FI82470B - Process for preparing 2-substituted 2-penem-3-carboxylic acid compounds and intermediates - Google Patents

Description

1 82470

This invention relates to the preparation of derivatives of the genus of antibacterial agents containing a 2-azetidinone (beta-5-lactam) ring. Chemically, these compounds are known as 2-substituted 2-penem-3-carboxylic acid compounds.

2-Substituted 2-penem-3-carboxylic acid compounds are described in U.S. Patent 4,155,912; BE Patent 866,845; In EP-A-636 and 2,210; and in the Journal of the American Chemical Society, 101, 2210 (1979). According to the summary published by Derwent Publications Ltd., JP-published patent application 66 694/1979 also describes 2-substituted 2-pe-nem-3-carboxylic acid compounds.

The invention relates to a process for the preparation of 2-substituted-2-penem-3-carboxylic acid compounds of the formula (I) and their pharmaceutically acceptable salts, wherein R is hydrogen, 1-hydroxyalkyl having 1 or 2 carbon atoms or wherein 1-hydroxyalkyl is substituted with a hydroxy protecting group; R 1 is (alk) -G, (alk) -G 1, G 1 or CH (G 2) 2, wherein (alk) is an alkyl group having 1 to 4 carbon atoms; G is hydrogen, alkoxy of 1 to 5 carbon atoms, 2- (alkoxy) ethoxy of 3 to 7 carbon atoms, alkylthio of 1 to 5 carbon atoms, phenoxy, thiophenoxy, azido, 35 amino, amino with a substituent amino protecting group, 2 82470 N-phenyl-N-alkylamino having 1-4 carbon atoms in the alkyl, N-alkanoylamino having 2 to 6 carbon atoms, N-alkoxyalkanoylamino having 3 to 10 carbon atoms, 2- (N-alkanoylamino) ) ethoxy having 4 to 8 carbon atoms, amino-5 carbonyl, aminocarbonyloxy, N-alkylaminocarbonylamino having 2 to 5 carbon atoms, alkanoylaminoacetylamino having 4 to 7 carbon atoms, N-alkylaminocarbonyloxy, aminocarbonylalkoxy, is 2 to 5 carbon atoms, N-alkylaminocarbonyl having 2 to 5 carbon atoms, 10 or N- (alkoxyalkyl) aminocarbonyl having 3 to 9 carbon atoms;

Gx is azetidinyl or azetidinyl substituted with N-alkanoyl having 2 to 6 carbon atoms or an amino protecting group; a five- or six-membered ring which is carbocyclic or heterocyclic and has one or two oxygen atoms, one, two, three or four nitrogen atoms, a sulfur atom, a nitrogen atom and an oxygen atom or a nitrogen atom and a sulfur atom, or said five- or six-membered ring having is a substituent alkyl having 1 to 4 to 20 carbon atoms, a dialkyl each having 1 to 4 carbon atoms, oxo, amino, amino having an amino protecting group as a substituent, alkoxycarbonyl having 2 to 5 carbon atoms, di- (alkoxycarbonyl) ) each having 2 to 5 carbon atoms, aminocarbonyl, alkoxyalkyl having 2 to 25 7 carbon atoms, phenyl, formyl, N-alkylaminocarbonyl having 2 to 5 carbon atoms, N-alkylaminocarbonylamino having 2 to 5 carbon atoms a carbon atom, an alkanoylamino having 2 to 5 carbon atoms, an alkoxy having 1 to 4 carbon atoms, a phenoxyacetyl or a heterocyclic nitrogen atom substituted with an amino-protecting group; G 2 is alkanoylaminomethyl each having 3 to 7 carbon atoms, or alkoxy each having 1 to 4 carbon atoms; R 2 is hydrogen, an ester group that hydrolyzes in the environment, or a carboxylic acid protecting group.

3,82470

The compounds of formula (I) are prepared according to the invention in that a) to a compound of formula (V), 5 N_ / 14 ir (V) o 10 CO 2 R 2 wherein R 7 is halogen, R 4 is alkyl of 1-7 carbon atoms , or alkyl substituted by alkoxy having 1 to 4 diatoms, and i is zero, and R and R 2 are as defined above, a xanthate salt of the formula M 1 -O- (C = S) -S ", wherein M * is metal cation and R 1 are as defined above, b) treating the thus obtained beta-lactam of formula (VI) with R 2 (O) 1 R 4 »(VI) -N 2 -N-SC-OR, o | 25 1 CO 2 R 2 wherein R, Rx , R 2, R 4 and i are the same as above, with sodium hydride in a reaction-inert solvent at -10 ° C to 5 ° C, followed by the addition of one molar equivalent of acetic acid to give the beta-lactam of formula (VII), S, 0> iR4 Γ S (VII) 35 o · ** 1-V / "5-ori CO 2 R 2 4 82470 c) halogenating the beta-lactam of formula (VII) thus obtained in a reaction-inert solvent at -40 ° C to 5 ° C with at least one molar equivalent of a halogenating agent to give a beta-lactam / R 5 I - ^ (III) 10 'CO 2 R 2 of formula (III) wherein R, R 1 and R 2 are the same as above, and R 5 is chlorine and d) cyclizing the beta-lactam of formula (III) thus obtained by treating it with a base in a reaction-inert solvent at a temperature of 0 to 25 ° C to give the desired compound.

The hydroxy protecting group may be benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, allyloxycarbonyl-20, 2,2,2-trichloroethoxycarbonyl or trialkylsilyl, each alkyl having 1 to 6 carbon atoms. When the hydroxy protecting group is trialkylsilyl, the process may comprise the additional step of removing the hydroxy protecting group with a tetraalkylammonium compound having 1 to 7 carbon atoms in each alkyl. Preferably, the tetraalkylammonium compound is a fluoride salt.

The carboxylic acid protecting group may be benzyl, p-nitrobenzyl, allyl or 2,2,2-trichloroethyl.

The amino protecting group may be benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl or an azido protected together with the nitrogen atom of the amine.

The process may include an additional step of removing the hydroxy protecting group, carboxyl protecting group or amino-35 protecting group by hydrogenation treatment with zinc or treatment with tetrakis (triphenylphosphine) palladium.

n 5 82470

In step (b), a base or a base and a trivalent phosphorus compound may be used. The preferred base is sodium hydride. The trivalent phosphorus compound is preferably a trialkylphosphine, a triarylphosphine or a trialkylphosphine, more preferably triphenylphosphine.

In step (d), a base may be used. Preferred bases are trialkylamine in which each alkyl has 1 to 4 carbon atoms or tetraalkylammonium hydroxide in which each alkyl has 1 to 7 carbon atoms. The more preferred 10 min base is diisopropylethylamine.

The process can be used to prepare compounds wherein R is hydrogen and Rx is methyl, ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1-methoxy-2-propyl, bis (methoxymethyl) methyl, 2- (2-methoxyethoxy) ethyl , 2-azidoethyl, aminocarbonylmethyl, 1- (aminocarbonyl) -1-ethyl, 1- (N-methylaminocarbonyl) -1-ethyl, bis (acetylaminomethyl) methyl, 2- (aminocarbonylmethoxy) ethyl, 2-N -methylaminocarbonyloxy) ethyl, 1- (N-methoxyethyl) aminocarbonyl) -1-ethyl, 2- (aminocarbonyloxy) ethyl, 2-20 (N-methylaminocarbonylamino) ethyl, 2- (methoxymethylcarbonylamino) ethyl, 2 - (acetylaminoacetylamino) ethyl, 2- (2-acetylaminoethoxy) ethyl, 1-acetylamino-2-propyl, 2- (acetylamino) ethyl, 2-azidocyclohexyl, 2-methoxycyclohexyl, 2-formylaminoocyclohexyl, 2-formylaminoocyclohexyl, 2- (N-methylaminocarbonylamino) cyclohexyl, 2-methoxycyclopentyl, 1-acetyl-3-azetidinyl, 1-acetyl-3-pyrrolidinyl, 1-ethylcarbonyl-3-pyrrolidinyl, 1-formyl Myl-3-pyrrolidinyl, 2-pyrrolidon-3-yl, 3-tetrahydrofuranyl, 2-tetra-hydrofuranylmethyl, 2- (1-imidazolyl) ethyl, 2- (4-methoxycarbonyl-1,2,3-triazolyl ) -ethyl, 2- (4,5-dimethoxycarbonyl-1,2,3-triazolyl) ethyl, 2- (4-aminocarbonyl-1H-1,2,3-triazolyl) ethyl, 1,3- dioxolan-2-ylmethyl, 1,3-dioxolan-4-ylmethyl, 2,2-dimethyl-3H-1,3-dioxolan-4-ylmethyl, 3-methyl-1,3-oxazolid-2-one-4 -ylmethyl, 2- (2H-1,2,3,4-tetraol-2-yl) ethyl, 6,82470 2-piperidon-5-yl, 1-methyl-2-piperidon-3-yl, 1-formyl Myl-3-piperidyl, 1-formyl-4-piperidyl, 1-acetyl-3-piperidyl, 1-phenoxymethoxycarbonyl-3-piperidyl, 1-ethylcarbonyl-3-piperidyl, 1-aminocarbonyl-5-piperidyl 1,1-aminocarbonylmethyl-2-piperidon-3-yl, 2-perhydropyrimidinon-5-yl-1,3-dioxan-5-yl, 2-phenyl-1,3-dioxan-5-yl, 2-methoxymethyl-1 , 3-dioxan-5-yl, 2-phenoxyethyl, 2-thiophenoxyethyl, 2-phenethyl, 2- (2-thienyl) ethyl, 2- (2-pyridyl) ethyl, 3- (3-pyrid-10-dy over) propyl, 2- (pyrazolinyl) ethyl, 2- (4-methylthiazol-5-yl) ethyl, 2- (o-phthalimido) ethyl, 2- (2-thiazolylthio) ethyl, 2- (N-methylanilino) ethyl, 2- (2-tetrahydropyranyloxy) ethyl, 2-tetrahydropyranylmethyl, 2- (1-morpholino) ethyl, 2-azido-2-phenethyl, 1-15 acetyl-2-pyrrolidylmethyl, 2- (2-pyrrolidon-1-yl) -ethyl, 2- (2-pyridinoylamino) ethyl, 2- (2-furanoylamino) ethyl, 2- (2-imidazolidinon-1-yl) ethyl-2-piperidone -3-yl or 2- (2-piperidon-1-ylacetylamino) ethyl; preferably R2 is p-nitrobenzyl.

Compounds that can be further prepared by this method are those wherein R is 1-hydroxyethyl or 1-hydroxyethyl substituted with a hydroxyl protecting group, and R 1 is 1-formyl-3-piperidinyl, 1,3-dioxan-5-yl, 1,3- dioxan-2-yl, 1,3-dioxolan-2-yl, 1,3-dioxolan-25-yl, 1,3-dioxolan-4-ylmethyl, 2-piperidinon-3-yl, 2-piperidinone-5-yl -yl, 2-pyrrolidinon-3-yl, 1-methoxy-2-propyl, 2-methoxyethyl, 3-methyl-1,3-oxazolidin-2-on-4-ylmethyl, 2-tetrahydropyranylmethyl, 1 -methyl-2-piperidinylmethyl or 2- (4-acetyl-1-piperazinyl) ethyl; wherein R 2 is preferably p-nitrobenzyl.

Other compounds that can be prepared by this method are those wherein R is hydrogen and R 2 is 2-azidoethyl, 2-aminoethyl, 1-azido-2-propyl, 1-amino-35-2-propyl, 1β-nitrobenzyloxycarbonyl -3-pyrrolidinyl, 3-pyrrolidinyl, 1-p-nitrobenzyloxycarbonyl-11,72470 1H-3-piperidinyl, 3-piperidinyl, 1-p-nitrobenzyloxycarbonyl-2-pyrrolidinylmethyl, 2-pyrrolidinylmethyl or 2- aminocyclohexyl; wherein R 2 is preferably p-nitrobenzyl.

The present invention comprises a process wherein R 2 is alkanoyloxymethyl having 3 to 8 carbon atoms, 1- (alkanoyloxy) ethyl having 4 to 9 carbon atoms, 1-methyl-1- (alkanoyloxy) ethyl having has 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, Ι-ΙΟ (alkoxycarbonyloxy) ethyl having 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl having 5 to 8 carbon atoms, N- (alkoxycarbonylaminomethyl having 3 to 9 carbon atoms, 1- (N- [alkoxycarbonyl] amino) ethyl having 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactol-15-yl, gamma-butyrolacton-4-yl or carboxyalkylcarbonyloxymethyl having 4 to 12 carbon atoms.

The invention also relates to intermediates of formulas (VII '), (m') and (VI *) according to claims 4, 5 and 6.

The compounds of formula I are useful as antibacterial agents, or precursors thereof, and are derivatives of a bicyclic core of the following formula: In this patent, the core of formula II is referred to as "2-penem". ", and the ring atoms are numbered 35 as shown. In this patent, β 82470 is also abbreviated "PNB" to denote a p-nitrobenzyl group.

When R is other than hydrogen, the bond between the hydrogen in the bridge end at carbon 5 and the hydrogen remaining in carbon 6 may be cis or trans. This invention encompasses both isomers as well as mixtures thereof. The trans isomer is generally preferred in pharmaceutical applications and the cis isomer can be readily converted to the trans isomer.

As will be appreciated, various optically active isomers may exist. This invention includes such optically active isomers as well as mixtures thereof.

By ester group, which is rapidly hydrolyzed in the body, is meant non-toxic ester residues that are rapidly degraded in the blood or tissues of the mammal to release the corresponding free acid (i.e., a compound of formula I wherein R 2 is hydrogen). Typical examples of rapidly hydrolyzable ester residues that can be used for R 2 include alkanoyloxymethyl of 3 to 8 carbon atoms, 1- (alkanoyloxy) ethyl of 4 to 9 carbon atoms, 1-methyl-1 - (alkanoyloxy) ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1- (alkoxy-carbonyloxy) ethyl having 4 to 7 carbon atoms, 1-methyl-1 - (alkoxycarbonyloxy) ethyl having 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl having 3 to 9 carbon atoms, 1- (N- [alkoxycarbonyl] amino) ethyl having 4 to 10 carbon atoms, 3- phthalidyl, 4-crotonilactoyl or gamma butyrolacton-4-yl. Another group of esters that are rapidly hydrolyzed in the body are carboxyalkylcarbonyloxymethyl esters having 4 to 12 carbon atoms; a pharmaceutically acceptable cation can be used with these esters.

35 The manner in which the compounds of formula I can be obtained

is prepared by reference to Scheme A. Formula I

II

g Compounds of formula 82470 are obtained from the corresponding compound of formula III. Rj represents all of the same groups listed previously, except those groups which contain a primary or secondary amino group. When 5 Rx contains a primary or secondary amino group, this is a special case discussed below.

Reaction Scheme A

R Rr 10 "--- 5 I s CO2R2 15__Ri

20 I I

V-N-- CO 2 R 2 Compounds of formula I are obtained by combining the corresponding compound of formula III as a ring as shown in Reaction Scheme A. The ring formation is normally carried out by treating a compound of formula III with a base, for example an excess, e.g. a ten to 30 times excess, of a trialkylamine having 1 to 4 carbon atoms in each alkyl, such as triethylamine or diisopropylethylamine, or tetraalkylammonium hydroxide, alkyl has 1 to 4 carbon atoms, e.g. diisopropylethylamine, in a reaction-inert solvent such as chloroform, tetrahydrofuran or dichloromethane. The reaction is carried out normally at a temperature in the range of about 0 to 40 ° C, preferably about 25 ° C, and is normally completed within a few hours, e.g. 2 to 24 hours. At the end of the ring formation reaction, the amine hydrochloride is removed by washing with water, and the product is recovered, for example, by evaporation of the solvent.

The manner in which the compounds of formula III are obtained is illustrated by reference to Reaction Scheme B. According to the invention, these compounds are obtained by halogenating a compound of formula VII. For example, chlorination of a compound of formula VII wherein i is zero is normally performed by treating the compound with one molar equivalent or more of chlorine in a chlorinated hydrocarbon solvent such as dichloromethane, chloroform or carbon tetrachloride at a temperature in the range of about -40 to 5 ° C, preferably about - 20 ° C. The reaction is normally complete within one or two hours, and the product is recovered by evaporation of the solvent. The chloro compound III is usually obtained as an oil, which is usually used directly, without purification, for the preparation of a compound of formula I.

Other suitable chlorination reagents may also be used. Furthermore, R5 does not need to be chlorine for change III-I to occur. Other halogens, e.g. bromine, may be used. These other halogens can be prepared by appropriate halogenation of compound VII; for example by bromination with bromine. Of course, R 5 may be any other suitable leaving group that allows ring formation of compound III to occur.

Il 11 82470

Reaction Scheme B

R S (0) .R.

5 \ _ / 1 4

I V

/-OF

r y J, C ° 2R2 10 R _ ^ 3 (0) iR4

I I § VI

Λ- ^ S-C-OR;

0 I

15 s / CO2R2 "γ_ / S (0» iR4

\ f VII

cT-V./C-0R1 20 * l CO2R2

III

Compounds of formula VII are obtained by desulfurization of a xanthate of formula VI. The desulfurization is usually carried out by treating a compound of formula VI with about one molar equivalent of a strong base such as sodium hydride in a reaction-inert solvent such as tetrahydrofuran at a temperature between about -10 ° and 5 ° C, preferably at about 0 ° C. The reaction normally takes place in about one or two hours, and then the reaction is stopped by adding about one molar equivalent of acetic acid. The product is then recovered by evaporation of the solvent. Although the compound thus obtained can be used directly for the preparation of the compound of formula III, 82470, it is common to purify compound VII. Purification can be performed by standard methods; a particularly convenient method is chromatography on silica gel.

In most cases, when converting a compound of formula VI to a compound of formula VII, it is preferred to add one molar equivalent of a trivalent phosphorus compound such as trialkylphosphine (e.g. tri-butylphosphine, tricyclohexylphosphine), triarylphosphine (e.g. triphenylphosphine) or triphenylphosphine. trimethylphosphite, triethylphosphite), preferably triphenylphosphine, to the reaction medium before adding a strong base.

Compounds of formula VI are obtained by coupling to a compound of formula V a xanthate salt of formula M + R 1 -O- (C = S) -S ', wherein M + represents a metal cation such as sodium or potassium. The coupling is normally performed by bringing equimolar amounts of the xanthate salt and the compound of formula V together in a two-phase mixture of organic matter and water such as dichloromethane and water in the presence of one molar equivalent or less of a phase transfer catalyst such as benzyltriethylammonium chloride. The reaction is normally carried out at a temperature of about 0 to 30 ° C, preferably about 0 ° C, and usually takes 1 to 25 hours. Once the reaction is complete, the product is in the organic phase and can be recovered by separating the layers and evaporating the solvent. The product can be purified by conventional methods for beta-lactam compounds, e.g. by chromatography on silica gel.

A process for the preparation of a compound of formula V.

Thus, it can be seen that the compound of formula V is prepared by halogenation of the corresponding hydroxy compound (XIII) with a halogenating agent such as thionyl chloride, methanesulfonyl chloride or methanesulfonyl bromide. Chlorination with thionyl chloride is performed by treatment of formula XIII

II

i3 82470 in tetrahydrofuran with a small molar excess of thionyl chloride in the presence of a hindered amine such as 2,6-lutidine at about 0 ° C. The reaction proceeds rapidly and after about 15 minutes the product 5 is obtained by evaporation of the filtered tetrahydrofuran solution.

