DE2757083A1 - 3BETA-AMINO- OR 3BETA-ACYLAMINO- 4ALPHA-ACETOXYAZETIDINONES AND PROCESS FOR THEIR PREPARATION - Google Patents

Description

- '■ 1' 'I I i .'_ J * J

tv.-i.Vv, ¹ . .u.! -W

X-4683 A

Eli Lilly and Company, Indiana po lis, Indiana, V.St.A.

3ß-Amino- or 3ß-acylamino-4alpha-acetoxyazetidinones and processes for their preparation

809827/0796

The invention relates to new 3ß-amino and 3ß-acylamino-4alpha-acetoxyazetidinones, the valuable antibacterial substances for combating ß-lactamase producing gram-negative bacteria and other pathogens or are intermediates in the manufacture of such antibiotics, as well as a new one Process for the preparation of these 3ß-amino- and 3ß-acylamino-4alpha-acetoxyazetidinones.

The subject of the invention are thus. ß-lactam antibiotics. In particular the invention relates to monocyclic β-lactam antibiotics which are 3β-acylaminoazetidin-2-ones.

The penicillins and the cephalosporins are known ß-lactam antibiotics, which are bicyclic compounds that contain a fused ring system. Both Penicillins is a 4-membered ß-lactam ring on a thiazolidine ring condensed, while in the cephalosporins the ß-lactam ring is condensed to a dihydrothiazine ring. Monocyclic ß-lactam antibiotics are less well known. Recently the monocyclic ß-lactam antibiotic is nocardicin found. It is discussed in BE-PS 830 934 and in the 15th Interscience Conference on Antimicrobial Agents and Chemotherapy, Dist. No. 97, Sept. 1975.

Nocardicin has the following structure! Formula:

0 H

HOOC-CH-CHz-CHs-oV V-C-C-N-f-J. , _

I N = · '"1-4-C- /> -0H

w ^COOH

Microbiologists and chemists are taking action because of the importance of ß-lactam antibiotics for the treatment of infectious diseases Great efforts are made to identify and develop other ß-lactam antibiotics that are compared to either a broader one

809827/0796

Spectrum of microorganisms are effective or which have a stronger effect than the previously available antibiotics.

Monocyclic ß-lactamazetidinones with an acetoxy group in position 4 have not yet become known.

The invention now relates to 3ß-amino- and 3ß-acylamino-4-alpha-acetoxyazetidinones of formula I.

0
Ii
.0-C-CHa

COORi

Yes'

a and a ¹ independently of one another are hydrogen, halogen, hydroxy, protected hydroxy, C ..- C ₄ -alkyl, C ₁ -C ₄ -AlkOXy, amino, protected amino, aminomethyl or protected aminomethyl,

R stands for amino or acylamino, and

R _{1 is} hydrogen or a carboxylic acid protecting group

is,

and, if the substituent R _{1 is} hydrogen, the pharmaceutically acceptable non-toxic salts thereof.

The invention is also directed to a process for the preparation of 3ß-amino- and 3ß-acylamino-4-alpha-acetoxyazetidinones of formula I.

809827/0796

-y-

R-

Il

^) - C-CHs

C00R1

a '

a and a ^{1 are} independently hydrogen, halogen, hydroxy, protected hydroxy, C ..- C ₄ -alkyl, Cj-C - alkoxy, amino, protected amino, aminomethyl or protected aminomethyl,

R stands for amino or acylamino and

R _{1 is} hydrogen or a carboxylic acid protecting group,

and, if the substituent R _{1 is} hydrogen, the pharmaceutically acceptable acid addition salts thereof,

which is characterized in that a non Thiazolidinazetidi- of the formula II

Shark
0

Il

Ra-C-

CL CHa.

II »

where Ra is C .. -C ^ .- alkyl , phenyl, benzyl or phenoxymethyl and R ₁ , a and a * have the meanings given above,

809827/0796

A -

Si

with mercury (II) acetate in the presence of acetic acid to one N-propenyl-4alpha-acetoxyazetidin-2-oneamide of the formula III

CHa
I.

OC = CHs
Ii i
Ra-C- Ν— f—

III

(f

COOUi

wherein Ra, R ₁ , a and a 'have the meanings given above,

converts the N-propenyl ^ alpha-acetoxyazetidin-2-oneamide obtained then to a 4alpha-acetoxyazetidin-2-one of the formula IV

Ra-C-NH-

.0-C-CH ₃ ·

COOR ι

IV

wherein Ra, R ₁ , a and a 'have the meanings given above,

hydrolyzed, of the 4alpha-acetoxyazetidin-2-ones obtained in this way, if desired, the one present in position 3 in a manner known per se Cleaving acyl group and thus obtaining compounds of the formula I in which R is amino, the compounds obtained in this way 3-Amino-4alpha-azetidin-2-ones, if desired, reacylated in a manner known per se and from the obtained in this way Compounds optionally removing the carboxy, hydroxy or amino protective groups in a manner likewise known per se,

809827/0796

-y-

and the compounds thus formed, if desired finally converted in the usual way into their pharmaceutically acceptable, non-toxic salts.

Preferred 3ß-amino and 3ß-acylamino-4-alpha-acetoxyazetidiones are those in which R is an acylamino group of the formula

0 H Il I R'-C-N-

means, where either

R 'represents C ₁ -C ₄ -alkyl, cyanomethyl, bromomethyl, chloromethyl, phenyl or a group of the formula

0 /

a " A ~ ^K "

R-O-C-CH-CHa-Cl la-O- · ^

NH

is where

R ^{a is} hydrogen, benzyl, diphenylmethyl or 4-methoxybenzyl,

R is hydrogen or an amino protecting group of the formula

il R ^C -OC-

means in the

R ^{c stands} for t-butyl, 2,2,2-trichloroethyl, benzyl, 4-nitrobenzyl, cyclopentyl or cyclohexyl, and

809827/0796

Z stands for = 0 or = N-OZ ', where Z' is hydrogen, Is acetyl, chloroacetyl, triphenylmethyl or p-methoxybenzyl, or

is a group of the formula R ¹ '-CH--, wherein R ¹ ' is a phenyl group of the formula

means in which b and b ¹ independently of one another are hydrogen, halogen, hydroxy, C ..- C ₄ -alkyl,

, Are amino or aminomethyl, or

R ¹¹ thienyl, furyl, thiazolyl, oxazolyl, isothiazolyl, tetrazolyl or an isoxazolyl group of the formulas

means in which

d hydrogen, methyl or a group of the formula

ν-

is, in which b and b ^{1 have} the meanings given above, and

Denotes hydrogen, methyl or chlorine, or 809827/0796

R ^{1 is} a phenoxymethyl group of the formula

. • -O-CHz-

wherein b and b ^{1 have} the meanings given above, represents, or

R ^{1 represents} a group of the formula R ¹ ^ -S-CH ₂ -, in which R ¹ "is a group of the formula

b '

wherein b and b ^{1 have} the meanings given above,

Represents 4-pyridyl, thiazolyl, thiadiazolyl or oxadiazolyl, or

a group of the formula

HI

R "" -ΟΙ Q

means in which

R "" for a pheny group of the formula

where b and b ^{1 have the} above meaning,

Thienyl or furyl and 809827/0796

-X-

Is amino, hydroxy, carboxy, -SO ₃ H, -NH-SO ₃ H or any protected form thereof, or

R 'is a group of the formula

Z "

means in which

R " ^{M has} the meaning given above and

Z ¹ 'represents hydrogen, acetyl or methyl,

or

a group of the formula

HI

R "" -ΟΙ

N-H I

C = O I ■ Y ■

represents where

R "" has the meaning given above and

Y is a dimethylureido group of the formula

CH3 0 H II I - N - C - N - CHa

809827/0796

an imidazolidin-2-one group of the formula

Il
0

wherein Y ^{1 is} hydrogen, C - C ₄ alkyl, C ₂ alkanoyl or methanesulfonyl, or

an N-methylacyl group of the formula

Chb 0
I i!
- N -CY "

means in which

Y ^{11 represents} C.-C ₄ alkyl or a group of the formula

is where

η stands for 0 or 1 and

a ¹¹ denotes hydrogen, nitro or chlorine.

809827/0796

Individual examples of phenyl groups according to the definition given above for the formula

Χ -. /

a '

are phenyl, 4-hydroxyphenyl, Ί - (tetrahydropyran-2-yloxy) phenyl, 4-benzyloxyphenyl, 3-hydroxyphenyl, 3,4-dihydroxyphenyl, 4-chlorophenyl, 3, 4-dichlorophenyl, 2,6-dichlorophenyl, 3-bromophenyl, 3-chloro-4-hydroxyphenyl, 3-chloro-4-methylphenyl, 4-t-butylphenyl, 3,4-dimethylphenyl, 2,4-dimethylphenyl, 4-ethylphenyl, 3-Methyj-4-hydroxyphenyl, 4-aminophenyl, 3-aminophenyl, 3-amino-4-raethylpheny], 2-aminomethylphenyl, 4-aminomethylphenyl, 4-methoxyphenyl, 2,6-dimethoxyphenyl, 3-ethoxy-4-hydroxyphenyl, 4-isopropoxyphenyl, 4-chloro-2-aminomethylphenyl, 3-bromo-4-methoxyi-ihenyl , H-MetLyl - 4-arainophenyl and similar phenyl-substituted Groups.

Individual examples of phenyl groups of the formula given above

are phenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 3-bromophenyl, 3-chloro-4-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxyphenyl, 3,4-dihydroxyphenyl, 4-methylphenyl, 4-t-butylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 3-ethoxy-4-hydroxyphenyl, 4-aminophenyl, 4-aminomethylphenyl, 3-methyl-4-aminophenyl, 2,6-dimethoxyphenyl , 3-bromo-4-methoxyphenyl and similar substituted groups.

Examples of amino protective groups in the above formula I with the formula

r "
ROC

809827/0796

are t-butyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, cyclopentyloxycarbonyl or Cyclohexyloxycarbonyl.

