Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
GC159
--1--
O-SULFATED 3-LACTAM HYDROX~MIC ACIDS
,
This invention is directed to a novel
family of B lactam anti~iotics, and to the use
of such compounds as an~i~actexial agen~s.
It has ~een discovexed that the ~ lactam
nucleus can ~e biologically activated ~y a
sulfa~e (-O-SOe3M~ su~sti~uen~ attache~ ~o the
nitroge~ atom in th.e nucleus.
~-Lactams having a sulfate su~stituent
in ~he l-posi~ion and an acylamino substitu~nt
in the 3-position exhibit activity against a
range o~ yram-negative and gxam-positive ~ackeria.
The preferred mem~ers of the noYel family
of ~lactam antibiotic~ of this invention are
those encompassed ~y the formul.a
_z R4
Rl-NH-I ~f R3
~ O~S03M .
In addition to th~ abov~ described ~lactams
ha~ing a sula~e substituen~ in the l~posi~io~
and an acyl~mino ~u~stituent in ~h~ 3~position,
this invention also encompasses ~-lactams having
a sulfate su~stituent .in the l~position and
a~ amino (NH2~ s~s~i~uent,including protected a~ino,
in the 3 position.
GC159
The preferred compounds of this type have the
formula
. Ia
12 R~
N~I2-C ~ C R3
0-S0~3M~
These compounds are intermediates useful f~r
the preparation of corresponding 3-acylamin~
compounds.
As u~ed in formula~ I and Ia, and th~ough-
out ~he ~peeiication, the symbols are as defined
belowO
Rl i~ acyl; Ri ls hydrogen, a~ amino
protecting group or acyl;
R2 is hydrogen or alkoxy of 1 to 4 carbons;
- R3 and R4 are the same or different and
2~ each is hydrogen or alkyl; and
M~ is hydrogen or a cationO
Lis~ed below are definitions of V~EioU5
terms us~d to descxibe the ~lactams o this
in~en-tion. These deinitions apply to the
te~ms as they are used throughou~ ~he spe~ifi-
cation (unless they are o~hexwi~e lLmi~ed
in specific instances~ either individually
or as paxt of a larger group.
2~2
--3--
The terms "alkyl" and "alkox~" refer to both
straight and branched chain groups. Those groups haviny
l to 10 carbon atoms are preferred.
The terms "cycloalkyl" and "cyc]oalkenyl" refer to
cycloalkyl and cycloalkenyl groups having 3,4,5,6, or 7
carbon atoms.
The term "alkenyl" refers to both` straight and
branched chain groups. Those groups having 2 to 10
carbon atoms are preferred.
The term "halogen" refers to fluorine, chlorine,
bromine and iodine.
The term "protected carboxyl" refers to a carboxyl
group which has been esteri~ied with a conventional ester
protecting group. These groups are well known in the
art; see, or example, United States patent 4,144,333,
issued March 13, 1979. The preferred protected carboxyl
groups are benzyl, benzhydr~l and t-butyl esters.
The term "acyl" includes all organic radicals
derived from an organic acid (i.e., a carboxylic acid)
by removal of the hydroxyl group. Certain acyl groups
are, of course, preferred, but this preference should
no~ be viewed as a limitation of the scope of this
inve~tion. Exemplary acyl groups are those acyl groups
which have been used in ~he past to acylate ~-lactam
antibiotics including 6-aminopenicillanic acid and
derivatives and 7-aminocephalosporanic acid and deriva-
tives; see, for example, Cephalosporlns and Penicillins,
edited by Flynn, Academic Press (1972)~ German
Offenlegungsschrift 2,716,677 published October 10, 1978,
Belgian patent 867,994, published December 11, 197
United States patent 4~152,432, issued
_4_ ;
May 1, 1979, United States patent 3,971,778,
issued July 27, 1976, United States patent
4,172,199, issued October 23, 1979, and British
patent 1,348,894, published March 27, 1974.
S The following list of acyl groups is presented
to further exempllfy the term "acyl"; it should
not be regarded as limitiny that term~ Exemplary
acyl groups are:
(a) Aliphatic groups having the formula
1 0 R
wherein R5 is alkyl; cycloalkyl; alkoxy; alkenyl;
cycloalkenyl; cyclohexadienyl; or alkyl or alkenyl
su~stituted with one or more halogen, cyano, nitro,
amino, mercapto, alkylthio, or cyanomethylthio
groups.
(b) Carbocyclic aromatic groups having the
formula
R6~ (CH2 ) r~ C
6~ ~ R2
R~ ~ CH2-O-C- ,
~ ~ 3 ~a~
. W ~f~ GC159
R6 ~O-CH -C -,
R7
R6~R~ 1,
S-CH2-C- or
j~; ~R 8
~=~CH2-S -C- ,
wherein n is 0, 1, 2 or 3; R6, R7, and R~ each
is independently hydrogen, halogen, hydroxyl,
nitro, amlno, cyano, trifluoromethyl, alkyl
of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon
atoms or aminomethyl; and Rg is amino, hydroxyl, a
carboxyl salt, protected carboxyl, formyloxy,
a sulfo salt, a sul~oamino salt, azido, halogen,
hydrazino, alkylhydrazlno, phenylhydrazino, or
~(alkylthio)thioxomethyl~thio.
Preferred carbocyclic aromakic acyl groups
include those having the formula
CH
CH `
.H2NH2
~3~
GC159
--6--
o
HO ~ CH-C- IRg is preferably
Xg
a carboxyl salt or sulfo sal t) and
~ CH-C- (.Rg is prererably
15a carboxyl salt or sulfo salt).
(c) Heteroaromatic yroups having the
:f ormula o
. . Il
~0- ( CH2 ) n~C~ '
~CH-~-
Rg .o
Rlo O-CH~2 -C- ,
..
Rlo-s-(:~H2-c- ~ or
o O
R~.o~(;~C~ ~ -
wherein n is 0, 1, 2 or 3; R9 is as def ined
above; and Rlois a substituted or unsubstituted
5 ,6-or ~membered heterocyclic ring containing
301, 2, 3 or 4 (preferably 1 or 2) nitrogen,
- oxygen and suLfur atoms. Exemplary .heterocyclic
~9 ~7 ~ GC159
--7
rings are thienyL, furyl, pyrrolyl, pyridinyl,
pyrazinyl, thiazolyl, morpllolinyl, pyrimidinyl
and tetrazolyl. Exemplary substituents are
halogen, hydroxyl, nitro, amino, cyano, trifluoro-
methyl, alkyl of 1 to ~ carbon atoms, or alkoxyof 1 to 4 carbon atoms~
Preferred heteroaromatic acyl groups
include those groups o~ the above formulas
wherein R1Ois 2-amino-4 thiazolyl, 2~amino--5-halo- ~
4-thiazolyl, 4-aminopyrimidin-2-yl, 5-amino-1,2,4-
thiad~azol-5-yl, 2-thienyl or 2-furanyl.
