Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
7~
- 2 - HOE 82/S 001
m is application is a divisional of Canadian Patent Appllcation Serial
number 424,484, filed March 25, 1983.
The present invention relates to certain intermediates
for the preparation of 7-oxo-4-thia-1-azabicyclo[3,2,0]-
heptane and hept-2-ene derivatives, and to a process for
their preparation.
7-Oxo-4-thia-1-azabicyclo[3,2,0]heptane and 7-oxo-4-
thia-1-azabicyclol3,2,0]hept-2-ene penem have the
following structures:
0~ 0~
Heptane Hept-2-ene
Certain derivatives of these basic structures have
antibiotic properties, see, for example, British Patent
Appllcations Nos. 2 074 563, 2 042 520 and 2 013 674. There
are, however, disadv~ntages in the methods proposed for
synthesising such compounds, for example~ the low yields
generally achieved, which are exacerbated by the isomeric
composition of the product: it i~ well known that certain
stereochemistry in penem compounds is desirable as isomers
having this stereochemistry are more biologically active
than other isomers. Many of the processes proposed for the
production of penem derivatives and their precursors do not
give predominantly the deslred isomers, and the cearch
continues for more effective methods of synthesising these
structures.
The present invention provides a compound of the general
formula Ia and its tautomer Ib
H ~OH
6 ~ C~3 8 C
(Ia) COOR
~2~772
- 3 - HOE 82/S 001
in which fon~ae R represents a ~r~l es ~ ifying group r~m~ble
by hydrolysis, photolysis, reduction, or en~ action to give the
free acid.
The term "a compound of the general formula I" and
"a compound of formula I" are both used herein.to denote a
compound of the general formula Ia, a compound of the
general formula Ib, or any mixture thereof. "A compound of
formula II" ls used to denote colle~tively compounds of
formulae IIa, IIb and IIc~ The terms "a compound of formula
III" and "a compound of formula IV" are used analogously.
The present invention also provides a process for the
production of a compound of the general formula I, which
comprises treating a compound of the general formula IIa,
IIb, or IIc
CH3 - ~ CN3- C/ S
2 ROOC
ROOC SCORb
~IIaj (IIb)
pH
3 ¢~"
30 ~ N
ROOC
(IIc)
in which R is as defined above,
R1 represents a chlorine or bromine atom, the radicals
R2 and Rb, which may be the same or different, each
represents an alkyl group having from 1 to 4 carbon atoms,
~2~77;~
- 4 - HOE 82/S 001
especially a methyl or t-butyl group, an aryl group,
especially a phenyl group, or an aralkyl group,
especially a benzyl group, and A represents a direct ~ond
or the residue of a dicarboxylic acid,
with a base.
The base used in the above reaction must be capable of
splitting a sulphur-carbonyl bond in the compound of formula
II and of bringing about ring closure. The base may he
inorganic or organic, for example, ammonia, or an alkali
metal (especially a sodium or potassium) carbonate,
bicarbonate, or hydroxide; a primary amine, for example,
methylamine, ethylamine, aniline or benzylamine; an alkali
metal alkoxide, for example, sodium methoxide; or a
heterocyclic base, for example, having a pK~ within the
range of from 5 to 9, for example, imidazole or pyridine or
a substituted pyridine, for example, an alkyl-, amino-, or
alkylamino-substituted pyridine, for example, 4-methyl- or
4~dimethyla~n~pyridine. Imidazole is particularly
preferred.
The reaction is generally ~arried out in a solvent or
diluent, the choice of which is wide, provided that it is
inert under the reaction conditions. Examples of solvents
and diluents are oxygenated hydrocarbons, for example,
alcohols, for example, having up to 4 carbon atoms, for
example, methanol and ethanol; ethers, for example, having
up to 4 carbon atoms, for example, diethyl ether, also tetra-
hydrofuran and dioxane; ketones, for example, having up
to 4 carbon atoms, for example acetone and methyl ethyl
ketone; esters,for example, methyl acetate and ethyl
acetate; and amides, for example, dimethylformamide and
dimethylacetamide; also chlorinated hydrocarbons, for
example, chloroform, methylene chloride and carbon tetra-
chloride; aromatic hydrocarbons, for example, benzene
and toluene; and other solvents, for example, aceto-
nitrile and nitromethane. A mixture of any two or moresolvents may be used, and solvents are preferably used
~``'`
'7;~
- S - HOE 82/S 001
in admixture with water, preferably a water-miscible
solvent in admixture with 5 to 20 ~ ~v/v) water,
especially a mixture of dioxane and water, preferably
5 to 10 % (v/v) water.
The reaction is generally carried out at a
temperature within the range of from 0 to 40C, preferably
from 0 to 20C .
An esterified carboxyl group -COOR is, for example,
an ester formed wlth an unsubstituted or substituted
aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,
aryl, araliphatic, heterocyclic or heterocyclic-ali-
phatic alcohol having up to 20 carbon atoms, or is,
for example, s silyl or stannyl ester.
R may represent, for example a straight or branched
chain substituted or unsubstituted alkyl, alkenyl or
alkynyl group having up to 18 carbon atoms preferably,
up to 8 carbon atoms, and especially up to 4 carbon atoms,
for example~ a methyl, ethyl, n-propyl, iso-propyl, n-
butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl,
allyl, or vinyl group.
An aliphatic group R, especially a methyl group, may
be substituted by a cycloalkyl, aryl or heterocyclic
group, or ~ may itself represent a cycloalkyl, aryl or
heterocyclic group.
A cycloaliphatic group R may have up to 1~ carbon
atoms and is, for example, a cyclopentyl, cyclohexyl or
adamantyl group. An aryl group may have up to 12 carbon
atoms and may have two or more fused rings. An aryl
group R is, for example, an unsubstituted or substituted
phenyl group, and an unsubstituted or substituted aralkyl
group is, for example, a benzyl,- ~-nitrobenzyl or benz-
hydryl group.
A heterocyclic group may have one or more hetero-
atoms, selected from oxygen, nitrogen and sulphur, and
up to 14 atoms in total. A heterocyclis group is, for
example, an oxygen-containing heterocyclic group, for
example, a tetrahydropyranyl or phthalidyl group.
,
~2~ 7~:
- 6 - HOE 82/S 001
A stannyl group R may have up to 24 carbon atoms, for
example, R may represent a stannyl group having three
substituents, which may be the same or different, selected
from alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy and
aralkoxy groups, for example, alkyl groups having up to 4
carbon atoms, for example, n-butyl groups, phenyl and
benzyl groups, especially three n- butyl groups.
A silyl group R may also have up to 24 carbon atoms
and three substituents, which may be the same or different,
selected from alkyl, alkenyl, cycloalkyl, aryl and aralkyl
groups, for example alkyl groups having up to 4 carbon
atoms, for example, methyl and t-butyl groups.
Any group R that is capable of substitution may be
substituted, for example, with a halogen atom, especially
a chlorine or bromi~e atom, or a nitro group.
The group R may be removable by hydrolysis, by
photolysis, by reduction or by enzyme action to give the
free acid, or two or more methods may be used, for example,
reduction followed by hydrolysis. A group R that may be
removed readily without substantial degradation of the rest
of the molecule is particularly useful as a carboxyl
protecting group. Examples of esters that are readily
split by reduction are arylmethyl esters, for example,
benzyl, ~-nitrobenzyl, benzhydxyl and trityl esters.
A stannyl ester, for example, a tri-n-butyl stannyl
ester, may be split readily by hydrolysis, for example,
by solvolysis, for example, using water, an alcohol, a
phenol or a carboxylic acid, for example, acetic acid.
