Ring-opening process for preparing azetidinone intermediates

Compounds of formula I ##STR1## wherein R.sub.1 and R.sub.2 is each H, halo or an organic group, R.sub.3 is H or organic group, n=1 or 2, M is a heavy mono- or divalent metal, or M.sub.2 A wherein M.sub.2 is a heavy divalent metal and A is an organic or inorganic group, are prepared by treating a starting penicillin in a solvent with a salt of M.sub.1 or M.sub.2 A in the presence of a base at a temperature of from -70.degree. to 100.degree. C.

The present invention provides a process for preparing azetidinones which 
are useful intermediates in the synthesis of .beta.-lactam antibiotics, 
esp. penems. In particular, the present invention relates to a 
straightforward process for converting penem compounds of formula (II) 
into heavy metal azetidinone mercaptides of formula (I) 
##STR2## 
wherein: 
R.sub.1, R.sub.2 are each independently hydrogen, halogen or an organic 
radical; 
R.sub.3 is hydrogen or an organic radical; 
n is 1 or 2; 
M is a heavy metal M.sub.1 in the +1 or +2 oxidation state, or a group 
M.sub.2 A wherein M.sub.2 is a heavy metal in the +2 oxidation state and A 
is an organic or inorganic group. 
When R.sub.1, R.sub.2 are halogen, they are preferably bromo. 
When R.sub.1, R.sub.2 are organic radicals, they are preferably substituted 
or unsubstituted C.sub.1 -C.sub.4 alkyl groups. The substituents may be 
chosen from hydroxy, amino, cyano, mercapto and trifluoromethyl groups, 
wherein the hydroxy, amino and mercapto group may be free or protected. 
Examples of hydroxy, mercapto or amino protecting groups are, in 
particular, tri-(C.sub.1 -C.sub.4 -alkyl)silyl ether, for instance, 
trimethylsilyl or dimethyl-tert-butyl-silyl groups; diaryl-C.sub.1 
-C.sub.4 -alkyl silyl ethers, for example a diphenyl-tert-butyl-silyl 
group; halo-substituted alkyl carbonates such as 2,2,2 
trichloroethoxycarbonyl and optionally substituted aryl-C.sub.1 -C.sub.4 
alkyl carbonates, for example benzyloxycarbonyl and 
p-nitrobenzyloxycarbonyl groups. 
As used in the specification, the term "aryl" includes phenyl, phenyl 
substituted by one to three C.sub.1-4 -alkyl groups as tolyl, xylyl, cumyl 
or ethylphenyl or a nitro derivative thereof. 
R.sub.1, R.sub.2 together can also be a group of the formula NR'R", wherein 
R' and R" together form a C.sub.4 -C.sub.15 -dicarboxylic acyl group, 
which may be that of an alkanedicarboxylic acid or an aryldicarboxylic 
acid such as a phthalidyl group. R' and R" together can also form an 
organic C.sub.1 -C.sub.15 -ylidene residue including such arylidines as 
benzylidene, p-nitrobenzylidene or o-nitrobenzylidene. 
In NR'R", R' can be hydrogen or tri-(lower alkyl)silyl, such as 
trimethylsilyl, and R" can be an N-protecting group such as, preferably, 
trityl, formyl, lower-alkoxycarbonyl (such as t-butoxycarbonyl) or 
arylalkoxycarbonyl (such as p-nitrobenzyloxycarbonyl) or a group, R'"CO, 
wherein R'" is C.sub.1 -C.sub.8 alkyl or alkenyl optionally interrupted by 
O, S, CO or NH or substituted by an O, S or N function or by a halogen, 
cyano, heterocyclyl, hydroxy, carboxy, aryl or cycloalkyl group or R'" is 
phenyl or heterocyclyl group. 
The term heterocyclyl group, as used in this specification designates 
preferably a saturated or unsaturated pentatomic or hexatomic heterocyclic 
ring containing at least one heteroatom chosen from O, S and N. Said ring 
can be unsubstituted or substituted by one or more substituents selected 
from hydroxy, C.sub.1 -C.sub.4 alkoxy, halogen, C.sub.1 -C.sub.4 alkyl, 
mercapto, C.sub.1 -C.sub.4 alkylthio and amino groups. A heterocyclic ring 
may be, for example, an optionally substituted thiazolyl, triazolyl, 
thiadiazolyl, tetrazolyl or triazinyl ring. Particularly preferred is a 
3-aminothiazol-5-yl group. 