(d) [[(4-Substituted-2,3-dioxo-1-piperazinyl)-
carbonyl~amino]arylacetyl groups having the formula
1~ li , 11 ~
~ C~CH-NE~WC~N N~R12
R
., 11 h~
O O
wherein R~ is an aroma~ic group (includlng
carbocyclic aromatics such as those of -the formula
6 ~ R8
~5
and heteroaromatics as included within the definition
of Rl~and ~ is alkyl, substituted alkyl
(wherein ~he alkyl group is substi~uted with one
or more halogen, cyano, nitro, amino or mercapto
groups)~ arylmethyleneamino (i.e , -N=CH Rll
wherein Rll is as defined above), arylcarbonylami~o
O
(l.e., ~NI~-C-R11 wherein Rllis as defined ~bove)
or alkylcarbcnylamino.
^` (iC~l~Y
--8--
Preferred [~14-substituted-2,3-dioxo-1-
piperazinyl)carbonyl]amino~arylacetyl groups
include those wherein R12 is ethyl, phenylmethylene-
amino or 2-furylmethyleneamino.
(e) (Substituted oxyimino)arylacetyl groups
having the formula
O , .
~C-C=N-O-R13
Rll
wherein ~llis as defined above and R13 is hydrogen,
alkyl, cycloalkyl, alkylaminocarbonyl, arylamino-
O
carbonyl (l.e., -~-NH-Rll wherein Rllis as defined
above) or substituted alkyl (wherein t~e alkyl
group is substituted with 1 or more halogen,
cyano, nitro, amino, mercapto, alkylthio,
aromatic group (as defined by Rl~, carboxyl
(includin~ salts thereof), amido, alkoxycarbonyl,
phenylmethoxycarbonyl, diphenyLmethoxycarbonyl,
hydroxyalkoxyphosphinyl, dihydroxyphosphinyl,
J hydroxy (phenyLme~hoxy)phosphinyl, or dialkoxy
phosphinyl substituents).
Preferred (substituted oxyimino)aryl~
acetyl groups include those wherein Rl1is
2-amino-4-thlazolyl. Also preferred are those
groups wherein R13 is methyl, ethyl, carboxy~
methyl, ox 2-carboxyisopropylO
(f) (Acylamino)arylacetyl ~roups having
the formula
O o
-~ cH-N~c-~l4
R~
wherein Rllis as defined above and R14 is
932'72 GG 159
_g_
R7
~ (CH2 ) n~~ ~ amino, alkylamino,
5 (cyanoalkyl ) amino, amido, alkylamido, (cyanoalkyL ) -
amido, -CH2-NH-J ~ ~ , -CEi~CH2-C-NH-CH3 ,
S02-N (CH2~c~2~0H) 2 ~ ~CH3 ~ .
OH
.
OH OH
~ ~N~ N ~ )l
20~ N ~ , or ~ ~ N ~ N~_JN~CE~ O
Pre~erred (acylamino)arylacetyl groups
of the above formula include those groups
wherein ~4 is amino, or amido. Also preferr~d
are those groups wherein R11is phenyl or 2-thienyl.
(g ) [ [ [3~Substituted-2-oxo-1-imidazoli-
dinyl ] carbonyl~ aminol arylacetyl groups having the
formula o
o Ol /C ~
-C-CH-N}~-C-N N-R15
RLl CH 2--CH 2
'~ GC159
--10--
wherein Rllis as defined above and R15 is hydrogen,
alkylsulfonyl, arylmethyleneamino (i.e.,
-N=CH-~1wherein R11is as defined above),
-C-R16 (wherein R16 is hydrogen, alk~l or
halogen substituted alkyl), aromati.c group (as
defined by R]1above), alkyl or substituted alkyl
(wherein the alkyl group is substituted with one
or more halogen,cyano, nitro, amino or mercapto
groups).
Preferred [[3-substituted-2-oxo-1-imidazoli-
dinyl]carbonyl]aminolarylace-tyl groups of the
above formula include those wherein Rllis phenyl
or 2-thienyl. Also preferred are those groups
wherein Rl's is hydrogen, methylsulfonyl, phenyl-
methyleneamino or 2-fur~lmethyleneaminoO
The term "cation", as used throughout the
specification, refers to any positively charged
atom or group o atoms. The "-O-S03M " ~u~stituent
~0 on the nitrogen atom of the B-lactams of this
invention encompasse~ all sulfat~ salts.
Pharmaceutically acceptable salts are, of
course, preferred, although other salts are also
useful in purifying the ~roducts of this invention
or as intenne~iates for the preparation of
pharmaceutically acceptable salts. The cationic
portion of the sulfonic acid salts of this
inve~tion can be obtained from either organic
or inorganic bases. Such cationic portion
includes, but is not limited to, the following
ions: ammonium; substituted ammonium, such as
alkylammonium (~ , tetra n butylammonium,
referred to herelnafter as tetrabutylammonium);
alkali metal, such as lithium, sodium and potassi~m;
alkaline earth metal, such as calcium and magnesium;
GC159
pyridinium; dicyclohexylammonium; hydrabaminium;
benzathinium; N-methyl~D~glucaminium.
As set forth in formula I, and in the
definitions following formula I, M can be hydrcgen
e~ially ~en the Rl group contams a basic
function. Such compounds are often re~erred
~o in the art as "inner salts" by virtue of a
positive and negative charge in the molecule.
Some of the compounds of this invention may
be crystallized or recrystallized from solvents
containing water. In these cases water of
hydration may be formed. This invention co~-
templates stoichiometric hydrates as well as
compounds containing variable amounts of water
that may be produced by processes suh as
lyophiliaation~
~ -Lactams having a sulfate substituent
in ~he l-position and an amino or acylamino
substituent in the 3-position contain at least
one chiral center - the carbon atom (in the
3~position of the B-lactam nucleus) to which
the amino or acylamino substituent is attached.
This invention is directed to those ~lactams
which have been described above, wherein the
stereochemistry at the chiral center in the
3-position of the ~-lactam nuclues is the same
as the configuration at the carbon atom in
the 6-position o naturally occurring penicillins
(~ ~, penicillin G) and as th2 con~iyuration at
the carbon atom in the 77position o na~urally
~32~ ~Cl59
-12
occurring cephamycins (e.g., cephamycin C).
