of:

; ;
; ;

where the ring where the ring contains three contains two carbon atoms; carbon atoms;

; ;

; ;

; ;

; ;

; ;

; ;

; ;

; ;

; ;

and where X = O, S, or NRC.

4. A compound of Claim 2 wherein the Type I.b. substituents are selected from the group consisting of:
; ;

; ;

;

where the ring contains three carbon atoms;

;

; ;

; ;

J J

; ;

; ;

; ;

; ;

; ;

and where X = O, S, or NRc and X' = O or S.

5. A compound of Claim 2 wherein the Type I.c. substituents are selected from the group consisting of:
-Ap-+N(CH3)3, -Ap-+N(CH2CH3)3, -Ap-+N(CH3)2CH2Rq, -Ap-+N(CH2CH3)2CH2CH2Rq, , , , , , , or where W is O, S, NR?, N(O)Re, SO, SO2 or N+(Re)2 and W' is N+Re or NO.

6. A compound of Claim 2 wherein the Type I.d. substituents are selected from the group consisting of:

;

;

;

and .

7. A compound of Claim 2 wherein Rc where attached to a ring carbon atom is selected from the group consisting of -NH2, -SCH3, -SOCH3, -CH2OH, -(CH2)2OH, -OCH3, -COOMb, -CH2COOMb, -CH2CH2COOMb, -CH2SOCH3, -CH2SCH3, CN, -SO3Mb, -CH2SO3Mb, -CH2CH2SO3Mb, -Br, -Cl, -F, -I, -CH3, CH2CH3, CH2CONH2 and CH2CON(C1-C4alkyl) where Mb is defined above.

8. A compound of Claim 2 wherein Rc where attached to a neutral ring nitrogen atom is selected from the group consisting of -CH2OH, -(CH2)2OH, -CH2COOMb, -CH2CH2COOMb, -CH2SOCH3, -CH2SCH3, CN, -CH2SO3Mb, -CH2CH2SO3Mb, -CH3, CH2CH3, CH2CONH2 and CH2CON(C1-C4alkyl) where Mb is defined above.

9. A compound of Claim 2 wherein Rd is selected from the group consisting of hydrogen, -CH3, CH2CH3, -CH2CH2CH3, -CH2COOMb, -CH2SO3Mb, -NH2 and O(-), where Mb is defined above.

10. A compound of Claim 2 wherein A is selected from the group eonsisting of -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -OCH2CH2-, -SOCH2- . -SO2CH2 . -SCH2CH2-, -SOCH2CH2-, -SO2CH2CH2-, -NHCH2CH2-, -N(CH3)CH2CH2-, -CH2N(CH3)CH2CH2-, -CONHCH2CH2-, -SO2NHCH2CH2-, -COCH2-, -CH=CHCH2- and -CH2OCH2CH2-.

11. A compound of Claim 2 wherein A' is selected from the group consisting of -CH2-, -CH2CH2- -CH2CH2CH2-, -CH2CH2CH2CH2-, -OCH2CH2-, -SOCH2-, -SO2CH2-, -SCH2CH2-, -SOCH2CH2-, -SO2CH2CH2-. -NHCH2CH2-, -N(CH3)CH2CH2-, -CH2N(CH3)CH2CH2-, -CONHCH2CH2-, -SO2NHCH2CH2-, -COCH2-, -CH=CHCH2-, -CH2OCH2CH2-, -O-, -S-, -NH-, -SO2-, -SO2NH-, -CONH-, -CH=CH-, -CH2S-, -CH2NH-, -CONHCH2- and -SO2NHCH2-.

12. A compound of Claim 2 wherein the Type II substitutents are selected from the group consisting of:

-OCH2CH2OH -Cl -F -I
-Br -OCOCH3 -SCH2CH2OH -SO2N(CH3)2 -COCH3 -CH=NOCH3 -CH=NOH -CO2CH2CH2OH
-CH=NOCMe2CO2Me -CONHCH3 -CON(CH3)2 -CONHOCH3 -tetrazotyl -CH=CHCN
-SCF3 -C?C-CN
-CONHSO2Ph -CH2N3 -SO2NHCONH2 SO2CH2CH2OH and -CH=CHCONH2 -CH2I.
-C?C-CONH2

13. A compound of Claim 1 or the formula I' wherein the substituents are:

No. R R2 Ra HAR-R?

1 H -CH(OH)CH3 H 2 H -CH(OH)CH3 Cl 3 H -CH(OH)CH3 Br 4 H -CH(OH)CH3 I H -CH(OH)CH3 SMe No. R R2 Ra HAR-R?

6 H -CH(OH)CH3 S(O)Me 7 H -CH(OH)CH3 SO2Me 8 H -CH(OH)CH3 F 9 H -CH(OH)CH3 H H -CH(OH)CH3 H 11 H -CH(OH)CH3 F 12 H -CH(OH)CH3 F No. R R2 Ra HAR-R?

13 H -CH(OH)CH3 Br 14 H -CH(OH)CH3 Br H -CH(OH)CH3 I 16 H -CH(OH)CH3 I 17 H -CH(OH)CH3 Cl 18 H -CH(OH)CH3 Cl 19 H -C(OH)CH3 No. R R2 Ra HAR-R?

