FR2541279A1 - Derivatives of 1-aza-7-oxobicycloÄ3.2.0Ühept-2-ene-2-carboxylic acid - Google Patents

Abstract

THE INVENTION CONCERNS THE COMPOUNDS OF FORMULA III OR V: (CF DRAWING IN BOPI) OR R IS HYDROGEN OR A METHYL GROUP, R IS A PROTECTIVE GROUP OR A PHYSIOLOGICALLY HYDROLYSABLE AND ACCEPTABLE ESTER GROUP AND R IS A ELIMINABLE GROUP. THESE COMPOUNDS ARE INTERMEDIATE PRODUCTS FOR THE PREPARATION OF PHARMACOLOGICALLY ACTIVE SUBSTANCES.

Description

 The present invention relates to 6 (1-fluoroethyl) and 6- (1'-fluoro-1'-methylethyl) -carbapenems, their method of preparation and their use in chemotherapy.

 European Patent No. 1628 discloses a large number of carbapene derivatives having antibiotic activity, but makes no mention of the fluoroalkyl compounds of the present invention and their advantageous antibiotic properties.

dans laquelle
R1 représente l'hydrogène ou un groupe méthyle et
R2 represente l'hydrogène ou un groupe alkyle inférieur,
un groupe alcényle inférieur ou un groupe cycloalkyle
chacun pouvant être non substitue ou mono ou poly
substitue par un groupe amino, mono ou di-(alkyl-infe-
rieur)-amino, acylamino inférieur, carboxy,
alcoxycarbonyle inférieur ou carbamoyle;;
un groupe de formule IIc
(CH2)p-R7 IIc
dans laquelle R7 représente un groupe phényle ou un
hétérocycle sature ou insaturé a 5 ou 6
chainons contenant 1 ou plusieurs hétéroatomes
choisis parmi 0, S et/ou N et qui peuvent
être non substitués ou mono ou poly substitués
par un atome de fluor, de chlore, de brome, un groupe
amino, mono ou di-(alkyl-inférieur)-amino, hydroxy,
alcoxy inférieur, mercapto, alkylthio, phenyl-
thio, sulfamoyle,guanidino, nitro, cyano,
acylamino inférieur, carboxy, alcoxycarbonyle
ou carbamoyleet p signifie 0, 1, 2 ou 3; ou un groupe répondant a l'une des formules

dans lesquelles
R4, R5 et R6 peuvent être identiques ou différents et
chacun représente l'hydrogène ou un groupe alkyle
inferieur ou R4 et R6 et/ou R5 et l'un des groupes CH2
peuvent former un cycle, de même que
R5 et R6 dans la formule II et R4 et R5 dans les
formules lia et IIb, ces cycles pouvant être non
substitues ou mono ou poly substitues par un groupe
alkyle, hydroxy, carboxy oudi-(alkyl-inferieur)-amino m signifie 2 ou 3, et n signifie 1, 2 ou 3 avec la condition que lorsque R1 représente l'hydrogène et que le groupe qui le contient présente la configuration I
R2 est autre qu'un groupe acétylaminoéthyle;; ou des formes protégées et/ou des esters physiologiquement hydrolysables et acceptables de cas composes; sous forme d'acides libres ou de sels ou sous forme d'ions amphotères.The invention relates more particularly to the compounds of formula I

in which
R1 represents hydrogen or a methyl group and
R2 represents hydrogen or a lower alkyl group,
a lower alkenyl group or a cycloalkyl group
each can be unsubstituted or mono or poly
substituted by an amino group, mono or di- (alkyl-infe-
amine, lower acylamino, carboxy,
lower alkoxycarbonyl or carbamoyl;
a group of formula IIc
(CH2) p-R7 IIc
wherein R7 represents a phenyl group or a
saturated or unsaturated heterocycle at 5 or 6
chains containing 1 or more heteroatoms
chosen from 0, S and / or N and which can
be unsubstituted or mono or poly substituted
by a fluorine, chlorine, bromine atom, a group
amino, mono or di- (lower alkyl) amino, hydroxy,
lower alkoxy, mercapto, alkylthio, phenyl-
thio, sulfamoyl, guanidino, nitro, cyano,
lower acylamino, carboxy, alkoxycarbonyl
or carbamoyl and p is 0, 1, 2 or 3; or a group responding to one of the formulas

in which
R4, R5 and R6 may be the same or different and
each represents hydrogen or an alkyl group
lower or R4 and R6 and / or R5 and one of the CH2 groups
can form a cycle, as can
R5 and R6 in formula II and R4 and R5 in
formulas IIa and IIb, these cycles possibly being
substituted or mono or poly substituted by a group
alkyl, hydroxy, carboxy or (lower) alkylamino m means 2 or 3, and n is 1, 2 or 3 with the proviso that when R 1 is hydrogen and the group containing it has the configuration I
R2 is other than an acetylaminoethyl group; or protected forms and / or physiologically hydrolyzable and acceptable esters of compound cases; in the form of free acids or salts or in the form of amphoteric ions.

dans laquelle
R1 et R2 ont les significations donnees plus haut,
R8 represente un groupe éliminable
R3 représente un groupe protecteur ou un groupe ester
physiologiquement hydrolysable et acceptable ou
B) en echangeant le groupe OH dans un compose de
formule IV

dans laquelle R1, R2 et R3 ont les significations donnees plus haut, ou un précurseur de ce composé, par un atome de fluor et le cas échéant, en éliminant le groupe protecteur du composé ainsi obtenu ou en convertissant le compose ainsi obtenu en un autre ester physiologiquement hydrolysable et acceptable et/ou en sa forme protegee ------------------------------ et en isolant le composé ainsi obtenu sous forme d'acide libre ou de sel ou sous forme d'un ion amphotère.The compounds of the invention can be prepared
A) introducing a -S-R2 group into a compound
of formula III

in which
R1 and R2 have the meanings given above,
R8 represents an eliminable group
R3 represents a protecting group or an ester group
physiologically hydrolyzable and acceptable or
B) by exchanging the OH group in a compound of
formula IV

in which R 1, R 2 and R 3 have the meanings given above, or a precursor thereof, with a fluorine atom and, if appropriate, by removing the protecting group from the compound thus obtained or converting the compound thus obtained into another a physiologically hydrolyzable and acceptable ester and / or its protected form and isolating the compound thus obtained under form of free acid or salt or as an amphoteric ion.

 Process A) can be carried out according to the usual methods, for example in an inert solvent such as an aromatic hydrocarbon, for example benzene, or acetonitrile, and preferably at reduced temperatures, for example to about 0 ° C.

 Process B) can be carried out according to the usual methods, for example using a dialkylamino-sulfuryl trifluoride such as diethylamino-sulfuryl trifluoride.

The removal of the protecting groups is carried out according to the usual methods, as is the i.so-
lation and purification of the products obtained.

The preparation and interconversion of the esters,
protected forms and salts, is also carried out according to the usual methods.

 Processes for the preparation of carbapenems in their various forms are also described in the literature, for example in the publications of European Patent Applications Nos. 1628, 10316, 17992, 37080, 37081, 388869, 50334, 33209, 44142, 60612, 61231. , 44170, 59478, 58317, and may even be used analogously for the preparation of the compounds of the invention.

dans laquelle
R1, R3 et R8 ont les significations données plus haut.The starting materials of formula III are new and can be prepared by introducing the R 8 group into a compound of formula V

in which
R1, R3 and R8 have the meanings given above.

 Examples of removable groups R 8 are those formed by the reaction of the hydroxy group with a phosphoric acid ester chloride, for example with a diphenyl chlorophosphate or with a sulfonic acid, for example with p-acid. sulphonic toluene.

The compounds of formula IV may be prepared in a manner analogous to that described for process A) mentioned above, from compounds of formula Va

The process is conventional and includes introducing the R8 group and then the -S-R2 group.

The compounds of formula V are also novel and may, for example, be prepared according to the following reaction schemes or analogously to the methods described in the reaction schemes mentioned above.

REACTION SCHEME 2:

 The reactions indicated on these schemes can be carried out according to the usual methods for the type of reaction concerned. The cyclization can for example be carried out in an inert solvent such as an aromatic hydrocarbon, for example benzene, in the presence of a transition metal catalyst. There may be mentioned rhodium acetate or copper acetylacetonate as examples of a transition metal catalyst.

The compounds of formula V and Va can exist in the following tautomeric forms

 The remaining intermediates are either known or can be prepared analogously to the known methods and / or as described hereinafter in the examples.

Carbapenems such as those of the present application contain 2 centers of chirality in the cycle (5 and 6)

 They may be present in the various configurations, as 6R, 5R, 6S, 5S, 6S, 5R or 6R, 5S isomers or as mixtures thereof. When the starting materials used have a particular configuration, the final products obtained will have the same configuration while the mixed starting products will produce mixed final products. Thus the configuration of these compounds does not change during reactions such as A) or B) described above. The isomer mixtures can be separated according to the usual methods such as fractional crystallization.

 It is known that the biological activity can be attributed to the compounds, in which position 5 is of R configuration.

 There is another center of chirality when R 1 is hydrogen and it remains unchanged during the reactions, such as A) described above.

However, in reactions such as B), where fluorine is introduced, inversion occurs. Therefore, by fluorination of 8-R-hydroxy starting material a final 8-S-fluoro product is obtained and vice versa.

The compounds of formula I in free form or in the form of an easily separable ester can be used as chemotherapeutic agents, in particular as antimicrobial agents as indicated by their inbibiting action on various bacteria, (for example Pseudomonas aeroginosa, Enterobacter cloacae,
Enterobacter agglomerans, Staphylococcus epidermidis,
Streptococcus aronson, Streptococcus pneumoniae,
Aerococcus viridans, Staphylococcus aureus, Streptococcuspyogenes, Streptocoecus faecalis, Escherichia coli, Proteus vulgaris, Proteus mirabilis, Proteus morganSi, Klebsiella pneumoniae, Serratia marcescens and Salmonella typhimurium) by a series of in vitro dilution tests at concentrations, for example, between 0.001 and 50 μg / ml, and by in vivo tests in the mouse, at doses of, for example, between about 0.1 and 100 mg / kg.

