CS215130B2 - Method of preparation of derivatives of the 1,1-dioxide of the penicilane acid - Google Patents

Abstract

A process for the preparation of penicillanic acid 1,1-dioxide and esters thereof readily hydrolyzable in vivo. Said process involves dehalogenation of a 6-halo or 6,6-dihalo derivative of penicillanic acid 1,1-dioxide or ester thereof readily hydrolyzable in vivo or a carboxy protected derivative thereof (e.g. by hydrogenolysis). The 6-halo and 6,6-dihalo derivatives of penicillanic acid 1,1-dioxides, esters thereof readily hydrolyzable in vivo, and carboxy protected derivatives thereof are novel intermediates. Penicillanic acid 1,1-dioxide, and esters thereof readily hydrolyzable in vivo, are known compounds which are useful as beta- lactamase inhibitors and for enhancing the effectiveness of certain beta-lactam antibiotics (e.g. the penicillins) in the treatment of bacterial infections in mammals, particularly humans.

Description

The invention relates to a process for the preparation of penicillanic acid 1,1-dioxide and its esters which are readily hydrolyzable in vivo. This new process involves the oxidation of - 6-halogen or 6,6-dihalogenated penicillanic acid derivatives or their esters readily hydrolyzable in vivo to the corresponding

1,1-dioxides and subsequent dehalogenation. The novel compounds used as intermediates are 6-halo and 6,6-dihalogenated derivatives of penicillanic acid 1,1-dioxide and their esters readily hydrolyzable in vivo.

Penicillanic acid 1,1-xitoxide and esters readily hydrolyzable in vivo are useful as β-actamase inhibitors and as agents that enhance the efficacy of certain. Akt -Actam antibiotics when used for the treatment of bacterial infections. . mammals, especially in humans. Previously, penicillanic acid 1,1-dioxide and its esters readily hydrolyzable in vivo were prepared from -6-bromopenicillanic acid or its ester, readily hydrolysable in vivo, by debromation to form penicillanic acid or its ester readily hydrolyzable in vivo, and subsequent oxidation to 1,1-dioxide. Although the process according to the invention is based on 6-halo-penilcianoic acid or its ester readily hydrolyzable in vivo, and includes the steps of dehalogenation and oxidation, it has been

surprisingly it has been found that when the oxidation step is carried out before the dehalogenation step, better product yields are obtained. Further descriptions of methods for preparing penicillanic acid 1,1-dioxide and esters readily hydrolyzable in vivo are described in Belgian Patent No. -867,859 of December 6, 1978 and in DOS No. 2,824,535.

6-Halogenpenicillanic Acids are described in Cignerelia-al, Journal of Organic Chemistry 27, 2668- (1962) and U.S. Patent No. 3,206,469, hydrogenolysis of 6-halopenicillanic acids to penicillanic acid is described in No. 1,072-108.

Harrison et al., Journal of Chemical Society (London), Perkin I, 1772 (1976)

a) oxidation of 6,6-dibrompenicillanic acid with 3-chloroperbenzoic acid to form a mixture of the corresponding α- and β-sulfoxides,

b) oxidation of methyl ^{6,6-dibromopenicillanate:} nicila'nátu

3-chloroperbenzoic acid to give

Methyl-6,6-dibro 1,1-dioxide, mpenicillanate,

c) oxidation of methyl O-.alpha.-chloropernitiolate with 3-chloroperbenzoic acid to form a mixture of the corresponding .alpha.-.alpha.-sulfoxides;

d) oxidation of methyl b-bromopenicilate with 3-chloropentyrenzoic acid with. formation of a mixture of the corresponding α- and D-sulfoxides.

Clayton, Jiolurnal of the Chemical Society (London) (C) 2123 (1969) discloses

(a) preparation of 6,6-dibromo- and 6,6-diiodo-penicillanic acid,

b) oxidation of 6,6-dibroiripenicillanic acid with sodium periodate to form a mixture of the corresponding sulfoxides,

c) hydrogenolysis of methyl -6,6-dibromopenicillanate. to m-ethyl-6-α-bromopenicilane,

d) hydrogenolysis of 6,6-dibrompenicilaic acid and its methyl ester to form penicillanic acid and its methyl ester,

e) hydrogenolysis of a mixture of methyl 6,6-diiodo penicilate and methyl 6-.alpha.-iodo penicilate to give pure methyl 6-.alpha.-iodine penicilinate.

The present invention provides a process for the preparation of penicillanic acid 1,1-dioxide derivatives of formula (I)

(1) or a pharmaceutically acceptable base salt thereof, wherein

R ¹ is a hydrogen atom or an ester-forming residue readily hydrolyzable in vivo, such as pivaloylioxymethyl or ethoxycarbonyloixyethyl, characterized in that the compound of formula III

or a corresponding base salt thereof, wherein R is a hydrogen atom, the remainder being an ester readily hydrolyzable in vivo or a conventional penicillan carboxy protecting group and X and Y are selected from the group consisting of hydrogen, chlorine, bromine and iodine, provided that when X and Y are the same, both bromine atoms must be dehalogenated, and optionally the carboxylic acid protecting group of penicillin is removed in conventional manner and converted to a salt.

Dehalogenation is preferably carried out by contacting a compound of formula III with hydrogen in an inert solvent at a pressure ranging from 0.09 to 9.8 MPa at a temperature of from about 0 to about 60; ° C and a pH in the range of about 4 to about 9 and in the presence of a hydrogenolytic catalyst. The hydrogenolytic catalyst is normally present in an amount of from about 0.01 to about 2.5% by weight, preferably. from about 0.1 to about 1.0% by weight, based on the compound of formula III.

A preferred value for X and Y is bromine.

The present invention includes intermediates of formula III wherein X and Y and R ¹ are as defined above. A preferred intermediate is 6,6-dibromopenicillanic acid 1,1-dioxide, a compound of formula III wherein X and Y are bromine and R ¹ is hydrogen.