H -CH(OH)CH3 21 H -CH(OH)CH3 22 H -CH(OH)CH3 23 H -CH(OH)CH3 24 H -CH(OH)CH3 -CHO H -CH(OH)CH3 -CN 26 H -CH(OH)CH3 -?NH2 No. R R2 Rn HAR-R?

27 H -CH(OH)CH3 -CHO 28 H -CH(OH)CH3 -CN 29 H -CH(OH)CH3 -?NH2 H -CH(OH)CH3 H 31 H -CH(OH)CH3 H 32 H -OH(OH)CH3 H 33 H -CH(OH)CH3 -SCH3 No. R R2 Ra HAR-R?

34 H -CH(OH)CH3 H -CH(OH)CH3 36 H -CH(OH)CH3 -SCH3 37 H -CH(OH)CH3 38 H -CH(OH)OH3 39 H -CH(OH)CH3 H H -CH(OH)CH3 F No. R R2 Ra HAR-R?
41 H -CH(OH)CH3 Cl 42 H -CH(OH)CH3 Br 43 H -CH(OH)CH3 -SCH3 44 H -CH(OH)CH3 -SCH3 H -CH(OH)CH3 46 H -CH(OH)CH3 47 CH3 -CH(OH)CH3 H No. R R2 Ra HAR-R?

48 H -CH(F)CH3 H 49 H -CH(F)CH3 H H -CH(F)CH3 H 51 CH3 -CH(OH)CH3 H 52 CH3 -CH(OH)CH3 H No. R R2 Ra HAR-R?
53 H -CH(OH)CH3 CN 54 H -CH(OH)CH3 CN H -CH(OH)CH3 CN 56 H -CH(OH)CH3 CN 57 H -CH(OH)CH3 CN No. R R2 Ra HAR-R?
58 H -CH(OH)CH3 CN 59 H -CH(OH)CH3 CN H -CH(OH)CH3 CN 61 H -CH(OH)CH3 CN 62 H -CH(OH)CH3 CN

14. A pharmaceutical composition comprised of a compound of Claim 1 in combination with a pharmaceutically acceptable carrier.

15. A method of treating a bacterial infection in a mammal comprising administering to said mammal a compound of Claim 1 in an amount which is effective to treat said bacterial infection.

16. A composition according to Claim 14 which further comprises an inhibitorily effective amount of a DHP inhibitor.

17. A composition according to Claim 16 wherein said DHP inhibitor is 7-(L-2-amino-2-carboxy-ethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptanoic acid.

18. A method according to Claim 15 which further comprises administering an inhibitorily effective amount of a DHP
inhibitor.

19. A method according to Claim 18 wherein said DHP
inhibitor is 7-(L-2-amino-2-carboxyethyl-thio)-2-(2,2-dimethyl-cyclopropanecarboxamide)-2- heptanoic acid.

20. A compound of the formula:

wherein;
R is H or CH3;
P' is a removable protecting group for hydroxy;
M is a removable protecting group for carboxy;
Ra is selected from the group consisting of H, OP', Cl, Br, I, SCH3, CN, CHO, SOCH3, SO2CH3, CO2M, CH2OP' or CONH2; and with the proviso that the -CH2Z substituent is in the 2- or 3-position of the heteroaromatic ring;
X is O or S, and Z is a leaving group selected from the group consisting of alkylsulfonyloxy, substituted alkylsulfonyloxy, arylsulfonyloxy, substituted arylsulfonyloxy.
fluorosulfonyloxy, and halogen.

21. The compound of Claim 1 where M is selected from the group consisting of alkyl, substituted alkyl, benzyl, substituted benzyl, aryl, substituted aryl, allyl, substituted allyl, and triorganosilyl.

22. The compound of Claim 1 wherein M is selected from the group consisting of benzhydryl, p-nitrobenzyl, 2-naphthylmethyl, allyl, 2-chloroallyl, benzyl, 2,2,2-trichloroethyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 2-(trimethylsilyl)ethyl, phenacyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl p-methoxyphenyl, 4-pyridylmethyl and t-butyl.

23. The compound of Claim 1 wherein P' is selected from the group consisting of trialkylsilyl, aryl(alkyl)alkoxysilyl, alkoxy(diaryl)silyl, diarylalkylsilyl, alkyloxycarbonyl, substituted alkyloxycarbonyl, benzyloxycarbonyl, substituted benzyloxycarbonyl, allyloxycarbonyl and substituted allyloxycarbonyl.

24. The compound of Claîm 1 wherein P' is selected from the group consisting of t-butylmethoxyphenylsilyl, t-butoxydiphenylsilyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl and allyloxycarbonyl.

2S. The compound of Claim 1 wherein Y is selected rom the group consisting of methanesulfonyloxy, trifluoromethanesulfonyloxy, fluorosulfonyloxy, p-toluenesulfonyloxy, 2,4,6-triisopropylbenzenesulfonyloxy, p-bromobenzenesulfonyloxy, p-nitrobenzenesulfonyloxy, chloro, bromo, and iodo.