Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
2 - JOE 82/S 001
The present invention relates to certain intermediates
for the preparation of 7-oxo-4-thia-1-azabicyclo[3,2,0]-
Hutton and Hutton derivatives, and to a process for
their preparation.
7-Oxo 4-thia-1-a~abicyclo[3,2,0]heptane and 7-oxo 4-
thia-1-azabicyclo[3,2,0~hept-2-ene penes have the
following structures:
I owe
Hutton Hutton
Certain derivatives of these basic structures have
antibiotic properties, see, for example, British Patent
Applications Nos. 2 074 563, 2 042 520 and 2 013 674. There
are, however, disadvantages in the methods proposed for
synthesizing such compounds, for example, the low yields
generally achieved, which are exacerbated by the isometric
composition of the product: it is well known that certain
stereochemistry in penes compounds is desirable as isomers
having this stereochemistry are more biologically active
than other isomers. Many of the processes proposed for the
production of penes derivatives and their precursors do not
give predominantly the desired isomers, and the search
continues for more effective methods of synthesizing these
structures.
The present invention provides a compound of the general
formula It and its tautomer It
H OH
6 SHEA -
COO COO
(It) (It)
~211~
- 3 - HOE 82/S 001
in which formulae R represents a carboxyl esterifying group removable
by hydrolysis, photolysis, reduction, or en eye Ashley 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 Ian a compound of the
general formula IBM or any mixture thereof. "A compound of
formula II" is used to denote collectively compounds of
formulae Ida, Jib and Tic. 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 Ida,
Jib, or Tic
SHEA R OH C / R1
1 X Scorn X S
ROOT Sorb ROOT
(IIaj (Jib)
DO
3 , p
ROOT
(Tic)
in which R is as defined above,
R represents a chlorine or bromide atom, the radicals
Ray and Rub, which may be the same or different, each
represents an alkyd group having from 1 to 4 carbon atoms,
I,,,
Lo
- 4 - HOE 82/S 001
especially a methyl or t~butyl group, an aureole group,
especially a phenol group, or an aralkyl group,
especially a bouncily group, and A represents a direct bond
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 be
inorganic or organic, for example, ammonia, or an alkali
metal (especially a sodium or potassium) carbonate
bicarbonate, or hydroxide; a primary amine, for example,
methyl amine, ethyl amine, aniline or benzylamine; an alkali
metal alkoxide, for example, sodium methoxide; or a
heterocyclic base, for example, having a Pea within the
range of from 5 to 9, for example, imidazole or pardon or
a substituted pardon, for example, an alkyd-, amino-, or
alkylamino-substituted pardon, for example, 4-methyl- or
4-dime~lylamino-pyridine. Imidazole is particularly
preferred.
The reaction is generally carried out in a solvent or
delineate, the choice of which is wide, provided that it is
inert under the reaction conditions. Examples of solvents
and delineates 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, deathly ether, also twitter-
hydrofuran and Dixon; kittens, for example, having up
to 4 carbon atoms, for example acetone and methyl ethyl
kitten; esters for example, methyl acetate and ethyl
acetate; and asides, for example, dimethylformamide and
dimethylacetamide; also chlorinated hydrocarbons, for
example, chloroform, ethylene chloride and carton twitter-
chloride; aromatic hydrocarbons, for example, Bunsen
and Tulane; and other solvents, for example, asset-
nitrite and nitromethane. A mixture of any two or more solvents may be used, and solvents are preferably used
I
- 5 - HOE US 001
in admixture with water, preferably a water-miscible
solvent in admixture with 5 to 20 % (v/v) water,
especially a mixture of Dixon 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 -COO is, for example,
an ester formed with an unsubstituted or substituted
aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,
aureole, araliphatic, heterocyclic or heterocyclic-ali-
phatic alcohol having up to 20 carbon atoms, or is,
for example, s sill or Stanley ester.
R may represent, for example a straight or branched
chain substituted or unsubstituted alkyd, 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, isopropyl n-
bottle, sec-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl,
ally, or vinyl group.
An aliphatic group R, especially a methyl group, may
be substituted by a cycloalkyl, aureole or heterocyclic
group, or R may itself represent a cycloalkyl, aureole or
heterocyclic group.
A cycloaliphatic group R may have up to 18 carbon
atoms and is, for example, a cyclopentyl, cyclohexyl or
adamantly group. An aureole group may have up to 12 carbon
atoms and may have two or more fused rings. An aureole
group R is, for example, an unsubstituted or substituted
phenol group, and an unsubstituted or substituted aralkyl
group is, for example, a bouncily, ~-nitrobenzyl or bent-
hydryl group.
A heterocyclic group may have one or more hotter-
atoms, selected from oxygen, nitrogen and Selfware, and
up to 14 atoms in total. A heterocyclic group is, for
example, an oxygen-containing heterocyclic group, for
example, a tetrahydropyranyl or phthalidyl group.
'I
I
- 6 - HOE 82/S 001
A Stanley group R may have up to 24 carbon atoms, for
example, R may represent a Stanley group having three
substituents, which may be the same or different, selected
from alkyd, alkenyl, cycloalkyl, aureole, aralkyl, alkoxy and
aralkoxy groups, for example, alkyd groups having up to 4
carbon atoms, for example, n-butyl groups, phenol and
bouncily groups, especially three n- bottle groups.
