Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~5~5
RAN 44~0/1?9
The known 3,4-cis-3-acylamino-azetidinones are
valuable intermediates for the production of antimicro-
bially active ~-lactam antibio~ics. Thleir manufacture is
usually carried out by the cycloaddi~ion of phthalimido-
or azidoacetyl chloride ~ith a corresponaing N-protected
imine (e.g. be~zaldehyde (2,4-dime~hoxybenzyl)imine) in
the presence of a base, whereafter the phthalimide or
azide group in the l-protected N-(2-o~o-3-azetidinyl)-
phthalimide or -azide obtained i6 converted into the amino
group (the phthalimide group by reaction with hydrazine.
methylhydrazine or dimethylaminopropanamine, the azide
grou~ by reduction with ammonium sulphid~ or,with elemen-
tary hydrogen and a catalyst such as palladium/carbon).
and the liberated amino group is protected by reaction
wi~h an acyl chloride, e.g. carbobenzoxy chloride, for
reason~ of the further processing.
The direct cycloaddition of N-carbobenzoxyglycine
chloride with a N-pratected imine gi~es, however, only low
yields of the desired azetidinone: ee J. Chem. Soc., 1880
(1975). N-Carbob~zoxyglycine chloride it6el~ iS an un-
stable compound which decomposes to unusable byproducts
even at low temperatures. This direct cycloaddition has
thus been regarded as being impracticable; see Tetrahedron
37. 2321 (1980).
It has now surprisingly been found tha~ a direct
cycloaddi~ion with good yields is achieved when a N-carbo-
benzoxyglycine alkali metal salt i6 used in place of N-car-
Nt/17.7~84
-- 2
bobenzoxyglycine chlo~ide and the cycloaddition with theN~protected imine undertaken in the presence of a base is
carried out under the additional in~luence of a specific
sulphonic acid chlocide, espe-cially of p-chlorobenzene~ul-
phonyl chloride.
By choosing a N-protected imine with suitable sub-
stitution ~see formula III hereina~er) ~wo new optical
centres are induced in the cycloaddition product
(a~etidinone), whereby the substituen~ in the 3- and
4-po6ition are i~ cis-relationship and, further; only on~ of
~he two possible diastereo~eric product~ is foLmed with high
diastereoselectivity. The present novel 6ynthesi6 therefore
leads to optically unifor~ process products, as will be
evident from the Pollowing.
The present invention i8 concerned, in particula~, with
a process for the manufacture of optically uniform azeti-
dinones of the general formula
R30
ROCONH ~ ~ ~ R2
~
o~ ~Rl
whecein R signifies benzyl, ~-(trimethyl-
8ilyl ) -lower alkyl or B-halo-lower alkyl,
R signifies a readily cleavable protecting
group, R signifies a lower, optionally oxy-
gen-containing, hydrocarbon group linked via
a carbon atom and R3 signifies a lowec
hydrocarbon group linked via a carbon atom,
whereby R~ and R~ ca~ also be linked with
one another to form a ring,
~.5~ 5;5
which proce~s comprises reacting an alkali metal ~alt of a
carboxylic acid of the general formula
XOCONHC~2COOH II
wherein R has the above significance.
with an optically unifor~ compound of the general formula
R30
H ~ R2 III
N
R
wherein Rl, R2 and R have the abovP
significance~
in the presence of a base and a ~ulphonic acid chloride of
the general formula
R -S02-cl IV
wherein R4 signifie~ phenyl. lower alkyl-
phenyl, halophenyl, lower alkyl or halo-
lower alkyl.
In the above proce~s products of formula I the fol-
lowing come i~to con~ideration, ~or ex~mple, as readily
cleavable protecting group~ Rl: benzyl, 2,4- or 3,4-di-
~ower alkoxy~benzyl, especially 2,4 or 3,4-dimethoxy-
benzyl, di~-(lower alkoxy)phenyl]methyl, especially di-
(4-methoxyphenyl)methyl, or 4-(lower alkoxy~phenyl, espec-
ially 4-methoxyphenyl: further, lower 2-alkenyl or a group
of the formula
-- 4
-CH2-CHtOR )2 (a~ or
. CH2CH2 - S ~ (b)
[~n
~he ein R5 signifie~ lower alkyl and n
~ignifies the number 0 or 1.
The term "readily cleavable protecting group" i~ to be
interpreted in the widest sense, and thus al80 lncludes
group~ which are not directly cleavable per 6e, but which
can be converted into a directly cleavable protecting
grvup by a simple chemical trans~ormation. Thus, e.g. the
~ollowing groups R are converted prior to the cleavage
into the cleavable groups given afterward~:
lower 2-alkenyl~ lower l-alkenyl
~5 -C~2-CH~oR5~2 -CH2-CHO--~-CO-CH(OH)2
--CH2CH2--S~ CH2CH2--S~ CH=CH2 ~ --CH0
The transformation and cleavage of the~e groups are
illustrated in more detail in European Patent Publication
No.101 598.
The ~erm t~lower 2-alkenyl~ denotes an olefi~ic hydro-
carbon group which can be straight-chain or branched.
which has a double bond in the 2-posi~ion and which
~,S ~L~5~;
-- 5
preferably contains up to 8, especially up to 4, carbon
atoms such as e.g. 2-propenyl (allyl), 2-methallyl, 2-
butenyl, 2-hexenyl, 2-heptenyl, 2-octenyl et~. The term
"lower alkyl" denotes a satura~ed hydrocarbon gro~p which
can be straight-chai~ or branched and which preerably
contains up to 8, especially up to 4, carbon atoms such as
e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-
butyl, sec-butyl, t-butyl, n-pentyl, i~opentyl, ~-hexyl, -
n-hep~yl, n-octyl etc. The term "lower alkoxy" denotes a
lower alkyl group linked via an oxygen a~om.
