DK167872B1 - Process for preparing 2-chlorosulphinylazetidin-4-one compounds - Google Patents

Description

DK 167872 B1

This invention relates to a particular process for the preparation of 2-chlorosulfinylazetidine-4-one compounds of the general formula I set forth in the preamble of claim 1. These sulfinyl chlorides can be treated with e.g. stannous chloride 5 to form 3-exomethylene cepham sulfoxides, which are known intermediates in the preparation of cephalosporin antibiotics.

U.S. Patent No. 3,843,682 discloses a process for preparing 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-imido-1-azetidinyl) -3-butenoate esters which also referred to as "2-chlorosulfinyl-3-imido-azetidin-4-ones".

These compounds are prepared from the corresponding penicillin sulfoxide esters by reacting the latter with 15 sulfuryl chloride at a temperature of 75-120 ° C. The compounds prepared by this known method are only 3-imido-substituted 2-chlorosulfinylazetidin-4-ones, the process being limited to the use of 6-imidopenicillin sulfoxide esters as starting material. The use or possible use of what is preferred and more readily available is not disclosed, namely 6-amidopenic xylinsulfoxide esters, including the conveniently obtainable penicillin sulfoxide derivatives of the naturally occurring penicillin G and / or penicillin 25 lin V. attempting to carry out the reaction described in U.S. Patent No. 3,843,682 using a 6-amidopenicillin sulfoxide ester as the starting material is the product obtained, a complex mixture not containing the 2-chlorosulfinylazetidin-4-one product or the 30 at least contains the latter in such a quantity that it cannot be detected by ordinary analytical techniques. This method described previously, because it requires the absence of an amide hydrogen at the 6-position of the penicillin sulfoxide starting material, has inherent and significant drawbacks, firstly requiring the replacement of the naturally occurring 6-substituent in a penicillin by an imido substituent and secondly,

UIV I0 / O / & D I

2 is the cleavage of the imido substituent to allow a reacylation to introduce the substituent which must be in the final antibiotic product.

Surprisingly, it has now been found that it is possible to prepare sulfinyl chloride intermediates from 6-ami-dopenicillin sulfoxide esters by changing the reaction conditions and the halogenating agent used. This avoids the previously required blockage of the amide hydrogen 10 at the 6-position of the penicillin sulfoxide starting material by converting it into an imide derivative.

The chlorosulfinylazetidinones produced by the process of the invention can be cyclized to form 3-exomethylene cepham sulfoxide esters. The cyclization of the 2-chlorosulfinylazetidin-4-ones to their corresponding 3-exomethylene cepham sulfoxides is carried out by means of a Friedel-Crafts catalyst which causes an intramolecular reaction between the chlorosulfinyl group and the alkenic portion of the azetidin-4-one starting material.

The process according to the invention for the preparation of the compounds of formula I is peculiar to the characterizing part of claim 1. Formula I means a carboxylic acid protecting group and preferably one which can be removed by acid treatment or hydrogenation. Preferred carboxylic acid protecting groups include, for example, alkyl of 1-4 carbon atoms, 2,2,2-trihaloethyl, 2-iodoethyl, benzyl, p-nitrobenzyl, succinimidomethyl, phthalimidomethyl, p-methoxybenzyl, benzhydryl, alkanoyloxymethyl of 2-6 carbon atoms. dimethylallyl, phenylacyl or p-halogenophenacyl, wherein halogen represents chlorine, bromine or iodine.

Specific illustrations of the preferred carboxylic acid protecting group are, for example, methyl, ethyl, η-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2,2-trichloroethyl, 2 , 2,2-tribromethyl, 2-iodoethyl, benzyl, p-nitrobenzyl, succinimidomethyl, phthalimidomethyl, p-methoxybenzyl, benzhydryl, acetoxymethyl, pyvaloyloxymethyl, propionoxymethyl, phenacyl, p-chlorophenacyl and p-bromophen.

Particularly preferred carboxylic acid protecting groups are methyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl and 2,2,2-trichloroethyl.

Of course, in the above definition, the carboxyl protecting group is not exhaustively described. The function of this group is to protect the reactive carboxyl group 15 during the preparation of a desired product. It is removed without destroying the rest of the molecule. Many such carboxyl protecting groups are well known to those skilled in the art and are equally useful in the process of the invention.

20

The compounds prepared by the process of the invention in which R is the amide function 0 25 3 1 R -C-NH-3 wherein R is as defined in the preamble of claim 1 are novel compounds.