The term thienyl refers to 2-thienyl or 3-thienyl, thiazolyl is understood to mean 2-thiazolyl or 5-thiazolyl, the term tetrazolyl refers to 1- or 2-tetrazolyl, Thiadiazolyl includes 1,3,4-, 1,2,5- or 1,2,4-thiadiazol-5-yl understood, and the term oxadiazolyl refers to 1,3,4-oxadiazolyl.

Individual examples of isoxazolyl groups of the formula given above I according to the formulas

or

are 3-methylisoxazol-5-yl, 3,4-dimethylisoxazol-5-yl, 4-chloroisoxazol-5-yl, 3-phenyl-4-chloroisoxazol-5-yl, 3- (4-chlorophenyl) -isoxazol-5 -yl, 3- (2-chlorophenyl) isoxazol-5-yl, 3- (2-chlorophenyl) -4-methylisoxazol-5-yl, 3- (2,6-dichlorophenyl) isoxazol-5-yl, 3- ( 2,6-dichlorophenyl) -4-methylisoxazol-5-yl, isoxazol-5-yl, 3- (2,4-dimethylphenyl) -4-methylisoxazol-5-yl, 3- (2,6-dimethylphenyl) -4 -chlorisoxazol-5-yl, 3- (4-methoxyphenyl) isoxazol-5-yl, 3- (2,6-dimethoxyphenyl) -4-chloroisoxazol-5-yl, 3- (3-chloro-4-hydroxyphenyl) - 4-methylisoxazol-5-yl, 3-methyl-5-chloroisoxazol-4-yl, 3,5-dimethylisoxazol-4-yl, 3-phenylisoxazol-4-yl, 3- (4-chlorophenyl) -5-methylisoxazole- 4-yl _/ 3- (2-chlorophenyl) -5-chloroisoxazol-4-yl, 3- (2,6-dimethoxyphenyl) -5-methylisoxazol-4-yl and similar isoxazoles.

The compounds of the formula I can be classified as monocyclic Designate ß-lactam antibiotics or azetidin-2-ones, which are substituted in position 1 by an alpha-carboxybenzyl group or a alpha-carboxybenzyl group are substituted and in Position 3 have a ß-amino group or a ß-acylamino group, and which are also substituted in position 4 by an acetoxy group.

609827/0796

The diazolidinazetidinone of the formula required as starting material II can be made in the following manner. L-cysteine is reacted with dry acetone at reflux temperature, whereby 2,2-dimethyl-4-thiazolidinecarboxylic acid is obtained. By acylating this acid with an acyl chloride in the presence of propylene oxide a 3-acyl-2,2-dimethyl-4-thiazolidinecarboxylic acid is obtained formula

CH; j, Qb

OOH

wherein Ra has the meaning given above. By coupling this thiazolidine carboxylic acid with an ester of a phenylglycine of formula

I V \

COORi ^a

in which a, a 'and R _{1 have} the meanings given above, an amide of the formula is formed

Ra-C-

To carry out this coupling reaction, the active ester of thiazolidine carboxylic acid is first formed with 1-hydroxybenzotriazole (HBT). Subsequently, it sets the thus obtained active ester in the presence of dicyclohexylcarbodiimide with phenylglycine ester in order.

809827/0796

Examples of phenylglycine esters that can be used to form the above Allow amides to be used are benzylphenylglycinate, 4-methoxybenzylphenylglycinate, Benzyl-4-methoxyphenylglycinate, benzyl-4-chlorophenylglycinate, Benzyl-3,4-dimethylphenylglycinate, benzyl-4-hydroxyphenylglycinate, 2,2,2-trichloroethylphenylglycinate, 4-methoxybenzyl-3-chloro-4-hydroxyphenylglycinate, benzyl-4-t-butylphenylglycinate, Benzyl 4-aminophenyl glycinate or 2,2,2-trichloroethyl-S 1-4 dichlorophenyl glycinate. If these phenylglycine esters are substituted with a reactive functional group, which can interfere with the desired coupling reaction (N-acylation), for example a phenolic hydroxyl group or a Amino group, then these groups become during the amidation reaction as well as blocked in subsequent reactions of the process. The amino group can be replaced, for example, by the t-butyloxycarbonyl group (t-BOC group) or through the benzyloxycarbonyl group. The phenolic hydroxyl group is blocked preferably with the Beiizyigruppe or the Tetrahydropyranylgruppe.

The thiazolidinamide of the given formula obtained in the above manner it is then heated in a hydrocarbon at reflux temperature as a solvent, such as benzene or toluene, with benzoyl peroxide, producing the 5-alpha-benzoate derivative of the formula

Ra-CH _T ".

arises. This benzoate is then reacted with hydrogen chloride in methylene chloride at about ⁰ ° C., whereby the corresponding 5-alpha-chlorine compound is formed with elimination of the benzoate function. Subsequent reaction of this 5-alpha-chloro amide with sodium hydride under anhydrous conditions in a halogenated hydrocarbon solvent, such as methylene chloride, at temperatures between about ⁰ ° C. and 30 ^° C. leads to the formation of the substituted thiazolidinazetidin-2-one with intramolecular cyclization Formula II

809827/0796

-M-

Ra-C-N ^ \

1 1 H H

J-Mx

COORι ^a

The compounds of the above formula are used herein for convenience referred to for the sake of thiazolidinazetidinone derivatives. These compounds are correctly referred to as 2-acyl-3,3-dialkyl-7-oxo-alpha- ^ substi tuierte-phenyl_ / - 4-thia-2, 6-diazabicyclo- / 3.2.O / heptane-6-acetic acid ester.

The compounds of Formula I are prepared by the method described above. The implementation of the Thiazolidinazetidinons with mercury acetate is carried out in acetic acid or in an inert cosolvent with acetic acid. As a cosolvent can beispitilsw.i se tetrahydrofuran, dioxane, dimethylformamide or use dimethylacetainide. It comes with a big one Excess acetic acid worked, 1 to 3 moles of mercury acetate also being used per mole of thiazolidine acetidinone. Preferably 1.5 to 2.0 moles of mercury acetate are used per mole of starting material.

The reaction is preferably carried out in acetic acid with heating to a temperature of 25 to 75 ⁰ C. After the reaction has taken place, the reaction mixture is filtered to completely remove insoluble mercury bonds and the resulting filtrate is evaporated. The desired product is then extracted from the residue obtained with an organic solvent which is immiscible with water, such as ethyl acetate. The resulting product, namely an N-propenylamide of the formula III given above, does not need to be purified for hydrolysis into the corresponding amide. The hydrolysis is best carried out at temperatures between 15 and 55 ^° C. in a water-miscible solvent, for example tetrahydrofuran, with dilute hydrochloric acid, for example amounts of 2 to 10 percent by weight hydrochloric acid. Diluted

809827/0796

- γί -

Sulfuric acid or dilute phosphoric acid can also be used for this purpose. Alternatively, the hydrolysis can also be carried out in aqueous tetrahydrofuran, preferably 50 percent aqueous tetrahydrofuran, with mercury acetate. It is preferable to work with an amount by weight of mercury acetate which corresponds to the amount of N-propenylamine used. The hydrolysis can be carried out at temperatures between 15 and 45 ^° C., preferably working at 20 to 25 ^° C.

After the hydrolysis of the N-propenylamide has ended, it is evaporated Reaction mixture, dissolves the resulting product-containing precipitate in a water-immiscible solvent, such as ethyl acetate, and then v / ash this solution for removal traces of acid with dilute base, such as sodium bicarbonate. The resulting product, namely an ester of 1- / alpha- (carboxy) benzyl- or -substituted-benzyiy-BB-acylamido-ialphaacetoxyazetidin-2-one of the formula IV given above, is obtained from the washed solution, and it can then be chromatographed Purify further over silica gel.

The 3ß-amino-4alpha-acetoxyazetidin-2-ones are prepared from the 3ß-acylamido-4alpha-acetoxy hydrolysis product by conventional means N-Deacylation / for example by reacting with phosphorus pentachloride in the presence of pyridine to form a Acylimidochloride as an intermediate, reacting this product with methanol to form an acylimido ether and final Hydrolysis of this ether.

The 3ß-acylaminoazetidin ~ 2-ones of the formula I, in which R is an acylamino group the formula

O H

η ι

R ¹ -CN-

means are by acylation of the 3ß-amino nucleus compounds manufactured. This acylation is carried out by methods known in cephalosporin and penicillin chemistry. For acylation it is best to use an active derivative of a carboxylic acid

809827/0798

Formula R ¹ -COOH. Active derivatives of these acids include the acyl halides, such as the acid chlorides, the acid bromides, the acid azides or the mixed anhydrides with methyl chloroformate, ethyl chloroformate or isobutyl chloroformate. The acylation can also be carried out using the free carboxylic acid as well as a condensing agent such as dicyclohexylcarbodiimide, and this process is described, for example, in US Pat. No. 3,218. For this acylation, preference is given to using the acid halide method or the method using a mixed anhydride. The acylation via an acid halide can be carried out in an aqueous or a non-aqueous solvent in the presence of a hydrogen halide acceptor such as sodium bicarbonate, a tertiary amine such as triethylamine or pyridine, or an alkylene oxide such as propylene oxide or butylene oxide. The method of acylation via a mixed acid anhydride is carried out under anhydrous conditions in the presence of triethylamine.

The carboxylic acids used for the synthesis of the compounds of the formula I. the formula

0
R'-C-OH

are either commercially available or in a manner known per se manufacturable.