A sill group R may also have up to 24 carbon atoms
and three substituents, which may be the same or different,
selected from alkyd, alkenyl, cycloalkyl, aureole and aralkyl
groups, for example alkyd 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 bromide atom, or a vitro 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,
bouncily, ~-nitrobenzyl, benzhydryl and tritely esters.
A Stanley ester, for example, a tri-n-butyl Stanley
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 physiological conditions, that is to say,
the esterifying group is split off in viva to give the
free acid or the carboxylate, for example, an acyloxy-
methyl ester, e.g. an acetoxymethyl or pivaloyloxymethyl
., .
)'"'
,,~ I
I
- 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 p-nitrobenzyl, phthalid~yl,
pivaloyloxymethyl, acetylmethyl and acetoxy-methyl esters.
A compound of the general formula Ida, Jib, or Tic
is preferably produced by halogenating a compound of the
general formula IIIa, IIIb or Icky, respectively,
OH / OH
SHEA c~3
ROOT Sorb ROOT
(IIIa) (IIIb)
OH
SHEA - I 3
SO O
CLUE )~. So O
ROOT
Icky
2 2
in which R, Ray Rub and A are defined as above, and
R3 represents an alkyd 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
group having up to 6 carbon atoms, especially an ally
group.
r r
I.
I
- 8 - HOE 82/S 001
The halogenation of a compound of formula IIIa,
IIIb or Icky 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 bromide,
sulphuryl chloride, sulphuryl bromide, t-butyl hype-
chlorite and cyanogen chloride.
The halogenating agent is generally used in an amount
of from 1 to 2 mole equivalents, calculated on the compound
I 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 delineate
that is aprotic and is inert under the reaction conditions,
for example, an ether, a hydrocarbon or a halogenated hydra-
carbon, for example, Dixon, Bunsen, chloroform ormethylene chloride. A mixture of two or more solvents may
be used. Examples of halogenating systems are: chlorine in
chloroform and, especially, chlorine in Bunsen and t-
bottle hypochlorite in Bunsen. 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 Icky is prefer-
ably produced by removing the protective group from a
compound of formula Ivan Ivy or Ivy, respectively,
o'er or
SHEA I sR3 SHEA - C, SR3
N Scorn N
ROOT Sorb ROW S
(Ivy) (Ivy)
I lull
- 9 - HOE 82/S 001
OR
SHEA - C
-- SR3
Oslo
ROOT
(Ivy)
in which R, R2, , 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; acutely and petal groups, for
example, of formula
o'er
- C - R6
~R5
in which R6 and Rut which may be the same or different,
each represents a hydrogen atom or a lower alkyd 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 alkyd group, preferably a methyl
or ethyl group.
- 10 - HOE 82/S 001
R4 may also represent a sill group, for example, as
described above in relation to R, for example, -SiR8R9R10
groups, in which R8, R9 and Rl0, which may be the same or
different, each represents a lower alkyd group or an
aureole group, for example, triethylsilyl, t-butyldimethyl-
sill and methyldiphenylsilyl groups; and Stanley groups,
for example, as described above in relation to R, for
example, Sir R R groups, in which R , R and R
which may be the same or different, each represents a lower
alkyd group, for example, a tri-n-butylstannyl group.
Preferred I groups are tetrahydropyranyl, 2-metho~yprop-
yule 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 EM
Hal, e.g., in tetrahydrofuran (of Belgian Patent Specie
ligation No. 881 o'er hydrogen chloride in twitter-
hydrofuran, dimethylformamide, Dixon, a lower alkanol,
or acetonitrile; Tetra(n-butyl)ammonium fluoride in an
acidic medium, e.g., in acetic acid (of Belgian Patent
Specification No. 882 764); or aqueous hydrogen fluoride
e.g., in the presence of acetonitrile (of J. Chum. Sock
Perking 1, 1981, 2055). (The term 'known' is used herein to
mean in actual use in the art or described in the literal
lure of the art).
A compound of the general formula IV may be prepared according to the following reaction scheme:
- I - HOE BUS 001
o'er o'er
OH - C Octal 9 SO
H
O I
VI I I
OR ~,~
OH - C SR3
I
ROOT
1;
I I 2 pi SR3 SHEA C, sR3
Scorn I
ROOT Sorb ROOT ROOT
Ivy Ivy Ivy
- 12 - HOE US 001
in which R, Ray Rub, R3, R4 and A are as defined above.
A compound of formula VOW may be prepared as
described in Belgian Patent Specification No. 882 764.
A compound of formula VOW 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 alkyd group, especially an ethyl
group, or a straight chain lower alkenyl group,
especially an ally group.
The reaction is generally carried out in a solvent,
preferably a erotic solvent, for example, water or an
alcohol, or an aprotic, water-miscible solvent which is
preferably polar, for example, dimethylformamide, dim ethyl
sulphoxide, tetrahydrofuran or dioxin. The reaction
temperature is, for example, from -20 to ~50, preferably
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
y1CH2C2R (IX)
in which R is as defined above and
ye represents a group that is capable of being
replaced by a nucleophilic group and is, for example, a
halogen atom, preferably a bromide or iodine atom, or a
modified hydroxy group, preferably a sulphonyloxy group
of the formula SYRIA in which R16 represents a lower
alkyd or -CF3 group, or a phenol group which is us-
substituted or is substituted by a nutria, Brigham or
p-methyl group.
I Lo
- 13 - HOE 82/S 001
Y preferably represents a bromide or iodine atom
or a methylsulphonate, trifluoromethylsulphonate~ toll-
sulphonate or benzenesulphonate group.