Certain ester groups may be split off by base
hydrolysis, for example, acetylmethyl and acetoxymethyl
ester groups.
There may be used an esterifying group that is
removable under physiol~gical conditions, that is to say,
the esterifying group is split off in vivo to give the
free acid or the carboxylate, for example, an acyloxy-
methyl ester, e.g. an acetoxymethyl or pivaloyloxymethyl
. ~ ~
~2~ 77~:
- 7 - HOE 82/S 001
ester, an aminoalkanyloxymethyl ester, for example, an
L-glycyloxymethyl, L-valyloxymethyl or L-leucyloxymethyl
ester, or a phthalidyl ester, or an optionally substituted
2-aminoethyl ester, for example, a 2-diethylamino-ethyl
or 2-(1-morpholino)-ethyl ester.
Preferred esters are the ~-nitrobenzyl, phthalidyl,
pivaloyloxymethyl, acetylmethyl and acetoxy-methyl esters.
A compound of the general formula IIa, IIb, or IIc
is preferably produced by halogenating a compound of the
general formula IIIa, IIIb or IIIc, respectively,
OH ~ OH
CH3 ~ ~ SCOR
ROOC SCORb
(IIIa) (IIIb)
OH
SR O
~0
ROOC
IIIc
in which R, Ra, Rb and A are defined as above, and
R3 represents an alkyl group having from 1 to
8, preferably from 1 to 6, and especially from 1 to 4
carbon atoms, for example, an ethyl group, or an alkenyl
gxoup having up to 6 carbon atoms, especially an allyl
group.
~Z~(~772
- 8 - HOE 82/S 001
The halogenation of a compound of formula lIIa,
IIIb or IIIc is carried out with an agent capable of
splitting a carbon-sulphur bond and introducing a halogen
atom. Such agents are well known in the art and include,
for example, molecular chlorine, molecular bromine,
sulphuryl chloride, sulphuryl bromide, t-butyl hypo-
chlorite and cyanogen chloride.
The halogenating agent is generally used in an amount
of from 1 to 2 mole equivalents, calculated on the compound
1o of formula III. The reaction is generally carried out at
a temperature within the range of from -40 to +20C. The
reaction is generally carried out in a solvent or diluent
that is aprotic and is inert under the reaction conditions,
for example, an ether, a hydrocarbon or a hal~genated hydro-
carbon, for example, dioxane, benzene, chloroform ormethylene chloride. A mixture of two or moxe solvents may
be used. Examples of halogenating systems are: chlorine in
chloroform and, especially, chlorine in benzene and t-
butyl hypochlorite in benzene. In the latter two cases,
the temperature is preferably from 5 to 20C, and especially
from 5 to 10C.
A compound of formula IIIa, IIIb, or IIIc is prefer-
ably produced by removing the protective group from a
compound of formula IVa, IVb or IVc, respectively,
~ R4 ~ oR4
CO ~ ~ N
(IVa) (IVb)
~2~ 77~
- 9 - HOE ~2/S 001
/OR
CH3 - C
'- ~ SR3 O
~ ~ ~ 1 O
ROOC
(IVc)
in which R, Ra~ ~, R3 and A are defined as above, and
R4 denotes a hydroxy protecting group.
Preferred groups R4 are those which are compatible
with the synthesis of the compound of formula IV and which
may be removed under reaction conditions in which the
resulting compound III is stable. Compound III has been
found to be stable in the presence of a proton source, for
example, hydrogen chloride, aqueous hydrochloric acid or
aqueous hydrofluoric acid. Accordingly, one type of
preferred hydroxy protecting groups R4 are those which may
be removed under acidic conditions. Such groups are well
known in the art and are for example, tetrahydropyranyl
and tetrahydrofuranyl groups; acetal and ketal groups, for
example, of formula
oR7
- C/- R6
~R5
in whlch R6 and R7, which may be the same or different,
each represents a hydrogen atom or a lower alkyl group,
preferably a methyl group, or R6 and R7 together with
the carbon atom to which they are attached represent a
cycloalkyl ring having from 4 to 7 carbon atoms, for
example, a tetrahydropyranyl or tetrahydrofuranyl ring;
and R5 represents a lower alkyl group, preferably a methyl
or ethyl group.
~ ,j
~z~
- 10 - HOE 82/S 001
R4 may also represent a silyl group, for example, as
described above in relation to R, for example, -SiR8R9R10
groups, in which R8, R9 and R10, which may be the same or
different, each represen~s a lower alkyl group or an
aryl group, for example, triethylsilyl, t-butyldimeth~l-
silyl and methyldiphenylsilyl groups; and stannyl groups,
for example, as described above in relation to R, for
example, SnR R R groups, in which R , R and R
which may be the same or different, each represents a lower
alkyl group, for example, a tri-n-butylstannyl group.
Preferred R4 groups are tetrahydropyranyl, 2-methoxyprop-
2yl and t-butyldimethylsilyl groups.
A t-butyldimethylsilyl group may be removed in a
known manner by acid hydrolysis, for example, using
moderately concentrated hydrochloric acid, for example 6M
HCl, e.g., in tetrahydrofuran (cf Belgian Patent Speci-
fication No. 881 012),or hydrogen chloride in tetra-
hydrofuran, dimethylformamide, dioxane, a lower alkanol,
or acetonitrile; Tetra(n-butyl)ammonium fluor~de in an
acidic medium, e.g., ln acetic acid (cf Belgian Patent
Specification No. 882 764); or aqueous hydro-gen fluoride
eOg., in the presence of acetonitrile (cf J. Chem. Soc.
Perkin 1, 1981, 2055). (The term 'known' is used herein to
mean in actual use in the art or described in the litera-
ture of the art).
A compound of the general formula IV may be preparedaccording to the followlng reaction scheme:
~,
~2~7'72
- 11 - HOE 82/S 001
4 C~)R4
CH3 ~ ~ R3
VI I Vl
oR4 ~/
CH 3 - C~ SR3
"I~'
ROOC
V
oR4 pR4
oR4
C~13-~col~ 3~
ROOC SCORb ROOC ROOC
IVa IVb IVc
~z~ 72
- 12 - HOE 82/S 001
in which R, R2~ ~b~ R3, R4 and A are as defined above.
A compound of formula VII may be prepared as
described in Belgian Patent Specification No. 882 764.
A compound of formula VII may be converted into a
compound of formula VI by reaction with a compound of
formula VIII
R3 - S - R14 ~VIII)
in which R3 is as defined above and R14 represents a
hydrogen atom or an alkali metal atom, especially a
sodium or potassium atom. R3 preferably represents a
straight chain lower alkyl group, especially an ethyl
group, or a straight chain lower alkenyl group,
especially an allyl group.
The reaction is generally carried out in a solvent,
preferably a protic solvent, for example, water or an
alcohol, or an aprotic, water-miscible solvent which is
preferably polar, for example, dimethylformamide, dimethyl
sulphoxide, tetrahydrofuran or dioxan. The reaction
temperature is, for example, from -20 to +50, pxeferably
from -10 to +20C.
To obtain a compound of formula V a compound of
formula VI may be reacted, in the presence of a base, with
a compound of formula IX
Y1CH2CO2R (IX)
in which R is as defined above and
y1 represents a group that is capable of being
replaced by a nucleophilic group and is, for example, a
halogen atom, preferably a bromine or iodine atom, or a
modified hydroxy group, preferably a sulphonyloxy group
of the formula SO3R16 in which R16 represents a lower
alkyl or -CF3 group, or a phenyl group which is un-
substituted or is substituted by a ~-nitro, ~-bromo or
~-methyl group.