Reaction Scheme C

O

M

CO-R, R O-C-CH,, 2. 2. V / 3

CH-OH I

10 Y / N

CROH jy \

I 0 ^ XH

C02R2 XI

ix 1 | R ▼ S {0) ± R4 15 H0 \ v00 ^ 5 i— (

ΌΗ J_N

I y / \ CO2R2 o h y xii 20 * j

\ I / 0, A

of

L_N OH

r XIII co2r2 i

V

A compound of formula XIII is prepared by coupling a compound of formula XII with an ethyl hemiacetal ester of glyoxylic acid (X). The coupling is performed by heating the two reagents under reflux in Bentene while performing continuous removal of water and ethanol by azeotropic distillation.

An alternative method is to treat compound XII (R is preferably 1-hydroxyethyl or hydroxymethyl-4 82470 with a hydroxy protecting group such as p-nitrobenzyloxycarbonyl) benzyloxycarbonylformaldehyde hydrate or hemiacetal to give compound XIII (R2 = benzyl group). The preferred benzyloxycarbon-5-ylformaldehyde hydrate is p-nitrobenzyloxycarbonylformaldehyde hydrate which is reacted with compound XII in an aprotic solvent such as benzene or dimethylformamide, preferably benzene, at a temperature of about 80 ° C.

The azetidine of formula XII is prepared from the corresponding 4-acetoxy-2-oxo-azetidine XI by reacting it with the sodium salt of a thiol, and the ethyl heme acetal ester of glyoxylic acid X is prepared by cleavage of periodic acid from the corresponding tartaric acid ester IX. 4-15 Acetoxy-2-oxoazetidines XI and tartrates IX are prepared by methods known in the art. The sulfide (XII or XIII, i is zero) can be oxidized to the sulfoxide (i is one) with an oxidant such as sodium periodate, ozone or preferably m-chloroperbenzoic acid. The oxidation with m-20 chloroperbenzoic acid is generally carried out in a reaction-inert solvent such as dichloromethane at a temperature between about -30 and 0 ° C, preferably at about -20 ° C.

v 11 i5 82470

Reaction Scheme D

• “ίςχ- O C02CH3 0 C02CH3

XIV XV

10 0 Hi co2ch3 co2ch3

XVII XVI

. ^ OAe R I V g

CO CH,, C00CH

XVIII Δ J XIX - -3

25 I V

R9 I _ ^. OAc i 1. .ΓΓΓι m <- R9'f ° 30 * 9 ° Laca3

XX

i6 82470

When R is 1-hydroxyalkyl or a hydroxy-protected derivative thereof, the compound of formula XII can be prepared according to Reaction Scheme D from a known dibromo penenam of formula XIV. Dibromipenam (XIV) undergoes a step 5 reaction with t-butyl magnesium chloride at a temperature between about -90 and -40 ° C, preferably at about -76 ° C in a reaction inert solvent such as tetrahydrofuran, diethyl ether or toluene, preferably tetrahydrofuran. Other organometallic reagents may also be used. The resulting reaction mixture is treated under natural conditions with the appropriate aldehyde; with acetaldehyde to the 1-hydroxyethyl derivative, with formaldehyde to the hydroxymethyl derivative. The aldehyde is added between -80 and -60 ° C, preferably at -76 ° C for acetaldehyde.

The resulting bromohydroxypenam XV is hydrogenated to remove the 6-bromo substituent. Preferred hydrogenation catalysts are noble metals such as platinum and palladium. A suitable hydrogenation catalyst is palladium on calcium carbonate. The reaction is carried out in a protic medium such as 1: 1 methanol-water or water-tetrahydrofuran, preferably 1: 1 methanol-water at a pressure of about 1-4 atm, preferably 4 atm, and at a temperature between about 0 and 30 ° C, preferably about 25 ° C. :in.

The hydrogenated compound XVI is treated to protect the hydroxyl with a hydroxyl protecting group, for example, a protecting group of the formula R 8 CO, such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl and the like. The hydroxyl is reacted, for example, with the chloride, bromide or iodide of the corresponding hydroxyl protecting group, for p-nitrobenzyloxycarbonyl the chloride is reacted with compound XVI in a suitable reaction-inert solvent such as dichloromethane at a temperature between about 0 and 30 ° C, preferably about 25 ° C.

The resulting alkanoylpenam XVII is treated with mercuric acetate in acetic acid at a temperature of about 90 ° C to give olefin XVIII.

When it is desired to obtain the desired azetidine XII, the olefin XVIII is ozonated in a reaction-inert solvent such as dichloromethane at a temperature between about -80 and 5 -40 ° C, preferably at about -76 ° C. The reaction product is not isolated but treated with an alkanol such as methanol to give azetidine XII.

Alternatively, the alcohol of formula XVI may be protected with a trialkylhalo-10 genesilane of the following formula

Rg-Si-Q

R9 wherein R9 in each case independently of one another is alkyl having 1 to 6 carbon atoms and Q is chlorine, bromine or iodine. Thus, dimethyl-t-butylchlorosilane in the presence of an amine proton acceptor such as imidazole in a polar, aprotic solvent such as dimethylformamide at a temperature between 5 and 40 ° C, preferably about 25 ° C, forms a trialkylsilyl hydroxyl protecting group. , as shown in formula XIX.

Treatment of mercury acetate with XIX under the conditions used with XVII gives olefin XX. Ozonolysis of this olefin XX by the same method used with compound XVIII gives compound XII wherein R is a trialkylsilyl derivative of 1-hydroxyethyl or hydroxymethyl.

The xanthate salts of formula M + R 1 -O- (C = S) -S 'are prepared from the appropriate alcohol of formula R 1 OH and carbon disulfide in the presence of a strong base. For example, an alcohol of formula R1-OH is reacted with an equimolar amount of sodium hydride or potassium t-butoxy, followed by a small excess of carbon disulfide, according to a well known method.

is 82470

By converting a compound of formula I wherein R 2 is an acid protecting group to a compound of formula I wherein R 2 is hydrogen, known methods can be used. For example, when R 2 is benzyl or p-nitrobenzyl, the preferred method is the usual hydrogenation reaction, and is carried out in a conventional manner suitable for this type of conversion. Thus, a solution of a compound of formula I (R 2 is an acid protecting group) is stirred or shaken in a hydrogen atmosphere or in an atmosphere in which hydrogen is mixed with an inert diluent such as nitrogen or argon in the presence of a catalytic hydrogenation catalyst such as a noble metal catalyst such as palladium calcium. Convenient solvents for this hydrogenation include lower alkanols such as methanol; ethers such as tetra-15 hydrofuran and dioxane; lower molecular weight esters such as ethyl acetate and butyl acetate; water; and mixtures of these solvents. However, it is common to choose conditions in which the starting material is soluble. The hydrogenation is usually carried out at about 25 ° C and a pressure of about 0.5 to about 5 kg / cm 2. The catalyst is usually present in an amount of about 10% based on the starting material, always in an amount equal to the weight of the starting material, although larger amounts may be used. The reaction usually takes place in about an hour, after which the compound of formula I (R 2 is hydrogen) is recovered simply by filtration, after which the solvent is removed in vacuo. If palladium is used with calcium carbonate as a catalyst, the product is often isolated as the calcium salt. The compounds of formula I can be purified by conventional methods for beta-lactam compounds. For example, compounds of formula I can be purified by gel filtration on Sephadex, or by recrystallization.

If in Compound I Rt is 1-hydroxyethyl or hydroxymethyl protected with benzyl derivatives such as p-35 nitrobenzyloxycarbonyl, the hydroxyl protecting group li 19 82470 can be removed using the hydrogenation method just described.

For compounds of formula I wherein R is 1-hydroxyethyl or hydroxymethyl, the hydroxyl group of which is protected by a trialkylsilyl group, the trialkylsilyl group is preferably removed before hydrogenation to remove the acid protecting group (I, R2 is an acid protecting group). The trialkylsilyl group can be removed with tetraalkylammonium fluoride, which generally has 10 to 7 carbon atoms in each alkyl, and an ether solvent such as tetrahydrofuran at about 25 ° C.

A compound of formula I wherein R 2 contains a primary amino group can be prepared from the corresponding azido compound by hydrogenation. The previously described conditions for the removal of R 2 from Compound I, wherein R 2 is an acid protecting group such as a p-nitrobenzyl group, can be used for this azohydrogenation reaction, but the reaction must be allowed to proceed until the reaction with hydrogen ceases. Thus, it will be appreciated that if a compound of formula I wherein R 2 O comprises an azido group is hydrogenated under the above conditions, partial hydrogenation will result in a compound of formula I wherein R 1 comprises an azido group; hydrogenation to the end results in a compound of formula I in which the azido group of Rx has been converted to a primary amino group.

Alternatively, primary or secondary amines may be protected with suitable amino protecting groups. A particularly preferred group of amino protecting groups are benzyloxycarbonyls such as benzyloxycarbonyl or p-nitrobenzyloxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl and the like. The corresponding benzyloxycarbonyl chloride or bromide, for example p-nitrobenzyloxycarbonyl chloride, can be reacted with an amine in a reaction-inert solvent such as dichloromethane in the presence of a tertiary amine at a temperature in the range of about -20 to 25 ° C, preferably about 0 ° C. An amino protecting group such as p-nitrobenzyloxycarbonyl can be removed by the same hydrogenation method as previously described.

The compounds of formula I are acidic and form salts with basic substances. Such salts are considered to be within the scope of this invention. These salts may be prepared by standard methods, such as contacting the acidic and basic components with one another, usually in a stoichiometric ratio, in an aqueous, anhydrous or partially aqueous medium, as appropriate. They are then recovered by filtration, mixing with a non-solvent and then filtering, evaporating the solvent or, in the case of an aqueous solvent, lyophilizing, as appropriate. Suitable basic substances for salt formation may be organic or inorganic, and include ammonia, organic amines, alkali metal hydroxides, carbonates, bicarbonates, hydrides, and alkoxides, as well as alkaline earth metal hydroxides, carbonates, and hydrides.

Representative examples of such bases include primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, and octylamine; secondary amines such as diethylamine, morpholine, pyrrolidine, and piperidine; tertiary amines such as triethylamine, N-ethylpiperidine, N-methylmorpholine and 1,5-diazabicyclo [4.3.0] non-5-ene; hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and barium hydroxide; alkoxides such as sodium ethoxide and potassium oxide; hydrides such as calcium hydride and sodium hydride; carbonates such as potassium carbonate and sodium carbonate; bicarbonates such as sodium bicarbonate and potassium carbonate; and alkali metal salts of long-chain fatty acids such as sodium 2-ethylhexanoate.

Il 2i 82470

Preferred salts of the compounds of formula are the sodium, potassium and calcium salts.

As previously indicated, the compounds of formula I and their salts are antibacterial agents.

The activity of the compounds of the formula I and their salts in the body can be demonstrated by measuring their mi-inhibitory concentrations (MICs) in pg / ml against various microorganisms. The method to be followed is that recommended by the International Collaborative Study on Antibiotic Sensitivity Testing (Ericsson and Sherris, Acta, Pathologica et Microbiology Scandinav, Supp. 217, Section B: 64-68 [1977]) and uses brain-heart infusion (BHI) agar and inoculum replicator. Overnight tubes are diluted 100-fold for use as standard inocula (20,000-10,000 cells in approximately 0.002 ml are placed on agar agar; 20 ml BHI agar / plate).

Twelve 2-fold dilutions of test compound are used at an initial concentration of 200 pg / ml of test drug. Individual colonies are not counted when reading plates after 18 hours at 37 ° C. The susceptibility (MIC) of the test organism is the lowest concentration of compound that produces complete growth inhibition that is observed with the naked eye.

The following examples and preparations are provided for further illustration only. Infrared (IR) spectra were measured with either potassium bromide tablets (KBr tablets), or as solutions in chloroform (CHCl 3), methylene chloride (CH 2 Cl 2), or dimethyl sulfoxide (DMSO), and diagnostic adsorption bands are reported as either wavelengths or microns (cm * 1). (micrometers). Nuclear magnetic resonance (NMR) spectra were measured for solutions in deuterochloroform (CDCl 3), perdeuterodewater (D 2 O) or perdeuterodimethyl sulfoxide (DMSO-d 6), or a mixture thereof, and the positions of the peaks are expressed in parts per million of tetramethylsilane. The following abbreviations for peak shapes are used: 22,82470 s, singlet; d, doublets; t, triplets; q, quartet; m, multiplet; c, complexes; b, wide. The abbreviations "ss" and "sss" mean that a particular proton appears as two or three singlets, respectively, due to the presence of diastereomers 5. Throughout the examples and preparations, the abbreviation "PNB" represents a p-nitrobenzyl group.

Example 1 p-Nitrobenzyl 2- (4-ethylthio-3-p-nitrobenzyloxy-carboxyoxyethyl-2-oxo-1-azetidinyl) -2- (1,3-di-10-oxan-5-yl-oxithiocarbonyl) acetate_

A solution of 8.40 g of p-nitrobenzyl 2- (4-ethylthio-3-p-nitrobenzyloxycarbonyloxyethyl-2-oxolacetidinyl) -2- (1,3-dioxan-5-yloxythiocarbonylthio) acetate and 2 .95 g of triphenylphosphine 200 in 15 ml of anhydrous tetrahydrofuran, cooled to 0 ° C under a nitrogen atmosphere, sodium hydride (550 mg of a 50% oil dispersion) was added and the reaction mixture was stirred at 0 ° C for 20 min. Acetic acid (0.65 mL) was then added dropwise at 0 ° C and the resulting solution was concentrated in vacuo. The residue was dissolved in 20 ml of ethyl acetate, and the solution was washed successively with 100 ml of saturated aqueous sodium bicarbonate solution and 100 ml of water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 25% ethyl acetate in chloroform to give 6.9 g of the title compound. The NMR spectrum in deuterochloroform showed absorbances at; 1.0 - 1.56 (c, 6 H); 2.58 (m. 2H); 3.4 (m, 1H); 3.86-4.1 (c. 5H); 4.63 - 5.46 (c, 9H); 7.5 (m, 4H) and 8.2 (m, 4H) ppm.

30 Example 2

Compounds of formula VII wherein R is p-nitrobenzyloxycarbonyloxyethyl, R 4 is ethyl, i is zero, R 2 is p-nitrobenzyl and the meanings of R are shown in Table I were obtained by desulfurization from the corresponding xanthate of formula VI using Example 1 method. For the compounds in Table I, NMR spectra were measured in deuterochloroform solutions.

n 23 82470

Table I

r NMR (ppm) δ 1.0-1.56 (c, 6H); 2.0-2.72 2-piperidinon-5-yl (c, 6H); 3.36 (m, 1H); 3.58 (c, 2K); 4.8-5.32 (c. 8H); 6.1 (b, 1 H); 7.48 (m. 4H); 8.2 (m, 4H) 1.0-2.2 (c, 1OH); 2.6 10 1-formyl-3-piperidyl (m, 2H); 3.1-4.1 (c. 5H); (IR: 5.64, 5.70 5.97 (m 2 1H), · S J 5 m 4 H) J 5 microns (CHCl 3)) 1.04-1.6 (c, 9H); 2.6 (m. 2H); 3.3 (s) and 3.26-3.6 (c, 6H); 4.96-5.4 (c. 7H); 5.66 (c, 1H); Δ 7.5 (m, 4H); and 8.2 (m, 4H) -1-methoxy-2-propyl 1.0-1.58 (c, 6H); 2.6 (m. 2H); 3.4 (m, 1H); 3 T 9 8 (b, 4H); 4.5 (d. 2H); 4.9-5.44 (c, 8H); 7.52 (m. 4H); and 8.2 (m, 4H) 2 O-2-pyrrolidinon-3-yl 0.98-1.66 (c, 6H); 2.26-3.0 (c. 4H); 3.0-3.5b (c. 3H); 4.75-5.46 (C, 8H); 5.9 (b, 1 H); 7.5 (m, 4H), and 8.2 (m, 4H): __-3-methyl-1,3-oxazole-1R-1.56 (c, 6H); 2.54 .... (m. 2H); 2.86 (s. 3H); din-2-on-4-ylmethyl 3,4- (m, 1H {; 3.9-5.42 (cf12H); 7.5 (m, 4H); and 8.2 (m, 4H) 1.3 -dioxolan-4-ylmethyl 1.02-1.68 (c, 6H), 2.58 (m, 2H), 3.42 (m, 1H), 3.6-4.66 (c, 5H), 4 , 68-5.4 ({c, 9H); 7.54 (m. 4H); and 8.2 (m, 4H) 2-methoxyethyl 1.06-1.58 (c, 6H); 2.6: (m, 2H), 3.36 (s) and 3.26-3.8 (c, 6H); Δ 4.54-5.4 (c, 8H); 6.52 (s, 1 H); 7.5 (m. 4H); and 8.2 (m, 4H) 2482470

Example 3 p-Nitrobenzyl 2- (4-ethylthio-2-oxo-1-azetidinyl) -2- (ethoxythiocarbonyl) acetate_______

To a stirred solution of 3.5 g of p-nitro-5-benzyl-2- (4-ethylthio-2-oxo-1-azetidinyl) -2- (ethoxythiocarbonylthio) acetate in 100 ml of tetrahydrofuran, 0 ° C: 545 mg of a 50% dispersion of sodium hydride in mineral oil was added. Stirring was continued at 0-5 ° C for 1 hour and then a solution of 713 mg of acetic acid in 5 ml of tetrahydrofuran was added dropwise. The reaction mixture was concentrated to dryness in vacuo, and the residue was partitioned between a mixture of 100 ml of chloroform and 50 ml of dilute hydrochloric acid.

The chloroform layer was removed and washed successively with 50 ml of water, 50 ml of saturated sodium bicarbonate and 50 ml of water. The chloroform solution was dried over anhydrous sodium sulfate. Evaporation in vacuo gave the title compound as a yellow viscous liquid. This product was purified by chromatography on silica gel 20 (150 g), eluting with 95: 5 chloroform: ethyl acetate. The product-containing fractions were combined and evaporated in vacuo to give 1.8 g of the title compound as a yellow liquid. The chloroform IR spectrum of the product showed absorption at 5.56 microns. The NMR spectrum in deuterochloroform showed adsorptions at:

II

25 82470

Table II IR NMR

Δ ......... (microns) - (ppm) - 2-methoxyethyl 5.56 lr 2 (t, 3H); 2f36 - 3.86 (m, 9H); 4.7 (m. 2H); 5.1 (m, 1H); Δ r 25, 5.35 5.4 (sss, 3 H); 7.55 (d. 2H); 8.25 (d, 2H) 10 2-phenoxyethyl 5.66 1.15 (m, 3H); 2.34 - 3.62 (m, 4H); 4.24 (m. 2H); 4.7 - 5.2 (m 3 H); 5.24 (s. 2H); 5.34 5.48 (ss, 1H); 6.7 - 7.68 (m, 7H); 8.14 (d, 2H); '- 2-thiophenoxyethyl 5.66 1.0-1.4 (m, 3H); 2.3-15.9 (m. 6H); 4.45 - 5.35 (m, 6H); 7.1 - 7.62 (m, 7 H); 8.16 (d, 2H) 2-phenylethyl 5.66 1.2 (t, 3H); 2.3 - 3.65 (m, 6 H): 4.6 - 5.14 (m, 3 H); 5.28 - 5.32 (ss, 3H); Δ 7 - 7.65 (m, 7 H); 8.22 (d, 2H) 2-azidoethyl 4.77 12 (t, 3H); 2.4 - 3.86 - 5.66 (m, 6H); 4.62 - 5.25 (m, 3 H); 5.3 5.4 (ss, 3 H)? 7.58 (d. 2H); Δ 8.25 (d, 2 H)

Example 5! p-Nitrobenzyl 2- (4-ethylthio-2-oxo-1-azetidinyl) -2- (2-acetamidoethoxythiocarbonyl) acetate: To a stirred solution of 1.02 g of p-nitro-3Q benzyl-2- (ethylthio 2-Oxo-1-azetidinyl) -2- (2-acetamidoethoxythiocarbonylthio) acetate and 514 mg of triphenylphosphine in 25 ml of tetrahydrofuran, at about 0 ° C, were added 101 mg of a 50% dispersion of sodium hydride in mineral oil. Stirring was continued for 1 hour at about 0 ° C, 35 and then 0.14 ml of acetic acid was added. The resulting solution was evaporated in vacuo and the residue was then dissolved in 50 ml of chloroform. The chloroform solution was washed with water, dried over anhydrous sodium sulfate, and evaporated in vacuo to give a solid residue (1.58 g).

