CH626604A5 - Process for the preparation of sulphinylazetidinone compounds - Google Patents

Abstract

Sulphinylazetidinone compounds of the formula <IMAGE> in which the substituents are defined in Claim 1, are prepared. The compounds of the formula II are obtained by reacting a corresponding halosulphinylazetidinone with a compound supplying the radical X, e.g. an alcohol or thioalcohol. The resulting compounds can be used as starting compounds for the preparation of intermediates which are used for the preparation of antibiotics.

Description

The invention relates to a process for the preparation of sulfinyl azetidinone compounds.

The compounds which can be prepared according to the invention can be used for the preparation of 3-methylcephamsulfoxides which are useful intermediates for the preparation of cephem antibiotics.

The penicillins and more recently the cephalosporins are known for their high level of antibacterial activity and are widely used to treat infectious diseases in humans. Significant research efforts have been made to chemically modify these compounds to find more active / 3-lactam antibiotics. Considerable efforts have been made in particular to vary the C6 acylamino substituent of penicillin compounds and both the C7 acylamino substituent and the C3 substituent of cephem compounds.

More recently, R.R. Chauvette and P.A. Pennington the use of 3-methylene cephams both for the production of 7-aminodesacetoxycephalosporanic acid and biologically active derivatives thereof (Journal of Organic Chemistry, 38 [1973] 2994) and for the production of new 3-methoxy and 3-halogensphemes (Journal of the American Chemical Society, 96 [1974] 4986). In both cases, the 3-methylene cepham intermediates from cephalosporanic acids were prepared by first treating the cephalosporanic acids with selected nucleophilic sulfur compounds, such as thiourea, thiobenzoic acid, potassium ethyl xanthate or sodium thiosulfate, and then treating the corresponding C3- Substituted-thiomethyl-cephem derivatives reduced either with Ra-ney-nickel in aqueous ethanol or with zinc in a formic acid-dimethylformamide mixture. The proven versatility of 3-methylene cephame as intermediates for the production of new cephem antibiotics has triggered the search for alternative processes for the production of such compounds from easily accessible, economical starting materials.

The sulfinyl azetidinone compounds which can be prepared according to the invention have the following formula

0 II

ri

\

/ x 1

\ / \

ioor

(ii)

in what formula

R is a carboxylic acid protecting group;

Ri (1) is an imido group of the general formula

15

30th

35

R2 represents an alkenyl group having 2 to 4 carbon atoms, an alkylene group having 2 to 4 carbon atoms, a 1,2-phenylene group or a 1,2-cyclohexenyl group; or

(2) an amido group of the general formula O

in the

R3CNH-

R3 (a) represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a halomethyl group or a 3- (2-chlorophenyl) -5-methylisoxazol-4-yl group;

(b) a benzyloxy group, a 4-nitrobenzyloxy group, a 2,2,2-trichloroethoxy group, a tert-butoxy group or a 4-methoxybenzyloxy group;

(c) a group R ", where R" is a 1,4-cyclohexadienyl group, a phenyl group or one with 1 or 2 substituents which independently of one another are protected from the halogen atoms, hydroxyl groups, nitro groups, cyano groups, trifluoromethyl groups, Alkyl groups having 1 to 3 carbon atoms and alkoxy groups having 1 to 4 carbon atoms are selected, substituted phenyl group;

(d) an arylalkyl group of the general formula

R "- (0) ra-CH2-

in which R "has the meanings given above and m represents 40 0 or 1; or

(e) a substituted arylalkyl group of the general formula

R "" CH—

I.

W

in which R "" has the same meanings as the above-defined group R "and W represents a protected hydroxyl group or a protected amino group,

means;

so (3) an imido group of the general formula

0

: n-

r'2-c,

r "- (0) ch" c '60 m 2 Ii

0

in which R "and m have the meanings given above, 65 and R2 'have an alkyl group with 1 to 3 carbon atoms, a haloalkyl group with 1 to 3 carbon atoms, an alkoxy group with 1 to 3 carbon atoms or a trichloroethoxy group; or Ra

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(4) an imidazolidinyl group of the general formula

\

Y- &

/ V

n *

in which R "has the meanings given above and Y represents an acetyl group or a nitroso group; and

X (1) a group of the general formula -OR4, in which R4 represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an arylalkyl group having 1 to 3 carbon atoms in the alkyl part or a haloalkyl group having 1 to 6 carbon atoms; or

(2) a group of the general formula -SRs in which Rs represents an alkyl group having 1 to 6 carbon atoms, an aryl group or an arylalkyl group having 1 to 3 carbon atoms in the alkyl part.

The process according to the invention for the preparation of compounds of the formula II is characterized in that a halosulfinyl-azetidinone compound of the general formula III

ri v

S

<r

(m)

in which Ri and R have the meanings given above and Hai represents a chlorine atom or a bromine atom, with a compound of the general formula Ri0B, in which R10 represents a group of the formulas -OR4 or -SRs, in which R4 and Rs have the meanings indicated above and B represents a hydrogen atom or an alkali metal cation.

In the above definition, the expression "alkyl group having 1 to 3 carbon atoms" stands for methyl group, ethyl groups, n-propyl groups or isopropyl groups. The term "alkyl group of 1 to 10 carbon atoms" usually includes methyl, ethyl, propyl, isopropyl, cyclo-hexyl, sec-butyl, heptyl, octyl, isooctyl, decyl, or Menthyl groups. The term «haloalkyl group with 1 to 6 carbon atoms is e.g. for groups such as the chloromethyl group, the bromoethyl group, the iodoethyl group, the 2-chloropropyl group, the 2-chlorocyclohexyl group or the 2-chlorobutyl group. The term “arylalkyl group with 1 to 3 carbon atoms in the alkyl part” includes the benzyl group, the 2-phenylethyl group, the 2-phenylpropyl group, the 4-chlorobenzyl group, the naphthylmethyl group or the 3- (2-nitrophenyl) propyl group. Examples of alkoxycarbonyl groups having 1 to 3 carbon atoms in the alkoxy part are the methoxycarbonyl group, the ethoxycarbonyl group and the isopropoxycarbonyl group. The representatives of «halomethyl groups» are the chloromethyl group, the bromomethyl group or the iodomethyl group. Examples of imido groups in which R2 represents an alkenylene group having 2 to 4 carbon atoms are the maleimido group, the 3-ethylmaleimido group or the 3,4-dimethylmaleinimido group

group. Examples of imido groups in which R2 represents a 1,2-cyclohexenylene or 1,2-phenylene group are the 3,4,5,6-tetrahydrophthalimido group or the phthalimido group.