The invention relates to the preparation of compounds of formula I and several intermediates thereof. In the description, these compounds are named as penicillanic acid derivatives of the general formula

IV.

Hv)

For penicillanic acid derivatives, the dashed lines of attachment of the substituent to the bicyclic nucleus indicate that the substituent is below the plane of the nucleus. This substituent has the configuration of a. The opposite fixed line of attachment of the substituent indicates that the substituent is above the plane of the core. This configuration is referred to as β -configuration.ee. Thus, the X group has the α-configuration and the Y group has the configuration of Formula II.

In the description, if R ¹ is an ester-forming moiety readily hydrolyzable in vivo, then it denotes a moiety derived from an alcohol of formula R 1 OH, such that the COOR ¹ moiety in such a compound of formula I represents an ester group. In addition, R ¹ is of a type such that the COOR ¹ group is readily cleaved in vivo to release the free carboxyl group (COOH). That is, R ¹ is a group of such type that when a compound of formula I wherein R ¹ is an ester-forming moiety readily hydrolyses in vivo, it comes into contact with the blood of the mammal or its tissues, then a compound of the formula I, wherein R ¹ is hydrogen. R ¹ groups are well known in the penicillin literature. In many cases, they improve the absorption characteristics of penicillan compounds. In addition, R ¹ should be of a type that improves and releases the pharmaceutical properties of the compound of Formula I

21513D pharmaceutically acceptable fragments for in vivo cleavage. The R ¹ groups are known and readily identified by those skilled in the art of penicillin chemistry. See, for example, West German DOS 2,517,316. Specific examples of R ¹ groups are 3-phthalidyl, 4-crotonolactonyl, γ-butyrolacton-4-yl, and groups of formulas V and VI,

R ² O ί ¹¹ a - С — O — C — R ⁴

R ³

R ² O

III — C — O — C — O — R ⁴

R ³ (V) (VI) wherein R ² and R ³ are selected from the group consisting of hydrogen, C 1 -C 2 alkyl and R ⁴ is C 1 -C 5 alkyl, but preferred R ¹ groups are alkanoyloxy methyl (C až-C uhlíku) alkyl, (C až-C alk)) alkanoyloxy, (C 1-C alk l) alkanoyloxy), (C--C 9 1) alkoxycarbonyloxymethyl, (C až-C, alko) alkoxycarbonyloxymethyl; (C 1 -C 7 alkoxycarbonyloxy) ethyl, 1-methyl-1-alkoxycarbonyloxy] ethyl of 5 to 8 carbon atoms, 3-phthalidyl, 4-kirotonalactonyl and t-butyrolactone-ethyl.

3-Phthalidyl, 4-crotonol: ktonyl and β-butyrolacton-4-yl have the formulas VII, VIII and IX. Wavy lines indicate one of the two epimers or a mixture thereof.

The starting compound used in the process of the invention is prepared by oxidation of the sulfide group in the compound of formula II

to a sulionic group to give a compound of formula III. A number of known oxidizing agents used for the oxidation of sulfides to sulfones can be used for this process. However, particularly suitable reagents are alkali metal permanganates, such as sodium and potassium permanganates, alkaline earth metal permanganates such as calcium and barium permanganates, and organic peracids such as peracetic acid and 3-chloro per benzoic acid.

When a compound of formula II wherein X, Y and R ¹ are as defined above, is oxidized to the corresponding compound of formula III, using a permanganate, the reaction of a compound of formula II with about 0.5 to about 10 molar equivalents and preferably about 1-4 molar permanganate equivalents in a suitable inert solvent system. A suitable inert solvent system is one that does not react adversely with either the starting materials or the product, and water is commonly used. Optionally, a solvent which is miscible with water but which does not react with permanganate, such as tetrahydrofuran, may be added. The reaction may be carried out at a temperature in the range of about -30 ° C, to about 50 ° C, and is preferably carried out at a temperature of about -10 ° C to about 10 ° C. At a temperature of about 0 ° C, the reaction is normally complete in a short time, for example about 1 hour. Although the reaction may be carried out under neutral, basic or acidic conditions, it is generally carried out at a pH in the range of about 4 to about 9, preferably 6 to 8. However, it is important to select conditions that prevent the β-lactam ring from decomposing II or III. In fact, it is often preferred to buffer the pH of the reaction medium close to the neutral reaction. The product is isolated by conventional methods. Excess permanganate is normally decomposed using sodium bisulfite and then, when the product precipitates out of solution, it is isolated by filtration. It is separated from manganese dioxide by extraction into an organic solvent and the solvent is then evaporated. Alternatively, if the product does not precipitate out of solution at the end of the reaction, it is isolated by conventional techniques such as solvent extraction.

When a compound of formula II, wherein X, Y and R ¹ are as defined above, is oxidized to the corresponding compound of formula III using a peiocarboxylic acid, then the reaction is conveniently carried out by reacting the compound of formula II with about 1 to about 6 molar equivalents. 2 molar equivalents of oxidizing agent in an inert organic solvent. Typical solvents are chlorinated hydrocarbons such as dichloromethane, chloroform and N-dichloroethane, ethers such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane. The reaction is normally carried out at a temperature of about -30 to about 50 ° C, preferably 15 to 30 ° C. At 25 ° C, the reaction time is normally between 2 and 16 hours. The product is isolated by evaporation of the solvent in vacuo. The reaction product can be purified by conventional methods well known in the literature. Alternatively, it can be used directly without further purification for the process of the invention.