 The compounds of the invention also exert an inhibitory effect on 5-lactamases at concentrations of between 0.1 and 10 Wg / ml.

The enzymatic activity of ss-lactamase preparations of gram-positive and gram-negative bacteria can be tested using nitrocaine as a chromogenic substrate (CH O'Callaghan, et al., Publication in Novel method for detection of ss-lactamases). by using a chromogenic cephalosporin substrate, Antimicrobial Agents and Chemotherapy, Vo 1, N 4, 283-288 / 1972). The inhibition of β-lactamases is determined in a 0.1 M phosphate buffer solution (pH = 7) using the same substrate. The enzymes are preincubated with the inhibitors at 25 ° C. and at appropriate concentrations or the inhibitors and the substrate (nitrocine) and inhibition of substrate hydrolysis caused by the inhibitors compared to uninhibited hydrolysis is measured. The activity is expressed as inhibition S or IC 50 (= concentration of the inhibitor, which inhibits 50% of the enzyme). This inhibitory effect is also apparent in the marked synergism demonstrated with other β-lactam antibiotics on β-lactamase producing bacteria. The compounds of the invention are stable with respect to ss-lactamases.

 The compounds of the invention can therefore be used in chemotherapy, in particular as active antibacterial antibiotics.

 For this use, the appropriate daily dose is between about 1 and 6 g, advantageously administered in divided doses 2 to 4 times daily, daily doses containing from about 250 to 3000 mg, or delayed release form.

 The compounds under free standard can be used in this form or in the form of a chemiotherapically acceptable salt, these forms having the same type of activity as the free forms. Suitable salts include alkali and alkaline earth metal and ammonium or amino acid salts.

 The compounds may be combined with conventional chemotherapeutically acceptable carriers or diluents, and may be administered in tablet, capsule or parenteral form.

Such compositions are also part of the present invention.

 The lower alkyl groups contain from 1 to 6 (for example 1 to 4) carbon atoms, in particular 1 or 2 carbon atoms. In the same way, the alkenyl and alkynyl groups contain from 2 to 4 carbon atoms, in particular from 2 to 3 carbon atoms. The cycloalkyl groups preferably contain 3 to 6 carbon atoms.

 By lower acylaminoalkyl group is meant for example -CH 2 CH 2 .NH.CO.C 2 H 5, -CH 3; -CH2CH2; NH.CO.CH2.C6Hs; -CH2CH2.NH.CO.CH2CH2.NH2; -CH2CH2.NH.CO.CH2.NH2.

et morpholino
Les groupes protecteurs sont ceux habituellement utilises en chimie des antibiotiques pour proteger les groupes OH,;4H2 et COOH. Ils comprennent les groupes p-nitrobenzyle* p-nitrobenzyloxycarbonyle, t-butyldiméthylsilyle et triméthylsilyle.Heterocycles like R7 include, for example

and morpholino
The protecting groups are those usually used in antibiotic chemistry to protect the OH, 4H2 and COOH groups. They include p-nitrobenzyl * p-nitrobenzyloxycarbonyl, t-butyldimethylsilyl and trimethylsilyl groups.

 Physiologically hydrolyzable and acceptable ester groups (also known as easily separable ester groups) are those which are hydrolysable under physiological conditions to provide bases which are themselves physiologically acceptable; such esters include acetoxymethyl, 1-acetoxyethyl, 1-ethoxycarbonyloxyethyl, 5-indanyl or, preferably, pivaloyloxymethyl, hexanoyloxymethyl, phthalidyl, ethoxycarbonyl methoxymethyl or 3-ethoxycarbonyl-1-acetonyl groups.

 Some protecting groups may also be physiologically hydrolyzable and acceptable groups and vice versa.

Preferred substituents are
R1 = a) H; b) CH3
R2 = a) a lower alkyl group or optionally
mono or disubstituted by a group
amino, mono or di- (lower alkyl) amino,
acylamino, carboxy;
b) - (CH2) p-R7
(c) II, IIa or IIb preferably IIa
R4, R5, R6
= a) H, an alkyl group, in particular a group
methyl
b) closed cycles
R7 = a) individual heterocycles as listed more
top
b) a methyltetrazolyl group, morpholino p = 0, 1, 2, 3 or preferably 0 or 2 m = 2 or 3, preferably 2 n = 1, 2, or 3, preferably 1
Combinations of these meanings and preferred forms are particularly interesting.

We can mention as. examples the compounds in which R 1 represents hydrogen or a methyl group;
R2 represents a lower alkyl group, or optionally
mono or disubstituted by an amino group,
alkylamino, dialkylamino, acylamino, carboxy, imino,
alkylimino and / or a heterocycle, for example a group
methyltetrazolyl or morpholino.

 Examples of groups of particular compounds of formula I are those in which R 1 is hydrogen and R 2 is hydrogen, lower alkyl, lower alkenyl, or cycloalkyl which may be substituted by an amino, mono or di ( lower alkyl) -amino, lower acylamino, carboxy, lower alkoxycarbonyl or carbamoyl, wherein the nitrogen may be part of the ring when the cycloalkyl group is substituted by an amino or mono or di- (lower alkyl) amino group; or a group of formula II or IIa, wherein R3, R4 and may be the same or different and represent hydrogen or lower alkyl, m and n have the meanings given above and the carboxy group at the 2-position is in the form free or protected or in the form of easily separable ester or in the form of a salt having an organic or inorganic cation (group of compounds P1 (2)).

Another group is the one in which
R1 represents hydrogen or a methyl group; R2 is hydrogen, lower alkyl, lower alkenyl, or cycloalkyl which may be substituted by amino, mono- or di- (lower alkyl) amino, lower acylamino, carboxy, lower alkoxycarbonyl or carbamoyl, the nitrogen being part of the ring when the cycloalkyl group is substituted by an amino or mono or di- (lower alkyl) amino group; a group of formula - (CH2) p-R7, in which p is 0, 1, 2 or 3 and
R7 represents a phenyl group or a 5- or 6-membered saturated or unsaturated heterocycle containing one or more heteroatoms selected from O, S and / or N; or a group of formula II or IIa, wherein R4, R5 and R6 may be the same or different and represent hydrogen or lower alkyl, m and n have the meanings given above and the carboxy group at the 2-position is free or protected form or in the form of easily separable ester in the form of a -sel having an organic or inorganic cation (Group of compounds P3).

 Particularly preferred compounds are (5RS, 6RS) -1-aza-6- (1 (RS) -fluoroethyl) 3- (N-dimethyl-N'-methylamidinomethylthio) -7-oxobicyclo [3.2.0] hept -2-ene-2-carboxylic acid and (5RS, 6RS) -1-aza-6- (1- (RS) -fl uoroethyl) -3- (N-dimethylamidinomethylthio) -7-oxobicyclo [3.2 .0] hept-2-ene-2-carboxylic acid.

 The following examples illustrate the invention in which the temperatures are expressed in degrees cel ci us.

EXAMPLE 1
(5RS, 6RS) -1-aza-6- [1 (RS) -fluoroethyl] -3- (2- (4-nitrobenzyloxycarbonyl) aminoethylthio] -7-oxobicyclo [3.2.0] hept 2-ene-2-carboxylate of 4-nitrobenzyl (method a)
To an ice cold solution of 90 mg of (5RS, 6RS) -1-aza-3,7-dioxo-6- [1 (RS) -fluoroethyl] -bicyclo [3.2.0] heptane-2-carboxylate of 4 nitrobenzyl in 20 ml of anhydrous acetonitrile is added 0.06 ml of diisopropylamine then 0.06 ml of diphenyl chlorophosphate. After 15 minutes at 00, 0.06 ml of diisopropylamine and then 73 mg of 4-nitrobenzyloxycarbonylcysteamine are added again in 5 ml of anhydrous acetonitrile. The reaction mixture is then stirred for a further hour at 0 ° and the reaction mixture is then partitioned between ethyl acetate and a saturated aqueous solution of
NaCl. After drying over MgSO 4, the organic phase is evaporated to dryness and the residue is chromatographed on silica gel (eluent: ethyl acetate / diisopropyl ether = 9/1).

NMR (CDCl 3): 1.52 (dd, 3, J = 25.6 H 2); 2.7-3t6 (n, 7); 4.26 (t 1, 1, J = 7 Hz): 4.98 (d 1, 1, J = 48.7 Hz); 5.22 (s, 2); c, 20 (d, 1, J = 13.5 Hz); 5.62 (c, 1, J = 13.5 Hz); 7.53 (d, 2, J = 9riz); 7.68 (d, 2.0 = 9 Hz); 8.25 (d, 4, J = 9 Hz).

Removal of the protecting groups to give (5RS, 6RS) -3- (2-aminoethylthio) -1-aza6- [1 (RS) -fluoroethyl] -7-oxobicyclo [3.2.0] hept-2-acid 2-ene carboxylic can be achieved as follows:
A suspension of 50 mg of (5RS, 6RS) -1-aza-6 [1 (RS) -fluoroethyl] -3- [2- (3-hydrogen)) was hydrogenated for 30 minutes at room temperature and under a hydrogen pressure of 3 bar. 4-nitrobenzyl (4-nitrobenzyloxycarbonyl) aminoethylthio] -7-oxobicyclo [3.2.0] hept-2-ene-2-carboxylate and 50 mg of 10% palladium on carbon in 20 ml of tetrahydrofuran and 10 ml of water in the presence of 5 ml of a 0.5 M buffer solution of 3-morpholino-propanesulfonic acid (pH 7). After filtering off the catalyst and washing the residue with water, the filtrates are combined, the overall phase is extracted with ethyl acetate and the aqueous phase is lyophilized. The lyophilisate thus obtained is purified by XAD chromatography. 2 (eluent: water).