With respeet to the preferred ~-lactams
of formulas I and Ia, the structural formulas
have been drawn to show the stereochemistry
at the chiral center in the 3-posi~ion. Because
of the nomenclature convention,those compounds
o formulas I and Ia wherein R2 is hydrogen
have the S-eonfiguration and those compounds
of formulas I and Ia wherein R2 is alkoxy have
the R configuration.
Also included within the scope of this
invention are raeemic mixtures which contain
the above-deseribed ~-laetams.
~,~
0~ GC159
13~
~ -Lactams having a sul~ate (-O-SO3M )
substituent in the l-position and an
acylamino substituent in the 3-position have
activity against a range o~ gram-n gative and
gram~positive organisms. The sulfate
substi~uent is essential -to the activity o~ the
compounds of this invention.
The compounds of this invention can be
used as agents to combat bacterial infections
(including urinary tract infections and respiratory
infections) in mammalian species, such as
domestica~ed animals (e.g., dogs, cats, cows,
horses, and the like) ~nd humans.
For aombating bactexlal infections in
mammals a compound of this invention can be
administered to a mammal in need thereof in
an amount of about 1.4 mg/kg/day to about
350 mg/kg/day, preferably about 14 mg/kg/day
to about lO0 mg/kg/day. All modes of adminis-
tration which have been used in the past to
deliver penicillins and cPphalosporins to the
site of the in~ection are also contemplated
for use with the novel family o~ Bolactams
of this invention. Such methods of administration
include oral, intravenous, intramuscular, and
as a suppository.
.
~93~ GC159
-14-
The B-lactams of thls invention can be
prepared from the corresponding hydroxamic acid
having the formula
II
R2 _4
Rl-NH I l R3
~C - N-OH.
A compound of formula II can be O-sulfated by
reacting the precursor compound with a complex
of pyridine and sulfur tr1oxidec The reaction
can be run in an organiC solvent ~ preferably
pyridineO~ This reaction yields a compound of
fo~mula I wherein M~ is pyrldinium ion~ Instead
of using a pre-formed complex of pyridine
~nd sulur trioxide, the complex can be formed
in situ, e g., using chlorosulfonyltrimethylsilyl
. ~ .
ester and pyridine as reagents. Alternatively,
a complex of dLmethylformamide sulfur txioxide
or 2,6-lutidine-Sulfurtrioxide can be used.
using conventional techniques (~ , ion-
exchange resins, crystallization, or ion pair
extraction) the pyridinium salt formed by the
above procedure can be converted to other salts.
These techniques are also useful for converting
the products of formula I or any of the inter~
mediates described herein to other salts.
~9~ GC159
-15-
Compounds of formula II can be prepared from
an amino acid having the formula
III tH~R4
NH2-lH C R3
~C - OH .
The amino group is first protected with a classical
protecting group (~ , t-butoxycarbonyl, benzyloxy-
carbonyl, o nitrophenylsulfenyl, etc.), yieldinga compound having the formula
XV OH R
~ ` 4
A~NH CH - ~ ;R3
' ,l - OH.
.In oxmula IV, and throughout the specification,
t~e symbol "A" refers to a nitrogen protecting group.
The carboxyl group o a protected amino
acid of ormula IV is then reacted with an amine
salt having the formula
Y-O-NH3Cl,
In formula V, and throughout the specification,
the symbol "Y" refers to benzyl or pivaloyl. The
reaction proceeds in the presence of a coupling agent
such as l ethyl~3~3-dimethylaminopropyl)carbodiimide
30 or dicyclohex~lcarbodiimide, and yields a compou~d
having the formula
~ 3~7æ GC159
-16
VI
OH
A-NH-f~I - C - R3
~,C - NH-O-Y.
O
The hydroxyl group o a compound of formula VI
is converted to a leaving group, using, for
example, a classical reagent such as methane
sulfonyl chloride (methanesulfonyl is referred
to hereinater as "Ms").
The fully protected compound having the
formula
VII OMs
, A~NH CH - C`- ~
~C - NH`O-Y
is cyclized by treatment with base, e.~.,
potassium carbonate. The reaction is preferably
carried out in an organic solvent such as acetone,
under reflux conditionsj and yields a compound
having the formula
VIXI . R4
A-NH~fH I ~3
C - N O~Y .
Alternatively, cyclization of a compound
of formula VI can be accomplished wit~out irst
co~verting th~ hydroxyl group to a leaving groupO
. ~932 ~ 2 GC159
~17-
Treatment of a compound o~ formula VI with
triphenylphosphlne and d ethylazodicarboxylate,
yields a compound of formula VIII.
Both of the methods disclosed above for
ring closure of a compound of formula VI re~ult
in the inversion of the stereochemistry of the
R3 and R4 substituents.
Deprotection of the 3-amino substituent
of a compound of formula VIII can be accomplished
using art-recognized techniques. If, for example,
the protecting group is t-butoxycarbonyl,
trifluoroacetlc acid can be used to deprotec~
the amino group. If the protecting group is
benzyloxycarbonyl catalytic (_ ~, palladiu~ on
15 charcoaL) hydrogenation can be used. If the
protecting group is o-nitrophenylsulfenyl,
~toluenesulonlc acid can be u~ed in combination
with ~thiocresol. The dep~otected compound has
the ~ormula
2~
IX _4
NH~-CH - C ~ R3
~C - N-O-Y .
Well known acylation techniques can be used
to convert a compound having the formula IX
to a compound having the formula
X -4
Rl-NH f ~ I R3
C - N-O-Y .
27:~
GClS9
-18-
Exemplary techniques include reaction wlth a
carboxylic acid (Rl-OH) or corresponding carboxylic
acid halide or carboxylic acid anhydride. The
reactions wi-th a carboxylic acid procee~ most readily
in the presence of a carbodiimide such as
dicyclohexylcarbodiLmide and a substance capable
o~ forming a reactive intermediate 1n situ
such as N hydroxybenzotriazole or 4-dlmethyl-
aminopyridine. In those instances wherein the
acyl group (Rl) contains reactive functionality
(such as amino or carboxyl groups) it may be
necessary to first protect these functional
groups, then carry out the acylation reaction,
and inally deprotect the resulting productO
Conversion of a compound of ormula X
to the corresponding compound having a 3 alkoxy
substituent can be accomplished by first
halogenating the amide nitrogen to obtain a
compound having the formula
~0
XI C1 R4
Rl-N-~IH I R3
~C - N~O-~ ~
Reagents and procedures for N chlorinating
amides are known in the art. Exemplary
reagents axe tert.~butyl hypochlorite, sodium
hypochlorite, and chlorine. The reaction can
be run in an organic solvent (~ , a lower
alkanol such as methanol) or in a two phase
solvent system (~ water/me~lylene chloride)
in the presence of a ~ase such as sodiu~
borate decahydrate. The reaction is preerably
run at a reduced temperature.