During the preparation of the compounds der.Formel I are possibly any reactive functional groups present, such as the amino, hydroxy or carboxy groups, with a suitable one Blocking group protected. For this purpose, the most diverse can be known in penicillin and cephalosporin chemistry Use carboxy, hydroxy and amino protecting groups. The amino group can for example by the t-butyloxycarbonyl group or the 2,2,2-trichloroethoxycarbonyl group. the Hydroxy group can be, for example, through the benzyloxycarbonyl group or through a substituted benzyloxycarbonyl group protect, for example by the 4-nitrobenzyloxycarbonyl group

809827/0796

or the protecting group formed by reacting the hydroxy group with methyl vinyl ether. Acid substituents, such as the carboxy, SuIfο or SuIfamino groups can have a suitable carboxylic acid protective group be protected, for example via ester groups such as the benzyl group, a substituted benzyl group such as 4-nitrobenzyl, 4-methoxybenzyl or 2,4,6-trimethylbenzyl, one Diphenylmethylestergruppe, a Trihalogenmothylestergruppe, such as 2,2,2-trichloroethyl, or any other suitable carboxylic acid blocking group. Appropriate blocking groups for the functional groups indicated above are those functional blocking groups selected which can easily be split off again after the actual reaction.

Those azetidin-2-ones of the formula I in which R is an acylamino group the form]

M '/ ^Z °

R ^a -OCC-CH ₂ -CH ₂ -O -. ^ "XCC-Nh- '· —_ ·

NH

means are prepared by adding a 3ß-aminoazetidin-2-one core compound with the amino-protected and esterified 4- (3-carboxy-3-aminopropoxy) phenylglyoxylic acid or the oxime or acylated protected oxime thereof. Acid, oxime, or protected Oximes of this type can be produced by the following method.

809827/0796

An amino protected salt of D-methionine of the formula

0 H Il I

M-O-C-C-CHz-CH ^ -S-CHa

for example a salt in which M is dicyolohexylammonium and R has the meaning given above, is converted into the trimethylsilyl ester and on the sulfur atom with an alkyl or Benzyl iodide, for example with methyl iodide, alkylated, followed by the resulting alkylsulfenium iodide of the formula

ü H -J- Il I

(CH ₃ ) a Si-OCC-CHa-CHa-S-CHa II NH CHa

in an inert solvent with potassium t-butoxide to form of the cyclic amino-protected D-homoserine lactone of the formula

implements.

II

This lactone is then amino-protected with an alkali hydroxide D-homoserinal alkali salt of the formula

H H

. I I

R ^b -NC-CH2-CHs5-0H

COOM *

809827/0796

where M ^{1 is} sodium or potassium, hydrolyzed, which is then converted into an acid-labile ester, for example diphenylmethyl ester. Subsequent coupling of this esterified D-homoserine with 4-hydroxyphenylglyoxylic acid p-nitrobenzyl ester with a trialkyl- or triarylphosphine, preferably with triphenylphosphine, and with diethylazodicarboxylate gives the amino-protected diester of the formula

OH 0

R ^a -0-CC-CH2-CH2-O- »f VC-COO-CH2- (/ -NO2

NH

The p-nitrobenzyl ester group is then selectively deesterified by reduction in such a way that the other ester group R ^a , which is an acid-labile ester group, remains essentially intact. The p-nitrobenzyl ester group is removed, for example, by reduction with sodium sulfide, and under these reduction conditions the ester group R ^a , which can be an acid-sensitive group such as the diphenylmethyl group, remains unaffected. The product obtained during this selective deesterification, namely the phenylglyoxylic acid obtained, has the formula

OH 0

MI "

R ^a -0-CC-CH2-CH2-0—

NH

The amino-protected and esterified phenylglyoxylic acid is then converted into an active ester, which is used for acylation a 3β-aminoacetidin-2-one core compound is used.

809827/0796

After the acylation has taken place, this is transferred as an intermediate product occurring alpha-ketoacylamide in the biologically active Oxime. The 4- / 3- (t-Butyloxycarbamido) -3- (diphenylmethoxycarbonyl) Propoxyy-phenylglyoxylic acid is transferred, for example in using the active ester with 1-hydroxybenzotriazole of dicyclohexyicarbodiimide as a condensing agent and then couples the resulting ester with 1- / alpha (benzyloxycarbonyl) -'l-benzyloxybenzyl / ^ ß-amino ^ alpha-acetoxyazetidin ^ -one, which leads to 1 - / alpha- (Benzy loxycarbonyl) -4-benzyloxybenzyl / -3ß- / 4- (3-t-butyloxycarbamido) -3- (diphenylmethoxycarbonyl) propoxy _ / - phenylglyoxylamido-4alpha-acetoxyazetidin-2-one the formula

0 Il

. ° ^C ~ ^CH3

OM ü 0 H

CQ ^ HhOV ")

t-BOC

arrives, in which the abbreviations given have the following meanings:

DPM = diphenylmethyl,
t-BOC = t-butyloxycarbonyl,
Bz = benzyl.

Reaction with hydroxylamine hydrochloride in the presence of a weak base such as sodium bicarbonate converts the above Alpha-ketoamide then into the oxime derivative, from which one can split off the t-BOC group, the DPM group and the benzyl group the antibiotic of the following formula I receives.

809827/0796

H
I.

HOOC-C-CH2-CH2-O— «

NHa

0 •
• Il O H , X-CHa
• COOH Il I
—CCNf- Il J I.
OH

> —OH

Optionally, the nocardicin side chain can also be synthesized, by first using the protected oxime of 4-hydroxyphenylg.lyoxylic acid ester forms, then couples the oxime ester with the amino-protected and esterified D-homoserine fragment and the resulting Glyoxylic acid ester is finally selectively de-esterified. For this purpose, for example, p-nitrobenzyl 4-hydroxyphenyl glyoxylate is used with hydroxylamine hydrochloride, whereupon the oxime obtained first with potassium t-butoxide and then with p-methoxybenzyl bromide converts, whereby the O- (p-methoxybenzyl) oxime is formed. By subsequent coupling of this oxime fragment by the method described above with D-3- (t-butyloxycarbamido) -3- (diphenylmethoxycarbonyl) propanol (an amino-protected and esterified D-homoserine) one obtains a p-nitrobenzyl-D-4- / 3- (t-butyloxycarbamido) -3- (diphenylmethoxycarbonyl) propoxy / phenylglyoxylate-O- (p-methoxybenzyl) oxime the formula

0 H

Il I /

DPM-O-C — C — CHz-CHa-O - * /

I ^X

N-H

t-BOC

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in which the individual abbreviations have the following meanings:

DPM = diphenylmethyl,

t-BOC = t-butyloxycarbonyl,

pMB = p-methoxybenzyl,

pNB = p-nitrobenzyl.

By subsequent removal of the p-nitrobenzyl ester group from the above compound by chemical reduction with, for example, zinc and acid or by electrolytic reduction ' the free carboxylic acid is obtained for the acylation of the 3ß-amino nucleus.

The following list gives examples of azetidin-2-ones of formula I, in which R stands for

H 0 I Il

R '· "' -C-C-NH-I

NH I

C = O I Y

which have the following structural formula:

809827/0796

ο υ η ti

Il I O-C-CH »

I.
Y

R ¹ '''Ϊ aa ¹

O phenyl -N (CH ₃ ) C-NH-CH ₃ H II

Phenyl 0
-N (CH ₃₎ C-NH-CHj 4-OH H 2-thienyl C)
-N (CH ₃ ) C-NH- H H 2-furyl 0
-N (CH ₃₎ C-NH-CH ₃ H 3-OH 4-hydroxy
phenyl O
-N (CH ₃₎ C-NH-CH ₃ H H Phenyl - ^, - " 4-OH J-Cl phenyl -Pt ^ J-SOaCHz
3 II . H 2-thienyl 0
-NHC-CH = CH0 4-OH 3-CH ₃ 2-furyl 0
-NHC-CH ₃ H H phenyl O
-NII-C-0 II 3-NH ₂

809827/0796

2757U83

Examples of antibiotic compounds of formula I, in which the substituent R is a radical of the formulaL

Il

K -C-C-NH-

Il N I

0 I Z ''

means, emerge from the following table:

Ü ti H

Il l ^ D- C-CHj

N _{ f , V -. \

CUOII

0-z ''

_K i i Z ¹ ' a a ¹ PhenyL II H II PhenyL CH, • 1-OH II PhenyL CII, II II PhenyL H 4 -C) H II PhenyL II 4-OH ) -CL 2-thienyL CII ₃ II II 2-thienyL II 4-OH II 2-thienyL CH, 4 -C L H 2-thienyL CH ₃ 4 -CH, II 2-thienyL CH ₃ 4-nitro II 2-FuryL H 4-C) H II 2-FuryL CH ₃ 4-OH H 2-FuryL CH, H II 2-Furyi CH ₃ 4-OH 3-Cl 2-Furyi H 4-Dr H 2-FuryL CH ₃ 3-CH, 4-CH

609827/0796

The alpha-oximino- and the alpha-methoximino-substituted azetidin-2-ones can have either syn or anti configuration, and mixtures of both configurations can be used in their preparation develop. The syn configuration is preferred.

Examples of compounds of the formula I in which R ^{denotes a radical of the formula R 1} '-CH - C (O) -NH- are shown in the table below, and they correspond to the following general formula:

0 0 H Il

Il I JO-C-CH: »

R-Cte-C-N -.- ·

(f IV =. \

COOH ^{a <}

R "aa ¹

Phenyl H 4-hydroxyphenyl 4-OH Phenyl 4-OH Phenyl 3-OH 2-thienyl H 2-thienyl 4-OH 2-thienyl 4-OH 2-furyl H 2-furyl 4-NH ₂ Thiazol-4-yl H Isothiazol-5-yl 3-Br Oxazol-5-yl H Oxazol-5-yl 4-CH ₃ Oxazol-5-yl 4-OH iH-tetrazol-1-yl H 1H-tetrazol-1-yl 4-NH-CH

3-Cl

3-CH.

809827/0796

a ¹

Isoxazol-4-yl H.

3-methyl-4-chloroisoxazol-5-yl 4-OH

3- (2-Chlorophenyl) -isoxazol-4-yl H.