30

As will be known to those skilled in the art of penicillin and cephalosporin science, any penicillin sulfur oxide starting material used in the present process can be readily prepared from available penicillin sources such as naturally occurring Penicillin sources.

QC

cillin G and / or Penicillin V * L / lv 10/0 / ^ Dl 4 6-aminopenicillanic acid (6-APA) can be prepared from each of the above naturally occurring penicillins by cleavage of the 6-acyl function using prior art.

5

It is possible to make all the starting materials according to the generally known technique from 6-APA. For example, 6-APA can be converted to the desired ester by esterification of the 3-carboxyl function in known manner.

10

Furthermore, the amino group of 6-APA can be acylated to produce any of the groups defined by 3 R CONH-. This is achieved by reacting 6-APA with an activated form of the acid containing the desired acyl group.

Such activated forms include the corresponding acid halogenides, anhydrides or activated esters such as pentachlorophenyl ester.

Similarly, the penicillin can be oxidized to sulfoxide 20 under known conditions, which also includes treating penicillin with m-chloroperbenzoic acid or sodium periodate.

These conversions, namely cleavage for 6-APA, esterification, acylation or oxidation, can be carried out in any order with the desired structural modifications. These conversions can be carried out using techniques, conditions and reagents which are readily available and known to those skilled in the art.

30

Preferred penicillin sulfoxide esters for use in the process are those having the formula:

/ \ "

> - (0) -CH -C-MK A VI

\ / n 2 \ / \, CH VI

c ®? - \ / ^

O X

wherein m is 0 or 1 and R 1 is a carboxylic acid protecting group.

Similarly, the preferred sulfinyl chlorides of formula I are compounds of formula: 15 C 1 -C 2 -C 1 -CH 2

20 i - k H-CH

* 1 COOR1 wherein m is 0 or 1 and is a carboxylic acid protecting group.

The substituted chlorosulfinylazetidinones produced by the process of the invention are formed by interaction between a penicillin sulfoxide ester and an N-monochloro-substituted amide, imide, sulfonamide or sulfimide at elevated temperature.

By "N-monochloro-substituted amide, imide, sulfonamide or sulfimide" is meant a reagent having at least one chlorine atom 35 directly linked to a nitrogen atom, wherein the residual group (s) in the structure of the reagent has an electron-withdrawing strength sufficient to act as a byproduct. 6

UK ΙΟ / Ο / Ζ D I

to produce a nitrogen-containing compound having the following characteristics: First, the nitrogen-containing compound produced is one which corresponds to the chlorinating agent, but which has the chlorine network replaced by a hydrogen atom. Secondly, because of the properties of the electron withdrawing group, the nitrogen-containing compound will be inert to the sulfinyl chloride product. The chlorinating agents used in the process of the invention are preferably compounds of the formula: R7

15 X

-10 N-Cl VIII

/ R 5 wherein R is hydrogen, alkyl of 1-3 carbon atoms, cyclohexyl, phenyl or phenyl substituted by chloro, bromo, methyl or nitro, and Ra is R -X- where R is alkyl of 1-3 carbon atoms , cyclohexyl, phenyl or phenyl substituted with chloro, bromo, methyl or nitro, and X is 0

II

Or R and R together with the nitrogen atom to which they are attached define a heterocyclic structure of the formula:

fV

Wherein Y is o-phenylene or - (CH 2) where n is 2 or 2 n 3; or of formula 10 wherein Z is Y, as defined above.

The preferred N-chloroamides which can be used in the process of the invention generally have the formula:

Cl 35 6 2q wherein R1 and R are as defined above.

Illustrative of these amides are the following compounds: N-chloroacetamide N-chloropropionamide N-chloro-N-methylacetamide N-chloro-N-cyclohexylacetamide N-chloro-N-ethylbenzamide N-chloro-p-chlorobenzamide N-chloro-p-toluamide N-chloro-N-phenylpropionamide N-chloro-N- (m-bromophenyl) butyramide N-chlorohexahydrobenzamide and N, 2,4-trichloroacetanilide.

Ul \ ID / O / ^ D I

8

The preferred N-chlorosulfonamides which can be used in the process of the invention have the formula: R7

5 6 I

ΰ R -SO2-N-C1 6 7 wherein R and R7 are as defined above.