The solid was chromatographed on 100 g of silica gel eluting with 95: 5 ethyl acetate: methanol. The product-containing fractions were combined and evaporated in vacuo to give 500 mg of the title compound. The IR spectrum in chloroform showed adsorptions at 5.66 and 5.98 microns. NMR spectrum in deuterochloroform showed adsorptions at: 1.2 (m, 3H); 2.0 (s. 3H); 2.4 - 3.9 (m, 6H); 4.7 (.2H); 5.13 (m, 1H); 5.28, 5.36 and 5.44 (sss, 3H); 7.0 (m, 1H); 7.64 (d. 2H); and 8.3 (d, 2H) ppm.

Example 6 Compounds of formula VII wherein R is hydrogen, R 4 is ethyl, i is zero, R 2 is p-nitrobenzyl and the meanings of R 2 are listed in Table III were obtained by desulfurization from the appropriate xanthate of formula VI using the procedure of Example 5. .

For the compounds in Table III, IR values were measured for solutions in chloroform unless otherwise indicated and NMR spectra were measured for solutions in deuterochloroform unless otherwise indicated.

11 27 82 470

Table III

R IR NMR

Δ 1_ micron_ (ppm) -2-ethoxyethyl 5.63 1.08-1.95 (m, 6H); 2.4 - 3.95 (m, 8 H); 4.58 (m. 2H); 5.17 im, 1H); 5.27, 5.38 and 5.43 (sss, 3H); 7.58 (d. 2H); 8.26 (d, 2H) 10 '2- (2-methoxy (ethoxy 5.63 1.22 (t, 3H)); 2.38-4.0 (i, m, 13H); 4.7 (m, 2H); ethyl 1.12.12 (m, 1h1; 5.25, 5.36, 5.42 (s, 3H); 7.58 (d, 2H); 8.22 (d, 2H) (morpholino) ethyl 5.64 1.2 (t, 3H), 2.32-3.8 (m, 14H), 4.62 (t, 2H), 5.1 (m, 1H), 5.2 and 5.3 (s, 3K), 7.52 (d, 2H), 8.22 (d, 2H) 2- (2-thienyl) ethyl 5.64 1.16 (t, 3H), 2.3-3.6 (m , 6H), 4.5 - 5.16 2U (m, 3H), 5.2, 5.24 and.

5.28 (sss, 3 H); 6.8 - 7.68 (m, 5H); 8.2 (d, 2H) 2- (2-pyridyl) ethyl 5.66 1.18 (t, 3H); 2.3-3.6 (m. 6H); 4.7 - 5.18 (m, 3 H); 5.2 and 5.25 (ss, 3H); 6.96 - 7.85 (m, 5H); 8.2 (d. 2H); 8.5 (m, 1H) 2- (1-pyrazolyl) 5.62 1.18 (m, 3H); 2.3 - 3.68 (m, 4H); 4.36 - 5.12 ethyl (m, 5H); 5.2 and 5.26 (ss, 3H); 6.22 (m, 1H); 7.34 - 7.7 (m, 4 H); 8.2 (d, 2H) 2- (4-methyl-5-thiazo-5.63 1.2 (t, 3H); 2.3-3.7 (m, 9H); 4.7 (m, 2H); ); yl) -ethyl 4.96-5.38 (m, 4H); 7.72 (α, 2 H); 8.22 (d. 2H); Δ 8.62 (s, 1 H)

R! IR NMR

___ microns_ (ppm) _ 28 82470 2- (2-oxo-1-imidate sol-5.66 1.22 (m, 3H); 2.38-3.78 δ dimethylmethyl 5.88 5.36 (ss, 3H ), 7.6 (d, 2H), 8-28 (d, 2K) 2- (2-oxo-1-pyrrolidine-5.65 1.2 (m, 3H), 1.7-3.8.,. (m, 12H), 4.62 (m, 2H), ethyl 5.1 (m, 1H), 5.2, 5.25 and 5.3 (sss, 3H), 7.56 ( d, 2H), 8.22 (d, 2H) 2- (2-thiazolylthio), 5.66 1.02-1.4 (m, 3H), 2.35-3.74 (m, 6H), 4 , 66-5.4 ethyl (m, 6H), 7.36-7.7 (m, 4H), 8.2 (d, 2H) 2-methoxycyclopentyl 5.66 1.0-1.4 (m , 3H), 1.6 - 2.0 (m, 6H), 2.0 - 4.0 (m, 5H), 3.3 (s, 3H), 5.2 (m, 1H), 5.3 ( m, 2H), 5.6 (m, 1H), 7.5 (d, 2H), 8.2 (d, 2H) 2 O-methoxycyclohexyl 5.65 1.0-2.2 (m, HH): 2 , 2 - 4.0 (m, 5H), 3.4 (s, 3H), 5.0 (m, 1H), 5.4 (d, 2H), 5.5 (m, 1H), 7.5 (d, 2H) 8.2 (d, 2H) 2-azidocyclohexyl 4.76 1.0 - 2.0 (m, 11H), 2.0 - 5.66 4.0 (m, 5H), 5.2 (m, 1H) 5 (1, d, 2H), 5.4 (m, 1H), 5 (d, 2H), 8.2 (d, 2H) -2-azidocyclopentyl 4.76 1.0-1.4 (m , 3H), 1.6 - 5.63, 2.0 (m, 6H), 2.2 - 3.8 (m, 4H), 4.1 (m, 1H), 5.2 (m, 1H), 5.3 (s, 2H), 5.4 (m, 1H), 7.5 (df2H); Δ 8.2 (d. 2H)

II

tetrahydrofuranyl 5.65 1.0 - 1.4 (t, 3H); 2.0 - 3.8 (m. 6H); 3.8 - 4.1 (m, 4 H); 5.0 (m, 1H); 5.3 (s. 2H); 6.9 (m, 1H); 7.8 (d. 2H); 8.2 (d. 2H)

R, IR NMR

micron (ppm) 2982470 1-acetyl-2-pyrrole-5.65 1.0 - * 14 (m, 5H); 2-O-dinyl (s, 3H); 2.2 - 4.0 (m, 8 H); 5.2 (m. 1H); 5.4 δ (S, 2 H); 5.9 (m, 1H); 7.6 (d. 2H); 8.2 (d, 2H) -1-acetyl-3-piper-5.66 1.0-1.4 (m, 3H); 1.4 - calcd 2 ° ° (m'4H); 2 H-dinyl-2.2 - 4.0 (m, 8H); 5.2 (m. 1H); 5.3 (s. 2H); 5.6 (m / 1 H); 7.5 (d, 2H); 8.2 (d, 2H) -2-tetrahydrofuranyl-5.65 1.0-2f4 (m, 3H); 1,6-methyl 2, δ 7 3 * 8 (m, 4Η), 3.8 * 4.1 (m, 3Η); 4.6 (d. 2H); 5.2 (m, 1Η); 5.4 (s. 2H); 7.6 (d. 2H); 8.2 (d, 2H) 2- (2-pyridinoylamino-5.64 1.15 (m, 3K); 2.5 (q, 2H);

no) ethyl V

(C, 4H); 7.2 - 8.7 (c, 9 H).

2N 1-formyl-3-piper-5.64 1.03 (t, 3H); 1.44 - 2.26 5.72 (c, 4H)? 2.38-4.1 dyl (C, 8H); 4.7 - 5.7 (c, 5 H); 7.56 (d. 2H); 7.82 - 8.36 (c, 3H).

N-methylaminocarbonyl-5.68 1.2 (m, 3H); 2.6 (q), 25 ... .. 5.98 2.76 (d) and 2.16-3.7 lymethyl 1 (c, 7H); 4.8 - 5.44 (c, 6H); 7.56 (c. 3H); Δ 2 (d, 2 H).

1- (aminocarbonyl) 5.67 1.07-1.7 (c, 6H); ... 5.92 2.32 - 3.84 (c, 4H); From 4.74 to 30 ethyl (CH-Cl, 5.4 (c, 4H); 5.7 (q, 1H); Δ 6.14 (b, 1H); 7.13 (b, 1H); 48 (d, 2H); 8.15 (d, 2H) 2- (methoxymethylcarb-5.66 1.26 (m, 3H); 2.66 (q, nonylamino) ethyl, 5196 2H); c 'all tc (CH-Cl2 9H) including 3.45 35 1 Z (s, 3hY, 3.76 1q, 2H *), 3.9 (s, 2H), 4.7 (m, 2H), 5.14 (m, 1H), 5.3 (d, 1H), 5.4 (s, 2H), 7.1 (b, 1H), 7.6 (d, 2H), 8.2 (d, 2H) .

30 82 470

R t L and nmr micron (ppm) -2- (aminocarbonyloxy) 5.65 1.18 (m, 3H); 2.58 ethyl δ 76 (m, 2H) γ 2.8 - 5.1 (c, 5 (CH 2 Cl 2 8)) δ -1 (<3 # 1H); 5.3 (s, 2H); 55 (m, 2H), 8.2 (d, 2H).

1,3-dimethoxy-2-propyl 5.65 1.25 (m, 3H); 2.5 (m. 2H); 2.84 - 3.9 (c, 12H) including 3.35 (5.6H); 4.9 - 5.46 (c, 10 4H); 5.8 '(m, 1 H)? 7.6 (d. 2H); 8.28 (d. 2H).

2- (2-furylcarbonyl- ["o '(c'4m]' 'amino) ethyl (CH C1J (m, 2H); 5.08 (m, 1H); 5.24 (d, 1H); 5.34 ( S, 2H), 6.5 (m, 1H), 7.0 (b, 1H), 7.1 (d, 1H), 7.42 (d, 1H), 7.5 (d, 2H) y 8.2 (d. 2H).

1,3-dioxan-5-yl 5.62 1.2 (t, 3H); 2.33 - 3.5 (c / 4H); 4.04 (ir., 4F); Δ 4.66 - 5.44 (c, 7H); 7.5 (m. 2H); 8.2 (d. 2H).

1-methyl-2-piperidinone-5.66 1.22 (m, 3H); 1.7 - 2.2: 6.04 (c, 4H); 2.6 (m. 2H); 3'YY11 '2.96 (5.3Ä); 3.0 - 3.65 (c, 4H) and 4.8 - 5.46 (cf4H); 5.86 (m, 1 H); 7f56 (d. 2H); Δ 8.2 (d. 2H).

1- (aminocarbonylmethyl-5.68 1.2 (m, 3H); 1.7-4.4 style) -2-piperidinone-3-®T® (c, 12H): 4.8-5.4 ( c, 5H); YY P P 6.0 (n, 2H); 7.5 (m, 2H); y yii 8.2 (d, 2H).

2- (2-acetylamino-5.68 1.25 (m, 3H); 2.0 (s, 3H); ethoxy) ethyl 6.0 2.6 (m, 2H); 2.8 - 4.0 (CH-Cl-) (c, 8H); 4.62 (m, 2H) and 4.95-5.4 (c, 4H)? 6.44 (b, 1 H); 7f52 (d, 2 H); 8.2 (d. 2H).

It piperidinone-3-yl 5.68 1.2 (unres. 3H); 1.6 - 3.66 5.98 (c, 8H); 4.8 - 5.4 (c, 5 H); Δ 6.4 (b, 1 H); 7.5 (d. 2H); 8.2 (d. 2H).

R! IR NMR

__micronia (ppm) - 3i 82470 2-pyrrolidinon-3-yl 5.66 1.2 (m, 3H); 2.36 - 3.8 5.85 (c, 8 H); 4.9 - 5T5 (c, 5H); 7T6 (c, 3 H); 8.2 (m. 2H) (DMSO-d 6).

2-piperidinon-5-yl 5.64 1.24 (m, 3H); 2.0-3.8 6.0 (c, 11H); 5.05 (m, 1K); 5.2 (m. 1H); 5.3 (5.2H); in 7.2 (b, 1H); 7.5 (d. 2H); 1U 8.2 (d. 2H).

3-methyl-1,3-oxazo-5.66 1.24 (m, 3H); 2.6 (q. 2H); . ., 2.9 (s, 3H); 3.1-4.8-lid-2-on-4-ylmethyl (1,7H); 5.0 (m, 1H); 5.22 (m, 1H); 5.35 (s. 2H); 7.5 (d. 2H); 8.2 (d. 2H).

1,3-dioxolan-4-yl-5.64 1 R 2 4 (m, 3H); 2.6 (m. 2H); (CH-Clp) 2.82 - 4.6 (cf7H); 4.9 2 2 (cl, 2H); 5.1 (m, 1H); 5.24 (d, 1H); 5.34 (s. 2H); 7.56 (d. 2H); 8.22 (d. 2H).

Example 7 p-Nitrobenzyl 2- (4-chloro-3-p-nitrobenzyloxycarbonyloxyethyl-2-oxo-1-azetidinyl-2- (1,3-dioxan-5-yloxothiocarbonyl) acetate_

Solution of 6.90 g of p-nitrobenzyl-2- (4-: 25-ethylthio-3-p-nitrobenzyloxycarbonyl-oxyethyl-2-oxo-1-azetidinyl) -2- (1,3-dioxan-5-yloxythiocarbo -yl) acetate in 110 mL of methylene chloride, cooled to -20 ° C under nitrogen. A solution of chlorine in carbon tetrachloride (98 ml of 0.1 M solution) was then added. The reaction mixture was stirred at -20 ° C for 75 min, then allowed to warm to 0 ° C and washed successively with 75 mL of saturated aqueous sodium bicarbonate solution (5 ° C), 75 mL of saturated aqueous sodium bicarbonate (5 ° C). ) and 75 ml of saturated aqueous sodium chloride solution.

The organic phase was dried over anhydrous sodium sulfate 35 and concentrated in vacuo to give 32 8 2 4 7 0 5.97 g of the crude title compound. The NMR spectrum in deuterochloroform shows adsorptions: 1.5 (d, 3H); 3.4 (m, 1H); 3.8 - 4.14 (c, 5H); 4.75 (s. 2H); 4.98-5.5 (c. 6H); 5.8 - 6.2 (c, 1H); 7.5 (m. 4H); 8.2 (m. 4H) ppm.

5 Example 8

Compounds of formula III wherein R is p-nitrobenzyloxycarbonyloxyethyl, R 5 is chlorine, R 2 is p-nitrobenzyl, and R 1 has the meanings shown in Table IV were prepared according to the procedure of Example 7. NMR spectra of these compounds were measured in deuterochloroform.

Table IV

NMR

15 - (PPm) -1-formyl-3-piperidyl-lr3 - 2.14 (c, 7H); 3.1 - 4.1 (IR (chloroform): 5.6 5.7 [mu] V, Z '* ΛΗ | and 5.97 microns) τ'ολ 7ί4 (mr4H); 7t94 (b, 1 H); 8.1 (m. 4H).

N-methoxy-2-propyl 1,1-1,6 (cr6H); 3.18 - 3.8 (c, 7 H); 4.9 - 5.4 (c, 6H); 5.96 (c, 1 H); 7.48 (m. 4H); 8.14 (m, 4H); 1,3-dioxolan-2-ylmethyl-1 * 5 (m, 3H); 3.5 - 4.0 (c, 5 H); ·· tvvli (c, 2H); 5.0 - 5.4 (c, 7 H); Δ 6.0 (c, 1 H); 7.5 (m. 4H); 8.2 (m, 4H) - [2-pyrrolidinon-3-yl] 1.5 (m, 3H); 2.5 (m. 2H); 3.3 (m. 2H); 3.7 (m, 1 H); 4.86 - 5.4 (3.7H); 6.0 (m, 1H); 7.48 (c. 5H); 8.18 (m. 4H).

2-piperidinon-5-yl (m, 3H); 1.9 - 2.94 (C, 4H); 3.3 - 3.94 (c, 3 H); 4.7 - 5.5 (c, 7 H); 5.9 (c, 1H); 6.6 (b, 1 H); 7.5 (m. 4H); 8.2 (m, 4H) 3-methyl-1,3-oxazo- (n, 3H); 2.92 (c, 3 H); 3.3 - 35 .... 0 ...... 5.4 (c, 12H); 5.9 (c, 1H); . 1H-2-on-4-ylmethyl 7β (m, 4H); 8.2 (m. 4H)

R1 NMR

(ppm) 33 82470 2-methoxyethyl lf5 (m, 3H); 3.32 (s) and b 3.13 3.4 (c, 4H); 3.62 (m. 2H); 3.96 - 4.6 (c, 3 H); 5.1 - 5.4 (c, 5 H); 6.0 (c, 1H); 7.5 (m. 4H); 8.16 (m, 4H) 1,3-dioxolan-4-ylmethyl 1,5 (d, 3H)? 3.5 - 4.52 (c, 6 H); 4.75 - 5.42 (c, 8H); 6.95 (c, 1 H); 7.5 (m. 4H); 8.2 (m. 4H)

Example 9 p-Nitrobenzyl 2- (4-chloro-2-oxo-1-azetidinyl) -2- (ethoxythiocarbonyl) acetate To a stirred solution of 214 mg of p-nitrobenzyl 2- (4-ethylthio-2- oxo-1-azetidinyl) -2- (ethoxythiocarbonyl) acetate in 20 ml of dichloromethane at about 0 ° C, 8.5 ml of a 0.1 M solution of chlorine in dichloromethane were added dropwise. Stirring was continued for 20 to 45 minutes at about 0 ° C. The reaction medium was then diluted with 30 ml of dichloromethane, and the resulting solution was washed successively with 40 ml of water, 40 ml of saturated aqueous sodium bicarbonate solution and 40 ml of water. The dried dichloromethane solution was evaporated in vacuo to give the title compound (387 mg). The IR spectrum (chloroform) of the product showed absorbances at 5.6 and 5.72 microns. NMR spectrum (deuterochloroform) showed adsorptions at: 1.4 (m, 3H); 3.0 - 3.8 (m. 2H); 4.3 (q. 3H); 5.32 and 5.35 (ss, 3H); 5.88 (m, 1H); 7.4 (d. 2H); and 8.2 (d. 2H).