~ ~,
~2~
- 13 - - HOE 82/S 001
Y1 preferably represents a bromine or iodine atom
or a methylsulphonate, trifluoromethylsulphonate, tolyl-
sulphonate or benzenesulphonate group.
The base may be inorganic, organic or ~rganometallic,
S for example, an alkali metal or alkaline earth metal
hydroxide, oxide, carbonate, bicarbonate or hydride,for
example, sodium hydroxide, magnesium oxide, potassium
carbonate, potassium bicarbonate or sodium hydride; a
tertiary amine, for example, a trialkylamine, for example,
triethylamine, DABCO (diazabicyclo[2,2,2]octane), pyridine,
or an alkyl-substituted or amino-substituted or
dialkylamino-substituted pyridine, for example, N,N-
dimethylaminopyridine, or collidine; a guanidine, for
example, tetramethylguanidine; DBN (diazabicyclo[4,3,0]non-
5-ene) or DBU (diazabicyclo~5,4,0]undec-7-ene), a polymeric
base i.e., a base attached to an inert polymeric support
e.g., Hunig's base (diisopropylethylamine attached to e.g.,
polystyrene); a metallated amine, for example, a metallated
alkyl- or arylamine, for example, lithium diisopropylamide
(LDA), lithium hexamethyldisilazide, lithium piperidide,
lithium 2,2,6,6-tetramethylpiperidide, or a Grignard
reagent, for example, methylmagnesium bromide. Preferred
bases are, for example, potassium carbonate, sodium
hydride, lithium diisopropylamide and triethylamine.
The reaction is generally carried out in an aprotic
solvent or diluent, for example, a tertiary amide, for
example, dimethylformamide, dimethylacetamide or hexamethyl-
phosphoramide; a hydrocarbon, for example, benzene or tol-
uene; or an ether, for example, diethyl ether, tetrahydro-
furan or dioxane; or acetonitrile, dimethyl sulphoxide, or
sulpholane. Dimethylformamide and dimethylacetamide are
preferred. A mixture of two or more solvents and/or
diluents may be used.
The reaction may be carried out at a temperature
generally within the range of from -80C to +30C
prefera~ly from -40 to +30C, and especially from -20 to
~20C.
~2~`77~:
- 14 - HOE 82/S 001
From 1 to 1.5 moles of compound IX are preferably
used per mole of compound VI especially from 1 to 1.1
moles of IX per mole of VI. The base is used in an amount,
for example, from 1 to 4 moles of base per mole of
compound VI.
The reaction is preferably carried out by dissolving
compound VI in a solvent, advantageously in dimethylform-
amide with stirring, adding the base, adding the compound
of formula IX and reacting at the desired temperature. The
resulting compound of foxmula V may be worked up and iso-
lated in the usual manner, for example, using chromato-
graphic and/or ~rystallisation techniques, or the subse-
quent reaction may be carried out directly on the
resulting reaction mixture after removal of any solvent
that is not compatible with the subsequent reaction.
If R in formula V represents a ~arboxyl esterifying
group, this group may be converted into another esteri-
fying group R, for example, to introduce a group R that
is more easily removable under desired conditions. This
transesterification is generally carried out as follows:
the ester for formula V is hydrolysed in a known manner
unsing, for example, acld or alkaline hydrolysis, prefer-
ably using an alkali metal hydroxide, especially sodium
or potassium hydroxide. The ester of formula V, for
example, a methyl ester, is preferably hydrolysed using
an alkali metal hydroxide, especially one mole thereof
per mole of the ester of formula V in a solvent, for
example ethanol, methanol or water, or an aqueous-organic
solvent, for example, tetrahydrofuran~water, ethanol/
water, or acetonitrile/water.
The reaction mixture may then be acidified to give
a solution of p~ 1 to 5, preferably 2 to 4, and the free
acid may then be isolated and, if desired, the free
acid i8 then esterified with an esterifying agent capable
of introducing a different esterifying group R, for example
with an alcohol ROH ~n the presence of an acid or another
~Z1~7Z
- 15 - HOE 82/S 001
activating agent, for example, dicyclohexylcarbodiimide,
or with an alkylating agent RY1 in which y1 is as defined
above. Preferably a salt may be isolated and esterified
directly.
A compound of formula V may be converted lnto a
compound of formula IV by treatment with a base in the
presence of carbon disulphide followed by reaction with an
acylating agent, or by treatment with a base, then with
carbon disulphide, and finally reaction with an acylating
agent. An acylating agent is generally an activated
carboxylic acid.
The actLvated carboxylic acid may be any activated
acid derivative comprising the group R2. Such derivatives
are well known in the art, and include acid halides, acid
anhydrides, and activated èsters. An anhydride may be
symmetrical or asymmetrical. scoR2
For the introduction of a group ~ a2 to give
a compound of formula IVa, the acylating SCO~
agent preferably has one of the formulae Xa to Xb
R2COZ (Xa) ~ COZ ( Xb)
O O O O
q " " q 2 " " 2
Ra ~ C - O - C - Ra Ra ~ C - O - C - Rb
(Xc) ~Xd)
O O
2 " " 2
Rb - C - O - C - Rb
(X e)
2 2
in which Ra and ~ are as defined above, and ~ represents
a halogen atom, especially a chlorine or bromine atom or
represents an activated ester or amide, or a radical
derived from an acid azide. Such coupling reagents are
well known in the art of peptide chemistry.
12~7~
- 16 - HOE 82/S 001
In the case of formula IVb, the group
/s
~)_o
S
may be introduced by means of an acylating agent of formula
XI O
Hal - C - Hal
in which Hal represents a halogen atom, especially a
chlorine atom.
For the introduction of a group ~ to give a
S ~
~0
to compound of formula IVc, a dicarboxylic acid derivative
of formula XII is used
~COZ
A
~ COZ
in which A and Z are as defined above~ and Z preferably
represents a halogen atom, especially a chlorine atom. As
mPntioned above, A represents the residue of a dicarboxylic
~cid or represents a direct bond A is derived~ for
example, from malonic, dimethylmalonic, succinic, glutari~,
adipic, pimelic or phthalic acid.
The compound of formula V is preferably reacted first
with a base, then with carbon disulphide, and then finally
with the acylating agent.
The base preferably has a pK~ 20, and is preferably a
metallated amine. Examples of preferred bases are lithium
diisopropylamide, lithium 2,2,6,6-tetramethyl-piperidide,
lithium cyclohexyl isopropylamide, lithium hexamethyl
disilazide, and sodamide.
The reaction is generally carried out in an inert
~olvent, for example, an oxygenated hydrocarbon, preferably
an ether, for example, diethyl ether, tetrahydrofuran,
~.L.`-"`
~l2~ ?;~7;~
- 17 - HOE 82/S 001
dio~ane, glyme or diglyme. The reaction temperature is,
for example, from -12~ to +30C, preferably from -100
to -20C.
The amoun~ of base used is for example, from 1 to 4
moles, calculated per mole of compound V, preferably from
2.0 to 3.0 moles of base. Carbon disulphide is preferably
used in amount of from t to 5 moles, especially from 2
to 3 moles, per mole of compound V.
The reaction is preferably carried out as follows:
to a stirred solution of compound V under an inert
atmosphere is added the base then carbon disulphide, if
desired in solution in the same solvent as compound V or in
a different solvent, and finally the acylating agent to
complete the reaction.
