Note: Descriptions are shown in the official language in which they were submitted.
- 1 --
~;~S~L~54
RAN 4410/175
The present invention is concerned with a process
for the manufacture of novel, op~ically uniform ~-lactams of
the general formula
15Rl H H i
~ H W
O
wherein Rl signifies Lower alkanoyl,
lower alkoxycarbonyl or benzoyl, R2 sig-
nifies hydrogen, lower alkyl, lower
alkanoyl, lower alkoxycarbonyl or cyano,
R3 signifies hydrogen or lower alkyl,
B signifies lower alkylidene, lower
cycloalkylidene or carbonyl and æ sig-
nifies lower 2-alkenyl or 2,4-di(lower
alkoxy)benzyl,
and their corresponding optical antipodes, which process
comprises reacting a salt of a carboxylic acid of the
general formula
Nt/14.12.83
~ ~5~
-- 2
Rl H
R2/~ ~,
R COOH II
wherein Rl, R2 and R3 have the above
significa~ce,
in the presence o a reactive derivative of an organlc
sulphonic acid and a base with an optically uniform com-
pound of the general formula
N
Z
wherein B and Z have the above sig-
nificance,
or the optical antipode thereof.
The term "lower" denotes groups and compounds con-
taining at most 7, preferably at most 4, carbon atoms. The
term "alkyl" denotes straight-chain or branched-chain
saturated hydrocarbon groups such as methyl, ethyl and iso-
propyl. The term "alkoxy" denotes alkyl ether groups such
as methoxy and ethoxy. The term "alkanoyl" denotes straight-
chain or branch~d-chain saturated fatty acid groups such as
formyl and acetylO The term "2-alkenyl'~ denotes straight-
chain or branched-chain hydrocarbon groups containing at
least 3 carbon atoms which have a double bond in the 2,3-
. ~
~J,,~i~
~5~
-- 3
position such as allyl. The term "alkylidene" denotes groupssuch as methylene and isopropylidene. The term "cyclo-
alkylidene" denotes cyclic hydrocarbon groups containing at
least 3 carbon atoms such as cyclohexylidene.
The term 'aryl" used below sign:Lfies phenyl
optionally substituted by halogen or lower alkyl. The term
"haloalkyl" used below denotes alkyl groups substituted by
halogen such as trifluoromethyl. The term "halogen" sig-
nifies fluorine, chlorine, bromine or iodine.
In a particular embodiment the present invention
embraces the manufacture of compounds of formula I in which
Rl signifies lower alkoxycarbcnyl, R2 signifies hydrogen,
B signifies lower alkylidene and Z signl~ies lower 2-alkenyl.
The compounds listed hereinafter are representative
compounds falling within formula I above:
~0
Methyl (Z)-3-~[(2S,3S)-l-allyl-2-[(R)-2,2-dimethyl-
1,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]amino]-2-butenoate,
(3S,4S)-l-allyl-3-[[(Z)-2-benzoyl-1-methylvinyl]-
amino]-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidi-
none,
diethyl ~[[(2S,3S)-l-allyl-2-[(R)-2,2-dimethyl-1,3-
dioxolan-4-yl]-4-oxo-3-azetidinyl]amino]methylene]malonate,
methyl (Z)-3-~[(2S,3S)-1-(2,4-dimethoxybenzyl)-2-
[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]-
amino]-2-butenoate and
(3S,4S)-3-[[(Z)-2-benzoyl-1-methylvinyl]amino}-1-
(2,4-dimethoxybenzyl)-4-[(R) 2,2-dimethyl-1,3 dioxolan-4
yl~-2-azetidinone.
The reaction in accordance with the invention is
a cycloadaition which is familiar to the person skilled in
the art. There is obtained a compound of formula I above
a,.
or the optical antipode thereof in which the substituents
in the 3- and 4-position of the azetidinone ring stand in
cis-rel tionship to one another as expec:ted. Howe~er, it
has surprisingly been found that the use of an optically
active compound of formula III (or the optical antipode
thereof) in ~he abo~e cycloaddition induces two new optical
centres in high optical yield. In the products obtained
the second possible cis-cycloaddition product, which would
be diastereoisomeric to the product actually obtained,
could not be detected.