The cycloalkyl group herein can be cyclopentyl or cycloheptyl, but 
preferably cyclohexyl. When R.sub.3 is an organic radical, it may be any 
group which, together with the COO moiety, forms an esterified carboxyl 
group. Examples of carboxyl protecting groups R.sub.3 are, in particular, 
C.sub.1 -C.sub.4 alkyl groups, for instance methyl, ethyl or tert-butyl; 
halo-substituted C.sub.1 -C.sub.4 alkyl groups, for example 
2,2,2-trichloroethyl; C.sub.2 -C.sub.4 alkenyl groups, for example allyl; 
optionally substituted aryl groups, for example phenyl and p-nitro-phenyl; 
optionally substituted aryl-C.sub.1 -C.sub.6 alkyl groups, for example, 
benzyl, p-nitrobenzyl and p-methoxybenzyl, aryloxy C.sub.1 -C.sub.4 -alkyl 
groups, for example, phenoxymethyl; or groups such as benzhydryl, 
o-nitro-benzhydryl, acetonyl, trimethylsilyl, diphenyl-tert-butyl-silyl, 
and dimethyl-tert-butyl-silyl. 
The definition of R.sub.3 as an organic radical includes also any residue, 
including for instance such alkanoylmethyl groups as acetoxymethyl, 
pivaloyloxymethyl or arylcarboxy groups such as phtalidyl, leading to an 
ester group which is known to be hydrolized "in vivo" and to have 
favorable pharmacokinetic properties. 
When M is a heavy metal M.sub.1 in the +1 oxidation level, it is preferably 
Ag.sup.I, and in the compounds of formula (I) n represents 1. When M is a 
heavy metal M.sub.1 in the +2 oxidation level, it is preferably Hg.sup.II, 
Cu.sup.II, or Pb.sup.II, and n represents 2. When M is a group M.sub.2 A, 
M.sub.2 preferably represents the above heavy metals M.sub.1 in the +2 
oxidation level, A is preferably lower alkanoyloxy, such as acetoxy and 
mathoxycarbonyl, and more preferably an aryl such as phenyl, and n 
represents 1. A as an inorganic radical can be the ion of an inorganic 
acid such as the nitrate ion. 
A particularly preferred substituted alkyl group that R.sub.1 or R.sub.2 
may represent is 1-hydroxyethyl, wherein the hydroxyl is preferably 
protected as a silyl ether, e.g. 1-tert-butyldimethylsilyloxyethyl, or as 
a carbonate, e.g. 1-trichloroethoxycarbonyloxyethyl. Still preferably, 
R.sub.2 represents such 1-hydroxyethyl groups and R.sub.1 is hydrogen, or 
R.sub.1 is hydroxyethyl and R.sub.2 is bromo. Particularly preferred 
R.sub.3 groups are methyl, trichloroethyl, p-nitrobenzyl, and 
acetoxymethyl. A particularly preferred heavy metal M.sub.1 in the +1 
oxidation level is Ag.sup.I ; a particularly preferred heavy metal M.sub.1 
in the +2 level is Hg.sup.II. 
A number of heavy metal salts of 4-mercaptoazetidinones are already known 
in the literature: R. Lattrell, Liebigs Ann. Chem., 1974, 1937; A. Longo, 
P. Lombardi, C. Gandolfi and G. Franceschi, Tetrahedron Lett., 22, 355 
(1981); A. Martel, P. Dextraze, J. P. Daris, R. Saintonge, P. Lapointe, T. 
T. Conway, I. Monkovic, G. Kavadias, Y. Ueda, P. Elie, S. Patil, G. Caron, 
J. L. Douglas, M. Menard, and B. Belleau, Can. J. Chem., 60, 942 (1982); 
F. Di Ninno, D. A. Muthard, R. W. Ratcliffe, and B. G. Christensen, 
Tetrahydron Lett., 23, 3535 (1982); W. J. Leanza, F. Di Ninno, D. A. 
Muthard, R. R. Wilkering, K. J. Wildonger, R. W. Ratcliffe, and B. G. 
Christensen, Tetrahedron Lett., 39, 2505 (1983); V. M. Girijavallabhan, A. 