The subject of the invention is a de215130 halogenation reaction. A preferred method of carrying out this transformation is by stirring or shaking a solution of the compound of formula III in an atmosphere of hydrogen or hydrogen mixed with an inert diluent, such as nitrogen or argon, in the presence of a hydrogenation catalyst. Suitable solvents for this hydrogenolytic reaction are those which sufficiently dissolve the starting compound of formula (III) but which do not themselves hydrogenate or do not hydrogenolysis. Examples of such solvents are ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, low-molecular esters such as ethyl acetate and butyl acetate, tertiary amides such as N, N-dimethylformamide, N , N-diim · ethylacetaimide and N-methylpyrrolidone, water and mixtures thereof. Further, the reaction mixture is conveniently buffered such that the reaction is carried out at a pH in the range of from about 4 to about 9, and preferably from about 6 to about 8. Typically, borate and phosphate buffers are used. The introduction of hydrogen into the reaction medium is conveniently carried out in a closed vessel containing a compound of formula III, a solvent, a catalyst and hydrogen. The pressure inside the reaction vessel may range from about 0.098 to about 9.8 MPa. The preferred pressure range, when the atmosphere inside the reaction vessel is substantially pure hydrogen, is about -0.19 to -0.49 MPa. The hydrogenolysis is generally carried out at a temperature of about 0 ° C to about 60 ° C, preferably about 25 to about 50 ° C. Using the preferred temperature range and pressure, hydrogenolysis is generally complete within a few hours, for example within 2 to 20 hours. The catalyst used in this hydrogeinolysis is a commonly known type of pro-transformation used and typical examples are noble metals such as nickel, palladium, platinum and rhodium. The catalyst is normally present in an amount of from about 0.01 to about 2.5 wt. from about 0.1 to about 1.0 wt. %, based on the compound of formula III. Often it is preferred to suspend the catalyst on a support, a particularly suitable catalyst is palladium suspended on an inert support such as coal.

Other methods may also be used for the reductive cleavage of the halogen atom from the compound of formula III, i.e. step b). For example, X- and Y may be removed using a metal-reducing reduction system, such as zinc in the form of dust in acetic acid, formic acid, or phosphate buffer, according to conventional techniques. Alternatively, the reductive cleavage of a halogen atom may be carried out using a tin hydride, for example a trialkyl tin hydride, such as tri-n-butyl tin hydride.

As is known in the literature, if a compound of formula I wherein R 1 is hydrogen is to be prepared, the compound of formula II wherein R ¹ is hydrogen atom is oxidized and reductively dehalogenated as described above. In other words, the reaction involves oxidation followed by dehalogenation of the 6-halogen or 6,6-dihalogenated penicillin acid derivative having a free carboxyl group at position 3. However, according to another aspect of the invention, the reactions can be carried out with a carboxyl group at position 3 protected by conventional carboxyl protecting groups. The protecting group may be removed during or after oxidation or after dehalogenation with the restoration of the free carboxyl group. A variety of protecting groups commonly used in penicillin chemistry for protecting the 3-carboxyl group can be used in this regard. The main requirements for protecting groups are such that they must be attachable to the compounds of formula II -or III and removable from the corresponding compounds of formula I -or III using the conditions under which the lactam ring remains substantially intact. Typical examples of steps a and b) include tert-hydroxyhydropyranyl, trialkylsilyl, benzyl, substituted beinzyl groups (e.g., 4-nitrobenzyl), benzhydryl, tert-butyl,

2,2,2-O-di-ethyl and phenacyl. Although not all protecting groups are applicable in all situations, one of ordinary skill in the art will readily select certain groups applicable in the particular situation. See, for example, U.S. Patent Nos. 3,632,850 and 3,197,466; British Patent No. 1,041,985 to Woodward et al., Joulin-the-American - Cheimical Society, 88, 802 (1966); Chauvette, Journal of Organic Chemistry, 36, 12.59 (1971); Sheehan et al., Journal of Organic Chemistry, 29, 2006 (1964); and "Cephalosporin and Penicillins, -Chemistry and Biology," publisher Η. E. Flynn, Academic Press, Inc., 1972. The carboxylic acid protecting group in penicillin is removed in a conventional manner with respect to the lability of the ring. system.

.alpha.-.alpha.-Chlorpenicillanic acid and 6-.alpha.-bromopenicillanic acid are prepared by diazotizing 6-aminopenicillanic acid in the presence of hydrochloric or hydrobromic acid (Journal of Organic Chemistry 27, 2668 [1962]). 6-.alpha.-Iodoenicillanic acid - is prepared by diazotization of 6-aminopenicillanic acid in the presence of iodine and then by hydrogenolysis (Clayton, Joan of the Chemical Society (C), 2123 [1969]). 6-chloropentanedioic acid, 6-i, -bromopromycanoic acid and 6-iodopenicillanic acid are prepared by reduction of 6-chloro-6-iodopentanilic acid, 6,6-dibromopenticillanic acid or 6, 6-diiodo-penicillanic acid with tri-n-butyl-anhydride. 6-Chloro-β-iodopenicillanic acid is prepared by diazotation of 6-aminopenicillanic acid in the presence of iodine chloride; -6,6-dibromopenicillanic acid was prepared according to the procedure described by Clayiton in the Journey.1 of the Chenical Society (London) (C) 2123 (1969) and 6,6-di-dicenoic acid by diazotization of 6-aminophenicicinic acid in the presence of iodine.

The compounds of formulas I, II and III, wherein R ¹ is hydrogen atom, are acidic and form salts with alkaline agents. These salts can be prepared by standard techniques, such as by contacting the acidic and basic components, typically in a stoichiometric ratio, in aqueous or non-aqueous or partially aqueous media. They are then isolated by filtration, non-solvent precipitation followed by filtration, evaporation of the solvent or, in the case of aqueous solutions, freeze-drying. Basic agents; which are suitably used in the formation of salts belong to both organic and inorganic types and include ammonia, organic amines, hydroxides, carbonates, bicarbonates, hydrides and alkoxides of alkali metals, as well as hydroxides, carbonates, bicarbonates, hydrides and alkoxides of alkali metals of soils. Examples of such bases are primary amines, such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, and octylamine; secondary amines such as diethylamine, morpholine, pyrrodidine and piperidine; tertiary amines such as triethylamine, N-ethylpiperidine, N-methylmorpholine and 1,5-diazabicyclo [4. 3.-O] non-5-ene; hydroxides such as sodium, potassium, ammonium and barium hydroxides; alkoxides such as sodium ethoxide and potassium ethoxide, hydrides such as · calcium hydride and sodium hydride, carbonates such as sodium carbonate, bicarbonates such as sodium bicarbonate and potassium bicarbonate, and alkali metal salts of long-chain fatty acids such as sodium 2-ethylhexyl & xyes ^aT:. Preferred salts of compounds of formula I i ^j! sodium, potassium and triethylammonium salts.