Illustrative of these sulfonamides which can be used as chlorinating agents are the following compounds: N-chloromethanesulfonamide N-cyclohexyl-N-chlorobenzene sulfonamide N-cyclohexyl-N-chloroethanesulfonamide 1s J N-chlorobenzenesulfonamide N-phenyl-N-chlorobenzene sulfonamide -p-toluenesulfonamide N-ethyl-N-chloro-m-nitrobenzenesulfonamide N-methyl-N-chloro-m-chlorobenzenesulfonamide N-methyl-N-chloro-p-toluenesulfonamide N-cyclohexyl-N-chlorocyclohexanesulfonamide Np-tolyl N-chloroisopropanesulfonamide N-propyl-N-chlorobenzenesulfonamide or Nβ-nitrophenyl-N-chlorocyclohexanesulfonamide.

25

Another preferred type of chlorinating agents which can be used in the process of the invention are sulfimimides of the formula: 30 fl v V-ci V_s / wherein Y is o-phenylene, -CH2 ~ CH2- or -CH2-CH2 ~ CH2- .

35 DK 167872 B1 9

These compounds include o-sulfobenzoic acid-N-chloro-imide, β-sulfopropionic acid-N-chloroimide and τ-sulfo-butyric acid N-chloroimide.

Further preferred chlorinating agents which can be used in the process of the invention are N-chloroimides of the formula: wherein R is o-phenylene, ~ CH 2 -CH 2 ~ or -Cl 2 -Cl ^ -CI ^ -.

These compounds include N-chlorophthalimide, N-chloro-succinimide, and N-chloro-glutarimide.

Many of the N-chloro halogenating agents used in the process of the invention are commercially available and can be prepared by well known methods.

N-chloro halogenating agents which are highly preferred for use in the process of the invention are N-chloroimides, and especially N-chlorosuccinimide or N-chloro-25-phthalimide.

The reaction between the penicillin sulfoxide and the chlorinating agent is generally carried out by mixing at least 1 mol and up to 1.5 mol of the halogenating agent with 1 mol of the penicillin sulfoxide ester. An even greater excess of halogenating agent can be used, but no benefit is obtained thereby. Preferably, therefore, the ratio of the reactants is 1.0 to 1.1 moles of halogenating agent per minute. mole of penicillin sulfoxide ester. The resulting mixture, which is preferably dissolved in a suitable inert organic solvent, is heated to a temperature of 75 - 135 ° C. Preferably, the temperature is 100-120 ° C and most preferably approx. 110 ° C.

10

Wolf Ib / b / * 'b I

By "inert organic solvent" is meant an organic solvent which, under the reaction conditions, does not react appreciably with either the reactants or with the products. Suitable inert organic solvents are those having a boiling point which is at least as high as the reaction temperature, and these include, for example, aromatic hydrocarbons such as benzene, toluene, ethylbenzene or cumene; halogenated hydrocarbons such as carbon tetrachloride, chlorobenzene, bromoform, bromobenzene, ethylene dichloride, 1,1,2-trichloroethane or ethylene dibromide; aliphatic nitriles, such as acetonitrile or propionitrile, and many other suitable inert organic solvents. Preferred solvents are those having a boiling point within the temperature range at which the reaction is carried out, so that it is possible to allow the reaction mixture to reflux and still maintain temperature control. Particular reaction conditions include the use of toluene or 1,1,2-trichloroethane as the solvent, the reaction temperature being that developed under reflux conditions.

A requirement of the present process is that it be carried out under anhydrous conditions. Under anhydrous conditions, not all absence of any trace of moisture is meant, but it is believed that the reaction mixture must be avoided with significant amounts of moisture. This can be done in known manner. Since the chlorinating agent will normally react with water, it will not be the source of introducing moisture into the reaction mixture. Typically, any excess moisture in the reaction system will come from the presence of moisture in the solvent used. Generally, therefore, the solvent is subjected to a pretreatment to remove residual water. The solvent can be rendered anhydrous by contacting a drying agent which binds moisture, effectively removing it from the solvent. Such typical drying agents include anhydrous sodium sulfate, magnesium sulfate, sodium carbonate, potassium carbonate, calcium carbide, calcium chloride, calcium hydride, potassium sulfate, calcium oxide or molecular sieves.

In the case where the solvent is one which forms azeotrope with water, moisture can be removed by subjecting the solvent to distillation using a known apparatus comprising the usual Dean-Stark trap or a Barrett type trap which collects the water when the XO boils off as an azeotrope.