K. Ganguly, P. Pinto, and R. Versace, Tetrahedron Lett., 24, 3179 (1983); 
V. M. Girijavallabhan, A. K. Ganguly, P. Pinto, and R. Versace, J. Chem. 
Soc., Chem. Commun., 908 (1983). 
The usefulness of the compounds of formula (II) as intermediates in the 
field of .beta.-lactam antibiotics is self-evident and in part documented 
in the literature referred to above. In fact, these salts can be readily 
alkylated, acylated and converted into a number of 
4-azetidinylthioderivatives, according to a reaction known per se in the 
art. These derivatives, in turn, can be further manipulated on the 
azetidinone N-appendage to give monocyclic .beta.-lactam antibiotics, e.g. 
monobactams: 
##STR3## 
or bicyclic .beta.-lactam antibiotics, e.g. penems and cephems. 
A straightforward synthesis of compounds of formula (I) was still in 
demand, and it is now provided by the present invention. In fact, the 
methods known in the art and referred to above usually exploit an 
azetidinyl trityl sulphide or an azetidinyl tetrahydropyranil sulphide, 
which has to be synthesized through a multistep sequence either by total 
synthesis or from natural penicillins. Instead, the present invetion 
allows a direct conversion of penicillins into the compounds of formula 
(I) under mild, non-critical conditions. Moreover, the products (I) need 
not be isolated but can be further converted in situ to closer precursors 
of the target compounds. 
According to the present invention, a solution of the starting penicillin 
of formula (II) in an aprotic organic solvent is treated with a strong, 
poorly nucleophilic base and an organic or inorganic salt of the heavy 
metal M.sub.1 or of the M.sub.2 A aggregate, wherein M.sub.1, M.sub.2 and 
A are as defined above. Preferred bases are diazabicyclononene (DBN), 
1,4-diazabicyclooctane (DABCO) and diazabicycloundecene (DBU); preferred 
solvents are acetonitrile, dimethylformamide, benzene, dichloromethane; 
preferred heavy metal salts; are silver nitrate, silver perchlorate, 
silver acetate, mercury (II) acetate, methoxycarbonylmercury (II) acetate 
and phenyl mercury (II) chloride. Best yields are generally obtained in 
the temperature range of about -70.degree. C./+100.degree. C.; in several 
instances, the reaction is conveniently carried out at room temperature of 
15.degree.-20.degree. C. As the poorly nucleophilic base there can be used 
teriary amines, preferably those sterically hindred. Protection from the 
light, an inert atmosphere and dry solvents are usually beneficial. If 
isolation of the product is desired, this can usually be performed by 
aqueous work-up; the compounds of formula (I) are usually extracted with 
standard organic solvents (e.g. ethyl acetate, dichloromethane). 
Alternatively, the heavy metal thiolates can be conveniently acylated or 
alkylated in situ, more preferably acylated. 
Alkylation of the heavy metal mercaptides of formula I can be performed 
with reactive halides, such as methyl iodide, allyl bromide, benzyl 
bromide, and the like. Alkylation with .alpha.-halo acyl derivatives of 
formula III 
##STR4## 
wherein Hal is bromo or chloro, R.sub.4 is hydrogen or lower alkyl, esp. 
methyl, X is oxygen, sulphur or a bond, and R.sub.5 is an organic group, 
gives azetidinyl derivatives of formula IV 
##STR5## 
wherein R.sub.1 R.sub.5 and X are as defined above, which are useful for 
the synthesis of classical and non-classical cephalosporin derivatives 
(see, for example, J. H. C. Nayler et al., J. Chem. Soc., Chem. Commun., 
1973, 57 and 59). 
A further object of the present invention is the acylation of heavy 
mercaptides of formula (I), which can be accomplished within a few minutes 
by the mere addition of an acylating agent of formula R.sub.6 COY, wherein 
Y represents a chlorine atom, an OCOR.sub.6, OCOR.sub.6 ' or imidazolyl 
group. 