Fractions with ultraviolet extinction at 300 nm were combined and freeze-dried to yield the title product. UV spectrum (pH 7 buffer): max = 295 nm (# = 8000).

EXAMPLE 2 (5RS, 6RS) -3- (2-acetylaminoethylthio) -1-aza-6- (1-fluoro-1-methylethyl) -7-oxobicyclo [3.2.0] hept-2-ene-2-carboxylic acid 4-nitrobenzyl ester process a)
To an ice cold solution of 150 mg of (5RS, 6RS) -1-aza-3,7-dioxo-6- (1-fluoro-1-methylethyl) bicyclo [3.2.0] heptane-2-carboxylate 4-nitrobenzyl in 10 ml of anhydrous acetonitrile is added 0.11 ml of N-ethyldiisopropylamine and 0.13 ml of diphenyl chlorophosphate. After 15 minutes at 0, another 0.22 ml of N-ethyldiisopropylamine and then 70 mg of N-acetylcysteamine in 5 ml of anhydrous acetonitrile are added. The mixture is stirred for 1 hour at 0 ° C. and the residue is partitioned between acetate. The organic phase is dried over MgSO 4 and evaporated to dryness. The residue is chromatography on silica gel
(ethyl acetate / acetone = 7/3).

EXAMPLE 3
(5RS, 6RS) -3- (2-acétylaminoéthylthio) -1-aza-6
(1-fluoro-1-methylethyl) -7-oxobicyclo [3.2.0] hept-2
4-nitrobenzyl ene-2-carboxylate (method b)
To a cooled solution at -78 of 0.12 ml
of diethylamino-sulfuryl trifluoride and 75 mg of
potassium fluoride in 5 ml of dichloromethane
anhydrous solution of 150 mg of (SRS, 6SR) -
3- (2-acetylaminoethylthio) -1-aza-6- (1-hydroxy-1-methylethyl) -7-oxobicyclo [3.2.0] hept-2-ene-2-carbohydrate;
4-nitrobenzyl xylate in 5 ml of dichloromethane
The mixture is stirred for 15 minutes at 780 hours.
then mixed with water. After having again
dichloromethane is added, the phases are separated,
Wash the organic phase with a saturated solution of
NaCl, dried over MgSO 4 and evaporated to
dryness. The residue is chromatographed on silica gel,
(ethyl acetate / acetone = 7/3), which gives the compound
of the title. F = 206-2100.

Analogously to the above examples, or as previously described, the following compounds of formula I can be prepared: (Configuration: 6RS, 5RS; when R3 = H: 8RS):

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EXAMPLE 23 (5R, 6R) -3- (2-acetylaminoethylthio) -1-aza-6- [1 (S) -fluoroethyl] 7-oxobicyclo [3.2.0] hept-2-ene-2-carboxylate 4 nitrobenzyl
The product is obtained by proceeding in a manner analogous to that described in Example 1.

EXAMPLE 24
Sodium salt of (5RS, 6RS) -3- (2-acetylaminoethylthio) -1-aza- [1 (S) -fluoroethyl] -7-oxobicyclo [3.2.0] hept 2-ene-2-acid carboxylic
The product is obtained by proceeding in a manner analogous to that described in Example 1. 1 max = 298.

EXAMPLE 25 (+) - (5R, 6R) -1-aza-6- [1 (R) -fluoroethyl] -3- (2S) - [2- (4-nitrobenzyloxycarbonyl) -2- (4-nitrobenzyloxycarbonylamino) - 4-nitrobenzyl ethylthio] -7-oxobicyclo [3.2.0] -hept-3-en-2-carboxylate
To a solution of 680.4 mg of 4-nitrobenzyl (5RS, 6RS) -3,7-dioxo-6- (1 (RS) -fluoroethyl) -1-azabicyclo [3.2.0] heptane-2-carboxylate in 20 ml of dimethyl 0.30 ml of diisopropylethylamine and 0.486 ml of diphenyl chlorophosphate are added to the mixture at 300 ° C. with stirring. The reaction mixture was allowed to stand for 30 minutes at -300 and mixed with 0.404 ml of diisopropylamine. A solution of 1.016 g of 4-nitrobenzyl ester of hexamethylamine was then added dropwise.
N- (4-nitrobenzyloxycarbonyl) -D-cysteine in 4 ml of anhydrous dimethylformamide, the mixture is stirred for 30 minutes at -300 and diluted with 200 ml of dichloromethane. The organic solution is washed successively with each time 140 ml of 0.1 M phosphate buffer of pH 8.4, pH 6.9 and pH 8.4 and dried with Na 2 SO 4.
This solution can be used for the preparation of optical isomers.

 [The racemic can be obtained by filtration of the dichloromethane solution by concentrating in vacuo to about 20 ml and chromatographing the residue on silica gel (benzene / ethyl acetate = 3/1).

Fractions of Rf 0.30 under UV light (benzene / ethyl acetate = 2/1) are collected and dried],
For the preparation of the isomer, the dichloromethane solution is evaporated to dryness. The residue is washed with 20 ml of chloroform and dried. The filtrate is evaporated to a syrup and chromatographed on silica gel (eluent: benzene / ethyl acetate = 3/1). The fractions are combined and evaporated to dryness under reduced pressure. The residue is treated with 5 ml of chloroform, filtered and washed with 10 ml of chloroform. A pale yellow amorphous powder is obtained, [&alpha;] 23 D = + 27.9 (c = 0.5 in dichloromethane). For further purification, this powder is dissolved in 20 ml of dichloromethane and filtered. The filtrate is concentrated to about 1 ml and then treated with 1 - 2 ml of chloroform to give an amorphous, pale yellow powder; [&alpha;] 23 D = + 29 (c = 0.5 in dichloromethane).

NMR SPECTRA
Examples: Spectra: 2.3 1.49 (d, 3, J = 20 Hz), 1.57 (d, 3, J = 20 Hz); 2.00 (s, 3); 2.87 (CDCl3) 3.53 (m, 7); 4.32 (td, 1, J = 10 Hz, 2.7); 5.25 (d, 1, J =
13.7 Hz); 5.52 (d, 1, J = 13.7 Hz); 5.89O r, 1); 7.67 (d, 2, J =
8 Hz); 8.24 (d, 2, J = 8 Hz).

1.52 (dd, 3, J = 25 and 6Hz); 2.7-3.6 (m, 7); 4.26 (tm, 1, J = (CDCl 3) 7 Hz); 4.98 (dq, 1, J = 48 and 7 Hz); 5.22 (s, 2); 5.26 (d, 1, J =
13.5 Hz); 5.52 (d, 1, J = 13.5 Hz); 7.53 (d, 2, J = 9 Hz); 7.68
(d, 2, J = 9 Hz); 8.25 (d, 4, J = 9 Hz).

s 1.68 (d, 3, J = 22.5 Hz); 1.74 (d, 3, J = 22.5 Hz); 2.00 (s, 3); (D20) 2.85-3.14 (m, 2); 3.16 (dd, 1, J = 17.5 and 9 Hz); 3.28 (dd, 1,
J = 17.5 and 9.5 Hz); 3.42 (@, 2, @ = 6.5 Hz); 3.65 (dd, 1, J =
17.5 and 9.5 Hz); 3.42 (t, 2, J = 6.5 Hz); 3.65 (dd, 1, J = 26.5
and 2.5 Hz); 4.27 (td, 1, J = 9.5 and 2.5 Hz).

1.42 (dd, 3, J = 24 and 7 Hz); 2.45 (t, 4, J = 4.5 Hz); 2.60 (t, (CDCl 3/2, J = 7.5 Hz), 2.94-3.10 (m, 2), 3.30-3.45 (m, 2), 3.60 (t , 4,
DMSO-d6) J = 4.5 Hz); 3.56 (ddd, 1, J = 25, 6 and 2.5 Hz); 4.23 (td, 1,
J = 9and 2.5 Hz); 5.03 (dq, 1, J = 49 and 6 Hz); 5.27 (d, 1,
J = 14 Hz); 5.45 (d, 1, J = 14 Hz); 6.98 (#, 1); 7.72 (d, 2, J =
9.5 Hz); 8.20 (d, 2, J = 9.5 Hz).

1.58 (dd, 3, J = 25 and 6.5 Hz); 3.06-3.76 (m, 11); 4.02-4.12 (D2O) (m, 4); 4.48 (td, 1, J = 9 and 3 Hz); 5.28 (dm, 1, J = 52 Hz).

1.43 (dd, 3, 3 = 26and 6.5 Hz); 2.59 (s, 3); 2.93 (dd, 1, J = 18 (D2O) and 9 Hz); 3.02 (dd, 1, J = 18 and 9.5 Hz); 3.56 (ddd, 1, J =
27.5 and 28 Hz); 4.09 (td, 1, J = 9.5 and 2.8 Hz); 5.12 (dm,
1, 3 = 48 Hz).

1r = width 1.45 (dd, 3, 3 = 25 and 6.5 Hz); 2.90-3.03 (m, 12); 3.07 to 3.57
(D2O) (m, 6); 3.67 (ddd, 1, J = 28, 5 and 2.5 Hz); 4.29 (td, 1, J = 9
and 2.5 Hz); 5.14 (dm, 1, J = 49 Hz).

