Note: Descriptions are shown in the official language in which they were submitted.
3~
SY-1767 .
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is directed to a new process for
the preparation of carbapenem antibiotics having a 2-substituent
of the formula
~ 63 5
-S-A- ~ -R
in which A represents a Cl-C6 straight or branched chain alkylene
group; R5 represents an optionally substituted aliphatic, cyclo-
aliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, hetero-
aryl, heteroaraliphatic, heterocyclyl or heterocyclyl-aliphatic
radical; and
N-
~ .
represents a nitrogen-containing aromatic heterocycle attached to
the alkylene group A at a ring carbon atom and quaternized by
substituent R5.
2. Description of the P.rior Art
The carbapenem derivatives prepared by the process of
the present invention are disclosed and claimed by my colleague,
~.
.
'
~ . "'
_ 3 _
Choung J. Rim, in U.S. Patent No. 4,644,061, is~ued F~bruary 17,
1987.
The a~orementioned U.S. P~tsnt No. 4,644,061 di~close~
preparation o carbapsnem ntibiotic~ of the formula
R~ A~3~R5
COOR
wherein R8 is hydrogen and Rl is selected from the group consist-
ing of hydrogen; substituted and unsubstituted: alkyl, alkenyl
~nd alkynyl, having from 1-10 caxbon atoms; cycloalkyl and
cycloalkylalkyl, having 3-6 carbon atoms in the cycloalkyl ring
and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl,
aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the
aliphatic portion has 1-6 carbon atoms; heteroaryl, hetero-
aralkyl, h~terocyclyl and heterocyclylalkyl wherein the hetero
atom or atoms in the above-named heterocyclic moieties are
selected ~rom the group consisting of 1-4 oxygen, nitrogen or
sulfur atoms and the alkyl moieties associated with said hetero-
cyclic moieties have 1-6 carbon atoms; wherein the substituent or
substituents relative to the above-named radicals are indepen-
dently selected ~rom the group consisting of
Cl-C6 alkyl optionally substituted by amino, halo, hydroxy or
caxboxyl
halo
-oR3
- ORCNR3 R4
RNR3 R4
~,V~73
-- 4
NR3R4
_<~, NR3
NR3 R4
- S~NR R
o
1
-NHCNR R
R3 CNR
- CO~R
=O
- OCR
-SR3
-~R
1l
-~R
-CN
N3 3
- OSO3R
R g
- O ISl - R
-NR3~-R
-O~ (O) (oR3 ) (OR )
-NR3C=NR
1 3
-NR3(::02R
~herein, relative to the above-named substituents, the gxoups R3
and R4 are independently selected from hydrogeni alkyl, alkenyl
0
-- 5 --
and alkynyl, having from 1-10 carbon atoms, cycloalkyl, cyclo-
alkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the
cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties;
phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety
is phenyl and the aliphatic portion has 1-6 carbon atoms; and
heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl
wherein the hetero atom or atoms in the above-named heterocyclic
moieties are selected from the group consisting of 1-4 oxygen,
nitrogen or sulfur atoms and the alkyl moieties associated with
said heterocyclic moieties have 1-6 carbon atoms/ or R3 and R4
taken together with the nitrogen to which at least one is at-
tached may form a 5- or 6-membered nitrogen-containin~ hetero-
cyclic ring; R9 is as defined for R3 except that it may not be
hydrogen; or wherein Rl and R8 taken together represent C2-C10
alkylidene substituted by hydroxy; R is selected from the group
consisting of substituted and unsubstituted: alkyl, alkenyl and
alkynyl, having from 1-10 carbon atoms; cycloalkyl and cyclo-
alkylalkyl, having 3-6 carbon atoms in the cycloalkyl ring and
1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aral-
kenyl and aralkynyl wherein the aryl moiety is phenyl and the
aliphatic portion has 1-6 carbon atoms; heteroaryl, hetero-
aralkyl, heterocyclyl and heterocyclyalkyl wherein the hetero
atom or atoms in the above-named heterocyclic moieties are
selected ~rom the group consisting of 1-4 oxygen, nitrogen or
sulfur atoms and the alkyl moieties associated with said hetero-
cyclic moieties have 1-6 carbon atoms; wherein the above-named R
radicals are optionally substituted by 1-3 substituents indepen-
dently selected from:
Cl-C6 alkyl optionally substituted by amino, fluoso, chloro,
carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
- oR3 ;
-oco2R3;
_ oco~ 3;
-OCONR R ;
o~ ~
-- 6 -- .
o
-O~-R9;
-oxo;
N~3R4;
R3CoNR4-;
-NR3Co2R ;
-NR3CoNR3R4;
- NR 3 S--R
-oR3,;
-~-R ;
O O
~ g
-S-R ;
-SO3R ;
-CO2R ;
-CONR R ;
-CN; or
phenyl optionally substituted by 1-3 fluoro, chloro, bromo, Cl-C6
alkyl ~ -oR3, -NR3R4, -So3R3, -Co2R3 ~r -CoNR3R , wherein R3, R4,
and R9 in such R substituents are as defined above; or R may be
attached to
N
at another point on the ring so as to form a ~used heterocyclic
or heteroaromatic ring, which ring may contain additional hetero
atoms selected from 0, S and N;
R15 is selected from the group consisting of hydrogen;
substituted and unsubstituted: alkyl, alkenyl and alkynyl,
having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and
alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring
and 1-6 carbon atoms in the alkyl moleties; spirocycloalkyl
having 3-6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl
wherein the aryl moiety is phenyl and the aliphatic portion has
1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and
~7;3~ 3
-- 7 ~
heterocyclylalkyl wherein the hetero atom or atoms in the
above-named heterocyclic moieties are selected from the group
consisting of 1-4 oxygen, nitrogen and sulfur atoms and the alkyl
moieties associated with said heterocyclic moieties have 1-6
carbon atoms; wherein the substituent or substituents relative to
the above-named radicals are selected from the group consisting
of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl,
mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino,
nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the
alkyl moieties of the above-recited substituents have 1-6 carbon
atoms;
A is Cl-C6~straight or branched chain alkylene; R2 is hydrogen,
an anionic charge or a conventional readily removable carboxyl-
protecting group, providing that when R2 is hydrogen or a pro-
tecting group, there is also present a counter ion; and
represents a substituted or unsubstituted mono-, bi- or poly-
cyclic aromatic heterocyclic radical containing at least one
nitrogen in the ring and attached to A through a ring carbon atom
and having a ring nitrogen which is quaternized by the group R5;
and pharmaceutically acceptable salts thereof, by the process
shown in the following reaction scheme:
R8 E~
R
~ N 2'
~' COOR
III
-- 8 --
R 8 ~I R ,
Rl~L H~
O~ N COOR2
Rl~
II .
Rl ~/~_S--A~N -R X
l l optional
0~ N 1~ COOR2 de-blocking
~ H R15
R1 ~--A~N -R
O COOR
In a preferred variant of the above process, the scheme
is modified as shown below:
. .
~'~7~`t:~ ~
_ g _
R15
R1 ~ -A ~ N de-blocking
N C~OR
II Rl5
R~
COOH
IIa 15
R1 ~ ~ N -R5
N COOe
Ia
To elaborate on the above pxocess, starting material
III is reacted in an inert organic solvent such as methylene
chloride, acetonitrile or dimethylformamide with about an equi-
molar amount of an agent R-L such as p-toluenesulfonic acid
anhydride, p-nitrobenzenesulfonic acid anhydride, 2,4,6-
triisopropylbenzenesulfonic acid anhydride, methanesulonic acid
anhydride, trifluoromethane sulfonic acid anhydride, diphenyl
chlorophosphate, toluenesulfonyl chloride, p-bromobenzenesulfonyl
chloride, or the like, wherein L is the corresponding leaving
group such as toluenesulfonyloxy, p-nitrobenzenesulfonyloxy,
diphenoxyphosphinyloxy, and other leaving groups which are estab-
lished by conventional procedures and are well-known in the art.
The reaction to establish the leaving group at the 2-position of
intermediate III is advantageously carried out in the presence of
a base such as diisopropylethylamine, triethylamine, 4~
dimethylaminopyridine, or the like, at a temperature of ~rom
about -20 to +40C, most preferably at about 0C. The leaving
group L of intermediate IV may also be halogen in which case such
group is established by reacting intermediate III with a halo-
genating agent such as 03PCl2, 03PBr2, (0O)3P~r2, o~alylchloride
or th~. like in a solvent such as CH2Cl2, CH3CN, THF, or the like,
in the presence o~ a base such as diisopropylethylamine, tri-
ethylamine, 4-dimethylaminopyridine, or the like. Intermediate
`'~ ,.
..:
a~ q
-- 10 --
IV may be isolated if desired, but is conveniently used for the
next step without isolation or purification.
Intermediate IY is next converted to intermediate II by
a conventional displacement reaction. Thus, intermediate IV may
be reacted with approximately an equimolar amount of a hetero-
aralkyl mercaptan reagent of the formula
HS -A ~ N
wherein A represents C1 C6 straight or branched chain alkylene
and
~ N
represents a mono-, bi- or polycyclic aromatic heterocyclic
radical containing a quaternizable nitrogen in the ring, said
ring being attached to A through a ring carbon atom, in an inert
organic solvent such as dioxane, dimethylformamide,
dimethylsulfoxide or acetonitrile and in the presence of a base
such as diisopropylethylamine, triethylamine, sodium hydrogen
carbonate, potassium carbonate or 4-dimethylaminopyridine. The
temperature for the displacement is not critical, but an advanta-
geous temperature range is from about -40C to 25C. Most
conveniently, the reaction is carried out with cooling, e.g. at
about 0C to -10C.
Quaternization of the ring nitrogen in the hetero-
aralkyl group of intermediate II i5 carried out by reacting
intermediate II in an inert organic solvent with at least an
equivalent lup to about a 50% molar excess) of an alkylating
agent of the formula
~5 X'
wherein R5 is as defined above and X' is a conventional leaving
group such as halo ~chloro, bromo or iodo, most preferably iodo)
or a sul~onate est~x moiety such as a mesylate, tosylate or
triflate. Examples of suitable non-reactive organic solvents are
chloroform, methylene chloride, tetrahydrofuran, dioxane,
acetone, dimethylsulfoxide and dimethylfonnamide. The
temperature for the alkylation reaction is not critical and
temperatures in the range of from about 0C to 40C are
preferred. Most conveniently, the reaction step is carried out
at room temperature.
Intermediate I' will have a counter ion X' (e.g.
derived from the alkylating agent used) associated with it which
at this stage or at a later stage, i.e. following the de-blocking
step, may be substituted by a different counter ion, e.g. one
which is more pharmaceutically acceptable, by conventional
procedures. Alternatively, the counter ion may be subse~uently
removed during the de-blocking step.
The de-blocking step to remove the carboxyl-protecting
group R2 of intermediate I' is accomplished by conventional
procedures such as solvolysis, chemical reduction or hydro-
genation. Where a protecting group such as p-nitrobenzyl,
benzyl, benzhydryl or 2-naphthylmethyl is used which can be
removed by catalytic hydrogenation, intermediate I' in a suitable
solvent such as dioxane-water-ethanol, tetrahydrofuran-a~ueous
dipotassium hydrogen phosphate-isopropanol or the like may be
treated under a hydrogen pressure of from 1 to 4 atmospheres in
the presence of a hydrogenation catalyst such as palladium on
charcoal, palladium hydroxide, platinum oxide or the like at a
temperature of ~rom 0 to 50C for from about 0.24 to 4 hours.
When R2 is a group such as o-nitrobenzyl, photolysis may also be
used for de-blockiny. Protecting groups such as 2,2,2-
trichloroethyl may be removed by mild zinc reduction. The allyl
protecting group may be removed by using a catalyst comprising a
mixture of a palladium compound and triphenyl phosphir.e in a
suitable aprotic solvent such as tetrahydrofuran, methylene
chloride or diethyl ether. Similarly, other conventional
iL~ 730~
-- 12 --
carboxyl-protecting groups may be removed by methods known to
those skilled in the axt. Finally, as mentioned above, compounds
of Formula I' where R2 is a physiologically hydrolyzable ester
such as acetoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl,
methoxymethyl, etc., may be administered directly to the host
without de-blocking since such esters are hydrolyzed in vivo
under physiological conditions.
The above-described process has several disadvantages.
Thus, for example, the process involves several steps which
advantageously could be reduced in number. The overall reaction
yield is also quite low and the quaternization step is per~oxmed
on the carbapenem compound per se. It would be desirable to have
a new process for producing compounds of Formula I which (1)
involves fewer steps, (2) gives higher yields, (3) allows the
quaternized amine to be formed first and then attached to the
carbapenem nucleus at a later stage in the synthesis and (4) can
be used to more easily form quaternary amine products with a wide
variety of amines, i.e. amines with steric hindrance and those
with low pKb values.
~73~
-- 13 --
SUMM~RY OF TH~: INVE:NTI ON
The present invention provides a novel process for
preparation of carbapenem derivatives of the formula
Rl~S-A~p_R5
COOR2
I
wherein R8 is hydrogen and R1 is selected from the group consist-
ing of hydrogen; substituted and unsubstituted: alkyl, alkenyl
and alkynyl, having from 1-lO carbon atoms; cycloalkyl and
cycloalkylalkyl, having 3-6 carbon atoms in the cycloalkyl ring
and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl,
aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the
aliphatic portion has 1-6 carbon atoms; heteroaryl, hetero-
aralkyl, heterocyclyl and heterocyclylalkyl wherein the hetero
atom or atoms in the above-named heterocyclic moieties are
selected from the group consisting of 1-4 oxygen, nitrogen or
sulfur atoms and the alkyl moieties associated with said hetero-
cyclic moieties have 1-6 carbon atoms; wherein the substituent or
substituents relative to the above-named radicals are i.ndepen-
dently selected from the group consisting of
Cl-C6 alkyl optionally substituted by amino, halo, hydroxy or
carboxyl
hal3o
-OR
_ollNR3R4
-CNR R
-NR3R
~NR
NR3R4
'
. ~ .. ,.. :.. - ..
,.
- 14 -
o
- S-NR R
o
-NO INR3R4
R3 ~NR4 -
-CO2 R
o
- ol IR3
-oR3
Il 9
-SR
-CN
-N
3 3
-OSO3R
R g
o
31l 9
-NR S-R
op(o)(oR3)(oR )
-NR3f=NR
R3
-NR3Co2R9
-N02
wherein, relative to the above-named substituents, the groups R3
and R4 are independently selected from hydrogen; alkyl, alkenyl
and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cyclo-
alkylalkyl and alkylcycloalkyl, havir;g 3-6 carbon atoms in the
cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties;
phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety
- 15 -
is phenyl and the aliphatic portion has 1~6 carbon atoms; and
heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl
wherein the hetero atom or atoms in the above-named heterocyclic
moieties are selected from the group consisting of 1-4 oxygen,
nitrogen or sulfur atoms and the alkyl moieties associated with
said heterocyclic moieties have 1-6 carbon atoms, or R3 and R4
taken together with the nitrogen to which at least one is at-
tached may form a 5- or 6-membered nitrogen-containing hetero-
cyclic ring; R9 is as defined for R3 except that it may not be
hydrogen; or wherein Rl and R8 taken together represent C2-C10
alkylidene substituted by hydroxy; R5 is selected from the group
consisting of substituted and unsubstituted: alkyl, alkenyl and
alkynyl, having from 1-10 carbon atoms; cycloalkyl and cyclo-
alkylalkyl, having 3-6 carbon atoms in the cycloalkyl ring and
1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aral-
kenyl and aralkynyl wherein the aryl moiety is phenyl and the
aliphatic portion has 1-6 carbon atoms; heteroaryl, hetero-
aralkyl, heterocyclyl and heterocyclyalkyl wherein the hetero
atom or atoms in the above-named heterocyclic moieties are
selected from the group consisting of 1-4 oxygen, nitrogen or
sulfur atoms and the alkyl moieties associated with said hetero-
cyclic moieties have 1-6 carbon atoms; wherein the above-named R5
radicals are optional.ly substituted by 1-3 substituents indepen-
dently selected from:
C1-C6 alkyl optionally substituted by amino, fluoro, chloro,
carboxyl, hydroxy or carbamoyl;
fluoro, chloro or bromo;
-oR3;
-oco2.3;
-OCOR ;
-ocoNR3R ;
1l
-Ol~-R ;
O
--o~. o;
NR3R4;
.