The compound of formula (I) wherein R ¹ is a hydrogen atom and the corresponding salts are active as moderate antibacterial agents both in vitro and in vivo, and the compounds of formula (I). wherein R 1 is an ester-forming moiety readily hydrolyzed in vivo, are antibacterial agents of moderate in vivo effect. The minimum inhibitory concentration (MIC) of penicillanic acid 1,1-dioxide for certain microorganisms is given in Table I.

Table I

An in vitro effect of penicillanic acid 1,1-dioxide in vitro

Microorganism MIC (µg / ml) Staphylococcus aureus 100 ALIGN! Streptococcus faecalis 200 Streptococcus pyogenes 100 ALIGN! Escherichia coli 50 Pseudomanas aerugiinosa 200 Klebsiella pneumoniae 50 Proteus mirabilis 100 ALIGN! Próteus morgani 100 ALIGN! Salmonella typhimurium 50 Pasteurella multicida 50 Serratia marcescens ilOO Enterobacter aerogenes 25 Enterobaoter clooae 100 ALIGN! CMrobacter freundii 50 Providencia 100 ALIGN!

Microorganism MIC jg / mlJ Staihpylococcus epidermis 200 Pseudomonas putida .200 Hemophilus influenzae '50 Neisseria gonorrhoeae 10, 312

The antibacterial effect of a compound of formula I wherein R 1 is a hydrogen atom and its salts in vitro allows their use as industrial antimicrobial agents, for example, in water treatment, slime control, preservation of dyes and wood, as well as topical applications in disinfectant applications. When using these compounds, for topical applications it is often advantageous to mix the active ingredients with a non-toxic carrier, such as a vegetable or mineral oil or a softened cream. Similarly, they may be dissolved or dispersed in liquid diluents or solvents such as water, alkanoyl, glycols, or mixtures thereof. In many cases, it is desirable to use concentrations of the active ingredient of from about 0.1% to about 10% by weight of the total composition.

The effect of the compounds of formula I wherein R ¹ is a hydrogen atom or an in vivo easily hydrolyzable moiety, and salts thereof, makes them useful for controlling bacterial infections in mammals, including humans, both oral and parenteral applications. The compounds are useful for controlling infections caused by bacteria in humans, for example in the treatment of infections caused by Neisseria gonorrhoeae strains.

. Taking into account the therapeutic use of the compounds of formula I or salts thereof in mammals, particularly humans, the compound may be administered alone or mixed with pharmaceutically acceptable carriers or diluents. It can be administered orally or parenterally, for example, intiramuscularly, subcutaneously or intraperitoneally. The carrier or diluent is selected on. based on the expected use. For example, when considering the oral route of administration, the compound may be used in the form of tablets, capsules, pills, powders, syrups, infusions, aqueous solutions and suspensions and the like in a manner known in the art of standard pharmaceutical practice. The appropriate ratio of active ingredient to carrier depends on the chemical type, solubility and stability of the active ingredient, as well as the expected dose. However, pharmaceutical compositions containing the antibacterial agent of formula I comprise. from about 20% to about 95% of the active ingredient. In the case of oral tablets, the carriers commonly used include lactose, sodium citrate and salts of phosphoric acid. Conventional dosing agents, such as starch, lubricants, are used in tablet formulations. is magnesium stearate, copper lauryl sulfate and talc. For oral administration in capsule form, useful diluents include lactose and high molecular weight polyethylene glycols. If aqueous suspensions are required for oral use, then the active ingredient. may be mixed with emulsifying and suspending agents. If desired, certain sweetening and flavoring agents may be added. For parenteral administration, which includes intramuscular, intraperttoineal, subcutaneous and intravenous use, sterile solutions of the active ingredient are prepared and the pH of the solutions is adjusted with suitable buffers. For intravenous use, the total concentration of the solutions must be controlled in order to prepare isosonic solutions.

The prescription of the physician determines the appropriate dose of the compound of Formula I for a particular individual and is expected to vary according to the age, weight of the individual patient as well as the severity of the patient's symptoms. The compound is usually used orally at doses of from about 10 to about 200 mg per kg body weight per day, and parenteral doses range from about 10 to about 400 mg per kg body weight per day. These data are illustrative only, but in some cases use outside these limits may be necessary.

Compounds of formula I wherein R ¹ is a hydrogen atom or an ester moiety readily hydrolyzable in vivo, or salts thereof, enhance the bacterial effect of the lactam antibiotics in vivo. Reduce the amount of antibiotics required for ^! protecting mice against otherwise lethal doses of certain β-lactamase producing bacteria. This ability is utilized in the simultaneous administration of (lactam antibiotics for the treatment of bacterial infections in mammals, in particular humans. In the treatment of bacterial infections, the compounds of formula I may be mixed with the β-lactam antibiotics and both agents administered simultaneously. For example, Compound ^{1 of} Formula I may be administered separately during treatment with (alaccamic antibiotics. In some cases, it is preferred to pre-dose the compound of Formula I before treatment with the / Mactam antibiotics.