5 If, according to the definition above, the group R "stands for a substituted phenyl group, the group R" can be a mono- or disubstituted halophenyl group, for example a 4-chlorophenyl group, a 2,6-dichlorophenyl group, a 2,5-dichlorophenyl group , a 3,4-dichloro-10 phenyl group, a 3-chlorophenyl group, a 3-bromophenyl group, a 4-bromophenyl group, a 3,4-dibromophenyl group, a 3-chloro-4-fluorophenyl group or a 2-fluorine -phenyl group; a protected hydroxyphenyl group such as a 4-benzyloxyphenyl group, a 3-benzyloxyphenyl group, 15 a 4-tert-butoxyphenyl group, a 4-tetrahydropyranyloxyphenyl group, a 4- (4-nitrobenzyloxy) phenyl group, a 2-phenacyloxyphenyl group, a 4- Benzhydroxyphenyl group or a 4-trityloxyphenyl group; a nitrophenyl group such as a 3-nitrophenyl group or a 4-nitrophe-20 nyl group; a cyanophenyl group, for example a 4-cyanophenyl group; a mono- or dialkyl-substituted phenyl group such as a 4-methylphenyl group, a 2,4-dimethylphenyl group, a 2-ethylphenyl group, a 4-isopropylphenyl group, a 4-ethylphenyl group or a 3-n-25 propylphenyl group; or a mono- or dialkoxyphenyl group, for example a 2,6-dimethoxyphenyl group, a 4-methoxyphenyl group, a 3-ethoxyphenyl group, a 4-isopropoxyphenyl group, a 4-tert-butoxyphenyl group or a 3-ethoxy-4-methoxyphenyl group . Furthermore, the group R "stands for disubstituted phenyl groups, the substituents of which may be different, for example for the 3-methyl-4-methoxyphenyl group, the 3-chloro-4-benzyloxyphenyl group, the 2-methoxy-4-bromophenyl group, the 4th -Ethyl-2-methoxyphenyl group, the 3-chloro-4-nitrophe-35 nyl group, the 2-methyl-4-chlorophenyl group and similar disubstituted phenyl groups which have different substituents.

The term "protected amino group", as used in the above definition, stands for an amino group 40 pe, e.g. is substituted with one of the commonly used amino blocking groups, such as the tert-butoxycarbonyl group (t-BOC), the benzyloxycarbonyl group, the 4-methylbenzyloxycarbonyl group, the 4-nitrobenzyloxycarbonyl group, the 2,2,2-trichloroethoxycarbonyl group or the 1-45 carbomethoxy-2-propenyl group formed with methyl acetoacetate. Amino protecting groups similar to those of J.W. Groups described in "Protective Groups in Organic Chemistry" (J.F.W McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 2) are also suitable. 50 The term "protected hydroxyl group" preferably stands for the groups which can be easily split off and are formed with a hydroxyl group, such as the formyloxy group, the chloroacetoxy group, the benzyloxy group, the benzhydryloxy group, the trityloxy group, the 4-nitrobenzyloxy group, the trime-55 thylsilyloxy group, the Phenacyloxy group, the tert-butoxy group, the methoxymethoxy group or the tetrahydropyranyloxy group. Other hydroxy protecting groups, including those from C.B. Reese in "Protective Groups in Organic Chemistry" (supra), Chapter 3, also fall under the 60 expression "protected hydroxy groups" as used herein.

The term "carboxylic acid protecting groups" or "protecting group for the carboxylic acid group" refers to the commonly used carboxylic acid protecting groups, which serve to block or protect the carboxylic acid group during reactions carried out on other functional groups of the compound. Such carboxy protecting groups are known to be readily hydrolytically or

can be split off hydrogenolytically to form the corresponding carboxylic acid. Examples of ester groups representing carboxylic acid protecting groups are the methyl group, the tert-butyl group, the benzyl group, the 4-methoxybenzyl group, the alkanoyloxymethyl group having 2 to 6 carbon atoms in the alkanoyl part, the 2-iodoethyl group, the

4-nitrobenzyl group, the diphenylmethyl group (benzhydryl group), the phenacyl group, the 4-halophenacyl group, the dimethylallyl group, the 2,2,2-trichloroethyl group, the trialkylsilyl group each having 1 to 3 carbon atoms in the alkyl groups or the succinimidomethyl group. Other known carboxy protecting groups, such as the groups described by E. Haslam in “Protective Groups in Organic Chemistry” (supra), Chapter 5, are also suitable according to the invention. However, the nature of these ester-forming groups is not critical.

The azetidinone sulfinic acid derivatives which can be prepared according to the invention preferably have an acid-labile carboxy protective group, such as a 4-methoxybenzyl group, a benzhydryl group, a tert-butyl group or a trialkylsilyl group having 1 to 3 carbon atoms per alkyl group. In a similar manner, the compounds of the formula II preferably have similar acid-labile hydroxyl or amino protective groups which are usually cleaved off under acidic conditions.

The azetidinone compounds which can be prepared according to the invention have these protective groups, since when the compounds mentioned are used for the preparation of 3-methylene cepham sulfoxides and their further processing to give cephem antibiotics, reactive functional residues should be protected. The type of protective groups is not critical for further processing. The preferred carboxylic acid ester protecting groups are the methyl group, the 2-iodoethyl group, the 4-nitrobenzyl group, the 4-haloacyl group and the 2,2,2-trichloroethyl group.

However, the above definitions for the hydroxy, amino and carboxy protecting groups are not exhaustive. The function of these groups is to protect the reactive functional groups during production, which groups can be split off at a later point in time without changing the rest of the molecule.

Many protective groups of this type are readily known to the person skilled in the art, so that other groups can also be used in further processing.

Representative representatives of the acylamino group of the general-O

II

My formula R3CNH- as defined above are the formamido group, the acetamido group, the propionamino group, the butylamido group, the 2-pentenoylamino group, the chloroacetamido group, the bromoacetamido group or the

5-tert-butoxy-carbonylamino-5-tert-butoxycarbonyl-

valeramido group.

Examples of special acylamino groups of the general-O

II

NEN formula R "CNH- are the benzamido group, the 2,6-dimethoxybenzamido group, the 4-chlorobenzamido group, the 4-methylbenzamido group, the 3,4-dichlorobenzamido group, the 4-cyanobenzamido group, the 3-bromobenzamido group or the 3-nitrobenzamido group.

Examples of acylamino groups of the general formula O

II

R3CNH-, in which R3 for a group of the formula R "(0) mCH2", in which m denotes o, are the cyclohexa-1,4-dienylacetamido group, the phenylacetamido group, the 4-

626 604

Chlorophenylacetamido group, the 3-methoxyphenylacetamido group, the 3-cyanophenylacetamido group, the 3-methylphenylacetamido group, the 4-bromophenylacetamido group, the 4-ethoxyphenylacetamido group, the 4-nitrophenylacet-3,4-amido-dimethyl group or the amido-dimido group; while representative acylamino groups of the above formula, in which m has the meaning of 1, the phenoxyacetamido group, the 4-cyanophenoxyacetamido group, the 4-chlorophenoxyacetamido group, the 3,4-dichlorophenoxyacetamido group, the 2-chlorophenoxyacetamido group, the 4-methoxyphenoxyacetamido group the 2-ethoxyphenoxyacetamido group, the 3,4-dimethylphenoxyacetamido group, the 4-isopropylphenoxyacetamido group, the 3-cyanophenoxyacetamido group or the 3-nitrophenoxyacetamido group.