. :
-- 16 --
R3 CO~R4-;
-NR3Co2R;
- NR 3 coNR3 R
-NR3S-R~;
- SR3;
~ g
-S-R;
O O
~ g
-S-R;
-S03R3;
- CONR 3 R
-CN; or
phenyl optionally substituted by 1-3 fluoro, chloro, bromo, C1-C6
alkyl ~ -oR3 ~ -NR3R4, -So3R3, -Co2R3 or -CoNR3R4, wherein R3, R4,
and R in such R substituents are as defined above; or R may be
attached to
C~0
at another point on the ring so as to form a fused heterocyclic
or heteroaromatic ring, which ring may contain additional hetero
atoms select~d from 0, S and N;
R15 is selected from the group consisting of hydrogen;
substituted and unsubstituted: alkyl, alkenyl and alkynyl,
having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and
alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring
and 1-6 carbon atoms in the alkyl moieties; spirocycloalkyl
having 3-6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl
wherein the aryl moiety is phenyl and the aliphatic portion has
1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and
heterocyclylalkyl wherein the hetero atom or atoms in the
above named heterocyclic moieties are selected from the group
consisting of 1-4 oxygen, nitrogen and sulrur atoms and che alkyl
moieties associated with said heterocyclic moieties have 1-6
carbon atoms; wherein the substituent or substituents relative to
.; ~ ~, .
the above-named radicals.are selected from the group consisting
of: amino, mono-, di- and trialkyla~.ino, hydroxyl, alkoxyl,
mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino,
nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the
alkyl moieties of the above-recited substituents have 1-6 carbon
atoms;
A is Cl-C6 straight or branchQd chain alkylene; R~ is hydrogen,
an anionic charge or a conventional readily removable carboxyl
protecting group, providing that when R2 is hydrogen or a pro-
tecting gxoup, there is also present a counter ion; and
~N~
represents a substituted or unsubstituted mono-, bi~ or poly-
cyclic aromatic heterocyclic radical containing at least one
nitrogen in the ring, said ring being attached to A through a
ring carbon atom and having a ring nitrogen which is quaternized
by the group R ; and pharmaceutically acceptable salts thereof,
which process comprises xeacting an intermediate of the formula
Rl~DCOOR2 '
IV
wherein R1, R8 and R15 are as defined above, R~ is a
conventional readily removahle carboxyl protecting group and L is
a conventional leaving group such as toluenesulfonyloxy, p-
nitrobenzenesulfonyloxy, diphenoxyphosphinyloxy or halo with a
thiol compound of the formula
~ ~3 5
HS-A - t -R VII
- 18 -
wherein A and
are as defined above and ~ i~ a countsr anion in an inert
solvent and in the presence of base to produce a
carbapenem product of the formula
R15
Rl ~ 5-A ~ 5
COOR2
I'
where$n Rl, R8, R15 R2' A
~ -R
and ~ are as deflned above and, if desired, removing the
carboxyl protecting group R2 to give the corresponding de-
blooked oompound of Foxmula I, or a pharmaoeutioally
aoceptable ~alt thereof.
Thus ln one embodiment oE t,he pre~ently olaimed
invention the invention providea a proaess for the
preparation of a compound oE the formula
B H
A ~----~
N C~o~2
.
": `
~7~
- 18a -
wherein R8 is hydrogen and ~1 iB ~elected from the group
consisting oE hydrogen, substituted and unsub~tituted:
alkyl, alkenyl and alkynyl, having f:rom 1-10 carbon atoms;
cycloalkyl and cycloalkylalkyl, having 3-6 carbon atoms
in the cycloalkyl ring and 1-6 carbon atoms in the alkyl
moieties; phenyl; aralkyl, aralkanyl and aralkynyl wherein
the aryl moiety is phenyl and the aliphatic portion has 1-
6 carbon atoms; heteroaryl and heteroaralkyl wherein the
heteroaryl moiety is selected from the group consisting of
thienyl, furyl, thiadiazolyl, oxadiazolyl, triazolyl,
isothiazolyl, thiazolyl, imidazolyl, isoxazolyl,
tetrazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, pyrrolyl, and pyrazolyl; heterocyclyl and
heterocyclylalkyl wherein the heterocyclyl moiety is
selected from the group consisting of morpholinyl,
piperazinyl, piperidyl, pyrazolinyl, pyrazolidinyl~
imidazolinyl, imidazolidinyl, pyrrolinyl and pyrrolidinyl
and the alkyl moieties associated with said heterocyclic
have 1-6 carbon atoms; wherein the substi~uent or
substituents relative to the above-named radicals are
independently selected from the group consistlng of
Cl-C6 alkyl c~ptionally su}stituted by smino, h~lo,
hydroxy or ~arboxyl
halo
-oR3
o
-oCNR3 R4
O
~1NR3R
-NR R
~NR3
\NR3R
O
-S-NR R
I
o
~ .
.3 .~ -NHCNR R
- 18b -
R CNR -
-Co2R3
G~ .
-oCR3
--S~
o
-SR
o
~I 9
-SR
Il
-C:N
-N3
o
-OS-R9
a
o
-NR3S-R
o
_op (O) (oR3) (OR )
-NR3C=NR .,
13
-NR3Co;~R
-N02
wherein, relative to the above-named substi~l~ents, the
yroups R3 and R4 are independently ~elected fror~ hydrogen;
a~Xyl, alkerJyl and alkynyl, ha~ing ~rom 1-10 c rbon atoms;
cy~loalkyl, cycloalkylalkyl and alkyl~ycloaLkyl, ha~iDg
3-6 carbon atoms in the cydt~ lkyl ring and 1-6 carbo~
atoms in t~le ;3 lkyl moie,kies; phe~yl; arzlkyl, aralkenyl
Pnd a~lXynyl whexein the RLryl ~DOiety is pheslyl an~ the
~' . !
~3~
-- 18c --
21ip~ pl~rt~ on ~a.~ o~r~o~ ~toms; ~etoroaryl elnd ~t~ro~r~lkyl
wh~r~in the heteroaryl ~noi~ty iB ~alact~d ~rom the grc)up
~onsi6ting of thianyl, furyl~ thiadlazc~lyl, oxadiazolyl,
triazolyl, i~c~thiazolyl, thiazolyl, imidaz~lyl, is~xazolyl,
tetrazolyl~ oxa olyl, pyrldyl, pyrazinyl, pyrimidinyl,
pyr$dazlnyl, ~yrrolyl, and pyrazolyl; het2rocyclyl and
heterocyclylalkyl wherein the heterocyclyl m~iety i5 BeleCted
from the ~roup con~i6ting of ~rpholirlyl, piperazinyl~ piperidyl,
pyrazolinyl, pyrazol~dlnyl, ~midazolinyl, lmidazolidinyl,
pyrrolinyl ~nd pyrrolidinyl ~nd the alkyl ~oietie~
associated wit;h said heterocyclic moieties ha~re 1-6 carbo~
atoms, or R3 and R4 taXen together with the nitrogen to
which at least one is attached may fo~m a ~-or 6 membered
nitr~gen-containing he.terocyclic ring; ~9 is as defined
~r R3 excep~ that it may not be hydrogen; or wherein Rl
and R8 taXen together represent C2-C~0 alkylidene ~r C2-C10
alkylidene substituted by hydroxy; R is selecte~ fro~ ~he
group consisting of subs~ituted and uns~bstituted: alkyl,
alkerlyl and aL'cynyl, ha~ing from 1-1~ carbon ato~; cyclo-
aIkyl and cycloalkylalkyl, ha~ing 3-6 carbon atoms in the
cycloalkyl ring and 1-6 c2rbon atoms in the alkyl moieties;
phenyl; aralkyl, ~r~lkenyl znd aralkynyl wherei~ ~he ~ryl
Cl-C6 alkyl optionally substituted by amino,
fluoro, chloro, carboxyl, hydroxy or c~rbamoyl;
fluoro, chloro or bromo;
-OR
-OC02R
_oc~3
-~CC)NR3R4
.
Il 9
-OS-R
o
-oxo
'~
~73
- 18d -
-NR3R4
R C~N~
NR3Co2R4
-~R3Co~R3R
O
-NR3S-R9
-SR
o
,~ g
-S~R
O O
tc ;'l g
-S-R
-503R
-C02R
CoNR3~
-CN; or
phenyl optionally substituted by 1-3 fluoro, chloro,
~romo, Cl-C6 alkyl, -oR3, -NR3R4, -503R3, -C02R3 or
-CoNR3~4, wherein ~ , R , and R in such R substituents
are ~s defined ab~ve;
os ~ may be at~ched to
~0
~ N -
at another point on the ring ~o as to form ~ fused hetero-
cyclic or heter~ar~ma~ic r~ng, whi~h xing ~ay cont~in
~dltional hetero Ato~ ec~ ro~ an~ N:
i~ Cl-C6 ~tr~ight or ~r~nched cha~n ~lkylene; R2 is hydrogen,
an ~ni~nic ch~rge ~r ~ conventional readily rem3v~ble carb~xylo
prot~eting ~roup, providing tb~t whe~ R2 ~ hydroge~ or ~ pr~
~e~n~ ~r~up, ~bere ~e ~1~D pre~e~t ~ eoun~er ~o~
:; .
,, .
3 27;~
- 18e -
represents an ~tic heb~xx~cli~ radical con ~ining at least
~ne ~i~s~yen in the riA~ ~id sing being ~tta~he~
~hrough ~ rin~ earb~ ~tom ~nd having a ring ni~r~gen whi~ ~5
quat~rR1~8 by th~ ~rou~ R~ ro~tlc het~rocyclio r~c~l
bein~ ~electad from the group ~onsi~t~ng o~ thiadi~zolyl,
oxadiazolyl, triaz~lyl, i B othi~zolyl, thiazolyl, i~idazolyl,
~soxazolyl, tetraz~lyl, oxa201yl, pyridyl, pyrazinyl,
pyrl~l~lnyl, pyr~dazlnyl, pyrrolyl ~d pyrazolyl or
~h~ac~utio~lly ~ce~pta~ alt thereof,
which process c~mprises reacting an intermediate
~f the ~or~ula H
R8 H
Rl~,
N COOR2'
o
IV
wherein R nnd R are as defined above, R2 i8 a conventional
readily removable carboxyl protecting group and L i8 a
conventional leaving group,with a thiol compound of the formula
~S -A ~ N -R VII
xe
wherein A and
r~ 5
tN -R
are as defined above and Xe is a counter anion,in an inert
solvent and in the presence of base to produce a carbapenem
product of the foxmula
.~
:
... ..
.
..... - .. i . ,
,
.
- l~f -
8 ~ H ~ ~
1 : ~ S -A- - N -R
R - ~ ~ X~
O COOR2
I'
wherein R , R , R , A,
~ N -R
and X5 are as defined abo~e and, if desired, removing the
carboxyl protecting group R2 to give the corresponding
de-blocked compound o~ ~ormula I, or a pharmaseutically
acceptable salt thereof.
In another embodiment the invention provide~ a
proce~s for the preparation of a compound of the formula
6~ IH3
OH ~ N-~
SCH2~=,~
N~ - COOR2
I
wherein R2 is hydrogen, an anionic charge or a oonventional
readily xemovable carboxyl-protecting group, providing that when
~2 is hydrogen or a protecting group, there i5 also present a
coun~er ion, or a pharmaceutically acceptable salt thereof, which
process comprises reacting an intermediate o~ the formula
O~ H
L
O N COOR2 2'
wherein ~ is a conventional l~a~ing yr~up and ~ is a conven-
tional readily remo~able carboxyl-protecting group with a thiol
compound of the ~ormula
. ~
. . , ~3
. ~''' :
,, :,: '
~t73~
- 18g -
~Is-cH2~
wherei~ a cl~unter anion, ir~ as~ inert ~ ent and in the
presen~e ~f base ~o produce a carbapenem pr~duct ~ the ~ormul~
~SC~2 ~
coo~2
.
whereirl ~2 2md ~3 are as defined above ~nd, if de ired, removi~g
~he protecting gr~up R2 to give she correspc~naing de-bl~cked
~omp~und of ~o~ula I, t~r a phar~naceutic~lîy n~cepta~le l;A3,'~:
ther~f .
Al60 provided by the present invention are
intermediates of Formula VII.
~ he carbapenem aompound~ of Formula I ara potent
antibaoterial agents or intermediates useful in the
preparation of ~uch agents.
The compounds o~ Formula I above contain the
oarbap0nem nucleus
6b ~ z
and may thus be ~amed a~ 1 carba-2~penem-3-carboxylic acid
derivatives. Alternatively, the compounds may be
considered to have the b~sic ~tructure
~;~
.' ' ,
. .
~L~7~
- 18h -
~^
and name as 7~oxo-1-azabicyclo (3.2.0)hept-2-ene-2-
carboxy11c acid derivatives. Whlle the present invention
includes compounds whexein the relative stereochemistry of
the 5,6-pxotons i8 ~is a~ well as ~PS, the preferred
compound~ have the 5R,6S ($~ ) 6tereochemistry as in the
case of thienamycin.
The compounds of ~ormula I may be un~ubstituted in
;,
, ,!, " ~
~ ,,
,,,~
' ' "~ `: "
':' .
.
-- 19 ~
the 6-position or æub~tituted by substltuent groups
previously di~olosed for other carbapenem dari~ative~.
More ~peci~ioally, RB may be hydrogen and R1 may be
hydrogen or a non-hydrogen ~ub6tituent disolo~ed, for
example, in European Patent Application 38,869 ( 8 ee
de~inition of R6). Alternatively, R8 and R1 take~
together may be C2-C10 alkylidene or C2-C10 alkylidene
substituted for Pxample, by hydroxy.
The compounds of Formula I may al~o be unsub6tituted
10 in the 1-position (R15=H) or sub~titutad by 6ubstituent
groups previou61y di6closed ~or other carbapenem
derivative~. More specifically, R15 may be hydrogen or
any of the non-hydrogen 1-~ub~tituents disclosed, for
example, in European Patent Application 54,917 (see
15 definition o~ R1 or R2 therein) or in U.S. Patent
4,350,631. Preferred non-hydrogen R15 6ubstituents
include C1-C6 alkyl, mo~t preferably methyl; phenyl; and
phenyl (C~-C6) alkyl. The non-hydrogen R15 ~ubstituent
may be in either the u- or B- configuration, and it i~
20 inte~ded that the pre~ent invention include the individual
a- and B-isomer~, as well a6 mixture6 thereof.
To elaborats on the defini-tions for R1, R8 and R15;
(a) The aliphatic "alkyl", "alkenyl" and "alkynyl"
group~ may b~ 6traight or branched chain having 1-10
25 carbon atom6; preferred are 1-6, most pre~erably 1-4,
carbon group~; when part of another sub6tituant, e.g. as
in cycloakylalkyl, or heteroaralkyl or aralkenyl, the
alkyl, alkenyl and alkynyl group preferably contain6 1-6,
most preferably 1-4, oarbon atoms.
(b) "hateroaryl" include6 mono-, bi- and polycyclic
aromatic heteroayclia group~ aontaining 1-4 0, N or S
atoms; preferred ara 5- or 6-membered heterocyclic rings
such as thienyl, furyl, thladiazolyl, oxadiazolyl,
triazolyl, l~othiazolyl, thiazolyl, imidazolyl,
35 isoxazolyl, tatrazolyl, oxazolyl, pyridyl, pyrazinyl,
~, ' ', ,
.
~73~
_ - 20 -
pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, etc.
~c) "heterooyc~yl" includes mono-, bi and
polycyclir saturated or un~aturated non-a~romatic
heterocyclic groups co~taining 1-4 O, N or ~ atoms;
preferred are 5- or 6-membered heterocyclic rings euch as
morpholinyl, piperazinyl, piperidyl, pyrazolinyl,
pyrazolidinyl, imidazolidinyl, pyrrolinyl, pyrrolidlnyl,
~c .
(d) "halo" inaludes chloro, ~romo, fluoro and iodo
and i~ preferably chloro, fluoro or bromo.
The term "conventional readily removable carboxyl
protecting group" refer~ to a known ester group which has
been employed to block a aarboxyl group during the
chemical reaction step6 described below and which can be
removed, if desired, by methods whiah do not result in any
appreciable destruction of the rema$ning portion of the
molecule, e.g. by ch~mical or enzymatic hy~roly6i~,
treatment with chemical reducing agents under mild
conditions, irradiation with ultraviolet light or
catalytic hydrogenation. Examples of such ester
proteating groups include benzhydryl, allyl, p-
nitrobenzyl, 2-naphthylmethyl, benzyl, trichloroethyl,
~ilyl 6uch a8 trimethylsilyl, phenacyl, p-methoxyben~yl,
aoetonyl, o-nitrobenzyl, 4-pyridylmethyl and C1-C6 alkyl
6uch as methyl, ethyl or t-butyl. Includad within such
protecting gxoupR are those whi¢h are hydrolyzed under
physio1ogical condition6 such as pivaloyloxymethyl,
acetoxymethyl, phthalidyl, indanyl and methoxymethyl. A
particularly advantageous carboxy protecting group is p-
nitroben~yl whioh may be readlly removed by catalytic
hydrogenoly6iæ.
The pharmaceutically acceptable salt~ referred to
above include the nontoxic acid addltion 6alt6, e.g. æalt6
with mineral acids such as hydrochloric, hydrobromlc,
hydroiodic, phosphoric, ~ulfuric, etc. and salts with
~1~,, jl
2l -
organic acids sueh a maleic, acetic~ citric, ~uccinic,
benzoic, tartaric, fumaric, mandelic, a~corbic, laetic,
gluconic and malic. Compound~ of fvrmula I in the ~orm
of acid addition salts may be wrltten a~
R~5
~DDE~2 --3~ xe
R2 = H or protecting group
where X ~ repre~ents the acid anion. The eounter anion
may be eelected 80 as to provide pharmaceutically
acoeptable salt6 for therapeutic admini~tration but, in
the case of intermediate compounds of formula I, X may
alco be a toxic anion. In ~uch a case the ion can be
subsequently removed or substituted by a pharmaceutically
acceptable anion to form an active end product ~or
therapeutic u~e. Whan acidic or ba~ic groups are pre~ent
in the R1 or ~5 group or on the
~ N -
radical, the present lnvention may al~o include ~ultable
~ase or acid saltg o~ the~e functi.onal groups, e.g. acid
addltion ~alts in the ca~e of a ba6ic group and metal
aalts (e.g. aod$um, potas~ium, calcium and aluminum), the
ammonium ~alt and salt~ with nontoxi¢ amine~ (e.g.
trialkylamlne~, proeaine, dibenzylamine, 1-ephenamine, N-
- benzyl-B-phenethylamine, N,N~-dlbenzylethylenediamine,
etc.) in the ca6e of an acidic group.