When 1,1-dioxide penicillanic acid and its salts and esters readily · ¹ · ^ hydrolysOivat Elne vivo · used to increase the efficiency · / .beta.-lactam antibiotics are applied · preferably in a mixture with standard pharmaceutical carriers or diluents. The formulation methods discussed previously for the use of penicillanic acid 1,1-dioxide or an ester readily hydrolyzable in vivo as a one-component anti-bacterial agent may be used when co-administered with other non-lactic antibiotics. A pharmaceutical composition comprising a pharmaceutical carrier, a lactam antibiotic, and penicillanic acid 1,1-dioxide or a readily hydrolysable ester thereof typically contains from about 5 to about 80% by weight of a pharmaceutically acceptable carrier.

When penicillanic acid 1,1-dioxide or its ester readily hydrolyzable in vivo in admixture with other lactam antibiotic is used, the kit may be administered orally or parenterally, for example, intramuscularly, subcutaneously or intraperitoneally. Although the prescriber decides after the dose to be used, the ratio of the daily dose of penicillanic acid 1,1-dioxide, its salt or ester to the lactam antibiotic is normally in the range of about 1: 3 to 3: 1. In addition, when a penicillanic acid 1,1-dioxide, salt or ester readily hydrolysable in vivo is used in combination with another (anactam antibiotic), the daily dose of each component is from about 10 to 200 mg per kg body weight and the daily parenteral dose of each component normally ranges from about 10 to 400 mg per kg body weight.This data is illustrative only, but in some cases dosages outside this range may be necessary.

Typical (--lamic antibiotics with which penicillanic acid 1,1-dioxide and its esters readily hydrolyzable in vivo may be mixed are:

6- (2-phenylacetamido) penicillanic acid,

6- (D-2-Amino-12-phenylacetamido) penicillanic acid,

6- [2-Carboxy-2-phenylacetamido] peniciliaic acid a

7- (2- [1-tetraisolyl] acetamido) -3- (2- [5-meso-1,3,4-biphenyl] thiomethyl) -3-desacetoxymethylcephalosporanic acid.

Typical microorganisms against which the antibacterial effect of the above-described / Mactam antibiotics are enhanced are:

Staphyloccocus aureus,

Haemop · hi lus inf luenzae

Klebsiella · pneumonlae a

Bacteroides fnagilis.

As is known to those skilled in the art, some / Mactam compounds are effective when administered orally or parenterally, while others are only effective when administered parenterally. When penicillanic acid 1,1-dioxide, its salt or ester readily hydrolysable in vivo is administered concurrently with β1a-β2-type antibiotics which are effective only for pareinteiral use, a formulation suitable for parenteral use must be used. When penicillanic acid 1,1-dioxide or its in vivo hydrolysable ester is used concurrently with a lactam antibiotic which is active orally or parenterally, combinations suitable for either oral or parenteral administration may be prepared. In addition, penicillanic acid 1,1-dioxide preparations or salts or esters thereof can be administered orally, while at the same time additional Dlactam antibiotic is parenterally administered. It is also possible to apply the penicillanic acid 1,1-dioxide preparations or the corresponding salts or esters parenterally, while the other [beta] -lactam antibiotic is orally administered at the same time.

Further details regarding the use and synthesis of the compounds of formula I are given in DOS No. 2,824,535.

The following examples and preparations are given for clarification only. The infrared spectra (IC) were measured in the form of potassium bromide tablets (КВт) and the diagnostic absorption bands are given in wavelengths (cm ¹ ). CD3COCD3), perdeuterodimethylsulfoxide (DMSO-de) or deuterium oxide (D10), and the band position is expressed in parts in millions (ppm) down from tetraimethylsilane or 2,2-dimethyl-2-silapenitan-5-sulfonate The following abbreviations are used for the shape of the strips: s-singlet, d-doublet, t-triplet, q-quartet, m-mulitiplet.

Example 1

Ga-Bromo-penicillanic acid 1,1-dioxide

To a stirred mixture of 560 ml of water, 300 ml of dichloromethane and 56 ml; g 6tf-bromo: nii ^! cilanic acid is added a 4N sodium hydroxide solution until a stable pH of 7.2 is reached. This requires 55 ml of sodium hydroxide. The mixture was stirred at pH 7.2 for 10 minutes and then filtered. The phases are separated and the organic phase is discarded. The aqueous phase is then rapidly drained into the oxidation mixture with stirring as follows.

In a 3 liter flask, 63.2 g of potassium permanganate, 1000 ml of water and 48.0 g of acetic acid are mixed. The mixture was stirred at 20 ° C for 15 minutes and then cooled to 0 ° C.

After addition of the .alpha.-bromopenicilaic acid solution to the oxidation mixture, the temperature of the cooling bath was maintained at -15 ° C. Indoor temperature! it rises to 15 ° C and then drops to 5 ° C in 2C 'minutes. At this temperature, 3'0.0 g of sodium metabisulfite was added over 10 minutes at a temperature of about 10 ° C. After a further 15 minutes the mixture was filtered and the pH of the filtrate was lowered to 1.2 by addition of 170 ml of 6N hydrochloric acid. The aqueous phase was extracted with chloroform and then with ethyl acetate. Both the chloroform and eithyliaceite extracts were dried over anhydrous magnesium sulfate and then evaporated in vacuo. The chloroform solution provided 10.0 g (16% yield) of the title compound. The ethyl acetate solution gave 57 g of an oil which was triturated with hexane to give a white solid which was filtered off. Yield 41.5 g (66%) of the title compound, mp 134 ° C (dec.).

Analysis: Calculated for CaHtoBrNO5S:

C 30.78, H 3.2.3, Br 25.60,

N 4.49, S 10.27%, found:

C 31.05, H 3.24, Br 25.54.

N 54.66, S 10.21%.

Example 2

Oxidation of 6α-chloropenicillanic acid and 6α-iodopenicillanic acid with potassium permanganate according to the procedure of Example 1 gives 6α-chloropenicilicinic acid 1,1-dioxide and 6α-iodo-peicicanoic acid 1,1-dioixide.