As reactive organic sulphonic acid derivatives
there come into consideration for the present purpose
primarily compounds of the general formula
R4-So2-X IV
wherein X signifies halogen or the group
-OS02-R and R4 signifies aryl, lower
alkyl or lower haloalkyl.
The preferred sulphonic acid derivatives are the compounds
of formula IV in which X signifies halogen, especially
chlorine,and R4 signifies phenyl optionally substituted by
halogen or lower alkyl, such as p-toluenesulphonyl chlo-
ride, p chlorobenzenesulphonyl chloride and ben~enesulphonyl
chloride.
As bases there are preferably used tertiary amines,
with tertiary aliphatic amines such as diisopropylethylamine
and triethylamine being especially suitable.
The carboxylic acid of formula II is introduced into
the reaction in the form of a carboxylic acid salt. Salts
which come into consideration are primarily alkali metal
~5~
-- 5
salts and ammonium salts derived from tertiary amines. In
an especially preferred embodiment an alkali metal salt,
especially the potassium salt, of carboxylic acids of formula
II are used.
Suitable inert organic solvents for the process in
accordance with the invention are, for example, ethers such
as tetrahydrofuran, diethyl ether, tobutyl methyl ether,
dioxan, ethylene glycol dimeth~l ether or the like, halo-
genated hydrocarbons such as methylene chloride, chloroform,
1,2-dichloroethane or the like, acetonitrile, dimethyl-
formamide or the like. Halogenated hydrocarbons such as
methylene chloride are especially suitable solvents. The
above cycloaddition is carried out in a temperature xange
of about -30C to about 50C. The reaction temperature
preferably lies in a range of about 0C to room temperature.
The compounds of formula III or their optical anti-
podes used as starting materials can be prepared by reacting
an aldehyde of the general formula
r
/~\
~ V
OHC
wherein B has the above significance,
or its opti~al antipode with an amine of the general
formula
H2N-Z VI
S~ 5~
-- 6
wherein Z has the above significance.
The reaction is preferably carried out in an inert organic
solvent, for ex~mple in a halogenated hydrocarbon such as
methylene chloride, chlorororm, 1,2-dichloroethane and the
like or in a hydrocarbon such as benzene, toluene and the
like. The water formed during the react:ion is preferably
removed continuously during the reaction, for example by
azeotropic distillation or by working in the presence of a
water entraining agent, for example in the presence of a
suitable molecular sieve, or of other customary drying agents
such as potassium carbonate, magnesium sulphate and the
like. When the water formed during the reaction is removed
azeotropically the reaction is carried out at the boiling
point of the chosen solvent; when a water-entraining
agent is used the reactlon is preferably carried out at
room temperature.
The compounds of formula III and their corresponding
~o optical antipodes, which surprisingly yield optically
uni~orm products in the cycloaddition described above, need
not necessarily be isolated, but can be subjected directly
to the cycloaddition in accordance with the invention.
The compounds of formula I obtainable in accordance
with the invention are novel and can be used for the
manufacture of antimicrobially active, optically uniform
substances which contain a ~-lactam ring. Such antimicro-
bially active substances can be manufactured from the
compounds of formula I obtainable in accordance with the
invention according to methods known per se, whereby the
choice of reagents and reaction conditions, depending on
the desired target compound, present no difficulties to the
person skilled in the art.
The compounds of formula I can be used, in par-
ticular, for the manufacture o antimicrobially active
compo~nds of the general formula
s
O H
~ - C ~ C - N ~ ~6 VII
10H2N OR ~ N~
O S03H
wherein R5 signifies hydrogen, lower
15alkyl or carboxy-lower alkyl and R6
signifies carbamoyl or carbamoyloxy-
methyl,
and their pharmaceutically acceptable salts. The use o~
the cycloaddition in accordance with the lnvention for the
manufacture o antlmicrobially active, optically uniform
substances containing a ~-lactam ring such as the afore-
mentioned compounds of formula VII is likewise an object of
the prPsent invention.
The compounds of formula VII can be manufactured,
for example, in accordance with the following Reaction
Scheme and ~he following description relating thereto. The
symbols Rl, R2, R3, R5, R6, B and Z used in the Reaction
Scheme have the above significance and Z' signifies a readily
cleavable N-protecting group, preferably a readily cleavable
acyl group such as t-butoxycarbonyl, trichloroethoxycarbonyl,
benzyloxycarbonyl and the like.