The penicillin sulfide ester ester used as a starting material may also contain moisture. This can be removed by subjecting the penicillin sulfoxide to a typical drying vacuum vacuum drying in an oven at a low temperature up to 50 ° C. Further, the penicillin sulfoxide ester can be added to the solvent and the mixture can then be boiled azeotropically to remove water. The mixture containing penicillin sulfoxide ester and chlorinating agent is generally heated to a temperature within the defined range for 0.5-4 hours and preferably for 1-2 hours, after which the sulfinyl chloride can be isolated from the reaction mixture, typically by evaporation - 25 in vacuo to remove the solvent. Although the sulfinyl chloride is isolated from the reaction mixture, it is not necessary that it be isolated before further reaction. 1 2 3 4 5 6

It has also been found that in many cases it is desirable to include 2 a non-alkaline acid binding agent 3 part in the reaction mixture. For reasons not yet understood 4, small amounts of hydrogen chloride may be released into the reaction system. A non-alkaline acid-binding compound will remain completely inert in the normal hydrogen chloride-free reaction medium, but will be activated to the extent necessary to react with any 12 amounts of hydrogen chloride formed, thereby removing it from the reaction mixture.

Typical non-alkaline acid binding agents include epoxide compounds such as ethylene oxide, propylene oxide, epichlorohydrin or 1,2-epoxy-3-phenoxypropane. These compounds exhibit non-alkaline properties, but will nevertheless react and remove acidic compounds from the reaction system. A more complete discussion of these 10 reagents is given in Hunsberger and Tien, Chem., Ind., 88 (1959) and also in Buddrus, Angew. Chem. Internat. Edit.,

Vol. 11 (1972), pp. 1041-1050.

The amount of non-alkaline acid binding agent that can be used in the sulfinyl chloride preparation is not critical. Preferably, the amount should be sufficient to at least remove any amount of hydrogen chloride that can be formed. Although an excess of non-alkaline acid binding agent may be used without adversely affecting the preparation of sulfinyl chloride, the presence of an excess of non-alkaline acid binding agent will be significant in cases where the reaction mixture contains the sulfinyl chloride product itself used in its conversion to the corresponding to 3-exomethylene cepham sulfoxide as discussed below. Therefore, before the cyclization reaction using stannous chloride, it is preferred that the sulphinyl chloride be separated from any product by non-alkaline acid binding agent and from any product formed by the reaction of acid binding agent with hydrogen chloride.

A typical preparation of a sulfinyl chloride by the process of the invention is carried out by mixing molar amounts of penicillin sulfoxide and chlorinating agent in a suitably dried solvent. The resulting mixture is heated to the desired temperature, which is preferably somewhat higher for a 6-amidopenicillin sulfoxide than for a 6-imidopenicillin sulfoxide. The reaction mixture is heated to the desired temperature for the desired period of time. Preferably, the solvent used is one which allows the reaction temperature to be obtained and maintained by boiling the reaction mixture. At the end of the reaction period, the reaction is terminated by cooling the mixture to room temperature, washing the mixture with water and drying it over an appropriate inorganic desiccant.

After evaporation of the solvent, the sulfinyl chloride product is normally recovered as an amorphous solid.

As an alternative to the above typical preparation method, the penicillin sulfoxide ester can be dissolved in the selected solvent, heated to the reaction temperature, and then added to the heated mixture, either alone or in solution, dropwise to the heated mixture. After the addition is complete, the resulting mixture usually reacts under the defined conditions. The work-up can be carried out by analogy or identical to the one described above.

Examples of substituted chlorosulfinylazetidines of formula I include: 2,2,2-trichloroethyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-acetamido-1-azetidinyl) -3-butenoate p-nitrobenzyl-3 -methyl-2- (2-chlorosulfinyl-4-oxo-3-butyramido-1-azetidinyl) -3-butenoate p-methoxybenzyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3- chloroacetamido-1-azetidinyl) -3-butenoate p-nitrobenzyl-3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4-nitrobenzyloxycarbamoyl) -1-azetidinyl] -3-butenoate