Exemplary representatives of acylamino groups in which R3 is a substituted arylalkyl group of the formula R "" - CH-,

W

where W represents a protected hydroxy group, are

2-formyloxy-2-phenylacetamido group,

the 2-benzyloxy-2- (4-methoxyphenyl) acetamido group, the 2- (4-nitrobenzyloxy) -2- (3-chlorophenyl) acetamido group, the 2-chloroacetoxy-2- (4-methoxyphenyl) acetamido group , the 2-benzyloxy-2-phenylacetamido group, the 2-trimethylsilyloxy-2- (4-chlorophenyl) acetamido group or the 2-benzhydryloxy-2-phenylacetamido group. Representative representatives of groups in which W represents a protected amino group are the 2- (4-nitrobenzyloxycarbonylamino) -2-phenyl-acetamido group,

the 2- (2,2,2-trichloroethoxycarbonylamino) -2-phenylacetami-dog group,

the 2-chloroacetamido-2- (1,4-cyclohexadien-l-yl) acetamido group,

the 2- (4-methoxybenzyloxycarbonylamino) -2- (4-methoxy-

phenyl) -acetamido group, the 2-benzhydryloxycarbonylamino-2-phenylacetamido group or the 2- (l-carbomethoxy-2-propenyl) amino-2-phenylacetamino-dog group.

Representative representatives of groups R1; when Rt is an imido group of the general formula

0 II

r 'c>

r "- (0) ch c m a"

0

represents ,, are the

N-acetyl-N-phenylacetylamino groups, the N-trichloroethoxycarbonyl-N-phenoxyacetylamino group, the N-propoxycarbonyl-N- (4-chlorophenoxy) acetylamino group or the N- (2-bromoacetyl) -N-phenoxyacetylamino group.

O

II

Examples of acylamino groups of the formula R3CNH—, in which R3 represents a heteroarylmethyl group of the general formula R “” - CH2-, are the 2-thienylacetamido group, which

3-thienylacetamido group, the 2-furylacetamido group, the 2-thiazolylacetamido group of the formula

5

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

626 604

0

\ / \ "s ch cnh-

2nd

or the 3- (2-chlorophenyl) -5-methylisoxazol-4-ylamido group of the formula

Representative imidazolidinyl groups R! the general formula

0 II

r ",

\

/ \

\

ch

20th

25th

30th

are the 2,2-dimethyl-3-nitroso-5-oxo-5-phenyl-l-imidazolidinyl group,

the 2,2-dimethyl-3-nitroso-5-oxo-4- (4-benzyloxyphenyl) -

1-imidazolidinyl group, the 2,2-dimethyl-3-acetyl-5-oxo-4- (1,4-cyclohexadien-1-yl) -

1-imidazolidinyl group or the 2,2-dimethyl-3-nitroso-5-oxo-4- (2-thienyl) -l-imidazolidinyl group.

The azetidinone sulfinyl chlorides and bromides used as starting materials for the process according to the invention are derived from the corresponding known penicillin sulfoxide esters and can be prepared from them by preferably treating these esters at elevated temperatures with a reagent which serves as a source of positive halogen an N-haloimide such as N-chlorosuccinimide (NCS). The conversion of the 6-imido-penicillin sulfoxide esters into the corresponding sulfinyl chlorides with sulfuryl chloride has already been described in the literature (S. Kukolja and S. R. Lammert, Angew. Chemie, 12 [1973] 67-68). In general, you get z. B. the sulfinyl chloride starting materials for the inventive method by reacting a penicillin sulfoxide ester with about 1,1 equivalents of N-chlorosuccinimide in a dry inert organic solvent, preferably 1,1,2-trichloroethane or toluene, at a temperature of about 70 to 120 ° C, the preferred temperature mainly depends on the nature of the C6 substituent. The conversion of the C6-imido-penicillin sulfoxides is usually accomplished at 70 to 100 ° C, while slightly higher temperatures (100 to 120 ° C) are preferred for the production of the sulfinyl chlorides from C6-acylamino-penicillin sulfoxides. The reaction is usually complete in 45 to 90 minutes at the preferred reaction temperature. The penicillin sulfoxide esters used as precursors to the sulfinyl chlorides are either known or readily available compounds, many of which have been used to make cephem compounds. You get it e.g. from known 7-acylamino- and 7-imido-penicillinic acids by (1) esterification and (2) subsequent oxidation, which is usually carried out with m-chloroperbenzoic acid or sodium periodate.

An example of the preparation of azetidinone sulfinyl chlorides is the following brief description of the preparation of

3'-nitrobenzyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-

acetamido-l-azetidinyl) -3-butenoate:

A solution of 5 mmol of 4'-nitrobenzyl-6-acetamidopennicil-lanate-l-oxide in 200 ml of toluene is heated to boiling under reflux and dried azeotropically by distilling approximately 20 ml of toluene from the mixture. After the mixture has cooled briefly, 5.5 mmol of N-chlorosuccinimide are added. The mixture is refluxed for a further 90 minutes, after which the solution is cooled to room temperature and filtered. Evaporation of the filtrate in vacuo gives

4'-nitrobenzyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3 -

acetamido-l-azetidinyl) -3-butenoate in the form of a foam.

In an analogous manner to the reaction of the penicillin sulfoxide esters with N-chlorosuccinimide to form azetidinone sulfonyl chlorides, penicillin sulfoxide esters which carry an imido group on the carbon atom-6 can be reacted with N-bromosuc-cinimide ( NBS) to form the corresponding azetidinone sulfinyl bromides. The reaction conditions for this conversion are identical to the conditions used in the preparation of sulfonyl chlorides using N-chlorosuccinimide described above. The above-described azetidinone-sulfinyl-chloride and the corresponding -sulfinyl-bromide have a similar chemical reactivity when used for the production of 3-methylene cepham sulfoxides. The azetidinone sulfinic acids of the general formula

0 II

55

60

65

ri

45

\

cf ySOH

1 & "\/\

Lor in which R and Rx have the meanings given above is preferably obtained from the corresponding sulfinyl chlorides by slurrying a solution of the sulfinyl chloride in ethyl acetate in an aqueous sodium bicarbonate solution for about 1 hour at room temperature. The aqueous layer containing the sulfinic acid salt is usually separated off, washed with ethyl acetate, mixed with further ethyl acetate and acidified. The organic layer can be separated, washed with brine, dried over anhydrous sodium sulfate and then evaporated to dryness in vacuo. The sulfinic acids isolated in this way are generally obtained in the form of colorless amorphous solids.