34 8 2 4 7 0

Example 10

Chlorination of a suitable compound of formula VII wherein R is hydrogen, R 1 is as shown in Table V, R 2 is p-nitrobenzyl, R 4 is ethyl and i is zero using the method of Example 9 gave compounds of formula III wherein R 5 is chlorine, in Table V. In Table V, IR spectra were measured as solutions in chloroform, NMR spectra as solutions in deuterochloroform, unless otherwise indicated.

Table V

R-1 IR NMR

(microns) (ppm) 2-methoxyethyl 5.62 3.0-3.8 (m, 7H); 4.18 - 5.72 4.7 (m, 2H); 5.2, 5.22 and 5.25 (sss, 3H); 5.86 (m, 1H); 7.4 (d. 2H); 8.05 (d, 2H) 2-ethoxyethyl 5.6 1.25 (m, 3H); 3.0 - 3.94 - 5.7 (m, 6H); 4.25 - 4.86 (m, 2 H); 5.38 (m. 5H); 6.0 (m, 1 H); 7.6 (d. 2H); 8.25 (d, 2H) 2- (2-methoxyethoxy) 3.0-4.0 (m, 11H); 4.4 ethyl 5.7 (m, 2 H); 5.1 - 5.4 (m, 3 H); 6.0 (m, 1H); 7.6 (d. 2H); 8.22 (d, 2H) -1-phenoxyethyl 5.6 3.0 - 3.86 (m, 2H); 4.22 5.7 (unres. Comp. H); 4.4 - 5.0 (m, 2 H); 5.16, 5.22 5.26 (sss, 3 H); 5.94 (m, 1 H); 6.64 - 7.72 (m, 7H); 8.1 (m. 2H)

R IR NMR

__ __ 1 ____________ (ppm) - 35 82470 2-Phenylthioethyl - δ, 6 3r0 - 3 | 95 (m, 4H); 4.35 - 5.7 (m. 2H); 4.82 (sflH); 5f3 and 5.35 (s, 2H); 5.9 δ (m, 1 H); 7.12 - 7f7 (m, 7H); Δf 2 (d, 2H) 2-azidoethyl 4.76 3.0 - 3.8 (m, 4H); 4.2 - 516 δ 4.8 (m, 2 H); 5.18 - 5r5 (m, 3H); 5.9 (m, 1H); 7.42 (df 2 H); 8.17 (d, 2H) - 2- (acetamido) ethyl 5.58 2.02 (s, 3H); 2.98 - 5.7 3.98 (m, 4 H); 4.2 - 5.82 - 5.97 (m, 2H); 5.38 (m. 3H); (CH 2 Cl 2) 5.98 (m, 1H) y 7.1 (m, 1H); 7.6 (d. 2H); 8.24 (d, 2H) 2- (morpholino) ethyl 5.6 2.4 - 3.94 (n, 12H); 4.4 - 5.7 (m, 2 H); 5.3, 5.34 (s, 3 H); 6.0 (m, 1H); 7.58 (d. 2H); 8.2 (d, 2H) 2-phenylethyl 5.6 2.9-3.86 (m, 4H); 4.45 - 5.72 (m, 2H); 5.16 - 5.4 (m, 3 H); 5.9 (sflH); Δ 7.15 - 7.65 (m, 7 H); 8.2 (d. 2H): 2- (2-thienyl) ethyl 5.6 2.98-3.8 (m, 4H); 4.34 - 5.7 (m, 2 H); 5.18, 5.22 (s, 3 H); 5.9 (m, 1 H); 6.7 - 7.15 (m, 3H); 7.4 (d. 2H); 8.1 (d, 2H) 2- (2-pyridyl) ethyl 5.6 3.0 - 3.8 (m, 4H); 4.6 - 5.7 (m. 2H); 5.3 (m. 3H); 5.9 (m, 1H); 7.3-7.9 (m, 5 H) y 8.16 (d, 2 H); 8.52 (m, 1H) -2- (1-pyrazolyl) ethyl-5.64 3.0 to 3.6 (mf2H); 4.32 -,. 5.7 - 5.06 (m, 4H); 5.22 δ (m, 3 H); 5.88 (m, 1H); 6.2 (ni, 1H); 7.3 - 7.64 '(m, 4H); 8.18 (d. 2H)

R1 IR NMR

t _______ (microns) - (ppm) - 36 82470 2- (4-methyl-5-thiazo-5.6 2.34 - 3.62 (m, 7H); 4.7

lyl> ethyl V

7.5 (d. 2H); 8.2 (d. 2H); 8.7 (s, 1H) 2- (2-oxo-1-imidazole-5,6 3,0 to 3,9 (m, 8H); 4,66-dinyl) -ethyl] -6.22 (d, 2H) 2 - (2-oxo-1-pyrrolidine-5.58 1.7-3.8 (m, 10H); 4.64 n., Mp 5.67 (m, 2H); 5.36 (m, 3H) (ethyl) -ethyl 5.94 5.9 (m, 1H); 7.58 (d. 2H); 8.2 (d, 2H) 2- (2-thiazolylthio) 5.6 3.0 - 3.8 (m, 4H); 4.56 - 5.7 (m, 2 H); 5.35 (unres. Comp. 3H); 6.0 eW11 (m, 1 H); 7 46 - 7.84 '(m, 4H 1; 8.3 (d, 2H) 2-methoxycyclopentyl 5.6 1.4 - 2.0 (m, 6H); 3.0 - 5.72 4.0 (m , 3H), 3.2 (s, 3H), 5.0 (m, 1H), 5.4 (s, 2H), 6.0 (m, 1H), 7.5 (d, 2H), 8.2 (d, 2H), ) • 2-methoxycyclohexyl 5.58 1.0 to 1.8 (m, 8H); 3.0 to 5.7 3.8 (m, 3H); 3.3 (s, 3H); 4.8 (m , 1H), 5.4 (s, 2H), 6.0 (m, 1H), 7.6 (d, 2H), 8.2 (d, 2H), 2-azidocyclohexyl 4.76, 1.4-2.2 (m , 8H), 3.0 - 5.6, 3.8 (m, 3H), 5.4 (m, 3H), 5.7, 6.0 (m, 1H), 7.6 (d, 2H), 8.2 (d, 2H) 2-azidocyclopentyl 4.76 1.4 - 2.0 (m, 6H), 3.0 - 5.6 4.0 (m, 3H), 5.3 (m, 3H), 5.7 6.0 (m (1H) -7.6 (d, 2H), 8.2 (d, 2H) -3-tetrahydrofuranyl 5.58 2.0 - 2.4 (m, 2H), 3.0 - 5.67 3.8 (m, 2H) ), 3.8 - 4.2 1 (m, 4H), 5.4 (m, 3H), 6.0 (m, 1H), 7.6 (d, 2H), 8.2 (d, 2H), ) 1 'I! 37 82470

R, IR NMR

1 __ (microns) __ (ppm) -1-acetyl-3-pyrrolidine-η 5 -1,4 (1,4, m); 2T3 mp 5.7 (s, 3H); 3.0 - 4.0 (m. 6H); YY 5.3 (m, 3K); 6.0 (m, 1H); 5,715 (d. 2H); 8.2 (d, 2H) -1-acetyl-3-piperidine-1.5t 2.2-2.2 (m, 4H); 2f3,. 5.7 (<3.3H); 3.0 - 4.2 η ^ γΐ1 (m, 6H); 5.0 (m, 1H)? 5.4 (s. 2H); 6.0 (m, 1 H); 7.6 (d. 2H); 8.2 (d, 2H) 10 2-tetrahydrofuranyl-δ, 6 ', 2.2 (m, 4H); 3.0 - Y 5.8 3.8 (m, 5H); 4.2 (s. 2H); methyl 5f4 (s, 2H), · 6.0 (m, 1H); 7.5 (d. 2H); 8.2 (d, 2H) 2-tetrahydropyranyl-, 3'-methyl (m, 3H); 6.0 (m, 1H); 7.57 (d. 2H); 8.22 (d, 2H) 1-acetyl-2-pyrrolidine-5.6 1.76-2.58 (m, 7H) 3.0-5.7 3.84 (m, 4H); 3.96-4.7 ylylmethyl (m, 3H); 5.3 (m. 3H); 5.9 (m, 1 H); 7.58 (d. 2H); 8.25 δ (d, 2H) • 2- (2-pyridinoylamino) -5-56 3.80-4.1 (c, 4H); ethyl δ δ 4.3 - 4.95 (m, 2H); ethyl 5.36 (m, 3H); 6.0 (m, 1H); 7.35 - 8.8 (c. 9H).

95 1-formyl-3-piperidyl-5,6,5-2,3 (c, 4H); 5.72 2.8 - 4.2 (C, 6H); (CHCl 3, 4.6-6.07 (c, 5H)); 7.56 (m, 2H); 82-8.34 (c, 3H).

N-methylaminocarbo- |, «6 | j || | Jl «I

Nylmethyl * 5.42 (c, 5H); Δ * 0 (m, 1 H); 7.6 (c. 3H); Δ 24 (d, 2H).

38 82 470

r IR NMR

-1-LEE !!) - 1- (aminocarbonyl) -5.6 1.6 (d, 3H); 3.1 - ,,. 5.9 319 (m. 2H); 4.83 - YY (CH 2 Cl 2) 5.52 (c, 4H); 5.82 (m, 1H); 6.3 (b, 1H); 7.5 (c. 3H); 8.2 (d. 2H).

2- (methoxymethyl-5.62 2.92-4.8 (c, 11H); carbonylamino) ethyl. * 1 \ 5, Λ! ? 7 6J °,]? 7) 2 (bf1H); 7.6 (d, 2H); 8.3 (d. 2H).

2- (aminocarbonyloxy) -5.6 3.2-5.2 (c, 8F); 5.3 ethanol 5.78 (unres. Comp. 3H); 5.9 (m, 1H); 7.55 YY (m. 2H); 8.2 (d, 2H).

5.58 2.9 - 3.84 (c, 12H) including 3.34 (s, 6H); 1,3-dimethoxy-2-pro-5.3 (m, 3H); 5.68 - 6.18 (c, 2 H); }, 6 PYYl1 (α, 2H)? Δ .26 (d, 2H).

2- (2-furylcarbonyl-5.57 3.0 to 4.04 (c, 4H), 6.0 4.5 (m, 2H), 5.4 (m, 3H), amino) ethyl (CH 2 Cl 2) 5, 98 (m, 1H); 6.5 (m # 1H); 7.16 (d, 1H); 7.6 (c. 4H); Δ F25 (m, 2 H).

1,3-dioxan-5-yl 5.6 3.0 - 4.3 (c, 6H); 4.63 - 5.42 (c, 5K); 6.0 (c, 1 H); 7.5 (m. 2H); Δ 18 (d, 2H).

: · 1-methyl-2-piperidine-5.62 1.7-2.34 (c, 4H); 6.02 2.84 and 2.94 (s, 3 H); ηοπ-3-yl 3.0 to 3.64f (c, 4H); 4.8 - 5.5 (c, 4 H); 5.9 (m, 1 H); 7.6 (m, 2 H); 8.2 (unres. Comp. H).

1- (aminocarbonylmethyl-5.6 1.72-2.4 (c, 4H); style) -2-piperidinone-3'-yl 5.94 (m, 1H); 7.1 (b. 2H); - 7.52 (m. 2H); 8.18 (d. 2H); iT

R IR NMR

____ (ppm) - 39 82470 2- (2-acetylamino-5.62 2.06 (s, 3H); 3.0-4.0% .6.6 r (c, 8H); 4.4 (m (2H) y ethoxy) -ethyl (CH 2 Cl 2) 5.3 (m, 3H); 6.0 (m, 1H); b 6.25 (b, 1H); 7.54 (d. 2H); 8.22 (d. 2H); 2-piperidinon-3-yl 5.6 1.6-2.4 (c, 4H); 5.98 - 2.9 - 3.9 (c, 4H); (CH 2 Cl 2) 4.76-5.4 (c, 4H); 5.9 (m, 1 H); 6.8 (b, 1H); Δ 7.54 (d, 2 H); 8.2 (d. 2H).

2-pyrrolidinon-3-yl-6,6 - [(1,9H); 5.85 - 4.9 - 5.5 (c, 4H); (CHCl 3) 5.9 (m, 1H); 7.45 (c. 3H); 8.1 (d. 2H).

is 2-piperidinon-5-yl 1.85-2.6 (c, 4H); 1 6.0 3.0 - 3 »8 (c, 5H); 5.3 (m. 3H); 5.82 (m, 1H); 6.6 (b, 1 H); 7.54 (d. 2H); 8.25 (d. 2H); 3-methyl-1,3-oxazo-5.6 2.9 (m, 3H); 3.15 - 4.84 •,. J 0 6 ° (c, 7H); 5.34 (m. 3H); 20 1 id-2-on-4-ylmethyl 5.9 (m # 1Hj; η 6 (d, 2H); style 8.25 (d, 2H).

1,3-dioxolan-4-yl-5.6 3.0-4.4 (c, 7H); • i (CH 2 Cl 2) 4.86 (df 2 H); 5.3 (m. 3H); .:. methyl 5.9 (56, d, 2H); : 8.2 (d, 2H).

40 82470

Example 11 p-Nitrobenzyl 6-p-nitrobenzyloxycarbonyloxy-2- (1,3-dioxan-5-yloxy) -2-penem-3-carboxylate, cis and trans isomers ____ 5 A solution of 6.75 g of p -Nitrobenzyl 2- (4-chloro-3-p-nitrobenzyloxycarbonyloxyethyl-2-oxo-1-azetidinyl) -2- (1,3-dioxan-5-yloxythiocarbonyl) acetate and 17.0 ml diisopropylethylamine 30 ml in methylene chloride, was stirred at 25 ° C under nitrogen for 3 hours. The reaction mixture was diluted with 150 ml of methylene chloride, and the resulting solution was washed successively with two 150 ml portions of 1N aqueous hydrochloric acid, 150 ml of water and 150 ml of saturated aqueous sodium chloride solution. The methylene chloride phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The coarse mixture of penems was purified by column chromatography on silica gel. Elution with 15% ethyl acetate in diethyl ether gave 1.25 g of the title cis compound and 480 mg of the title trans compound.

The NMR spectrum of the title cis compound in deuterochloroform showed peaks at: 1.6 (d, 3H); 3.9-4.3 δ (c, 6H); 4.84 (s, 2H); 5.0-5.4 (c. 5H); 5.76 (d, 1H); 7.55 (m. 4H); and 8.22 (m, 4 H). NMR spectra of the title trans compound in deuterochloroform showed peaks at: 1.5 (d, 3H); 3.8-25: 4/38 (c, 6H); 4.84 (s. 2H); 5.0-5.5 (c. 5H); 5.62 (d, 1H); 7.6 (m. 4H); and 8.2 (m. 4H).

Example 12

The procedure of Example 11 was applied to the corresponding 4-chloroazetidinyl acetates of formula III to give the cis and trans isomers of the compounds of formula I listed in Table VI wherein R is p-nitrobenzyloxycarbonyloxyethyl, R 1 is as indicated in Table VI and R 2 is p -nitrobentsyyli. NMR spectra were measured in deuterochloroform.

Il 4i 82470

Table VI

NMR (ppm) δ 1-formyl-3-piperidyl (trans) 1.3-2.2 (c, 7H); 2.94 - (IR (chloroform): 5.64, 5.70, 5.97 microns (m, 4H); 7.9 (b, 1H); 8 * 13 (mf4H) (cis) (IR (chloroform) 5.58 , 5.71, “2r2 (c» 7H); 3.0 3, 30, 3, 4, 4.46 (c, 5H), 4.64 - 5r45, 5.97 microns (c, 6H); m, 1H), 7.52 (m, 4H), 7.96 (b, 1H), 8.2 (m, 4H) 1,3-dioxolan-4-ylmethyl 1.5 (d, 3H), 3.6 - 4t 4, (c, 6H), 4.95 (d) and 4.7 - (trans) 5.4 (c, 7H), 5.6 (d, 1H), 7.5 (m, 4H) ), 8.18 (m, 4H) (cis), 1.6 (d, 3H), 3.68 - 4.45 (c, 6H), 4.95 (d, 2H), 5.05 - 5.4 ( c, 5H), 5.74 (d, 1H), 7.5 (m, 4H), 8.2 (m, 4H) 1-methoxy-2-propyl (trans) 1.2-1.6 (c, 6H ), 3.35 δ (s, 3H), 3.5 (d, 2H), 3.9 (m, 1H), 4.2 (b, C, 1H), 49-5.4 (c, 5H), 5.6 (d, 1H), 7.54 (m, 4H), 8.18 (m, 4H) (cis) 114-1.7 (c, 6H), 3.36 (s, 3H) 3.5 (d, 2H), 4.1 (m, 1H), 4.3 (b, c, 1H), 5.0-5.4 '(cf5H), 5.7 (d, 1H), 7.54 (m , 4H), 8.2 (m, 4H, 1,3-dioxolan-2-ylmethyl 1,5 (d, 3H); 3.8-4.12 (trans) (c, 5H); 4.2 ( α, 2H), δt-30 (trans, δ4.4 (Cf6A), 5.62 (d, 1H), 7.56 (m, 4H), δf2 (m, 4H)) 4282470_ NMR (ppm) ( cis) 1.6 (d, 3H), 3.8-4.12 (c, 5H), 4.2 (d, 2H), 5.0 - 5.5 (c. 6H); 5.75 (d, 1H); 7.52 (m. 4H); 8.2 (m, 4H) 2-pyrrolidinon-3-yl [5 (d, 3H); 2.5 (m. 2H); 3.36 (m. 2H); 3.92 (m, 1H); 4.7 (m, 1 H); 4.5 - 5.4 (C, 5H); 5.54 - 5.65 (d, 1H); 7.1 (b. 1H); 7.52 (m. 4H); 8.18 (m, 4 H) δ (cis); 1.6 (d, 3 H); 2.44 (m. 2H); 3.34 (m. 2H); 4.06 (m, 1H); 4.72 (m, 1H); 4.9 - 5.4 (c, 5H); 7.5 (m. 4H); 8.18 (m, 4H) -2-piperidinon-5-yl 1.5 (d, 3H); 1.86 - 2.68 (c, 4H); 3.56 (c. 2H); 3.86 (m, 1H); 4.56 (c, 1H); 5.0 - 5.32 (c, 5H); 5.6 (d, 1H); 6.6 (b, 1 H); 7.48 (m. 4H); 8.2 (m. 4H) (cis); 1.6 (d, 3H); 1.9 - 2.68 - (c, 4H); 3.6 (C, 2 H); 4.1 2U (m. 1H); 4.62 (c, 1H); 4.9 - 5.46 (c, 5H); 5.76 (d, 1 H); 7.0 (b, 1H); δ.5 (m, 4H); 8.2 (m, 4H) 3-methyl-1,3-oxazolidine-2-1.48 (d, 3H); 2.9 (s. 3H); 3.76 - 4.46 (c, 6H); 4.95-25-on-4-ylmethyl 5.36 (C, 5H); 5.62 (d, 1H); 7.52 (m. 4H); 8.2 (m. 4H) (Cis) 158 (d, 3H); 2.9 (s. 3H); 3.8 - 4.44 (c, 6H); 4.94 - 5.30 (c, 5H); 5.74 (d, 1H); 7.5 (m. 4H); 8.18 (m, 4H) 2-methoxyethyl 1.48 (d, 3H); 3.36 (s. 3H); 3.62 (m. 2H); 3.86 (m, 1H); 4.3 (m. 2H); 5.0 - 5.36 (c, 5H); 5.56 (d, 1H); 7.46 (m. 4H); 8.16 (m, 4 H) (cis); 1.6 (d, 3 H); 3.36 (s. 3H); Δ 3.64 (m, 2 H); 3.9-4.4 (c. 3H); 5.1 - 5.36 (c, 5H); 5.7 (d, 1 H); 7.5 (m. 4H); 8.18 (m. 4H)

II

43 82470

Example 13 p-Nitrobenzyl 6-p-nitrobenzyloxycarbonyloxyethyl 2- (1,3-dioxan-5-yloxy) -2-penem-3-carboxylate, trans isomer 5 A solution of 960 mg of p-nitrobenzyl 6-p-Nitrobenzyloxycarbonyloxyethyl 2- (1,3-dioxan-5-yloxy) -2-penem-3-carboxylate, cis isomer, 96 mg hydroquinone and 150 ml toluene were refluxed under nitrogen for 90 min. The reaction mixture was cooled to 25 ° C and concentrated in vacuo. The residue was dissolved in 100 ml of ethyl acetate, and the resulting solution was washed successively with two 100 ml portions of 1N sodium hydroxide solution, 100 ml of water and 10 ml of saturated aqueous sodium chloride solution. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel. Elution with 15% ethyl acetate-diethyl ether gave 425 mg of the cis-penem starting material and 300 mg of the title compound.