3,4-dichloroisoxazol-5-yl

4 - OH

3-chloro-4-methylisoxazol-5-yl H

3,5-dimethylisoxazol-4-yl 4-OCH

H H

3-Cl H 3-OCH

Examples of compounds dor formula I in which the radical R is an acylamino group of the formula R ¹ ^ -S-CH ₂ -C (O) -NH- are shown in the following table, and they correspond to the following general formula:

O H Il I

R "'-S-CH ₂ -CN-

DC-CH ₃

COOH

^a '

a ¹

Phenyl H H Phenyl 4-OH H Phenyl 4-Cl H 3,4-dichloro
phenyl 4-OH 3 3,5-dichloro
phenyl 4-OH 3

3-OCH

3-Cl

809827/0796

ι _ς

3-methyl-4-
hydroxyphenyl 4-OH H 4-pyridyl H H 4-pyridyl H 3-OH 4-pyridyl 3-Ci H 4-pyridyl 4-Br H 4-pyridyl 3-OC ₂ H ₅ 4-OH 2-thiazolyl 4-OH H 1,3,4-thiadia
zol-2-yl H H 1,3,4-thiadia
zolyl-2-yl 4-OH 3-Cl 1 / 3,4-oxadiazole
2-yl II H 1,3,4-oxadiazole
2-yl 3-CH ₃ 4-CH ₃

Examples of compounds of the formula I in which R is a radical of the formula

H 0 I Il

R '"' -C-C-NH-I

are shown in the table below, and they correspond following general formula:

HOO H I II I 0-C-CHa

R "

XI

COOH ^a '

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_R ,.,. Q Phenyl NH ₂ Phenyl NH ₂ Phenyl NH ₂ Phenyl NH ₂ 2-thienyl NH ₂ 2-furyl NH ₂ 2-thienyl NH ₂ Phenyl OH Phenyl COOH Phenyl SO ₃ II 2-thienyl COOH 4-hydroxyphenyl NII ₂ 4-hydroxypheny1 COOH 2-furyl SO ₃ II J-chlorine-1-
hydroxyphenyl OH 2-thienyl OH 2-thienyl SO ₃ II 4-chlorophenyl OH

a '

II II 4-OH H 4-OH 3-Cl 4-Cl II 4-OH H 4-OH II 4-OCH ₃ 3-CH ₃ 4-OH H H II 4-OH 3-OH II II II H 4-OH 3-Cl H 2-OCH 4-OH II 4-Cl H 4-OC ₂ H ₅ H

4-OH

3-CII

The 3ß-acylaminoazetidin-2-ones of the formula I, in which the substituents R., R ^a , R and Z ^{1 are} each hydrogen, a and a ^{1 are} something other than protected hydroxy, protected amino or protected aminomethyl and Q is not a protected one Rest represents are interesting antibiotics that stimulate growth

B09827 / 0796

inhibit pathogenic microorganisms. These compounds resist inactivation by β-lactamases and are opposed to gram-negative bacteria that produce these enzymes, such as Proteus, Pseudomonas, Enterobacter sp., Serratia or Klebsiella.

The compounds of the invention are used parenterally, for example administered subcutaneously, intramuscularly or intravenously, preferably in the form of their pharmaceutically acceptable non-toxic salts.

The esterified, amino-protected, oxime-protected, and hydroxy-protected Azetidinones of the formula I are suitable as intermediates for the synthesis of the antibiotic compounds.

The azetidin-2-one antibiotics of the formula I have a acidic carboxylic acid group which forms salts with suitable bases. Appropriate pharmaceutically acceptable salts include the alkali salts, such as the sodium, potassium or lithium salts, the calcium salts and those with pharmaceutically acceptable Amines formed salts, such as the salts with mono- and diethanolamine, procaine, cyclohexylamine, dicyclohexylamine, Dibenzylamine, abietylamine, trimethylamine or triethylamine.

Those 3ß-acylaminoazetidin-2-ones of the formula I in which Q stands for an amino group can form acid addition salts, for example hydrochlorides or hydrobromides. ^{If a substituent a or a 1} and b or b 'present on the phenyl group contains an amino group, then these antibiotics can likewise form acid addition salts.

B09827 / 0796

-3y-

Furthermore, such 3ß-amino and 3ß-acy! Amino compounds, which have an alpha-amino substituent in their side chains (Q = NH-), intramolecular salts (hermaphrodites? ions) if the substituent R. is hydrogen.

The 3β-aminoazetidin-2-one core compounds of the formula I in which the substituent R stands for an amino group are valuable Intermediate products for the preparation of the antibiotic 3ß-acylaminoazetidin-2 ones. Is the phenyl group one Alpha-carboxybenzyl substituents in position 1 of the azetidin-2-one ring substituted by hydroxy or amino, then such groups are during the synthesis, for example during the N-acylation or N-deacylation, preferably blocked by a suitable blocking group. Core compounds that have such blocking groups and the esters of these core compounds are also valuable intermediates. Examples of such Core compounds are shown in the following list, and they fall under the following formula

Il

/) - C-CH3 H2N-1

ttes- *?

ν * ^ΧΙ1

COORi ^a

Benzyl

Benzyl

DPM ¹

pNB ²

a a ' H H 4-OH H 4-benzyloxy H 4-Cl H H 2-Cl 4-O-pNB 3-Cl

809827/0796

ι "

a '

pNB 4-benzyloxy H 4-OH pMB ³ 2-CH ₃ O H 2-Cl pNB 4-NH-Bz ⁴ Benzyl 2-CH ₂ NH-Bz 1 = diphenylmethyl 2 = p-nitrobenzyl 3 = p-methoxybenζy1 4 = benzyloxycarbonyl

3-CH ₃

3-Br

4-CH ₃ O

6-Cl

The carboxylic acid protective groups R _{1 of} the formula I are carbon esters such as are customary for temporary protection or for temporary blocking of the carboxylic acid function in other β-lactam antibiotics, for example in the penicillins and cephalosporins. Examples of such ester groups are the haloalkyl groups such as the trichloroethyl group and the tribromethyl group, the benzyl group and the substituted benzyl group such as p-nitrobenzyl, p-methoxybenzyl, 3,5-dimethoxybenzyl, 2,4,6-trimethylbenzyl, diphenylmethyl (benzhydryl), 4-methoxydiphenylmethyl or t-butyl The methods for splitting off these ester groups are known from the literature.

The 3-amino group or 3-acylamino group present in position 3 as a substituent R in formula I has the β-configuration. The acetoxy substituent present in position 4 is obtained in the present process in the alpha configuration.

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The ones on the nitrogen atom of the azetidin-2-one ring (position 1) alpha-carboxybenzyl group or substituted alpha-carboxybenzyl group present may have either the D-configuration or the L-configuration, with the D-configuration preferred will. The process described here for the preparation of the 3ß-amino-4alpha-acetoxyazetidin-2-one nucleus leads to the preferred one D-configuration, if the phenylglycine is used in the D-configuration in this process.

Similarly, those compounds of the formula I in which R is an acylamino group of the formula

0 H Il I

R '"' -CH-C-N-I

stands, either the D-configuration or the L-configuration to have. However, the compounds described preferably have the D configuration.

Certain compounds of Formula I are preferred over others. A preferred group of compounds from the Formula I are those in which the substituent R is an acylamino group of the formula

0 ZO

R ^a -OC-CH-CH2-CH2-O— <■) · —CC-NH-I · = ·

NH
I.

R ^b

^r r δ 9 8 2 7 / O 7 9 6

Of these preferred compounds, in turn, more preferred are those in which R ^a and R each represent hydrogen, Z is the hydroxyimino group, a is 4-hydroxy and a ^{1 is} hydrogen. In particular, this becomes the 4-alpha-acetoxynocardicin of the formula

H
HÖOC-C-CHss-CHe-

_D -

NH ₂

* ^v

OH-C-C-N-f ~

J4

Il
.0-C-CHa

XIII

DI ^Ν
COOH

preferred.

As an intermediate for the production of the above 4alpha-acetoxynocardicin becomes the compound of the formula

OH Il I

DPM-OCC-CHs-CHz-O-. NH ₂

OH

»>
· —CCN— · -

O I

ρ MB

O II O-C-CH ₃

I ^χ · ~ ι COODPM

XIV

preferred.

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-A-

Another preferred group of compounds of the formula I include those in which R is benzoylamino, phenylacetylamino or phenoxyacetylamino. These compounds are formed during the synthesis of the 4-acetoxy-substituted-acetidin-2-ones and can be used for the synthesis of the 3-amino-4-acetoxyazetidin-2-one nucleus described above be used.

The invention is further illustrated by the following examples.

Manufacturing 1

2-Benzoyl-3, S-dimethyl-T-oxo-alpha- (4-benzyloxyphenyl) -4-thia-2, 6-diazabicyclo / ^. 2 .O / heptane-6-acetic acid benzyl ester

A suspension of 100 g of L-cysteine in 2 l of dry acetone is heated to reflux temperature for about 17 hours. Subsequently, the reaction mixture is allowed to about 30 ⁰ C to cool down the unreacted cysteine was filtered off and recrystallized, the obtained 2,2-dimethyl-4-thiazolidine carboxylic acid from the filtrate. Successive filtration gives three crops of product. The product obtained weighs a total of 83 g.

A suspension of 16 g (100 mM) of the above product in 300 ml of dry acetone is treated with 21 ml of propylene oxide. 11.6 ml (100 mM) benzoyl chloride are then added dropwise with vigorous stirring. The temperature of the reaction mixture increases slowly from about 25 ^° C. to about 33 ^° C. After about one hour, all of the thiazolidine has gone into solution and the reaction solution begins to cool. As soon as the temperature has ^{dropped to 30 °} C., the reaction solution is evaporated. The resulting white solid as a residue is dissolved in acetone, and by diluting this solution with

27/0796

Hexane crystallizes the desired 3-benzoyl-2,2-dimethyl-4-thiazolidinecarboxylic acid which are filtered off and dried. The dried product weighs 18.7 g.