ULU / O / C Dl 14 p-Methoxybenzyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenylacetamido-1-azetidinyl) -3-butenoate p-nitrobenzyl-3-methyl 2- [2-chlorosulfinyl-4-oxo-3- (2 ', 5'-dichlorophenylacetamido) -1-azetidinyl] -3-butenoate benzyl-3-methyl-2- [2-chlorosulfinyl-4-oxo-3 - (3 '-bromophenoxy-acetamido) -1-azetidinyl] -3-butenoate tert-butyl-3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4'-chloroacetoxyphenylacetamido) -1 -azetidinyl] -3-butenoate isobutyl-3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (3'-formyl-oxyphenoxyacetamido) -1-azetidinyl] -3-butenoate p-nitrobenzyl-3- methyl 2- [2-chlorosulfinyl-4-oxo-3- (2'-nitrophenylacetamido) -1-azetidinyl] -3-butenoate p-methoxybenzyl-3-methyl-2- [2-chlorosulfinyl-4- oxo-3- (4'-nitrophenoxyacetamido) -1-azetidinyl] -3-butenoate benzhydryl-3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (3'-cyano-phenylacetamido) -1- azetidinyl] -3-butenoate p-bromophenacyl-3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2 '- cyanophenoxyacetamido) -1-azetidinyl] -3-butenoate propionoxymethyl-3-methyl-2- [2-Chlorosulfinyl-4-oxo-3- (4'-trifluoromethylphenylacetamido) -1-azetidinyl] -3-butonate 2,2,2-tribromethyl-3-methyl-2- [2-chlorosulfon inyl 4-oxo-3- (3'-trifluoromethylphenoxyacetamido) -1-azetidinyl] -3-butenoate 2-iodoethyl-3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2'-ethyl -phenylacetamido) -1-azetidinyl-3-butenoate DK 167872 B1 acetoxymethyl-3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (4'-isopropylphenoxyacetamido) -1-azetidinyl] -3-butenoate -butyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (3'-ethoxy-5-phenylacetamido) -1-azetidinyl] -3-butenoate and p-nitrobenzyl-3-methyl-2- [ 2-chlorosulfinyl-4-oxo-3- (4'-isopropoxyphenoxyacetamido) -1-azetidinyl] -3-butenoate.

As mentioned earlier, the present compounds are useful as intermediates and can be cyclized to corresponding 3-exomethylene cepham sulfoxides by treatment with a Frie-part-Crafts catalyst, e.g. tin (IV) chloride.

The 3-exomethylene cepham sulfoxide cyclization products are useful as intermediates in the preparation of antibiotic compounds. Sulfoxides can be reduced in known manner, typically with phosphorus trichloride or phosphorus tribromide in dimethylformamide, to give corresponding 3-exomethylene cepham compounds.

The exomethylene cepham compounds can be used in the preparation of new cepham antibiotics of the formula:

R S

25 \ _j / \

0 T

COOH

Wherein B is, for example, chlorine, bromine or methoxy. Such chemical conversions of 3-exomethylenepepham compounds are described in the chemical literature [Robert R. Chauvette and Pamela A. Pennington, Journal of the American Chemical Society, 96, 4986 (1974)].

The following examples serve to further illustrate the invention.

35

Wolf Ib / b / Z b l

Preparation of methyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl) -3-butenoate EXAMPLE 1 16

A solution of 18.8 g (50 mmol) of methyl 6-phthalimido-2,2-dimethylpenam-3-carboxylate-1-oxide and 6.7 g (50 mmol) of N-chlorosuccinimide in 1000 ml of dry carbon tetrachloride was boiled under reflux for 70 minutes. The mixture was cooled and washed with water and saturated brine. After drying over magnesium sulfate, the solvent was evaporated and 19.5 g (95%) of the compound was obtained as a colorless solid. The NMR spectrum (CDCl3) indicated that the product was as above.

NMR Spectrum (CDCl3) δ 1.97 (broad, s, 3), 3.86 (s, 3), 5.05 (br, 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).

EXAMPLE 2

Preparation of p-nitrobenzyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl) -3-butenoate

A solution of 49.7 g (0.1 mole) of p-nitrobenzyl-60-phthalimido-2,2-dimethylpenam-3-carboxylate-1-oxide and 13.4 g (0.1 mole) of N-chlorosuccinimide in 1.5 liters of 1,2-dichloroethane was refluxed for 70 minutes. The mixture 30 was cooled, washed with water and saturated brine and dried over magnesium sulfate. The solution was evaporated and the residue dried in vacuo for 3 hours to give 52.0 g of the above compound. 1 NMR Spectrum (CDCl 3) δ 1.97 (s, 3), 5.05 (s, 1), 5.4 (s, 2), 5.76 (d, 1, J = t Hz), δ , 91 (d, 1, J = 5 Hz), 7.83 (m, 4, Ar-H).

Preparation of p-nitrobenzyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate EXAMPLE 3 17

A solution of 500 mg (1 mmol) of p-nitrobenzyl-60-phenoxy-acetamido-2,2-dimethylpenam-3-carboxylate-1-oxide and 134 mg (1 mmol) of N-chlorosuccinimide in 40 ml of well-dried 1.1 2-Trichloroethane was refluxed for 90 minutes.

The mixture was cooled, washed with water and brine, dried, and the solvent evaporated in vacuo. According to the NMR spectrum, the desired substance was obtained in an almost quantitative yield.