GC159
-19
Reaction of a compound of formula XI
with an alkoxylating agent, e , an alkali
metal alkoxide, yields a compound (in combination
with its enantiomer) having the formula
XII
0-alkyl R4
R -NH~C ~ C-R
1 1 1 3
C -N-0-Y
The reaction can be run in an organic solvent,
e.q., a polar organic solvent such as tetxa-
hydrouran, at a reduced temperature.where Rl
functions as an amino protecting group, it can be
removed by con~entional pro~edure~ to give the
amino derivative.
Alternatively, a compound of formula X
can be converted to a compound o formula XII
using a single step proceduxe. The alkoxylatiny
agent can first be mixed with a compound of
2G formula X and the N-chlorinatlng rea~ent then
added to the reaction mixture.
Reduction of a compound of formula X
or XII to yield the corresponding compound of
formula II, iue.,
II -2 -4
Rl-NH-C - C-R
O~C N~OH
can be accomplished by catalytic hydrogenation
ox, if Y is pivaloyl, by treatment with a base
such as sodium sulfide or sodium hydroxide.
Alternatively, ~ benzyloxycarbonyl-
~aminoxy-D-alanine, methyl ester hydrochloride,
or other compounds having the "NH-0~" grouping,
2~2
GC159
-20-
.
can be used in place of an amine salt o formula V
in the above described synthesis.
An alternative synthesi~ for the compounds
of this invention wherein R2 is hydrogen
comprises preparation o~ a compound of formula
VIII followed by deprotection o the l-hydroxy
group of that co~pound to yield a compound having
the formula
IX R4
-
A-MH-CH - C-R
I 1 3
0~C N-O~ .
Deprotection can be accomplished using art~recognized
procedures, ~ ~, if Y is pivaloyl, treatment with
hydrogen peroxide and a base or treatment with sodium
sulfide, or ifY i5 benzyl, by hydrogenolysis.
. Sulfation of a compound of formula IX or XII
using the above-described procedures (lOe.,
reaction of the precursor compound with a
compLex of pyridine and sulfur trioxide,
dime~hylformamide and sulfur trioxide or
2,6.lutidine and sulfur trioxide) yields
a compound having the formula
XIII l2 R~
A-NH-f - C R
C - N-O-S03M~.
O~
Removal of the protecting group "A" from a
compound of ~ormula XIII yields a ~ey
~9~
GC159
~21-
intermediate having the formula
XIV l2 _4
NH -C -C - R
~C N-O~S03M
The technique used for removal of the pxotecting
group will depend on the particular protectin~
group. For example, i~ A is ~enzyloxycarbonyl,
catalytic hydrogenation can be used.
Acylation of an intermediate of formula XIV
using any of the ~echniques described above
yields a corresponding product of formula I~
The following examples are specific
embodiments of this invention.
.
~9 327 ~ GC159
-22-
Example 1
(3S-trans)~4-Methyl-2-oxo-3-[(phenylacetyl)amino]-
l-azetidin 1 sulate, ~vridine salt
_ _ Y- '
A) N~(Phen lacet l)-L-threonine
L-Threonine (3S.7 g) is dissolved in lN
sodium hydroxide (1 liter) and chilled to 5
to -10C. To the cold, mechanically stirred
solution is added dropwise phenylacetyl chloride
(46.3 g). The reaction mixture is stir.red ~or
about 16 hours as the temperature rises to 26C.
The mixture is washed with ether, acidified to
pH 2 wi~h hydrochloric acid, and extracted wi~h
e~hyl acetate (two times). The combined extracts.
axe dried over sodium sulate and concentrated
under reduced pressure until crystalline solids
form. Ether is added to the mixture and the
c~ystals are collected (34.8 g); melting point
161~163C.
B) N2~Phenylacet l)-N-( henvlmethox )~-threoninamide
N-(Ph2~ylacetyl)-L-threonine (9.5 g) is
suspended in water (approximakely 50 ml), and
a solution of O~benzylhydroxylamine hydrochloride
(7.04 g) in water (50 ml) is added. The pH of
the stirred mixture is adjusted ~o 4.2 with lN
potassium hydroxide~ and a solution o~ 8.43 g
o 1-ethyl-3-(3-dimethylaminopropyl)carbodilmide
hydrochloride in water (50 ml~ is added. The p~
is maintained at 4 . 2 with lN hydrochloric acid .
~ ~ ~ GC15~ -
-23
After thirty minutes an oily precipitate is
present in the reaction vessel. The product is
partitioned ~etween ethyl acetate and brine,
and the organic layer is then dried over sodium
sul~ate and concentrated to a solid (.8.7 g).
`C) (3S-trans)-4-Methyl-3-(phenylacetyl)-l-
_
To a cold (.0C~ solution of N (phenylacet~11-
N-(phenylmethoxy)-L-threoninamide (7.5 g) in
dry tetrahydrofuran (200 ml) is added diethyl-
azodicarboxylate (4.2 g) followed ~y triphenyl-
phosphine (6.34 g). The reaction mixture is
stirred for about 16 hours at 26C under nitrogen.
The solven~ is then removed, and ~he residue
chromatographed on silica gel (ether~hexane)
to afford the title compound (200 g) white solids.
R~crystallization from chloroform/hexane
affords a purified sample, ~elting point 97099C.
D) (3S trans)~l-Hydroxy4~methyl 3~(phenylacetyl)-
amino]-2-azetidinone
A solution of (3S-trans)~4-me~hyl 3 (phenyl-
__
acetyL) l-(phenylmethoxyJ-2-azetidinone (0.5 g)
in ethanol (15 mL) containing O . 250 of lO~
palladium on charcoal is hydrogenated at 26 C
for one hour. The reaction mixture is ~iltered,
the catalyst washed with ethanol, and the combined
filtrates evaporated to an oily residue. Ether
(approxLmately lO ml) is added and the resulting
~9 ~7 ~ GC153
-24-
solids are hardened and collected yielding 0.34 gof the title compound, melting point 118 135 C, dec.
AnalO Calc'~. for C12Hl4M203:
C, 61.52, H, 6.02; N, 11.96
Found:
C, 61.06; H, 6.03; N, 1]..80
Ej (3S trans)-4 Methyl-2-oxo-3-[(phenylacetyl)~
__
amino~ azetidin~l sul~ate, ~yridine salt
To a solution of (3S-trans)-l-hydroxy-4
methyl-3-~(phenylacetyl)amino]-2-azetidinone
(0.225 g) in dry pyridine (9 ml) is added
molecular sieves 4A (1 ml) followed by pyridine-
sulfur txioxidP complex ~0.61 g)0 The rPaction
mixture is stirred under nitrogen or five hour5 .
at 26C, f~lterad and concentrated under reduced
pxessure. Purification on HP~20 resin (water/
acetone) affords 0013 y of ~he produot as a
hygroscopic solid.