There may then be admixed a protic source having a
pK less than 10, and especially from 5 to 2,for example,
acetic, citric, oxalic or formic acid.
The compound of the general formula I has R stereo-
chemistry at position 5. This is the stereochemistry
found in naturally occurring penicillins and is, in general,
prefera~le to 5S stereochemistry, more 5R compounds being
antibioti~ally active than are 5S compounds.
We have found a process that gives predominantly the
desired 5R compound of formula I. It has been proposed
prevlously ~British Patent Application 2074563A) to
halogenate a compound of formula IV i.e., a compound having
a protected hydroxy group in the stde chain attached to the
3-position, but we have found that this process gives only
a 4R halogenated compound, which in its turn, gives a
compound analogous to that of formula I but having the
undesired 5S stereochemistry. We have found that, very
surprisingly, if the protective group is removed from
compound IV prior to halogenation, the resulting halogenated
compound of formula II is predominantly 4S. The isomer
ratio 4S:4R in compound II resulting from the halogenation
varies according to the reaction conditions but ~s, for
~lZ1~72
- 18 - HOE 82/S 001
example, in the range of from 3:1 to as high as 9:1. More-
over, the 4R and 4S isomers of formula II can be separated
easily, for example, by chromatography.
The 4S halogenated intermediates of formula II give
virtually exclusively a compound of formula I with the 5~
stereochemistry as shown. The presumed participation of the
free hydroxyl group of ~he side chain of formula II in
giving the more sterically hindered compound of formula I
is also unexpected and constitutes a valuable advance in
the preparation of the penem compoun~ of formula I.
The compound of formula I is itself a very useful
starting material for the preparation of various deri-
vatives substituted at position 3, especially by -SR3,
wherein R represents alkyl having 1-10 carbon atoms or
substituted alkyl; particularly alkyl having 1-4 C-atoms,
i.e., in the synthesis of 3-substituted 7-oxo-4-thia-1-
azabicyclo[3,2,0]hept-2-ene 2-carboxylate derivatives,
that possess antibacterial properties and wh~ch are useful
for the treatment of bacterial infections in humans and
animals.
The following Examples illustrate the invention. In
them, temperatures are given in degrees Celsius.
\
~z~ 7;~
- 19 - HOE 82/S 001
Example 1
4-(R)-Allvlthio-3(S)-[1'(R)-~dimethYl-{2-methvl~ProP-2-Yl~ -
silvlox~y ? ethyl]azetidin-2-one
To a stirred solution of 1.14 ml of allyl mercaptan
and 0.4 g of sodium hydroxide in 25 ml of water under an
argon atmosphere was added a solution of 2.87 g of 4-
acetoxy-3(S~-[1'-(R)- dimethyl-~2-methylprop-2-yl~
silyloxy~ ethyl]azetid-in-2-one in 10 ml of methanol.
After 30 minutes, the mixture was partitioned between
dichloromethane and water. The separated organic layer
was washed with water, was dried over magnesium sulphate,
evaporated t~ dryness,and then chromatographed on silica
gel. Elution with ethyl acetate / hexane mixtures afforded
1.8 g of the title compound as white crystals.
1 ~ -1
3 3420, 1767 cm
(CDC13) 0.05 (6H,s)
0.88 ~9H, s)
1.20 (3H, d, J6Hz)
2.9 - 3.2 (3H, m)
3.9 - 4.3 (lH, m, H-1')
3.84 (1H, d J3 4 2Hz, H-4)
4.95 - 6.3 (3H, m)
7.28 (lH, broad s)
Example 2
Methyl 2-(4(R)-allYlthio-3-(S~-[1'(R)-~dimethvl- 2-
methylProP-2-vl~ silvloxy~ ethvl]azetidin-2-on-1-vl)
acetate
To a ætirred solution of 1.76 g of 4(R)-allylthio-
3-(S)-11'(R)- dimethyl- ~2-methylprop-2-yl~ silyloxy~
ethyl]azetidin-2-one in 60 ml of dry dimethylformamide was
added 3.52 g of finely ground potassium carbonate and
0.6 ml of methyl bromoacetate. After 18 hours, the mixture
was filtered and then partitioned between ethyl acetate
and water. The æeparated organic layer was washed with
~.
~Z1~772
- 20 - HOE 82/S 001
water and dried over magnesium sulphate. Evaporation
in vacuo afforded a crude product which was chromato-
graphed on silica gel. Elution with ethyl acetate/hexane
mixtures afforded 1.56 g of the title compound as a
5 pale yellow oil.
~maxCDCl3 1753, 1768 cm
d^ (CDC13) 0.06 ~6H, s)
0.86 (9H, s)
1.23 13H, d 6J.5Hz)
3.2 (3H, m)
3.70 (3H, s)
3.6 - 4.3 (3H, m~
4.87 (1H, d J 2Hz, H-4)
4.9 - 6.3 (3H, m)
Example 3
4-NitrobenzY1 2-54(R)-allYlthio-3(S)-[1'-(R)-dimethYl-2-
20 methYlproP-2-Yl}silvloxv3ethvl]azetid~n-2-on-1-Yl)acetate
To a stirred solution of 3.04 g of potassium hydroxide
in 80 ml of 95 % ethanol was added a solution of J6 g of
methyl 2-(4(R)-allylthio-3~S)-[1'(R)-dimethyl~2-methylpr~
2-yl~ silyloxy~ethyl]azetidin-2-on-1-yl)acetate. After
25 10 minutes, the mixture was evaporated to about 1/5 of
its original volume; 2 ml of dimethyl acetamide were
added, followed by a solution of 9.25 g of 4-nitrobenzyl
bromide in S0 ml of dimethylacetamide. After 1 hour, the
mixture was partitioned between 0.01M H;:1 and ethyl
30 acetate. The separated organic layers were washed with
0.01M HCl, with water, with cold, saturated sodium bi-
carbonate, and with brine, and were then dried and
evaporated. The resulting crude product was chromato-
graphed over silica gel; elution with ethyl acetate/
35 hexane mixtures affored 19.5 g of the title compound
as an oil.
lZ~72
-- 21 -- HOE 82/S 001
~maX(CDcl3) 1755, 1769 cm 1
cr(CDCl3) 0.07 and 0.09 (6H, two singlets)
0.88 (9H, s)
1.25 (3H, d J6Hz~
3.2 (3H, m)
3.7 - 4.5 t3H, m)
4.95 (lH, d J2Hz, H-4)
4.9 - 6.3 (5H, m)
7.5 - 8.35 (4H, m)
Example 4
4-Nitrobenzyl 3,3-di(acetylthio)-l(3S ! 4R)-4-allylthio
3-[1'~R)-dimethvl-~2-methYlprop-2-yl~ silyloxy~ ethYl]
2-azetidinon-1-yl)ProPenoate
A solution of lithium hexamethyldisilazide was pre-
pared by the addition of n-butyllithium in hexane (2.79 ml
of a 1.6 M solution) to 0.982 ml of hexamethyldisilazane
in 8 ml of dry tetrahydrofuran at -10C, while stirring
under argon. The solution was cooled to -78C and added
by cannula to a solution of 0.98 g of 4-nitrobenzyl 2-
(4(R)-allylthio-3(S)-[1'(R3-dimethyl-~2-methylprop-2-yl~
silyloxy~ ethyl]azetidin-2-on-1-yl) acetate in 8 ml of
dry tetrahydrofuran at -78C, with stirring under argon.