1.41 (dd, 3, J = 6 and 25 Hz); 2.80-3.65 (m, 5); 3.75-3.97 (m,
(D20) 1); 4.29 (dt, 1, J = 2.5 and 8.5 Hz); 5.11 (m, 1, 9 = 6, 7.5 and
48.8 Hz);
1.46 (dd, 3, J = 24 and 7 Hz); 3.10-3.57 (m, 11); 3.63 (ddd, 1,
CDCl3 / J = 24.6 and 2.5 Hz); 4.15 (d, 1, J = 12.5 Hz); 4.27 (d, 1, J =
DMSO-d6) 12.5 Hz); 4.33 (td, 1, J = 9 and 2.5 Hz); 5.05 (dm, 1, J =
49 Hz); 5.29 Cd, 1, J = 14 Hz); 5.51 (d, 1, J = 14 Hz); 7.70 (d,
2, J = 9 Hz); 8.28 (d, 2, J = 9 Hz); 8.90 (1r, 1).

1.46 (dd, 3, J = 25 and 6.5 Hz); 3.12 (s, 3); 3.15 (s, 3); 3.25
(D2O) (dd, 1, J = 18 and 9 Hz); 3.32 (dd, i, 3 = 18 and 10 Hz); 3.36
(s, 3); 3.71 (ddd, 1, J = 27, 5 and 2.8 Hz); 4.01 (d, 1, J =
12.5 Hz); 4.09 (d, 1, J = 12.5 Hz); 4.35 (td, 1, J = 9.5 and
2.8 Hz); 5.25 (dm, 1, J = 49 Hz).

1.44 (dd, 3, J = 25 and 6.5 Hzz, 3.4 (d, 2, J = 9.5 Hz);
(D2O) (s, 3); 3.30 (s, 3); 3.71 (ddd, 1, J = 28, 5 and 2.5 Hz); 4.00 (s,
@ 2); 4.31 (td, 1, J = 9.5 and 2.5 Hz); 5.15 (dm, 1, J = 49 Hz).

0.70-1.05 (m, 3); 1.22-1.60 (m, 6); 1.52 (dd, 3, J = 25 and
(CDCl 3) 7 Hz); 2.67-3.00 (m, 2); 3.02-3.54 (m, 3); 4.28 (dt, 1, J = 9.5
and 2.5 Hz); 5.02 (dm, 1, J = 49 Hz); 5.26 (d, 1, J = 12.5 Hz);
5.52 (d, 1, J = 12.5 Hz); 7.68 (d, 2, J = 9 Hz); 8.26 (d, 2, J =
9 Hz).

0.8-1.02 (m, 3); 1.20-1.56 (m, 6); 1.51 (d, 3, J = 25 Hz);
(CDCl3) 1, 58 (d, 3, J = 21.5 Hz); 2.86 (t, -2, J = 7 Hz); 3.11 (dd, 1, J =
16 and 7 Hz); 3.33 (dd, 1, J = 16 and 8 Hz); 3.39 (dd, j, J = 18
and 3 Hz); 4.32 (dt, 1, J = 8 and 3 Hz); 5.27 (d, 1, J = 14 Hz);
@r = width
5.55 Cd, 1, 3 = 14 Hz); 7.70 (d, 2, J = 9 Hz); 8.26 Cd, 2, J =
9 Hz).

1.51 (dd, 3, J = 24.5 and 7 Hz); 2.0-2.4 (m, 2); 2.64-3.04 (m, (CDCl3) 1); 3.10-3.90 (m, 5); 4.0-4.9 (m, 2.5); 5.1-5.64 (, 6.5); 7.34
7.67 (m, 6); 8.04-8.36 (m, 6).

1.20-1.37 (m, 3); 1.50 (dd, 3, 3 = 24 and 8 Hz); 2.62-3.56 (m, (CDCl3) 6); 3.95-4.30 (m, 1); 4.80-5.32 (m, 1); 5.22 (s, 2); 5.28 (d, 1,
j = 14.5 Hz); 5.54 (d, 1, J = 14.5 Hz); 7.52 (d, 2, J = 9 Hz);
7.70 (d, 2, J = 9 Hz); 8.26 (d, 4, 3 = 9 Hz).

1.48 (d, 3, J = 21.5 Hz); 1.56 Cd, 3.5 = 21.5 Hz); 2.56 (s, 3); (CDCl3) 2.70-3.53 (m, 5); 4.25 (td, 1, J = 9.5 and 2.5 Hz); 4.51 (t, 2,
J = 7 Hz); 5.28 (d, 1, J = 13.5 Hz); 5.52 (d, 1, J = 13.5 Hz);
7.68 (d, 2, J = 9 Hz), 8.28 (d, 2, J = 9 Hz).

1.50 (dd, 3 J = 24.5 and 6.5 Hz); 2.56 (s, 3); 2.74-3.56 (m, 5); (CDCl3) 4.24 (td, 1, J = 9 and 2.5 Hz); 4.30-4.60 (m, 2); 5.02 Cdm, 1,
J = 49 Hz); 5.27 (d, 1, J = 14.5 Hz); 5.49 (d, 1, J = 14.5 Hz);
7.67 (d, 2, J = 9 Hz); 8.27 (d, 2, J = 9 Hz).

1.45 (dd, 3, J = 24 and 6.5 Hz); 3.11 (s, 3); 3.23 (s, 3); 3.30 (CDCl3 / 3.60 (m, 2); 3.71 (ddd, 1, J = 25, 5.5 and 2.5 Hz); 4.26 (s, 2);
DMSO-d6 4.30 (td, 1, J = 10 and 2.5 Hz); 5.04 (dm, 1, J = 48 Hz); 5.30
Cd, 1, J = 15 Hz); 5.50 Cd, 1, J = 19 Hz); 7.72 (d, 2, J = 9 Hz);
8.25 (d, 2, J = 9 Hz); 9.03 (br, 1); 9.75 Cl (1 r, 1).

1.57 (dd, 3, J = 23.5 and 6.3 Hz); 2.0 (s, 3); 2.87-3.74 (m, 7); (CDCl3 / 4.34 (td, 1, J = 9 and 2.7 Hz), 5.02 (dm, 1, J = 49 Hz);
Aceton-d6) (d, 1, J = 16 Hz); 5.55 (d, 1, J = 16 Hz); 6.78 (1r, 1); 7.72 (d,
2, j = 9 Hz) δ 8.28 (d, 2, J = 9 Hz).

The required starting materials can be prepared as follows:
1r = width
A) (5RS, 6RS) -1-aza-3,7-dioxo-6- [1 (RS) -fluoroethyl]
bicycloC3.2.0] 4-nitrobenzyl heptane-2-carboxylate
(for examples 4, 6-8, 10-16, 18, 19, 21):
[reaction scheme 1 steps g) to k)]
a) (3RS, 4RS) -3- [1 (RS) -Fluoroethyl] -2-oxoazetidine-4
yl-benzyl acetate
To a solution cooled to -78 of 1.5 ml
of diethylamino-sulfuryl trifluoride in 4 ml of
anhydrous dichloromethane a solution of 2.52 g is added
Benzyl (3SR, 4RS) -3- [1 (SR) -hydroxyethyl] -2-oxoazetidin-4yl-acetate (prepared in a similar manner to
described by DG Melillo et al. in Tetrahedron
Letters 21, 2783 [1980]) in 4 ml of dichloromethane
The mixture is stirred for 5 minutes at -780 and
the mixture with an excess of saturated cold solution of NaHCO 3.

After adding more dichloromethane, separate
the phases, the organic phase is dried over sulphate
of magnesium and evaporate to dryness. Chromatography
the residue on silica gel (cyclohexane / ethyl acetate =
2/1), which gives the title composo. F = 40-43.

specters:
IR (CHCl 3): 1765, 1730 cm -1
NMR (CDCl 3): 1.45 (dd, 3, J = 24, 6.5 Hz); 2.65 (dd, 1, J = 16.9 Hz); 2.86
(dd, 1, J = 16, 5.5 Hz); 3.01 (ddd, 1, J = 18.5%, 2.5 Hz); 4.02 (ddd, 1, J = 9,
5.5, 2.5 Hz); 4.97 (dq, 1, J = 48, 6.5 Hz); 5.18 (s, 2); 6.25 (@@, 1); 7.40 (@, 5).

b) (3RS, 4RS) -3- [1 (RS) -Fluoroethyl] -2-oxoazetidine
4-yl-acetic acid
A mixture of 700 mg of corresponding benzyl ester and 50 mg of palladium on carbon is hydrogenated for 30 minutes under a hydrogen pressure of 10 bar.
10% in 5C ml of ethanol. By filtration and concen
filtrate to dryness, the compound is obtained
of the title. F 137-141.

specters:
IR (KBr): 3317, 2983, 2323, 2577, 1720 cm -1
NMR (CDCl 3 / CO 3 OD): 1.43 (dd, 3, J = 23.5, 6.5 Hz); 2.62 (dd, 1, J = 16.9 Hz); 2, @ 0 (dd, 1, J = 16, 4.5 Hz); 3.01 (ddd, 1, J = 21, 6.5, 2.5 Hz); 4.00 (ddd, 1 J = 9, 4.5, 2.5 Hz); 4.98 (dq, 1, J = 49, @, 6.5 Hz).

c) [(3RS, 4RS) -3-tl (RS) -fluoroethyl] -2-oxoazetidine-4-
yl] - 2 - 4-nitrobenzyl oxobutyrate
A solution of 352 mg of (3RS, 4RS) -3- [1 (RS) -fluoroethyl] -2-oxo-azetidin-4-yl-acetic acid in 15 ml of tetrahydrofuran is stirred for 5 hours at room temperature. anhydrous.with 359 mg of carbonyldiimidazole. During this time, a solution of 995 mg of mono-4-nitrobenzyl malonate in 15 ml of anhydrous tetrahydrofuran is mixed with 253 mg of magnesium ethanolate and stirred for one hour at room temperature. The two solutions are combined and stirred for 16 hours at room temperature. The mixture is diluted with ether and washed with 0.1 N HCl solution. The aqueous phase is again extracted with ethyl acetate, the organic extracts are combined, dried over MgSO4 and evaporated to dryness. The residue is chromatographed on silica gel (ethyl acetate) to give the title compound. F = 115-118.