The base may be inorganic, organic or organometallic,
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 hydrides a
tertiary amine, for example, a trialkylamine, for example,
triethylamine, DABCO (diazabicyclo[2,2,2]octane), pardon,
or an alkyl-substituted or amino-substituted or
dialkylamino-substituted pardon, for example, NUN-
dimethylaminopyridine, or colliding; a guanidine, for
example, tetramethylguanidine; DUN (diazabicyclo[4,3,0]non-
15 ennui) or DUB (diazabicyclo[5,4,0]undec-7-ene~, a polymeric
base i.e., a base attached to an inert polymeric support
e.g., Hunks base (diisopropylethylamine attached to e.g.,
polystyrene); a mutilated amine, for example, a mutilated
alkyd- or arylamine, for example, lithium diisopropylamide
(LEA), lithium hexamethyldisilazide, lithium piperidide,
lithium 2,2,6,6-tetramethylpiperidide, or a Grignard
reagent, for example, methyl magnesium bromide. Preferred
bases are, for example, potassium carbonate, sodium
hydrides lithium diisopropylamide and triethylamine.
The reaction is generally carried out in an aprotic
solvent or delineate, for example, a tertiary aside, for
example, dimethylformamide, dimethylacetamide or hexamethyl-
phosphoramide; a hydrocarbon, for example, Bunsen or lot-
gene; or an ether, for example, deathly ether, tetrahydro-
Furman or Dixon; or acetonitrile, dim ethyl sulphoxide, or
sulpholane. Dimethylformamide and dimethylacetamide are
preferred. A mixture of two or more solvents and/or
delineates may be used.
The reaction may be carried out at a temperature
generally within the range of from -80C to +30C
preferably from -40 to +30C, and especially from -20 to
~2~C.
I
Jo .,
I
- 14 - HOE 82/S 001
From 1 to 1.5 moles of compound It 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-
aside with stirring, adding the base, adding the compound
of formula IX and reacting at the desired temperature. The
resulting compound of formula V may be worked up and is-
fated in the usual manner, for example, using cremate-
graphic and/or crystallization techniques, or the subset
quint 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 carboxyl esterifying
group, this group may be converted into another ester-
lying 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 hydrolyzed in a known manner
using, for example, acid 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 hydrolyzed 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 pi 1 to 5, preferably 2 to I, and the free
acid may then be isolated and, if desired, the free
acid is then esterified with an esterifying agent capable
of introducing a different esterifying group R, for example
with an alcohol ROW in the presence of an acid or another
. . ,
~21~
- 15 - HOE 82/S 001
activating agent, for example, dicyclohexylcarbodiimide,
or with an alkylating agent RYE in which ye is as defined
above. Preferably a salt may be isolated and esterified
directly.
A compound of formula V may be converted into a
compound of formula IV by treatment with a base in the
presence of carbon disulphide followed by reaction with an
assaulting agent, or by treatment with a base, then with
carbon disulphide, and finally reaction with an assaulting
agent. An assaulting agent is generally an activated
carboxylic acid.
The activated 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
androids, and activated esters. An android may be
symmetrical or asymmetrical. SCORN
For the introduction of a group a to give
a compound of formula Ivan the assaulting Sorb
agent preferably has one of the formulae Pa to Xb
R2COZ (Pa) RbCOZ ( Xb)
O O O O
Ray C - O - C - Rare _ C - O - C - Rub
(Xc) (Ed)
O O
q ,- " q
Rub - C - O - C - I;
(X e)
in which Ray and Rub are as defined above, and Z represents
a halogen atom, especially a chlorine or bromide atom or
represents an activated ester or aside, or a radical
derived from an acid aside. Such coupling reagents are
well known in the art of peptize chemistry.
I
- 16 - HOE 82/S 001
In the case of formula Ivy/ the group
S
I
S
may be introduced by means of an assaulting 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
Jo
to compound of formula Ivy, a dicarboxylic acid derivative
of formula XII is used
Casey
A
CASEY
in which A and Z are as defined above, and Z preferably
represents a halogen atom, especially z chlorine atom. As
mentioned above, A represents the residue of a dicarboxylic
acid or represents a direct bond. A is derived, for
example, from Masonic, dimethylmalonic, succinic, glutaric,
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 assaulting agent.
The base preferably has a pi 20, and is preferably a
mutilated amine. Examples of preferred bases are lithium
diisopropylamide, lithium 2,2,6,6-tetramethyl-piperidide,
lithium cyclohexyl isopropylamide, lithium hexamethyl
dieselized, and sodamide.
The reaction is generally carried out in an inert
solvent, for example, an oxygenated hydrocarbon, preferably
an ether, for example, deathly ether, tetrahydrofuran,
, .
~211~1~8
- 17 - HOE 82/S 001
Dixon, glum or diglyme. The reaction temperature is,
for example, from -120 to +30C, preferably from -100
to -20C.
The amount 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 1 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 assaulting agent to
complete the reaction.
There may then be admixed a erotic source having a
pi less than 10, and especially from 5 to pharaoh 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,
preferable to US stereochemistry, more OR compounds being
antibiotically active than are US compounds.
We have found a process that gives predominantly the
desired OR compound of formula I. It has been proposed
previously (British Patent Application AYE) to
halogen ate a compound of formula IV i.e., a compound having
a protected hydroxy group in the side chain attached to the
3-position, but we have found that this process gives only
a OR halogenated compound, which in its turn, gives a
compound analogous to that of formula I but having the
undesired US 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 US. The isomer
ratio 4S:4R in compound II resulting from the halogenation
varies according to the reaction conditions but is, for
I 118
- 18 HOE 82/S 001
example, in the range of from 3:1 to as high as 9:1. More-
over, the OR and US isomers of formula II can be separated
easily, for example, by chromatography.