The following compounds are representative of the sulfinic acids obtained according to the invention:

7

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4'-nitrobenzyl-3-methyl-2- (2-sulfino-4-oxo-3-phenyl)

acetamido-l-azetidinyI) -3-butenoate,

2 ', 2', 2 'trichloroethyl 3-methyl-2- (2-sulfino-4-oxo-3-

acetamido-l-azetidinyl) -3-butenoate, 2'-iodoethyl-3-methyl-2- (2-sulfino-4-oxo-3-chloroacetamido

l-azetidinyl) -3-butenoate, 4'-methoxybenzyl-3-methyl-2- (2'-sulfino) -4-oxo-3-

phthalimido-l-azetidinyl) -3-butenoate, tert-butyl-3-methyl-2- [2-sulfino-4-oxo-3- (2-bromo-

acetamido) -l-azetidinyl] -3-butenoate, benzhydryl-3-methyl-2- [2-sulfino-4-oxo-3- (4-chlorophen-

oxyacetamido) -l-azetidinyl] -3-butenoate, 4'-nitrobenzyl-3-methyl-2- [2-sulfino-4-oxo-3- (4-nitro-benzyloxycarbonylamino) -l-azetidinyl] -3-butenoate , 2 ', 2', 2'-trichloroethyl-2-methyl-2- [2-sulfino-4-oxo-3- (2,2-dimethyl-3-nitroso-5-oxo-4-phenyl-l- imidazolidinyl) -1-azetidinyl] -3-butenoate, '2'-iodoethyl-3-methyl-2- [2-sulfino-4-oxo-3-acetamido-l-

azetidinyl] -3-butenoate and 4'-nitrobenzyl-3-methyl-2- [2-sulfino-4-oxo-3- (4-chloro-benzamido) -l-azetidinyl] -3-butenoate.

It is understood that other derivatives of the azetidinone sulfinylchloride, including the sulfinate esters, the thiosulfinates, the mixed carboxylic and sulfonic anhydrides, the sulfinamide and sulfinimide derivatives thereof, are made from the sulfinic acids and their precursor sulfinyl chlorides can. These derivatives can be prepared by well known common procedures used to prepare carboxylic acid derivatives such as esters, thioesters, anhydrides, amides and imides from carboxylic acids and carboxylic acid chlorides. Some azetidinone sulfinamide derivatives could be made directly from penicillin sulfoxides [p. Terao, T. Matsuo, S. Tshus-hima, N. Matsumoto, T. Miyawaki and M. Miyamoto, J.

Chem. Soc. (C) (1972) 1304], It is further understood that such derivatives can be cyclized to 3-methylene cepham sulfoxide compounds using the procedures and process conditions given below.

The azetidinone sulfinates (sulfinates) of the general formula r \

r

1\

</

/ 0r4

n *

• i \ / \

Lor.

Examples of alcohols which can be used to prepare the sulfinates mentioned are methanol, ethanol, isopropanol, cyclohexanol, 4-chloro-cyclohexanol, sec-butanol, n-heptanol, menthol, benzyl alcohol, 2-phenylethanol, 3- Pehnylpropanol, 2-chlorobenzyl alcohol, 4-meth-oxybenzyl alcohol, 2- (4-nitrophenyl) ethanol, 2-chloroethanol,

2-bromoethanol, 3-bromocyclohexanol, 4-chlorobutanol or

3-chloropropanol.

Representative representatives of the azetidinone sulfinic acid esters produced according to the invention are: 4'-nitrobenzyl-3-methyl-2- (2-isobutoxysulfinyl-4-oxo-3-

acetamido-l-azetidinyl) -3-butenoate, benzhydryl-3-methyl-2- [2- (2-chloropropoxysulfinyl) -4-oxo-

3-phenoxyacetamido-l-azetidinyl] -3-butenoate,

2 ', 2', 2 '-Trichloräthyl-3-methyl-2- [2- (2-bromäthoxysul-

finyl) -4-oxo-3- (2-formyloxy-2-phenylacetamido) -l-azetidinyl] -3-butenoate, 2'-iodoethyl-3-methyl-2 - [- 2- (4-bromobenzyloxysulfinyl) -

4-oxo-3-phthalimido-l-azetidinyl] -3-butenoate, tert-butyl-3-methyl-2- (2-methoxysulfinyl-4-oxo-3-benzyl-

oxy-carbonylamino-l-azetidinyl) -3-butenoate, 4'-chlorophenacyl-3-methyl-2- [2- (2-phenylisopropoxysul-finyl) -4-oxo-3- (2-chlorobenzamido) -l-azetidinyl ] -3-butenoate,

25 4'-methoxybenzyl-3-methyl-2- [2-cyclohexylsulfinyl-4-

oxo-3- (2,2-dimethyl-2-nitroso-5-oxo-4-phenyl-l-imide-azolidinyl) -l-azetidinyl] -3-butenoate and methyl 3-methyl-2- [2- (3-phenylpropoxysulfinyl) -4-oxo-3- (4-chlorophenoxyacetamido) -l-azetidinyl] -3-butenoate. The azetidinone thiosulfinate esters of the general formula

10th

15

20th

30th

45

50

in which R and Rt have the meanings given above and R4 denotes an alkyl group with 1 to 10 carbon atoms, an arylalkyl group with 1 to 3 carbon atoms in the alkyl part or a haloalkyl group with 1 to 6 carbon atoms, according to the invention from the above azetidinone derivatives derived from penicillin sulfoxide Obtained sulfinyl chlorides by reacting the sulfinyl chloride with the corresponding alkanol with 1 to 10 carbon atoms, the corresponding aryl alkanol with 1 to 3 carbon atoms in the alkyl part or the corresponding haloalkanol with 1 to 6 carbon atoms. Typically, the sulfinic acid esters are prepared by directly adding the desired alcohol to the reaction mixture in which the azetidinone sulfinyl chloride is formed from a penicillin sulfoxide. The product sulfinic acid ester is then usually isolated using conventional isolation procedures, including evaporation, crystallization, and chromatography.

60

65

0 II

't

</

40

/ SRs

I &

Y

c00r in which R and Rt have the meanings given above and Rs represents an alkyl group with 1 to 6 carbon atoms, an aryl group or an arylalkyl group with 1 to 3 carbon atoms in the alkyl part, according to the invention from the above-described azetidinone sulfinyl chlorides by reacting these compounds with the corresponding alkylthiol having 1 to 6 carbon atoms, the corresponding arylthiol or the corresponding arylalkylthiol having 1 to 3 carbon atoms in the alkyl part. The thiolsulfinate esters are usually prepared and isolated using standard experimental techniques. Their preparation is directly analogous to the preparation of the carboxylic acid thioesters from the carboxylic acid chlorides.

Representative thiols or mercaptans that can be used to prepare the azetidinone thiosulfinate esters are methanethiol, ethanethiol, 2-propanethiol, 2-methyl-2-propanethiol, cyclohexanethiol, 2-pentanethiol, 1-butanethiol, thiophenol, 4-chlorothiophenol, 2 -Phenylethanethiol and benzyl mercaptan.