Example 3

N, N-Chlorophenicilanoic acid 1,1-dioxide

The oxidation solution is prepared from 185 mg of potassium permanganate, 0.063 ml of 85% phosphoric acid and 5 ml of water. This oxidizing solution was added dropwise to a solution of 150 mg of 6-chloro-penticilanoic acid sodium salt in 5 ml of water at 0-5 ° C until the purple color of potassium permanganate was maintained. About half of the oxidation solution is consumed. At this point, the color of the potassium permanganate was removed by adding solid sodium bisulfite, and then the reaction mixture was filtered off. Ethyl acetate was added to the filtrate and the pH was adjusted to 1.8. The phases were separated and the aqueous phase was re-extracted with ethyl acetate. The combined ethyl acetate phases were washed with water, dried and evaporated in vacuo. This afforded 118 mg of the title compound. The NMR spectrum (in CD3COCD3) shows absorption

5.82 (d, 1H),

5.24 (d, 1 H),

4.53 (s, 1 H),

1.62 (s, 3H) and

1.50 (s, 3H) ppm.

The product prepared above was dissolved in tetrahydrofuran and an equal volume of ¹ water was added. The pH is adjusted to 6.8 with dilute sodium hydroxide solution ¹ , the tetrahydrofuran is evaporated in vacuo and the residual dry solution is freeze-dried. There was thus obtained the sodium salt of the title compound.

Example 4

6-bromo-pentenoic acid, 1,1-dioxide

K of solution 255 _; mg of 6β-bromopenicillanic acid sodium salt in 5 ml of water is added at 0 to 5 degrees Celsius a solution of 140 mg of dibasic permanganate, 0.11 ml of 85% phosphoric acid and 5 ml of water at 0 to 5 ° C. The pH is maintained between 6.0! to 6.4. The reaction mixture was stirred at pH 6.3 for 15 minutes and the purple solution was overlaid with ethyl acetate. The pH was adjusted to 1.7 by adding 30 mg sodium bisulfite. After 5 minutes, the phases were separated and the aqueous phase was further extracted with ethyl1,21,130

16 dad. Saved. the ethyl acetate solutions were washed with sodium chloride, dried over magnesium sulfate and evaporated in vacuo. 216 mg of the title compound are obtained as white crystals. The NMR spectrum (in D 2 O) shows absorption at

5.78 (d, 1H, J = 4Hz);

5.25 (d, 1H, J = 4 Hz), 4.20 '(s, 1H),

1.65 (s, 3H) and 1.46 (s, 3H) ppm.

Example 5

Penicillanic acid 1,1-dioxide

To 100 ml of water was added 9.4 g of 1,1-dihydro. Bromobornicillanic acid at 22 degrees Celsius, then sufficient 4N sodium hydroxide is added until a stable pH of 7.3 is reached. 2.52 g of 5% palladium carbonate were added, followed by 6.9 g of trihydrate. KzHPOd. This mixture was ¹ · shaken under hydrogen at a pressure of from 0 'to 34 0.17 MPa. Once . the hydrogen uptake is complete, the solids are filtered off and the aqueous solution is overlaid with 100 ml of ethyl acetate. The pH is slowly reduced from 5.0 to 5.0. 1.5 with 6N hydrochloric acid. The phases were separated and the aqueous phase was further extracted with ethyl acetate. The combined ethyl acetate phases were washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was triturated in ether and the solid material was filtered off. This afforded 4.5 g (65%) of the title compound.

Analysis for CaHiiNOsS calculated:

C 41., 20, H 4.75, N 6.00, S 1.3.75%, cheaper:

H, 4.81; N, 6.11; S, 13.51%.

Example 6

14-Dioxidivaloyoylmethyl 6α-bromopenic ilate

The oxidation solution is prepared by mixing. 4.26 grams of potassium permanganate ¹ , 2.655, g of 85 percent phosphoric acid and 40 ml of water. The mixture was stirred for one hour and then slowly during 20 minutes added at · '· 5 to 10 ° C. to a stirred solution of 5.32 g pivaloyl ^ ^ t was DymethylO brompemcilíanátu-70 in ¹ mL of acetone and 10 ml ·. water. The mixture was stirred at 5 ° C for 30 minutes and 100 mL of ethyl acetate was added. After a further 30 minutes, a solution of 3.12 g of sodium bisulfite in 30 ml of water was added at 115 ° C over a period of 115 minutes. The reaction mixture is further stirred for an additional 30 minutes at 5 ° C and then filtered. The organic phase is separated and washed with a saturated sodium chloride solution. The dried phase was evaporated to give 5.4 g of the title compound as an oil which slowly crystallized. The NMR spectrum (in CDCl 3) shows absorption at

5.80 (q, 2H).

5.15 (d. 1H);

4.75 (d, 1 H),

4.50 (s, 1H);

1.60 (s, 3H);

1.4 (s, 3H) a

1.20 · (s, 9H) ppimExample 7 ЬЫЬЫхххх pivvlohlODhmethyldenicilanate

A solution of 4.4 g of plvalohloxymethyl-.alpha.-biroimpenicilate 1,1-diODide in 60 ml of tetrahlorofuran is added to 0.84 g of sodium bicarbonate ¹ in 12 ml of water. The solution is shaken under an atmosphere of hydrogen in the presence of 2.0 g of a 5% palladium on carbon at 0 to 32 bar. The reaction mixture is then filtered and the residue is washed with 100 ml of ethyl acetate and 25 ml of water. The combined filtrates and washings were separated. The organic phase was washed with saturated sodium chloride solution, dried (MgSO4) and evaporated to give the title compound as an oil. This oil was dissolved in ethyl acetate (20 mL). Hexane (100 ml) was added to the solution and the precipitate was filtered off. Yield 2.4 g. NMR spectrum (in DMSO-d6) shows absorption at

5.75 (q, 2 H),

5.05 (m, IH);

4.40 (s, 1 H),

3.95-2.95 (m, 2H),

1.40 (s, 3H),

1.25 (s, 3H);

1.10 (s, 9H)

Example 8

1,1-Dihydro-2,2,2,2-trichloroethyl 6a-biphenylicilate

2,2,2-Trichloromethyl-6-bromobenzillanate was oxidized with potassium permanganate according to the procedure of Example 16 to give the title compound in 79% yield. The NMR spectrum of the product (CDCl 3) shows absorption at

5.30 · · to 4.7 © (m, 4H)

60 · (s, 1 H),

1.70 (s, 3H);

1.50 (s, 3H) ppm.