NMR Spectrum (CDCl3) δ 1.91 (wide, s, 3), 4.53 (s, 2), 5.05 (broad, s, 1), 5.23 (m, 2), δ , 33 (s, 2), 5.57 (d, J = 4.5 Hz), 6.18 (dd, 1, J = 4.5 Hz), and 6.9-8.1 (m, 9, Ar-H).

EXAMPLE 4

Preparation of p-nitrobenzyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate

A mixture of 6.0 g (12 mmol) of p-nitrobenzyl-6-phenoxy-acetamido-2,2-dimethylpenam-3-carboxylate-1-oxide in 500 ml of dry toluene was boiled for 10 minutes using a Dean -Stark trap to remove traces of water. After drying, 1.8 g of N-chlorosuccinimide was added and the mixture was refluxed for 90 minutes. The mixture was cooled to 50 ° C and evaporated to give the desired product.

35

Preparation of 2,2,2-trichloroethyl-3-methyl-2- (2-chlorosulfinyl-4-QKO-3-phenylacetamido-1-a-ethidinin) -3-butenoate EXAMPLE 5 18

UK ΙΟ / Ο / έ D I

A solution of 500 mg of 2,2,2-trichloroethyl-6/5-phenylacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide and 134 mg of N-chlorosuccinimide in 40 ml of dry toluene was refluxed 90 minutes. The mixture was cooled, washed with water and brine and dried over magnesium sulfate, and the solvent was evaporated on a rotary evaporator. The desired product was obtained as a colorless foam.

NMR Spectrum (CDCl3) 61.90 (s, 3), 3.55 (s, 2), 4.8 (m, 2), 4.95 (d, 1, J = 4.5 Hz) , 5.03-5.21 (m, 3), 5.65 and 5.70 (ABq, 1, J = 4.5 Hz), 7.3 (s, 5) and 7.5 (d, NH , J = 10 Hz).

EXAMPLE 6

Preparation of methyl 3-methyl-2- [2-chlorosulfinyl-4-oxo-3- (2,2-dimethyl-3'-nitroso-5'-oxo-41-phenylimidazoli-25-din-11-yl) -1-azetidinyl] -3-butenoate

To 55 ml of dry benzene further dried by azeotropic removal of water was added 0.896 g (2 mmol) of methyl 6- (2,2-dimethyl-3-nitroso-5-oxo-4-phenylimidazolide) -1-yl) -2,2-dimethylpenam-3-carboxylate-1-oxide and 5.536 g (4 mmol) of N-chloro-succinimide. The mixture was bubbled with nitrogen and boiled for about 1 hour. The resulting reaction mixture was a solution of a greenish-yellow color. The mixture was cooled and the solvent was evaporated from part of the mixture in vacuo to give the product as residue. NMR analysis of the residue indicated the presence of the correct product.

EXAMPLE 7 19

Preparation of methyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phthalimido-1-azetidinyl) -3-butenoate 5

To 300 ml of carbon tetrachloride was added 3.7 g (10 mmol) of methyl 6-phthalimido-2,2-dimethylpenam-3-carboxylate-1-oxide and 2.2 g (10 mmol) of N-chloro-N-methyl -p-toluenesulfonamide. The mixture was heated to reflux 10 for 90 minutes. The reaction mixture was cooled to room temperature, washed with water and brine, dried over magnesium sulfate and divided into two equal parts.

The first part was evaporated to dryness in vacuo to give the desired compound as a residue and the structure verified by NMR analysis.

NMR Spectrum (CDCl 3) δ 2.0 (s, 3, allylic CH 2), 3.84 (s, 3, CH 2 ester), 5.1 (s, 2, vinyl CH 2), 5.2 (s, 1, C4-H) and 5.6-6.0 (m, 2, Cg-H and C7-H).

EXAMPLE 8 Preparation of p-nitrobenzyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate

To 150 ml of distilled and molecular sieve-dried toluene was added 3.0 g (6 mmol) of p-nitrobenzyl-6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide and 1.3 g (6 mmol) of N -chloro-N-methyl-p-toluenesulfonamide. The mixture was refluxed for 60 minutes; whereupon the resulting reaction mixture was cooled to room temperature. An aliquot of 15 ml was separated, washed with water and brine, dried over magnesium sulfate and evaporated to dryness in vacuo. The NMR spectrum of the residue was consistent with the desired product contaminated with some N-methane.

Ulv lb / 8 / Z bl 20 thyl-p-toluenesulfonamide.