Anal. Calc'd. for C H gN30 SH20:
- 17 1 6
C, 49.62; H, 5014; N, 10c21; S, 7~79
Found:
C, 50.37; H, 5007, N, 10~32, S, 7.73
7~
25- GC159
Example 2
[3S-[3~(R*)4Bl]-3-[[~(4-Ethyl-2,3-di.oxo-l-~iperazlnyl)
,
carbonyl]amino]pherlylacetyl]amino~-4-methyl-2-oxo-
l-azetidinyl sulfate, pyridine aalt (1:1)
A) 2-Nitrophenylthio-L-threonine
L~threonine (11.9 g) is added to dioxane
(125 ml) and ZN sodium hydroxide (50 ml). To
the vigorously stirred solution, o-nitrophenyl-
sulfenyl chloride (20.9 g) is added in ten equalportions over ifteen minutes, while 2N sodium
hydroxide ( 60 ml) is slowly added dropwise. -After
five more minutes the reaction mixture is diluted
with water (400 ml) and acidified to pH 2.5 wi~h .
10% potassium hisulate. The organic layer is
immediately ex~racted with ethyl acetate (three
200 ml portions), and the combined extracts are
dried over sodium sulfate, and then concentrated
to an oil. The product crystallizes on scratching
(20.0 g). Rec~ystallization of 17 g from
acetone/hexane affords g.5 g o crystals, melting
point 145-148C which are stor~d in a freezer
and used promptl~.
B) MZ-[(2-NitroPhenYl)thio] N~(phenylmethoxY)
~5 ~
L-threoninamide
.
2-Ni~rophenylthio-Lrthreonine (39.0 g)
and O-benzylhydroxylamine hydrochloride (22.92 g)
are suspended .in water (500 ml) and with VigOEOuS
stirring the pH is adjusted to 4 . 2 with lN sodium
hydroxide. ~ solution of l~ethyl-3~(3-dimethyl
GC159
-26- .
aminopropyl)carbodiimide hydrochloride in water
(100 ml) is added portionwise, while the pH is
controlled at 4.2 with addition of 10~ potassium
bisulfate. The addition lasts five minutes,
and stirring and pH control is continued ~or an
additional thirty minutes, whereupon a heavy
granular precipitate is present. The reaction
mixture is extracted with ethyl acetate (foux 300 ml
portions) and the com~ined extracts are dried
over sodium sulfate and concentrated to an oil
(approximately 50 g).
Chromatography on SilicAR CC-7 (2 kg/
methylene chloride~50% methylene chloride/ethyl-
acetat~) affords the product as a foam tl9.5 g).
A portion is crystallized and recrystallized
from acetone/hexane to provide an analytical
sample, melting point 130-133~C.
C) (3S-trans)-4-Methyl-3-~L(2 nitrophenyl~thio~-
To a cold solution (0C) of N -[(2-nitro~
phenyl)thio]-N-~phenylmethoxy)-L~hreoninamide
~9.4 g) in pyridine (34 ml) is added methane~
sulfonyl chloride (8.58 g). After two hours at
0C the mixture is poured into ice water (100 ml)
and extracted with ethyl acetate (five ~G0 ml
portions). The extracts are washed with ice cold
10~ po-tassium bisulfate (four 100 ml portions),
dried over sodium sulfate, and concentrated
under reduced pressure without heat, yielding
GC159
-27-
9.6 g of a residue.
A solution of the residue in acetone (125 ml),
is added dropwise over thirty-five minutes to
a refluxing mixture o~ anhydrous potassium
carbonate (10 g) and acetone (approximately
600 ml). Ater 2.5 hours the mixture is cooled
to 26C, ~iltered, and evaporated ~o a foam.
Chromatography on SilicAR CC-7 (methylene chloride/
hexane 9:1~methylene chloride)- affords the
product as a clear oil (2.15 g). Crystallization
and recrystallization from chloroform/hexane
produces an analytical sample, melting point.
97 laOC.
D) (3S trans) 3-Amino-4 methyl-l (phenylmethoxy)~
Z azetidinone,toluenesulfonate
. . , . . _
To a stirred solution of (3S-trans)~4-
methyl~3-L[(2-nitrophenyl~thio~amino]-1-(phenyl-
methoxy)-2-azetidinQne (1.07 g) in methylene
chloride (20 ml) is added ~-tolusnesulfonic
acid (0.57 g) and ~thiocresol (0.74 g). The
reaction mixture i5 stirred under nitrogen for
tw~ hours, whereupon the solvents are removed
in acuo, and the residue is triturated with
ether (four 25 ml portions), to afford 0.9 g
of the title compound.
~93272 GC15~
-28-
E) (3S-trans)-3-[[[l(4-Ethy1-2,3-dioxo-1
_
i erazinvl)carbonYl]aminolphenylacetyl]amino~-4-
~ ~ ,, ., ~
methy~-l-(E~nYlmethoxyL__-azetidinone
A suspension of ~-[[(4-ethyl-2,3-dioxo-1-
piperazinyl)carbonyl]amino]benzeneacetic acid
(0.879 g) hydroxybenzotriazole (0.42 g), and
dicyclohexylcarbodiimide (0.56 g), in dimethyl-
formamide (15 ml) is stirred at 26 C ~or one
hour, at which point a solution of (3S-trans)-
3-amino-4-methyl-l~(phenylmethoxy)-2-azetidinone,
toluenesulfonate (0.95 g) and diisopropylethyl-
amine (0.44 ml) in dimethylformamide (5 ml) is
addedO The reaction mixture is stirred at room
t~mperature for about 16 hours, then poured i~to
water (lOO~ml) and extracted with ethyl acetate
(thLee 100 ml portions). The combined organic
~extracks are washed with wa~er (three 100 ml
portions) and aqueous sodium bicarbonate solution
(one 100 ml portion), then dried over sodium
2Q sulfate and concentrated und~r reduced pressure
to a semi~solid residue. Liquid chromatography
(ethyl acetate) affords the desired product as
a foam ~0.599 g). Recrystallization from
chloroorm/isopropyl ether ,yields the title
compound, melting point 100~105C.