The US halogenated intermediates of formula II give
virtually exclusively a compound of formula I with the OR
stereochemistry as shown. The presumed participation of the
free hydroxyl group of the side chain of formula II in
giving the more starkly hindered compound of formula I
is also unexpected and constitutes a valuable advance in
the preparation Go the penes compounds of formula I.
The compound of formula I is itself a very useful
starting material for the preparation of various don-
natives substituted at position 3, especially by -SR3,
wherein R represents alkyd having 1-10 carbon atoms or
substituted alkyd; particularly alkyd 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 which 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.
....
I
- 19 - HOE 82/S 001
Example 1
4-(R)-Allylthio-3lS)-[11(R)-~dimethyl-~2-methylproopal -
silyloxy~ eth~l]azetidin-2-one
To a stirred solution of 1.14 ml ox ally 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-
Aztecs'-- dimethyl-~2-methylprop yule
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 sulfite,
evaporated to dryness and then chromatographed on silica
gel. Elusion with ethyl acetate / hexane mixtures afforded
1.8 g of the title compound as white crystals.
-1
)cDcl3 3420, 1767 cm
(CDCl3) 0.05 ohs
0.88 (OH, s)
1.20 (OH, d, J6Hz)
2.9 - 3.2 (OH, m)
3.9 - 4.3 (OH, m, H-1')
3.84 (OH, d Jo 4 2Hz, H-4)
4.95 - 6.3 (OH, m)
7.28 (OH, broad s)
Example 2
Methyl 2-(4(R)-allylthio-3-(S)-[1'(R)- methyl 2-
methylprop-2-yl~ silyloxy~ ethyl]azetidin-2-on-1-yl)
acetate
To a stirred solution of 1.76 g of 4(R)-allylthio-
3-(S~-[1'(R)- dim ethyl ~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 separated organic layer was washed with
I Lo
- 20 - HOE 82/S 001
water and dried over magnesium sulfite. Evaporation
in vacua afforded a crude product which was cremate-
graphed on silica gel. Elusion with ethyl acetate/hexane
mixtures afforded 1.56 g of the title compound as a
pale yellow oil.
CDCl3 1753, 1768 cm 1
(CDC13) 0006 (OH, s)
0.86 (OH, s)
1.23 (OH, d 6J.5Hz)
3.2 (OH, Al)
3.70 (OH, s)
3.6 - 4.3 (OH, m)
4.87 (lo, d J 2Hz, Ho
4.9 - 6.3 (OH, m)
Example 3
4-Nitrobenzyl 2-(4(R)-allylthio-3(S)-[1'-(R) dimethYl 2-
meth~lprop~2-yl~silyloxy~ ethyl]azetidin-~-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 16 g of
methyl2-(4(R)-allylthio-3tS)-[1'(R)-dimethyl~2-methvlprfop-
2-yl~silyloxy~ethyl]azetidin-2-on-1-yl)acetate. After
10 minutes, the mixture was evaporated to about 1/5 of
its original volume; 2 ml of dim ethyl acetamide were
added, followed by a solution of 3.25 g of 4-nitrobenzyl
bromide in 50 ml of dimethylacetamide. After 1 hour, the
mixture assay partitioned between 0.01M Hal and ethyl
acetate. The separated organic layers were washed with
0.01M Hal, with water, with cold, saturated sodium bit
carbonate, and with brine, and were then dried and
evaporated. The resulting crude product was cremate-
graphed over silica gel; elusion with ethyl acetate/
hexane mixtures afford 19.5 g of the title compound
as an oil.
I
- 21 - HOE 82/S 001 _
Max (CDC13) 1755, 1769 cm 1
~(CDC13) 0.07 and 0~09 (OH, two singlets)
0.88 (OH, s)
1.25 (OH, d J6Hz)
3.2 (OH, m)
3.7 - 4.5 (OH, m)
4.95 (OH, d J2Hz, H-4
4.9 - 6.3 (OH, m)
I - 8.35 (OH, m)
Example 4
4-Nitrobenzyl 3, 3-di(acetylthlo)-[(3S,4R)-4-allylthlo
3~[1'(R) dimethyl-~2-methylprop-2-yl~ silyloxy~ ethyl]
2-azetidinon-1-yl)propenoate
A solution of lithium hexamethyldisilazide was pro
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 Connally to a solution of 0.98 g of 4-nitrobenzyl 2-
(4(R)-allylthio-3(S)-[1'(R)-dimethyl-~2-methylproopal
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 android. 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 lo Hal, with water,
and with a 12 % sodium chloride solution, and were then
dried over magnesium sulfite 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 fluent to give 0.800 g of the title compound
in purified form.