After 5 minutes, 0.357 ml of carbon disulphide was added
by syringe, followed by 0.748 ml of acetic anhydride. The
mixture was allowed to warm to room temperature, and 30 ml
of dichloromethane was added, followed by 30 ml of water.
The organic layer was separated, and the aqueous layer
was extracted with further dichloromethane. The combined
organic extracts were washed with lM HCl, with water,
and with a 12 % sodium chloride solution, and were then
dried over magnesium sulphate and evaporated to give
1.38 g of an orange oil. 1.21 g of this crude product was
chromatographed on silica gel using ethyl acetate/hexane
mixtures as eluent to give 0.800 g of the title compound
in purified form.
...~,.
. ~ .
~2~72
- 22 - HOE 82/S 001
~CDCl3) 1778, 1745 cm~
~lCDCl3) 0.06 (6H, s)
0.85 (9H, s)
1.26 (3H, d J6Hz)
2~25 (3H, s)
2.35 (3H, s)
3~ 3.52 (3H, m, 3-H)
3.35 (2H, d, J 6Hz)
4.14 - 4.39 (lH, m)
4.95 - 6.30 (6H, m)
5.35 (2H, s)
5.56 (1H, d J3Hz, 4-H~
7.44 - 8.38 (4H~ m)
ExamPle 5a
4-NitrobenzY1 3~3-di(acetYlthio)-2-~(3S~4R)-4-allylthio-
3-~11(R)~hydrox~ethyl~-2-azetidinon-1-yl]propenoate
To a solution of 0.601 g of 4-nitrobenzyl 3,3-di-
(acetylthio~-2-[(3S,4R) 4-allylthio-3-(1'(R)-~dimethyl-
2-methylprop-2-yl~silyloxy~ethyl)-2-azetidinon-1-yl]-
propenoate in 12 ml tetrahydrofuran was added a solution
of 1 ml of concentrated hydrochloric acid and 1 ml of
tetrahydrofuran. The solution was set aside for 24 hours
and then evaporated in vacuo. Benzene was added and the
mixture was evaporated to remove residual water to give
0.424 g of crude title product. A portion (0.197 g) of
this crude material was chromatographed on sili~a gel
eluting with ethyl acetate - hexane mixtures to give
0.142 g of pure title compound.
max 1774, 1738 cm 1
(CDC13) 1.26 (3H, d, J6Hz)
2.24 (3H, s)
2.38 (3H, s)
3.35 (2H, d, J7Hz)
3.22 - 3.48 (3H, m~
3.98 - 4.45 (lH, m~
~Z~772
- 23 - HOE 82/S 001
5.30 (2H, s)
4.95 - 6.1 (6H, m)
7.42 - 8.23 (4H, m)
Example 5b
4-Nitrobenzyl 3,3-di(acetYlthio)-2-[(3S,4R)-4-allYl-
thio-3-~ R)-hydroxvethYl3-2-azetidinon~1-yl]pro~oate
To a stirred solution of 0.088 g of 4-nitrobenzyl
3~3-di-(acetylthio)-2-[(3s~4R)-4-allylthio-3-(1~(R)-
~dimethyl-2-methylprop-2-yl~silylox ~ ethyl)-2-azetidinon-
10 1-yl]propenoate in 5 ml of acetonitrile was added 2.35 ml
of concentrated (40 ~ hydrofluoric acid. A further
volume of acetonitrile (5 ml) was added after 5 minutes,
and the solution was guenched with a saturated aqueous
sodium bicarbonate solution. The resulting solution was
extracted with dichloromethane. The resulting organic
phas2 was washed with water, with sodium bicarbonate,
and then with brine. It was then dried over MgS04 and
chromatographed on silica gel, eluting with ethyl acetate -
hexane mixtures to give 0.03 g of recovered starting
material and then 0.0296 g of the title compound.
For spectral details see Example 5a.
ExamPle 5c
4-Nitrobenzvl 3,3-di(acetYlthio)-2-[(3S,4R)-4-
allylthio-3~ R)-hvdroxYethYl~-2-azetidinon-1-Yl]
propenoate
To a solution of 5.58 g of 4-nitrobenzyl 3,3-di-
(acetylth$o)-2-[~3S, 4R)-4-allylthio-3-11'(R)-~dimethyl-
~2-methylprop-2-yl~silyloxy~ethyl)-2-azetidinon-1-yl]-
propenoate in 6.5 ml of tetrahydrofuxan was added a
freshly pr~pared solution of 3.72 g of hydrogen chloride
in 32 ml of tetrahydrofuran.
The solution was set aside at room temperature un~il
the reaction was complete, and was then evaporated in
cuo. Chromatography on silica gel, eluting with ethyl
acetate -hexane mixtures gave 3.10 g of the title compound.
For spectral details see Example 5a.
~,
~Z~77~
- 24 - HOE 82/S û01
Example 6a
4-Nitrobenzyl 3,3-di(acetYlthio)-2-[(3S,4S)-~-chloro-
3-~1'(R)-hydroxyethyl~-2-azetidinon-1-Yl]Propenoate
To a solution of 0.246 g of 4-nitrobenzyl 3,3-di-
(acetylthio)-2-[(3S,4R)-4-allylthio-3-(1'(R)-hydroxyethyl)-
2-azetidinon-1-yl]propenoate in 13 ml of benzene was added
under an inert atmosphere 0.095 ml of t-butylhypochlorite.
When the starting material had been consumed the
reaction mixture was chromatographed on silica gel to give
as the minor product 0.045 g of 4-nitrobenzyl 3,3-di-
(acetyl-thio)-2-l~3S,4R)-4-chloro-3-(11(R)-hydroxyethyl)-
2-azetidinon-1-yl]propenoate (20 %) and as the major
product 0.121 g of the title compound.
For spectral details see Example 13a.
Example 6b
4-Nitrobenzyl 3~di(acetYlthio)-2-[(3S,4S)-4-
chloro-3-~1~(R)-hydroxYethyl~-2-a_etidinon-1-yl~ropenoate
To a solution of 3.10 g of 4-nitrobenzyl 3,3-di-
(acetylthio)-2-l(3S,4R)-4-allylthio-3-11'(R)-hydroxyethyl)-
2-azetidinon-1-yl]propenoate in 70 ml of dry benzene
cooled to 6 was added dropwise a solution of 1.5 mol
equivalent of chlorine in 9.5 ml of carbon tetrachloride.
When the starting material had been consumed, the solution
was reduced in volume ~n vacuo and chromatographed on
silica gel, eluting with ethyl acetate - hexane mixtures
to give as the minor product 0.695 g of 4-nitrobenzyl
3,3-di-(acetylthio)-2-[(3S,4R)-4-chloro-3-(1(R)-hydroxy-
ethyl)-2-azetidinon-1-yl]propenoate, and as the major
product 1.808 g o~ the title compound.
For spectral details see Example 13a.
Example 7
4-Nitrobenzyl (5R,6S) 6-8'(R)-hYdroxYethY~-7-oxo-4-
thia-3-thioxo-1-azabicYclo[3,2,o]hePt-2-ane 2-carboxvlate
To a st~lution of 0.525 g of 4-nitrobenzyl 3,3-di-
(acetylthio)-2-[(3S,4S)-4-chloro-3-(1'(R)-hydroxyethyl)-
~'
,;
~Z~72
- 25 - HOE 82/S 001
2-azetidinon-1-yl]propenoate in 15 ml of dioxan and 1.5 ml
of water was added 0.227 g of imidazole. When the reac-
tion was complete the solution was diluted with ethyl
acetate and water, acidified with dilute hydrochloric acid
and extracted. The aqueous phase was extracted with a
second volume of ethyl acetate. The combined ethyl acetate
solution was washed with water and then with brine, dried
over MgSO4 and evaporated in vacuo to give the title
compound as an orange solid in quantitative yleld.