Compound6 of formula I wherein R~ is hydrogen, an
anionic eharg~ o.r a physiolugi~ally hydrolyzable eiter
group together with pharmaeeutically aeceptabls ~alts
ther00f are ueeful as antibaeterial agents. The remaining
S compounds of formula I are valuable intermediate~ which
can be converted into the above-mentioned biologieally
active eompounds.
A preferred embodiment of the present invention
comprises compound~ of foxmula I wherein R8 is hydrogen
and R1 is hydrogen, CH3CH2-
CH3 ~ OH
~CH- ~C- 3
CH3~ CH3f~
Among this subcla~s, the preferred oompounds are those in
whieh R1 is
OH
C 3C ~ most preferably compounds having
the absolute configuration 5R, 6S, 8R.
Another preferred embodiment eomprises oompounds of
formula I in whieh R1 and R8 taken together ~orm an
alkylidene radical of the formula
HOCH2
--C3
CH3 /
~he alkylene ti.e. substituent "A") radical in the
eompound~ of formula I may be ~traight or branehed ehain
and may eon~ain from 1 to 6 earbon atoms. A preferred
smbodiment oompriie those eompounds in whiçh A is
-(CH2)-n in whieh n is 1 or 2 and a partieularly preferred
embodiment eomprises tho~e oompounds where A is -CH2-.
~7~
-- 23
The alkylene moiety ~A~ i8 attac:hed via a rinç
carborl atom to an N-substituted quaternized aromatic
heterocycle OI the general formula
f ~N~3 R 5
wherein the RS su~stituent i~ preferably an optionally
substituted C1-C6 alkyl, C2-C1o alke~yl, C2-C10 alXynyl,
C3-C6 cycloalkyl, C3-C6 cycloalkyl-C1-C6 alkyl, phenyl,
ph~nyl-Cl-C6 alkyl, phenyl-C2-C6 alkenyl, phenyl-C~-C~;
alkynyl, heteroaryl, heteroaralkyl in which the alkyl
moiety has 1-6 carbon atom~, heterocyalyl or
heterocyclylalkyl ln which tha alkyl molety has 1-6 carbon
atoms. The heteroaryl (or heteroaryl portion of
heteroaralkyl ) R5 substituent may be a mono-, bi- or
polycycl.ic aromatic heterocyclio group containing 1-4 O, N
or S atoms; preferred are 5- or 6-membered heterocyclic
ri ngs s uch as thi enyl, f uryl, thi adi az ol yl, oxadi az ol yl,
triazolyl, isothiazolyl, thiazolyl, imidazolyl,
isoxazolyl, tetrazolyl, oxazolyl, pyridyl, pyrazinyl,
pyrimidir~yl, pyridazinyl, pyrrolyl and pyrazolyl. The
heterocyclyl (or heterocyclyl portion o~
heterocyclylalkyl ) R5
.~...~
. ~,
-- 24 --
substituent may be a mono-, bi- or p~lycyclic sa~rate~ ~
unsatur2,ed non-aromatic heterocyclic group containin~ 1-4 O,
N or S atoms; preferred are 5- ~r 6-membered heterocycl-c rings
such zs morpholinyl, piperazinyl, piperidyl, pyrazolinyl,
py~ azolidinyl, imid2zolinvl, imid2zoli~inyl, pyrrolir~yl and
pyrroli diny 1.
The R substi.uent may-be option211y subs,ituted by 1-3
subs.ituents independently selected fr~m:
(a) Cl-C6 alkyl optionally ~ubstituted by, preferably 1-3,
am~no, f luoro, chloro, carboxyl, hydroxy or carbamoyl
groups;
(b) fluoro, chloro or bromo;
( c) -OR
(d) -OC02R
(e) -OCOR
(f) -OCONR R
(g) o
-OS-R9;
o
(h) -oxo
( i ) - NR R
(i ) R3CoNR4_
(k) ~-NR3Co2R
(1) NR3CoNR3R
(rn) O
-NR3S-R9;
o
(n) -SR3;
(o) -SOR
(p) O
-S-R
o
(q) -S03R
(r) CO2R
( s ) - CoNR3R4
(t) -CN ; or
-- 25 --
(u) phenyl optior,ally substituted by 1-3 substituents in-
dependently selected ~rom fluor~, chloro, br~no, Cl-C6
alkyl, ~oR3, NR3R4, -So3R3, --C:02R3 c:r -CONR R, wher~in,
rela~ive ~o the abo~e-na~ned ~5 s~sti~uents, the groups
R3 and ~4 are irldependently selected from hydrogen; al~yl,
æOcenyl and æl~cy~yl~ ha~ing- 1-10 carboa~ atQ~s, cyclo~
alkyl, cyc:loal~cyl~lXyl ~nd alkylcy~loal~l ~ ~2~iag
3-6 carbon a~ms ~ cy~loal)cyl ring ~nd 1~6 ezr~oa
a~ n ~he alkyl moiPtie~; phes~yl; ær~lkyl, arzlXenyl
2nd 2ra~c~nyl ~herein the ~ryl m~iety is phes~yl ~ad ~e
alip~atic por,ion h~s 1-6 carbD~ atoms; 2nd heter~zryl,
heteroaral);yl, he,erocyclyl ænd ~eterocyclyl~ yl wherein
~,hD heter~zryl ~a~d heterocyclyl group cr p~ o~ o:E a
sroup is as ~e~ine~ 2bo~Je :Eor ~ ~e zlkyl ~oieties
~ssociated wit~ said hetert~cyclic 3~0ieties h2~e ~-6
- ca~bon ato;ns; or :~3 al~d R4 tzke~ ~oget~er with ~he ~itroges:
t~ which zt l~ast o2~e i5 at~ ~ched mzy fo~ a 5- or '
6-mem~ered nit~ges~-containing heterocy~lic (2S t3e~ ea
2bo~re for ~5~ ing,o' a~a R9 is æs de~ined 2bo~e ~or R3
excep.. th~.' it ~ay ~t ~e hydroges~ A mc~s' pre'e-2e~
su~s'ituen is C~ 6 al~cyl~ espec~ally methyl.
In addition, the R substituent, together with. anot~er
Xilag 2t:0m C~ the ~
moie~y, may form a ~use~ heterocyclic or heteroz:romatic ri~g,
whioh ring may contain additional, preferably 1 or 2, hetero
ato~ns selected ~rom O, N and S. ~or exampie,
CN~ ~S may be ~
~1 or ~?
! "
3~
- 26 -
The group
preferably represents a substituted or unsubstituted mono-, bi-
ox polycyclic aromatic heterocycle containing at least one
nitrogen in the ring and 0-5 additional ring hetero atoms selected
~rom 0, S and N, said heterocyclic ring being attached to A
through a ring carbon atom and ha~ing a ring nitrogen atom
~uaternized by the group R5.
The heteroaromatic
/~\ ~
~ N-
ring may be optionally substituted at available ring carbon
atoms by preferably 1-5, most pre~erably 1-3, substituents in-
dependently selected from the group consisting of Cl-C4 alkyl;
Cl-C4 alkyl substituted by, pre~erably 1-3, hydroxy, amino,
C1-C4 alkylamino, di(C1-C4)alkylamino, Cl-C4 alkoxy, carboxy,
halo (hereinafter intended to mean chloro, bromo, fluoro or iodo;
preferably chloro, bromo or ~luoro) or sulfo; C3-C6 cycloalkyi;
C3-C6 cycloalkyl(Cl-C4)alkyl optionally substituted by 1-3
substituents mentioned above in connection with Cl-C4 alkyl;
Cl-C4 alkoxy; Cl-C4 alkylthio; amino; Cl-C4 alkylamino;
di(Cl-C4)alkylamino; halo; Cl-C4 alka.poylamino; Cl-C4 alkanoyloxy;
carboxy; sulfo; O
-C-O-Cl-C4 alkyl;
hydroxy; amidino; guanidino; phenyl; phenyl substituted by 1-3
substituents independently selected from amino, halo, hydroxy,
trifluoromethyl, Cl-C4 alkyl, Cl-C4 alkoxy, Cl-C4 alkylamino,
di(C1-C4)alkylamino, carboxy and sulfo; phenyl(Cl-C4)-
alkyl in which the phenyl portion may be optionally
substituted by 1-3 substituents mentioned above in
connection w.ith phenyl and the alkyl portion may be
optionally substituted by 1-3 substituents mentioned above
in connection with Cl-C4 alkyl; and heteroaryl or hetero-
aralkyl in which the hetero atom or atoms are selected from
the group consisting of 1-4 O, S or ~ atoms and the alkyl moiety
3~
- 27 -
associated with heteroaralkyl has 1-6 carbon atoms, said
heteroaryl and heteroaralkyl groups being optionally substituted
in the heterocyclic ring moiety by 1-3 substituents independe~tly
selected from hydroxy, amino, halo, trifluoromethyl, Cl-C4 alkyl,
Cl-C4 alkoxy, Cl-C4 alkylamino, di(Cl-C4)aIkylamino, carboxy and
sul~o and in the alkyl moiety by 1-3 substituents selected Lrom
hydroxy, amino, Cl-C4 alkyl2mino, di(Cl-C4)alkylamino, Cl-C4
alkoxy, carboxy, halo and sulfo. In addition, available ring
nitrogen atoms (other than the ~uaternized nitrogen) may be
substituted by 1-3 substituents independently selected from the
group consisting o~ Cl-C4 alkyl; Cl-C4 alkyl substituted by,
pre~erably 1-3, hydroxy, amlno, Cl-C4 alkylamino, di(Cl-C4)-
alkyl2mino, Cl-C4 alkox~r, carboxy, halo or sulfo groups;
C3-C6 cycloalkyl; C3-C6 cycloalkyl(Cl-C4)alkyl
optionally substituted by 1-3 substituents mentioned
above in connection with Cl-C4 alkyl; phenyl; phenyl
substituted by 1-3 substituents independently selected from
amino, halo, hydroxy, trifluoromethyl, Cl-C4 alkyl, Cl-C4 alkoxy,
Cl-C4 alkylzmino, di(Cl-C4)zlkylzmino, carboxy and sulfo;
phenyl(Cl-C4)alkyl in which the phenyl port.ion may be optionally
substituted by 1-3 substituents mentioned above in connection with
phenyl and the alkyl portion may be optionally substituted by
1-3 substituents mentioned above in connection with Cl-C4 alkyl;
znd heteroaryl or heteroaralkyl in which the hetero atom ox
atoms are selected from the group consisting of 1-4 O, S or N
atoms and the alkyl moiety associated with heteroaralkyl has
1-6 carbon atoms, said heteroaryl and heteroaralkyl groups being
optionally substituted in the heterocyclic ring moiety by 1-3
substituents independently selected from hydroxy, 2mino, halo,
trifluoromethyl, Cl-C4 alkyl, Cl-C4 alkoxy, Cl-C4 alkylamino,
di(Cl-C4)alkylamino, carboxy and sulfo and in the alkyl moi.ety
by 1-3 substituents selected from hydroxy, zmino, Cl-C~ alkyl2mino,
di(Cl-C~)alkylamino, Cl-C4 alkoxy, carboxy, halo ~d sulfo The
most pre erred ring carbon and nitrogen substituents are Cl-C6 alkyl,
especizlly methyl.
~73
28
Within t~e aboYe descri~e~ preferred em~t~dimesltl the
prefer~e~ coanpoun~s are those in w~ich ~ ~s - tC~I2) n in which
n is 1 or 2, most prefera~ly. ~hose in which ~ is -Ç~2~ and
wherein ~a) R~ d R~ ~aken ~ogether xepreseslt
t~2~
C
C~3
or (b~ R i5 hydrogen and R repres ~t5 hydxogen, C~3OEI2-J
c~3~ 3~ IOE~ 0
C~ ~ . C- . , or C~3C~-
. 3 C~3
Par~ ul~ly 3?referre~ are the co~po~mds wherei~ Rc8 ishy d:~ogen and }~ is
7~
C~13C~I-, especially compoun~ls
ha~ing the a~solute configuratio~ SR, 6S, 8:R.
In a pref2rred e~odiment the group
~ .
_ _
represents an a~omatic ~- or 6- membered, N-cont~ining hete-o-
cyclic ring r~ntaining 0~3 additional hetero atoms selected ~rom
0, S or N. Such aromatic heterocycle may, where possible, ~e
fused to another ring which.mz~ be a saturated or unsaturated
carbocycli ~ ng, pref~rably C,l-C7 carb~cyclic ri~g, zn aromatic
car~ocyelic rins~ preferably a phenyl ring, a 4-7 mesr~ered hetero~
cyclic xing ( sa~urated or unsaturate~) cont2ining 1-3 ~e~ero a'oms
selected fro~n 0, S, ~ or NRll in which Rll is hydr~gerl, Cl-C6 al~yl
op~ionzlly substituted ~y 3-2 substituents in~ependently selected
ro~n 0~3, -NR3R4, -Co2R3, ~xt~, phenyl, f~uoro, chloro, bromo,
~3~0
- 29 -
-503R3 and -C~R3R4, or phenyl optionally substitut~d by 1-3
substituents independently selected from Cl-C6 alkyl, -~R3,
-NR3R4, ~lu~ro, chloro, brom~, -So3R3, -Co~R3 and -CoNR3R4/
wherein R3 and R4 in such Rll substituents are 2S ~efined above
in connection ~i~h substituent R , or a 5-6 membered hëLer~-
zrom2,ic ring containing 1-3 heter~ atoms selected ~rom 0, S,
N or N~ll in which Rll is as defined ~bo~e. The 5- or 6- membered
2romatic quaternized ring or, where apprDpri~te, the c2rbocyclic,
heterocyclic or heteroaromatic r~ng ~used thereto, or bo~h such
rings, m2y be optionally substituted on 2vail2ble ring
2t~ms by, pre er~ly up to a tot21 of five sub~ti.uents ~r
the tot~l ring system, ,he substituents me~tioned above in
connection with the group
N
~ iithin ,he a~o~re-descxibed pre~erred embodiment, Lhe
preTerred compounds are those in which A is -(CH2)~ in which
n is 1 or 2, most preferably those in which ~ is -C~2- and
wherein (a) Rl and R8 taken together represent
HOC~I2
\
CH f'
or (b) R8 is hydrogen and Rl represents hydro~en, CH3C~2-,
CH3~ 3\P P
CH- , C- , or CH3CH-
C~3 C~3
?~rticul~rly preferred zre the oompounds wherein R is hydrogen
2~d Rl is
~H
CH3CH-, especially compounds having the 2bsolute
co~iguration 5R, 6S, 8Ro
, .