specters:
IR (CH 2 Cl 2): 3407, 2928, 1770, 1720, 1525, 1350 cm -1
NMR (CDCl 3): 1.47 (dd, 3, J = 19.7 Hz); 2.86 (dd, 1, J = 18.5, 10Hz); 2.94 (ddd, 1, J = 18, 7.2 Hz); 3.09 (dd, 1, J = 18.5, 4 Hz); 3.58 (s, 2); 4.00 (ddd, 1,
J = 10, 4.2 Hz); 4.93 (dq, 1, J = 48.7 Hz); 5.28 (?, 2); 6.18 Gr, 1); 7.52 (d, 2,
J = 9 Hz); 8.26 (d, 2, J = 9 Hz).

d) W3RS, 4RS) -3- [1 (RS) -Fluoroethyl] -2-oxoazetidine-4-
yl] -2-oxo-3-diazo-4-nitrobenzylbutyrate
To a solution cooled by
ice of 469 mg of (3RS, 4RS) -3- [1 (RS) -fluoroethyl] -
4-nitrobenzyl 2-oxoazetidin-4-yl- (2-oxo) butyrate and
374 mg of 4-carboxybenzenesulfonyl azide in
15 ml of ethyl acetate is added in one part 0.67 ml
of triethylamine. After removing the cooling bath,
stirring is continued at room temperature. Filter
the precipitate that has formed and the filtrate is washed
with saturated NaHCO3 solution and dried
on MgSO4. The title compound is obtained by eliminating
the solvent. F = 138-141.

ghosts
IR (KBr): 3414, 3204, 2135, 1760, 1720, 1650, 1520 CM-1
NMR: (CDCl 3): 1.45 (dd, 3, J = 23.5, 7Hz); 3.04 (ddd, 1, J = 19, 7.2 Hz); 3.06 (dd, 1, J = 18, 10 Hz); 3.44 (dd, 1, J = 18.4 Hz); 4.04 (ddd, 1, J = 10.4, 2 Hz); 498 (dq, 1, J: 48, 7Hz); 5.38 (s, 2); 6.17 (1r, 1); 7.58 (d, 2, J = 9 Hz); 8.31 (d, 2, J = 9 Hz).

e) (5RS, 6RS) -1-aza-3,7-dioxo-6-tl (RS) -fluoroethyl] -bi-
cyclo [3.2.0] heptane-2-carboxylic acid 4-nitrobenzyl ester
It is heated for 5 minutes in an atmosphere
of argon a suspension of (3RS, 4RS) -3- [1 (RS) -fluoroethyl] -
2-oxoazetidin-4-yl- (2-oxo-3-diazo) butyrate 4
nitrobenzyl and 2 mg of rhodium-II acetate in 5 ml
anhydrous benzene. After cooling to tempe
ambient temperature, the catalyst is filtered and evaporated
the filtrate to dryness. The title compound is obtained
in the form of a colorless foam.

specters:
IR (CH 2 Cl 2): 1775, 1750, 1525, 1350 cm -1
NMR (CDCl 3): 1.53 (dd, 3, J = 25.7 Hz); 2.52 (d 1, 1, J = 18.5, 7.5 Hz); 2.96 (dd, 1, J = 18.5, 7Hz); 3.35 (ddd, 1, J = 18, 8, 2 Hz); 4.20 (td, 1, J = 7.2 Hz); 4.80 (?, 1); 5.11 (dm, 1, J = 48 Hz); 5.26 (d, 1, J = 12.5 Hz); 5.37 (d, 1,
J: 12.5 Hz); 7.58 (d, 2, J = 9 Hz); 0.29 (d, 2, J = S Hz).

8) (5RS, 6RS) -1-aza-3,7-dioxo-6- (1-fluoro-1-methylethyl) bicyclo [3.2.0] heptane-2-carboxylic acid 4-nitrobenzyl ester (for examples 2, 5 , 9, 17 and 20): [(Reaction Scheme 1 steps a) ak) a) 2-oxo-3-trans- (1-hydroxy-1-methylethyl) -4- (2-trimethyl)
silyldithian-2-yl-methyl) -1- (tert-butyldimethyl)
silyl) azetidine
To a solution of 10.1 g of diisopropylamine in 500 ml of anhydrous tetrahydrofuran is added 75.75 ml of a 1.6 N solution of n-butyllithium in hexane. After 20 minutes at -75, 20 g of 1-tert are added. butyldimethyl-2-oxo-4- (2-trimethylsilyldithian-2-yl-methyl) -azetidine, then after 20 minutes, 17 ml of anhydrous acetone.

The reaction mixture is diluted with 500 ml of saturated NH4Cl solution and extracted with ethyl acetate. Drying and concentration of the extracts gives the title compound.

NMR (CDCl3): 0.26 (s, 15); 0.98 (s, 9); 1.24 (@, 3); 1.40 (@, 3); 1.80-2.10 (m, 2); 2.34 (d, 1, J = 1 Hz); 2.40 (@, 1); 2.60-3.00 (m, 4), 3.19 (d, 1, J = 2 Hz); 3.80 (s, 1); 3.90 (m, 1).

b) trimethylsilyl- [2-oxo-3-trans- (1-hydroxy-1-methylethyl) -1-tert.

butyldimethylsilylazetidine-4-yl-methyl-ketone
28 g of 2-oxo-3-trans- (1-hydroxy-1-methylethyl) -4- (2-trimethylsilyldithian-2-ylmethyl) -1- (tert-butyldimethylsilyl) azetidine are refluxed for 1 hour. 23.65 g of red mercuric oxide and 43 g of mercuric chloride in 400 ml of 95% methanol. After filtration of the mercury salts, the filtrate is concentrated and the residue is partitioned between ethyl acetate and saturated NH 4 Cl solution. Drying and concentration of the organic phase gives the title compound as a colorless oil.

NMR (CDCl3): 8.22 (s, 6); 0.24 (s, 9); 0.98 (s, 9); 1.30 (s, 3); 1.34 (s, 3); 2.84 (d, 1, J = 2 Hz); 2.58 (dd, 1, J = 19 and 10 Hz); 3.28 (dd, 1, J = 19 and 3.6 Hz): 3.86 (ddd, 1, J = 10, 3.6 and 2 hz).

(c) [1-tert-butyldimethylsilyl-2-oxo-3-trans]
(1-hydroxy-1-methylethyl) azetidin-4-yl] -acetic acid
5 g of trimethylsilyl- [2-oxo-3-trans- (1-hydroxy-1-methylethyl) -1-tert.-butyldimethylsilylazetidin-4-yl-methyl] ketone are heated under reflux for 1 hour in 120 ml of methanol with 10 ml of hydrogen peroxide at 30%. After concentration to dryness, the residue is taken up in ethyl acetate extracted twice with 5% aqueous NaHCO 3, and the aqueous phase is again extracted with ethyl acetate. The aqueous phase is covered with ethyl acetate, the pH is adjusted to 3.5 with half-concentrated HCl and after separation of the ethyl acetate phase, the mixture is extracted twice more with ethyl acetate. 'ethyl acetate. After drying and removing the combined ethyl acetate extracts from the sol, the title compound is obtained as a colorless oil.

NMR (CDCl 3): 0.22 (s, 3), 0.24 (s, 3), 0.96 (s, 9), 1.32 (s, 3), 1.34 (s, 3); 2.56 (dd, 1, J = 19 and 10 Hz), 2.92 (dd, 1, J = 19 and 3.6 Hz), 3.11 (d, 1, J = 2 Hz); 3.86 (ddd, 1, J = 10, 3.6 and 2 Hz).

d) [1-tert-butyldimethylsilyl-2-oxo-3- (trans) - (1
hydroxy-1-methylethyl) -azetidin-4-yl] acetate
benzyl
5 g of acid [1-tert.

butyldimethylsilyl-2-oxo-3-trans- (1-hydroxy-1-methylethyl) azetidin-4-yl-acetic acid, 1.71 ml of benzyl alcohol and 300 mg of 4-dimethylaminopyridine in 30 ml of anhydrous dichloromethane with a solution of 4 g of dicyclohexylcarbodiimide and stirred for a further 2 hours at room temperature. After addition of 50 ml of ether and 50 ml of diisopropyl ether was filtered, the residue was carefully washed with ether and the filtrate was evaporated to dryness. The residue is chromatographed on a small amount of silica gel to give the title compound as a colorless oil.

NMR (CDCl3): 0.16 (s, 3); 0.18 (s, 3); 0.90 (s, 9); 1.24 (s, 3); 1.26 (s, 3); 2.53 (dd, 1, J = 16.2 and 10.6 Hz): 2.63 (s, 1); 2.52 (dd, 1, J = 16.2 and 4 Hz); 3.02 (d,
1, J = 2.7 Hz); 3.83 (ddd, 1, J = 10.6, 4 and 2.7 Hz); 5.10 (s, 2); 7.37 (s, 5); e) [(3SR, 4RS) -3- (1-hydroxy-1-methyl) -2-oxoazetidine
4-yl] benzyl acetate
To an ice cold solution of 3.7 g of 1-tert. Benzyl butyldimethylsilyl-2-oxo-3- (trans) - (1-hydroxy-1-methylethyl) azetidine-4-ylacetate in 130 ml of a 9/1 mixture of methanol and water is added 6.6 ml. concentrated HCl.