~max (liquid film) 1791, 1751 cm 1
d (CDC13) 1.39 (3H, d, J6Hz)
3.00 t1H, s) C H
3.76 (1H, 2d, J6B~ c~c~~ 4Hz~ J6B,5a2H ~ )
4.05 - 4.53 (1H, m)
5.35 (2H, s)
5.45 ~1H,s)
5.95 (1H, d, 5-H)
7.36 - 8.45 ~4H, m).
ExamPle 8
3(S)-~1~(R)-~imethvl(2-methvlProP-2-Yl)silYloxyethy~ -4
(R)-ethylthioazetidin-2-one
To a stirred solution of 2.03 g of sodium hydroxide
in 70 ml of water at 0C under an argon atmosphere was
added 3.94 g of ethanol thiol. After 30 minutes stirring,
a solution of 12.6 g of 3(S)-{1'(R)-dlme~hyl(2-methylprop-
2-yl)silyloxy-ethyl~-4-acetoxyazetidln-2-one in 200 ml
of methanol was added The mixture was warmed to room
temperature and, after 90 minutes, was partitioned between
ethyl acetate and water. The aqueous layer was further
washed with ethyl acetate. The combined organic layers
were back-washed with brine, dried over sodium sulphate,
and evaporated to dryness. 6.9 g of the title product
were obtained. Yield: 54 %
~, ~
123~77;~
- 26 - HOE 82/S 001
~max (CDC13) 1765 cm~
(CDCl3) 0.10 (6H,s)
0.90 (9H, s)
1.26 (3H, d, J = 6 Hz)
1.33 ~3H, t, J = 7 Hz)
2.68 (2H, q, J = 7Hz)
3.16 (1H, m)
4.1 - 4.3 (1H, m)
4.85 (1H, d, J = 2 Hz)
6.78 (1H, broad s~.
ExamPle 9
Methyl 2-[3(S)-{11(R)-(dimethYl(2-methy~eroP-2-yl)silyl-
oxyethYl3-4(R)-ethylthio azetidin-2-on-1-Yl]acetate
To a stirred solution of 6.9 g of 3~S)-~1'(R)-di-
methyl(2-methylprop-2-yl)silyloxyethyl3-4(R)-ethylthio -
azet~dln-2-one in 150 ml of dry dimethylformamide was
added 13.15 g of finely ground anhydrous potassium
carbonate and 2.82 ml of methyl bromoacetate. After 24
hours, the mixture was filtered and then partitioned between
ethyl acetate and water. The aqueous layer was adjusted
to pH 2 by dropwise addition of dilute hydrochloric
acid t and then back-extracted with ethyl acetate. The
combined organic layers were washed with water, dried
over sodium sulphate, and evaporated in vacuo to give
an orange oil, which was chromatographed over silica gel.
Elution with ethyl acetate/hexane mixtures afforded
6.37 g of the title compound as a pale yellow oil.
Yield: 72 %.
max (CDC13) 1749 (ester) and 1760 (B-lactam) cm
(CDCl3) 0.06 (6H, s)
0.86 (9H, s)
1.3 (6H, m~
2.58 (2H, q) J = 6Hz)
3.12 (lH, dd, J = 2Hz and 4 Hz)
3.70 (3H, s)
3.93 (2H, dd, J gem = 17 Hz)
4.3 (1H, m)
~, ~ 4.92 (lH, d, J = 2Hz).
~l2~77;~
-- 27 -- HOE 82/S 001
Example 10
4-Nitrobenzyl 2-t3-(~ (R)-dimethvl-(2-methYlprop-
2-yl)-silyloxYethY13-4 (R)-ethylthio-azetidin-2-on-1-Yl]-
acetate
To a solution of 6.37 g of methyl 2-l3(S)-~1l(R)-
dimethyl(2-methylprop-2-yl)silyloxyethyl}-4(R)-ethylthio-
azetidin-2-on-1-yl]acetate in 25 ml of 95 % ethanol
was added a solution of 1.16 g of potassium hydroxide in
25 ml of 95 % ethanol. After 15 minutes, the mixture was
evaporated in vacuo to dryness. The product was
dissolved immediately in 25 ml of dimethy~acetamide, and
4.24 g of solid 4-nitrobenzyl bromide were added with
vigorous stirring. After 60 minutes, the mixture was
partitioned between ethyl acetate and water. The separated
aqueous layer was washed with further ethyl acetate; the
c~mbined organic layers were backwashed with water, then
with brine, and were then dried over sodium sulphate and
evaporated ~n vacuo to afford an orange oil. Chromato-
graphy over silica gel, eluting with ethyl acetate/hexane
mixtures afforded the title compound as a pale yellow,
viscous oil. Yield: 6.18 g, 80 ~.
~max (CDC13) 1765 (B-lactam) and 1755 ~ester)cm 1
(CDC13) 0.05 (3H, 5)
0.08 (3~, s)
0.88 (9H, æ)
1.25 (3H, t, J = 7Hz)
1.28 (3H, d, J = 6 Hz)
2.58 (2H, q, J = 7Hz)
3.18 (1H, dd, J = 2 Hz and 4 H~)
4.05 (2H, dd, Jgem = 18 Hz)
4.1 - 4.3 (lH, m)
4.93 (lH, d, J = 2Hz)
77~
- 28 - HOE 82/S 001
ExamPle 1 1
4-Nitrobenzyl 3,3-di(acetYlthio)-2-[(3S,4R)-4-
ethvlthio-3-(1l(R)-dimethyl-~2-methylpro~-2-vl~si
ethyl)-2-azetidinon-1-yl]propenoate
A solution of 2.0 g of 4-nitrobenzyl 2-13S,4R)-4-
ethylthio-3-(1'(R)-dimethyl-2-methylprop-2-yl~silylox~ -
ethyl)-2-azetidinon-1-yl]acetate in 30 ml of dry tetra-
hydrofuran was held under an inert atmosphere and cooled
to -78. To the well-stirred solution was added a cooled
(-78C) preformed solution of lithium hexamethyldisilazide
(prepared by addition of butyl lithium (1.55 molar,
6.01 ml, 9.31 mmol) to a tetrahydrofuran solution (20 ml)
of hexamethyldisilazane (2.05 ml) cooled to -10). After
5 minutes, 0.747 ml of carbon disulphide was added,
followed after a further 5 minutes stirring by 1. 56 ml
of acetic anhydride, and the solution was warmed to -20.
80 ml of ethyl acetate was added to the solution, followed
by 150 ml of dilute hydrochloric acid (0.4 molar). The
aqueous layer was extracted with a further volume
of ethyl acetate. The combined ethyl acetate phase was
washed with brine, then dried over magnesium sulphate
and evaporated in vacuo to yield 3.03 g of the title
compound, which was used subsequently without further
pur~fication.
~ max (CDCl3) 1776, 1739, 1715 cm 1
d (CDC13) 0.06 ~6H, s)
0.85 ~9H, s)
1.06 - 1.64 (6H, m)
2.10 - 3.16 (8H, m)
2.23 (3H, s)
2.35 (3H, s)
3.25 - 3.50 (1H, m, 3-H)
4.05 - 4.67 (1H, m)
5.34 (2H, s)
5-56 (1H~ d~ J4a~33 3HZ~ 4-H)
7.37 - 8.44 (4H, m).