~v~
- 30 -
- Still another~preferred el~odiment of the present invention
comprises compounds o~ formula I wherein
N - R
represen,s a radical selected from the group consisting of
~a) ~ ~
¦ ~ R
~<
~ 10
wherein R6, R7 and R10 are independently selected ~rom hydrog~n ;
Cl-C4 zlkyl; Cl-C4 alXyl substituted by, preferably 1-3, hydroxy,
Cl-C4 alkylamlnQ, di(Cl-C4 zlkyl~mino, Cl--C4 alkoxy, amino, sulfo,
carboxy or halo (chloxo, bromo, fluo~o or iodo; p_eferably chloro,
fluoro or bromo); C3-C6 cycloalkyl; Cl-C4 alkoxy; Cl-C4 alkylthio;
amino; Cl-C4 zlkylamino; di(Cl-C4 alkyl)amino; halo (chlor~,
bromo, fluoro or iodo; preferably chloro, fluoro or bromo); Cl-C4
2 Ikanoyl~mino; Cl-C4 alka~oyloxy; czrboxy;
O
-C-OCl-C4 alkyl; hydroxy; amidino; guanidino; phenyl; phenyl
substituted by one, two or three amino, halo (chloro, bromo,
fluoro or iodo; preferably chloro, fluoro or bromo), hydroxyl,
trifluorome.thyl, Cl-C4 alkyl or Cl-C4 alkoxy sroups;
phenyl (Cl-C~)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connectlon with phenyl and the alkyl portion
may be optionally substituted by 1-3 substituents mentioned
above ln connectlon with Cl-C4 alkyl:; and heteroaryl
and heteroa~alkyl in which the hetero atom or atoms.in the above-
named heterocyclic moieties are selected from the g~oup consis~ing
of 1-4 oxygen, nitrogen or sulfur atoms and the alkyl moiety
associ~te~ Wit}l said heteroarzlkyl moiety has 1-6 carbon atoms;
or where.n two of R6, R7 or Rl taXen together may be a fused
saturzted carbocyclîc ring, a fused aroma,ic carbocyclic r~ng,
2 fused non-aromatic heterocyclic ring or a ~used heteroaromatic
ring, said fused rin~s being optiona~ly substituted by 1 ~r 2 of
.he substituents defined above for R6, R7 ~nd R10;
~ ~73~
- 31 -
~/ ~ o~
el
~ N 3 ~
o~ionally substituted on'a caTbon atom by one to three subw
stitu~nts inâependently selected from Cl-C4 .zlkyl, Cl-C4
alkyl substituted by, preferzbly 1-3 t hydroxy, Cl.-C4 zlkylamino,
sulfo, di(Cl-C4 alkyl)amino, Cl-C4 alkoxy, amino, carboxy or halo
(chloro, bromo, ~luoro or iodo; preferably chloro, luoro or
bromo); C3~C6 cyclozl~l; Cl-C4 alkoxy; Cl-C4 alkylthi~; amino;
Cl-C4 alkyl~mlno; di(Cl-C4 zlkyl)amino; halo'(chloro, b~omo,
fluoro or iodo; preferably chloro, fluoro or bromo); Cl-C4
alX2noyl~mino; Cl-C4 alkanoyl~xy; carboxy;
O
-C~OCl-C4 alkyl; hydroxy; amidi~o; yuanidino; ph~nyl; phenyl
s~jstituted by o~e, two or three amino, halo (chloro, bromo,
fluoro or iodo; prelerably chloro, fluoro or bromo), hydroxyl,
trifluoromethyl, Cl-C4 alkyl or Cl-C4 alkoxy groups~,
phenyl (Cl-C4)alkyl in which the phenyl portion may be
optionally substituted by 1-3 substituents mentioned
above in connection with phenyl and the alkyl portion
may be optionally substituted by 1-3 substituents mentioned
above in connection with Cl~C4 alkyl:;.and heteroaryl
or heteroaralkyl in which the hetero atom or a~oms in the
above-named heterocyclic moieties are selected ~rom the group
consisting of 1-4 oxygen, nitrogen or sul~ur ztoms znd the zlkyl
moiety associ2ted with said heteroaralkyl moiety hzs 1-6 carbon
atoms, or optionaily s~bstitutea so zs tc ~orm a fused carbo-
cyclic, heterocyclic or he't'eroaromat'ic ring optionally substitute
by 1 or 2 of the substi,uents ~efined above;
;. .
.. ~
~73
_ 32 --
R5 R5 ~5
~1 el el
(c~ N~ ~ N~ N ~N~
.,~N ,
R~ - ~5
optionally substituted on a c~rboA ato;~ by one ox t:wo su~sti-
tuents independently selected from Cl-C,L alXyl; Cl-C4 al3cyl
su}s~itute~ by, prefes~bly 1-3, hydroxy, Cl-C,a Plkyl~m;no, sul~o,
di-tCl-C4 alkyl)amiAo, Cl-C4 alkoxy, ~smino, carboxy 9r halo
(chloro, ~romo, fluoro or iodo; prefe2a:tly chlo~Q, lu~ro or
br~mo); C3-C6 cycloa:L3cyl; Cl-C4 a3~ xy; Cl-C4 z-lkylthio; a~rlo;
Cl-C4 a~cyla~no; di (Cl-C4 alXyl) ~no; h210 (chloro, bromo,
~luoro or iodo; preferably chloro, fluoro or brom~); Cl-C4
lXznoylzmi~o; Cl-C~a 21kanoyloxy; car~oxy;
o
-C-OCl-C4 ~lkyl; hydro~y; amidino; guznidino, phenyl; phenyl
su~stituted by one, two or three ~no, halo ~hïoro"~romo,
fluoro or iodo; pre~ers}:~ly chloror ~luoro or bromo~, hydroxyl,
trifluoromethyl, C:l-C4 alkyl or Cl- C4 alkt:xy groups;
phenyl ~Cl-C4)alkyl i~ whi~ the phenyl portion may be
optionally substituted ~y 1-3 su~stituents mentioned
7~bo~e in conne~tion with phenyl and the alkyl portion
may be optionally substituted by 1~3 substituents ~nentioned
abo~e in connectioal with CloC4 alkyl; and heteroaryl
or ~eteroaralXyl in whi~h th~ he~ero atom or atoms
in the abo~re-na~ned heterocycli~ m~ieties are selected ~rom the
group consisting o~ 1-4 oxy~en, r~itrogen cr sulfur atoms and
the alkyl moie~y asst~cia~ed with said hetexoaralkyl moie~y has
1-6 carbon atoms, or optionally subs~i~uted so 25 t~ fo:r;n a fused
carbocyclic, heterocyclic or he~cero2rom2tic ring op~i~nally
subs~i~u~ed ~y 1 ~r 2 of the subs~ituen,s defined aboYe;
.. . ~ .
3L~7;3~
~ ~'N ~ ~N
N~ ~ ~N
.S ~,5
or
N~ ~ N,~ ~
op'ionally substituted o~ a czrbor~ ~tom ~ a substituerlt
independently selected ~so~n Cl;-C~ 21kyl;~ t:4 a:!ky.l su3:~stit~a~ed
~y, preferably 1---3,..hydroxy~ C1-~4 ~lXylamino, di(Cl-C4 aL~cyl)-
a~nin~, sulfo, Cl-C4 a~koxy, a~oino, carbo~ or halo (chloro, bromo,
~luo~o or iodo; prefer2~ly chloro, 'luoro or ~omo~; C~ C6
c5~:1021kyl; Cl-C4 alkoxy; Cl-C4 alkylthio; 2mino; C~-C4 alkyl-
ami~o; di (Cl-C4 alkyl) amino; halo (chloro, ~romo, ~luoro or
iodo; prefera}~ly chloro, ~luoro or bromo); Cl-C4 zlkanoylzmino;
Cl-C4 alka~oyloxy; carboxy;
n
-C-OCl-C,~ zl~rl, hydro~y; amidino; gu2nidino., phenyl; phenyl
s~stitu~ed by on~,~two or three ~nino, halo (chl~so, bromo,
fluoro or iodo; preferably chloso, ~luoro or bromo), hydroxyl,
xome~chy~ C4 al)cyl or ~ 1-C4 2~C0~y groupS
phenyl t~l-C4)~1kYl in which t~e phenyl portion may 3~e
optionally substi~uted by 1-3 sub~titu~nts mentioned
above in connection with phenyl and the ~lkyl poxtion
~ay be sptionally su}:stituted by 1-3 su}:sti~uents mentioned
a~ove in connection wi~h Cl-C4 alkyl: and het~roaryl
or heteroaxallcyl in which the het~ro atom or atoms
in . the 2bo~e-named heterocyclic moiet~es are selec~ed from tha
yroup eonsisting of 1-4 oxygen, nitrogen or sulfur atoms and
the alkyl moiety 2ssociated with said hete:roaral'cyl moiety has
1-6 car~on atoms;
'~3 . ,
~7~
- 34 -
~ ~ 5
(e) r~=~=~-R5 ~ R
_ _ ~ or - ~ X ~
wherein X is 0, S or NR in which R is Cl-C~ alkyl; Cl-C4 alkyl
substituted by 1-3 hydroxy, amino, Cl-C4 alkylamino, di(Cl-C4)-
alkylamino, Cl-C9 alko~y, carboxy, halo or sulfo groups;
C3-C6 cycloalkyl; C3-C6 cycloalkyl(Cl-C4)alkyl
optionally substituted by 1-3 substituents mentioned
above in connection with Cl-C4 alkyl; phenyl; phenyl
substituted by 1-3 substituents independently selected from
amino, halo, hydroxy, trifluoromethyl, Cl-C4 alkyl, Cl-C4 alkoxy,
Cl-C4 alkylamino, di(Cl-C4)alkylamino, carboxy and sul~o;
phenyl(Cl-C4)alkyl in which the phenyl portion may be optionally
substituted by 1-3 substituents mentioned above in connection
with phenyl and the alkyl portion may be optionally subs~ituted
by 1-3 substituents mentioned above in connection with Cl-C4 alkyl;
and heteroaryl and heteroaralkyl in which the hetero atom or atoms
are selected from the group consisting of 1-4 O, S or N atoms and
the alkyl moiety associated with heteroaralkyl has 1-6 carbon
atoms, said heteroaryl and heteroaralkyl groups being optionally
substituted in the heterocyclic ring moiety by 1-3 substituents
independently selected from hydroxy, zmino, halo, txifluoromethyl,
Cl-C4 alkyl, Cl-C4 alkoxy, Cl-C4 alkylamino, di~Cl-C4)alkylamino,
carboxy and sulfo and in the alkyl moiety by 1-3 substituents
selected from hydroxy, amino, Cl-C4 alkylamino, di~Cl-C4)alkylamlno,
Cl-C4 alkoxy, carboxy, halo and sulfo; said heteroaromatic radical
being optionally substituted on a caxbon atom by one or more
substituents independently selected from Cl-C4 alkyl; Cl~Cq alkyl
substituted by, preferably 1-3, hydroxy, amino, Cl-C4 alkylamino,
di(C1-C4 alkyl)amino, Cl-C4 alkoxy, sulfo, carboxy or halo
(chloro, bromo, fluoro or iodo; preferably chloro, fluoxo or bromo);
C3-C6 cycloalkyl; Cl-C4 alkoxy; Cl~C4 alkylthio; amino; C1--C4
alkylaminc; di(cl-c4 alkyl)amino; halo (chloro, bromo, fluoro or
iodo; preferably chloro, fluoro or broino~; Cl-C4 alXanoylami~o;
Cl-C4 alkanoyloxy; carboxy; O
-C-OCl-C4 alkyl; hydroxy; 2midino;
~3~
- 35 -
guanidino; phenyl; phenyl substituted by one, two or thrse
amino, halo (chloro, bromo, fluoro or iodo; preferably
chloro, fluoro or bromo), hydroxyl, trifluoromethyl, C1-C4
alkyl or C1-C4 alkoxy groups; phenyl (C1~C4) alkyl in
which the phenyl port~o~ may be optionally ~ub~titut~d by
1-3 substituent6 mentioned above in ~onnection with phenyl
and the alkyl portion may be optionally ~ubstituted by 1-3
substituents mentioned above tn connectlon with C1-C~
alkyl; and heteroaryl or heteroaralkyl in which the hetero
atom or atoms in th~ above-~amed heterocyclic moieties are
selected from the group consisting of 1-4 oxygen, nltrogen
or sulfur atoms and the alkyl moi~ty as60ciated with 6aid
heteroaralkyl moiety has 1-6 carbon atoms, or optionally
substltuted so as to form a fu6ed carbocyclic,
hetero~yclic or heteroaromatic ring optionally ~ubstituted
by 1 or 2 of the 6ubstituents deflned above;
R5
R5~ x
~ 5
- -N-R N ~ N-R
or ~ J
.J
o~v
- 36 -
wherein X i8 O, S or NR in which R is C1-C4 alkyl; C1-C4
alkyl 6ubstituted by 1-3 hydroxy, amino, C1-C4 alkylamino,
di(C1-C4)-alkylamino, C1-C4 alkoxy, carboxy, halo or sulfo
groups; C3-C6 cycl~alkyl; C3-C6 cycloalkyl (C1-C4)alkyl
optionally substituted by 1-3 6ubstituents mentioned a~ove
in connection with C1-C4 alkyl; phenyl; phenyl ~ubstituted
by 1-3 substituents independently selected from amino,
halo, hydroxy, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy,
C1-C4 alkylamino, di(C1-C4) alkylamino, carboxy and sulfo;
phenyl (C1-C4) alkyl in which the phenyl portion may be
optionally B ubstituted by 1-3 6 ubstituent~ mentioned above
in connectlon with phenyl and the alkyl portion may be
optionally ~ubstituted by 1-3 substituents mentioned above
in connection with C1-C4 alkyl; and heteroaryl and
heteroaralkyl in which the hetero atom or atoms are
~elected from the group consisting of 1-4 0, S or ~ atoms
and the alkyl moiety a~sociated with heteroaralkyl has 1-6
carbon atoms, said heteroaryl and heteroaralkyl groups
being optionslly subst~tuted in the heterocyclic ring
moiety by 1-3 ~ub~tituents independently 6elected from
hydroxy, amino, halo, trifluoromethyl, C1-C4 alkyl, C1-C4
alkoxy, C1-C4 alkylamino, di(C1-C4) alkylamino, carboxy
and sulfo and in the alkyl .moiety by 1-3 substituents
seleGtod from hydroxy, amino, C1-C4 alkylamino, di(C1-C4)
alkylamino, C1-C4 alkoxy, carboxy, halo and 6 ul fo; 8 aid
heteroaromatic radical being optionally ~ubstituted on a
carbon atom by a substituent selected from Cl-C4 alkyl;
C1-C4 alkyl ~ubstituted by, preferably 1-3, hydroxy,
amino; C1-C4 alkylamino, di(C1-C4 alkyl)amino, C1-C4
alkoxy, 6ulfo, carboxy or halo (chloro, bromo, fluoro or
iodo; preferably chloro, fluoro or bromo); C3-C6
cycloalkyl; C1-C4 alkoxy; C1-C4 alkylthio; amino; C1-C4
alkylamino; d-(C1-C4 alkyl)amino; halo (chloro, bromo,
fluoro or iodo; preferably chloro, fluoro or bromo); C1-C4
alkanoylamino; Cl-C4 alkanoyloxy; carboxy;
D
~7~01.0
- 36a -
-C-OCl-C4 alkyl; hydroxy; amidino;
guanidino; phenyl; phenyl substituted by one, two or three
amino, halo (chloro, brom, fluoro or iodo; preferably
chloro, fluoro or bromo), hydroxyl, trifluoromethyl, C1-C~
alkyl or C1-C4 alkoxy groups; phenyl (C1-C4)alkyl in which
the phenyl portion may be optionally substituted by 1-3
substltuents mentioned above in sonnection with phenyl
and the alkyl portion may be optionally substituted by 1-
3 substituents mentioned above in connection with C1-C4
alkyl; and heteroaryl or heteroaralkyl in which the hetero
atom or atoms in the above-~ame heterocyclic moieties are
selected from the group aonsisting of 1-4 oxygen, nitrogen
or sulfur atoms and the alkyl moiety associated with said
heteroaralkyl moiety has 1-6 carbon atom~; and
.,
:.
37
!55 ~9 '
~g7 N~ R R --N t~ N~N
R ~ R
~- N-R ~--N ~2
S ~ r 5
N ~;N ~ ~ N
;,
wherein ~ is Cl-C~ cyl; CL-C,~L alXyl su~stituted by 1-3
hydroxy, ~no~ Cl-C,~ aL~cyl2~i~0, di (Cl-C4~ ~Lkylamino,
t l-C4 alXoxy~ c~xbo~y, halo or ~ulfo gr~ups; C3 C6 cyclo-
Y ; ~3 ~6 cycloa~cyl (Cl-C4) a:Ucyl
optionally substituted by 1-3 substituents mentioned
~ ov~ ia con~ection with Cl-C4 alkyl; phenyl; phenyl
su~stituted ~y 1-3 s~st~tue~ts isldepeslde~tly ~ele~tea fro~
~ai~o, ~alv, hy~roxy, 'csi..luoromet~yl, Cl-C4 al~cyl, CiC4 a~oxy,
Cl-C4 21ky~1!!mi~0~ ~i (Cl~C4) ?l~CylCnO~ car3~oxy ~d sulfo;
henyl(Cl-C~)~lXyl i~ which the phenyl portion ~n2y be optio~Ally
su~stituted by 1-3 su!~stituents me~tio~e~ e i~ cc~nection
wit~ p~enyl ~ the alkyl portion m~y b~ optionzlly sul:stituted
~y 1-3 substituents me3~tione~ a~ov~ ~n connection w~t~ CiC4 ~
~nd heteroaryi ~nd hetero~raikyi ial which the hetero atom os atoms
ær~ selected fx~m th~ group c~nsisting o~ 1-4 0, S or N ato~ns ~d
~he &lXyl m~iety ~ssodatea wit~ heteroaral3cyl has 1-6 carbo~
at~ms, s~i~ heteroa~yl 2n~ h~e:roar~lkyl grou3?s ~e~ng optios~lly
s~st~tuted in the heteroeyc~ic riDg mo~et~ by 1~ 3 s~stitues~ts
indepe~dent~y ~el~ct~d frosn hydro~, an~no, ~210~ t~ luorome~chyl,
Cl-C4 ~Xyl, C iC~Ç~ alko:t~y, CiC,~ al3cylamino, di~Cl-C4)~1Xyla~o,
c2r~0~ d sul~o zn~!l ia the . lXyl ~oiety by 1-3 su3~stituentS
seleete~ ~rom ~ydro~, 2~n~ C~ 4 ~ky~ 9~ 4)alkY
Cl-C4 2lkcxyo.. ~ oxy, ~lo a~d sulfo. The R and R5 groups m2y
: .. ' ' . '
~" .
.
. ~ ., .
,:
-:,
3~
- 38 -
also be taken together to orm a fused heterocyclic or
heteroaromatic ring.