Example 9

Ic, βίοχίά denicillinic acid

To a stirred suspension of 6.5 g of zinc dust in 100 ml of a mixture of 70:30 glacial acetic acid and tetrahydrofuran was added portionwise over 5 minutes 4.0 g of 2,2,2-trichloroethyl 6-broimpenicilate 1,1-dioxide. . The mixture was stirred at room temperature for 3 hours and then filtered. The filtrate is concentrated to a volume of about 10 ml and the solution is mixed with 50 ml of water and 10 ml of ethyl acetate. The pH of the solution is adjusted to 1.3 and the phases are separated. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and then concentrated to dryness in vacuo. The residue is triturated in ether and allowed to stand for 20 minutes. This afforded 553 mg of the title compound as a solid. The NMR spectrum (in CDCl 3 / DMSO-d 6) shows absorption at

11.2 (broad s, 1H),

4.65 (m, 1H).

4.30 (s, 1H),

3.4 / 0 (m., 214)

1.65 (s, 3H);

1.50 (s, 314) ppm.

Example 1 0, 1, 1-Dtoxidobenzyl-6-tf-bromopeni 'read here

The compound was treated with potassium permanganate following the procedure of Example 6 to give the title compound in 94% yield. The NMR spectrum (in CDCl 3) shows absorption at

7.35 (s, 5H);

5.10 (m, 3H);

4.85 (in, 1H), 4.40 '[s, .114],

1.50 (s, 3H);

1.25 (s, 3H) ppm.

They did

Penicillanic acid 1,1-dioxide

A solution of 4.0 g of beinzyl-6-.alpha.-bromophenicilate 1,1-dioxide in 50 ml of tetrahydrofuran was mixed with a solution of 1.06 g of sodium bicarbonate in 50 ml of water. To this mixture was added 2.0 g of a 50% slurry of 5% palladium on carbon in water, and the mixture was shaken for 20 minutes under a hydrogen atmosphere at a pressure of 321-345 kPa. The catalyst was removed by filtration and then 30 ml of tetrahydrofuran and 3.0 g of a 50% slurry of 5% palladium carbon were added. The resulting mixture was shaken under a hydrogen atmosphere at a pressure of 10 to 50 psi for 65 minutes. The reaction mixture was then filtered and the tetrahydrofuran was evaporated. Ethyl acetate was added to the aqueous residue and the pH was adjusted to 7.1. The ethyl acetate layer was removed and fresh ethyl acetate was added to the remaining aqueous phase. The pH was lowered to 1.5 and the layers were separated. The aqueous phase is further extracted with ethyl acetate and the combined ethyl acetate solutions are washed with saturated sodium chloride solution and dried over magnesium sulfate. Evaporation in vacuo gave a gum which was triturated in ether. 31 mg of penlcianoic acid 1,1-dioxide are obtained in the form of a yellow solid. The NMR spectrum (in CDCl3 / DMSO-d6) shows absorption at 9.45 [broad s, 1H], 4.60 (t, 1H),

4.25 (s, 1H), 3.40 (d, 2H), 1.65 (s, 3H) and 1.30 (s, 3H) ppm.

Example 12

6,6-Dibrompenicillanic acid dioid

The dichloromethane solution of 6,6-dibriompenicillanic acid from Preparation K was added with 300 ml of water and then 105 ml of 3N sodium hydroid was added dropwise over 30 minutes. The pH is stabilized at 7.0. The aqueous layer was removed and the organic layer was extracted with water (2 x 100 mL). To the combined aqueous solutions is added at -5 ° C a solution prepared from 59.25 g of potassium permanganate, 18 ml of concentrated phosphoric acid and 600 ml of water until a pink color of the permanganate remains. The addition lasts 50 minutes and 550 ml of oxidizing agent is required. 500 ml of ethyl acetate are then added and the pH is lowered to 1.23 by the addition of 105 ml of 6N hydrochloric acid. 25.0 ml of 1M sodium bisulfite are then added over 10 to 15 minutes at about 10 ° C. During the addition of the sodium bisulfite solution, the pH is maintained at 1.25 to 1.35 by the addition of 6N hydrochloric acid. The aqueous phase was saturated with sodium chloride and the two phases were separated. The aqueous solution was extracted with additional ethyl acetate (2 x 150 mL) and the combined ethyl acetate solutions were washed with brine and dried (MgSO 4). An ethyl acetate solution was obtained

6,6-Dibromopentilicanoic acid 1,1-dioxide.

6? 6 -Dibnompenicillanic acid 1,1-dioxide can be isolated by removing the solvent in vacuo. A sample obtained from the analogous preparation had a melting point of 201 ° C (decomposition).

NMR ^(CDCl; 3 / DMSO-d6) showed absorptions at 9.35 [s, IH), 5.30 (s, IH), 4.42 (s, IH), 1.63 (s, 3H) and 1.50 (s, 3H) ppm.

The IC spectrum (KBr) shows absorption at 13846-2 2500, 1818, 1754, 1342 and 1250-11110 cm ^-1 .