Representative representatives of azetidinone thiosulfinate esters which can be prepared according to the invention are:

4'-nitrobenzyl-3-methyl-2- (2-methylthiosulfinyl-4-oxo

3-formamido-l-azetidinyl) -3-butenoate, 2'-I-ethyl-3-methyl-2- [2- (2-methyl-1-propanthiosulfonyl) -4-oxo-3- (4-methoxybenzyloxycarbonylamino ) -l-azetidinyl] -3-butenoate,

626 604

2 ', 2', 2'-trichloroethyl-3-methyl-2- [2- (l-hexanthiosulfinyl) -4-oxo-3- (4-trifluoromethylbenzamido) -l-azetidi-nyl] -3-butenoate , Benzhydryl-3-methyl-2- [2-benzylthiosulfinyl-4-oxo-3- (4-methylphenoxyacetamido) -1-azetidinyl] -3-butene noate and tert-butyl-3-methyl-2- [2-phenylthiosulfinyl-4-oxo

3- (4-nitrobenzyloxycarbonylamino) -l-azetidinyl] -3-butenoate.

Preferred starting materials of the formula III and compounds from which these can be prepared are listed below: Tert.-butyl-3-methyl-2- (2-chlorosulfinyl) -4-oxo-3-

phthalimido-l-azetidinyl) -3-butenoate from tert-butyl-6-phthalimidopenicillanate sulfoxide. Benzyl-3-methyl-2- (2-chlorosulfinyl) -4-oxo-3-benzyloxy-

carbonylamino-l-azetidinyl) -3-butenoate from benzyl-6-benzyloxycarbonylamino-penicillanate sulfoxide. 4'-methoxybenzyl-3-methyl-2- (2-sulfino-4-oxo-3-phenoxy-

acetamido-l-azetidinyl) -3-butenoate.

From 2 ', 2', 2'-trichloroethyl-6-phenylacetamido-penicillanat-

sulfoxide 2 ', 2', 2'-trichloroethyl 3-methyl-2- (2-chlorosulfinyl) -4-oxo-3-phenylacetamido-l-azetidinyl) -3-butenoate. From benzhydryl-6- (2,2-dimethyl-3-nitroso-5-oxo-4-phenyl-l-imidazolidinyl) -penicillanate sulfoxide- [hetacillin-benzhydryl ester] benzhydryl-3-methyl-2- [2 -chlorosulfonyl-4-oxo (2,2-dimethyl-3-nitroso-5-oxo-4-phenyl-l-imide-azolidinyl) -l ~ azetidinyl] -3-butenoate. 2'-iodoethyl-3-methyl-2- (2-sulfino-4-oxo-3-chloroacetamido

l-azetidinyl) -3-butenoate. From dimethylallyl-6-maleimido-penicillanate sulfoxide dimethylallyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-4-maleimido-1-azetidinyl-3-butenoate.

From succinimidomethyl-6-6-cyanoacetamido-penicilIanat-sul-foxid succinimidomethyl-3-methyl-2- (2-chlorosulfinyl) -4-oxo-

3-cyanoacetamido-l-azetidinyl) -3-butenoate. 4'-nitrobenzyl-3-methyl-2- [2-sulfino-4-oxo-3- (4-

nitrobenzyloxycarbonylamino) -l-azetidinyl] -3-butenoate. From 4'-nitrobenzyl-7- (4-chlorobenzamido) penicillanate sulfoxide 4'-nitrobenzyl-3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4-chlorobenzamido) -l-azetidinyl ] -3-butenoate. Àus Benzhydryl-6- (2-tert-butoxycarbonylamino-2-phenyl-acetamido) -penicillanate sulfoxide-Benzhydryl-3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2-tert.-butoxycarbonylamino-2 -phenyl-acetamido) -l-azetidinyl] -3-butenoate. From 4'-methoxybenzyl-6- (2-benzyloxy-2-phenylacetamido) penicillanate sulfoxide 4'-methoxybenzyl-3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2-benzyloxy-2- phenyl-acetamido) -l-azetidinyl] -3-butenoate.

From 2 ', 2', 2'-trichloroethyl-6- (2-benzyloxy-2-phenylacetamido) -penicillanate sulfoxide 2 ', 2', 2'-trichloroethyl-3-methyl-2- [2-chlorosulfinyl -4-oxo-3- (2-benzyloxy-2-phenylacetamido) -l-azetidinyl] -3-butenoate.

4'Nitrobenzyl-3-methyl-2- (2-isopropoxysulfinyl-4-

oxo-3-benzamido-l-azetidinyl) -3-butenoate. 2'-iodoethyl-3-methyl-2- (2-cyclohexyloxysulfinyl-4-oxo-3-

chloroacetamido-l-azetidinyl) -3-butenoate. From 2'-iodoethyl-6-phthalimido-penicillanate sulfoxide 2'-iodoethyl-3-methyl-2- (2-bromosulfinyl-4-oxo-3-phthalimido-l-azetidinyl) -3-butenoate.

4'-nitrobenzyl-3-methyl-2- (2-phenylthiosulfinyl-4-oxo-3-

phenoxyacetamido-l-azetidinyl) -3-butenoate. Phenacyl-3-methyl-2- [2- (2-phenylethylthiosulfinyl) -

4-oxo-3- (2-benzyloxy-2-phenylacetamido (-l-azedidinyl] -3-butenoate.

From 4'-chlorophenacyl-6-formamido-penicillanate sulfoxide 4'-chlorophenacyl-3-methyl-2- [2- (2-chloroethoxy-sulfinyl) -

4-oxo-3-formamido-l-azetidinyl] -3-butenoate.

The yield of the products varies depending on the particular reagents used, the relative amounts of the reagents and the other reaction conditions mentioned above.

The products prepared by the process according to the invention can be isolated and purified using conventional experimental techniques. These techniques include chromatographic separation, filtration, crystallization and recrystallization.

The most preferred side chains Ra in the process according to the invention in the general formulas above are those side chains which are found in penicillins which have been formed directly by fermentation, in particular the phenylacetamido and the phenoxyacetamido side chains. Such penicillins can be esterified and oxidized to the corresponding penicillin sulfoxide esters (although not necessarily in this order), from which the sulfinyl chlorides and other starting materials used as intermediates for the process according to the invention are prepared. It should be noted that the preferred side chains mentioned above are preferred mainly for economic reasons. Penicillin precursors with such side chains are easily accessible and relatively cheap. The advantage of carrying out the process according to the invention with the sulfinyl intermediates described above which are derived from these materials is readily apparent; Of course, penicillin sulfoxides which have other known side chains can be readily produced (by acylation of 6-APA or 6-APA esters and subsequent oxidation) and used in the process according to the invention.

The following preparations and examples serve to further explain the invention. In the following examples and production examples, the nuclear magnetic resonance spectra are abbreviated to NMR. These nuclear magnetic resonance spectra were determined using a spectrometer (Varian T-60) using tetramethylsilane as the reference standard. The chemical shifts are given in parts per million (ppm) and the coupling constants (J) in Hertz (Hz) in cycles per second.