Within the abcve-described preferred embodiment, the
preerred compounds are those in which A is -(CH2)n in which
n is 1 or 2, most preferably tho~e in which A is -CH2- and
wherein (a) Rl and R8 taken together represent
HOCH2~
/ C=
c~3
or (b) R8 is hydrogen and Rl represents hydrogen, C~3C~2-,
~ C~- , 3 ~¦ ~ or C~3C~-
c~3 C~3
Particul2rly preferred are the compounds wherein R~ is
hydrogen znd Rl is
(~3
CH3CH-, espe~ially compounds hzving the
zbsolute configuration 5R, 6S, ~R.
~ particularly preferred embodiment of the present
invention comprises compo~nds of formula I wherein
~ R
~J
represents a radical of the formula
RlD'
~herein R6, R7 and R10 are independently selected f~om the
grou~ consisting cf hydrogen, Cl-C~ ~lXyl, Cl C4 alkoxy,
carbo~yl and carbamoyl and R is 2S deined above, and is
preferzbly Cl-C6 alkyl, most pre.erzbly -CH3.
7~
- 39 -
Wi~hi~ the above-described pre~erred embodiment, the
preferred compounds are those in which A is -(CH2)nr in whioh
n is 1 or 2, most preferably those in which A is -CH2- and
~herein (a) Rl and R8 ~a~en t~gether represent
H C~C~i 2
or (b) R8 is hydrogen and Rl represents hydroge~, C~3C~2-,
CH3~.
~ ",C- , ~r CX3
c~3 c~3
Pzrticul2rly preferred are the compounds wherein R8 is
hydrogen and Rl is
10~
C~3CH-, especially compounds having
.he zbsolute configuration 5R, 6S, 8R.
Another preferred embodiment comprises compounds of
formulz I wherein
~ N-R5
represents a radical of the formula
R5 ~ 6
~ !J
~,
wherein R5 is Cl-C~ alkyl, most preferably methyl, and R6
represents hydrogen or Cl-C~ alkyl;
"' ~';
.,"'
.
. ,:~ ..,
~3~
- 40
R5
(b) ~I R6
N~_~
~ 7
where'n R5 is Cl-C~ alkyl, most preferably methyl and R6
and R are hydrogen or Cl-C4 alkyl;
( C) ~-R5
wherein R5 is Cl-C4 alkyl, most preferably methyl and R is
Cl-C4 alkyl or phenyl~Cl-C4)alkyl;
(d) ~
11 .
R5
wherein R5 is Cl--C4 alkyl, most preferably methyl and R6
is Cl-C~ alkyl, most preferably methyl;
R5
(e)
R
wherein R5 is Cl-C4 alkyl, most preferably methyl and R is
Cl-C~ alkyl, most preferably methyli ~r
~3~
- 41
(f) N
~S ,.~ N - R5
wherein R5 is Cl-C4 alkyl, most preferably methyl.
Within the above-described e~bodiment, the preferred
compounds are those in which A is -(CH2) n~ in which n is
1 or 2, most preferably those in which A is ~CH2- and wherein
(a) Rl and R8 taken together represent
HOCH~
C=
CH3/
or (b) R8 is hydrogen and Rl represents hydrogen, CH3CH~-,
CH~ 3 1 ~H
CH- , ~ C- , or CH3C~- .
CH3 CH3
Particularly preferred are the compounds wherein R8 is hydrogen
and Rl is
OH
CH3CH-, especially compounds having the absolute
configuration 5R, 6S, 8R.
A most preferred embodiment of the present invention
comprises compounds of fo.rmula I wherein
~ N-R
represents a radical of the formula
, ~.. :. ,. ~ , .
'"' '
.. , " ' .
. ,
-- 42 --
( a ) ~ N~CH 3 4
~\CH 3
C~ .
(c) ~3 ( d)~ 2 2OE13
CH3~ ICH3
( e ) ~/~3 ~ CH
~9 ~ 3 CH3 ~ ~ CH3
3 ( h ) ~N~ CH 3
C~ 3
I N
CH3 N~/
CH3
:~7;~
- 43 -
(k)
CH3
N . N
(m) ~ ~ ; or (n)
CH3
Within this above-described embodiment, the preferred compounds
are those in which A i5 -(CH2)n- in which n is 1 or 2, most
preferably those in which A is -(CH2)- and wherein (a) R and
R8 taken together represent
HOCH~
~C=
CH3
or (b) R8 is hydrogen and Rl represents hydrogen, CH3CH2-, .
CH~ CH~ OH ~H
CH- , ~ C- , or CH3CH-
CH3 CH3
Particularly preferred are the compounds wherein R is hydrogen
and R is OH
CH3~H-, especially compounds having the absolute
configuration 5R, 6S, 8R.
Specific prefer.red compounds of the present invention
are those of the formula
,, . .. ' .
. .... .. .
,,
- 44 -
0~
(R) ` ~ S -A ~ ~ R5
o oOR2
wherein R2 is hydrogen, an anionic charge or a con~entional
readily removable caxboxyl protecting group, providing that
when R2 is hydrogen or a protecting group, there is also
present a counter ion and wherein
- S ~ A ~ 0 R5 is
(a) -SCH2 ~ N - CH3
CH3
(C) -scH2 ~ SCE: l=~
\CH3
CH3
(e)~SCH2CH2 ~ (f) -SC~2 ~ / ~/ CH2CH2
~273~
CH3
\ ~ CH3
g -SCH2- ~ (h~ -SCH2 ~ ~ ~ H3
0NH3 C ~ ~, ~CH3
scH2~ 3 2 S ~ c~3
C~3
SCH2~\ 3 ~1) sCE~3 CH3
H3
Cl ~ 2
~m) -SCH2 ~ ~ ~n) -SCH
CH3 3
CH3
~ N/ ~ H ~ ~
wherein the lHMMR(D20) spectrum shows characteristic peaks
at ô: 1.23(3H, d, J=6.~ Hz), 3.12(2H, q, J=1.4, 8.9 Hz),
3.39(1H, q, J=2.7, 6.0 Hz), 9.07-~.68(10H, m), 8.19(1H, s);
(~ ) -SCH2~\~
N~ H~
CH3
wherein the lHNMR(D20) spectrum shG~s characteristic peaks
~t o: 1.23(3H, d, J=6.4 Hz), 3.15(2H, ~, J-3.7, 9.0 Hz),
3.37~1H, c, J=2.6, 6.0 Hz), 3.95-4.65(10H, m), 8.62(1H, s);
~5
: . . ,. :
:'
:' '
, .
3S)~
- 46 ~
/ OOe
2 ~ \ -SCH2 ~ 3
(t) CH3 (u) NH3
2 ~ /~ -SCH2 ~ ~ or
N - CH2COO N _ N
(v) fH3 CH3
~/ I
\~ N
~1
CH3
A most preferred embodiment o~ the present invention
comprises compounds of formula I wherein
6 5
~N--R
represents ICH3
~13
Within ~he above-described em~odiment, .the preferred
compounds are those in which A is -(CH2)n in which n is 1 or 2,
mos. pre erably those in which A is -CH2 and wherein (a) Rl and
R. taken together re~resent
H OCH 2 ~
or (b) R8 is hydrogen and Rl represents hydr~gen, CH3CH2~,
CH3~ 3 ~ ~ ~H
CH- , / C- , cr CH3CH- .
C:~ CH3
~ ~73~
- 47 -
Particularly preferred are the compounds wherein R8 is hydrogen
and Rl is 0~
CH31H-, especially compounds having the absolute con-
figuration 5R, 6S, 8R.
The pror_ess of the present invention utilizes the
interrnediate of the formula
~8 H R15
Rl ~ j ~ L
~ N ~ ooR2l
which has been disclosed, for example, in European Patent Appli-
cation 38,869 and European Patent Appl.ication 54,917 and which
may be prepared by the general methods described therein. L
represents a conventional leaving group (defined as "X" in
~uropezn Patent Application 38,869) such as chloro, bromo, iodo,
benzenesulfonyloxy, p-toluenesul~onyloxy, p-nitrobenzene-
sulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy,
diphenoxyphosphinyloxy or di(trichloroethoxy)phosphinyloxy . The
preferred leaving group is diphenoxyphosphinyloxy Intermediates
of Formula IV are generally formed in situ by reacting an
intermediate of the formula
R8 H R15
Rl ~ 2'
O COOR
ï~l
wherein R1, R8, R15 and R2 are as defined abo~e with a suitable
acylating agent R -L. The preferred intermediate IV where L is
diphenoxyphosphinyloxy may be prepared by reacting keto ester III
in an inert organic sol~rent such as methylene chloride,
acetonitrile or dirnethylformamide with about an equimolar amount
of diphenyl chlorophosphate in the presence of a base such as di
isopropylethylamine, triethylamlne, 4-dimethylaminopyridine or
:,-
~f"~3~S~
- 48 -
the like a~ a temperature of from about -20C to ~40~C, most
preferably at about O~C. Intermediate IV may be isolated, if
desired, but is conveniently used as the starting material f~r
the process o~ the present invention without isolation or puri
fication.
In the present process, carbapenem intermediate IV is
reacted with a quaternary amine thiol compound of the formula
~S-A ~ -R
VII X~
wherein
A ~ )R5
is as defined above and ~ is a counter anion. The reaction is
carried out in an inert solvent such 2S acetonitrile,
acetonitrile-dimethylformamide, tetrahydrofuran, tetrahydro-
furan~H2O, acetonitrile-H2O or acetone in the presence of base.
The nature of the base is not critical. Examples o~ suitable
bases include sodium hydroxide, diisopropylethylamine, 1,8-
diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene
and tri(Cl-C4)alkylamines such as triethylamine, tributylamine or
tripropylamine. Reaction oi intermediate IV and thiol VII may be
carried out over a wide temperature range, e.g. -15C up to room
temperature, but is preferably done at a temperature in the range
of from about -15C to ~15C, most preferably at around 0C.
~ he carbapenem product produced by reaction of the
quaternary amine thiol VII with intermediate IV will have a
counter anion associated with it [e.g. (C6H5O)2PO2 ~, Cl ~ or
the anion associated with the quaternary thiol] which may at this
stage be substituted by a different counter anion, e.g. o~e which
is more pharmaceutic211y acceptable, by conventional procedures.
Alternatively, the counter anion may be removed duriny the
subsequent de-blocking step. Where the quaternized carbapenem
o
~73~
~9
compound and counter anion form an insoluble product, the product
may crystallize out as it is ormed and be collected pure by
filtration.
Following formation of the desired carbapenem product,
the carboxyl protecting group R of Compound I' may be option-
ally removed by conventional procedures such as solvolysis,
chemical reduction or hydrogenation. Where a protecting group
such as p-nitrobenzyl, benzy~, benzhydryl or 2-naphthylmethyl is
used which can be removed by catalytic hydrogenation, intermedi
ate I' in a suitable solvent such as dioxane-water-ethanol,
tetrahydrofuran-diethylether-buffer, tetrahydrofuran-aqueous
dipotassium hydrogen phosphate-isopropanol or the like may be
treated under a hydrogen pressure of from 1 to 4 atmospheres in
the presence of a hydrogenation catalyst such as palladium on
charcoal, palladium hydroxide, platinum oxide or the like at a
temperature of from 0 to 50~C for from about 0.24 to 4 hours.
When R2 is a group such as o-nitrobenzyl, photolysis may also be
used for deblocking. Protecting groups such as 2,2,2-
trichloroethyl may be removed by mild zinc reduction. The allyl
protecting group may be removed by using a catalyst comprising a
mixture of a palladium compound and triphenyl phosphine in a
suitable aprotic solvent such as tetrahydrofuran, methylene
chloride or diethyl ether. Similarly, other conventional car-
boxyl protecting gxoups may be removed by methods known to those
skilled in the art Finally, as mentioned above, compounds of
Formula I' where R is a physiologically hydrolyzable ester such
as acetoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl,
methoxymethyl, etc., may be administered directly to the host
without de-blocking since such esters are hydrolyzed in vivo
under physiological conditions.
It will be understood that where the R1, R8, R5 or R15
substituent or the quaternized heteroaromatic group attached to
substituent A contain a functional group which might interfere
~it.h the int~nded course of reaccion, such group may be protected
by a conventional blocking group and then subsequently de-blocked
to regenerate the desired functional group. Suitable blocking
groups and procedures for introducing and removing such groups
are well-known to those skilled in the art.
3~t3
- 50 ~
As in the case of other B-lactam antibiotics, compounds
of general Formula I may be converted by known procedures to
pharmaceutically acceptable salts which, for purposes of the
present invention, are substantially equivalent to the non-salted
compounds. Thus, for example, one may dissolve a compound of
Formula I wherein R is an anionic charge in a suitable inert
solvent and then add an equivalent of a pharmaceutically accept-
able acid. The desired acid addition salt may be recovered by
conventional procedures, e.g. solvent precipltation, lyo-
philization, etc. Where other basic or acidic functional groups
are present in the compound of Formula I, pha~maceutically
acceptable base addition salts and acid addition salts may be
similarly prepared by known methods.
A compound of Formula I where R is hydrogen or an
anionic charge, or a pharmaceutically acceptable salt thereof may
also be converted by conventional procedures to a corresponding
compound where R2 is a physiologically hydrolyzable ester group,
or a compound of Formula I wherein R is a conventional carboxyl-
protecting group may be converted to the corresponding compound
where R is hydrogen, an anionic charge or a physiologically
hydrolyzable ester group, or a pharmaceutically acceptable salt
thereof.
It will be appreciated that certain products within the
scope of Formula I may be formed as optical isomers as well as
epimeric mixtures thereof. It is intended that the present
invention include within its scope all such optical isomers and
epimeric mixtures. Por example, when the 6-substituent is
hydroxyethyl, such substituent may be in either the R or S
configuration and the resulting isomers as well as epimeric
mixtures thereof are encompassed by the present invention~
The thiol intermediates of Formula VlI may be prepared,
for example, from the corresponding thioacetate compound of the
formula
CH3CS-A ~ N
~7~
-- 51 --
wherein A is as defined above and
_ ~ h
represents a mono-, bi- or polycyclic aromatic heterocyclic
radical containing a ~uaternizable nitrogen in the ring, said
ring being attached to A through a ring carbon atom. The thio-
acetate compound is quatexnized by reacting it in an inert
organic solvent such as diethyl ether, dichlorsmethane, methylene
chloride, dioxane, benzene, xylene, toluene or mixtures thereof
with a suitable alkylating agent of the formula
R -X'
wherein R5 is as defined above and X' is a conventional leaving
group such as halo ~chloro, bromo or iodo, most pre~erably iodo)
or a sulfonate ester moiety such as mesylate, tosylate or
triflate. The temperature for the alkylation reaction is not
critical, and temperatures in the range of from about 0C to 40C
are preferred.
Prior to reaction with carbapenem intermediate IV, the
~uaternized thioacetate compound is subjected to acidic or basic
hydrolysis to generate quaternary thiol intermediate VII. This
hydrolysis is preferably done immediately prior to coupling with
IV so as to minimize decomposition of the relatively unstable
quaternary thiol VII.
By proper selection of the solvents, the reaction from
intermediate III to end product I may be carried out without
isolation of the various intexmediates, i.e. in a "one-pot"
process. An example of such a process is illustrated below in
Example 7.
The carbapenem derivatives of general Formula I wherein
R2 is hydrogen, an anionic charge or a physiologically hydro-
lyzable carboxyl protecting group, or the pharmaceutically
~3~
- 52 -
acceptable salts thereof, are potent antibiotics active against
various gram-positive and gram-negative bactexia and they may be
used, for example, as animal feed additives for promotion of
growth, as preservatives in food, as bactericides in industrial
applications, for example in waterbased paint and in the white
water of paper mills to inhibit the growth of harm~ul bacteria,
and as disinfectants for destroying or inhibiting the growth of
harmful bacteria on medical and dental equipment. They are
especially useful, however, in the treatment of infectious
disease in humans and other animals caused by gram-positive or
gram-negative bacteria.
The pharmaceutically active compounds of this invention
may be used alone or formulated as pharmaceutical compositions
comprising, in addition to the active carbapenem ingredient, a
pharmaceutically acceptable carrier or diluent. The compounds
may be administered by a variety of means; those of principal
interest include: orally, topically or parenterally (e.g. intra-
venous or intramuscular injection). The pharmaceutical composi-
tions may be in solid form such as capsules, tablets, powders,
etc. or in liquid form such as solutions, suspensions or emul-
sions. Compositions for injection, the preferred route of
delivery, may be prepared in unit dose form in ampules or in
multidose containers and may contain formulatory agents such as
suspending, stabilizing and dispersing agents. The compositions
may be in ready to use form or in powder form for reconstitution
at the time of delivery with a suitable vehicle such as sterile
water.
The dosage to be administered depends to a large extent
on the particular compound being used, the particular composition
formulated, the route of administration, the nature and condition
of the host and the particular situs and organism being treated.
Selection of the particular preferred dosage and route of appli-
cation, then, is left to the discretion of the therapist. In
general, however, the compounds may be administer2d pa~enterally
or orally to mammalian hosts in an amoun~ of from about 5 to 200
- 53 -
mg/kg/day. Administration is generally carried out in di.vided
doses, e.g. three to four times a day.
i
~, .. . . .
.
.:
' '' ':
. . ; . .
.. .
; " - .
~7~
- 54 -
The following examples illustrate but do not limit
the scope of the present invention.