EXAMPLE 9 Preparation of p-nitrobenzyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate 425 ml of toluene was heated in equipment equipped with a Dean-Stark water trap to azeotropically remove the moisture present, thereby distilling off 25 ml of toluene. The residual toluene was added 10.0 g (20 mmol) of p-nitrobenzyl-6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide, keeping the toluene at a temperature slightly below the boiling point. 200 ml of the two-lute were distilled off separately and 4.0 g (22 mmol) of N-chlorophthalimide was added. The resulting mixture (warm) was added dropwise to the solution of penicillin sulfide ester over 30 minutes. The mixture remained a pale yellow solution during the addition. The mixture was refluxed for 55 minutes, after which a sample was taken and NMR analysis showed practically complete conversion of the penicillin sulfoxide ester to the desired compound.

EXAMPLE 10

Preparation of benzhydryl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate 1 2 3 4 5 6

To 800 ml of dried toluene was added 20 g of benzhydryl-6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide.

3

The mixture was refluxed in a system 4 containing a Dean-Stark water trap for azeotropic removal of moisture present, thereby distilling off 100 ml of toluene. To the mixture was added 13.2 g of N-chlorosuccinimide. Refluxing was continued for 1.5 hours. NMR analysis of the product was consistent with the structure of the desired product.

NMR Spectrum (CDCl3) δ 1.88 (s, 3), 4.53 (s, 2), 4.90 (s, 1), 5.14 (s, 2), 5.54 (s, 1) , J = 4.5 Hz), 6.24 (q, 1, J = 4 Hz and 8 Hz), 6.95 (s, 1), 7.15-7.4 (m, 15) and 8.0 (d, 1, J = 8 Hz).

EXAMPLE 11 10

Preparation of p-nitrobenzyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-acetamido-1-azetidinyl) -3-butenoate 500 ml of toluene was heated in an equipment equipped with a Dean-Stark - water trap for azeotropic removal of any moisture present. The dried toluene was added 1.0 g (2.4 mmol) of p-nitrobenzyl-6-acetamido-2,2-dimethyl-penam-3-carboxylate-1-oxide and the resulting mixture was boiled again using the water trap to remove 20 additional water present. The mixture was cooled and 400 mg (2.9 mmol) of N-chloro-succinimide was added. The mixture was boiled for 1 hour. A sample of the reaction mixture was taken and the solvent was removed. The obtained product was, by NMR analysis, consistent with the structure of the above compound.

NMR Spectrum (CDCl3) 61.86 (br, s, 3), 2.04, 2.09 (2s, 3), 4.80 (m, 1), 5.2 (m, 2), δ , 28 (s, 2), 5.63 (m, 1), 6.05 (d, 1, J = 4 Hz) and 7.4-8.4 (q, 4, ArH).

EXAMPLE 12 22 υκ Tb / a / z b i

Preparation of 2,2,2-trichloroethyl-3-methyl-2- [2-chlorosulfinyl-4-oxo-3- [4'-nitrobenzyloxycarbamoyl) -1-azetidinyl] -3-butenoate

A mixture of 300 ml of 1,1,2-trichloroethane and 10.26 g of 2,2,2-trichloroethyl-6- (4'-nitrobenzyloxycarbamoyl) -2,2-dimethylpenam-3-carboxylate-1-oxide. The mixture was boiled 10 to remove approx. 75 ml of the solvent to obtain a dry reaction medium. The mixture was cooled and propylene oxide was added followed by 4 g of N-chlorosuccinimide. The temperature of the mixture was raised to 102 ° C and the mixture was boiled for 2.5 hours. A sample of the reaction mixture was taken and the solvent evaporated. NMR analysis of the residue was consistent with the structure of the title compound.

NMR Spectrum (CDCl3) δ1.94 (br, s, 3), 4.83 (s, 2), 5.25 (s, 2), 5.0-5.4 (m, 3), 6.20 (d, 1, J = 4 Hz), 7.55 (d, 2, J = 8 Hz) and 8.24 (d, 2, J = 9 Hz).