A solution of 48 g (181 mM) of the 3-benzoyl-2,2-dimethyl-4-thiazolidinecarboxylic acid prepared in the above manner in 1.5 l of tetrahydrofuran 27.8 g (181 mM) 1-hydroxybenzotriazole are added and then with 37.4 g (181 mM) dicyclohexylcarbodiimide. The resulting mixture is stirred at room temperature for 30 minutes. Precipitation of dicyclohexylurea turns the reaction mixture into a viscous sludge. The sludge is 63 g (181 mM) benzyl-D-4-benzyloxyphenylglycinate added, and this The reaction mixture is then stirred for about 2 hours at room temperature. The dicyclohexylurea is then filtered from the reaction mixture off, the filtrate is evaporated under reduced pressure and the resulting residue is dissolved in ethyl acetate. The solution is made sequentially with 5 percent hydrochloric acid, water, aqueous sodium bicarbonate, and then again washed with water. The washed solution is dried, treated with activated charcoal and dried under reduced pressure evaporated to give 107 g (99% yield) of N- / benzyl-alpha- (D-4-benzyloxyphenyl) acetate / -3-benzoyl-2,2-dimethyl-4-thiazolidinecarboxamide receives.

The above thiazolidine carboxamide ester (107 g, 0.18 M) is dissolved in 4 l of benzene and the solution is then treated with 175 g (0.72 M) Benzoyl peroxide. The solution is then heated to reflux temperature for 4.5 hours, after which the whole is brought to room temperature cools down. The reaction mixture is then poured into a silica gel packed column and the column is eluted with benzene. The excess of benzoyl peroxide comes out first Column off, and after further elution with benzene comes the desired product. By subsequent evaporation of the product

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containing eluate under reduced pressure gives N- / benzylalpha- (D-4-benzyloxyphenyl) acetate / -3-benzoyl-2,2-dimethyl-4-thiazolidinecarboxamide-5alpha-benzoate in the form of an oil. This product can be crystallized from diethyl ether.

The above product has the following structural formula:

O = C

· - * s

NMR (T6O, CDCl ₃ ): 2.16 (s, 2CH ₃ ), 5.08 and 5.16 (2s, ₂

5.13 (s, CH), 5.54 (d, CH), 6.54 (s, CH) and 6.83-8.16 (m, aromatic H and NH) delta.

A solution of 25.5 g (35.8 inM) of thiazolidine-4-carboxamide-5alpha-benzoate in 1 l of dry methylene chloride is ^{cooled to 0} ° C., whereupon hydrogen chloride is passed into the cold solution for about 2 hours. A corresponding thin-layer chromatographic analysis of the reaction mixture at this point in time with development with a mixture of benzene and ethyl acetate under a volume ratio of 7: 3 shows that the reaction has ended. The methylene chloride is therefore evaporated under reduced pressure, whereby the desired product is obtained in the form of a foam. The foam is dissolved in methyl acetate and the solution is washed with a dilute aqueous sodium bicarbonate solution and with brine. Then dry

809827/0 796

bb

the solution is over magnesium sulphate, treated with activated charcoal and finally evaporated under reduced pressure Dry up. In this way, 22.4 g of N- / benzyl-alpha- (D-4-benzyloxyphenyl) acetate / -3-benzoyl-2,2-dimethyl-5alphachlor-4-thiazolidinecarboxaiaid are obtained in the form of a white foam with the following formula:

•egg

Λ - ·

OOOCHa-βζ ^.

NMR (T6O, CDCl ₃ ): 2.12 (s, CH ₃ ), 2.26 (s, CH ₃ ), 5.08 and

5.16 (2s, 2CH ₂ ), 5.16 (s, CH), 5.44 (d, CH), 5.83 (s, CH) and 6.08-7.5 (m, 2OH, aromatic H and NH) delta.

A solution of 22.4 g (35.8 mM) of the 5alpha-chloro-4-thiazolidine carboxamide in 800 ml of methylene chloride and 200 ml of dimethylformamide, 1.72 g of sodium hydride (50 percent Suspension in mineral oil, 35.8 mM). The reaction mixture is then stirred for about 50 minutes at room temperature, whereupon a thin-layer chromatographic analysis (benzene: ethyl acetate, 7: 3) indicates the completion of the reaction. The reaction mixture is added to destroy excess sodium hydride therefore with 2 ml of acetic acid and then pour it

809827 / 079S

in 5 percent hydrochloric acid. The organic layer is separated and washed with 5 percent hydrochloric acid and water before drying over magnesium sulfate. The dried extract is treated with activated charcoal, filtered and evaporated to dryness under reduced pressure. The resulting residue is dissolved in about 30 ml of ethyl acetate. On standing, 10.1 g (crop 1) of 2-benzoyl-3, S-dimethyl-T-oxo-alpha- (4-benzyloxyphenyl) -4-thia-2,6-diazabicyclo / 3.2.0 / heptane-6 crystallize benzyl acetate from. The crystals are filtered off and the filtrate is treated with petroleum ether to the cloud point. If this filtrate is left to stand with stirring, a further 5.5 g (crop 2) of crystalline product are obtained. This second crop of material is also filtered off, whereupon the filtrate is evaporated to dryness. In this way, another product is obtained in the form of a foam. The foam is treated with a mixture of ethyl acetate and ethyl alcohol, which gives 2.2 g more crystalline product (crop 3).

NMR analysis (T 60) of the above product crops shows that Harvest 1 is the D-isomer of the cyclic product of the following formula, while Harvest 2 is the corresponding one L-isomer and crop 3 is a mixture of both isomers.

* COOCHz- /

NMR (T60, CDCl ₃ ): 1.70 (s, CH ₃ ), 1.91 (s, CH ₃ ), 5.08 and

5.16 (2s, 2CH ₂ ), 5.45 (s, CH), 5.52 (m, 2CH) and 6.83-7.67 (m-19H, aromatic H) delta.

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The above thiazolidinazetidinone is also prepared starting from 5alpha-chlorothiazolidine carboxamide by the process described below and the base diazabicyclo / 5.4.0 / undec-5-en (DBU).

A solution of 1.01 g (1.6 mM) of the 5alpha-chloro-4-thiazolidincarboxamids D-configuration in 50 ml of methylene chloride is cooled to about 0 ⁰ C. 0.243 g (1.6 mM) DBU are then added to the cooled solution. The reaction mixture is first ^{stirred for 2 hours at 0 °} C., then washed with 5 percent strength hydrochloric acid and with sodium chloride solution and finally dried over magnesium sulfate. Subsequent evaporation of the solution gives a crude reaction product mixture. The mixture is crystallized from benzene petroleum ether, whereupon the crystals are filtered off. The IR spectrum of this product shows an absorption maximum at 1775 cm for the β-lactam carbonyl, while the NMR spectrum and circular dichromism show that the material is optically pure.

example 1

1- / alpha- (benzyloxycarbonyl) ^ - benzyloxybenzylZ-Sfl-benzamido- '4alpha-acetoxyazetidin-2-one

A slurry of 300 mg (0.505 mM) 2-benzoyl-3,3-dimethyl-7-oxo-alpha- (4-benzyloxyphenyl) -4-thia-2,6-diazabicyclo / 3.2.0 / -heptan- 6-acetic acid benzyl ester in 25 ml of acetic acid, while stirring, it is treated with 240 mg (0.75 mM) of mercury acetate (mercury (II) acetate). The reaction mixture is heated on a water bath for 10 minutes, mixed with a further 100 mg of mercury acetate and heated for another 5 minutes. The insoluble mercury (I) acetate is then filtered off from the reaction mixture and evaporated the whole thing then to dryness. The resulting residue is

809827/0796

dissolved in ethyl acetate, whereupon the solution is washed with dilute aqueous sodium bicarbonate solution and with sodium chloride solution, dried and finally evaporated to dryness. In this way, 1- / alpha- (benzyloxycarbonyl) -4-benzyloxybenzyl ₁ / -3- (N-propenylbenzamido) -4-alpha-acetoxyazetidin-2 of the formula is obtained

° ^Ac

· —OCHa- \) ·

• rr

The above product is dissolved in 50 ml of tetrahydrofuran and 5 ml of 5% hydrochloric acid is added to the solution. After stirring for 15 minutes at room temperature, evaporate the solution is evaporated to dryness under reduced pressure and the residue obtained is dissolved in ethyl acetate. The ethyl acetate solution is washed with dilute aqueous sodium bicarbonate solution and with water, dried and then evaporated to dryness. By subsequent chromatography of the residue obtained in this way on a preparative thin-layer silica gel plate using a mixture of benzene and ethyl acetate in a volume ratio of 7: 3 for development is obtained as Hydrolysis product 144 mg "! - / alpha-benzyloxycarbonyl) -4-benzyloxybenzyl / -3β-benzamido-4-alpha-acetoxyazetidinone-2.

809827/0796

Example 2

1- / alpha- (Benzyloxycarbony1) -4-benzyloxybenzyl / -3ß-phenoxy acetamido-4alpha-acetoxyazetidin-2-one

The procedure described in Example 1 is used to prepare with benzyl ester the 2-phenoxyacetyl-3,3-dimethyl-7-oxo-alpha- (4-benzyloxyphenyl) -4- ^ 18-2, ö-diazabicyclo / S. 2.0 / heptane-6-acetic acid.

Example 3

1 - / alpha- (benzyloxycarbonyl) -4-benzyloxybenzy_l / -3β-amino-4alpha acetoxyazetidin-2-one

A solution of 250 mg (0.432 mM) 1- / alpha- (benzyloxycarbonyl) -4-benzyloxybenzy] ./- 3ß-benzamido-4-alpha-acetoxyazetidinone-2, prepared according to the process described in Example 1, in 50 ml of dry benzene, 132 mg (0.64 mM) of phosphorus pentachloride are added and 50 mg (0.64 mM) pyridine. The mixture is stirred

Heated to about 65 ^° C. for 2 hours. A subsequent thin-layer chromatographic examination of the reaction mixture shows that the starting material used has been converted into the corresponding imidochloride.