Exam~le 1
Prepara~ion of 3-[4-(N,N-dimethyl-1,?,3-triazolium?-
meth~lthio] 6~-[1-(R)-hydroxyethyl]-7-oxo-1-azabic~clo
(3.2.0)hePt-2 _ne-2-carboxylate
OH
H
cJ~e /\~
A. Preparation of isomer A
H H
SAc a) MeOTi ~ 5~ le
M ?~ ~ )2 CO ~3
2 NB
d) H2/Pd-c
:
:
.,. .~. . .
-- 55 --
Me~hyltrifluoromethzne sulfonate (0.58 mI, 5.16
mmol) was added dropwise to an ice-cooled, stirred, solu-
tion of 4-(methanethiolacetate)-1-methyl-1,2,3-triazole
(590 mg, 3.S2 mmol) in dry ~ethylene chloride (2 mL) under
nitrogen. After 0.5 h, the bath wzs removed and after 1 h,
the solvPnt was removed with an 2spirator. The residual
oil was dissolved in a few mL o~ water and this solution
was cooled in an icebath. A cold solution of sodium
hydroxidè (305 mg, 7.59 mmol) in a few mL of water was then
added and the reaction was left stirring ~or 0.75 h~ The
solution was diluted to 25 mL with water and the p~ was
adjusted to 7.~ by the addition o~ solid sodium dihydrogen
phosphate monohydrate. Then, 14 m~ of this solution (ca.
1.9 mmol of the triazolium thiol) was added t~ an ice-
cooled, stirred, solution of the enol phosphate (1.0 g,
1.72 mmol) in tetrahydrofuran (THF) (10 mI). This W25
left stirring for 0.7S h (some crystalline material,
presumahly Na2HP04 is deposited during the course of this
reaction). The suspension was transferred to a pressure
bottle with the aid o~ some ~P (20 mL) and water (~0 mL).
Ether (30 mL) and 10% palladium on charcoal (1.0 9) were
added and the mixture hydrogenated (40 P.S.I.) for 1 h.
The organic phase was separated and washed with water
(2 x 5 mL). The combined a~ueous phases were filtered
and the ~iltrate was concentrated under high ~acuum (ca.
0.5 mm, l.Sh). The yellow solution was then chromatog~aphed
(medium pressure reverse phase column, 35 x 90 mm, H20 as
eluent) to afford, after lyophilization, 395 mg of the
carbapenem slightly contaminated with s~me inorga~ic
material. It was puri~ied by ~P~C (10 x 300 m~ Waters
Microbondapack C-18 col~mn, multiple injectionsl H2~ as
.. . .
* Trademark
. , :::.
.~:
. .
c~
_56
eluent) to give 310 mg (57~) of isomer A as a tan-colored
powder: lHNMR (D20) ~: 1.23 (3H, d, J=6.4 Hz), 3.10 (2~,
d, J=9.1 ~z), 3.24 (lH, q, J=2.7, 6.1Hz), 4.03-4.71 (lOH,
m), 8;46 (IH, s); I~ (N~jol) 1760 cm ; uv (phosphate
buffer, pH 7.4, M=0.05) ~max 296 (E=7~500) .
B. Preparation of isomer B and isomer C
0~
a) MeOTf ~ H
SAc b) ag. NaOH ) ~ ~ S, ~ ~ Me2
Me - ~ C2
(tentative ~ N ~ 1l(~)
structure) Co2pl~B
d) H2/Pd-C
Methyltrifluoromethane sulfonate (1.60 mL, 1400
mmol) was added dropwise tv an ice-cooled solution of 4-
(methanethiolacetate)-2-methyl-1,2,3-triazole (1.20 g,
7.02 mmol) in dry methylene chloride (6 mL) under nitrogen.
This was allowed to warm to room temperature and left
stirring ~or 16 h. Additional methyltri~luoromethane
sulfonate (0.40 m~, 3.56 mmol) was added and after 3 h at
room temperature, the solvent was removed with an aspirator.
The residual oil was triturated with ether and the resulting
gum was dissolved in water (5 mI). This was cooled in ~n
icebath and a solution of sodium hydroxide (844 mg, 21.1
mmol) in water (5 mL) was a~.~ed. After stirrin~ for O.75 h,
this solution was diluted to 60 mL with water and the pH
adjusted to B by the addition of solid potassium dihydrogen
phosphate. Then, 40 mL o~ this solution tca. 4.7 mmol of
a mixture of isomeric triazolium thiols) was added to an
*Trad~mark for liquld paraffln (liquid petrolatum); see The Merck
Index, 10th Edltion (1963), page 1033, ltem 7048, for fur~her
., .
.~': ' ' . ' . '
;. " : ": ' :
73~
- 5Y -
ice-cooled, stirred, solution of the enol phosphate
(2.00 g, 3.45 mmol) in TH~ (60 mL). This mlxture was
left stirring in the icebath for 0.5 h after which it
was ~ransferred to a pressure bottle co~taining a sus-
pension of 10% palladium on charcoal (2.00 g) znd ether
(60 mL). The mixture was hydr~genated (40 P~S.I.) ~or
1 h. The organic phase was separated and washed wi~h
watex t2 x 10 mL) n The combined aqueous phases were
filtered and the filtrate was concentrated under high
vacuum (ca. 0.5 mm, 1.5 h). The remaining solution was
then chromatographed (medium pressure reverse phase column,
45 x 130 mm, H20 as eluent) to a~ford, after lyophilization,
595 mg of a mixture of isomeric carbapenems which were
contaminated with a little inorganic material. These were
separated and purified by HPLC (10 x 300 mm Waters Micro-
b~ndapack C-18 column, multiple injections, H2O 2S eluent)
to ~fford, in order of elution: isomer B; 153 mg (13%);
XNMR (D20) ~: 1.23 (3H, d, J=6.4 Hz), 3.12 (2H, q, J=1;4,
8.9 Hz), 3.39 (~1, q, J=2.7, 6.0 Hz), 4.07-4.68 (lOH, m),
~1 -** _1
8.19 (lH, s); IR (N,ujol) 1755 Gm ; uv (phosphate buffer,
pH=7.4, M=0.05) ~na~: 296 nm (~=6,700); and isomer C; 28q mg
(24%); lHNMR (D2O) ~: 1.23 (3H, d, H=6.4 Hz), 3.15 (2~, q,
J=3.7, 9.0 Hz), 3.37 (lH, q, J-2.6, 6.0 Hz), 3.95-4.65 (10~,
m), 8.62 (lH, s); IR lNujol) 1750 cm ; uv (pho~phate buffer,
pH 7.4, M=0-05) ~max 298 nm (E~71600).
*Trademark
**Trademark
~ .
~7;3~
- 58 -
Example 2
(5R,6S) 6-(lR-hydroxyethyl)-3-(2-methyl-1,2,3-thiadiazolium-
4-ylme hylthio)-7-oxo-1-azabicyclo[3._.0]hept-2-e_e-2-
czrboxylate
~3 .
O/~
A. ~thyl 1,2,3-thiadiazol-4-ylcarboxylate
,
~N~COÆt SOC12 ~OEt
C}~3 ~ ~ ~OEt ~5
A solution of ethyl ~-N-carbethoxyhydrazonoproprionate
(31.2 g, 0.154 mol) in thionyl chloride (80 mL) was stirred at
23C for 3 h and heated at 70C for 20 min. Thionyl chloride was
evzporated and the residue was triturated in hexane (4 x 30 m~).
The red solid was dissolved in dichloromethane (150 mL) and the
solution was washed with saturated sodium bicarbonate solution
and water. After drying over Na2S0~ the solution was concentrated
until the compound crystallized. ~fter standing at 23C for a
while, the crystals were filtered; 16.8 g, mp 86C, 69%. The
filtrate was concentrated and purified by chromatography on a
silica gel column with dichloromethane as eluting solvent to give
3.17 g, mp 86C, 13~, ir (K~r)vmax: 1720 (ester) cm 1; Hmr (CDC13)
~: 1.52 (3H, t, J=7.1 Hz, CH3CH2O), 4.57 ~H, q, J-7.1 Hz, CH3CH2O),
9.47 (lH, s, H of thiadiazole).
1C.D. ilurd and R.I. ~ori, J. Am. Chem. Soc., 77, 5359 (1955).
.,; .
~ , .
'
,.;:
~73
59
B . 1, 2, 3~ t hiadi azol- 4-ylme th
Li;~lH4 h~ ~
To a suspension o~ ethyl 1,2,3-thiadiazol-4-ylcarboxylate
(18.3~ g, 0.116 mol) in ether (400 mI) was adde~ p~rtionwise
lithium aluminum hydride (2.47 g, 0.065 mol) over 1 h peri~d. The
reaction mixture was stirred at 23~C for 7 h and treated with
lithium aluminum hydride (2.47 g, D.065 mL). The stirring was
continued for 24 h before adding successively water (7 m~), 15%
sodium hydroxide solution (7 m~) and water (21 mL). After stirring
for 15 mi~, the ether solution was deeanted and the gum was
extracted with ether ( 5 x 100 ml). The ether extrac's were
co~bined, dried (MgS04) a~d concentrated ~5.4 g). The crude
material was purified on a silica gel column (120 g, 4 x 16 c~),
with ether zs eluting solvent to gi~e 1.3 g (7%) of ethyl 1;2,3-
thiadi2zol~4-ylcar~oxylate and 2.45 g (18%) of 1,2,3-thia~iazol-4-
ylmethanol; ir (film)vmax: 3380 (OH) cm ; Hmr (CDC13)~: 2.31
(lH, s, OH), 5.22 (~H, s, CH20), 8.~0 (1~, s, H of thiadiazole).
S.I. Rzmsby, S.O. Ogren, 9.B. Ross and N.E. Stjernstrom,
Asta Pharm. Succica., 10, 285-96 (1973); C.A., 79, 137052~ (1973).
.. '~ .
~iJ30~
-- 60 --
C. 1 2, 3-thiadia~ol-4-ylmethanol methanesulfonate
CH OH ,CH OMs
N~ 2 . N ~ 2
sc~ s~
A s~luti~n of 1,2,3-thiadiazol-4-ylmethanol (0.75 g,
6. 5 mmol) in dichloromethane ~20 mL) w2s cooled to 5C under a
nitroge~ atmosphere ~nd treated with trie ~ylamlne (1.018 mL,
7.3 mmol) and methanesulfonyl chloride (0.S65 mL, 7.3 mmol).
P.fter lS min, the ice-bath was removed and the reaction mixture
w2s stirred for 2 h. The solution was washed with lN hydrochloric
acid soluti~n ~2 x 2 mL) and water, dried ~MgSO4 + MgO) and
concentrated. The residue was purified by chromatography ~silica
gel column 1.5 x 21 cm) with ether as eluting solve~t ~o give
0.90 g (71%) of 1,2,3-thiadiazol-4-ylmethanol methanesulfonate;
max ~ 2) cm , 1172 ~52) cm~l 1H
3.0g ~3~, s, CH3), 5.75 ~2H, s, CH2), 8.72 ~lH, s, H of thia~
diazole); uv ~C~2C12)~max: 251 ~El990) . Anal. calcd for
C6H6N2O3S: C 24.73, H 3.11, N 14.42, S 33.02; found: C 24.78
H 3.09, N 14.66, S 31.94 and 0.13 g (19%) of di-(1,2,3-thiadiazol-
4-ylmethyl)ether; ir (film)vmax: 1272, 1242, 1200, 986, 805,
728 cm 1; lHmr (CDC13)~: 5.16 ~s, 4H, CH2), 8.42 (s, 2H, H's of
thiadiazole).
. ..
., . : : :
.
~. ~ '':
- 61 -
D. 4~acetylthiomethyl-1,2,3-thiadiazole
CB~O~s cH3~s~a ~ c~ s~Q
To a solution of 1,2,3-thiadiazol-4-ylmethanol
methanesulfonate (0.90 g, 4.6 mmol) in tetrahydrofuran (9 mL)
was added an aqueous solution (2 mL.) of sodium thiolacetate
[prepared from thiolacetic acid (0.38 mL, 5.3 mmol) and sodium
bicarbonate (0.445 g, 5.3 mmol)]. The resultins mixture was
stirred at 23C for 1 h and diluted with ether (75 mL). The
organic solution was washed with water (3 x 3 mL), dried
(MgS04) and concentrated. The crude mlxture was purified
by chromatography (silica gel column: 1.4 x 19 cm) with 50~
e,her in hexane as eluting solvent to give 0.60 g (75~); ir
(film)~max: 1675 (C=O) cm ; Hmr (CDC13)~: 2.37 (3H, s, CH3),
4.58 (2H, s, CH2), 8.44 (lH, s, H of thiadiazole). Anal. calcd
for C5H6N2OS2: C 34.47, H 3.47, N 16.08, S 36.80; found:
C 34.48, H 3.83, N 16.28, S 36.80.
...
73 O~)
- 62 -
E. 4-acetylthiomethYl-2-methyl-1,2,3-thiadiazolium tr~.fluoro-
methanesulfonate and 4-acetvlthiomethvl-3-methvl-1,2,3-
thiadiazolium trifluromethane sulfonate
CH S~Q S~ 3 S~CH
~ 2 3 Cr SO ~e ;~ 3 ~+~ 2 3
?~s ~ ~ ~s~ C:F3503 ~5~ 3 3
To a solution of 4-acetylthiomethyl-1,2,3-thiadiazole
(O.60 g, 3.44 mmol) in a mixture of ether (4 mL) and dichloro-
methane (0.4 mL) were added a few crystals of the title compounds
and trifluoromethanesulfonate (0.407 mL, 3.6 mmol) over 5 min
period. The reaction mixture was stirred at 23C under a
nitrogen atmosphere for 6 h. The white solid that was a mixture
of -the two title compounds W2S filtered and washed with e~her,
1.05 g, 90~; ir (X3r)~max: 1675 (C=O) cm ; Hmr (DMS~, d-6)~:
2.43 (3H, s, CH3COS), 3,33 (s, CH3 on N-3), 4.57 (s, CH3 on N-2~,
4.66 (2H, s, CH2), 9.55 (H on thiadiazolium N-2), 9.66 ( H on
thiadiazolium N-3). Anal. calcd for C7HgN2O4S3F3 C 20.27, H 2.38,
N 9.45, S 32.46; found: C 24.61, H 2.57, N 8.47, S 28.21.
~7~3~3
-63
P. 4-mercaPtomethyl-2-methyl-1,2,3-thiadiazolium trifluoro-
methznesulfonate and 4~mercaptornethy~l-3-methyl-1,2,3-
thiadiazolium trifluoromethanesulfonate
'~e N~ 2 3 HCl, 6N ~ ~e ~+~25H
5 3 3 ~ S t~3S~3 . .
A solution of a mixture of 4-acetylthiomethyl-2-
methyl-1,2,3-thiadiazolium trifluoromethanesulfonate and 4-
acetylthiomethyl-3-methyl-1,2,3-thiadiazolium trifluoromethane-
sulfonate (1.05 g, 3.1 mmol) in 6N hydrochloric acid (10 mL)
w2S heated at 65C under a nitrogen atmosphere for 1.75 h.
The solvent was evaporated under reduced pressure leaving a.
yellow syrup 0.91 g. This compoun~ was used in the next step
without purification.
- 64 -
. (5~,6S) 6-tlR-hydxoxyethyl)-3 (2~methyl~1,2,3~thi~di~zolium-
~ . .
Me ~2
;V C~3S~3
P ( ~Ph ) 2 .
1:) ~ pH 7.2
t~)PNB
J~
lD~ Pd~C ~\
,~S ~ --N
~:the, 2~3F, ~ ~ CO~ '5
~ cold (5C) solution of (5R,6S) pær&nitrobenzyl 6-
(lR-hydroxyethyl)-3-(diphenylphosphono)-7-oxo-l-az2bicyclo(3.2.0)-
hept-2-ene-2-carboxylate ~1.7 g, 2.92 mmol) in te-lrahydxofur~n
(10 m~) w2s treated with a solution of 2 crude mixture of 4-
mercaptomethyl-2-methyl-1,2,3-thiadi2zolium tri~luoromethane-
sulfonate and 4-mercaptomethyl 3-methyl 1,2,3-thiadi2zolium
trifluoromethanesulfonate (0.9 g) in a n~xture of phosphate
~uffer (p~ 7.2, 0.3M, 15 mL) and ~etr2hydrofuran (5 mL). The
reaction mixture w~s s~irred for 1 h and ~he pH was kep~ at 7.2
with 2N sodium hydroxide solu~ion. r~he s~irring was continued
~or one more hour before ad~ing ether (50 ml,) and 10% palladium
on charcc~al ( 1 g ) . The resulting mixture was hydrogenated }~t
23DC under 45 psi ~or 2 h and ~iltered throu~h a Celite"pad.