Preerred groups Rl are: Z-propenyl (allyl), 2,2-di-
methoxyethyl, ~,2-diethoxyethyl, 2-phenylthioethyl, 2-
phenyl~ulphinylethyl, 2,4- or 3,4-dimethoxyben2yl a~d
benzyl. Allyl, benzyl and 2,4-dimethoxybenzyl are the mos~
preferred groups denoted by R .
Preferred groups ~ 2 are those in which R2
~ignifies lower alkyl, phenyl-lower alkyl, lower alkoxy-
alkyl, e.g. lower alkoxymethyl, and R3 si~nifie~ lower
alkyl or phenyl-lower alkyl~ The groups H 2
~ R
ca~ also repre ent a S- or 6-membered 0-heterocycle which
optionally contains a further oxygen atom no~ direc~ly
linked with the centre o~ shirality and which can be
optionally substituted by lower alkyl, lower alkoxy, oxo
or spirocyelo-lower alkyl. Examples of ~uch groups, which
are llkawise preferred, areo
~s~ s
-- 6 --
~ CH~
The group ~ ~(~)-2,2-dimethyl-1,3-dioxolan-4-yl
is egpecially preferred.
In the p~ocess product~ of for~ula I ~ i~ preferably
benzyl. However, as already men~ioned, R can also ~ignify
R~(trimethylsilyl)-lower alkyl, e.g. ~-(trimethylsilyl)-
ethyl, or ~-halo-lower alkyl, e.g. ~-trichlo~oethyl, ~-di-
chloroethyl, B-chloroethyl or ~-trichloroisopropyl.
A~ alkali metal fialts of a carboxylic acid of ~ormula
II there come into con~ideration th~ potassium, ~odium and
also the llthium ~alt~. The potas~ium ~alts are pre~er-
red. ..
As the sulphonic acid chloride of formula IV there i~
preferably used p-chlorobenzene~ulphonyl chloride. For
~he purpose of the present invention there are, however,
also suitable p-toluenesulphonyl chloride and methanesul-
ph0nyl chloride~
The reaction of the compound~ of formulae II, III and
IV i~ carLied out in the presence of a base, for example a
~ertiary amine such a~ triethylamine, and preferably in an
i~ert organic solvent, especially in anhydrous form~whereby ethers ~uch a8 tetrahydcofuran, diethyl ethec,
t-butyl methyl ether, dioxan, ethylene glycol dimethyl
ether or the like, halogenated hydrocarbons such as
methylene chloride. chloroform, 1,2-dichloroethane or the
like, acetoni~rile, dimethylformamide or ~he like prefer-
ably com0 into consideration. The temperature of the
reaction preferably lieæ in the r~ange of about -300 to
about 500C.
The conversion o~ a compound of formula I into ~n
antimicrobially valuable ~-la~am antibiotic is de6cribed
e.g. in European Patent Publication No. 73061 and in
European Patent Publication No. 101 598. The cleavage of
R in the significa~cQ "benzyl" which is necessary is
carried out in the 6ame manner as when Rl is "2,4- or
3,4-di(lower alkoxy)benzyl", i.e. oxidatively with the aid
of a b~fered peroxodisulpha~e such as pota6sium peroxodi-
sulphate/dipotas~ium hydrogen ~ulphate. The benzyl group
can, however. alfio be cleav~d off reductively by the
actio~ of an alkali metal. Q.g. oP sodium or lithium, in
liquid ammonia.
Exam~le 1
30 g of anhydrous magnesium sulphate and 17.7 g (71.6
mmol) of N-carbobenzoxyglycine potas6ium salt are dis-
per~ed in 400 ml of methylene chloride. After the ad-
dition of 20 ml (1~3 mmol) of triethylamine the suspen~ion
obtained i8 stirred vigorously at room temperature for 1
l/Z hours and ~ubsequently cooled to 5C. Thi6 6uspen~i.0n
i8 trea~ed ~ith 10.0 g (35.~ mmol) of isopropylidene-D-
glyceraldehyde (2,4-dimethoxybenzyl)imine (prepared from
2~-dimethoxybenzylamine and isopropylidene~L-glyceralde-
hyde in 20 ml of methylene chloride). lS.l g (~1.6 mmol)of p-chlorobenzene~ulphonyl chloride in 50 ml of methylene
chloride are subsequently added dropwise at 5C within 45
minute~. The su~pension is stirred at room temperature
for 3 hours and filtered. Ths filtrate is evaporated, the
yellow-brown oil obtained is dissolved in 300 ml of ethyl
acetate and wa6hed successively twice ~with 190 ml of lN
aqueous hydrochloric a~id, twice with loO ml of 5% aqueous
sodium bicarbonate solution and once with 100 ml of
aqueou8 Bodium chloride solution. The organic phase is
evaporated and the oily yellow residue is crystallized at
0C by the addition of 300 ml o~ ether. There are
obtained 10.5 g (62%) of benzyl (3S,4S)-cis-1-(2,4-di-
methoxybenzyl)-4-t(~)- 2,2-dimethyl-1,3-dioxolan-4~yl)-2-
oxo-3-azeeidinecarbamate of melting point 113-114C.
.
When allylamine i8 u~ed in Example 1 in place of
2,4-dimethoxybenzylamine there are obtained in the same
manner, af~er chromatography on 6ilica gel (0.040 to 0.063
mm), 7.05 g (67~) of benzyl (3S,4S)-ci6-l-allyl-4-[(R)-
2,2-dimethyl-1,3-dioxolan-4-yl)-2-oxo-3-azetidinecarbamate
of ~elting point 94-96C.