~ 3%7~ GC159
F) (3S-trans)-3-[[[[(4-Ethyl-2,3-dioxo-1-piperazinyl)-
carbonyl]amino]phenyla etyl~amino]-l-hydroxy-4-
methyl-2-azetidinone
(3S-trans)-3-[~[~(4~ethyl-2,3-dioxo-1-
piperazinyl)carbonyl]amino]phenylacetyl]amino~-4-
methyl l-(phenylmethoxy)-2~azetidinone (0.270 g~ is
dissolved in ethanol (25 ml) and hydroyenated over 10
palladium on charcoal catalyst (130 mg) ~or two
hours. The reaction mixture is filtered and
concentrated to a solid (0.220 g)~
G) ~3s~[3u(R*)~4B]~3-[I[~(4-Et-hyl-2~3-di
m
15 salt (1~
To a solution of (3S trans)-3~[[[[(4~ethyl=
2,3 dioxo~l piperazinyl)carbonyl~aminoi l~hydroxy~
4.methyl-2~azetidinone (0.220 g) in pyridine
(7 ml) is added 4A molecular sieves (approximately
1 ml) and pyridine-sulfur trioxide complex
(O.33 g). After stirring under nitrogen at
26C for 4.5 hours, the xeaction mixture i5
filtered and concentrated to an oil. Chroma-
tography on HP 20 AG resin (water/acetone)
followed by lyophilization of the appropriate
fractions afrords the desired product as a
powder (0.080 g).
Anal. Calc d. f ~19 23 5 9 5 5 Z
C, 47O05; H, 5.26; N, 13.72
Found:
C, 46.36; H, 4.74; N~ 13O42
GC159
-30-
Example 3
[3S(Z)}3-[~(2-Amino-4-thiazolyl)(methoxyimino)-
acetyl~aminoJ-2~oxo-1-azetidinyl sulfate, po-tassium
salt
s
A) -[(Phenylmethyl?oxy]-~-aminoxy-~-alanine
methyl ester hydrochloride
Hydrogen chloride gas is bubbled into ice
cold methanol (200 ml) for twenty minutes.
lo ~-L (phenylmethyl)oxy]-D-cycloserine (5.0 g) is
added, and the cloudy solution is stirred at
26C for twelve hours. The reaction mixture
is iltered and concentrated into a semisolid
residue which upon titration with ether (two
200 ml por~ions) gives 4.6 g o solid, melting
point 110 112C.
[A more quantitative alternative procedure
c~mprises preparation of ca. lN methanolic
hydrogen chloride solution by adding 7.1 ml
acetyl chloride dropwise to 100 ml of chilled,
stirred, me~hanol. After thirty minutes,
a f ~phenylmethyl)oxy]cycloserine (5.0 g) is
added, the mixture is evaporated after l2 hours,
and the residue is triturated wlth ether. The
resulting cxystalline mass is collected by
filtration and dried ln vacuo yielding 5~7 g
of t~e title compound.]
~i93~ GCl59
-31-
B) N -[[(Phenylmethyl~oxy]carbonyl]-N-[2-[[[(phenyl-
methyl)oxy]carbonyl]amino]-3~methoxy-3-oxopropoxy]-
L-serinamide
To a suspension of N-[[(phenylmethyl]oxy]-
carbonyl]-L~serine (3.46 g) in water (15 ml),
is added an aqueous (lS ml) solution o
a- r (phenylmethyl)oxy] ~-aminoxy-D-alanine methyl
ester hydrochloride (4.49 g). The mixture is
vigorously stirred (air stirrer), while adjusting
to pH 4.2 with lN potassium hydroxide. A
solution of 1-ethyl-3-(3-dimethylaminopropyl)-
carbodiimide in water (10 ml) is added portionwise
over five minutes, while the pH is maintained
at 40 ~ by addition of lN hyd~ochloric acid~
After stirring or an additional twenty minutes,
the reaction mixture is saturated with sodium
chloride and extracted with ethyl acetate (five
. t~mes). The combined ethyl acetate extxacts are
dried over sodium sulfate and concentrated under
reduced pressure to a V15COU5 oil (508 g~
c~ ) ~.v~ ~ _~D~-
amino]~2-azetidinone
To a cold (0 5C) solution of N ~[(phenyl-
methyl)oxy]carbonyl]-N-[2-[[~(phenylmethyl)oxy~-
carbonyl]amino]-3-methoxy-3-oxopropoxy~-L-serinamide
(6008 g) in distilled tetrahydro~uran (lO0 ml)
is added triphenylphosphine (3.6 g) followed by
diethylazodicarboxylate (2.15 ml, 2~38 g). The
reaction mixture is allowed to stir for twelve
~9327~ GC159
-32-
hours under nitrogen, whereupon 7.0 ml of1,8-diazabicyclo E5.4 .O.]undecan-7-ene is added.
After 30 minutes, tetrahydrofuran is removed by
evaporation and the resulting residue is partitioned
5 between ethyl acetate and saturated sodium
bicarbonate. The aqueous layer is washed once
with ethyl acetate, then adjusted to pH 2 with
saturated potassium bisulfate, and extracted with
ethyl acetate (five times). The combined
extracts are dried and concentrated to a
crystalline solid (1.8 g). A portion is
recrystallized ~xom acetone/hexane (two times)
to give an analytiGal sample, melting point
12~131Co
D) ~
To a solution of (3S)-l~hydroxy 3-[[[(phenyl-
' methyl)oxy]carbonyl~amino~azetidinone (lol g)
in dry pyridine (45 ml) containing 4A molecular
sieves (caO 1 ml) is added pyridine-sulfur
trioxide complex (1.48 g~. After stirring for
two.hours at 26C, under nitrogen, the pyrldine
is removed under reduced pressure, and the
residue is partitioned between pH 403 buffer
(O.S M monobasic potassium phosphate, 50 ml)
and ethyl acetate (50 ml). The aqueous layer
is washed once more with ethyl acetate (50 ml),
then treated with tetrabutyl ammonium hydrogen
sulfate (1.57 g), and extracted with methylene
. ~93~ GC159
-33
chloride (three 50 ml portions)O The combined
organic extracts are dried over sodium sulfate
and concentrated to a viscous oil (1.81 y).
The material is puxified on SilicAR CC-4 using
methylene chloride/methanol (1% to 8%) as eluant
to afford 0.71 g of oil.
E) [3S(Z)]-3-~[(2-Amino-4-thiazolyl)_(methoxyimino)-
acetyl]amino]-2-oxo-1-azetidin~l sulfate, potassium
1 0 5_
A solution of (3S)-3-[[[(phenylmethyl)oxy]-
carbonyl]amino]-2-oxo-1-azetidinyl sulfate,
tetrabutyLammonium salt (0.70 g) in dimethyl-
formamide i5 hydrogenated for 6.5 hours using
10% palladium on charcoal catalyst (0.35 g)~
After filtration to remove catalyst, (Z) 2 amino-
a (methoxyimino) 4 thiazoleacetic acid. (0.251 g)
dicyclohexylcarbodiimide, followed by hydroxy~
benzotriazole (0.191 g) are added to the mixture
and it was stirred for about 16 hours at 26C.