The organic residue R.sub.6 may be any of the substituents at 2-position of 
the penem framework; the penem are the final useful antibiotic compounds 
which are well known in the art, see Formula VII below. For example, 
R.sub.6 can be an optionally substituted C.sub.1 -C.sub.4 alkyl, 
methyl-phenyl, or methyl-C.sub.5-7 cycloalkyl group. The substituents are 
chosen from optionally protected hydroxy, amino or carbamoyloxy groups, 
halogen atoms, heterocyclylthio groups such as thiazolylthio, 
triazolylthio, thiadiazolylthio, tetrazolylthio, triazinylthio, 
tetrazolopyridazinylthio optionally substituted by a substituent chosen 
from amino, hydroxy, oxo and C.sub.1 -C.sub.4 alkyl group optionally 
substituted and quaternary ammonio groups such as 
##STR6## 
optionally substituted as above. 
As the substituents of R.sub.6, the hydroxy, amino or carbamoyloxy 
protecting groups, which may be present, are those usually employed in 
penicillins and cephalosporins for this kind of function. 
They may be, for instance, optionally substituted, especially 
halo-substituted, acyl groups, e.g. acetyl, monochloroacetyl, 
dichloroacetyl, trifluoroacetyl, benzoyl or p-bromophenacyl; triarylmethyl 
groups, in particular triphenylmethyl; silyl groups, in particular 
trimethylsilyl, dimethyl-tert-butyl-silyl, diphenyl-tert-butyl silyl; or 
also groups such as tert-butoxycarbonyl, p-nitro-benzyloxycarbonyl, 2,2,2 
trichloroethoxycarbonyl, benzyl and pyranyl. 
When, in particular, the R.sub.6 group is an alkyl or methylphenyl group 
substituted by hydroxy, preferred protecting group of the hydroxy function 
are p-nitrobenzyloxycarbonyl; dimethyl-tert-butyl silyl; 
diphenyl-tert-butyl silyl; trimethyl silyl; 2,2,2-trichloroethoxycarbonyl; 
benzyl; p-bromo-phenacyl; triphenylmethyl and pyranyl. 
The radical R.sub.6 ' is an organic radical different from R.sub.6 and can 
be a C.sub.1 -C.sub.4 alkyl group such as the tertiary butyl group, or a 
C.sub.1 -C.sub.4 alkoxy group, such as methoxy, ethoxy or isopropoxy. It 
may also be an arylalkoxy group such as benzyloxy or p-nitrobenzyloxy. 
In a preferred embodiment Y is chlorine and R.sub.6 is methyl or 
tert-butylidiphenylsilyloxymethyl. 
R.sub.6 is an organic radical and R.sub.6 ' is an organic radical different 
from R.sub.6. Preferably Y is a chlorine atom, and R.sub.6 is a methyl or 
tert-butyl-diphenylsilyloxymethyl group. 
The product thereby obtained is an azetidinyl thioester of formula (V) 
##STR7## 
wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.6 are defined as above. 
The importance of azetidinyl thioesters in the synthesis of penems is well 
known (see, for example, I. Ernest in "Chemistry and Biology of 
.beta.-Lactam Antibiotics", Morin and Gorman ed., Academic Press, NY, 
1982, vol. 2, pp. 315-359); several routes from penams to these 
intermediates have been devised but they all suffer from major drawbacks 
(see M. Alpegiani et al., Tetrahedron Lett., 1983, 1638, 1627, and 
references therein). On the contrary, preparation of azetidinyl thioesters 
of formula (V) from penams according to the present invention is a single, 
high-yield, stereoselective one-pot process, exploiting as reagents the 
acyl chlorides of formula R.sub.6 COCl, handy and often commercially 
available compounds. 
A particularly convenient procedure whcih for the first time elecits the 
synthesis of penem compounds of formula (VII) from penam compounds of 
formula (II) in a mere three-step process is herebelow described as 
illustrative of the merits of the present invention: 
##STR8## 
In step (a), the penam compound of formula (II) is converted into the 
azetidinyl thioester of formula (V) as above described. Conversion of the 
compound of formula (V) into a trialkoxyphosphorane of formula (IV), step 
(b), is simply accomplished by ozonolysis and quenching of the ozonide 
with excess trialkylphosphite P(OR.sub.7).sub.3, wherein R.sub.7 is a 
lower alkyl group, preferably ethyl or methyl, according to what is 
described by E. Perrone et al., Tetrahedron Lett., 1984, 2399. Just 
heating of the intermediates of formula (VI) then affords the desired 
penem of formula (VII).