Preparation 1 Methyl I-7-phthalimido-3-methylcepham-4-carboxylate-1-oxide (7-phthalimido-3-methylene cepham-4-carbonate-methyl ester-1-oxide) A mixture of 18.8 g (50 mmol) is heated Methyl 6-phthalimidopenicillanate sulfoxide and 6.7 g (50 mmol) of N-chlorosuccinimide in 1.1 dry carbon tetrachloride are refluxed for 70 minutes, then the crude product is cooled to room temperature, filtered, washed with water (1 X 500 ml) and dried over magnesium sulfate The solvent is then evaporated to dryness in vacuo The NMR spectrum indicates complete conversion to the sulfinyl chloride.

NMR spectrum (CDC13) à

1.97 (broad, s, 3), 3.86 (s, 3), 5.05 (broad s, 2), 5.2 (d, 1 J = 2 Hz), 5.77 (d, 1 , J = 4 Hz), 5.9 (d, 1, J = 4 Hz) and 7.83 (m, 4).

The sulfinyl chloride obtained as product is then dissolved in 11 dry methylene chloride and 6 ml (50 mmol) of anhydrous tin (IV) chloride are then added. The solution obtained is stirred for 45 minutes, washed with 2 × 200 ml of 1N hydrochloric acid solution and dried over magnesium sulfate. Evaporation in vacuo gives 18.4 g (98.4%) of a mixture of the R- and S-sulfoxides (in a ratio of about 3: 2 according to the NMR spectrum) in the form of a light yellow foam. Part of this

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626 604

Mixture (1.26 g) is separated chromatographically on silica gel and using a chloroform / ethyl acetate mixture as solvent. Fractions 6 to 10 contain the pure R-sulfoxide (340 mg), which is recrystallized from a methylene chloride / cyclohexane mixture (melting point 201 to 202 ° C.).

NMR spectrum (CDC13) ò

3.62 and 4.12 (ABq, 2, J = 14 Hz), 3.85 (s, 3), 4.88 (d, 1, J = 4.5 Hz), 5.25 (broad s, 1) , 5.58 (m, 2), 5.97 (d, 1, J = 4.5 Hz) and 7.84 (m, 4).

Mass spectrum, m / e

374, 358, 346, 298, 287, 239, 220.

IR spectrum (KBr)

1780, 1745 and 1390 cnr1.

Analysis: C17Ha4N206S (374.37)

Ber: C 54.54 H 3.77 N7.48 O 25.64 S 8.56%

Found: C 54.41 H 4.06 N7.26 0 25.59 S 8.41%

Fractions 11 to 18 contain a mixture of the R-sulfoxide and the S-sulfoxide, while fractions 19 to 35 give 210 mg of the S-sulfoxide, which is recrystallized from a methylene chloride / cyclohexane mixture. NMR spectrum (CDC13) ò

3.63 (s, 2), 3.82 (s, 3), 4.90 (d, 1, J = 4.5 Hz), 5.32 (s, 1), 5.46 (broad s, 1) , 5.64 (d, 1, J = 4.5 Hz), 5.77 (s, 1) and 7.84 (m, 4).

Mass spectrum, m / e

374, 358, 346, 298, 287, 200.

IR spectrum (KBr)

1775, 1745, 1725, 1390, 1205, 1111, 1051, 730 and 715 cm-1.

Analysis: c17h14n2o6s

Calc .: C 54.54 H 3.77 N 7.48%

Found: C 54.33 H 3.76 N 7.36%

Preparation 2

A mixture of 6.0 g (12 mmol) of 4'-nitro-benzyl-6-phenoxyacetamido-penicillanate-l-oxide and 500 ml of dry toluene is refluxed for 10 minutes, using a Dean-Stark trap used to remove trace amounts of water. Then 1.8 g of N-chlorosuccinimide are added and the mixture is heated to reflux for 90 minutes and then cooled to about 50.degree.

example 1

4'-nitrobenzyl-3-methyl-2- (2-sulfino-4-oxo-3-phthalimido-l-azetidinyl) -3-butenoate A solution of 49.7 g (0.1 mol) of 4'- Nitro-benzyl-6-phthalimido-penicillanate-l-oxide and 13.4 g (0.1 mol) of N-chlorosuccinimide in 1.5 11,2-dichloroethane for 70 minutes at the reflux. After cooling, the reaction mixture is washed with water and brine and dried over magnesium sulfate. The solvent is evaporated to dryness in vacuo, and 52.0 g of the azetidinone sulfinyl chloride product are obtained.

NMR spectrum (CDC13) <5

1.97 (s, 3), 5.05 (s, 1), 5.4 (s, 2), 5.76 (d, 1, J = 5 Hz), 5.91 (d, 1, J = Hz), 7.83 (m, 8 (ArH).

The sulfinyl chloride is converted to the sulfinic acid by slurrying an ethyl acetate solution with a 5% sodium bicarbonate solution at room temperature for 2 hours. Acidification of the aqueous layer with hydrochloric acid in the presence of ethyl acetate gives, after separation, drying over magnesium sulfate and evaporation of the organic layer in vacuo, the desired sulfinic acid in the form of a colorless foam. NMR spectrum (CDCl3j ò

1.92 (s, 3), 4.88 (s, 1, J = 4.5 Hz), 5.00 (s, 2), 5.18 (broad s, 1), 5.38 (s, 2), 5.67 (d, 1, J = 4.5 Hz) and 7.5 to 8.3 (m, ArH).

EXAMPLE 2 Methyl 3-methyl-2- (2-sulfino-4-oxo-3-phthalimido-l-azetidinyl) -3-butenoate A mixture of 3.76 g of methyl 6-phthalimi-do-penicillanate is heated. sulfoxide and 1.4 g of N-chlorosuccinimide in 250 ml of dry (CaCl2) carbon tetrachloride for 70 minutes at reflux. The mixture is cooled to room temperature, filtered, washed with water and brine and dried over magnesium sulfate. Evaporation to dryness in vacuo gives

Methyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phthalimido-l-

azetidinyl) -3-butenoate in the form of a white foam (cf. Example 1A).

2 drops of water are added to a solution of 0.20 g of the sulfinyl chloride in 25 ml of chloroform. The mixture is heated to reflux for 30 minutes, cooled and dried (MgSO4) and evaporated to dryness in vacuo to give the title compound in the form of a colorless foam.

NMR spectrum (CDC13) Ó

1.93 (s, 3, -CH3), 3.80 (s, 3, -COOCH3) 4.88 to 5.15 (m, 4, C3-H, = CH2, / 3-lactam-H), 5.70 (d, 1, J = 5.0 Hz, /? - Lac-tam-H), 7.80 (m, 4, ArH)

The sulfinyl chloride is also converted to the title sulfinic acid compound by standing at room temperature in air for 2 days.