Example 14 p-Nitrobenzyl 2-ethoxy-2-penem-3-carboxylate

To a solution of 387 mg of p-nitrobenzyl-2-. . (4-chloro-2-oxo-1-azetidinyl) -2- (ethoxythiocarbonyl) acetate in 20 ml of dichloromethane, 1.74 ml of diisopropylethylamine were added. The reaction mixture was stirred overnight at room temperature and then diluted with 30 mL of dichloromethane. The resulting solution was washed successively with 40 ml of dilute hydrochloric acid (2 times) and 40 ml of water (2 times), and then dried using anhydrous sodium sulfate. Evaporation in vacuo gave the title compound as a yellow viscous liquid. This crude product was purified by column chromatography on 35 g of silica gel, eluting with 95: 5 chloroform-ethyl acetate. The product-containing fractions were combined and evaporated in vacuo to give the title compound as a solid (yield: 100 mg). The IR spectrum of the product in chloroform gave absorbances at 5.6 and 5.88 microns.

44 82470 NMR spectrum in deuterochloroform gave adsorptions at: 1.45 (t, 3H); 3.21-4.1 (m. 2H); 4.25 (g. 2H); 5.25 (d. 2H); 5.6 (m, 1H); 7.5 (d, 2H) and 8.1 (d, 2H) ppm.

Example 15 Ring formation of a suitable compound of formula III wherein R is hydrogen, R 1 is as shown in Table VII, R 2 is p-nitrobenzyl and R 5 is chlorine, with diisopropylethylamine, essentially according to the method of Example 14 gave the corresponding compounds of formula I compounds in Table VII. For the compounds in Table VII, NMR spectra were measured in deuterochloroform unless otherwise specified, IR spectra were measured in the indicated medium.

Table VII

15 1 H NMR

microns (ppm) 2-methoxyethyl 5.57 3.25-4.0 (m, 7H); 4.3 - 5.88 (t, 2 H); 5.3 (d. 2H); 5.65, q (CHCl 3) (m, 1H); 7.54 (d. 2H); 8.2 (d, 2H) -1-ethoxyethyl 5.58 1.16 (t, 3H); 3.2 - 4.03 - 5.88 (m, 6H); 4.32 (m. 2H); 5.3 (CHCl 3) (d, 2H); 5.62 (M, 1H); Δ J 58 (d, 2 H); 8.2 (d, 2H) 2 O 2- (2-methoxy) -5.6 3.22-4.1 (m, 11H); 4.36 ethoxy) ethyl c * eo (m, 2H); Δ 32 (d, 2H); 5.68 - 5.88 (m, 1 H); 7-6 (d. 2H); 8.2 (d, 2H) 2-phenoxyethyl 5.57 3 ^ 2 - 4.0 (m, 2H); 4.25 - 5.88 (m, 2 H); 4.55 (m. 2H); 5.3 (CHCl 3) (d, 2H); 5.7 (m, 1H); 6.75 - 7.42 (m, 5H); 7.5 (d. 2H); 8.1 (d, 2H) + <5 82470

R1 IE NMR

____ microns_ (ppm) - 2- (phenylthio) ethyl 5.57 3.2 - 4.0 (m, 6H); 5.3 - 5.88 (d. 2H); 5.65 (m, 1H); (CH, C 15) 7.1 - 7.7 (m, 7H); 8.2 δ (d, 2H) 2- (azido) ethyl 4.76 3.25-4.06 (m, 4H); 4.3 - 5.56 (t, 2 H); 5.3 (d. 2H); 5.68 5.88 (m, 1H); 7.55 (d. 2H); 8.2 (CHCl 3) (d, 2H) 2- (acetamido) ethyl 5.58 1.95 (s, 3H); 3.22 - 4.4 δ 5.88 (m, 6H); 5.3 (d. 2H); 5.65 - 6.0 (m, 1 H); 6.6 (m / 1H); 7.6 (CHCl 3) (d, 2H); 8.26 (d, 2H) 2-phenylethyl 5.58 2.3-3.0 (m, 6H); 3.16 - 5.88 4.1 (m, 6H); 4.34 (t, 2 H); (CHCl 2) 5.3 (d, 2H)? 5.66 (m, 1H); Δ 7.6 (d. 2H); 7.8 (d, 2H) 2- (2-thienyl) 5.58 3.15-4.05 (m, 4H); 4.45 ethyl 5.88 (t, 2 H); 5.36 (d. 2H); 5.68 (CH 2 Cl 2) (m / 1H); 7.14 - 7.62 (m, 7H); 8.25 (d, 2H) 2- (2-pyridyl) 5.58 3.0-4.1 (unres. 4H); 4.36 ethanol 5.86 (t, 3H); 5.3 (d. 2H); 5.6 ** (CHCl 3) (m, 1H); 6.74 - 7.3 (m, 3R); 7.5 (d. 2H); 8.14 (d, 2H) 2- (1-pyrazolyl) 5.58 3.1-4.06 (unres. Comp. 4H); 4.66 - 5.88 (t, 2 H); 5.3 (df2H); 5.68 ethyl (CHCl 3) (m, 1H); 7.04 - 7.82 (n, 5H); 8.26 (d, 1H); 8.62 (m, 1H) 2- (4-methyl-5 - 5.58 3.2 - 4.04 (m, 2H) - 4.54 ... 5.88 (m, 4H), 5.32 (d, 2H), 5.62 thiazolyl) ethyl (CH 2 Cl 2) (m, 1H); 6.25 (n, 1H); Δ 2 - 7.7 (m, 4H); 8.2 (d. 2H); 5.57 2.42 (s, 3H); 3.06 - 4.08 δ 87 (m, 3H); 4.38 (t, 2 H); 5.32 (CH 2 Cl 2) (d, 2H); 5.65 (m, 1H); 7.6 (d. 2H); 8.2 (d. 2H); Δ 6 (s, 1H) 46 82 470

R1 IR NMR

______ microns (ppm) - 2- (2-oxo-1-imidazo-5.58 3.04 - 3.8 (m, 8H); 4 | 28,..., 5.88 (m, 2 H) 5.24 (d, 2H), 5.6 lidinyl) ethyl (CHCl 3, (ra, 1H), 7.5 <d, 2H); 8.1 δ (d, 2H) 2- (2-oxo-1-pyrrolidine-5R 58,7 - 2,6 (m, 4H); 3,3-ynyl) -ethyl 5f98 4, 5, 34 (d, 2H); methyl (CHCl 3, 5.7 (m, 1H); 7.62 (d, 2H); 8.26 (d, 2H) 2- (2-thiazolylthio) 5.58 3.35-4.1 ( m, 4K), 4.5 δ 5.88 (t, 2H), 5.26 (s, 2H), 5.72 ethyl (CHCl 3) (m, 1H), 7.46 - 7.8 (m, 4H), 8.2 (d, 2H) (DMSO-d 6) 2-methoxycyclopentyl-5.58 1.4-2.0 (m, 6H), 3.3, 5.88 (s, 3H); 2.8 - 4.0 (m, 2 H); 11 (CHCl 3) 3.7-4.1 (m, 1H); 4.5 δ (m, 1 H); Δ <3 (s, 2 H); 5.7 (m, 1H); 7.6 (d. 2H); 8.2 (d, 2H) 12-methoxycyclohex-5.60 1.2 - 2.0 (m, 8H); 2.8 - ςνν-Η 5.85 4.0 (m, 2H); 3.4 (s. 3H); γ (CHCl 3) 3.8 - 4.2 (m, 2H); 5.39n (d. 2H); 5.6 (s, 1H); 7.6 (d. 2H); Δ R 2 (d, 2H) 2-azidocyclohexyl4.76 1.2-2.0 (m, 8H); 3.0 - 5.65 - 4.0 (m, 4H); 5.3 (d. 2H); 5.85 5.7 (q, 1H); 7.6 (d. 2H); (CHCl 3) 8.2 (d, 2H) • 2-azidocyclopentyl-4.75 1.4 -2.0 (m, 6H); 2.9 - 5.65 - 4.0 (m, 3H); 4.3 (m, 1H); Δ 5.85 5.2 (d. 2H); 5.6 (q, 1H); (CHCl 3) 7.5 (d, 2H); 8.2 (d, 2H) 2-tetrahydrofuran-5.58 2.0-2.4 (m, 2H); 2.9-yl-183 ° C (m, 2K); 3.4-4.1 yY (CHCl3) (m, 4H); 4.9 (m, 1H); 5.3 (d. 2H); 5.7 (q, 1H); 7.6 (d. 2H); 8.3 (d. 2H)

R, IR NKR

__micron_ (ppm) -1-acetyl-3 - δt58 1.2 - 1.6 (m, 2H); 2.0 ..,. ,. 5.85 (s. 3H); 3.4 - 4.0 (m. 4H); pyrrolidinyl (CHCl 3) 5.0 (m, 1H); 5,4 \ d, 2H); Δ 5.7 (m, 1 H); 7.6 (d. 2H); 8.2 (d, 2H) -1-acetyl-3 - 5.58 1γ2 ~ 2.0 (m, 4H); 2.0 piperidinyl 5.85 (s, 3H); 3.0 - 4.4 (m. 7H); (CHCl 3) 5.3 (s, 2H); 5.7 (s, 1H); 7.6 (d. 2H); 8.2 (d, 2H) δ 2-tetrahydrofuranyl- 5.60 1.8 - 2.1 (m, 4H); 2.9 - lymethyl 5.86 4.0 (m, 2 H); 3.8-4.1 (CHCl 2) (m, 3H); 4.2 (s. 2H); 5.3 (d. 2H); 5.6 (q, 1 H); 7.6 (d. 2H); 8.2 (d, 2H) 2-tetrahydropyranyl-5.58 1.14 - 1.96 (m, 6H); 3.16-15 lymethyl 5.88 4.28 (m, 7H); 5.3 (d. 2H);

Yy (CHCl2) 5.68 (m, 1H); 7 ^ 6 (d, 2K); 8.2 (d, 2H) 1-acetyl-2-pyrrole-5.58 1.7-2.3 (m, 7H); 3.22 - dinylmethyl 5.88 4.02 (m, 4H); 4.02 - 4.52 (CHCl 3) (m, 3H); 5.34 (d. 2H); $ 688 (m, 1H}; 7.6 (d, 2H); 8.22 (d, 2H) 1- (2-pyridinoylamino-5.57 3.23-4.6 (c, 6H); 5.4 5.85 (d, 2H), 5.62 (m, 1H); no) ethyl 6C, 7.25-8.7 (c, 9H) (c 2 Cl 2) -1-formyl-3-piperidine-1.08 - 2.3 (c, 4H), 3.04 - ....... .., 4.44 (c, 7H), 5.3 (d, 2H), dyl (less polar (1H); 7.54 (d, 2H); diastereomer); 7.9 3 (d, 1H); 8, 14 (d, 2H) (more polar diastereo-). (c, 7H); 5.3 (s, 2H); 30 mers) 5.7 (m, 1H); 7.58 (d, 2H); 7.96 (s, 1H); 8.2 (d , 2H) 48 82470

R IR NMR

_1__ (ppm) -N-methylamino-5.56 2f8 (d, 3H); 3.3-3.84 carbonylmethyl 5.84 (m, 2H); 4.6 (s. 2H); 5.32 - 5.92 (d, 2H); 5.7 (m, 1H); 7-62 δ 5.97 (c, 3H); 8.2 (d, 2H) (CHCl 3) 1- (aminocarbonyl) -5.56 1.46 (d, 3H); 3.12 ~ 4.08 5.85 (m, 2 H); 4.68 (q, 1H); 5.34 and YY 5.95 (d, 2H); 5.72 (m, 1H); 7.5 (CHCl 3) (b, 2H); 7.7 (d. 2H); 8.26 1Q (d, 2H) (DMSO-d 6) 2- (methoxymethyl-5.58 3.45 (ε> 3Η); 3.5-4.1 (c) carbonylamino) 5.96 and 3.95 (s , 2H) (size 6H); (CH-C12) 4.35 (t, 2H); 5.4 (d. 2H); ethyl 5.7 (c, 1H); 7.15 (b, 1H); 7f64 (d. 2H); 8.26 (d, 2H) 2 O 2- (aminocarbonyl) 5.58 3.2-4.5 (c, 6H); 5.25 - 5.78 (m, 2H); 5.64 (m, 1H); ethyl 5.88 6.25 (b, 2 H); 7.5 (d, 2 F); (CEC 13) 8.1 (d, 2H) 1,3-dimethoxy-2- 5.57 3.34 (s, 6H); 3.3-4γ2 and 5.84 (c, 6H); 4.4 (m / H); 5.26 propyl (CHCl 3) (d, 2H); 5.6 (m, 1H); 7 * 54 (d. 2H); 8.14 (d, 2H) 2- (2-furylcarbo- 5.56 3.2-4.5 (c, 6H); 5.3 5.84 (d, 2H); 5.6 (m, 1H); 6.42 nylamino) ethyl 6f0 (m, 1H); 7.0 (m, 1K); 7.05 (CHCl 3) (d, 1H); 7.36 (m, 1H); 7.54 (d. 2H); 8.15 (d, 2H) 25 ', 1,3-dioxan-5-yl 5.57 3.23-4.37 (c, 7H); 4.8 5.88 (s, 2H); 5.29 (d. 2H); 5.64 (CHCl 3) (m, 1H); 7.57 (d. 2H); 8.14 (d, 2H) -1-methyl-2-piperidine-5.57 1.7-2.4 (c, 4H); 2.94 94, δ 5.88 (s, 3H); 3.18 - 3.8 (c, 4 H); non-3-yl 6f0 4.56 (m, 1H); 5.3 (d, 2 H); (CKCl 3) 5.65 (m, 1H); 7.6 (d. 2H); 8.2 (d. 2H)

It 49 82470

R IR NMR

.......... microns_ _ (PP "0_ 1- (aminocarbonylmethyl-7 - 2,4 (c, 4H); 3,1 - ... 0.,. 1 (c, 6H) - 4,6 (m, 1H) -ethyl) -2-piperidmon-6 -? - 5.26 (m # 2H) - 5.6 (m, 1H); 3-yl (CHCl3) 6, 1 (b / 1H), 6.5 (b, 1H), δ 7.5 (d, 2H), 8r2 (d, 2H) 2- (2-acetylamino-5.56 1.9 (s, 3H) ; 3.1-4.1 ethoxy) ethyl 5'88 <C'8H> '' 4.3 (m, 2H); 5.62 ethoxyS ethyl 6.0 (m, 1H); 7.1 (b, 1H); 5.24 (CHCl 3) (m, 2H); 7.54 (d, 2H); 6.12 (d, 2H) 2-piperidinone-3 - 5.57 1.6 - 2.4 (c, 4H); 3.0-3.1, 5.88 (c, 4H), 4.54 (m, 1H), 5.28 and 5.98 (m, 2H), 5.7 (m, 1H) 7.6 (CHCl 3) (d, 2H), 7.85 (b, 1H), 8.2 (d, 2H) 2-pyrrolidinone - 5.55 2.02 (m, 2H), 3.06 - 4.06 3-m / z 5.85 (c, 4H), 4.86 (m, 1H), 5.3 yY 5.9 (d, 2H), 5.74 (m, 1H), (CHCl3) 7, Δ (b, 1H J; 7.64 (d, 2H); 8.22 (d, 2H) (DMSO-d 6) 2-piperidinone-5 - 5.57 1.9 - 2.3 (c, 4H); , 22 - 5.85 4.14 (c, 5H), 5.25 (S, 2H), 6.0 5.74 (m, 1H), 7.4 (b, 1H), (CHCl 3) 7.6 (d, 2H), 8.2 (d, 2H) 3-methyl-1,3-oxa-5.57 2.9 (s, 3H), 3.24-4.5, 5.7 (c, 7H), 5.2 (d, 2H), 5.6 solid-2-on-4-yl-5.88 (m, 1H)? Δ 45 (d, 2 H); 8.1 methyl (CHCl 3) (d, 2H) δ 1,3-dioxolan-4- 5.57 3.2-4.5 (c, 7H); 4.9,. . . . 5.88 (d. 2H); 5.26 (d, 2H) · ylmethyl (CHCl 3) 5.64 (m, 1H); 7.58 (d. 2H); 8.2 (d. 2H).

50 82 470

Example 16 2-Ethoxy-2-penem-3-carboxylic acid, calcium salt

A suspension of 140 mg of 5% palladium on calcium carbonate in 10 ml of water was shaken under a hydrogen-5 atmosphere at a pressure of about 50 psi (about 380 kPa) until the evolution of hydrogen ceased. A solution of 140 mg of p-nitrobenzyl 2-ethoxy-2-penem-3-carboxylate in 10 ml of tetrahydrofuran was added and this mixture was shaken under a hydrogen atmosphere at about 55 psi for 1 hour. The catalyst was then removed by filtration and the tetrahydrofuran was removed from the filtrate by evaporation in vacuo. The resulting aqueous solution was washed with ethyl acetate, and then lyophilized to give the title compound as an amorphous solid of 50 mg. The IR spectrum (potassium bromide tablet) showed absorption at 5.7 microns. The NMR spectrum (deuterochloroform) showed peaks at: 1.4 (t, 3H); 3.2-4.4 (m. 4H); and 5.58 (m, 1H) ppm.

Example 17

Hydrogenation of compounds of formula I wherein R 20 is hydrogen, R 2 is as shown in Table VII and R 2 is p-nitrobenzyl, according to the procedure of Example 13, gave compounds of formula I wherein R 2 is calcium ion as shown in Table VIII. IR and NMR spectra were measured in the indicated medium.