~l2~72
- 29 - HOE 82/S 001
Example 12
4-Nitrobenzvl 3,3-di(acetYlthio)-2-[13S,4R)-4-
ethylthio-3-~1~(R)-hydroxyethv~ -2-azetidinon-1-Yl]
~ropenoate
0.303 g of 4-nitrobenzyl 3,3-di(acetylthio)-2-
l(3S,4R)-4-ethylthio-3-(1'(R)-~dimethyl-2-methylprop-
2-yl~-silyloxy~ethyl)-2-azetidinon-1-yl]propenoate was
dissolved in a solution of 12 mol equivalent of hydrogen
chloride in 5 ml of tetrahydrofuran. The solution was
stirred for 6 hours then evaporated in vacuo to 1/3
of its volume. Ethanol-free chloroform was added and the
solution evaporated. The residue was chromatographed on
silica gel eluting with ethyl acetate - hexane mixtures
to give 0.066 g of recovered starting material and 0.12g
of the title compound.
(max) 1770, 1738 cm 1
(CDCl3) 1.03 - 1.63 (6H, m)
2.00 - 3.18 (9H, m)
3.19 - 3.48 (1H, m, 3-H)
3.95 - 4.46 (1H, m)
5.30 (2H, s)
5.43 (1H, d, J4~,3B, 3Hz, 4 H)
7.33 - 8.37 (4H, m).
Example 13a
4-NitrobenzY1 3,3-di(acetYlthio)-2-[(3S,4S)-4-
chloro-3-1'(R)-hYdroxyethyl~-2-azetidinon-1-yl]Propenoate
A solution of 0.10 g of 4-nitrobenzyl 3,3-di(acetyl-
thio) 2-[(3S,4R)-4-ethylthio-3-~11(R)-hydroxyethy~ -2-
azetidinon-1-yl]propenoate in 1.3 ml of ethanol-free
chloroform was cooled to -60 under an inert atmosphere.
To this solution was added a solution of chlorine in
carbon tetrachloride until the starting material had
been consumed. The reaction was evaporated in vacuo and
chromatographed on silica gel to give 0.032 g of the
title compound.
~Q77~
- 30 - HOE 82/S 001
~max (liquid film) 1790, 1739 cm
J (CDCl3) 1.37 (3H, d, J7Hz)
2.24 (3H, s)
2.39 (3H, s)
3.58 (1H, 2d, J3~, ~-CH-CH3 10Hz, J3B 4B
5 Hz, 3-H)
4.00 - 4.56 ~1H, m)
5.30 (2H, s)
6.27 (1H, c, 4-H)
7.38 - 8.2~ (4H, m).
Example 13b
4-Nitrobenzyl 3,3-di(acetylthio)-2-[(3S,4S) 4-
chloro-3-~1'(R)-hvdroxYethYl-2-azetidinon-1-yl]propenoate
To a solution of 0.10 g of 4-nitrobenzyl 3,3-di-
(acetylthio)-2-[(3S,4R) 4-ethylthio-3-~1'(R)-hydroxyethyl-
2-azetidinon-1-yl]propenoate in 2 ml of dry benzene
cooled to 6 was added slowly a solution of 1.5 mole
equivalent of chlorine in carbon tetrachloride until the
starting material had been consumed. The solution was then
chromatographed on silica gel, eluting with ethyl acetate -
hexane mixtures to give as a minor product 0.011 g
of 4-nitrobenzyl 3,3-di(acetylthio)-2-l(3S,4R) 4-chloro-
3-(1'(R)-hydroxyethyl)-2-azetidinon-1-yl]propenoate, thenas
the major product, 0.065 g of the title compound.
For spectral details see Example 13a.
Example 14
4-Nitrobenzvl 3,3-di(acetYlthio)-2-[(3S,4R)-4-
chloro-3-(1'(R)-~dimethyl-~2-methYlProP-2-vl~silYlox
ethyl)-2-azetidinon-1-yl]ProPenoate
A stirred solution of 3.519 g of 4-nitrobenzyl-
3,3-di(acetylthio)-2-[(3S,4R)-4-allylthio-3-(1'(R)-~di-
methyl-~2-methylprop-2-yl}silyloxy}ethyl)-2-azetidinon-
1-yl]-propenoate in 20 ml of ethanol-free chloroform
was cooled to -60. To it was added a solution of 0.48 g
of chlorine in 5.6 ml of carbon tetrachloride. The
resultung'solution was maintained at -60 for 20 minutes,
~"l ;-~
~2~7~
- 31 - HOE 82/S 001
and was then warmed to room temperature, evaporated in
vacuo and chromatographed on silica gel to yield 2.32 g
of the title compound. mp 145-146 (from ethylacetate/
hexane)
max (CDCl3) 1795, 1743 cm 1
CD~13) 0.06 (6H, s)
0.85 (9H, s)
1.31 (3H, d, J6Hz)
2.25 (3H, s)
2.40 (3H, s)
3.53 (1H, 2d, J3g~4a 2Hz~ J3B,SiOCH
3Hz, 3-H)
4.08 - 4.50 (1H, m)
5.37 (2H,s)
6.28 (1H, d, 4-H)
7.45 - 8.42 (4H, m)
Example 15
4-NitrobenzYl(5S,6S) 6-l8(R)-~dimethvl-~2-methyl-
ProP-2-yl~silyloxy~ethyl)-7-oxo-4-thia-3-thioxo-1-_
azabicyclo[3,2,0]hePt-2-ane-2-carboxYlate
To a stirred solution of 0.741 g of 4-nitrobenzyl
3,3-di(acetylthio)-2-[(3S,4~)4-chloro-3-(1(R)-dimethyl-
~2-methylprop-2-yl~ silylox~ ethyl-2-azetidinon-1-yl]-
propenoate in 20 ml of dioxan and 2 ml of water was
added 0.247 g of imidazole. After 20 minutes the
solution was diluted with 120 ml of ethyl acetate
and extracted with dilute hydrochloric acid, followed
by brine. The organic phase was dried over MgSO4 and
evaporated in vacuo to give the title compound in
quantitative yield.
~max (liquid film) 1793, 1755 cm 1
(CDCl3) 0.11 ~6H, s)
0.89 (9H, s)
1.41 (3H, d, J6Hz)
3.96 (1H, 2d~ J6B SiOCH 4~Z~ 6B~5B
9Hz, 6-H)
~p
~Z~7~
- 32 - HOE 82/S 001
4.13 - 4.63 (lH, m)
5.25 - 5.48 (3H, m)
5.36 (~H, s)
6.05 (lH, a, 5-H)
7.37 - 8.45 (4H, m)
Example 16
4-Nitrobenzyl 5~R),3-ethylthio-6-(S)-~8(R)-hYdr~
ethYl~-7-oxo-4-thia-1-azabicYclo[3,2,0]hePt-2-ene 2-
carboxylate
To a stirred solution of 0.18~ g of 4-nitrobenzyl
(5R,6S)-~1'(R)-hydroxyethyl3-7-oxo~-thia-3-thioxo-1-a ~ icyclo
I3,2,0]heptane 2-carboxylate in 10 ml of dry tetra-
hydrofuran was added 0.094 ml of ethyl disopropylamine
followed by 0.119 ml of iodoethane. When the reaction
was shown to be complete (by means of thin layer chroma-
tography) the solvent was removed in vacuo and the
residue chromatographed on 10 g of silica gel (eluting
with ethyl acetate-hexane) to give 0.14 g of the title
compound.