~.~5~
REACTION SCHEME
H 2N_~ z ~ ~N
O Z O ~Z O ~zO ~Z
I VIII XI
o -- 1
H2H~/ ~ N~CH20CONN2 N~OH Z--No~CHO
IX XIV Z XIII XII
N~ /R COOCN3 ~N~OOCR3 ,N
O ~R ~ -- ~
O~SO H ~ ~ H~NOH
XXI II XXII XXI
H H
2 ~R6
J_N
O ~SO H
XVI I ~ O E~
N ~R~;
H2N`OR '~ SO3H
VII
~ ~ - 9
A compound of formula VIII is obtained by the mild
acidic hydrolysis of a compound of formula I. The hydro-
lysis of a compound of formula I can be carried out, for
example, by treating the compound of formula I with an acid
in the presence of water and optionally a water-miscible
solvent such a~ acetone, tetrahydrofuran, dioxan, dimethyl
sulphoxide, dimethylformamida or the like. As acids ~here
come into consideration, for example, mineral acids such as
hydrochloric acid and sulphuric acid, or organic acids such
as p-toluenesulphonic acid, pyridinium p-toluenesulphonate
or the like, or sulphuric acidic ion exchangers. Depending
on the conditions used the dioxolan ring is also cleaved
during this reaction, there being obtained a compound of
formula IX.
By treating a compound o~ formula VIII or IX with
an agent yielding the group Z' there is obtained a compound
of formula X or XI. Suitable agents yielding the group Z'
are, for example, chlorformic acid esters sucn as benzyl
chloroformate, t-butyl chloroformate, 2,2,2-trichloxoethyl
chloroformate and the like. This reaction is conveniently
carried out in an inert organic solvent, for example in a
halogenated hydrocarbon such as methylene chloride, chloro-
form and the like, and conveniently in the presence of anacid-binding agent such as butylene oxide, triethylamine,
quinuclidine etc. The reaction is conveniently carried
out at room temperature.
The hydrolysis of a compound of formula X to give
a compound of formula XI is preferably carried out under
mild acidic conditions. In a preferred embodiment the
desired reaction is carried out by trans-acetalization in
a lower alcohol such as methanol or ethanol and in the
presence of a suitable acidic catalyst. Suitable catalysts
are, for example, sulphuric acidic ion exchangers, pyridinium
$~
-- 10
p-toluenesulphonate, p~toluenesulphonic acid and the like.
In this case the hydrolysis is preferably carried out at
room temperature. The hydrolysis can, however, also be
s carried out readily in the presence of water and a water-
miscible solvent such as tetrahydrofuran, dioxan, dimethyl
sulphoxide,dimethylformamide or the like.
The cleavage of the diol grouping in a compound of
formula XI is carried out according to methods which are
known per se and which are familiar to any person skilled
in the art, and can be accomplished, for example, using
sodium periodate in water. If desired, this reaction can
be carried out in the presence of a solubilizer such as
tetrahydrofuran, dioxan, methanol, ethanol or the like.
This reaction yields an aldehyde of formula XII.
The reduction of an aldehyde of formula XII to give
a primary alcohol of formula XIII is alsv carried out
according to methods which are known per se and which are
familiar to any person skilled in the art, for example by
treatment with sodium borohydride in a lower alcohol such
as ethanol, isopropanol or the like.
By reacting a compound of formula XIII with chloro-
sulphonyl isocyanate in an inert organic solvent there is
obtained a compound of formula XIV. Suitable solvents are,
for example, ethers such as diethyl ether r t-butyl methyl
ether and ethylene glycol dimethyl ether, halogenated
hydrocarbons such as methylene chloride and chloroform,
acetonitrile, dimethylformamide, dimethyl sulphoxide,
acetone and the like. The reaction is preferably carried
out in a temperature range of about 0C to about room
temperature.
By cleaving the protecting group denoted by Z from
a compound of formula XIV there is obtained a corresponding
5~
compound of formula XV. The cleavage of a 2,4~di(lower
alkoxy)benzyl group is conveniently carried out by mild OXl-
dation. Suitable oxidation agents are, for example, potas-
sium peroxyd.isulphate or ammonium peroxydisulphate, theoxidation being carried out in water at a pH of 6-8. A
suitable buffer is, for example, disodium hydrogen phos-
phate.