25 Table VIII

R-1 IR NMR

____ (microns) _ (ppm) _ 2-methoxyethyl 5.7 3.25 (s, 3H); 3.2 - 4.1 (KBr tablet) (m, 4H); 4.2 (m. 2H); 5y5 (m, 1H) (DMSO-dg) 2-ethoxyethyl 5.65 1.1 (t, 3H); 3.2-3.88 (KBr tablet) (m, 6H); 4.22 (m. 2H); 5.56 (m, 1H) (DMSO-d 6) of 51 82470

E IR NMR

1 (microns) - (ppm) - 2- (2-methoxyethoxy) - 5.65 3.16 - 3.86 (m, 11H); 4-22. ,. (CHCl 3) (m, 2H); 5.56 (m, 1H) ethyl] 3 (DMSO-d-) 156-phenoxyethyl 5f75 3.2-4.0 (m, 2H); 4.2 (KBr-tablet) (m, 2H), 4.42 (m, 2H), 5.54 (m, 1H), 6.76 (m, 5H) (DMSO-d 6) 2- (phenylthio) δ , Δ 3.14 - 3.9 (m, 4H), 4.22 ln (KBr-tabl) (m # 2H), 5.52 (m, 1H), 7.04 ethyl 1 - 7.56 (m, 5H) (DMSO-d 6) 2-azidoethyl 4.75 3.3-3.98 (m, 4H), 4.3 5.7 (m, 2H), 5.66 (m, 1H) (KBr- tabl.) (DMSO-d 6) '2- (acetamido) 5.65 1.82 (s, 3H); 3.18-4.11 P + -w14 6.10 (m, 6H); 5.56 ( m # 1H); 9.0 yy (KBr-tablet) (m, 1H) (DMSO-d6) 2- (morpholino) 5.65 2.32-2.7 (m, 6H); 3.26 - ethyl (CHCl 3) 3.98 (m, 6H), 4.22 (m, 2H), 5.62 (m, 1H) (DMSO-d 6) 2 2-phenylethyl 5.75 2.98 (m, 2H); 3.3 - 4.0 (KBr_tabl.) (M, 2H), 4.3 (m, 2H), 5.58 (m, 1H), 7.3 (s, 5H) (DMSO-d 6) 2- (2 -thienyl) 5.75 3; 1-3.88 (m, 4H); 4.3 ethyl (KBr tablet) (m, 2K); 5.54 (m, 1H); ethyl 6.94 (n , f2H), 7.34 (m, 1H) (DMSO-d6) 2- (2-pyridyl) 5.75 3.02 - 3.92 (m, 2H), 4.46 o.vvl1 (KBr tablet) .) (m, 2H), 5.54 (m, 1H), 7.14 YY - 7.44 (m, 2H), 7.7 (m, 1H), 8.5 (m, 1H), (DMSO-d 6) 2- (1-pyrazolyl) 5.65 3.1-3.9 (m, 2H), 4.46 ethyl (KBr tablet) (m, 4H), 5.54 (m / H), 6.23 (m , 1H); 7, 48 (m, 1H); 7.8 (m, 1 H) (DMSO-d 6) 52 82,470

R IR NMR

__ (microns) - (ppm) - 2- (4-methyl-5-thiazo-5.65 2.36 (s, 3H); 2.96-4.0 g) -btyl (KBr-tabl (m, 4H), 4.3 (m, 2H), 5.56 yy eryyn (m, 1H), 8.8 (s, 1H) δ (DMSO-d 6) 2- (2-oxo-1-imidazole-5.75 2 | 96 - 3.8 (m, 8H), 4.14 dinyl (i, ethyl) (KBr - tablet) (m, 2H), -> 58 (m, 1H) (DMSO-d 6) 2- (2-oxo-1-pyrro-5.65 1.6-2.46 (m, 4K); lidinyl (KBr_tabl ·. 3.0-4.44 (mr8H); 5.56 10 (πι, ΙΗ) ' (DMSO-d 6) 2- (2-thiazolylthio) 5.65 3.22-3.96 (m, 4H), 4.4 ethyl (KBr tablet) (m, 2H), 5.58 (n, 1H), 7.72 YY (m, 2H) (DMSO-d 6) 12-methoxycyclopentyl 5 55 15 6125 (DMSO) 2-methoxycyclohexyl 5.65 6.25 (DMSO) 2-azidocyclohexyl 4.75 6j25 (DMSO) 2- aminocyclopentyl 5.65 6.25 (DMSO) '2 2-tetrahydrofuranyl 5.65 6.25 (DMSO) 1-acetyl-3-pyrrolidin-5,730-yl (KBr-tablet) 1-acetyl-3-piperidine nyl 6,10 6,15 (DMSO) 2-tetrahydrofuranyl-5,65 methyl 6,25 (DMSO) 53 8 2470

r IR NMR

1 - (micron) - (ppm) -2-tetrahydropyranyl-5.65 0.98-1.88 (m, 6H); 3.04 - methyl (KBr-tablet) 4f22 (m, 7H); 5.56 (m, 1H) (DMSO-d6) δ-acetyl-2-pyrrole-5.62 1.7-2.24 (mf7H); 3.08 (KBr_tabl) (m, 7H); 5.54 (m, 1H) dmylime style - (DMSO-dc)

D

2- (2-pyridinonylamino-5.65 3.15-3.9 (c, 4H); 4.25 no) -ethyl 6 ° (m, 2H); 5.55 (m, 1H); 7.6 no, eryxy (KBr-tabl) (m, 1H); 8.05 (m. 2H); 8.65 (m, 1H); 9.05 (m, 1H) δ (DMSO-d 6) 1-formyl-3- 5.68 piperidyl 5.93 (DMSO) N-methylamino-5.65 2.62 (d, 3H); 3.2 - 3.94 δ (m, 2H); 4.44 (s. 2H); 5.64 carbonylmethyl (Kbr-tabl) (m, 1H) (DMSO-dc)

O

1-aminocarbonyl) 5.65 1.42 (d, 3H); 3.1-4.0 g 5.9 (m, 2H); 4.6 (m, 1H); 5.7 YY 6.25 (m, 1H) (DMSOd-,) (KBr 6 20 2- (methoxymethylcarb-5.65 3.1-4.3 (c) and 3.3 (s, 3H) carbonylamino) ethyl 6.05 (11H), 5.58 (m, 1H);

Donynamine and yy (KB2vtabl ·.), 8.46 (b, 1H) (DMSO-d6) 2- (aminocarbonyl-5.75 3.2-4.7 (c, 6H); 5.56 oxy) -ethyl 5185 (m, 1H); 6.6 (b, 2H) (DMSO-d 6) (KBr-tablet) 1,3-dimethoxy-2-pro-5.7 3.4 (S, 6H); 3.3-3. 94 (c, 6H);

Dvlli (KBr-tablet) 4.48 (m, 1H); 5.66 (m, 1H) (DMSO-d 6 D 2 O) 2- (2-furylcarbonyl-5 - δ 3f 2 - 3.9 (c, 4H); 4.2 (m, 2H); amino) ethyl 5.58 (m, lH); 6.6 (m, 1H); (KBr-tablet) 7.32 (m, 1H); 7.82 (m, 1H); : 9.18 (m, 1H) (DMSO-d 6) 1,3-dioxan-5-yl 5.65 3.2-4.4 (c, 7H); 4.82 (KBr-tabL) (s, 2H); 5.56 (m, 1H) (DMSO-d 6) 54 82 470

R IR NMR

1 ____ (microns) - (ppm) - 1-methyl-2-piperidine-5.6 1.64-2.28 (c, 4H); 2.84 non-3-yl 6T1 (s, 3H); 3.14 - 3.9 (c, 4 H); YY (KBr-tablet) 4.66 (m, 1H); 5.58 (m, 1H) (DMSO-d 6) δ 1- (aminocarbonyl-5.7 1.7-2.36 (c, 4H); 3.14-6.0 4.06 (c, 6H); 4.74 (m, 1H); methyl) pipette 6f 5.56 (m, 1H); 7114 (b, 1H); non-3-yl-KRr-tabl ·) 7.56 (b, 1H) (DMSO-dg) 2- (2-acetylamino-5f7 1.82 (s, 3H); 3.06-4.42 iπ ethoxy ) ethyl (c, 10H); 5.58 (m, 1H); 8.08 (tablet) (b, 1H) (DMSO-d 6) 2-piperidinon-3-yl 5.7 1.5-2.3 (c, 4H); 2.94 - 6.1 4.0 (c, 4 H); 4.6 (m, 1H); (KBr-tablet) 5.56 (m, 1H); 8.16 (b, 1H) (DMSO-d 6) δ 2-piperidinon-3-yl 5.65 5.90 (KBr-tablet) 2-piperidinone-5- 5.7 1.78-2, 46 (c, 4 H); 3.1 - wli 6.1 4.2 (c, 5H); 5.6 (m, 1H); YY (KBr tablet) 7.56 (b, 1H) (DMSO-d 6) 2 O-methyl-1,3-oxazo-5.65 2.8 (m, 3H); 3.2 - 4.54 lit-2-on-4-yl- (KBr-tablet) (c, 7H); 5.6 (m, 1H) style (DMSO-d 6) 1,3-dioxolan-4- 5.7 3.2-4.4 (c, 7H); 4.86 ylmethyl (KBr tablet) (d, 2H); 5.56 (m, 1H)

Yy yy (DMso-d6r

II

55 82470

Example 18

Trans-6-hydroxyethyl-2- (1,3-dioxan-5-yloxy) -2-panem-3-carboxylic acid, calcium salt The procedure of Example 16 was used for p-nitrophenyl-trans-6-p-nitrobenzyloxycarbonyloxyethyl-2- (1 For the hydrogenation of (3-dioxan-5-yloxy) -2-penem-3-carboxylate to give 205 mg of the title compound. The infrared spectrum of the title compound from the potassium bromide tablet showed adsorptions at 2.93 and 5.65 microns.

Example 19

The procedure of Example 16 was applied to the corresponding compounds listed in Table VI to give compounds of formula I wherein R is hydroxyethyl, R 2 is calcium as a divalent cation and R 1 is as shown in Table IX as potassium bromide tablets measured together with IR spectra.

Table IX

20

R 1 IR (micron) 1-formyl-3-piperidyl (trans) 2,992,6,6,6,6,3-dioxolan-4-ylmethyl (trans) 294,565

A J

1-Methoxy-2-propyl (trans) -2,9,9,5,7-dioxolan-2-ylmethyl (trans) 2,5,9,5,7-2-pyrrolidinon-3-yl (trans) -2,9,5,7,5,5,9 ° 2-piperidinon-5-yl (trans) -2,4,9,5,6,7,6-methyl-1,3-oxazolidin-2-one-2,992,5,5,5,7,7-4-ylmethyl (trans) ) 2-methoxyethyl (trans) 2 ^ 9, 5 ^ 7 56 82470

Preparation A

p-nitrobenzyl 2- (4-ethylthio-2-oxo-l-azetidinyl-2- (etoksitiokarbonyylietio) asetaatti_

To a stirred mixture of 3.2 g of potassium methyl-5-xanthate, 5.4 g of benzyltriethylammonium chloride, 100 ml of water and 50 ml of dichloromethane at 0 ° C was added a solution of 7.12 gp-nitrobenzyl-2- (4 -ethylthio-2-oxo-1-azetidinyl) -2-chloroacetate in 75 ml of dichloromethane. Stirring was continued at 0-5 ° C for 1 hour 10 and then the organic phase was removed. The aqueous phase was extracted with 100 ml of dichloromethane, and then the combined dichloromethane layers were washed successively with 75 ml of dilute hydrochloric acid, 75 ml of saturated aqueous sodium bicarbonate solution and 75 ml of water. The dichloromethane-15 solution was dried over anhydrous sodium sulfate and evaporated to dryness in vacuo, and the residue was purified by column chromatography on 200 g of silica gel, eluting with 95: 5 chloroform-ethyl acetate. The product-containing fractions were combined and concentrated in vacuo to give 4.3 g of the title compound. IR spectrum (chloroform) showed adsorption at 5.66 microns. NMR spectrum (deuterochloroform) showed peaks at: 1.02-1.6 (m, 6H); 2.35 - 3.65 (m, 4H); 4.4-5.1 (m. 3H); 5.3 (s. 2H); 6.3 and 6.4 (ss, 1H); 7.4 (d. 2H); and 8.2 (d, 2H) ppm.

25 Preparation B

Reaction of p-nitrobenzyl 2- (4-ethylthio-2-oxo-1-azetidinyl) -2-chloroacetate with the appropriate xanthate of formula K + Rp-O- (C = S) -S, Rp of which is shown in Table X; according to Preparation A, gave the corresponding compounds of formula VI in Table X. The IR spectrum was measured for chloroform solutions and the NMR spectra were measured for deuterochloroform solutions.

n 57 82470

Table X

r IR NMR

1 ______ (microns) _ (ppm) _ c 2-methoxyethyl 5.66 1.23 (t, 3H); 2t4 - 3.84 (m, 9H); 4.56 - 5.14 (m, 3H) t 5.3 (s, 2H); 6.24 and 6.3 (ss, 1H); 714 2 (d. 2H); 8.16 (d, 2H) 2-ethoxyethyl 5.65 1.0 - 1.4 (m, 6H) 2.4 - 3.9 (m, 8H); 4.6 - 5.18 (m, 3H); 5.34 (s. 2H); 6.3 and 6.36 (s s, 1K); 7.52 (d. 2H); 8.22 (d, 2H) 2- (2- (methoxyethoxy) 6.63 1.22 (t, 3H), 2.4-4.0 ethyl f 4.62-2.2 YY (m, 3H); 5.33 (s, 2H), 15, 34 and 6.4 (ss, 1H), 7.58 (d, 2H), 8.25 (d # 2H), 2-phenoxyethyl 5.66 1.2 (m, 3H), 2.3-3.55 (m, 4H), 4.2 (m, 2H}, 4.6-5.1 (m, 3K), 5.22 (s, 2H), 6.2 and 6 , 3 (ss, 1H), 6.68-7.56 (m, 7H) δ 8.12 (d, 2H) 2- (phenylthio) ethyl 5.66 1.22 (t, 3H); 38 - 3.9 5.7 (m, 6H), 4.6 - 5.14 (m, 3H), 5.3 (s, 2H), 6.3 and 6.42 (ss, 1H), 7.2 - 7.68 (m, 7H); 8.2 (d, 2H) 2-azidoethyl 4.76 1.22 (t, 3H); 2.38-3.82 5.6 (m, 6H); 4.6-5 14 (m, 3H), 5.3 (s, 2H), 6.3 and 6.4 (ss, 1H), 7.5 (d, 2H), 8.2 (d, 2H) 2 O 2- (acetamido) ) ethyl 5.66 1.3 (t, 3H), 2.08 (s, 3H), 6.0 2.46 - 3.9 (m, 6H), 4.5 - 5.35 (m, 3H), 5.42 (s, 2H), 6.43 and 6.56 (ss, 1H), 6.9 (tn, 1H), 7.6 (d, 2H), 8.32 (d, 2H),

R IR NMR

1_______ (microns) - (ppm) - 58 82 470 2- (morpholino) ethyl, 66.3, 25 (t, 3H); 2.4 - 3.86 (m, 14 H); 4.6 - 5.26 (m, 3H); 5.36 (s. 2H); 6.36 and 6.42 (ss, 1H); Δ 7.57 (d, 2 H); 8.22 (d, 2H) 2-phenylethyl 5.66 1.25 (t, 3H); 2.38 - 3.7 (m. 6H); 4.65 - 5.12 (m, 3H); 5.34 (s. 2H); 6.36 and 6.5 (ss, 1H); 7.15 - 7.75 (m, 7 H); 8.26 (d, 2H) 2- (2-thienyl) ethyl 5.64 1.2 (t, 3H); 2.35 - 3.7 (m, 6 H); 4.6-5.1 (m, 3H; 5.26 (s, 2H); 6.25 and 6.38 (ss, 1H); 6.7-7.26 (in, 3H); ((3.2η); 8.14 (d, 2H) 2- (2-pyridyl) ethyl 5.63 1.2 (t, 3H); 2.36-3.56 (m, 6H); Δ 5.1 (m, 3H1, 5.22 (s, 2H); 6.2 6.33 (ss, 1H); 6.9-7.7 (m, 5H); 8.14 (d, 2H); .46 (m, 1H) 2 O 2- (1-pyrazolyl) 5.62 1.24 (m, 3H); 2.2-3.7 t. (M, 4H); 4.42-5.22 ethyl 1 (m / 5H), 5 ^ 2 (s, 2H), 6.2 - 6.5 (m, 2H), 7.4 - 7.75 (m, 4H), 8.24 (d, 2H) 2 - (4- methyl 5-thiazo-5.64 1.24 (t, 3H), 2.36-3.64, (m, 9H), 4.68-5.18 yl) ethyl (m, 3H); Δ (s, 2H), 6.38 and 6.5 (ss, 1H), 7.58 (d, 2H), 8.28 (d, 2H), 8.64 (s, 1H) 2 - ( 2-oxo-1-imidazole-5β, 1,2 (t, 3H), 2.36-3.8 dinyl) ethyl 5.88 (m, 10H), 4.5-5.12 L (m, 3H) ); 5.32 (s, 2H); 6.32 and 6.45 (ss, 1H); 7.5 (d, 2H); 8.2 (d, 2H) 59 82 470

IR NMR

______ (microns) - (ppm) - 2- (2-oxo-1-pyrrolidine-5.66 1.25 (t, 3H); 1.7-3.8 5.98 (m, 12H); 58-5.1 yl) ethyl (m, 3H); 5.26 (s. 2H); 6.3 and 6.4 (ss, IK); Δ 7f46 (d, 2H); 8.18 (d, 2H) 2- (2-thiazolylthio) 5.65 1.20 (t, 3H); 2.36 - 3.78 (m, 6H); 4.72-5.2 ethyl (m, 3H); 5.33 (s. 2H); 6.32 and 6.42 (ss, 1H); 7.4 - 7.72 (m, 4 H); 1Q 8.22 (d, 2H) 2-methoxycyclopentyl 5.62 1.0-1.2 (m, 3H); 1.4 - 2.0 (m. 6H); 2.2 - 4.0 (m. 5H); 3.3 (s. 3H); 5.0 (m, 1 H); 5.3 (s. 2H); 5.7 (m, 1H); 6.2 (s s, 1 H)? 7.5 (d. 2F); 8.2 (d, 2H) δ 2-methoxycyclohexyl 5.62 1.0 - 2.0 (m / 1H); 2.2 - 4.0 (m. 5H); 3.3 (s. 3H); 5.0 (m, 1 H); 5.4 (m. 2H); 5.6 (m, 1 H); 6.3 (s s, 1 H); 7.5 (d. 2H); 8.2 (d, 2H) -> 2-azidocyclohexyl 4.75 * 10 ~ 2.2 (m, 11H); 2.2 - 5.65 - 4.0 (m, 5H); 5.0 (m, 1H); 5.3 (s. 2H); 5.5 (m, 1H); 6.4 (ss, 1 H); 7.5 (d. 2H); 8.2 (d, 2H) 2-azidocyclopentyl 4.75 1.0 - 1.5 (m, 3H); 1.6 - 5.65 - 2.2 (m, 6H); 2.2 - 4.0 (m, 4 H); 4.2 (m, 1H); 5.0 (m, 1 H); 5.3 (s. 2H); 5.6 (m, 1H); 6.3 (ss, 1 H); 7.5 (d. 2H); 8.2 (d, 2H) -3-tetrahydrofuranyl 5.65 1.0-1.6 (m, 3H); 2.0 - 4.0 (m, 6 H); 4.0 (m. 4H); 5.0 (m, 1H); 5.4 (s. 2H); 6.0 (m, 1 H); 6.4 (s s, 1 H); 7.5 (d. 2H); 8.2 (d. 2H)