I 8
- 22 - HOE 82/S 001
(cDcl3) 1778, 1745 cm 1
~(CDCl3) 0.06 (OH, s)
0.85 (OH, s)
1.26 (OH, d J6Hz~
2.25 (OH, s)
2.35 (OH, 5)
3.11 - 3.52 (OH, m, 3-H)
OWE (OH, d, J 6Hz)
4.14 4.39 (IT, m)
4.95 - 6.30 (OH, m)
5.35 (OH, s)
5.56 (IT, d J3Hz, 4-H)
7.44 - 8.38 (OH, m)
Example pa
4-Nitrobenzyl 3,3-di(acetylthio)-2-[(3S,4R)-4-allylthio-
3-~1'(R)-hydroxyethyl~-2-azetidinon-1-yl]propenoatlo
To a solution of 0.601 g of 4-nitrobenzyl Dow-
(acetylthio~-2-[(3S,4R)-4~allylthio-3-(1'(R)-dimeethyl-
2-methylprop-2-yl~silyloxy~ethyl)-2 azetidinon-1-yl]-
preappoint 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 vacua. Bunsen 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 silica gel
eluding with ethyl acetate - hexane mixtures to give
0.142 g of pure title compound.
Max 1774, 1738 cm 1
(CDCl3) 1.26 (OH, d, J6Hz)
? 24 (OH, s)
2.38 (OH, so
3.35 (OH, d, J7Hz)
3.22 - 3.48 (OH, m)
3.98 - 4.45 (OH, m)
,. . .
I so
,...
- 23 - HOE 82/S 001
.
5.30 (OH, s)
4.95 - 6.1 (OH, m)
7.42 - 8.23 (OH, m)
Example 5b
4-Nitrobenzyl 3,3-di~acetylthio)-2 [issuer
thio-3-~1'(R)-hydroxyethyl~-2-azetidlnon-1 yl1propenoate
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~silyloxy3ethyl~ 2-azetidinon-
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 quenched with a saturated aqueous
sodium bicarbonate solution. The resulting solution was
extracted with dichloromethane. The resulting organic
phase was washed with water, with sodium bicarbonate,
and then with brine. It was then dried over McCoy and
chromatographed on silica gel, eluding 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 pa.
Example_5c
4-Nitrobenzyl 3,3-di(acetylthio)-2-[(3S,4R)-4-
allylthio-3-1'(R)-hydroxyethyl~-2-azetidinon-1-yll]
preappoint
To a solution of 5.58 g of 4-nitrobenzyl Dow-
(acetylthio)-2-[(3S, 4R)-4-allylthio-3-(1'(R~-dimethyl-
~2-methylprop-2-yl~silyloxy~ethyl~ 2-azetidinon-1-yl]-
preappoint in 6.5 ml of tetrahydrofuran was added a
freshly prepared solution of 3.72 g of hydrogen chloride
in 32 ml of tetrahydrofuran.
The solution was set aside at room temperature until
the reaction was complete, and was then evaporated in
vacua. Chromatography on silica gel, eluding with ethyl
acetate -hexane mixtures gave 3.10 g of the title compound.
For spectral details see Example pa.
I
- 24 - HOE 82/5 001
Example pa
4-Nitrobenzyl 3,3-di(acetylthio)-2-[(3S,4S)-4-chloro
3-~1'(R)-~ydroxyeth~l~-2-azetidinon-1-yl]pro~enoatlo
To a solution of 0.246 g of 4-nitrobenzyl Dow-
(acetylthio)-2-[(3S,4R)-4~allylthio-3-(1'(R)-hydrooxyethyl)-
2-azetidinon-1-yl]propenoate in 13 ml of Bunsen 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 Dow-
(acetyl-thio)-2-[(3S,4R)-4-chloro-3~ (R)-hydroxyethyl)-
2-azetidinon-1-yl]propenoate (20 I) and as the major
product 0.121 g of the title compound.
For spectral details see Example aye.
Example 6b
4-Nitrobenzyl 3,3-di(acetylthio)-2-[(3S,4S)-4-
chloro-3-~1'(R)-hydroxyethy~ -2-azetidinon-1-Yl]propenoate
To a solution of 3.10 g of 4-nitrobenzyl Dow-
(acetylthio)-2-[(3S,4R)-4-allylthio-3-(1'(R)-hydrooxyethyl)-
2-azetidinon-1-yl]propenoate in 70 ml of dry Bunsen
cooled to 6 was added drops a solution of 1.5 mow
equivalent of chlorine in 9.5 ml of carbon tetrachloride.
When the starting material had been consumed, the solution
was reduced in volume in vacua and chromatographed on
silica gel, eluding 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)-hyydroxy-
ethyl)-2-azetidinon-1-yl]propenoate, and as the major
product 1.808 g of the title compound.
For spectral details see Example aye.
Example 7
4-Nitrobenzyl (5R,6S) 6-~8'(R)-h~droxyethyl~-7-oxo-4-
thia-3-thioxo-1-azabicyclo[3,2,o]hept-2-ane 2-carboxylate
To a solution of 0.525 g of 4-nitrobenzyl Dow-
35(acetylthio)-2-[~3S,4S)-4-chloro-3-(1'(R)-hydroxyeethyl)-
I,
- 25 - HOE 82/S 001
2-azetidinon-1-yl]propenoate in 15 ml of dioxin and 1.5 ml
of water was added OWE g of imidazole. When the react
lion 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 McCoy and evaporated in vacua to give the title
compound as an orange solid in quantitative yield.
Max (liquid film) 1791, 1751 cm 1
(CDCl3) 1.39 (OH, d, J6Hz)
3.00 (OH, s) C H
3.76 (OH, Ed, JOB c~c~ 4Hz~ Joy
4.05 - 4.53 (OH, m)
5.35 (OH, s)
5.45 us
5.95 (OH, d, 5-H)
7.36 - 8.45 (OH, m).