The rPaction mixture is concentrated under high
vacuum (40C), diLuted with acetone (25 ml),
and.then filtered. The solids are washéd with
a small amount of acetone and the combined
filtrate is treated with a solution of potassium
perfluorobutane sulonate (0O425 g) in aceto~e
(2 ml). Precipitation occurs at once. Ether
(20 ml) is added and the precipitated solids
are collected by filtration (0.250 g). Purification
by HP~20AG chromatography using water-acetone
~93272 GC159
-34-
(0-5~) as eluant gives the product as a powder
after lyophilization (O.Q45 g).
Anal. Calc'd. for CgHloN5S207K:
C, 26.79; H, 2.50; N, 17.36; S, 1~.89; K, 9.69
Found: C, 2g.63; H, 3.. 16; N, 16.95; S, 17.69; K, 1.78
The product is a mixture of tlle potassium salt and
zwitte.rion, and displays appropriate IR and NMR spectra.
Exam~le 4
(S) 2-Oxo~3-[( hen lacetvl)amino]-l~azetidinyL
P _ Y ~ ~
sulfate, pyridine salt
A) N -(Phenylacetyl)-N-[(~e~lmethyl)~y]-L~
serinamide
~ .
N-Phenylacetyl L-serine (808 g), l-hydroxy-.
benzotriaz~le hydrate (6.03 g) and o-benzyl~
hydroxylamine (4.84 g) are dissolved in tetra
hydrofuran (450 ml) and chilled to 0C. A solution
of dicyclohexylcarbodiimide (8~1 g), in tetra~
hydrofuran (50 ml) is added over a 0c5 hour
period. The reaction is allowed to warm to 26 C
and stir for about 16 hours. The mixture is
filtere~, and the iltrate concentrated under
reduced pressure to a se~i-solid residué. The
addition of ethyl acetate (50 ml) causes crystal-
lization. The solids are collected and dried(6.9 g, melting point 150-151C).
The filtrate is washed with sodium bicarbonate,
water, potassium bisulfate, and water (~wice~,
and then dried over sodium sulfate and concentrated
30 until a second crop o crystals is obtained
(2.6 g), melting point 131 135C.
~ 3~
GC159
-35-
B) (S?-3-~(Phenylacetyl)amino]-l-[(phenylmethyl)-
ox~]-2-azetidinone
To a cold solution (0C) of N~-(phenylacetyL)-
N-[(phenylmethyl)oxy]-L-serinamide (6.88 g)
in di.stilled tetrahydrofuran (300 ml), under
nitrogen, is added triphenylphosphine (11.~0 g)
followed by diethylazodicarboxylate (6,60 ml).
The solution is allowed to warm to 26C and
stirred for twelve hours. After removal of solvent
under reduced pressure the resulting residue
is applied to a silica gel column (eluant ether/
hex~ne-~ether). Combination of fractions gives two
batches; 1O3 g (pure) and 2~5 g (ca. 60% pure)
(total yield ca~ 20 2 g)O The pure material is
recrystallized from ethyl acetate/hexane to give
solids; melting point 130-131C.
,
Cl (S) l-Hydroxy-3-~(phenylacetyl)amino~-2-
azetidino_
To an ethanolic (100 ml) solution o
(S)-3-[(phenylacetyl)amino~ [(phenylmethyl)
oxy~-2-azetidinone (0.8 g, contaminated
with triphenylphosphine) is added 10~ palladi~n :
on charcoal catalyst (0.4 g) and the mixture is
hydrogenated under ca. 1 atom pressure for one
hour~ The reaction mixture is iltered through
prewashed Celite and concentrated under reduced
pressure to an oily residue. The product is
partitioned between 50% sodium bicarbonate
solution and et~yl acetateO The
* Trade Mark
GC159
-36-
aqueous layer is acidified with potassium bisulfate
and extracted with ethyl acetate (three 50 ml
portions). The combined extracts are dried
over sodium sulfate and concentrated to a
crystalline solid (ca. 200 mg~. Recrystalli2ation
from met~anol/chloroorm a~fords an analytical
sample, melting point 145-146C dec.
D~ (S)-2-Oxo-3-~(phenylacetyl)amino]-1-azet _inyl
sulfate, ~Yridine salt
1 0 ~
(S)-l-Hydroxy-3-[(phenylacetyl)amino]-2-
azetidinone (0 ol50 g) is dissol~ed in dry pyridine
Clo ml) containing 4A molecular sieves. Pyridine
5ul~ur trioxide complex (0O216 g) is added and
lS the solution is stirred under nitrogen for two
houxs. After concentration under reduced
p~essure, and vacuum drying, the product i5
purified on HP~20AG (25 ml). Elution with water
and then 5% acetone/water, followed by lyophilization
f the desired fractions affords the product
(0.110 g) a~ a hygxoscopic powder;
~]D6= ~5.9 (c=0.645, water)
Anal. Calc'd. for C16H17N3O6 2
C,. 4~.15; H, 4.74; N, 10~71; S, 8.34
Found:
C, 49.47; H, 4.67; N, 10~81; S, 8.25
.
~ `~ GC159
-37-
Example 5(S)-2-Oxo-3-[~ henylacetyl)amino]-l-azetidin~l
sulfate, potassium salt
-
(S)-2-Oxo-3-[(phenylacetyl)amino]-1-azetidinyl
sulfate, pyridine salt (1.5 g; see example 4) is
dissolved in water and applied to a column
containing 150 ml Dowex 50-X2K resin. Elution
with 1500 ml double distilled water gives fi~e
300 ml fractions which are lyophilized. Fraction
1 contains 1.33 g of the title compound.
Anal. Calc d- for Cll 11 2 6 2
C, 36.15; H, 3.86; N, 7.66; S~ 8.77; K,- 10.70
Found:
C~ 36014; H, 3.15; N, 7020; S, 9.81; K~ 14.01
Exam~le 6
(S)-2-Oxo-3-[(phenylacetyl)amino]-l-azetidinyl
sulate, tetrabutylammonium salt
_
(S)-2-Oxo--3-[(phenylacetyl)amino~ aæetidinyl
sulfate, potassium salt ~93 mg, see exam~le S) i5
dissolved in water (5 ml) and tetrabutylal~nonium
hydrogen sulfate (102 mg) is added. The solution
is $haken for a few m,inutes, saturated with sodi~m
chloride and extracted with methylene chloride
(four times). The combined extracts are dried
over sodium sulfate and concentrated under
reduced pressure to an oil (112 mg).