R IR NMR

1__ (microns) - (ppm) - 1-acetyl-3-pyrro-5.66 1.0-1.4 (m, 5H); 2.0 lidinyl; 2.2 - 40 (m, 8H); 5 * 0 (m, 1H); 5.3 δ (s, 2 H); 5.9 (m, 1 H); 6.4 (ss, 2 H); 7.5 (d, 2H) 8.2 (d, 2H) -1-acetyl-3-piperidine-5.66 1.0-1.2 (m, 3K); 1.4 - 2 * 0 (m, 4 H); 2.0 (ε, ίϊΗ); nyyl 1.2 - 4.0 (m, 8H); 5.0 (m, 1 H); 5.2 (s. 2H); 5.4 (m, 1H); 6.3 (ss, 1H); 7.4 (d. 2H); 8.2 (d, 2H) 2-tetrahydrofuranyl-5.66 1.0-1.2 (m, 3H); 1,6-lymethyl? 3.8 - 4.1 (m. 3H); 4.6 (m. 2H); 5.0 (m, 1H); 5.4 (s, 2H); 6.4 (ss, 1H); 7.6 (d, 2H); 8.2 (d, 2H) 2-tetrahydropyranyl-5.66 1.02-2.04 (m, 9H); lymethyl 2136 - 4TO 8 (m, 7H); YY 4.46 (d, 2 H); 4.74, 5.0 (m, 1 H); 5.24 (s. 2H); 6.18 is and 6.27 (ss, 1H); 7.42 (d. 2H); 8.14 (d, 2H) -1-acetyl-2-pyrrolidine-5.66 1.22 (t, 3H); 1.7-2.3-ylmethyl (m, 7H); 2.4 - 3.67 (m, 6 H); 4 * 22 - 5 * 16 (m, 4H); 5.35 (s. 2H); 6.32 and 6.42 (ss, 1H); Δ 7.5 (d. 2H); 8.2 (d, 2H) 2- (2-pyridinoylamino) 5.66 1.25 (t, 3H); 2.6 (q. 2H); ethyl V8 2.8-4.05 (c, 4H); 4.75

Yy (m, 2H); 4.95 - 5.35 (c, 4H); 7.2-8.7 (c, 9H) 30-formyl-3-piper-5.65 1.27 (t, 3H); 1.46 - 2.27 dyl 5f72 (c, 4H); 2.4 - 4.1 (c, 8 H); 4.7 - 5.6 (c, 4 H); 6.3, 6.46 (s, 1 H); 7.54 (d. 2H); 7.88 - 8.36 (3H)

II

R1 IR NMR

_____ (microns) _ (ppm) _ 6i 82470 N-melphylaminocarbo- 5.7 1.2 (m, 3H); 2.3 - 3.68, δ 5.98 (c, 7H); 4.68 - 5.38 (c, 5H); nylmethyl 6,16, 6f34 (s, 1H); 6.78 δ (b, 1H); 7.4 (d. 2H); 8.1 (d, 2H) -1-aminocarbonyl-δ R 6 1.06 - 1.74 (c, 6H); 2.36 - ethyl 5.9 3.7 (c, 4K); 4.76 -5.4 (c, 3K); 5.6 - 6.8 (c, 4 H); 7.54 (d. 2H); 8.26 (d, 2H) 10 2- (methoxymethylcarbon-5f661f22 (t, 3H); 2.62 (a, 2H); aminoamino) ethyl> 3.9 (s, 2H); 4.55 (m. 2H); 4.8 - 5.2 (c, 1 H); 5.32 (s. 2H); 6.4 (d, 1 H); 7.1 (b. 1H); 7.55 (d, 2H)? 15 81 2 (d, 2H) 2- (aminocarbonyl-5.66 1.2 (m, 3H); 2.6 (q, 2H); oxy) ethyl 5.76 2.9-3.6 (c, 2H) ; 4.34 (m, 2H); 4.75 (m, 2 K); 5.05 (b. 3H); 5.3 (s. 2H); 6.36 (d, 1 H); 7.5 (d. 2H); 8.2 (3.2H) 1,3-dimethoxy-2- 5.65 1.25 (m, 3H); 2.6 (m, 2H) propyl 2 * 8 ′ (c, 12H) including 3.35 (s, 6H), 4.8 and 5.06 (m, 1H); 5.34 (s. 2H); 5.9 (m, 1 H); 6.26 (d, 1H); 7.55 (d. 2H); 8.26 (d, 2K) 25 r 2- (2-furylcarbonyl-5.68 1.22 (m, 3H); 2.58 (q, 2H); 6.0 2 * 8 - 3.96 (c, 4H) 4.65 liaino) ethyl f (m, 2H); * 4.6 - 5.2 (c) 1H); 5.25 (s. 2H)? 6.36 (c, 2K); 7.06 (d, 1 H); 7.26 (b, 1H); 7.5 (c, 3H); Δ 0.2 (d, 2H) 30

R IR NMR

1 (microns) - (pprri) - 62 82470 13-dioxan-5-yl 5166 22 Jr3® "3 * 6 (c, 4H); 4.06 (m, 4H); 4 T 6 6-5, 58 (c, 6K); 6.16, 6.37 (S, 1H) γ 7.46 (d, 2H); b 8 r 2 (d, 2H) -1-methyl-2-piperidine-5.66 1.2 (m, 3H ), 1.76 to 2.34, 6.02 (c, 4H), 2.6 (m, 2H), 2.95 non-3-yl (s, 3H), 3.0 to 3.6 (c (4H), 5.0 (m, 1H), 5.3 (sf2H), 6.06 (m, 1H), 6.32 (d, 1H), 7.52 (d, 2K), 2 (d, 2H) 1- (aminocarbonyl- 5.68 1.2 (m, 3H); 1.7-5.32 ... 5.98 (c, 16H) y 6.0 ( b, 2K) (methyl) -2-piperidinone- <6l4 and 6.38 (d, 1K).

3-yl (7.5 - 3.2H); 8.2 (d, 2H) -15 2- (2-acetylamino-5.68 1.26 (m, 3H); 2.64 (q, 2H); β; ο 2.86-4.0 (c. 8H); 4.72 (ethoxy) ethyl (m, 2H); 4.8: 5.05 (m, 1 H); 5.34 (s. 2H); 6.38 (d, 1 H); 6.4 (b, 1H); 7.54 (d, 2H); 8.24 (d, 2H) -2-piperidinon-3-yl 5.66 1.2 (m, 3H); 1.7 - 3.6 δ 5.98 (c, 8H); 4.75-5.35 (c, 4H); 6.34 (d, 1H); 6.74 (b, 1 H); 7.54 (d, 2H); 8.25 (d, 2H) 2-pyrrolidinon-3-yl 5.66 1.24 (m, 3H); 2.05 - 3.62 5.85 (c, 8H); 4.7 - 5.2 (c, 2 H); 5.26 (s, 2H); 6.2 and 6.3 (d, 1 H); 7.44 (c. 3H); 8.1 (d, 2H) -2-piperidinon-5-yl 5.65 1.24 (t, 3H); 2.0 - 3.78 δ (c, 11H); 4.8 and 5.0 '(m, 1 H); 5.3 (s. 2H); 6.25, n and 6.42 (s, 1H); 6.96 (D, 1 H), 7.5 (d, 2H), 8.2 (d, 2 H)

R IR WMF

1 (microns) - (ppm) __ 63 82470 3-methyl-1,3-oxazo-5.66 1.22 (t, 3H); 2.6 (q, 2 H); ,,,,,. . . . 2.9 (d, 3K); 3.0 - 3.62-1-2-on-4-ylmethyl (c, 2H); 3.9-4.9 (c. 5H); Δ 5.02 5.3 (s. 2H); 6.25 and 6.4 (d, 1H); 7.5 (α, 2 H); 8.2 (d, 2H) 1,3-dioxolan-4-yl-5.67 1.24 (m, 3H); 2.64 (t, 2 H); methyl 218-4t <C'7H2Rr9, (d, 2H); 5.1 (m, 1K); 5.3 in (s, 2K); 6.34 (m, 1H); 7.5 (d. 2H); 8 j2 (d, 2K)

Preparation C

p-Nitrobenzyl 2- (4-ethylthio-3-p-nitrobenzyloxycarbonyloxyethyl-2-oxo-1-azetidinyl) -2-1,3-dioxan-5-yloxythiocarbonylthio) acetate__

The method of Preparation A used p-nitrobenzyl 2- (4-ethylthio-3-p-nitrobenzyloxycarbonyl-oxyethyl-2-oxo-1-azetidinyl) -2-chloroacetate (11.6 g) and potassium 1,3- dioxan-5-yl xanthate (4.8 g) as starting materials to give 8.4 g of the title compound.

The NMR spectrum in deuterochloroform showed peaks at: 1.02-1.56 (c, 6H); 2.6 (m. 2H); 3.4 (m, 1H); 3.6 4.2 (c. 5H); 4.6 - 5.56 (c, 8H); 6.34 (d, 1H); 7.5 (m, 4H) and 8.2 (m, 4H) ppm.

Preparation D 25

The method of Preparation A was used with compounds of formula V wherein R is p-nitrobenzyloxycarbonyloxyethyl, i is zero, R 2 is p-nitrobenzyl, R 4 is ethyl and R 7 is chlorine and the formula R 1 -O (C = S) - S-xanthate with a potassium salt of formula wherein R 1 is as shown in Table XI to give the corresponding compounds of formula VI having the NMR spectrum in deuterochloroform shown in Table XI.

64 82470

Table XI

NMR (ppn) δ 1-formyl-3-piperidyl 1 H 2 O-2.2 (c, 10H); 2.58 (IR (chloroform); B, 64, 5.70, 5.98 microns) (m, 1H); 6f22, 6-4 (s, 1H); Δ 44 (m, 4H); 7.8-8.2 (c, 5H) -1,3-dioxolan-4-yl-1.04-1.56 (c, 6H); 2f6 10 methyl 3 <4 3.55 - 4.75 YY (C, 5H); 4.75-5.4 (c, 8F); 6.3, 6.4 (s, 1 H); 7.52 (m. 4H); Δ f2 (m, 4H) 1.0 - 1.6 (c, 9H); 2.6 (m. 2H); 3.32 (s) and 1'-methoxy-2-propyl 3.23-3.64 (c, 6H); 4.8 - 5.34 (c, 6H); 5.78 (c, 1H); 6.3, 6.35 (s, 1 H); 7.44 (m, 4H); 8.18 (m, 4H) 1,3-dioxolan-2-ylmethyl 1.0-1.6 (c, 6H); 2.6 (m. 2H); 3.36 (m, 1H); 9n 3.98 (b, 4H); 4.56 (d. 2H); 4.96 - 5.44 (c, 7H); 6.34 (s, 1 H); 7.5 (m, 4H); 8.2 (m, 4K) -2-pyrrolidinon-3-yl-1H-cis (c, 6H); 2.15 - 3.0 (c, 4 H); 3f22 - 3.62 (C, 3H); 4.7 - 5.42 (c, 7H); Δ 6.02 (m, 1 H); 6.34 (b, 1H); 7.5 (m, 4H); 8.2 (m, 4H) 2-piperidinon-5-yl-1H-1.6 (c, 6H); 1.9 - 2.8 (c, 6 H); 3.36 (m, 1H); 3 «6 2 (c, 2H); 4.7 - 5.4 (c, 6H); 5.84 (c, 1H); Δ 6.t2ς '6.42 (s, 1H); 6.62 (b, 1 H); 7.5 (m. 4H); 8.2 (m, 4H) n 65 82 470 NMR (ppm) 3-methyl-1,3-oxazolidine-1.0-1T6 (c, 6H); 2.56 2-on-4-ylmethyl ((H); ? 1®? (t'j? H) 7J312 "** 5t46 (c, 12H); 6.0-6r46 c (c, 1F); 7.46 (m, 4H); 8.16 δ (m, 4H) 2-methoxyethyl 1.06-1 .58 (c, 6H); 2.6 (m, 2H); 3.36 (s); 3.26 -3.6 (c, 6H); 4.54 - 5.4 (c, 8H); 6.52 (s, 1H); 7.5 (m, 4H), 8.2 (m, 4) 10

Preparation E

p-Nitrobenzyl 2- (4-ethylthio-3-p-nitrobenzyloxycarbonyloxyethyl-2-oxo-1-azetidinyl) -2-chloroacetate__________________ ^ Solution containing 11.3 g of p-nitrobenzyl 2- (4 ethyl thio-3-p-nitrobenzyloxycarbonyloxyethyl 2-oxo-1-azetidinyl) -2-hydroxyacetate and 3.02 ml of 2,6-lutidine in 175 ml of anhydrous tetrahydrofuran were cooled to 0 ° C under nitrogen. in the atmosphere. Thionyl chloride (1.75 ml). ... ,.

was added dropwise and the resulting mixture was stirred at 0 ° C for 20 min. The mixture was filtered through Supercel and the filtrate was concentrated in vacuo. The concentrate was dissolved in methylene chloride and the resulting solution was washed successively with 200 ml of 1N aqueous hydrochloric acid, 200 ml of saturated aqueous sodium bicarbonate solution and 200 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate (above) in oil and concentrated. the title compound. The NMR spectrum of the title compound showed peaks at: 1.04-1.6 (c, 6H); 2.6 (m. 2H); 3.4 (m, 1H); 4.8-5.4 (c. 6H); 5.85, 5.9, 5.98, 6.1 (s, 1H); 7.5 (m. 4H); 8.2 (m. 4H) ppm.

66 82470

Preparation F

p-nitrobenzyl 2- (4-ethylthio-2-oxo-l-azetidinyl) -2-chloroacetate _______

To a stirred solution of 6.8 g of p-nitro-5-benzyl-2- (4-ethylthio-2-oxo-1-azetidinyl) -2-hydroxyacetate in 200 ml of tetrahydrofuran at 0-5 ° C 2.98 ml of 2,6-dimethylpyridine was added, followed by dropwise addition of a solution of 1.73 ml of thionyl chloride in 20 ml of tetrahydrofuran over 5 minutes. Stirring was continued at 0-5 ° C for 15 minutes, and then the reaction mixture was filtered. . The filtrate was evaporated to dryness in vacuo and the residue was dissolved in 200 ml of dichloromethane. The resulting solution was washed successively with dilute hydrochloric acid and water, and then dried over anhydrous sodium sulfate. Evaporation in vacuo gave 7.12 g of the title compound as a yellow viscous liquid. The IR spectrum of the product in chloroform showed adsorption at 5.63 microns. The deuterochloroform NMR spectrum of the product showed peaks at: 1.3 (t, 3H); 2.47-3.7 (m. 4H); 4.9-5.3 (m, 1H); 5.4 (s. 4H); 6.06 and 6.18 (ss, 1H); 7.58 (d. 2H); and 8.22 (d, 2H) ppm.

Preparation G

p-Nitrobenzyl 2- (4-ethylthio-2-oxo-1-azetidinyl) -2-hydroxyacetate_ 25 A solution of 12.3 g of 4-ethylthio-2-oxoacetidine and 25.5 g of p-nitrobenzylglyoxylate ethyl hemiacetal in 900 mL of benzene, was heated at reflux for 16 hours. During heating for 16 hours, water and ethanol were removed from the reaction mixture by azetropic 30 distillation using a Dean-Stark trap. At this point, the benzene was removed by evaporation in vacuo and the residue was dissolved in 700 ml of dichloromethane. The dichloromethane solution was washed three times with water, and then dried over anhydrous sodium sulfate. Evaporation of the residue gave 32.5 g of the title compound as a yellow semi-solid. The IR spectrum of the product in chloroform gave an absorption of about 67,82470 at 5.65 microns. The NMR spectrum of the product in deuterochloroform showed peaks at: 1.25 (t, 3H); 2.35 - 3.62 (m, 4H); 4.3 (s, 1H); 4.85 (m, 1H); 5.22 and 5.54 (ss, 1H); 5.38 (s. 2H); 7.5 (d. 2H); and 8.2 (d, 2H) ppm.

5 Preparation H

p-Nitrobenzyl 2- (4-ethylthio-3-p-nitrobenzyloxycarbonyloxyethyl-2-oxo-1-azetidinyl) -2-hydroxyacetate-4-ethylthio-3-p-nitrobenzyloxycarbonyloxy-10-ethyl-2-oxoazetidine ( 9.0 g), p-nitrobenzylglyoxylate ethyl hemiacetal (8.15 g) and benzene (350 ml) were heated at reflux for 20 hours under nitrogen using a Dean-Stark water separator. The solution was then concentrated in vacuo and the residue was dissolved in 15,700 mL of dichloromethane. The dichloromethane solution was washed twice with water, dried over anhydrous sodium sulfate and concentrated in vacuo to a yellowish semi-solid (15.0 g) which was the title compound. The NMR spectrum in deuterochloroform showed peaks at: 1.02-1.52 (c, 8H); 2.6 (m. 2H); 3.3 (m, 1H); 4.1 (b, 1H); 4.78-5. 56 (c, 5H); 7.48 (d. 4H); and 8.18 (d, 4H) ppm.

The IR spectrum in dichloromethane showed adsorptions at 5.62 and 5.7 microns.

Preparation I

25 4-ethylthio-2-oxoazetidine

To a solution of 8.0 g of sodium hydroxide in 200 ml of water cooled to 0-5 ° C was added 15.5 ml of ethanethiol. The cold solution was stirred for 5 minutes and then a solution of 25.8 g of 4-acetoxy-2-oxetazetidine in 200 ml of dichloromethane was added in one portion.

The mixture was stirred at 0-5 ° C for 90 minutes and then the pH was adjusted to 6 using 6N hydrochloric acid. The dichloromethane layer was removed and the aqueous layer was extracted with additional amounts of dichloromethane. The combined dichloromethane solutions were washed with water and then with saturated sodium chloride and then dried over Na 2 SO 4 · 68 82470

Evaporation in vacuo gave 23.4 g of the title compound as an oil.

Preparation J

p-Nitrobenzylglyoxylate ethylhemiacetal 5 A stirred solution of 32.0 g of tartaric acid bis- (p-nitrobenzyl ester in 850 ml of tetrahydrofuran) was cooled to 0-5 ° C and 26.0 g of periodic acid were all added in one portion. The reaction mixture was filtered, 100 ml of ethanol was added to the filtrate, and the resulting solution was evaporated in vacuo, and the residue was dissolved in 700 ml of chloroform and washed successively with concentrated aqueous thiosulfate solution (5 times) and water (2 times). The chloroform solution was dried over anhydrous sodium sulfate and then evaporated in vacuo to give

25.5 g of the title compound was obtained as a viscous liquid. Preparation K

Sodium 2- (morpholino) etyyliksantaatti

To a stirred solution of 4.91 g of N- (2-20 hydroxyethyl) morpholine in 250 ml of anhydrous tetrahydrofuran at room temperature was added 1.79 g of a 50% dispersion of sodium hydride in mineral oil. A precipitate formed. The mixture was stirred for 30 minutes and then 2.75 ml of carbon disulfide was added to give the original precipitate as a solution. The reaction mixture was stirred for 30 minutes while more precipitate formed. To the mixture was added 200 ml of anhydrous ether, and the precipitate was collected by filtration. The solid was washed with ether, and dried to give 8.8 g of the title compound.