A lower 2-alkenyl group is cleaved by isomerization
thereof to a l-alkenyl group and subsequent oxidative
cleavage of the latter. The isomeriæation of the double
bond is preferably carried out with the aid of an isomeri-
zation catalyst, for example with a palladium dihalicle such
as palladium dichlorlde or with a tris(triphenylphosphine)-
rhodium (I) hallde (e.g. with the corresponding chloride) or
also with palladlum-on-carbon in the presence of a protonic
acid such as hydrochloric acid or phosphoric acid. As
the solvent there is conveniently used ethanol, methylene
chloride or a mixture thereof with water. The reaction
temperature conveniently lies in a range of about 50C to
the boiling point of the reaction mixture.
The oxidative cleavag~ of the lower l-alkenyl group
can be carried out, for example, by treatment with an
alkali metal permanganate, Eor example potassium permanganate,
there being preferably used an aqueous potassium perman-
ganate solution. If desired, the oxidation can be carried
out with the aid of an alkali metal periodate (e.g. potas-
sium periodate) in the presence of a catalytic amount ofthe mentioned alkali metal permanganate. The reaction is
preferably carried out in an aqueous, bufered medium,
especially an aqueous medium buffered to pH 7-8, but it can
also be carried out in a water-miscible organic solvent,
for example in acetone, dimethoxyethane, dioxan or tetra-
hydrofuran, with the addition of a weak organic base such as
- 12 ~ S ~
pyridine or in a mixture of one of these solvents with the
mentioned aqueous buffer. The reaction can, however, also
be carried out in a two-phase system using a phase transfer
catalyst. Methylene ~hloride or benzene, for example, can
be used as th~ organic phase which is not miscible with
water. Conventional phase transfer catalysts can be used,
especially organic quaternary ammonium halides such a~
benzyltriethylammonium chloride, tetra-n-butylammonium
bromide and cetyltrimethylammonium bromide. The oxidative
cleavage is preferably carried out at a temperature between
about 0C and 25C.
The compounds of formula XV in which R6 signifies
carbamoyl can be obtained by oxldizing an aldehyde of
formula XII according to methods known per se to give a
carboxyllc acid of formula XVIII, esterifying the carboxylic
acid o ormula XVIII, or example with methyl iodide in
the presence o potassium carbonate, cleaving off the
protecting group denoted by Z in the manner described above
from the resulting compound of formula XIX and treating the
compound of formula XX obtained with hydroxylamine.
The compounds of ormula XV in which R6 signifies
carbamoyl can, however, also be obtained by treating a
compound of formula XII with hydroxylamine, converting the
resulting oxime o formula XXI in a manner known per se into
the nitrile of ormula XXII, cleaving off thererom the
protecting group denoted by Z as described above and
saponifying the nitrile group in the resulting compound of
formula XXIII in a manner known per se to the carbamoyl
group.
By treating a compound of formula XV with sulphur
trioxide or a suitable complex of sulphur trioxide there is
obtained a compound of formula XYI. Suitable sulphur tri-
- 13 ~.~ S~6~
oxide complexes are, for example, complexes with pyridine,
trimethylamine, picoline, dimethylform~mide and the like.
An ether such as dioxan, pyridine, acet:onitrile, dimethyl-
formamide or the like is conveniently used as the solvent.
The preferred solvent is acetonitrile. The reaction is
preferably carried out at a temperature between about 0C
and 80C.
By cleaving off the protecting group denoted by Z'
from a compound of formula XVI there is obtained a compound
of formula XVII. A benzyloxycarbonyl group can be cleaved
off, for example, hydrogenolytically, for example by
treatment wlth elemental hydrogen in the presence of
palladium-on-carbon. A t-butoxycarbonyl group aan be
cleaved off, for example, by treatment with trifluoroacetic
acid or ormic acid. A trichloroethoxycarbonyl group can
be cleaved off, for example, by treatment with zinc in the
presence of an acid such as acetic acid or hydrochloric
acid.