This mixture is stirred for 30 minutes at C and for 3 1/2 hours at 250. The solution is concentrated and the residue is taken up in ethyl acetate and then washed once with an aqueous solution of NaCl. dry on MgSO4 and evaporate to dryness to give the title compound
NMR (CDCl3): 1.24 (s, 3); 1.34 (s, 3); 2.60-2.84 (m, 3); 2.87 (d, 1, J =
1.8 Hz); 3.94 (ddd, 1, J = 8, 6.3 and 1.8 Hz); 5.13 (s, 2); 6.57 (1r, 1); 7.37 (s, 5).

f) [(3RS, 4RS) -3- (1-fluoro-1-methylethyl) -2-oxoazetidine
4-yl] benzyl acetate
To a solution cooled to -78 with 3 ml of diethylamino-sulfuryl trifloride and 1.7 g of potassium fluoride in 80 ml of dichloromethane is added a solution of 3.2 g of [(3SR, 4RS) -3- ( Benzyl 1-hydroxy-1 methylethyl) -2-oxoazetidin-4-yl] -acetate in 170 ml of dichloromethane. This mixture is stirred for 15 minutes at -78 and mixed with water.

After further dichloromethane addition, the phases are separated and the organic phase is washed with saturated NaCl solution, dried over MgSO 4 and evaporated to dryness. The residue is chromatographed on silica gel (ethyl acetate / cyclohexane = 1/1) to give the title compound. F 112-116.

specters:
NMR (CDCl 3): 1.42 (d, 3, J = 21.5 Hz); 1.52 (d, 3, J = 21.5 Hz); 2.6 @ (dd, 1,
J = 16.2 and 9 Hz); 2.84 (dd, 1, J = 16.2 and 4.5 Hz); 3.00 (dd, 1, J = 21.5 and 2.7 Hz); 4.01 (ddd, 1, J = 9, 4.5 and 2.7 Hz); 5.16 (s, 2); 6.14 (1r, 1); 7.35 (s, 5).

g) [(3RS, 4RS) -3- (1-fluoro-1-methylethyl) -2 acid
oxoazetidine-4-yl] -acetic acid
A mixture of 1 g of r (3RS, 4RS) -3- (1-fluoro-1-methylethyl) -2-oxoazetidin-4-yl is hydrogenated for 3 hours at 1 bar of hydrogen pressure. benzyl acetate and 0.5 g of 10% palladium on carbon in 80 ml of methanol. Filtration and concentration to dryness of the filtrate gives the title compound. F = 118-122.

NMR (CDCl3 / DMS? -D6): 1.43 (d, 3, J = 21.6 Hz): 1.52 (d, 3, J = 21.6 Hz);
2.57 (dd, 1, J = 16.2 and 5 Hz), 2.72 (dd, 1, J = 16.2 and 5.4 Hz). 3.00 (dd, 1,
J = 23.5 and 2.5 Hz), 3.96 (ddd, 1, J = 5.4, and 2.5 Hz).

h) [(3RS, 4RS) -3- (1-fluoro-1-methylethyl) -2-oxoazetidine-4-yl]
4-nitrobenzyl 2-oxo-butyrate
700 mg of C (3RS, 4RS) -3- (1-fluoro-1-methylethyl) -2-oxoazetidin-4-yl] -acetic acid are dissolved in 20 ml of tetrahydrofuran, mixed with -20 with 600 mg of carbonyldiimidazole and stirred for 3 hours at +200. During this time, 900 mg of 4-nitrobenzyl malonate and 420 mg of magnesium ethanolate are suspended in 20 ml of tetrahydrofuran and stirred for 3 hours at room temperature. The two solutions are combined and stirred overnight. The mixture is then poured into ether and extracted with a 1N solution of HCl and water. By drying the organic phase and then column chromatography of the residue, the title compound is obtained.

NMR (CDCl 3): 1.44 (d, 3, J = 21.5 Hz); 1.52 (d, 3, J = 21.5 Hz); 2.86 (dd, 1,
J = 138 and 10 Hz) 2.98 (dd, 1, J = 20 and 3.5 Hz); 3.06 (dd, 1, J = 18 and 4.5 Hz); 3.58 (s, 2); 4.32 (dt, 1, J = 10 and 3.5 Hz); 5.30 (s, 2); 6,16 @r, 1); 7.59 (d, 2,
J = 9 Hz); 8.28 (d, 2, J = 9 Hz).

j) (3RS, 4RS) -3- (1-fluoro-1-methylethyl) -2-oxoazetidin-4-yl
(2-oxo-3-diazo) -4-nitrobenzylbutyrate
To a solution cooled with ice of 22 g of (3RS, 4RS) -3-
(1-Fluoro-1-methylethyl) -2-oxoazetidin-4-yl- (2-oxo) butyrate
4-nitrobenzyl and 0.17 g of 4-carboxy-benzene azide
sulfonyl in 20 ml of acetonitrile is added 0.34 ml of triethylamine. After removing the cooling bath, stirring is continued for 30 minutes at room temperature. We
100 ml of ethyl acetate are added to the mixture, the mixture is washed with a 5% solution of NaHCO 3 and then with water and dried over MgSO 4. By removing the solvent, the title compound is obtained.

j) (5RS * 6RS) -1-aza-3,7-dioxo-6- (1-fluoro-1-methylethyl) bicyclo
[3.2.0] 4-nitrobenzyl heptane-2-carboxylate
A suspension of 0.19 g of (3RS, 4RS) -3- (1-fluoro-1-methylethyl) -2-oxoazetidin-4-yl- (2-oxo) was heated for 10 minutes at 80 under an argon atmosphere. 3-diazo) 4-nitrbenzyl butyrate and 20 mg of rhodium-II acetate in 100 ml of benzene.

Cool to room temperature, filter the catalyst and evaporate the filtrate to dryness to give the title compound.

C) (5RS, 6RS) -1-aza-3,7-dioxo-6- (1-fluoro-1-methylethyl) bicyclo [3.2.01heptane-2-carboxylic acid 4-nitrobenzyl ester (for Examples 2, 5, 9, 17 and 20): [(Reaction Scheme 2 a), b) ii) ae) ii) a) 1-tert-butyldimethylsilyl-2-oxo-3- (trans) - [(1-hydroxy-1)
methylethyl) -azetidine-4-yl] - (2-oxo) butyrate
4-nitrobenzyl
1.2 g of 1-tert-butyldimethylsilyl-2-oxo-3-trans- (1-hydroxy-1-methylethyl) azetidin-4-yl-acetic acid are dissolved in 20 ml of tetrahydrofuran. with 1 g of carbonyldiimidazole and stirred for 3 hours at 20. During this time, 1.9 g of 4-nitrobenzyl malonate and 0.7 g of magnesium ethanolate were suspended in 30 ml of tetrahydrofuran and stirred for 3 hours at room temperature. The subsequent reaction and extraction are carried out in a manner analogous to that described in Example B) h).

NMR (CDCl3): 0.22 (s, 6); 0.96 (s, 9); 1.32 (s, 6); 2.74 (s, 1); 2.86 (dd, 1, J = 18 and 9 Hz); 2.97 (d, 1, J = 2.7 Hz); 3.14 (dd, 1, J = 18 and 4 Hz); 3.6 @ (s, 2); 3.88 (ddd, 1, J = 9.4 and 2.7 Hz); 5, (s, 2); 7.54 (d, 2, J = 9 Hz); 8.28 (d, 2,
J = 9 H =).

b) 2-oxo-3- (trans) - (1-hydroxy-1-methylethyl) azetidine-4-yl
(2-oxo) 4-nitrobenzyl butyrate
To an ice cold solution of 1.4 g of 1-tert.butyidimethylsilyl-2-oxo-3- (trans) - (1-hydroxy-1-methylethyl) azetidin-4-yl- (2-oxo) 4-nitrobenzyl butyrate in 60 ml of a 9/1 mixture of methanol and water is added 2 ml of concentrated HCl. The mixture is stirred for 30 minutes
at 0 and for 5 1/2 hours at 250. The subsequent treatment is carried out in a similar manner to that described in Example B) e).

NMR (CDCl3): 1.26 (s, 3); 1.35 (s, 3); 2.82 (d, 1, J = 2.7 Hz); 2.86 (dd, 1, J = 19
and 8.6 Hz); 3.06 (dd, 1, J = 19 and 5 Hz); 3.60 (s, 2); 3.96 (ddd, 1, J = 8.6, 5 and 2.7 Hz); 5.28 (s, 2); 6.37 Gold, 1); 7.57 Cd, 2, J = 9 Hz); 8.27 (d, 2, J = 9 Hz).

c) 3- (1-hydroxy-1-methylethyl) -2-oxoazetidin-4-yl- (2-oxo-3)
diazo) 4-nitrobenzyl butyrate
To an ice-cooled solution of 0.45 g of 4-nitrobenzyl 2-oxo-3- (trans) - (1-hydroxy-1-methylethyl) azetidin-4-yl- (2-oxo) butyrate and 0.33 g of 4-carboxy-benzenesulfonyl azide in 30 ml of acetonitrile was added 0.77 ml of triethylamine. Then treated analogously to that described in Example B) i).

NMR (CDCl3) 1.30 (s, 3); 1.38 (λ, 3), 2.94 (d, 1, J = 2.2 Hz); 3, @@ (dd, 1, J = 18
and 8.8 Hz); 3, @ 7 (du, 1, J = 18 and 5Hz); 3.98 (ddd, 1, J =?, 8.5 and 2.2 Hz);
5.38 (s, 2); 6.10 (1r, 1); 7.56 (d, 2, J = 9 Hz); 8.3 @ (d, 2, J = 9 Hz).

d) (5RS, 6SR) -1-aza-3,7-dioxo-6- (1-hydroxy-1-methylethyl) bicyclo
[3.2.0] 4-nitrobenzyl heptane-2-carboxylate
The mixture is heated for 10 minutes under an argon atmosphere.
suspension of 0.4 g of 4-nitrobenzyl 3- (1-hydroxy-1-methylethyl) -2-oxoazetidin-4-yl (2-oxo-3-diazo) butyrate and 40 mg of rhodium acetate-II in 250 ml anhydrous benzene. Then treated analogously to that described in Example B) j).