Example 17
Potassium 5(R), 3-ethYlthio-6lS)-~8lR)-hydroxyeth
7-oxo-4-thia-1-azabicyclo[3,2,0 _ePt-2-ene 2-carboxylate
To a solution of 0.139 g of 4-nitrobenzyl 5(R),
3-ethylthio-6(S)-~1(R)-hydroxyethyl}-7-oxo~-ff~-1-a ~ icyclo
13,2,0]hept-2-ene 2-carboxylate 15 ml of ethyl acetate
was added 15 ml of an aqueous solution of 0.034 g of
potassium bicarbonate followed by 0.28 g of palladium
on charcoal. The mixture was hydrogenated at 50 psi for
one hour then filtered through '~YFLO' which is a trade
mark for a filtration aid. The aqueous phase was extracted
once with 10 ml of fre~h ethyl acetate and then hydro-
lysed to give 0.06 g of the title compound.
772
- 33 - HOE 82/S 001
Example 18
4-Nitrobenzvl 2-(4(R)-ethvlthio-3(S)-~1~(R)-dimethyl
[2-methvlprop-2-yl]silYloxyethyl]-2-azetidinon-1-yl)-2-
(4-oxo-1,3-dithietan -2-ylidene)acetate
A solution of lithium hexamethyldisilazide was
prepared by the addition of n-butyllithium in hexane
(4.21 ml of a 1.6M solution) to 2.13 ml of hexamethyl-
disilazane in 10 ml of dry tetrahydrofuran at 0C while
stirring under nitrogen. The solution was added via
a cannula to a solution of 1.08 g of 4-nitrobenzyl
2-(4(R)-ethylthio-3(S)-[1'(R)-dimethyl-~2-methylprop-2-yl~
silyloxyethyl]-2-azetidinon~1-yl)acetate in 10 ml of dry
tetrahydrofuran at -78C, with stirring under nitrogen.
After 5 minutes, 0.35 ml of car~on disulphide was
added by syringe and after a further 90 minutes
phosgene in toluene ~3.56 ml of a 12.5 % solution)
was added by syringe. The mixture was stirred fox 90
minutes and poured into 50 ml of diethyl ether and 10 ml
of 2M acetic acid. The organic layer was separated,
washed with water, 12 % sodium chloride solution, dried
over magnesium sulphate and evaporated to give an orange
oil. Chromatography over silica gel using diethyl ether/
hexane mixtures as eluent gave 0.485 g of the title
compound in purified form.
Ymax (CDC13) 1770, 1760 ~m~
o(CDC13) 0.04 (6H, s)
0.81 (9H, s)
1.18 (3H, t, J = 7 Hz)
1.22 (3H, d, J = 7 Hz)
2.51 (2~, q, J = 7 Hz)
3.18 (lH, dd, J = 2L7 and 3.7 Hz)
4.24 (lH, dq, J = 2.7 and 7 Hz)
5.31 (lH, d, J = 2.7 Hz)
5.23, 5.45 (2H, AB, J = 13 Hz)
7.55, ~.23 ~2H, A2B2, J = 9 Hz)
J~ -
77~
- 34 - HO~ 82/S 001 _
Example 19
4-Nitrobenzyl-2-(4(R)-ethylthio-3lS)-[1'(R)-hydroxy-
ethyl]-2-azetidinon-1-yl~-2-(4-oxo-1,3-dithietan-2-ylidene)
acetate
0.30 g of 4-Nitrobenzyl 2-(4(R)-ethylthio-3(S)-
[1(R)-dimethyl~2-methylprop-2-yl}silyloxyethyl]-2-
azetidinon-1-yl)-2-(4 oxo-1,3-dithietan-2-ylidene)
acetate was dissolved in 4 ml of dry DMF containing a
trace of para-quinol under a nitrogen atmosphere
protected fr~m light. The solution was treated with 5 mol
equivalent of hydrogen chloride in 2.2 ml of DMF. The
solution was stirred for 4 hours and diluted with 5 ml
of water, poured into 20 ml of diethyl ether and the
organic layer separated. The aqueous portion was re-
extracted with a further volume of diethyl ether and theorganic fractions combined washed with water, dried
over magnesium sulphate and evaporated to give a yellow
oil. Chromatography over silica gel using diethyl ether/
hexane mixtures as eluant gave 0.21 g of the title
compound in purified form.
~max (CDCl3) 34 50, 1785, 1760 cm 1,
~ (CDCl3) 1.13 (3H, t, J = 7 Hz)
1.18 (3H, d, J = 7 H~)
2.39 (1H, br s)
2.51 (2H, q, J = 7 Hz)
3.17 (1H, dd, J = 2.7 and 3.3 Hz)
4.22 (1H, m)
5.24 (1H, d, J = 2.7 Hz)
5.29 (2H, s)
7.52, 8.17 (2H, A2B2, J = 9 Hz)
Example 20
4-NitrobenzYl 2-(4(S)-chloro-3(S)-11'(R)-hYdroxyethyl]-
2-azetidinon-1-yl~2-(4-oxo-1,3-dithietan-2-ylidene)
acetate_
,J
- 35 - HOE 82/5 001
A solution of 0.208 g of 4-nitrobenzyl 2-14(R)-
ethylthio-3(S)-[1'(R)-hydroxyethyl]-2-azetidinon-1-yl)-2-
(4-oxo-1,3-dithietan-2-ylidene)acetate in 1 ml of ethanol-
free chloroform was cooled to -30C under a nitrogen
atmosphere and treated with 1.1 mol equivalent of
chlorine in 0.82 ml of carbon tetrachloride. The
reaction mixture was permitted to warm to room temp~ra-
ture and the solvent evaporated in vacuo. Chromatography
on silica gel using diethyl etherthexane mixtures as
eluant gave 0.015 g of 4-nitrobenzyl 2-(4(R)-chloro-3(S)-
[1(R)-hydroxyethyl]-2-azetidinon-1-yl-2-(4-oxo-1,3-
dithietan-2-ylidene)acetate and 0.03 g of the title
compound.
~max (CDCL3) 177
(CDCl3) 1.45 (3H, d, J = 6.3 Hz~
3.59 (lH, dd, J = 4.4 and 9.3 Hz)
4.37 (lH, m)
5.33, 5.40 (2H, AB, J = 13 Hz)
6.08 (1H, d, J = 4.4 Hz)
7.53 , 8.27 (4H, A2B2, J = 8.6 Hz)
Example 21
4-Nitrobenzyl (5R, 6S) 6-(8(R)-hydroxyethyl)-7-
oxo-4-thia-3-thioxo-1-azabicyclo[3,2,0]hept-2-ane-2-
carboxylate
To a solution of 0.028 g 4-nitrobenzyl 2-(4(S)-
chloro-3(S)-[1'(R)-hydroxyethyl]~2-azetidinon-1-yl-2-
(4-oxo-1,3-dithietan-2-ylidene)acetate in 1 ml of 10 %
a~ueous dioxane at 5C was added a trace of imidazole.
When the reaction was complete the solution was diluted
with diethyl ether and water, acidified with dilute
hydrochloric acid and extracted. The aqueous phase was
extracted with a second volume of diethyl ether and the
organic portions ~ombined, washed with water, 12 %
~lZ~7Z
- 36 - HOE 82/S 001
sodium chloride solution, dried over magnesium sulphate
and evaporated to give 0.01 g of crude product. Comparison
of its NMR spectrum w.ith that of the product of example 7
proved the existence of the title compound in ~he
S product mixture.