The reaction mixture is therefore evaporated under reduced pressure and the resulting residue is mixed with 50 ml of dry methyl alcohol. The methyl alcohol solution is about 30 minutes at Room temperature stirred. The subsequent thin-layer chromatographic analysis of this solution shows up in the thin-layer chromatogram a new spot.

The solution is evaporated under reduced pressure, whereupon the residue is mixed with 20 ml of water and with 20 ml of tetrahydrofuran added and the resulting solution then stirred for about 20 minutes at room temperature. Then you evaporate

809827/0796

remove the tetrahydrofuran from the solution and slurry the aqueous concentrate with ethyl acetate. The pH of the slurry is then adjusted to pH 7, whereupon the ethyl acetate layer separated, dried and finally evaporated under reduced pressure. This is how you get to 210 g of a reduction product mixture. The NMR spectrum (T 60) of this product mixture shows that it is about 60% of the contains desired N-deacylation product, namely 1- / alpha- (benzyloxycarbonyl) -4-benzyloxybenzyiy-3ß-amino ~ 4alpha-acetoxyazetidinone-2 the formula

"COOCHa— · <

The subsequent purification of this crude product by preparative thin-layer chromatography over silica gel thick-layer plates gives 62 mg of the desired product and 60 mg of starting material.

Example 4

1- / alpha- (carboxy) -4-hydroxybenzyl / -3ß- (D-mandelamido) -4alpha acetoxyazetidin-2-one __

A solution of 1- / alpha- (p-nitrobenzyloxycarbonyl) -4-benzyloxybenzy] y-3ß-amino-4alpha-acetoxyazetidin-2-one is kept at 0 to 5 ⁰ C and treated with pyridine and with O-formylmandeloyl chloride

puts. The mixture is stirred in the cold for about 2 hours and then evaporated. The residue is mixed with water and the acylation product extracted with ethyl acetate. The extract

809827/0796

is washed with water, dilute acid and again with water, whereupon it is dried and evaporated. In this way, the esterified N-acylation product 1- / alpha- (p-nitrobenzyloxycarbonyl) -4-benzyloxybenzyl / -3ß- (O-formylmandelamido) -4alpha-acetoxyazetidin-2-one is obtained. De-esterification of this ester with zinc and acetic acid results in splitting off the 4-benzyloxy group is the compound named in the title.

Example 5

1- / alpha- (carboxy) -4-hydroxybenzy] _L / -3 [beta] / 2- / 4- P-carboxy-S-aminopropoxy) phenyjL / -2-hydroximinoacetamido / 4alpha-acetoxyazetidin-2-one

A solution of 32 mg of 1- / alpha- (benzyloxycarbonyl) -4-benzyloxybenzyl / -3ß-amino-4alpha-acetoxyazetidin-2-one in about 5 ml of dry methylene chloride is treated with 4- (3-diphenylmethoxycarbonyl-3-t-butyloxycarbamidopropoxy) phenylglyoxylic acid offset. The mixture is stirred at room temperature under nitrogen, and 14 mg of dicyclohexylcarbodiimide are added. This will make the Solution immediately dark yellow. After 10 minutes the solution has turned light yellow with precipitation of dicyclohexylurea. One corresponding thin-layer chromatographic analysis of the reaction mixture on silica gel plates using a Mixture of benzene and ethyl acetate in a volume ratio of 7: 3 shows that the reaction has ended. The reaction mixture is therefore filtered and the filtrate evaporated to dryness.

Purification of the acylation product obtained in this process on preparative thick-layer plates (silica gel) gives 41 mg purified intermediate.

This intermediate product is added to the hydroxyimino derivative with hydroxylamine hydrochloride in aqueous tetrahydrofuran which contains pyridine around. The oxime thus obtained is then trifluoroacetic acid

809827/0796

converted into anisole, whereby the t-BOC amino protecting group and the diphenylmethyl ester group of the side chain are removed. After treatment with the acid, the reaction mixture is evaporated to dryness and the residue obtained is treated with diethyl ether. The resulting insoluble 1- / alpha- (benzyloxycarbonyl) -4-benzyloxybenzyl./-3ß-/2-/4- (3-carboxy-3-aminopropoxy) phenyI ₁ / -2 ~ hydroxy iminoacetamido / -4alpha-acetoxyazetidine 2-ontrifluoroacetate is filtered off and dried.

The above salt is then dissolved in dry methylene chloride, whereupon the solution obtained to remove both benzyl ester groups with an excess of aluminum chloride and Anisole treated in nitromethane. The reaction mixture is then quenched with water and the pH is adjusted with sodium bicarbonate to about 8.0. The solution is then washed with ethyl acetate and ion exchanged based on of a three-dimensionally cross-linked polysaccharide obtained by cross-linking linear macromolecules of dextran (Sephadex). By evaporating the resulting Eluate leads to the title compound in the form of the disodium salt.

The course of the debenzylation reaction is monitored by thin layer chromatography over silica gel plates using a mixture of acetic acid and acetone in a volume ratio tracked by 4: 1 to development.

Example 6

1- / alpha- (Diphenylmethoxycarbonyl) -4-hydroxybenzyl _L / -3ß- amino-4alpha-acetoxyazetidin-2-one

A solution of 4 g of 2-benzoyl-3, S-dimethyl-T-oxo-alpha- (4-hydroxyphenyl) -4-thia-2,6-diazabicyclo / 3.2.0 / heptane-6-acetic acid and 5 g of diphenyldiazomethane in 500 ml of dry tetrahydrofuran is about

809827/0796

Stirred for 18 hours at room temperature. The reaction mixture is then evaporated to dryness under reduced pressure, whereupon the residue is dissolved in ethyl acetate. The desired 2-benzoyl-3,3-dimethyl-7-oxoalpha- (4-hydroxyphenyl) -4-thi crystallizes from this solution a-2,6-diazabicyclo / 3.2.0 / heptane-6-acetic acid diphenylmethyl ester the end. This gives 3.5 g of the diphenylmethyl ester.

A suspension of 1 q of the above diphenylmethyl ester in about 100 ml of acetic acid are mixed with 1 g of mercury (II) acetate while stirring. The reaction mixture is then heated on a water bath for about 10 minutes with continued stirring. It is then filtered the insoluble constituents from the reaction mixture and the filtrate is evaporated to dryness under reduced pressure. That included Resulting reaction product mixture is dissolved in ethyl acetate, whereupon the solution with dilute aqueous sodium bicarbonate solution as well as washes with saline solution, dries and evaporates to dryness. In this way, 1.1 g of 1- / alpha- (diphenylmethoxycarbonyl) are obtained -4-hydroxybenzy] ./- 3- (N-propenylbenzamido) 4alpha-acetoxyazetidinone-2.

650 mg of the above propenyl-4alpha-acetoxyazetidin-2-ondiphenylmethyl ester 'Dissolve in 50 ml of water and 50 ml of tetrahydrofuran, whereupon the whole thing with 650 mg of mercury (II) acetate offset. The reaction mixture is stirred for about 1 hour at about room temperature, after which it is added under reduced pressure Evaporate dry. The resulting residue containing hydrolysis product is dissolved in ethyl acetate. The ethyl acetate solution is washed with dilute aqueous sodium bicarbonate solution and water, whereupon they are dried and evaporated to dryness. A corresponding NMR analysis (T 60) of the material obtained in this way shows that the hydrolysis of the N-propenyl group has ended. The 1- / alpha (diphenylmethoxycarbonyl) -4-hydroxybenzyl ./-3ß-benzamido-4alpha-acetoxyazetidinone-2 obtained (600 mg) is used without further purification in the following procedure.

809827/0796

A solution of 510 mg of the 4alpha-acetoxyazetidinone-2-diphenylmethyl ester prepared in the above manner in 40 ml of dry tetrahydrofuran is mixed with 2 ml of dihydropyran and a small catalytic amount of p-toluenesulfonic acid. The reaction mixture is stirred for about 17 hours at about room temperature. A corresponding analysis by thin layer chromatography over silica] shows that both the starting material and the desired tetrahydropyranyl ether with the hydroxybenzyl group in position 4 are present. About 0.5 g of sodium carbonate is therefore added to the reaction mixture with further stirring. After stirring for 15 minutes, the solvent is evaporated and the residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with sodium bicarbonate and with water, whereupon it is dried and evaporated to dryness. Starting material and product present in the residue are separated on silica gel chromatography plates using a mixture of toluene and ethyl acetate in a volume ratio of 7: 3 for elution. In this manner there is obtained 280 mg of 1- / alpha (diphenylmethoxycarbonyl) -A- tetrahydropyranyloxybenzy] ./- 3.beta.-benzamido-4alpha-acetoxyazetidinone-2 and 178 mg of starting material.

A solution of 78.5 mg (0.38 mM) phosphorus pentachloride and 29.9 mg (0.38 mM) pyridine in about 20 ml of dry methylene chloride is added with stirring at room temperature and under nitrogen with 168 mg (0.26 mM) of the 4alpha-acetoxyazetidin-2-one tetrahydropyranyl ether diphenyl methyl ester obtained in the above manner. The reaction mixture is stirred under nitrogen at room temperature, periodically adding a portion of the reaction mixture withdrawn and thin-layer chromatography using a mixture of benzene and ethyl acetate with a Investigated volume ratio of 7: 3 for elution. After about

809827/0796

The one-hour implementation time shows the thin-layer chromatography Analysis of the reaction mixture only shows a trace of the starting material and a new spot corresponding to the imino chloride. The methylene chloride is therefore evaporated and the concentrate is added with 30 ml of dry methyl alcohol. The methyl alcohol solution is stirred for about 2 hours at about room temperature. The methanol is then evaporated off and the residue obtained is mixed with 20 ml of water and 20 ml of tetrahydrofuran. The aqueous solution is stirred for about 1 hour at about room temperature, after which the tetrahydrofuran is evaporated from it. The resulting aqueous concentrate is extracted with ethyl acetate, whereupon the extract is dried and dried to dryness evaporates. The crude residue obtained in this way is purified by chromatography on silica gel, and obtained in this way to 81 mg of 1- / alpha (diphenylmethoxycarbonyl) -4-hydroxybenzyl / -3ß-amino-4alpha-acetoxyazetidin-2-one.