Preparation 3

4'-Nitrobenzyl-3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (N-phenoxyacetyl-N- (2,2,2-trichloroethoxycarbonyl) amino) -l-azetidinyl] -3 butenoate A. A mixture of 4.855 g (10 mmol) of 3'-nitrobenzyl-6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate is prepared,

16.94 g (80 mmol) of 2,2,2-trichloroethyl chloroformate, 18 ml of N, 0- (bis-trimethylsilyl) trifluoromethylacetamide and 20 ml of methylene chloride. The mixture is left to stand at room temperature overnight, then heated to reflux for 7 hours, after which it is again left to stand at room temperature overnight. The mixture is then heated for a further 6 hours, the mixture is evaporated to a residue, the residue is dissolved in benzene and the solution obtained is added to a large excess of heptane. The insoluble material obtained is filtered off, dissolved in benzene and chromatographed on silica gel, for which purpose a benzene / ethyl acetate elution gradient is used. 4.76 g (72%) of 4'-nitrobenzyl-6- [N-phenoxyacetyl-N- (2,2,2-trichloro-

ethoxycarbonyl) amino] -2,2-dimethylpenam-3-carboxylate as product.

NMR spectrum (CDC13) <5

1.41 (s, 3), 1.62 (s, 3), 4.61 (s, 1), 4.84 (d, 1, J = 12 Hz), 4.99 (d, 1, J = 12 Hz), 5.20 (s, 2), 5.30 (s, 2), 5.56 (s, 2), 6.8 to 7.4 (m, 5), 7.53 (d , 2, J = 9 Hz) and 8.22 (d, 2, J = 9 Hz).

B. Preparation of Sulfoxide To about 75 ml of acetone is added 2.54 g (3.84 mmol) of the above product. The mixture is cooled to -70 ° C. and the reaction mixture is treated with excess ozone in an amount of about 1.17 mmol per minute for 9 minutes, after which the reaction mixture turns blue. The mixture is left at -70 ° C for about 35 minutes, after which it is warmed to room temperature. The solvent is removed in vacuo and 2.76 g of 4'-nitrobenzyl-6- [N-phenoxyacetyl-N- (2,2,2-trichloroethoxycarbonyl) amino] -2,2-dimethylpenam- 3-carboxylate-1 oxide.

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NMR spectrum (CDC13) ó

1.22 (s, 3), 1.62 (s, 3), 4.60 (s, 1), 4.78 (d, 1, J = 5 Hz), 4.93 (s, 2), 5.26 (s, 2), 5.30 (s, 2), 5.93 (d, 1, J = 5 Hz), 6.8 to 7.4 (m, 5), 7.51 (d , 2, J = 9 Hz) and 8.20 (d, 2, J = 9 Hz).

C. Preparation of Sulfinyl Chloride To 40 ml of dry benzene are added 792 mg (about 1 mmol) of the above product and 155 mg (about 1.2 mmol) of N-chlorosuccinimide. The mixture obtained is refluxed for 1 hour. The NMR spectrum of the reaction mixture indicates the presence of the title compound.

NMR spectrum (CDC13) ó

1.92 (s, 3), 4.89 (s, 1), 4.96 (s, 2), 5.05 (s, 2), 5.23 (s, 2), 5.26 (s , 1), 5.34 (s, 2), 5.64 (d, 1, J = 5 Hz), 5.95 (d, 1, J = 5 Hz), 6.10 (d, 1, J = 5 Hz), 6.8 to 7.5 (m, 5), 7.56 (d, 2, J = 9 Hz) and 8.23 (d, 2, J = 9 Hz).

Preparation 4.

Benzhydryl-3-methyl-2- (2-chlorosulfinyl-4-oxo

3-phenoxyacetamido-l-azetidinyl) -3-butenoate 20 g are added to 800 ml of dried toluene

Benzhydryl-6-phenoxyacetamido-22-dimethylpenam-3-carb-oxylate-l-oxide and heats the mixture in a system equipped with a Dean-Stark water trap to azeotropically remove the moisture present, to boil at reflux . 12.2 g of N-chlorosuccini-mid are then added to the mixture and the mixture is heated under reflux for a further 1.5 hours. The product is analyzed via the NMR spectrum, which is consistent with the structure of the title compound.

NMR spectrum (CDC13) ô

1.88 (s, 3), 4.53 (s, 2), 4.90 (s, 1), 5.14 (s, 2), 5.54 (d, 1, J = 4 Hz), 6.24 (g, 1, J = 4 Hz and 8 Hz), 6.95 (s, 1), 7.15 to 7.4 (m, 15) and 8.0 (d, 1, J = 8 Hz).

A sample of the reaction mixture is taken and the solvent is evaporated off. The NMR spectrum of the residue is consistent with the structure of the title compound: NMR spectrum (CDC13) ô

1.94 (bs, 3), 4.83 (s, 2), 5.25 (s, 2), 5.0 to 5.4 (m, 3), 6.2 (d, 1, J = 4 Hz), 7.55 (d, 2, J = 8 Hz) and 8.24 (d, 2, J = 8 Hz).

Preparation 5

4'-nitrobenzyl-3-methyl-2- (2-chlorosulfinyl-

4-oxo-3-acetamido-l-azetidinyl) -3-butenoate

500 ml of toluene are heated in a device equipped with a Dean-Stark water trap in order to azeotropically distill off any moisture which may be present. 1.0 g (2.4 mmol) of 4'-nitrobenzyl-6-acetamido-2,2-dimethylpenam-3-carboxylate-1-oxide are added to the dried toluene obtained.

The resulting mixture is refluxed again using a Dean-Stark water trap to remove any additional water that may be present. The mixture is then cooled and 400 mg (2.9 mmol) of N-chlorosuccinimide are added. The mixture is then heated to reflux for 1 hour, after which a sample of the reaction mixture is taken and the solvent is evaporated. The product obtained is in agreement with the structure of the title compound due to the NMR spectrum.

NMR spectrum (CDC13) <5

1.86 (bs, 3), 2.04, 2.09 (2s, 3), 4.80 (m, 1), 5.2 (m, 2), 5.28 (s, 2), 5 , 63 (m, 1), 6.05 (d, 1, J = 4 Hz) and 7.4 to 8.4 (q, 4, ArH).