30 Preparation L

Potassium 2- (2-oksopyrrolidino) etyyliksantaatti

To a stirred solution of 5.16 g of N- (2-hydroxyethyl) -2-oxopyrrolidine in 200 ml of anhydrous tetrahydrofuran at room temperature was added 4.48 g of potassium t-butoxy. A rubbery precipitate formed. The mixture was stirred for 1 hour and then 3.6 ml of 6982470 fidi of carbon disulfide were added. The mixture was stirred for 2 hours and then 100 ml of anhydrous ether was added to form a gummy precipitate. The solvent was decanted off from the gummy precipitate and the gummy precipitate was dried under high vacuum to give the title compound as a foam (5.0 g).

Preparation M

4-Ethylthio-3-p-nitrobenzyloxycarbonyloxyethyl-2-oxoazetidine To a cooled (0 ° C) solution of 572 mg of sodium hydroxide in 50 ml of water was added 1.32 ml of ethanethiol. After 10 minutes, a solution of 5.02 g of 4-acetoxy-3- (p-nitrobenzyloxycarbonyloxyethyl) -2-oxoazetidine in 100 ml of dichloromethane was added and the mixture was stirred vigorously at 0 ° C for 30 minutes and then for 25 minutes. ° C for 3 hours. The dichloromethane layer was separated and the aqueous phase was extracted with two 70 ml portions of dichloromethane. The combined dichloromethane extracts were washed with 70 ml of water, then with 70 ml of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo to an oil. The crude product was purified by column chromatography on silica gel, eluting with 5: 1 chloroform-ethyl acetate to give 4.15 g of the title compound.

Preparation N

25 p-Nitrobenzyl 2- (4-ethylthio-2-oxo-1-azetidinyl) -2- [2-ethoxyethylthio (thiocarbonyl) thio] acetate

A solution of 3.58 g of aluminum 2-ethoxyethyl trithiocarbonate and 3.7 g of benzyltriethylammonium chloride in 100 ml of methylene chloride was cooled to 0 ° C under a nitrogen atmosphere and a solution of 5.3 g of p- nitrobenzyl 2- (4-ethylthio-2-oxo-1-azetidinyl) -2-chloroacetate in 50 ml of methylene chloride was added dropwise.

The reaction mixture was stirred for 1 hour, then washed with three 50 mL portions of water, dried over anhydrous sodium sulfate and concentrated in vacuo to an oil (8.6 g).

7o 82470

The crude product was chromatographed on silica gel eluting with 5% ethyl acetate in chloroform to give 2.3 g of the title compound as an oil. The IR spectrum of the chloroform solution of the title compound had adsorption at 5.65 microns; 5 and the NMR spectrum in deuterochlorodorm showed peaks at: 1.2 (m, 6H); 2.34 - 3.77 (c, 10H); 4.7, 4.98 (m, 1H); 5.26 (s. 2H); 6.62, 6.86 (s, 1H); 7.43 (m. 2H); and 8.16 (m. 2H). ppm.

Preparation O

The method of Preparation N was used by reacting compounds of formula V wherein R is hydrogen, R 2 is p-nitrobenzyl, R 4 is ethyl, R 11 is chlorine and i is zero to give R 1-potassium trithiocarbonate to give compounds of formula VI. The products are tabulated in Table VII with the IR solution spectra measured in chloroform, unless otherwise indicated, and with the NMR solution spectra measured in deuterochloroform.

Table VII

IR (microns) NMR (ppm) ethyl 5.66 lf26 (m, 6H); 2.4-3.62 (c, 6H); - 4.7.5.0 (m, 1H); 5.3 (s, 2H); 6f68,6,92 (s, H)? 7.48 (m. 2H); and 8.2 (m. 2H).

3-phenylpropyl 5.68 1.2 (m, 3H); 2.02 (m, 2H); Δ 2.35-3.6 (c, 8 H); 4.7 4197 (m, 1H), 5f22 (s, 2H); 6.6 and 6187 (s, 1H), 7p12 (m, 5H); 7.4 (m, 2 H), and 8.1 (m, 2 K).

35 11 τι 82470 R1 IR (microns) _ΝΜΗ | ΡΡπ) methyl 5.64 l, 22 (mf3F); 2.6 (rn.2H); 2.8 (s, 3H); 3.02 - 3.88 δ (m, 2H); 4.78 and 5.02 (m, 1 H), 5.34 (s, 2 H); 6.7 and 6.94 (s, 1H), 7.5 δ (d, 2H); and 10 2- (acetylamino-5.65 and 5.98 1.22 (m, 3H); 1.96 (s, 3H); no) -ethyl 2 - 62 (m, 2H)? 3 ^ 0-3f72 (c, 6H); 4,8,5,02 (in, 1H); 5.32 (s, 2H); 6.36 (b, H); 6.7 and 6.9 (s, 1H), 7.54 (m / 2H); and 8j24 (m, 2H).

2-methoxyethyl 5.67 1.24 (m, 3H); 2.6 (m, 2H); 3.25 (s) and 3.0-3.72 (c, 9H); 4.64 and 5.0 (m, 1H), 5.3 (s, 2H), 6.9 and 7t22 (s, 1H), 7.4 δ (m, 2H); and 8.2 (m. 2H).

2- (methylthiazole, 65 1.26 (t, 3H) and 2,4 2 (s) 5-yl) ethyl 2,3-3.8 (C, 11H); 4.76, 5.0 ( m, lH); 5.34 (s, 2H); 6.67.6 <93 (s, 1K), 7.5 (d, 2H); and 8.2 (d, 2H).

30 propyl 5.66.16 (m, 6H); l, 76 (m, 2K); 2.62 (10.2.86-3.86 (0.4 «), 4.76 and 5.0 (m, 1K), 5.32 (s, 2H), 6.7 and 6.9 (s, 1H), 7.46 (d, 2H), and 8.2 (d, 2H).

72 82470 R-, IR (microns) - N, N (P) (ppm) 1,3-dioxolane-, 64 1.22 (m, 3H); 2.17-4.08 2-ylmethyl (c, 1OH) -4 * 57-5.4 (c, 4K); Δ 6.66.6.9 (s, 1H), 7.5 (m, 2H); and 8.22 (m. 2H).

2- (2-pyrrole-5.64 6fO 2 1.24 (m, 3H); 1.82-3.68 don-1-yl) (c, 14H); 4.8.5.05 (m, 1H); Ethyl 5.35 (s, 2H), 6.7, 6.94 (s, 1H); 7.5 δ (m, 2 H); and 8.24 (m. 2H).

2- (2-furanoyl-5,65 6,03 1,2 (m, 3H); 2,24-3,78 amino) -ethyl] -2,2,2 (c, 8H); 4.58-5.02 (c, 1 H); 5.24 (s, 2 H), 6.36 (m, 1H); 6,57,6,8 (s, 1H); and 6.98 (d, 1H); Δ 2,2-diethoxy-5.65 1.22 (m, 9H); 2.4-4.34 ethyl (c, 10F); 4.5-5.4 (c, 4H); 6,66,6,9 (m, lH); 7.5 (m, 2H); and 8.23 (m, 2H).

2- (p-nitrobenz-5.66 5.8 1.22 (c, 3H); 2.38-3.74 syloxocarbonyl- (c, 8H); 4.67-5.4 (c, 5H) amino) ethyl 6f67,6,92's, 1H), 7.53 (c, 5H); and 8.28 (m. 4H).

2- (2-pyridyl) 5.66 1.2 (m, 3H); 2.74 (m, 2H); ethyl 2.9-3.94 (c, 6H), 4.66, 4.94 (m, 1H), 5.2 (s, 2H); 6.6, 6.83 (s, 1 H), 7.0 δ (m, 2 K); 7.44 (c, 3H); 8.14 (m, 2H); 35 and 8.4 δ (m, 1H).

I) 73 82470

Preparation P

p-nitrobentsyyliglyoksylaattietyylihemiasetaali

A stirred solution of 32.0 g of tartaric acid bis (p-nitrobenzyl) ester in 850 ml of tetrahydrofuran was cooled to 0-5 ° C and 26.0 g of periodic acid was added in one portion. Stirring was continued for 2 hours at 0-5 ° C and then the reaction mixture was filtered. To the filtrate was added 100 ml of ethanol and then the resulting solution was evaporated in vacuo. The residue was dissolved in 700 ml of 10-10 roform and washed successively with concentrated aqueous sodium thiosulfate solution (5 times) and water (2 times). The chloroform solution was dried over anhydrous sodium sulfate and then evaporated in vacuo to give the title compound as a viscous liquid (yield: 25.5 g).

Preparation Q

Potassium 2-etoksietyylitritriokarbonaatti

To a solution of 6.79 g of potassium t-butoxide in 300 ml of anhydrous tetrahydrofuran was cooled to 20 ° C under a nitrogen atmosphere, 6.42 g of 2-mercaptoethylethyl ether was added. The resulting slurry was stirred at 25 ° C for 1 hour, then 4.4 mL of carbon sulfide was added dropwise at 0 ° C. The resulting solution was stirred at 25 ° C for 30 minutes. It was then concentrated in vacuo. Diethyl ether (300 mL) was added and the mixture was filtered, washed with ether and dried under nitrogen to give 12.6 g of the title compound as a yellow solid.

Also prepared by this method using the appropriate mercaptan starting material were the following potassium trithiocarbonates: 1,3-dioxolan-2-ylmethyl; 2- (p-nitrobenzyloxycarbonylamino) ethyl; 2- (4-methyl-thiazol-5-yl) ethyl; 2- (acetylamino) ethyl; 2- (2-pyridyl) ethyl; 2,2-diethoxyethyl; 2- (2-furanoyyliami-amino) ethyl; and 2- (2-pyrrolidon-1-yl) ethyl.

74 82470

Preparation R

Sodium 2-metoksietyylitritiokarbonaatti

To a solution of 1.62 g of sodium methoxide in 75 ml of anhydrous ethanol cooled to 0 ° C under a nitrogen-5 atmosphere was added dropwise a solution of 4.02 g of 2-methoxyethylthioacetate in 25 ml of anhydrous ethanol. The solution was stirred at 0 ° C for 1 h, then 2.36 g of carbon disulfide was added dropwise. The resulting yellow solution was stirred at 25 ° C for 1 h, concentrated in vacuo. The residue was triturated with hexane and the hexane was decanted. The residue was then triturated with ether and filtered to give 3.7 g of the title compound as a yellow solid.

Also prepared using the appropriate thio-15 acetate starting material by this method were the following sodium trithiocarbonates: 1,3-dioxolan-2-ylmethyl; 2- (p-nitro benzyloxycarbonylamino) ethyl; 2- (4-methylthiazol-5-yl) ethyl; 2- (acetylamino) ethyl; 2- (2-pyridyl) ethyl; 2,2-diethoxyethyl; 2- (2-furanoyyliamino) ethyl; 20 and 2- (2-pyrrolidon-1-yl) -ethyl.

of

Claims (12)

75 82470 A process for the preparation of 2-substituted-2-penem-3-carboxylic acid compounds of the formula (I) and their pharmaceutically acceptable salts, wherein R (p) (I) -N-1 ° 2R 2 10 in which R is hydrogen, 1-hydroxyalkyl having 1 or 2 carbon atoms or wherein 1-hydroxyalkyl is substituted with a hydroxy protecting group; R 1 is (alk) -G, (alk) -G 2, G 2 or CH (G 2) 2, wherein (alk) is an alkyl group having 1 to 4 carbon atoms; G is hydrogen, alkoxy of 1 to 5 carbon atoms, 2- (alkoxy) ethoxy of 3 to 7 carbon atoms, alkylthio of 1 to 5 carbon atoms, phenoxy, thiophenoxy, azido, 20 amino, amino with a substituent amino protecting group, N-phenyl-N-alkylamino having 1 to 4 carbon atoms in alkyl, N-alkanoylamino having 2 to 6 carbon atoms, N-alkoxyalkanoylamino having 3 to 10 carbon atoms, 2- (N-alkanoylamino) ethoxy of 4 to 8 carbon atoms, amino-25 carbonyl, aminocarbonyloxy, N-alkylaminocarbonylamino of 2 to 5 carbon atoms, alkanoylaminoacetylamino of 4 to 7 carbon atoms, N-alkylaminocarbonyloxy, aminocarbonylalkoxy of 2 -5 carbon atoms, N-alkylaminocarbonyl having 2 to 5 carbon atoms, or N- (alkoxyalkyl) aminocarbonyl having 3 to 9 carbon atoms; G 1 is azetidinyl or azetidinyl substituted with N-alkanoyl having 2 to 6 carbon atoms or an amino protecting group; a five- or six-membered ring which is carbocyclic or heterocyclic and has one or two oxygen atoms, one, two, three or four nitrogen atoms, a sulfur atom, a nitrogen atom and an oxygen atom or a nitrogen atom 76 82470 sulfur atom, a nitrogen atom and an oxygen atom or a nitrogen atom, or said five or six membered ring substituted with alkyl of 1 to 4 carbon atoms, dialkyl each having 1 to 4 carbon atoms, oxo, amino, amino substituted with an amino protecting group, alkoxycarbonyl having 2-5 carbon atoms, di- (alkoxycarbonyl) each having 2-5 carbon atoms, aminocarbonyl, alkoxyalkyl having 2-7 carbon atoms, phenyl, formyl, N-alkylaminocarbonyl having 10 to 5 carbon atoms, N- alkylaminocarbonylamino having 2 to 5 carbon atoms, alkanoylamino having 2 to 5 carbon atoms, alkoxy having 1 to 4 carbon atoms, phenoxyacetyl or a heterocyclic nitrogen atom substituted with an amino protecting group; G 2 is alkanoylaminomethyl each having 3 to 7 carbon atoms, or alkoxy each having 1 to 4 carbon atoms; R 2 is hydrogen, an ester group that is hydrolyzed in the body, or a carboxylic acid protecting group; characterized in that a) to a compound of formula (V), wherein R 7 is halogen, R 4 is alkyl of 1-7 carbon atoms; atom, or alkyl substituted with alkoxy of 1 to 4 carbon atoms, and i is zero, and R and R 2 are as defined above, a xanthate salt of the formula M * R 1 -O- (C = S) -S 'is added, wherein M * is a metal cation and R 2 is as defined above, li 77 82470 b) treating the beta-lactam of formula (VI) thus obtained R 2 - s (°) iR 4 Process according to Claim 1, characterized in that the hydroxy-protecting group is trialkylsilyl and is removed in a further step with tetraalkylammonium fluoride, in which each alkyl contains 1 to 7 carbon atoms. Process according to Claim 1, characterized in that it comprises the further step of removing the hydroxy-protecting group, the carboxyl-protecting group or the amine-protecting group by hydrogenation, treatment with zinc or treatment with tetrakis (triphenylphosphine) palladium. A compound of formula (VII1) ^ S (O) .R4 15. n (VII ') jr N \ ^ OR o Y CO2R2 20 wherein R is hydrogen, 1-hydroxyethyl or p-nitrobenzyloxycarbonyloxyethyl, R2 is p- nitrobenzyl or calcium, R 1 is (alk) -G, (alk-G 1 Gx or CH (G 2) 2, wherein (alk) is an alkyl group having 1 to 4 carbon atoms; G is hydrogen, alkoxy having 1 to 5 carbon atoms, 2-25 (alkoxy) ethoxy having 3 to 7 carbon atoms, alkylthio having 1 to 5 carbon atoms, phenoxy, thiophenoxy, azido, amino, amino having an amino protecting group as a substituent, N-phenyl-N-alkylamino in which alkyl has 1 to 4 carbon atoms, N-alkanoylamino having 2 to 6 carbon atoms, N-alkoxy-sialkanoylamino having 3 to 10 carbon atoms, 2- (N-alkanoylamino) ethoxy having 4 to 8 carbon atoms, aminocarbonyl 1, aminocarbonyloxy, N-alkylaminocarbonylamino having 2 to 5 carbon atoms, alkanoylaminoacetylamino having 4 to 7 carbon atoms, N-alkylaminocarbonyloxy, 35 aminocarbonylalkoxy having 2 to 5 carbon atoms, N-alkyl- 79 82 470 l aminocarbonyl having 2 to 5 carbon atoms, tax N- (alkoxyalkyl) aminocarbonyl having 3 to 9 carbon atoms; Gx is azetidinyl or azetidinyl substituted with N-alkanoyl having 2 to 6 carbon atoms or an amino protecting group; a five- or six-membered ring which is carbocyclic or heterocyclic and has one or two oxygen atoms, one, two, three or four nitrogen atoms, a sulfur atom, a nitrogen atom and an oxygen atom or a nitrogen atom and a sulfur atom, or said five- or six-membered ring is a substituent alkyl having 1 to 4 carbon atoms, a dialkyl each having 1 to 4 carbon atoms, oxo, amino, amino having an amino protecting group as a substituent, alkoxycarbonyl having 2 to 5 carbon atoms, di- (alkoxycarbonyl) , each having 2 to 5 carbon atoms, aminocarbonyl, alkoxyalkyl having 2 to 7 carbon atoms, phenyl, formyl, N-alkylaminocarbonyl having 2 to 5 carbon atoms, N-alkylaminocarbonylamino having 2 to 5 carbon atoms , alkanoylamino having 2 to 5 carbon atoms, alkoxy having 1 to 4 carbon atoms, phenoxyacetyl or a heterocyclic nitrogen atom substituted with an amino protecting group; G 2 is alkanoylaminomethyl each having 3 to 7 carbon atoms, or alkoxy each having 1 to 4 carbon atoms; And R 4 is alkyl of 1 to 7 carbon atoms, or alkyl substituted with alkoxy of 1 to 4 carbon atoms, and i is zero. A compound of formula (III ') R \ __ ^ R5 i S UH ·) J_'TOR-, ύ 1 CO2R2 35 wherein R, R1 and R2 are as defined in claim 4 and R5 is chlorine. so 82470 5 I »(VI) -Nv 2 -S-C-OR 0 Y c ° 2r 2 wherein R, Rx, R 2, R 4 and i are as defined above, with sodium hydride in a reaction inert solvent at -10 ° C to 5 ° C, followed by the addition of one molar equivalent of acetic acid to give the compound of formula (VII) beta-lactam according to R, S (O) .R. C) halogenating the beta-lactam of formula (VII) thus obtained in a reaction-inert solvent at a temperature of -40 ° C to 5 ° C with at least one molar equivalent of halo. a generating agent to give a beta-lactam of formula (III) wherein R, R 1 and R 2 are the same as above, and R 5 is chlorine, and d) cyclizing the thus obtained beta-lactam of formula (III). The beta-lactam of (III) is treated with a base in a reaction-inert solvent at a temperature of 0 to 25 ° C to give the desired compound. 78 82 470 A compound of formula (VI ') R S (O). R \ i 4 »(VI ·) c ^ Nv, S-C-OR, 3 o -''- 1 CO2R2 wherein R, R2, R4 and i have the same meaning as in claim 4. not 82470