Example 8
3(S)-~1'(R)-Dimethyl(2-methylprop-2-yl)silyloxyethHoyle
(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 they'll. After 30 minutes stirring,
a solution of 12.6 g of 3(S~-{1'(R)-dimethyl(2-methylprop-
2-yl)silyloxy-ethyl~-4-acetoxyazetidin-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 sulfite,
and evaporated to dryness. 6.9 g of the title product
were obtained. Yield: 54 %
'I
I
- 26 - HOE 82/S 001
Max lCDCl3) 1765 cm
J (CDCl3) 0.10 ohs
0 90 (OH, s)
1026 (OH, d, J = 6 Ho)
1.33 (OH, t, J = 7 Ho
2.68 12H, q, J = 7Hz)
3.16 (OH, m)
4.1 - 4.3 (OH, m)
4.85 (OH, d, J = 2 Ho)
6.78 (OH, broad s).
Example 9
Methyl 2-[3(S)-~ (R)-~dimeth~l(2-methylprop-2-yl)s lye-_
oxyethyl}~4(R)-ethylthio-azetidin-2-on-1-yl]acetatlo
To a stirred solution of 6.9 g of Dow-
methyl(2-methylprop-2-yl)silyloxyethyl3-4(R)-ethyllthio -
azetidin-2-one in 150 ml of dry dimethylformamide was
added 13.15 g of finely ground an hydrous 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 pi 2 by drops addition of dilute hydrochloric
acid, and then back-extracted with ethyl acetate. The
combined organic layers were washed with water, dried
over sodium sulfite, and evaporated n vacua to give
an orange oil, which was chromatographed over silica gel.
Elusion with ethyl acetate/hexane mixtures afforded
6.37 g of the title compound as a pale yellow oil.
Yield: 72 %.
Max (CDCl3) 1749 jester) and 1760 (B-lactam) cm
(CDCl3) 0.06 (OH, s)
0.36 (OH, s)
1.3 (OH, m)
2.58 (OH, q) J = 6Hz)
3.12 OH dud, J = 2Hz and 4 Ho)
3.70 (OH, s)
3.93 (OH, dud, J gem = 17 Ho)
4.3 (lo, my
4.92 (OH, d, J = 2Hz)~
I
- 27 - HOE 82/S 001
Example 10
4-Nitrobenzyl 2-[3-(S)-~1~(R)-dimethyl-(2-methylprop-
2-yl)-silyloxyethyl3-4(R)-e~ylthio-azetidin-2-on-1yule]-
acetate
To a solution of 6 .37 g of methyl 2-[3(S)-1'(R)-
dimethyl(2-methylprop-2-yl)silyloxyethyl~-4(R)-ethhealth-
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 vacua to dryness. The product was
dissolved immediately in Z5 ml of dimethylacetamide, 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
combined organic layers were backwashes with water, then
with brine, and were then dried over sodium sulfite and
evaporated in vacua to afford an orange oil. Cremate-
graph over silica gel, eluding with ethyl acetate/hexane
mixtures afforded the title compound as a pale yellow,
viscous oil. Yield: 6.18 g, 80 %.
Max (CDCl3) 1765 (B-lactam) and 1755 (ester)cm 1
(CDC13) 0.05 (OH, s)
0.08 (OH, s)
0.88 (OH, s)
1.25 (OH, t, J = 7Hz)
1.28 13H, d, J = 6 Ho)
2.58 (OH, q, J = 7Hz)
3.18 I dud, J = 2 Ho and 4 Ho)
4.05 (OH, dud, Gem = 18 Ho)
4.1 - 4.3 (OH, m)
4.93 (OH, d, J = 2Hz)
,
~29~L18
- 28 - HOE 82lS 001
Example 11
4-Nitrobenzyl 3,3-di(acetylthio)-2 [(3S,4R) 4-
ethylthio-3-(1l(R)-(dimethyl-~2-meth~lprop-2-yl~siilyloxy~
ethyl)-2-azetidinon-1-yl]propenoate
A solution of 2.0 g of 4-nitrobenzyl 2-[3S,4R)-4-
ethylthio-3-l1'(R)-~dimethyl-2 -methylprop-2-yl~ silylox~ -
ethyl)-2-azetidinon-1-yl]acetate in 30 ml of dry twitter-
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 bottle lithium (1.55 molar,
6.01 ml, 9.31 Molly) 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 android, 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 sulfite
and evaporated in vacua to yield 3.03 g of the title
-
compound, which was used subsequently without further
purification.
Max (CDCl3) 1776, 1739, 1715 cm 1
d (CDC13) 0.06 (OH, s)
0.85 (OH, s)
1.06 - 1.64 OH m)
2.10 - 3.16 (OH, m)
2.23 (OH, s)
2.35 (OH, s)
3.25 - 3.50 (OH, m, 3-H)
4.05 - 4.67 (OH, m)
5.34 (OH, s)
5.56 (OH, Ahab
7.37 - 3.44 (OH, m).
IT
'I
I
- 29 - YE 82/S 001
Example 12
4-Nitrobenzyl 3,3-di(acetylthi_ -2-[(3S,4R)-4-
ethylthio-3~ (R)-h~droxyethyl,3-2-azetidinon-1~y~
preappoint
0.303 g of 4-nitrobenzyl 3,3-di(acetylthio)-2-
[(3S,4R)-4-ethylthio-3-(1'(R)-~dimethyl-~2-methylpprop-
2-yl~-silylox~ ethyl)~2-azetidinon 1-yl]propenoate was
dissolved in a solution of 12 mow equivalent of hydrogen
chloride in S ml of tetrahydrofuran. The solution was
stirred for 6 hours then evaporated in vacua to 1/3
of its volume. Ethanol free chloroform was added and the
solution evaporated. The residue was chromatographed on
silica gel eluding 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 (OH, m)
2.00 - 3 18 (OH, m)
3.19 - 3.48 (OH, m, 3-H)
3.95 - 4.46 (OH, m)
5.30 (OH, s)
5. 3 OH 4~.,3B'
7.33 - 8.37 (OH, m).