Preparation 6

Methyl 3-methyl-2- (2-bromosulfinyl-4-oxo-3-phthalimido-l-azetidinyl) -3-butenoate A mixture of 1.88 g of methyl 6-phthalimidopenicillanate l-oxide and 890 mg of N-bromosuccinimide in 150 ml of carbon tetrachloride for 80 minutes at reflux. The reaction mixture is then cooled, washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo to give 1.82 g of the title compound. NMR spectrum (CDC13) <5

1.98 (bs, 3), 3.82 (s, 3, COOCH3), 5.0 to 5.35 (m, 3), 5.8 to 6.2 (m, 2, / 3-lactam- H) and 7.80 (bs, 4, ArH)

Example 3

4'-nitrobenzyl-3-methyl-2- (2-isopropylthiosulfinyl-4-oxo-3-phenoxyacetamido-l-azetidinyl) -3-butenoate To a solution of 10 g 4'-nitrobenzyl-3-methyl-2- ( 2-chlorosulfinyl-4-oxo-4-pheno-xyacetamido-l-azetidinyl) -3-butenoate in 450 ml of toluene are added 1.9 ml of isopropyl mercaptan and 3.5 ml of propylene oxide. The mixture is left to stand at room temperature for several days and then evaporated to dryness in vacuo to give an oil which is chromatographed on a column filled with silica gel using a toluene / ethyl acetate gradient. A total of 6.62 g of the title compound is isolated.

NMR spectrum (CDC13) <3

1.40 (d, 6, J = 6.0 Hz, SCH (CH3) 2), 2.01 (s, 3), 3.55 (m, 1, SCH (CH3) 2), 4.60 ( s, 2, side chain CH2), 5.1 to 5.4 (n, 3), 5.33 (s, 2, ester CH2), 6.20 (dd, 1, J = 4.5 and 10 , 0 Hz, / 3-lactam-H), 6.9 to 8.3 (m, 9, ArH) and 8.6 (d, 2, J = 10.0 Hz, NH).

Example 4

4'-nitrobenzyl-3-methyl-2- (2-tert-butylthiosulfinyl-4-oxo-3-phenoxyacetamido-l-azetidinyl) -3-butenoate. The procedure described in Example 3 is used with the difference that uses 2.4 ml of tert-butyl mercaptan instead of isopropyl mercaptan. After chromatography, 4.69 g of the title compound are isolated. NMR spectrum (CDC13) <5

1.43 (s, 9, tert-butyl), 2.01 (s, 3), 4.57 (s, 2, side chain-CH2), 5.0 to 5.4 (m, 5) , 6.20 (dd, 1, J = 4.0 and 11.0 Hz, / 3-lactam-H), 6.8 to 8.2 (m, 9, ArH) and 8.64 (d, 1 , J = 11.0 Hz, NH).

Example 5

4'-nitrobenzyl-3-methyl-2- (2-methoxysulfinyl-4-oxo-3-phenoxyacetamido-l-azetidinyl) -3-butenoate To a solution of 4'-nitrobenzyl-3-methyl-2- (2- chlorosulfinyl-4-oxo-3-

phenoxyacetamido-l-azetidinyl) -3-butenoate,

that was obtained from 10 g of 4'-nitrobenzyl-6-phenoxyacetamido-penicil-lanate-l-oxide and 2.68 g of N-chlorosuccinimide, in 400 ml of toluene, 25 ml of dry methanol were added. The reaction mixture is stirred overnight at room temperature and then washed successively with aqueous sodium bicarbonate solution (2x), water and brine (2x). Evaporation to dryness in vacuo gives 10 g of the impure title compound, which is purified by chromatography on silica gel washed with acid using a toluene / ethyl gradient. The product is isolated in the form of a mixture of the isomers (R and S sulfinates). The NMR spectrum of the predominantly isomer is as follows:

NMR spectrum (CDC13) <5

1.90 (s, 3), 3.74 (s, 3, -OCH3), 4.52 (s, 2, side chain CH2), 4.8 to 5.3 (m, 5), 5.32 (s, 2, ester-CH2), 5.76 (dd, 1, J = 5.0 and 9.0 Hz, / 3-lactam-H) and 6.8 to 8.2 (m, 9, ArH ).

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Claims (4)

626 604 2. The method according to claim 1, characterized in that 65 4'nitrobenzyl-3-methyl-2- (2-sulfino-4-oxophenylacetamido l-azetidinyl) -3-butenoate. 626 604 (2) a group of the general formula -SRä, in which R5 represents an alkyl group having 1 to 6 carbon atoms, an aryl group or an arylalkyl group having 1 to 3 carbon atoms in the alkyl part; characterized in that a halosulfinylazetid-inone compound of the general formula III ri \ ✓ 55 ^ SHal P \ / \ Lor (iii) in which Rx and R have the meanings given above and Hai represents a chlorine atom or a bromine atom, with a compound of the general formula Ri0B, in which Ri0 60 a group of the formulas -OR4 or -SRs, in which R4 and R5 have the meanings given above have and B represents a hydrogen atom or an alkali metal cation. (2) an amido group of the general formula 35 O II R3CNH- in the R3 (a) represents a hydrogen atom, an alkyl group having 1 to 3 40 carbon atoms, a halomethyl group or a 3- (2-chlorophenyl) -5-methylisoxazol-4-yl group; (b) a benzyloxy group, a 4-nitrobenzyloxy group, a 2,2,2-trichloroethoxy group, a tert-butoxy group or a 4-methoxybenzyloxy group; 45 (c) a group R ", where R" is a 1,4-cyclohexadienyl group, a phenyl group or one with 1 or 2 substituents which independently of one another are protected from the halogen atoms, hydroxyl groups, nitro groups, cyano groups, trifluoromethyl groups, Alkyl groups having 1 to 3 carbon atoms and alkoxy groups having 1 to 4 carbon atoms are selected, substituted phenyl group; (d) an arylalkyl group of the general formula in which R "has the meanings given above and Y represents an acetyl group or a nitroso group; and X (1) a group of the general formula —OR4, in which R4 represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an arylalkyl group having 1 to 3 carbon atoms in the alkyl part or a haloalkyl group having 1 to 6 carbon atoms; or 2nd PATENT CLAIMS 1. Process for the preparation of sulfinylazetidinone compounds of the general formula II 3. The method according to claim 1, characterized in that one 4'nitrobenzyl-3-methyl-2- (2-isopropylthiosulfinyl- (3) an imido group of the general formula ri ■ 0 II \ / x ri il (ii) 10th S - \ / \ ioqr in the R is a carboxylic acid protecting group; Ri (1) is an imido group of the general formula R "- (0) m-CH2— in which R "has the meanings given above and m represents 0 or 1; or (e) a substituted arylalkyl group of the general formula R "" CH— W in which R "" has the same meanings as the above-defined group R "and W represents a protected hydroxyl group or a protected amino group, means; r "- (0) ch ma in which R" and m have the meanings given above and R2 'is an alkyl group with 1 to 3 carbon atoms, a haloalkyl group with 1 to 3 carbon atoms, an alkoxy group with 1 to 3 carbon atoms or a trichlor represents ethoxy group; or Rx (4) an imidazolidinyl group of the general formula 0. ii R ". 25th 30th v Y-n a ^ ch in which R2 represents an alkenylene group with 2 to 4 carbon atoms, an alkylene group with 2 to 4 carbon atoms, a 1,2-phenylene group or a 1,2-cyclohexenylene group; or 4-oxo-3-phenoxyacetamido-l-azetidinyl) -3-butenoate.