Example 7 4alpha-acetoxynocardicin

A solution of 300 mg (0.65 inM) of the 4alpha-acetoxyazetidin-2-one-kernediphenylmethyl ester, prepared according to the method described in the above example, and 435 mg (0.65 mM) 4- / 3- (diphenylmethoxycarbonyl) -3- (t-butyloxycarbamido / propoxy / phenylglyoxylic acid-0- (4-methoxybenzyl) oxime in about 25 ml of dry methylene chloride is kept at about room temperature and under nitrogen 135 mg (0.65 mM) dicyclohexylcarbodiimide were added. The reaction mixture is left for about 2 hours at about room temperature stirred under nitrogen, whereupon it is filtered and the filtrate

809827/0796

evaporated to dryness. By subsequent chromatographic work-up the residue on a preparative silica gel plate using a mixture of toluene and ethyl acetate with a volume ratio of 1: 1 to elution, 391 mg of the acylated product, namely 4alpha-acetoxynocardine, are obtained of the following formula with slotted through t-butyloxycarbonyl Amino group, carboxyl groups protected by benzylhydryl and oxime group protected by 4-methoxybenzyl. That The NMR spectrum of this product (T 60) shows a trace of contamination. By further purifying this product in the same chromatographic System, 332 mg of purified product are obtained.

ü H 0

Il
CV-C-CH ₃

Il I Λ- * H

DPM-OCC-CHz-CHz-O- · (^ »- C — C — NH-» Ψ.

^ ,, ._ COOOPM

The protected bisdiphenylmethyl ester of 4alpha-acetoxynocardicin the above formula is mixed with 12 ml of trifluoroacetic acid containing 24 drops of anisole for 3 minutes at about room temperature, treated. The reaction mixture is evaporated to dryness, and followed by vigorous treatment of the residue with diethyl ether, 157 mg of 4alpha-acetoxynocardicin trifluoroacetate salt are obtained.

NMR: DMSO (D ₆ ), D ₃ O (trimethylsilane) 1.95 (s, -C (O) CH ₃ ), 2.31 (t, CH ₂ ), 4.15 (t and d, -CH- CH ₂ ), 4.74 (d, -CH-), 5.2O (s, -CH-), 5.88 (d, -CH-) and 6.66-7.52 (aromatic H) delta.

809827/0796

Claims (39)