~nalO Calc d- for Cll~llN26SCl6H36N
C, 59085; H, 8.74; N, 7.75, S, 5091
Found:
C, 60025; M, 9.40; N, 7.13; S/ 5.51
* Trade Mark
GCl59
-38-
Example 7(S)-2-Oxo-3-[(2-thienylacetyl)amino]-1-azetidinyl
sulfate, potassi~m salt
A solution of (3g)-3~ (phenylme~hyl)oxy]-
carbonyl]amino]-2-oxo-1 azetidinyl sul~ate,
tetrabutylammonium salt (l.O g; see example 3a)
in dimethylformamide (.20 ml) containing lO~
palladium on charcoal. (0.5 g) is hydrogenated
or six hours at 26C. The mixture is filtered
to remove catalyst~ Hydroxybenzotriazole (0.261 g)
is added, followed by thiopheneacetic acid
(0.243 g) and finally dicyclohexylcarbodiimide
DCC (0.352 g). The reaction mixture i5 stirred
at 26C or about 16 hours, and then Goncentrated
at 4QC un~er high vacuum. The residue is diluted
with acetone (lO ml) and the resulting precipitate
is filtered and washed with acetone (2 ml).
To the acetone filtrate is added potassium
perfluorobutane sulfonate (0.867 g) in acetone
(2 ml). T~e solution is treated with ether
(approximately lO ml) and the precipitate is
filtered and dried in hiyh vacuwm. Chromatography
on EP ~O resin (water~5~ acetone/water) affords
the product after lyophilization as a solid
(51 mg). This material contains approximately
50% potassium perfluo.robutane sulfonate.
Anal. Calc'd. Eor CgH906N2S2K:
C, 31038; H, 2.63; N, 8.14; S, 18.62; K, 1~o55
Foundo
C, 22.58; H, 1.30; N, 4~17; S, 14.63; K, 8G62
GC159
39~
In an attempt t.o further purify this material,
the substance is dissolved in a small amount of
acetone and ether is added. The precipitate is
collected, dissolved i,n water and lyophilized.
The filtrate is e~aporated, dissolved in water
and lyophilized. The precipitate yives 13 mg
of 60% pure product and the filtrate yields 16 my
of 44% pure product.
lG Example 8
(3S-trans~-3~[(-2,~imethoxybenzoyl)amino~-4-
methvl 2~oxo l-a-zetidinvl sulfate, Pyridine (1:1~ salt
A) (3S trans)-3r-[-(2,6 Dimethoxybenzoyl)amino~-4~
_ ____
methyl-l-t~henylmethyl)oxv~-2 azetidinone
' ' To a cold (~10C) solution of (3S~trans)-
3-amino-4-methyl~l (phenylmethoxy)~2-azetidinone,
toluenesulfonate (0O95 g; see example 2D) in
methylene-chloride (50 ml) is added 2,6~d.imethoxy~
benzoyl chloride (0.60 g) and 4~dimethylamino
pyridine (0.61 g). The reaction is stirred under
nitro~en and allowed to rise to 26C over ~ive
hours. The reaction mixture is concentrated to
an oil and partitioned between ethyl aceta~e and
aqueous hydrogen sulfate solution. The organic
layer is washed with aqueous sodium bicarbonate,
and brine, dried over sodium sulfate and concentrated
to a foam (0.848 g).
GC15~ -
-40-
B) (3S-trans)-3- L ( 2, 6-Dimethoxybenzoyl)amino]-
-
l-hydroxy-4-methyl-2 azetidinone
To a stirred solution of (3S-trans)-3-
[(2,6-dLmethoxybenzoyl)aminoJ-4-methyl-1-
[(phenylmethyl)oxyj-2-azetidinone ~0.848 g) in
absolute ethanol (20 ml) under nltrogen is added
1,4-cyclohexadiene (8 ml) and ~reshly prepar~d
palladium black (approximately 0.85 g). After
one hour the reaction mixture is filtered and
evapoxated to a solid (0.605 g).
C) (3S-trans )!-3- [ ( 2,6-Dimethoxybenzoyl)amino]-4~
met~l 2 oxo-l-azetidinYl sulfate vridine (1 1) salt
~ P~
To a solution of (3S-trans)-3 [(2,6~dimethoxy-
, .
benzoyl)amino]~l-hydroxy-4-methyl-2 azetidinon~
(0.6~ g) in dry pyridine ~20 ml) under nitrogen
is added 4A molecular sieves (approximately 3 ml)
a~d pyridine-sulfur trioxide complex (1.35 g)O
After three hours the reaction mixture is flltered
Z0 and the filtrate concentrated and applied to an
~P-20AG resin column (acetone/water)O The desired
fractions are lyophilized to afford the title
compound (0.19~ g) as a powder.
Anal. Calc d- for 18 21 3 8
C, 48.21; H, 4.94; N, 9.37; S, 7.15
Found:
C, 48.23; H, 4.94; N~ 9.37; S, 7~10
GC159
-41-
Examples 9-69
.
Following ~he procedure of example 3, but
substituting the carboxylic acid lis-ted in column
I for (Z)-2-amino a ~ (methoxyimino)-4-thiazole-
acetic acid, yields the potassium salt of the
compound 1isted in column II.
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GC159
--47--
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7~
" GC159
-50-
Example 70
2-Oxo-3-methox -3-[( henvlacet~l)amino]-l-
P _ ~ _
azetidinyl sulfate,-pyridine salt
A) 3-Methox -3-[( hen lacet 1)amino]-l-[( hen 1-
Y P ~ ~ P Y
methyl)ox~]~2-azetidinone
To a solution of (S)-3-~(phenylacetyl)a~ino]-
l-~(phenylmethyl)oxy]-2~azetidinone (lmM; see
example 4B) in freshly distilled tetrahydrouran
(10 ml) at -78C is added via syringe a solution
of lithium methoxide (3mM1 in dry methanol (5 ml).
After 5 minutes, t-butyl hypochlorite tl30 ~1)
is added and the mixture is stirred at ~78C
for 30 mi~utes. The reaction mixture is pouxed
into 0.5 ~ monobasic potassium phosphate ~uffer
and extracted with two 100 ml portions of methylene
chloride. The combined organic extracts are
dried over sodium sulfate and concentrated to
an oily residue~ The title compound is isolated
by column chromatograp~y as a racemateO
B) ~o- ne~
azetidinvl sul~a~e, PYridine salt
Following the hydrogenolysis and sulfation
procedures described in example 4, parts C and
D, but utilizing 3-methoxy-3-~(phenylacetyl)amino]-
l-[tphenylmethyl)oxy] 2-azetidinone in place of
(S)-3 ~(phenylacetyl)amino~ l~[(phenylmethyl)oxy]-
2-azetidinone, yield~ the title compoundO