By acylating a compound of formula XVII with a
reactive functional derivative of a carboxylic acid of the
general formula
~C_ COOH XXIV
~ ~R
H2N
wherein R5 has the above significance,
there is finally obtained the desired target compound of
formula VII. It will be appreciated that the compound of
formula XXIV must be suitably protected when R5 signifies
hydrogen or carboxy-lower alkyl, the protecting group is
removed after the acylation has been carried out. As
reactive functional derivatives of compounds of formula XXIV
there can be used, for example, corresponding acid an~
hydrides, mixed anhydrides, benzthiazolyl thioesters and
the like.
- 15 - ~ ~ 5~
The following Examples illustrate the present inven-
tion in more detail; they are, however, not intended to
be limiting in any manner. All temperatures are given in
degrees Celsius.
a) 12 g (92.16 mmol) of isopropylidene-~ glyceralde-
hyde are dissolved in 200 ml of methylene chloride, treated
firstly with 60 g of magnesium ulphate and then dropwise
over a period of 10 minutes with 5.26 g (92.16 mmol) of
3-amino-1-propene in 50 ml of methylene chloride and the
suspension is stirred at room temperature ~or 5 hours.
The magnesium sulphate is filtered off and the cleax colour-
less solution ls evaporated on a rotary evaporator. 14.6 g
(86.3 mmol; 93.6~) of pure isopxopylidene-L-glyceraldehyde
allylimine are obtalned.
b) 8.64 g (51.1 mmol) of isopropylidene-L-glyceralde-
hyde allylimine are dissolved in 400 ml of methylene chlo-
ride, treated firstly with 10.32 g (102.2 mmol) of tri-
ethylamine and then with 10.79 g (51.1 mmol) of potassium
N-(l-methyl-2-methoxycarbonyl~inyl)aminoacetate, the sus-
pension is cooled to 0 and treated dropwise within 5 min-
utes with 9.74 g (51.1 mmol) of p-toluenesulphonyl chlo-
ride in 50 ml of methylene chloride. The cooling bath is
removed, the mixture is stirred at room temperature for 8
hours, treated with 200 ml of water, the organic phase is
separated and evaporated. The crude product is chromato-
graphed on silica gel while eluting with hexane/ethyl
acetate (8:2). There are obtained 13.0 g (40.0 mmol; 78~)
of methyl (Z)-3-[~(2S,3S)-l-allyl~2-[(R)-2,2-dimethyl-1,3-
dioxolan-4-yl]-g-oxo 3-azetidinyl]amino]-2-butenoate as
an oil which solidifies slowly upon standing. A product
of melting point 98~ is obtained by crystallization from
ether/hexane.
Example 2
1.7 g (10 mmol) of isopropylidene-L-glyceralde-
hyde allylimine are dissolved in 80 ml of methylene chlo-
ride, treated firstly with 3~03 g (30 mmol) of triethyl-
amine and then with 2.6 g (10 mmol) of potassium N~
methyl-2-benzoylvinyl)aminoacetate and the suspensio~ is
cooled to 0. 2.85 g (15 mmol) of p-toluenesulphonyl
chloride in 10 ml of methylene chloride are added dropwise
thereto, the mixture ls stirred at room temperature Eor 5
hours, washed with 100 ml of water and evaporated. The.
crude product is purifled on silica gel using hexane/ethyl
acetate (7:3) ~or the elution. There are obtained 1.5 g
(4.04 mmol; 40%) o~ ~3S,4S)-l-allyl-3~[~(Z)-2-benzoyl-1-
methylvinyl]amino]-4-[(R)-2,2-dlmethyl-1,3-dioxolan-4-yl]-
2-azetidlnone as a pure oil which crystallizes out from a
mixture of ether and hexane and then has a melting point of
154-156.
Ex~mp e 3
;
1.7 g (10 mmol) of isopropylidene-L-glyceraldehyde
allylimine are dlssolved in 80 ml of methylene chloride and
treated firstly with 3.03 g (30 mmol) of triethylamine and
then with 2.8 g (10 mmol) of potassium N-(2,2-diethoxy-
carbonylvinyl)aminoacetate. 2.85 g (15 mmol) of p-toluene-
sulphonyl chloride in 20 ml of methylene chloride are then
added dropwise to the solution which is cooled in ice and
the mixture is stirred at room temperature for 5 hours. The
mixture is subsequently washed with 100 ml of water, the
organic phase is evaporated and the crude product obtained
is chromatographed on silica gel while eluting with hexane/
ethyl acetate (7:3). There are obtained 1.15 g (2.9 mmol;
29%) of pure diethyl [[[(2S,3S)-l-allyl-2-[(R)-2,2-dimethyl-
~.2.S~
17
1,3-dioxolan-4-yl]-4 oxo-3-azetidinyl]amino]methylene]-
malonate as an oil.