Example aye
4-Nitrobenzyl 3,3-di(acetylthio)-2-[(3S,4S)-4-
chloro-3-~1'(R)-h~droxyethyl~-2-azetidinon-1-yl]prrepent
A solution of 0.10 g of 4-nitrobenzyl dustily-
thio)-2-[(3S,4R)-4-ethylthio-3-~11(R)-hydroxyethyllo
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 awoke and
chromatographed on silica gel to give 0.032 g of the
title compound.
or
I,
~21~L~8
- 30 - HOE 82/S 001
Max (liquid film) 1790, 1739 cm 1
d (CDC13) 1.37 (OH, d, J7Hz)
2.24 (OH, s)
2.39 (OH, s)
3.58 (OH, Ed, JOB, O-CH-CH3 10Hz, JOB
5 Ho, 3-H)
4.00 - 4.56 (OH, m)
5~30 (OH, s)
6.27 (OH, I, 4-H)
7.38 - 8.25 (OH, m).
Example lob
_Nitrobenzyl 3,3-di~acetylthio)-2-~3S,4S) 4-
chloro-3-~1'(R)-hvdroxyethyl-2-azetidinon~1-yl]proopenoate
To a solution of 0.10 g of 4-nitrobenzyl Dow-
15 (acetylthio)-2-[(3S,4R) 4-ethylthio-3-~1'(R)-hydroxyethyl-
2-azetidinon-1-yl]propenoate in 2 ml of dry Bunsen
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, eluding with ethyl acetate -
hexane mixtures to give as a minor product 0.011 g
of 4-nitrobenzyl 3,3-di(acetylthio)-2-[(3S,4R) sheller-
3-(1'(R)-hydroxyethyl)-2-azetidinon-1-yl]propenoatlo, thetas
the major product, 0.065 g of the title compound.
For spectral details see Example aye.
Example 14
4-Nitrobenzyl 3,3-di(ace~y~_hio)-2-[(3S,4R)-4-
chloro-3-(1'(R)-dimethyl-~2-methylprop-2-yl~silyllucks
ethyl)-2-azetidinon-1-yl]propenoate
A stirred solution of 3.S19 g of 4-nitrobenzyl-
3,3-di(acetylthio)-2-[(3S,4R)-4-allylthio-3-(1'1R)Dow-
methyl 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
resulting solution was maintained at -60 for 20 minutes,
_, I
Lo
- 31 - HOE 82/S 001
and was then warmed to room temperature, evaporated in
vacua and chromatographed on silica gel to yield 2.32 g
of the title compound. my 145--146 (from ethyl acetate/
hexane)
Max (CDCl3) 1795, 1743 cm 1
(CDCl3) 0.06 (OH, s)
0.85 (OH, s)
1.31 (OH, d, J6Hz)
2.25 (OH, s)
2.40 (OH, s)
3.53 (OH, Ed, J3B,4~ 2Hz~ J3B/SiOCH
3Hz, 3-H)
4.08 - 4.50 (OH, m)
5.37 ohs
6.28 (OH, d, 4-H)
7.45 - 8.42 (OH, m)
Example 15
4-Nitrobenzyl ! 5S,6S) 6-(~(R)-dimethyl-2-methyl-
prop-2-yl}silyloxy~ethyl)-7-oxo-4-thia-3-thioxo-1--
azabicyclor3,2,0]hept-2-ane-2-carboxylate
To a stirred solution of 0.741 g of 4-nitrobenzyl
3,3-di(acetylthio)-2-[(3S,4R)4-chloro-3-(1(R)-~dimmethyl-
~2-methylprop-2-yl~ silyloxy3 ethyl-2-azetidinon-1-yl]-
preappoint in 20 ml of dioxin 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 McCoy and
evaporated in vacua to give the title compound in
quantitative yield.
Max (liquid film) 1793, 1755 cm 1
tCDC13) 0.11 (OH, s)
0.89 (OH, s)
1.41 (OH, d, J6Hz)
3.96 (OH, Ed, JOB Seiko OH 6B,5B
9Hz, 6-H)
- 32 - HOE 82/S 001
4.13 - 4.63 (OH, m)
5.25 - 5.48 (OH, m)
5.36 (OH, s)
6.05 (lo, d, 5-H)
7 37 - 8.45 (OH, m)
Example 16
4-Nitrobenzyl 5(R),3-ethylthio-6-(S)-~8(R)-hydroxy-
ethyl oxo-4-thia-1-azabicyclo[3,2,0]hept-2-ene 2-
carboxylate
To a stirred solution of 0.1~ g of 4-nitrobenzyl
(5R,6S)-~1'(R)-hydroxyethyl3-7-oxo-~-thia-3-thioxoo-1-azabicyclo
[eighteen 2-carboxylate in 10 ml of dry twitter-
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 chrome-
tography) the solvent was removed in vacua and the
residue chromatographed on 10 g of silica gel (eluding
with ethyl acetate-hexane) to give 0.14 g of the title
compound.