The organic phase was separate~, diluted with ether (50 mL~ a~d
phosphate buffer ~pH 7~2, 0.3M, 24 m~) and hydrogenated (2 g of
10% palladium on ch2rcc~al) for 2 h u~der 50 psi. The aqueous
phases were combined ~:Erom the ~irst and second hydrogenolysis),
w2shed with ether and puri~ied by chromatogxaphy on"PrepPak"**
500-C/18 with ~7ater ~s eluting sol~ent to ~i~e 0 . Z2 y o~ crude
m2teri21. It was repurified by hplc with water as eluting
*~rade~ark ~or ~ ~r~nd of ~1 ~to~aceou0 ( ~ U6 ori al ) oarth
* ~Tr~le~arlc
~3~
solvent to give 0.040 ~ (4%~ of the title compound after
lyophilization, ir (KBr)vmax: 3400 (br, OH), 1745 (C=O of
B-lactam), 1580 (carboxylate) cm 1; ~mr (D20) ~: 1.23 (3H,
~, J=6.3 Hæ, CH3CHOH), 3.04, 3.05, 3.16 (2H, m, E[-4), 3.38
(lH, dd, J=2.8 Hz, J=Ç.0 Hz, H-6), 3.9-4.6 ~2H, m, H-5,
CH3CHOH), 4.51, 4.53 (2"sl', SCH2), 4.61 (s, N CH3); uv
(H20) ~m2x 224 (E4345), 262 (E4980), 296 (E6885), [~V 18
(c 0.1, H2O); Tl/2=9. 8 h (measured ~t a concentration of
M irl phosphate buffer p:EI 7.4 at 36.8C).
.,'
-- 66 --
~:xam~le 3
____
~3 ~ H 2
HC~ ~d 1) I,AH ACS~ ~\
2 ) ~sCl/NEt3
XSCC)U33
BrC~2BOEt
0~ 5 ~N ~r
C~ , ) KOH
C02PNB
C) ~12~d-C
., " ' .
., .
~L~7;~
- 67 -
~ ithium aluminum hydride (2.83 g, 70.g mmol) was
added in small portions to a stirred suspension of l-methyl-
1,2,3-triazole-4-carboxylic acidl (9.00 g, 70.9 mmol) in dry
T~F (200 mL). The mix,ure w2s lef~ stirring at ro~m temperature
for 15 h after which a 20% aqueous solution of sodium hydxoxide
(20 mL) was carefully added in ca. 1 mL aliquots. ~he resulting
granular suspension was filtered and the solid washed with
additional THF (5 x 75 mL). The combined THF solutions were
dried (~gSO~) and the solvent removed. The residual yellow oil
wzs flash chromatographed on a silica gel column (90 x 35 mm)
[100 mL portions of hexane, mixtllres of ethyl acetate-hexane
(1:1) and (1:3), and lastly ethyl acetate-methanol (9:1) as
eluent~. This afforded 4-hydroxymethyl~l-methyl-1,2,3-triazole
(3.18 g, 40~) as a colourless oil: 1HNMR (CDC1 ) ~ 4.07 (3~, S),
4.73 (2H, d), 7.52 (lH, s); IR (neat) 3320 cm ~.
Methanesulfonyl chloride (3.82 mL, 49.6 mmol) was
added dropwise to an ice-cooled, stirred, solution of the alcahol
(4.67 mL, 41.3 mmol) and txiethylamine (7.47 mL, 53.7 mmol) in
methylene chloride (20 m~). After 0.5 h, the solvent was removed
and the residual solid was taken up in acetonitrile (30 m~).
Potassium thiolacetate (7.06 g, 62.0 mmol) was then added and the
suspension was left stirring at room temperature for 3 h. An
additional quantity of potassium thiolacetate (3.0 g, 26.3 mmol)
was added and the suspension was left stirring for a further
16 h. The dark-coloured suspension was then concentrated and
water (10 mL) was added. This mixture was extracted with methylene
chloride (5 x ~0 mL). The combined extracts were dried (MgSO~)
and the solvent removed. The residual oil was flash chromatographed
on 2 silica gel colu~m (90 x 36 mm) [hexane followed by a mixture
C. Pederson, Acta. Chem. Scand., 1959, 1~, 888
73~
- 68 _
of hexane-ethyl acetate (1:1) being used as eluent~. This
afforded 4-(methanethiolacetate)-l-methy~ 2~3-triazole
(5.95 g, 84%) as a ~aint pink coloured s~lid: ~NMR (CDC13)
2.40 (3H, s), 4.10 (3H, s), 4.20 (2H, s), 7.S3 (lH, s);
.. .,*
IR (Nujol mull) 1675 cm
A solution of the triazole (1.00 g, 5.85 mm~1) 2nd
ethyl bromoacetate (1.48 mL, 13.3 mmol~ in dry acetonitrile
(10 mL) was heated at 60D for 90 h under nitrogen. The
solvent W2S removed and the residual oil was triturated with
e.her (4 x 25 mL) to leave 1-methyl-3-(ethyl carboxymethyl)-~-
methanethiolacetate-1,2,3-trizzolium br~mide as a brownish
gum which was used directly.
A cold sol~tion of KOH (~.66 g, 12 mmcl~ in water
(5 mL) was added to an ice-cooled, stirred, solution of the
triazolium bromide in water (20 mL). A~ter 20 ~n, this was
diluted to 35 mL and sufficient solid potassium dihydrogen
phosphate was added to bring the pH of this solution to 8Ø
This was then added to a stirred, ice-cooled, solution of the
enol phosphate in THF (35 ~L). After 0.~ h, this mixture was
txansferred to a pressure bottle containing ether (35 mL) and
10% palladium on charcoal (1.5 g). It was hydrogenated at
40 p.s.i. for 55 min. The organic phase was then separated
2nd washed with wat~r (2 x 5 T~). The combined aqueous phase~
were ~iltered and the filtrate concentrated under high vacuum.
The~residual material was chromat~graphed on a reverse phase
column ~35 x 120 mm) with water as eluent. Lyophilization o~
the carbapen~m containing fractions left 1.20 g o~ a green-
coloured solid. This was rechromatographed on a Waters Prep.
500 HPLC (Prep~AX-500/Cl8 column) with 2% acetonitrile-water
~s eluent. The fractions containing the carbapenem were
co~bined and lyophilized. This material W25 again rechromato-
graphed by HP~C ~10 x 300 mm Waters Microbondapack C-18 column)
*rl':rademark
~I~t~ ' . .
', ;.
'' '
. .
'
~3~ ~
-- 69 --
with water ~s eluent ~c~ a~rd, after lyophilizatic~n, pure
title compound (190 mg, 17%) as a pale yellc~w solid: l:HNMR
(D20) ~ 1.24 (3H, d, J=6.4 ~Iz) r 3.07 (2E~ d~ J~::9 Hz) 1 3.38
(1~1, q, J-2.7, 6.0 Elz), 4.02-4.~0 (3}3, m), 4.29 (3}1, s),
5.23 (2~, s), 8.52 ~1~, s); IR (Nuiol mull) 1750 ~sn 1; VV
(p~osphate buffer, pE[ 7. 4) ~`max '296 nm (E~-7~52U) .
EXtmD1e 4
Pot2ssium 3- l 4~ c2rboxyla~0~ethYl-3-meth}~ 2,3-
tri2zoli~ methanethio] -6~- [ 1- (~) -hydroxye .hvl~-7-
oxo- 1- a zab i cy cl o l 3 . 2 . a ~ he~t- 2- ene- 2- carboxsrlate
~,s
co2~)~NS
'Co~
o,8
HO~-_ H ~=~ C2~ t
N~
E:t O~?CH2N3
= N ~ ~O2Et
b ) N~l~H4 >_o~
P~3
~S~CH3
*Trad~nark .
' ~
~3(3~
- 7C-
OH
s ~ AcS ~ CO~Et
CO ~ N~ ~3
c) ~ ~(~2
C~2
A mixture of ethyl azidoacetate (30.0 g, 0.23 mol)
and propiolic acid ~14.3 ml, 0.23 mol) in toluene (75 mL) was
stirred at room temperature. The reaction remained mlldly
exothermic for 1.5 h after which it quickly became vigorously
exothermic and cooling with an ice bath was necessary. After
this exothermic phase had passed, the reaction was heated at
reflux for 0.5 h. After being cooled in an ice bath, the
crystalline material W25 collected by ~iltxation and washed
with ~ little toluene. The crude materi21 obtained in this
manner (33.3 g, 72%) consisted of a single isomer [ ~NMR
(DMSO-d~) ~ 1.20 (3H, t, J=7 Hz), 4.15 (2H, q, J=7 Hz), 5.42
(2H, s), 8.67 (lH, 3)], presumably l-(ethyl carboxyme~hyl)-
1,2,3-tria~ole-4-carbo~ylic acid by analogy with earlier work .
A solution of the caxboxylic acid (5.~0 g, 25.1 mmol)
and triethylamine (3.68 mL, 26.4 mmol) in dry methylene chloride
(50 mL) w2s added to an ice-cooled, stirred, solution of ethyl-
chloroformate ~2.52 mL, 26.4 mmol) in dry methylene chloride
(50 mL). The purple coloured solution was left stirring for
0.5 h afterwhich it was washed with water (10 mL), dried (MgSO~)
and the solvent removed. The crude mixed anhydride was dissolved
in THF (50 m~) and added slowly to an ice-cooled suspensiorl of
sodium borohydride (0.72 g, 18.9 mmol) in THF (50 mL). After
stirring for D.5 h, additional sodium borohydride (0.30 g,
7.9 ~mol) was added and the reaction was left in the ice bath
for 1 h. Water (5 mL) was then added and a~ter 10 min, this
was followed by 10% aqueous HCl (3 mL). After gas evolution
had ceased, solid potassium carbonate ~2 g) was added with
lC. Pederson, Acta. Chem. Scand., 1959, 13, 888
... .
. .
3 ~
- 71 _
stirring. The organic phase was then removed and the resid~al
white paste w~s extracted with additional TH~. ~he combined
organic phases were dried (MgS04) and the solvent removed.
Flash column chromakography on silica gel, eluting with hexane,
mixtures of ethyl acetate-hexane, and finally ethyl acetate
afforded l-~ethyl carboxymethyl)-4-hydroxymethyl-1,2,3-triazole
(2.04 g, 44%) as a crystalline solid: ~ NMR (CDC13) ~ 1.28
(3X, t, J=7 Hz), 4.23 (2~t q, J=7 Hz), 4.75 (2B, s), 4 85
(2H, s), 7.73 (lH, s).
Diisopropylazodicarboxylate (4.11 mL, 20.8 mmol) was
added dropwise to an ice-cooled solution of triphenylphosphine
(5.47 g, 20.8 mmol) in dry THF (100 m~) under nitrogen. After
0.5 h, an ice-cooled solution of the alcohol (1.93 g, 10.4 mmol)
znd thiolacetic acid (1.49 mL, 20.8 mmol) in dry T~F (50 mL)
under nitrogen was added to this mixture. This was left for
2 h in the ice bath and then for an additional 12 h at room
temperature; after which the solvent was removed. The reaction
mixture was flzsh chroma~ographed on silica gel (40 g; eluting
with 100 mL portions of hexane, 5%, 10%, 15~...5~% ethyl acetate-
hexane). Fractions containing the thiolacetate were com~ined
and rechromztographed on silica gel (60 g) [elution with 200 mL
portions o: hexane, 5~, 10~, 15~, 20~ ethyl acetate-hexane and
22.5, 25, 27.5...35~ ethyl acetate-hexaneJ. Thi~ afforded 1.24 g
(49%) of l-(ethyl carboxymethyl)-4-methanethiolacetate-1,2,3-
triazole as a crystalline solid [~NMR ~ 1.28 (3~ , J=7 Hz),
2.37 (3H, s), 3.~7 (2H, s), 3.90 (2H, ~, J=7 Hz), 5.12 (2H, s),
7.63 (lH, s); IR (Nujoi mull), 1735, 1780 cm 1] and an additional
1.~0 g of material contaminated with txiphenylphosphine oxlde.
*Trad~E~k
:
. ~ . ,
~ ~ ~ 3~3~
-72
~ ethyl trifluoromethane sul~onate (D.51 m~, 4.53 mmol)
was added dropwise to an ice-c~oledl stirred, solution of the
triazole (1.00 g, 4.12 ~nol) in dry methylene chloride (5 mL).
The bath W2S removed after 0.5 h and after an additi~nal 0.5 h,
the sol~ent was removed with an aspirator ~acuum. This left a
white solid which W25 suspended in water (15 mI) and this stirred
mixture W2S co~led in an icebath. A s~lution o~ XO~ (0.69 g,
12.4 mmol) in water (5 mI) was added and the reaction was left
stirring for 1 h. It was then diluted to 30 ml ~ith water ~nd
solid potassium dihydrogen phosphate was added to bring the pH
to 8Ø A portion of this solution (22 mL, ca. 3.0 mmol o~ the
thiolcarboxylate) was added to an ice-cooled, stirred solution
of the enol phosphate (1.60 g, 2.76 mmol) in T~F (30 mL). After
0.5 h, the reaction was taken and put under high vacuum to
remo~e the THF. The yellow solution w~s then chrom2tographed
on a reverse phase column (35 x 120 ~n) eluting with water (300
mL) followed by 100 mL portions of 5, 10, 15...30% acetonitrile-
water. ~yophilization of the desired fractions af~orded the p-
nitrobenzyl ester as 2 yellow solid (930 mg). This was trans-
ferred to a pressure bottle containing ether (25 m~), THF (25 mL),
and phosphate buffer [25 mL, prepared by dissolving potassium
dihydrogen phosphate ~1.36 g, 0.01 mol) in water (100 mL) and
adjusting the pH to 7 4 by adding 45% a~ueous KOH] and 10%
palladi~ on charcoal (900 mg). The hydrogenation was conducted
at 40 p.s.i. ~or 1 h after wh.ich the organic phase was separated
and washed with water (2 x 5 mL). The combined a~ueous phases
were filtered and then concentrated under high vacuum. The
residual solution was chromatographed on a reverse ph~se column
(35 x 120 mm) eluted with water. ~ractions containing the
~2rbapenem were combined and lyophili~ed to afford 1.21 g of a
pale greenish solid. This was then purified by HPLC (10 x 300 mm
water ~cx~bondapac~' C-18 column~ H20 as eluent) to give pure
title product, 480 mg (41~ NMR (D20) ~ 1.23 (3~., d, ~=6.4 Hz),
*I~ademark
.
~30
- 73
3.11 (2H, d, J=9 Hz), 3.37 (1~, q, J=3.0, 6.1 ~z), 4.02 (7H, m),
5.18 (2H, s), 8.53 (lH, s)~ Nujol mull) 1750 ~n 1 ~V
(phosphate buffer, P~ 7 4)~m2x 205 ~m (E-7,810).
Exam~ le
3-~s-(1,4-Dime-,n~1-1,2,4-t_ az ~
hydroxy~hyl~-7-cxo~ z2bicvclol3 2-~]hePt~2~ene-2-ca~Q~vlate
," ~c~
A. l-~ethYl-5-meth2nethl cetate-~ =5aL:3
ox ~) ~sCl/~t ~ ~ 5
t
3 ~ / 3 ~ N
MethanesulfOnyl chloride (0.46 m~, 6.0 ~mol) w2s added
dropwise to an ice-cooled, stirred, solution o~ l-methyl-5-
hydrox~methyl-1,2,~-triazole* (565 mg, 5.0 ~nol.) ~nd triethylamine
(0.91 m~, 6.5 mmol) in.methylene chloride (5 m~). After 20 min,
additional triethylamine ~1.05 mL, 7.5 ~nol) followed by thiol-
acetic acid (0.53 m~, 7.5 mmol) was added and stirrins was
continued for 45 mun. The reac~ion was then diluted with
.G. Jones and C. Ainswor,h, J. ~mer. Chem. Soc., 1955, 77, 1938.
~ .
"
~ ' ,.
3~
- 74 _
methylene chloride and washed with water. The aqueous phase
was extracted with methylene chloxide t3 x 5 mL) and the
combined organic phases were dried (MgSO~) and the solvent
removed. Column chromatography on silica gel a~orded pure
l-methyl-5-methanethiolacetate-1,2,4-triazole (570 mg) as a
yellow oil [in addition, an impuxe fraction (200 mg) was
rechromatographed (preparative TLC, silica gel) to give a
further 100 ms of pure material (total yield: 85~)]: ~ MR
(CDC13) ~ 2.38 (3H, s), 3.90 (3~, s), 4.25 (3H, s), 7.B0
(lH, s).
B. 3-[5-(1,4-di_ethYl-1,2,4-triazolium)-methanethio] 6~-
~l-(R)-hvdroxyethyl]-7-oxo-l-azabicYclo[3~2.0]hePt-2
ene-2-çarboxylate
__
~:i
- 2) MeOTf ~
1~ N ,~c b) NaO~ ~ 1~ S ~N~3
~ c) J~~ 2 CO (~)
C02P~
d) H2~Pd-C
Methyl trifluoromethanesulfonate (1.20 mL, 10.7 mmol)
was added dropwise to an ice-cooled solution of l-methyl-5-
methanethiolacetate-1,2,4-triazole ~730 mg, 4.27 mmol) in
methylene chloride (7 mL). The reaction mixture was slowly
allowed to wanm to room temperature over 3 h after which it was
concentrated. The residual oil was triturated with ether to
leave crude 1,4-dimethyl-5-methanethiolacet2te-1,2,4-triazolium
trifluoromethanesulfonate (1.46 g) which was used directly.
. .................................... .
~73~
A solution of sodium hy~roxide (512 mg, 12.8 mmol)
in water ~5 mL) was added to an ice-cooled solution of the
triazolium salt (1.45 g, 4.35 mmol) in water (5 mL). After
45 min, this was diluted to 25 m~ with water and ~he pH was
adjusted to 7.6 with solid potassium dihydrogen phosphate.