IR spectrum (film): bands, inter alia, at 1755, 1740, 1700,
1660 and 1600 cm 1.
3~75 g (13.44 mmol~ of isopropylidene-L-glyceralde-
hyde (2,4-dimethoxybenzyl)imine [obtained from isopropyl-
idene-L-glyceraldehyde and 2,4-dimethoxybenzylamine in a
manner analogous to that described in Example la)] are
dissolved in 150 ml of methylene chloride and treated with
3.25 g (32.25 mmol) of triethylamine. 3.40 g (16.12 mmol)
of potassium N~ methyl-2-methoxycarbonylvinyl)aminoacetate
are added and the suspension is cooled ko 0. 3.40 g
~16.12 mmol) of p-toluenesulphonyl chloride in 50 ml o~
methylene chloride are added dropwise thereto withln 5
minutes and the mixture is stirred at room temperature for
15 hours. After washing with 100 ml of water and evapo-
rating the organic phase, the residue is purified by chroma-
tography on silica gel using hexane/ethyl acetate (7:3) as
the eluting agent. There are obtained 3.45 g (7.94 mmol;
59%) of pure methyl ~Z)-3-[[(2S,3S)-1-(2,4-dimethoxybenzyl)-
2-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-oxo-3-a~etidinyl]-
amino]-2-butenoate as an oil which solidifies slowly.
After crystallization from ether/hexane, the product has
a melting point of 121.
Examp~e_5
2.8 g (10 mmol) of isopropylidene-L-glyceraldehyde
(2,4-dimethoxybenzyl)imine are dissolved in 125 ml of
methylene chloride and treated with 3.03 g (30 mmol~ of
triethylamine. 2.6 g (10 mmol) of potassium N-(l-methyl-
1 benzoyl-vinyl)aminoacetate are then added and the sus-
pension is stirred strongly at 0. 2.85 g (15 mmol) of p-
- 18 - ~ ~ S~
toluenesulphonyl chloride in 50 ml of methylene chloride
are slowly added dropwis~ thereto and the mixture is stirred
at room temperatuxe for 5 hours. The mixture is then
treated with 100 ml of water, the orgallic phase is separated
and evaporated. The residue is chromatographed on silica
gel using hexane/ethyl acetate (7:3) as the eluting agent.
There are o~tained 1.4 g (2.91 mmol; .29%) of pure ~3S,4S)-
3-[[(Z)-2-benzoyl-1-methylvinyl]amino]--1-(2,4-dimethoxy-
benzyl)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-azetidi-
none which crystallizes out from ether/hexane and then has
a meltlng point of 177-179.
Example 6
6.48 g (20 mmol) of methyl (Z)-3-[[(2S,3S)-l-allyl-
2-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-oxo-3-azetidinyl]~
amino]-2-butenoate are dissolved in 40 ml of acetone and
treated with 3.80 g (20 mmol) of p-toluenesulphonic acid
monohydrate in 20 ml of acetone. The clear solution is
stirred at room temperature for 15 minutes and then treated
slowly with 120 ml of ether. The precipitated product is
filtered off and dried. There are obtained 6.4 g (15.3 mmol;
77%) of pure (3S,4S)-cis-3-amino-1-allyl-4-[~R~-2,2-dimethyl-
1,3-dioxolan-4-yl]-2-azetidinone p-toluenesulphonate of
melting point 165.
Identical products are obtained when (3S,4S)-l-
allyl-3~[[(Z)-2-benzoyl-1-methylvinyl]amino]-4 [(R)-2,2-
dimethyl-1,3-dioxolan-4-yl]-2-azetidinone and diethyl [[[(2S,
3S)-l-allyl-2-[(R)-2,2-dimethyl-1,3-dioxolan~4-yl]-4-oxo-3-
azetidinyl]amino]methylene]malonate are subjected to the
same reaction conditions. The yields lie between 75% and
80%.