K'EINiO - LEViK * - CF ¹ OTT Patent claims 1 / 3ß-amino and 3ß-acylamino-4-alpha-acetoxyazetidinones of formula I. 0 Il ι, COORi ^a wherein a and a ¹ independently of one another are hydrogen, halogen, hydroxy, protected hydroxy, C ₁ -C ₄ -AIlCyI, C ₁ -C ₄ -AIkOXy, amino, protected amino, aminomethyl or protected aminomethyl, R stands for amino or acylamino and R _{1 is} hydrogen or a carboxylic acid protecting group, and, if the substituent R _{1 is} hydrogen, the pharmaceutically acceptable non-toxic salts thereof. 809827/0796 ORIGINAL INSPECTVD 2. 3ß-Amino- and 3ß-Acylamino-4-alpha-acetoxyazetidinones of the formula I mentioned in claim 1, wherein R is an acylamino group the formula 0 H Il I R '- C-N- means, where either for Cj-C.-alkyl, cyanomethyl, bromomethyl, Chloromethyl, phenyl or a group of the formula Ii NH is where R ^{a is} hydrogen, benzyl, diphenylmethyl or 4-methoxybenzyl, R is hydrogen or an amino protecting group of the formula Il R ^C -OC- means in the R ^{C stands} for t-butyl, 2,2,2-trichloroethyl, benzyl, 4-nitrobenzyl, cyclopentyl or cyclohexyl, and 809827/0796 Z stands for = 0 or = Ν-ΟΖ ', where Z ^{1 is} hydrogen, acetyl, chloroacetyl, triphenylmethyl or p-methoxybenzyl, or R ^{1 is} a group of the formula R ¹ '-CH ₂ - in which R ¹ ' is a phenyl group of the formula means in which b and b ^{1 are} independent of one another Hydrogen, halogen, hydroxy, C ₁ -C ₄ -AlKyI, C.-C.-alkoxy, amino, or aminomethyl, or R ' ¹ thienyl, furyl, thiazolyl, oxazolyl, isothiazolyl, tetrazolyl or an isoxazolyl group of the formulas means in which d hydrogen, methyl or a group of the formula is, in which b and b 'have the meanings given above, and d 'is hydrogen, methyl or chlorine, or 809827/0796 R ^{1 is} a phenoxymethyl group of the formula , »- O-CHa- wherein b and b 'have the meanings given above, represents, or R 'is a group of the formula R ¹¹ ^ -S-CH ₂ -, in which R ¹ "is a group of the formula where b and b 'have the meanings given above, Represents 4-pyridyl, thiazolyl, thiadiazolyl or oxadiazolyl, or a group of the formula HI R "" -ΟΙ denotes where R "" represents a phenyl group of the formula wherein b and b ^{1 have the} above meaning , is thienyl or furyl and 809827/0796 Q Amino, hydroxy, carboxy, -SO ₃ H, -NH-SO ₃ H or any protected form thereof means, or a group of the formula R C- Il N I> O Z " means in which R "" has the meanings given above and Z ^{11 represents} hydrogen, acetyl or methyl, a group of the formula HI R "" -ΟΙ N-H I C = O I Y represents where R "" has the meaning given above and Y is a dimethylureido group of the formula CHa 0 HI II I -NCN-CH ₃ 809827/0796 an imidazolidin-2-one group of the formula Il wherein Y ^{1 is} hydrogen, C ₁ -C ₄ -AllCyI, C ₃ -alkanoyl or methanesulfonyl, or an N-methylacyl group of the formula CH ₃ 0
I Il
-N - C - Y ' means worm Y ¹ 'for C ₁ -C ₄ -AlKyI or a group of the formula - (OCCH) _n - «f _χ · is where η stands for 0 or 1 and a ¹¹ denotes hydrogen, nitro or chlorine. 809827/0796 3. A compound according to claim 1 or 2, characterized characterized in that R ^{1 is} a radical of the formula R ^a -0-C-CH-CH2-CHz-0- «f _/ \ ^x «rr · ti NH Z stands in which R, R and Z have the meanings given in claim 2. 4. A compound according to claim 3, characterized in that Z is oxygen. 5. A compound according to claim 3, characterized in that Z stands for = N-OZ '. 6. A compound according to claim 1 or 2, characterized characterized in that R * is a group of the formula R "" -CH- means in which R "" has the meaning given above and Q is amino, hydroxy or carboxy. 7. A compound according to claim 1 or 2, characterized in that R * phenyl, benzyl or Means phenoxymethyl. 809827/0796 8. Compound according to claim 1, 2 or 7, thereby characterized in that R ^{1 is} phenyl. 9. A compound according to claim 1 or 2, characterized characterized in that R 'is a group of the formula R * '- CH ₂ - represents, in which the substituent R ¹ 'has the meaning given in claim 2. 10. A compound according to claim 9, characterized in that R "is phenyl, 2-thienyl, Is 2-furyl or 1-tetrazolyl, 11. A compound according to claim 1 or 2, characterized in that R ^{1 is} a group of the formula v * ~ means in which b and b ^{1 have} the meanings given in claim 2. 12. A compound according to claim 1 or 2, characterized in that R 'is a group of the formula R ¹ "-S-CH ₂ - means in which R ¹ "has the meaning given in claim 2. 809827/0796 13. A compound according to claim 1 or 2, characterized in that R 'represents a group of formula R "" -C- It NI 0 I 7 " where R "" is phenyl, 2-furyl or 2-thienyl and Z ' ^{1 has} the meaning given in claim 2. 14. A compound according to claim 1 or 2, characterized characterized in that R ^{1 is} a group of the formula .el R "" -CH- I N-H C = I Y means in which R "" and Y have the meanings given in claim 2. 15. A compound according to claim 14, characterized that Y is a divalent dimethyl ureido group the formula ' CHa 0 H I II I - N - C - N - CHa means. 809827/0796 16. A compound according to claim 14, characterized in that that Y is a group of the formula ο
represents, wherein Y ^{1 has} the meaning given in Claim 2 17. Compound according to claim 14, characterized in: that Y is an N-methylacyl group of the formula CH 3 0 I Il - N-C- Y ' is wherein Y ^{11 has} the meaning given in claim 2. 18. A compound according to claim 1, characterized in that R is amino. 1 9. 1- / alpha- (benzyloxycarbonyl) -4-benzyloxybenzyl / -3β-benzamido-4alpha-acetoxyazetidin-2-one. 20. 1 - / alpha- (benzyloxycarbonyl) -4-benzyloxybenzyl / -3β-phenoxyacetamido-4-alpha-acetoxyazetidin-2-one. 21. 1 - / alpha- (benzyloxycarbonyl) -4-benzyloxybenzyj _L / -3βamino-4alpha-acetoxyazetidin-2-one. 009827/0798 - atf - 22. 1 - / alpha- (carboxy) -4-hydroxybenzyV ~ 3ß- (D-mandelamido) - 4alpha-acetoxyazetidin-2-one. 23. 1- / alpha- (benzyloxycarbonyl) -4-benzyloxybenzy] ./- 3β- / 2- / 4 ~ O-diphenylmethoxycarbonyl-S-t-butyloxycarbamidopropoxyJpheny] ./- glyoxylanu.no/-4alpha-acetoxyazetidin-2-one. 24. 1- / alpha- (diphenylmethoxycarbonyl) -4-hydroxybenzy_l / -3ß- benzamido-4alpha-acetoxyazetidin-2-one. 25. 1- / alpha- (diphenylmethoxycarbonyl) -4-hydroxybenzyl _: / -3ß- amino-4alpha-acetoxyazetidin-2-one. 26. 1- / alpha- (carboxy) -4-hydroxybenzy] _L / -3ß- / 2- / 4- (3-carboxy- 3-aminopropoxy) pheny2 _; / -2-hydroxyiminoacetamido / -4alpha-acetoxyazetidin-2-one. 27. 1 - / alpha- (Diphenylmethoxycarbonyl) -4-hydroxybenzyl./-3ß- /2-/4-(S-diphenylmethoxycarbonyl-S-t-butyloxycarbamidopropoxy )-phenyl./-2-(4-methoxybenzyloxy) iminoacetamido _ / - 4alpha-acetoxyazetidin-2-one. 28. Process for the preparation of 3ß-amino and 3ß-acyl amino-4-alpha-acetoxyazetidinones of the formula I 809827/0796 Il ^R "T— COORi a and a ¹ independently of one another hydrogen, halogen, hydroxy, protected hydroxy, Cj-C.-alkyl, , Amino, protected amino, aminomethyl or protected aminomethyl mean, R stands for amino or acylamino and R is hydrogen or a carboxylic acid protecting group is, and, if the substituent R _{1 is} hydrogen, the pharmaceutically acceptable acid addition salts thereof, characterized in that a thiazolidinazetidinone of the formula II HsC. CHa ' X Ra-C f / ^X ^ COORi ^a ' wherein Ra is C ₁ -C, -alkyl, phenyl, benzyl or phenoxymethyl and R., a and a 'have the meanings given above, 809827/0796 with mercury (II) acetate in the presence of acetic acid to one N-propenyl- ^ alpha-acetoxyazetidin - ^ - onamid of the formula III CHa IO
OC = CHz H
II I JO-C-CH3
Ra-C- Ν— f— I ·· \ COORi wherein Ra, R ₁ , a and a ^{1 have} the meanings given above, converts the N-propenyl-4alpha-acetoxyazetidin-2-oneamide obtained then to a 4alpha-acetoxyazetidin-2-one of the formula IV 0 ii II X) -C-CH ₃ Ra-C-NH-t- · _H .__, * IV, μι-ct COORi ^a wherein Ra, R ₁ , a and a ^{1 have} the meanings given above, hydrolyzed, of the 4alpha-acetoxyazetidin-2-ones obtained in this way, if desired, the one present in position 3 in a manner known per se Cleaving acyl group and thus obtaining compounds of the formula I in which R is amino, the compounds obtained in this way 3-Amino-4alpha-azetidin-2-ones, if desired, reacylated in a manner known per se and from the obtained in this way Compounds optionally removing the carboxy, hydroxy or amino protective groups in a manner likewise known per se, 809827/0796 Ak and the compounds thus formed, if desired finally converted in the usual way into their pharmaceutically acceptable, non-toxic salts. 29. The method according to claim 28, characterized gekennzeichne t, by heating the Thiazolidinazetidinon to a temperature of 25 to 75 ⁰ C. 30. The method according to claim 28 or 29, characterized in that the thiazolidinazetidinone with 1.5 to 2.0 moles of mercury (II) acetate per mole of thiazolidinazetidinone heated. 31. The method according to claim 28 to 30, characterized characterized in that the N-propenyl-4alphaacetoxyazetidin-2-oneamide hydrolyzed with mercury (II) acetate in an aqueous solvent. 32. The method according to claim 28 for the preparation of 1- / alpha- (benzyloxycarbonyl) -4-benzyloxybenzyl ^ / - 3ß-benzamido-4alphaacetoxyazetidin-2-one, characterized in that 2-benzoyl-3,3-dimethyl-7 -oxo-alpha- (4-benzyloxyphenyl) -4-thia-2,6-diazabicyclo / 3.2.0 / heptane-6-acetic acid benzyl ester is heated with mercury (II) acetate in the presence of acetic acid and the compound obtained is then heated with aqueous hydrochloric acid hydrolyzed. 609827/0796 33. The method according to claim 28 for the preparation of 1- / alpha- (benzyloxycarbonyl) -4-benzyloxybenzyl _ / - 3ß-phenoxyacetaniido-4alpha-acetoxyazetidin-2-one, characterized in that 2-phenoxyacetyl-3,3-dimethyl-7-oxo-alpha- (4-benzyloxyphenyl) -4-thia-2,6-diazabicyclo / 3.2.0 / -heptane-6-acetic acid benzyl ester heated with mercury (II) acetate in the presence of acetic acid and the resulting compound then hydrolyzed with aqueous hydrochloric acid. 34. The method according to claim 28 for the preparation of 1- / alpha- (benzyloxycarbonyl) -4-benzyloxybenzyl _: / -3ß-amino-4alpha-acetoxyazetidin-2-one, characterized in that 2-benzoyl-3,3-dimethyl -7-oxo-alpha- (4-benzyloxyphenyl) -4-thia-2,6-diazabicyclo / 3.2.O / heptane-6-acetic acid benzyl ester heated with mercury (II) acetate in the presence of acetic acid, the resulting compound then with hydrolyzed aqueous hydrochloric acid and the 3ß-benzamido-4alpha-acetoxyazetidin-2-one obtained is reacted with phosphorus pentachloride in pyridine and finally hydrolyzed. 35. The method according to claim 28 for the preparation of 1- / alpha- (carboxy) -4-hydroxybenzy] ₁ / -3ß- (D-almondamido) -4alpha-acetoxyazetidin-2-one, characterized in that 2-Benzoy1- 3,3-dimethyl-7-oxo-alpha- (4-benzyloxyphenyl) -4-thia-2,6-diazabicyclo / 3.2.O / heptane-6-acetic acid p-nitrobenzyl ester with mercury (II) acetate in the presence of Acetic acid is heated, the compound obtained is then hydrolyzed with aqueous hydrochloric acid, so that 3ß-benzamido-4alpha-acetoxyazetidin-2-one is reacted with phosphorus pentachloride in pyridine and subsequently hydrolyzed, the 3ß-amino-4alpha-acetoxyazetidin-2- on reacts with O-formylmandeloyl chloride and finally removes the carboxy and hydroxyl protective groups from the resulting compound. 809827/0796 36. The method according to claim 28 for the production of 1- / alpha- (benzyloxycarbonyl) -4-benzyloxybenzy] y-3ß -_ / 2- / 4- (3-diphenylmethoxycarbony1-3-t-butyloxycarbamidopropoxy) phenyl / -glyoxy1-amido / -4alpha-acetoxyazetidin -: - one, characterized in that 2-benzoyl-3,3-dimethyl-7-oxo-alpha- (4-benzyloxyphenyl) -4-thia-2,6-diazabicyclo / 3.2.0 / -heptane-6-acetic acid benzyl ester heated with mercury (II) acetate in the presence of acetic acid, the resulting compound then hydrolyzed with aqueous hydrochloric acid, the 3ß-benzamido-4alpha-acetoxyazetidin-2-one thus obtained is reacted with phosphorus pentachloride and then hydrolyzed and the 3β-amino-4alpha-acetoxyazetidin-2-one thus formed with 4- (S-diphenylmethoxycarbonyl-S-t-butyloxycarbamidopropoxy) phenylgiyoxylic acid implements. 37. The method according to claim 28 for the preparation of 1- ^ alpha- (Diphenylmethoxycarbony 1) -4-hydroxybenzy] _L / -3ß-benzamido-4alphaacetoxyazetidin-2-one, characterized in that 2-benzoyl-3,3-dimethyl -7-oxo-alpha- (4-hydroxyphenyl) -4-thia-2,6-diazabicyclo / 3.2.O / heptane-6-acetic acid diphenylmethyl ester heated with mercury (II) acetate in the presence of acetic acid and the resulting compound then with aqueous mercury (II) acetate hydrolyzed. 38. The method according to claim 28 for the preparation of 1- / alpha- (Dipheny lme thoxycarbony 1) -4-hydroxybenzyl ^ / - 3ß-amino-4alphaacetoxyazetidin-2-one, characterized in that 2-benzoyl-3,3 ~ dimethyl-7-oxo-alpha- (4-hydroxyphenyl) -4-thia-2 , 6-diazabicyclo / 3.2 .O / heptane-6-acetic acid diphenyl methyl ester heated with mercury (II) acetate in the presence of acetic acid, the resulting Compound then hydrolyzed with aqueous mercury (II) acetate and the resulting 3ß-Benzami do-4alpha-acetoxyazetidin-2-one finally reacted with phosphorus penta chloride in pyridine and then hydrolyzed. 809827/0796 39. The method according to claim 28 for the preparation of 1- / alpha- (carboxy) -4-hydroxybenzyl _: / -3ß- / 2- / 4- P-carboxy-S-aminopropoxy) pheny_l / -2-hydroxyiminoacetamido / -4alpha- acetoxyazetidin-2-one, characterized in that 2-benzoyl-S ^ -dimethyl-T-oxo-alpha- (4-hydroxyphenyl) -4-thia-2, 6-diazabicyclo / S ^ .O / heptane-ö -acetic acid diphenylmethyl ester heated with mercury (II) acetate in the presence of acetic acid, the compound obtained is hydrolyzed with aqueous mercury (II) acetate, the 3ß-benzamido-4alphaacetoxyazetidin-2-one obtained is converted with phosphorus pentachloride in pyridine and then hydrolyzed 3ß-Amino-4alphaacetoxyazetidin-2-one thus formed reacts with 4- (3-diphenylmethoxycarbonyl-3- (tbutyloxycarbamido) propoxy) phenylglyoxylic acid O- (4-methoxybenzyl) oxime and finally the carboxy of the compound obtained in this way -, hydroxyl and amino protecting groups removed. 809827/0796