This solution was then added to 2n iee-cooled, stirred,
solu~ion of the enol ph~sphate (2.00 g, 3.45 mmol) in ~HF
(25 mL). ~fter 30 min, the reaction muxture W2S transferred
to a pressuxe bottle containing ether (40 mL) and 10% palladium
o~ charcoal (2.0 g). This was hydrogenated (45 p.s.i.) for
1.25 h. The reaction mixture W2S then diluted with ether (25 mL)
and filtered. The org2nic phase w25 separated and washed with
water (2 x 5 mL). The combined aaue~us ph~ses were washed with
ether (3 x 25 mL) and then concentrated under vacuum. Column
chromatography (reverse phase, 45 x 130 mm, water 2S eluent),
followed by lyophilization o~ the carbapenem-containing ~ractions,
af~orded 650 mg of crude material. This was rechromatographed
to give pure title product (450 mg, 39%): HNMR (D2O) ~ 1.2
(3H, d, J=6.4 Hz), 3.19 (2H, q, J=2.6, 9.2 H7), 3.45 (lH, q,
J=2.8, 6.0 Hz), 3.91 (3H, s), 4.06 (3H, s), 4.08-4.36 ~2H, m),
4.54 (2H, d, J=2.8 Hz), 8.71 (lH, s~; IR (Nujol mull) 1755 cm 1;
W (phosphate buf~er, pH 7 4) ~max 294 ~m (E=8,202); T
(phosphate buffer, pH 7.4, M=0.067, T~37C) 9.1 h.
*Trad~k
.~1
, j . ,~
~'. .
~L~73
_ 76 --
Example 6
(l'R,5R,6S) 3-[(1,3-dimethyl-5-tetrazol um)-methylthlo]-6-
(l-hvdroxvethvl)-7-oxo-1-azabi cvcloI 3.2.0~he~t-2-ene- 2-
carboxylate
o~ .
~ ~C~
A. 5-carbethoxy-2-methyltetrazole and 5-carbethoxy-1-
me~hyltetrazole
N _N . C~21''2 ~_N O )~N~,~
3 2 4 ~ 3
la. ~ ylation with diazomethane
A solution oE 5-carbethoxytetrazolel (9.17 g, 0.064
mmol) in ethyl ether~ (80 mL) was cooled to 0C and treated
D.~oderhack, Chem. Ber., 108, 887 (1975).
The use of a mixture of ethanol and ether gave the same ratio
of isomers.
.... . . . ..
: .' '
~730
-- 77 _
dropwise (15 min) with a solution of dia~ometh2ne (3 g, O.D7~ mmol)
in ether (200 mlJ). The light yellow sc:lution was.stirred for
3~ min and the excess of diazomethane w25 destroyed by addition
of acetic acid (1 mL). Evaporation of the solvent and dis~
tion of the residue gave a clear oil: bp 95-100C/O.S torr; 9.~4
g, (96%). ~r indicated a mixture of l-methyl and 2-methyl
isomers in a ratio 6: 4. Separation of the two isomers cGuld not
be done by distillation nor hplc: ir (film) ~max 1740 cm 1
(C=O of ester); ~mr (CDC13) ~: 1.53 (3H, two overlapping t,
J=7.0, CH2CH3), 4.46 and 4.53 (3~, 2S, CH3 of l-methyl and 2-
methyl tetrazoles, ratio 6: 4. The methyl o~ the 2-i~omer is at
lower field and is the minor pxoduct), 4.5 ppm (2H, two.overlapping
q, CH~CH3~.
lb. 5-Carbethoxy-?-methyltetrazole
N--~ CB 3 I ~N
C~2~' ~ ~ ~ C~2 130'C ~>r 2
~CH3 CH3 H3
.
A ~ixture of 5-carbethoxy-2-methyltetrazole and 5-
carbethoxy-l-methyltetrazole (0.~52 g, 1.61 mmol, ratio of the
two isomers 1:1) in iodomethane (0.5 mL) was sealed in a glass
tube and heated at 100C for 15 h and at 130C for 6 h.
Distillation of the reaction nixture gave the title compound as
a light yellow oil: û.139 g (55%); bp 95-100C/0.5 torr (air
bath telT~erature): ir (film) vmaX: 1i40 cm 1 tcco Qf ester),
Hmr (CDC13) ~: 1.46 (3H, t, J=7.0, CH3CH2), 4.53 (3H, .s, CH3-2),
4.5 (2H, q, J=7.0, CH2CH3).
~ X73~0
-- 78 --
. Methylation with dimethyl sulfate
A solution of 5-carbethoxytetrazole (1.42 g, 0~01 molj
in dry acetone (20 mL) was treated wi~h anhydrous potassium
carbonate (1.38 g, 0.01 mol) and dimethyl sulfate (1.26 g, 0.01
mol). The mixture was heated under reflux for 12 h. The
carbonate was ~iltered and the solvent e~aporated under reduced
pressure. The residue was diluted with dichloromethane ~3~ mL),
washed with saturated sodium bicarbonate (10 mL), brine (10 mL)
and dried over anhydrous sodium sulfate. Evaporation of the
solvent and distillation under vacuum gave a clear oil: 1.45 g
(93~); b.p. 85-1109C/0.5 torr. ~mr indicated the prese~ce of
two isomers in a ratio 1:1.
B 5-Hvdroxvmethvl-2-methYltetrazole
,, ~
CH3~ COz~t + ~3H4 ~ >
1 By reduction of the mi~ture of esters.
A mixture of S-carbethoxy 1 methyltetrazole and ~-
carbethoxy-2-methyltetrazole katio 6:4) (7.60 g, 0.049 mol)
in dry tetrahydrofuxan (50 mL) was cooled to o r C and treated
with lithium boroh~dride (1.06 g, 0.049 mmol) added in small
portions over 15 min. The mixture was maintained at 10C ~or
30 addit.ior, min .~nd t.hen stlrred at 2~C for 4 h. The mi~ture
was cooled to O~C and the excess hydride was care~ully destroyed
by addition of 6~ HCl ~pH of 7 after n~ more gas was evolved).
The solvent was concentrated under vacuum and the residual oil
diluted with dichloromethane (200 mL), washed with brine (10 mL)
znd finally dried over Na250~. Concentration of the solvent
.:` ' '
' . ' " ' "
~3~
- 79 -
and distillation of the residue under vacuum gave 1.83 g
(33%) of a clear oil. lHmr of this material indicated the
product was 5-hydroxymethyl-2~methyltetrazole.
2. By reauction of 5-carbetho~y-2-methyltetrazole.
To a solu~ion of 5-carbethoxy-2-methyl~etrazole
(0.139 g, 0.89 mmol, obtained by isomerization of the mixture
of esters with methyl iodide) in dxy tetrahydrofuran (1 m~)
at lO~C was added solid lithium borohydride (0.019 g, 0.87
mmol). The mixture was slowly warmed up to room temperature
and stirred for 4 h. The excess borohydride was destroyed by
czreful addition of 6N HCl at O~C (pH 7). The solvent was
evaporated znd .he residue dissolved in dichloromethane (25 mL)
and dried ovex anhydrous sodi~m sulfate. Evaporation o~ the
solvent gave the title compound as a clear oil: 0.092 g (91~);
bp 90-120~C/0.5 torr with decomposition; ir (film) vmax:
3350 cm 1 (broad, O~); lHmr (CDC13) ~: 4.4 (2H, s, CH3-2), ~.93
(2H, s, CH2-5).
C. 5-Acetylmercaptomethyl-2-methyltetrazole
1) Mscl, Et~
5N~ 2 ~ N
_ 80 _
To a solution of 5-hydroxymethyl-2-methyltekrazole
(1.83 g, 11.7 mmol) in dry dichloromethane (25 mL~ at O~C was
added methanesulfonyl chloride ~1.47 g, 12.9 mmol) followed by
triethylamine (1.30 g, 12.9 mmol) added dropwise over five min.
The mixture w2s stirred at 0C for 1 h, and then treated with
a solution of potassium thioacetate (1.60 g, 14.0 mmol) in dry
N,N-dimethylformamide (10 mL). The resulting gel was stirred
at O~C for 3 h~ The reaction mixture was diluted with dichloro-
methane (200 mL), washed with brine (20 mL) and dried over
anhydrous sodium sulfate. Evaporation o~ the solvent under
vacuum and chromatography of the resulting oil over silica gel
(2 x 15 cm, eluting with dichloromethane and dichloromethane-
acetone 5~) gave the title compound as a clear oil: 1.31 g (65~);
ir (film) vmax: 1696 cm 1 (C=O of thioester); ~mr (CDC13) ~:
2.43 (3H/ s, SAc), 4.36 (3H, s, 2-CH3), 4.38 ppm (2H, s, 5-CH2).
D. 5-mercaptomethyl-1,3-dimethyltetrazolium trifluoromethane-
sulfon2te
~C~3 c~3So3
N ~N Ct--. SO C~ ~aOH ~
J ,~C~i25Ac - 3 ~ 3 ~ JN~ 2
3 3
A solution of 5-acetylmercaptomethyl-2-methyltetrazole
(0.400 g, 2.32 mmol) in dry dichloromethane (3 mL) was treated
with methyltriflate (0.76 g, 4.64 l~nol) and stirred at 22C for
16 h. Ev~poration of the solvent under ~acuum ya~e a red oil.
This salt was dissolved in cold oxygen-~ree water (5 mL) and
.
.
.
..
~ 81 -
tr~ated wit~ 4 M sodium ~ydroxi~e (O. 8 snL, 3.2 ~ The
mixture was stirred at O~C for 40 ~;Lin, diluted wi~ water
(7 mL), and ~e p~I was ~djusted to 7. 3 with saturated ~2P04 .
The clear resulting solution was maintained under ~itrogen
and used immediately for t:he ~ollcwing s~ep.
~,
c2r~xylate
3 ~3SC)3
~ ( ~' ) 2 ~ ~2
2 CH 3
~_ N--N~CN3
Co PMs 3
2 C~35~ ~)
~H
H2Pd/C ~, --~ f C!A3
CO ~) 3
A solu~;on of enol phosphate ~0.915 g, 1.58 mmol) in
tetrahydrofuran (B mL) was cooled to O~C ~nd treated dropwise
with the solution o~ 5-mercaptomethyl-1,3-dimethyl~etrazolium
trifluoromethanesulfona~e (2.32 mmol, prepared ~bove) ~er a
period of 20 min. The pH of the reaction mixture was sta~le
at 6.5 throughout ~he additi~n. After 20 additional min. the
pH of the solu~ion w~s adjusted to 7.0 with satur2ted ~odium
bicarbon2te. The mixture was transferred to a hydrogen2tion
73 ~1
-- 82
bottle, diluted with THF (10 mL), e her (20 ~L) and ice (20 g).
The carbapenem was hydrogenated over 10% palladium on activated
carbon under 45 psi while slowly increasing the temperature to
22~C for 9G min. The catalyst was filtered and washed with cold
water (5 mL) and ether (20 m~). The aqueous phase was wa~hed
with ether (20 ~L) and maintained under vacuum for 20 min to
remove traces of organic sol~ent. Chromatogrzphy on PrePaX
500-C/18 and elution wi~h water gave ~he title compound as a
white powder after lyophilization 0.265 g (49%); ~D +1~
(c 1.04, H2O); W (H2O, pH 7 4) ~max 294 nm (F7,500~; ir (KBr)
~max 1755 (C=O o~ B-lactam), 1600 cm (~road, C=~ ~f carboxyl2te);
Hmr (D2O) ~: 1.24 (3H, d, J=6.4 Hz, CH3CHOH), 3.0-3.3 ~2H, m,
H-4), 3.42 (lH, dd, J=5.8, J=2.9, ~-6), 4-4.2 (2H, m, H-5 and
CB3CROH), 4.34 and 4.57 (2 x 3H, 2S, CH3-1 and 3 ~f tetrazole),
..49 2nd 4.51 (2H, 2s, CH25). The pr~duct has a half life of
10.5 h 2t 37~C (c of 10 4 M in pH 7.4 phosphate buffer.
*Trad$Erk
'; . '' `;
.
, .,
~7~
Exarnple 7
hvdroxvethYl] -7-oxo-1 azabicvclo [3 . 2 . 0] -he~t-2-ene~ 2 carboxYlate
~ _ -- . -- -- . 11. , _ _ _
Via "One Pot" Process
CF SO (~
OH CH 3 3
~'~0 ~S~c
2 PNB
CH3CN ¦ ClP (~) 2 NaOH
0C, 45 min. EtN (ii?r)2 H20, 0C, 1 h.
~ / ~ /
OH
~ (~) ~ + ~ SH
2 PN13
2 \ / 4
~/
pEI 6.5-7.5
TH~, H2
'J~
- 84 -
~ e ¦ ~ 0~ (0~)
¦ H2 Pd-C 10
5C, 2 h.
0~
A. Preparation of enol phosphate (2)
OH
/~NB C02PIIB
An ice-cooled solution of ketone 1 ~3 g, 8.62 mmoles)
in acetonitrile (30 ml) was treated with ethyl diisopropylamine
(9 mmoles, 1.04 e~, 1.57 ml) (addition time ca. 2 minutes) and
chlorodiphenyl phosphate (9 mmoles, 1.04 eq, 1.87 ml) (addition
time ca. 2 minutes). The xeaction was stirred for 45 minutes and
TLC (ethyl acetate, silica gel) showed disappearance o~ ketone 1.
The solution was diluted with ethyl acetate (60 ml), washed with
cold water (2 x 50 ml) and brine, dried over sodium sulfate and
concentrated (bath temperature below 20C) to give a ~oam which
was used as such.
.............. .. ..
. : .- ... . :
~, ..;
..
,. '
3 ~3
- ~5 -
B. Preparation of thiol (4)
C~l~ SAc 0~, 1 h.~ CH3
23 KH2PO4 `~'
An ice-cooled solution of thioacetate 3 (3.31 g, 10
mmoles~ in water purged with nitrogen for 5 minutes was treated
dr~pwise (ca. 5 minutes) with a cool~d solution of sodium hydrox-
ide (1.75 eq, 17.5 mmoles, 0.7 g) in water (8 ml). The mixture
became yellow. Af~er 75 minutes under nitrogen the p~ was
adjusted to 7.4 with saturated aqueous solution of KH2PO4. The
reaction mixture was diluted with water (1~ ml). This aqueous
solution of thiol 4 (50 ml, 0.2 mmoles/ml) was used as such.
C. Coupling
OH
~ ~(~)2 p~ 6.5-7 5
, 1 h.
CO2PNB
2 OH
C02PNB
An ice-cooled solution of 2 (crude, prepared in A, 8. 62
mmoles) in tetrahydrofuran (50 ml) was treated dropwise with the
aqueous solution of thiol 4 prepared in B (5 ml of solution every
5 minutes). During the course of the reaction the pH of the
reaction mixture was maintained around 6.5-7.5 (prefexably 7) by
adding cooled 2N sodium hydroxide solution. The reaction was
followed by ~LC (a) silica gel ethyl acetate; (b) reversed phase
Analtech"RPSF, CH3CN- p~ 7 buffer (4:63.
*Trad~k
~..
~73~
- 86 _ ,
At the end 1.15 eq o~ khiol was used (50 ml of 50~
lution). The reaction was complete afteI 1 hour at 0C and the
mixture was used as such for the hydrogenation after the pH was
adjusted to 7.
D. Hydro~enation
3 ~2/ M -C 1~
N THF-H2O-ether
CO2PNB 0CC, 2 h.
~C~
The reaction mixture containing 5 (prepared in C) was
transferred into a Parr flask with THF ~10 ml), phosphate buffer
(pH 7, 0.1 M) (10 ml), ether (~5 ml) and Pd-C 10% (5 g) and
hydrogenated at 45 psi at 3-10~C for 2 hours. Then the catalyst
was filtered, washed with water (3 x 10 ml) and the pH adjusted
to 6.2 carefully with cold 2~ NaOH. Ether was added and the
aqueous phase was separated and washed again with ether. The
aqueous phase was purged of organic solvent under vacul~m and then
purified on a ~ondapak C-l~ column (100 g, 4.5 x 13 cm) with cold
distilled water. The light yellow fractions containing the
product (checked by V.V. and TLC) were lyophilized to give 1.46 g
(50%)* of 6 as a yellow powder. ~293, E- 9000, ~271, ~= 11064
*yield calculated from bicyclic ketone
**Trademark
,~ 1
., ':
,
.,
~ ~73 i~ ~
-- 87 --
E~le 8
OH C~13 CH3
~od~ cJ
~'~ C~ ~ CF3503~)
N
C2 PNB
O
l Cl~P (0) 2
H H3 R ~ ~H3 ~CF3S03~)
( 0 ) 2 , ~ SH
C 2 PNB
O
N ~ ~~ 3
O 0~ PNB
CH3
~Co2~
If in the procedure of Example 7, the keto intermediate
1 is replaced hy an equirnola~ amourit of the correspondin~ lB-
methyl intermediate, there is obtained the carbapenem end-prQduct
indicated above.
- 8B -
OH CH f H3
'~0~
If in the procedure of Example 7, the keto intermediate
1 is replaced by an equimolar amount of the corresponding
l~-methyl intermediate, there is obtained the carbapenem end
product indicated above.
.
. .