EXAMPLE 13 --- 25

Preparation of p-nitrobenzyl-3-methyl-2- [2-chlorosulfinyl-4-oxo-3- [N-phenoxyacetyl-N- (2 ', 2', 2'-trichloroethoxy-carbonyl) amino] -1 -azetidinyl3-3-butenoate 1 2 3 4 5 6

A mixture of 4,855 g (10 mmol) of p-nitrobenzyl-6-phenoxyacetamido-2,2-dimethylpenam-3-carboxy 3 lat, 16.94 g (80 mmol) of 2,2,2-trichloroethyl chloroformate was prepared. 18 4 ml of N, O-bis (trimethylsilyl) trifluoromethylacetamide and 20 ml of 5 methylene chloride. The mixture was allowed to stand at room temperature overnight and then heated to reflux for 7 hours, after which it was again allowed to stand at room temperature overnight. Then, it was heated for an additional 6 hours, evaporated to a residue and dissolved in benzene, after which a large excess of heptane was added. The resulting insoluble compound was filtered off, dissolved in benzene and chromatographed over silica gel using a benzene-ethyl acetate elution gradient. 4.76 g (72%) of p-nitrobenzyl-6- [N- (phenoxyacetyl) -N- (2,2,2-trichloroethoxycarbonyl) amino] -2,2-dimethylpenam-3-carboxy was obtained. - as a product.

NMR Spectra 61.41 (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- 7.4 (m, 5), 7 , 53 (s, 2, J = 9 Hz) and 8.22 (d, 2, J = 9 Hz).

To about 75 ml of acetone was added 2.54 g (3.84 mmol) of the above product. The mixture was cooled to -70 ° C and an excess of ozone was passed through the reaction mixture 20 with approx. 1.17 mmol per minute for 9 minutes, during which the reaction mixture turned blue. The mixture was kept at -70 ° C for 35 minutes, then warmed to room temperature and the solvent removed in vacuo to give 2.76 g of p-nitrobenzyl-6- [N- (phenoxyacetyl) -N- 25 ( 2,2,2-trichloroethoxycarbonyl) amino] -2,2-dimethylpenam-3-carboxylate-1-oxide.

NMR Spectrum 61.22 (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 = Hz), 6.8-7.4 (m, 5), 7, 51 (d, 2, J = 9 Hz) and 8.20 (d, 2, J = 9 Hz).

To 40 ml of dry benzene was added 792 mg (about 1 mmol) of the above product and 155 mg (about 1.2 mmol) of N-chlorosuccinimide. The resulting mixture was heated to reflux for 1 hour and the spectrum of the reaction mixture's NMR-24 UK Ib / b / Z b l spectrum indicated the presence of the title product.

NMR spectrum α1, 92 (s, 3, 4.87 (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), 6.8-7.5 (m, 5), 7.56 (d, 2, J = 9 Hz), and 8.23 (d, 2, J = 9 Hz).

10 15 20 25 30 35

Claims (6)

A process for preparing 2-chlorosulfinylaze-5-tidin-4-one compounds of the general formula α / S ° I - f ch2 1 10 ii Υγ COOR1 in which R is a carboxylic acid protecting group and R is phthalimido, 2,2-dimethyl-3-nitroso-5-oxo-4-phenylimidazolidine-1- yl, N-phenoxyacetyl-N- (2 ', 2', 2'-trichloroethoxy-carbonyl) amino or a group of the formula Wherein R is hydrogen, alkyl of 1-3 carbon atoms, benzyl, phenoxymethyl or 4-nitrobenzyloxy, characterized in that a penicillin sulfoxide of the formula: 0 * 11 Wherein R 1 and R are as defined above are reacted with a UK-1b / o7Z d anhydrous conditions. Process according to claim 1, characterized in that the reaction is carried out in the presence of a non-alkaline acid binding agent. Process according to claim 1 or 2, characterized in that the reaction is carried out in the presence of toluene as solvent. A process according to any one of claims 1-3, characterized in that a compound of the formula R7 \ N-Cl VIII / N is used as the N-chloro halogenating agent. R 5 7 wherein R is hydrogen, alkyl of 1-3 carbon atoms, cyclohexyl, phenyl or phenyl substituted with chlorine, 5 6 6 bromine, methyl or nitro, and R is R -X- where R ° is - 25 alkyl with 1 -3 carbon atoms, cyclohexyl, phenyl or phenyl substituted with chlorine, bromine, methyl or nitro, and X is O 30 -C- or -SO2 ~ 75 or R and R together with the nitrogen atom to which they are attached define a heterocyclic structure of the formula: Process according to claim 4, characterized in that the N-chloro halogenating agent has the formula: V / S wherein Z is o-phenylene or -CH 2 -CH 2 - Wherein V is o-phenylene, or - (Cl 2) where n is 2 or 3, or of the formula: X wherein Z is Y, as defined above. Process according to claim 5, characterized in that the N-chloro halogenating agent is N-chlorosuccinimide. Process according to claim 5, characterized in that the N-chlorohalogenating agent is N-chlorophthalimide.