Example 17
Potassium 5(R), 3-ethylthio-6(S)-~8(R)-hydroxyethyl-~
7-oxo-4-thia-1-azabicyclo[3,2,0]hept-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-~-thia ~-azabicyclo
[eighteen 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 '~YFI,O' which is a trade
mark for a filtration aid. The aqueous phase was extracted
once with 10 ml of fresh ethyl acetate and then hydra-
lucid to give 0.06 g of the title compound.
lZl~ 8
- 33 - HOE 82/S 001
Example 18
4-Nitrobenzyl 2-(4(R)~ethylthio-3(S)-[1'(R)-dimethyl
[2-methylprop-2-yl]silyloxyethyl]-2-azetidinon-1-yyule-
(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 Connally to a solution of 1.08 g of 4-nitrobenzyl
2-~4(R)-ethylthio-3(S)-[1'(R)-dimethyl-~2-methylprRipley
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 carbon disulphide was
added by syringe and after a further 90 minutes
phosgene in Tulane (3.56 ml of a 12.5 % solution)
was added by syringe. The mixture was stirred for 90
minutes and poured into 50 ml of deathly ether and 10 ml
of EM acetic acid. The organic layer was separated,
washed with water, 12 sodium chloride solution, dried
over magnesium sulfite and evaporated to give an orange
oil. Chromatography over silica gel using deathly ether/
hexane mixtures as fluent gave 0.485 g of the title
compound in purified form.
of ax (CDC13) 1770, 1760 cm
6(CDCl3) 0.04 (OH, s)
0.81 (OH, s)
1.18 (OH, t, J = 7 Ho)
1.22 (OH, d, J = 7 Ho)
2.51 (OH, q, J = 7 Ho)
3.18 (OH, dud, J = 2.7 and 3.7 Ho)
4.24 (OH, do, J = 2.7 and 7 Ho)
5.31 (OH, d, J = 2.7 Ho)
5.23, 5.45 (OH, ABE J = 13 Ho)
7.55, 8.23 (OH, AHAB, J = 9 Ho)
. . .
I
-- 34 - HOE 82/S 001
Example 19
4-Nitrobenzyl-2-(4(R)-ethyl-thio-3(S)-[1'(R)-hydroox-
ethyl]-2-azetidinon-1-yl)-2-(4-oxo-1,3~dithietan-22-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 -queenly under a nitrogen atmosphere
protected from light. The solution was treated with 5 mow
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 deathly ether and the
organic layer separated. The aqueous portion was no-
extracted with a further volume of deathly ether and the organic fractions combined washed with water, dried
over magnesium sulfite and evaporated to give a yellow
oil. Chromatography over silica gel using deathly ether/
hexane mixtures as eluant gave 0.21 g of the title
compound in purified form.
Max (CDC13) 34 50, 1785, 1760 cm 1,
o (CDCl3; 1.13 OH t, J = 7 Ho
1.18 (OH, d, J = 7 Ho)
2.39 (OH, by s)
2.51 (OH, q, J = 7 Ho)
3.17 (OH, dud, J = 2.7 and 3.3 Ho)
4.22 (OH, m)
5.24 (OH, d, J = 2.7 Ho)
5.29 (OH, s)
7.52, 8.17 (OH, AHAB, J = 9 Ho)
Example 20
4-Nitrobenzyl 2-(4(S)-chloro-3(S)-[1'(R)-hydroxyethyl]-
2-azetidinon-1~ 2-(4-oxo-1,3-dithietan-2-ylidene)_
acetate
X
~2~118
- 35 - HOE 82/S 001
A solution of 0.208 g of 4-nitrobenzyl 2-(4~R)-
ethylthio-3(S~-[1'(R)-hydroxyethyl]-2-azetidinon-1yule-
(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 mow equivalent of
chlorine in 0.82 ml of carbon tetrachloride. The
reaction mixture was permitted to warm to room tempera-
lure and the solvent evaporated in vacua. Chromatography
on silica gel using deathly ether/hexane mixtures as
10 eluant gave 0.015 g of 4-nitrobenzyl 2-(4(R)-chloro-3(S)-
[1(R)-hydxoxyethyl]-2-azetidinon-1-yl-2-(4-oxo-1,33-
dithietan-2-ylidene)acetate and 0.03 g of the title
compound.
Mecca (CDCL3) 1775 cm 1.
(CDC13) 1.45 (OH, d, J = 6.3 Ho)
3.59 (OH, dud, J = 4.4 and 9.3 Ho)
4.37 (OH, m)
5.33, 5.40 (OH, ABE J = 13 I
6.08 t1H, d, J = 4.4 Ho)
7.53 , 8.27 I AHAB, J = 8.6 Ho)
Example 21
4-Nitrobenzyl (OR, US) 6-(8(R)-hydroxyethyl)-7=
oxo-~-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-yll-2-
30 (4-oxo-1,3-dithietan-2-ylidene)acetate in 1 ml of 10 %
aqueous Dixon at 5C was added a trace of imidazole.
When the reaction was complete the solution was diluted
with deathly ether and water, acidified with dilute
hydrochloric acid and extracted. The aqueous phase was
extracted with a second volume of deathly ether and the
organic portions combined, washed with water, 12 %
r
Jo
- 36 - HOE 82/S 001
sodium chloride solution, dried over magnesium sulfite
and evaporated to give 0.01 g of crude product. Comparison
of its NOR spectrum with that of the product of example 7
proved the existence of the title compound in the
product mixture.