NMR (CDCl3): 1.40 (s, 3); 1.46 (s, 3), 2.49 (dd, 1, J = 19 and @, 6 Hz); 2.92 (dd, 1,
J = 19 and 7.2 Hz); 3.26 (d, 1, J = 2 Hz); 4.16 (td, 1, J = 7.4 and 2 Hz); 4.60
(s, 1); 5.28 (d, 1, J = 13.5 Hz); 5.34 (d, 1, J = 13.5 Hz); 7.4 @ (d, 2 J = 9 Hz);
8.28 (d, 2, J = 9 Hz).

e) (5RS, 6RS) -1-aza-3,7-dioxo-6- (1-fluoro-1-methylethyl) bicyclo
[3.2.0] 4-nitrobenzyl heptane-2-carboxylate
To a solution cooled to -78 with 0.3 ml of diethylamino-sulfuryl trifloride and 170 mg of potassium fluoride in 8 ml of dichloromethane is added a solution of 0.35 g of (5RS, 6RS) -1-aza- 4-nitrobenzyl 3,7-dioxo-6- (1-hydroxy-1-methylethyl) -bicyclo [3.2.0] -heptane-2-carboxylate in 17 ml of anhydrous dichloromethane. The mixture is stirred for 15 minutes at -78 and mixed with water. Then treated analogously to that described in Example B) f). F = 132-135.

NMR (CDCl 3): 1.51 (d, 3, J = 21 Hz); 1.58 (d, 3, J = 21 Hz); 2.56 (dd, 1, J = 18.4
and 7.5 Hz) 2.64 (dd, 1, J = 18 and 6.7 Hz); 3.36 (dd, 1, J = 21 and 2.2 Hz); 4.07-4.31 (@, 1); 4.78 (s, 1); 5.24 (d, 1, J = 9.5 Hz); 5.40 (d, 1, J = 9.5 Hz); 7.58 (d, λ, J = 9 Hz); 8.23 (d, 2, J = 9 Hz).

4-nitrobenzyl D (3RS, 4RS) -3- (1-fluoro-1-methylethyl) -2-oxoazetidin-4-yl] -2oxo-butyrate (Reaction Scheme 2 (b) (i), (c) i).

a) (3RS, 4RS) -1-tert-butyldimethylsilyl-3- (1-fluoro-1-methylethyl)
4-nitrobenzyl 2-oxo-azetidin-4-yl- (2-oxo) butyrate
To a solution cooled to -780 of 14.4 ml of dimethylamino-sulfuryl trifloride and 18 g of potassium fluoride in 500 ml of dichloromethane is added a solution of 18 g of (3SR, 4RS) -1-tert.butyldimethylsilyl- 4-nitrobenzyl 3- (1-hydroxy-1-methylethyl) -2oxoazetidin-4-yl (2-oxo) butyrate in 400 ml of dichloromethane. Then treated analogously to that described in Example B) f) (eluent: dichloromethane / ethyl acetate = 20/1).

IR (CH 2 Cl 2): 1740, 1520 cm -1.

b) [(3RS, 4RS) -3- (1-fluoro-1-methylethyl) -2-oxoazetidine-4-yl]
2-oxo-4-nitrobenzyl butyrate
To an ice-cold solution of 5.8 g of [(3RS, 4RS) -1-tert.-butyldimethylsilyl-3- (1-fluoro-1-methylethyl) -2-oxoazetidin-4-yl] -2 was added. 4-nitrobenzyl oxo-butyrate in 250 ml of a 9/1 mixture of methanol and water is added 8.3 ml of concentrated HCl. The mixture is stirred for 30 minutes at 0 and for 5 hours at 250. The methanol is distilled off and the product is crystallized.

E) (5RS, 6SR) -3- (2-acetylaminoethylthio) -1-aza-6- (1-hydroxy-1-methylethyl) -7-oxobicyclo [3.2.0] hept-2-ene-2-carboxylic acid 4-nitrobenzyl ester ( for example 3)
To an ice cold solution of 300 mg of (5RS, 6SR) -1-aza-3,7-dioxo-6- (1-hydroxy-1-methylethyl) bicyclo [3.2.0] heptane-2-carboxylate of 4-nitrobenzyl in 20 ml of anhydrous acetonitrile, 0.22 ml of N-ethyldiisopropylamine and then 0.26 ml of diphenyl chlorophosphate are added. After 15 minutes at 0, another 0.22 ml of N-ethyldiisopropylamine and then 140 mg of N-acetylcysteamine in 5 ml of anhydrous acetonitrile are added.

The mixture is stirred for a further hour at 0 and the reaction mixture is partitioned between ethyl acetate and saturated NaCl solutions.

The organic phase is dried over MgSO 4, evaporated to dryness and the residue is chromatographed on silica gel (ethyl acetate / acetone = 7/3).

NMR (CDCl 3): δ, 36 (s, 3 @ 1.44 (s, 3); 2.00 (s, 3); 2.86-3, (m, 7); 4.28 (td); , 1,
J = 9 and 2.7 Hz); 5.25 (d, 1, J = 13.5 Hz); 5.56 (d, 1, J = 13.5 Hz); 5.93 (1r.

 @); 7.65 (d, 2, J = 9 Hz); 8.2 @ (d, 2, J = 9 Hz).

F) (5R, 6R) -1-aza-3,7-dioxo-6- [1 (S) -fluoroethyl] bicyclo [3.2.0] heptane-2-carboxylic acid 4-nitrobenzyl ester (for Examples 23 and 24) ) a) 6 (R) - [1- (S) fluoroethyl] penicillanic acid methyl ester
10 ml of diethylamino-sulfuryl trifloride are added at -78 and under an argon atmosphere to a suspension of 6.5 g of potassium fluoride in 200 ml of anhydrous dichloromethane. A solution of 12.5 g of 6-trans- [1- (R) hydroxyethyl] penicillanic acid methyl ester is then added to this suspension.

After 45 minutes at -78 the cooling bath is removed and stirring is continued for 1 hour at room temperature.

The reaction mixture is extracted twice with water, dried over MgSO 4 and concentrated. The residue is chromatographed on silica gel (dichloromethane) to give the title compound as an oil.

NMR (CDCl3): 1.48 (s, 3); 1.54 (dd, 3, J = 23.5 and 6.5 Hz); 1.65 (s, 3); 3.55 (ddd, 1, J = 28, 3.5 and 2 Hz); 3.79 (s, 3); 4.52 (s, 1); 5.03 (ddq, 1, J = 49, 6.5
and 3.5 Hz); 5.55 (d, 1, J = 2 Hz).

## STR2 ## y7) -2-oxoazetidine
To a solution of 7.1 g of methyl ester of 6 (R) - [1- (S) fluoroethyl] penicillanic acid in 200 ml of ethyl acetate is added 21 21.7 g of mercuric acetate. and the mixture is stirred for 1 hour at 1000. After cooling the mixture is filtered, evaporated to dryness and evaporated three times with toluene. The residue is taken up in ethyl acetate and the insoluble part is filtered off. The filtrate is washed 3 times with 400 ml of water, dried over Mg 504, concentrated and the title compound is crystallized. Mp 94-970.

IR (CHCl 3): 1770, 1720 cm -1.

(c) Methyl ester of isopropylidene- [3 (R) - (1- (S) fluorinated
ethyl) -4 (R) - [2- (4-nitrobenzyloxycarbonylmethyl) allyl] -2-oxoazetidin-1-yl] acetic acid
To a solution of 6.5 g of the product obtained under b) and 8.77 g of 4-nitrobenzyl 3-methylene-4-trimethylsilylbutyrate (prepared according to the method of K. Itoh et al., Chem Chem.

1977, 500) in 30 ml of nitromethane is added slowly at -20 and under argon atmosphere 9.2 ml of trimethylsilyl-trifluoro-methanesulfonate. After 15 minutes at -20 the cooling bath is removed and stirring is continued for 2 hours at room temperature. The mixture is diluted with 100 ml of ethyl acetate, extracted with a buffer solution (pH7) and dried over MgSO4 before being evaporated to dryness. It is chromatographed on silica gel dichloromethane / ether = 10/1) to give the title compound as an oil.

NMR (CDCl 3): 1.54 (dd, 3, J = 24 and 7 Hz); 1.94 (s, 3); 2.20 (s, 3); 2,4 (dd, 1,
J = 15 and @, 5 Hz); 2.56 (dd, 1, J = 15 and 5.5 Hz); 3.13 (ddd, 1, J = 24.5, 5.5 and 2.5 Hz); 3.14 (s, 2?, 3.74 (s, 3); 4.17 (ddd, 1, J = 8.5, 5.5 and 2.5 Hz); 4.98 (cm, 1); , J = 48 Hz), 5.02 (m, 2), 5.22 (s, 2), 7.52 (d, 2, J = 9 Hz), 8.22 (d,
2, J = 9 Hz).

 IR (CHCl3); 1750 cm-1.

d) 4- [3 (R) - (1 (S) fluoroethyl) -2-oxoazetidine-4 (R) -yl] -3-oxo
4-nitrobenzyl butyrate
A-78 o @ passes ozone through a solution of 850 mg
methyl ester of isopropylidene- [3 (R) - (1- (S) fluoroethyl) -4 (R) - [2- (4-nitrobenzyloxycarbonylmethyl) allyl-2-oxoazetidin-1-yl] acetic acid in 10 ml of dichloromethane, until
the solution turns blue. Nitrogen is then added until the color disappears. After addition of 1 ml of dimethylsulfide, the mixture is warmed to room temperature and stirred for 2 hours. The dichloromethane is removed and the residue is dissolved in 5 ml of methanol and after addition of a drop of triethylamine, the mixture is stirred for 30 minutes. After removal of the solvent, the residue is mixed with 200 ml of ether and extracted. 3 times with water, dried over MgSO 4 and concentrated.

By chromatography on silica gel, the title compound is obtained in the form of an oil.

NMR (CDCl 3): 1.52 (dd, 3, J = 24.5 and 7 Hz); 2.86-3.06 (m 2); 3, @ 7 (ddd, 1,
J = 27, 3.5 and 2.7 Hz); 3.60 (s, 2); 4.01 (ddd, 1, J = 7.5, 6.5 and 2.7 Hz);
5.04 (λ = 1, J = 46 Hz); 5.30 (s, 2); 6.08 (1r, 1); 7.56 (d, 2, J = 9 Hz); 8.29 (d,
2.3 = 9 Hz).

e) 4- [3 (R) - (1 (S) fluoroethyl) -2-oxoazetidine-4 (R) -yl] -3-oxo-2
4-nitrobenzyl diazobutyrate
To a solution of 100 mg of 4-nitrobenzyl 4- [3 (R) - (1 (S) fluoroethyl) -2-oxoazetidine-4 (R) -yl] -3-oxo-butyrate and 77 mg of azide of 4-carboxy-benzenesulfonyl in 5 ml of acetonitrile 0.31 ml of triethylamine are added dropwise with stirring and with ice-cooling and the mixture is stirred for a further 15 minutes at room temperature. The mixture is then diluted with 40 ml of ethyl acetate, washed once with 5% bicarbonate solution and twice with water, dried over MgSO 4 and concentrated to give the title compound.

NMR (CDCl 3): 1.52 (dd, 3, J = 24.5 and 7 Hz); 3.10 (d 1, 3 = 25 Hz); 3.17 (dd, 1, @ = 1 @ and 8.5 Hz); 3.33 (dd, 1, J = 13 and 5 Hz); 4, @ 2 (ddd, 1, @ = 8.5, 5 and 2.5 Hz); 5, @ 3 (dm, 1, J = 42.5 Hz); 5.39 (s, 2); 6.0 @ (1r, 1); $ 7.58 d, 2,
J = 9 Hz); 8.30 (d, 2, J = 9 Hz).

IR (CH 2 Cl 2): 2150, 1770, 1720, 1675 cm -1.

f) (5R, 6R) -1-aza-3,7-dioxo-6- [1 (S) -fluoroethyl [bicyclo [3.2.0] heptane
4-nitrobenzyl 2-carboxylate
For 15 minutes, with stirring, a solution of 100 mg of acid 4 is degassified by vigorous passage of argon.
4-nitrobenzyl [3 (R) - (1- (S) fluoroethyl) -2-oxoazetidine-4 (R) -yl] -3-oxo-2-diazobutyrate in 20 ml of benzene. A catalytic amount of rhodium acetate II is added and the reaction flask is placed in a bath preheated to 80 ° C. After 15 minutes at 800, filter and concentrate the filtrate to give the title compound.

NMR (CDCl 3): 1.59 (dd, 3, J = 24 and 7 Hz); 2.50 (dd, 1, J = 18 and 8 Hz);
2.94 Cdd, ', J = 1 and 7 Hz); 3.40 (ddd, 1, J = 26, 4 and 2.5 Hz); 4, t2 (td, 1,
J = 7 and 2, @ Hz); 4.10-4.92 (m, 0.5); 4.80 (s, 1); 5.16-5.50 (m, 2.5); 7.56 (d,
2, J = 9 Hz); 8.30 (d, 2, J = 9 Hz).

G) N, N, N ', N'-tetramethyl-N "- (2-mercapt) ethyl guanidine hydroiodide (for example 10) a) N, N, N', N'-tetramethyl iodide S-methylisothiourea-urea
On cooling with ice, 30 g of tetramethylthio-ureea (100 ml of methyl iodide) and 200 ml of dichloromethane were added and the mixture was stirred for 3 hours in the dark and at room temperature. After addition of 500 ml of ether, the title compound which precipitated (F = 1700) can be used directly for the next reaction.

b) N, N, N ', N'-tetramethyl-N "- (2-mercapto) ethyl hydroiodide
guani dine
A solution of 2.27 g of cysteamine hydrochloride in 20 ml of anhydrous dimethylformamide is admixed with 2.77 ml of triethylamine at room temperature and stirred for 2 hours. The precipitate is removed and the filtrate is mixed with 5.48 g of N, N, N ', N'-tetramethyl-5-methylisothiourea iodide. After stirring for 2 hours at room temperature, 100 ml of diisopropyl ether are added to the mixture and the resulting brown oil is decanted. This oil is digested in 10 ml of isopropanol after which the title compound crystallizes. After filtration the residue is washed once with isopropanol and once with
diisopropyl ether. then we dry it, which gives the
composed of the title. F = 95.

 NMR (CDCl3): 2.10 (1r, 1): 2.90-3.30 (m, 14); 3.42-3.70 (m, 2); 7.66 (1r, 1).

 IR (KBr): 1615, 1580 cm -1.

H) N, N, N ', - trimethylmercapto acetamidine nonafluorobutanesulfonate (for example 12) a) a-tritylthio-N-methylacetamide
To a solution of 26.55 g of sodium in 1800 ml of ethanol is added 288.8 g of triphenylmethane thiol. Then, while cooling with ice, a solution of 111.8 g of N-methylchloroacetamide in 1000 ml of ethanol is added dropwise, which causes the formation of a gray-white precipitate. When the addition is complete, stirring is continued at room temperature for 45 minutes between the mixture and half of its volume. The precipitate is filtered, washed with isopropanol, water and further isopropanol and dried to give the title compound. F = 200-210.

NMR (CDCl 3): 2.48 (d, 3, J = 5.5 Hz); 3.13 (s, 2); 6.00 (14.1); 7.10 to 7.60 (m, 15).

b) &alpha; -tritylthio-N-methylthioacetamide
It is stirred for 6 hours at 500 325 g of a-tritylthio
N-methylacetamide and 400 g of Lawesson's reagent in 4000 ml of toluene. After concentration at about 1300 ml, the insoluble products are removed and the residue is washed with ethyl acetate
The original filtrate and the ethyl acetate phase are combined and evaporated to dryness. The oily residue is crystallized by treatment with a little ethanol to give the title compound; more product can be obtained by chromatography of the mother liquor on silica gel.

NMR (CDCl 3): 2.75 (d, 3, J = 5.5 Hz), 3.85 (s, 2), 7.20-7.60 (m, 15; )
IR (KBr). 1520, 1440, 136 @ cm-1.

c) Hydrochloride of the S-methyl ester of α-tritylthio acid
N-methylthioacetimidic
For 20 hours at room temperature, 136 g of α-Tritylthio-N-methylthioacetamide is stirred in darkness in 800 ml of methyl iodide. 1500 ml of ethyl acetate are then added, the mixture is filtered and washed twice with ethyl acetate, giving the title compound. F = 130-140.

 NMR (C2D2Cl4): 2.2 @ 3), 3.08 (2.3); 9, 7 (s, 2) δ, 7.20-7.60 (m, 1).

 IR (KBr): 1 @@@ cm-1.

d) N-Tritylthio-N, N, N '-trimethylacetamidine hydroiodide
On a dry ice bath, dimethylamine is condensed with stirring in a suspension of 170 g of N-methylthioacetimidic acid S-methylic acid hydroiodide ester in 750 ml of anhydrous dichloromethane at room temperature. (about 200 ml); the then clear solution is stirred for a further 3 hours at room temperature. Evaporate to dryness and crystallize the residue by trituration with ethyl acetate. Filtration and drying gives the title compound. F = 1900.

NMR (C2D2Cl4): 2.80-3.06 (m, 9); 3.32 (s, 2); 7.25-7.60 (m, 15): 8.58 (1r, 1).

IR KBr): 164 @ cm-1.

e) N1N1N ', -trimethylmercaptoacetamidine onafluorobutanesulfonate
6 g of N, N, N ', - trimethylacetamidine hydroiodide are distributed between a 6N solution of NaOH and ether to give the free base and then dissolved in 100 ml of methanol.

During this time, a solution of 4.2 g of silver nitrite in 500 ml of methanol and 2.5 m of pyridine is prepared. The solutions are combined and stirred for 90 minutes at room temperature. The resulting black-brown precipitate is filtered and washed thoroughly with methanol and ether. It is then suspended in 400 ml of anhydrous dichloromethane to which a drop of pyridine is added and H2S is passed for about 20 minutes at 00. After filtration on a sintered glass, the filtrate is concentrated, mixed with toluene and it is evaporated again to dryness. Dry by high vacuum, the residue is taken up in about 100 ml of a 1N solution of HCl and extracted 3 times with ethyl acetate. 10 g of potassium nonafluorobutanesulfonate are added and the mixture is extracted five times with dichloromethane. After concentrating the combined extracts, the title compound is crystallized. F = 60-65 (decomposition).

NMR (CDCl3): 2.42 (1r, 1); 3.10-3.26 (m, 6); 3.37 (s, 3); 3.64 (1r, 2); 8.04 (1r, 1);
IR (KBr): 1650 cm -1.

Claims (1)

 CLAIM Compounds of formula III or V

 in which R1 represents hydrogen or a methyl group, R3 represents a protecting group or an ester group  physiologically hydrolyzable and acceptable and R8 represents a removable group.