Example 13

1,1- dioxide-6-6- chloir; ^antifoam: cilanové acid

To a solution of 4.9 g of 6-chloro-6-iodopenicilanic acid in 50 ml of dichloromethane was added 50 ml of water, and then the pH was adjusted to 7.2 using 3N sodium hydroxide, the layers were separated and the aqueous layer was cooled to. Low: 14 ° C. To this solution was then added dropwise a solution of 2.61 g of potassium permanganate, 1.75 ml of concentrated phosphoric acid and 50 ml of water dropwise over 20 minutes. During the addition, the pH is maintained at 6 and the temperature is kept below 10 ° C. 100 ml of ethyl acetate were then added and the pH was adjusted to 1.5. 510 ml of 10% sodium bisulfite are then added to the reaction mixture while the temperature is kept below 10 ° C and the pH is maintained at about 1.5 by addition of 6N hydrochloric acid. The pH was then lowered to 1.25 and the layers were separated. The aqueous layer was saturated with sodium chloride and extracted with ethyl acetate. The combined organic solutions were washed with brine, dried (MgSO4) and evaporated in vacuo to give 4.2 g of the title compound, mp 143-145 ° C.

The NMR spectrum (CDCl3) shows absorption at 4.8V (s, 1Ή), 4.38 (s, 1H), 1.60 (s, 3H) and 1.4.3- (s, 3H) ppm,

The IC spectrum (KBr) shows absorption at 1800, 1740, and 1250 - 1110 cm ^-1 .

Example 14

6-Bromo-6-iodopenicilic acid 1,1-dioxide

To a solution of 6.0 g of O-bromo-O-iodopenicilanic acid in 50 mL of dichloromethane was added 50 mL of water. Using 3N sodium hydroxide, the pH was raised to 7.3 and the aqueous layer was removed. The organic layer was extracted with 10 mL of water. The combined aqueous phases are cooled to 5 ° C and a pre-prepared solution of 284 g of potassium permanganate in 2 ml of concentrated phosphoric acid and 50 ml of water is added dropwise at 5 to 10 ° C over 20 minutes. 50 ml of ethyl acetate were then added and the pH of the reaction mixture was reduced to 1.5 with 6N hydrochloric acid. To this two-phase system was added dropwise 50 ml of 10% sodium bisulfite, maintaining the pH at about 1.5 by the addition of 6N hydrochloric acid. An additional 50 mL of ethyl acetate was then added and then the pH was lowered to pH = 1. 1,23. The layers were separated and the aqueous layer was saturated with sodium chloride. The saturated solution was extracted with ethyl acetate (3 x 50 ml) and the combined ethyl acetate layers were washed with brine, dried (MgSO 4) and evaporated in vacuo. The residue was dried under high vacuum zíiská 4.2 g of the title compound, mp 145-147 C. ^q

The NMR spectrum (CDCl 3) shows absorption at 4.90 '(s, 1H), 4.30 (s, 1H), 1.60 (s, 3H), and 1.42 (s, 3H) ppm.

The IC spectrum (KBr) shows absorption at

1-800, 1740, 1330 'and 1250-111-0 cm ¹ .

Example 15

Penicillanic acid 1,1-dioxide

The ethyl acetate solution of 6-6-dibroimpenicilianic acid 1,1-dioxide of Example 12 was mixed with 705 ml of saturated sodium bicarbonate solution and 8.88 g of 5% palladium on carbon catalyst. The mixture was shaken under a hydrogen atmosphere at a pressure of about 5 bar for about one hour. The catalyst was filtered off and the pH of the aqueous phase of the filtrate was adjusted to 1.2 with 6N hydrochloric acid. The aqueous phase is saturated with sodium chloride. The layers were separated and the aqueous phase was further extracted with ethyl acetate (3 X 200 mL). The combined ethyl acetate solutions were dried over magnesium sulphate and evaporated in vacuo to give 33.5 g of penicillinic acid 1,1-dioxide (5.8; yield from 6-aminopenicillanic acid). This product was dissolved in EtOAc (80 mL), decolorized with charcoal and the solvent evaporated in vacuo. The product was washed with hexane. 31.0 g of pure product are obtained.

Example 1 a d 16

Penicillanic acid 1,1-dioxide

To a stirred suspension of 786 mg of chloro-6-iodopenicilianic acid 1,1-diioxide 6 in 10; ml of benzene is added at about 0 DEG C. to 0.3 ml of triethylamine and then 0.25 ml of trimethylsilyl chloride.

Stirring was continued for 5 minutes at about 0 C, ^G, and then heated 30i minutes at reflux temperature. The reaction mixture was cooled to 25 ° C and the precipitated substance was filtered off. The filtrate is cooled to about 0 ° C and 1.16 g of tri-n-butyltin hydride and a few mg of azobisisobutyronitrile are added. The reaction mixture is stirred and irradiated with ultraviolet light for 1 hour at about 0 ° C and then heated at the boiling point of the solvent for 3.5 hours. An additional amount of tri-n-butyltin hydride (1.1 mL) and a catalytic amount of -azobisisobutyronitrile were added and stirring and irradiation at boiling point were continued for an additional 1 hour. The reaction mixture was then nlaleje into 50 ml of cold ¹ 5% sodium bicarbonate solution and the biphasic system was stirred for 30 minutes. Ethyl acetate (50 ml) was added and the pH was adjusted to 1.5 with 6N hydrochloric acid. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate solutions were washed with brine, dried (MgSO 4) and evaporated in vacuo. The residue was triturated with hexane and filtered off. This afforded 0.075 mg of the title compound.

Example 17

Penicillanic acid 1,1-dioxide

To a stirred suspension of 0.874 g of 6-bromo-6-iodopenicilanic acid 1,1-dioxide in 10 ml of benzene was added at about 5 ° C 0.3 ml of trieithylamine and then 0.25 ml of trimeithylsilyl chloride.

Stirring is continued at 5 ° C for 5 minutes and then for 30 minutes at the boiling point of the solvent. The reaction mixture was then cooled to room temperature and the solids were filtered off. The filtrate was cooled to about 5 nia ^q C and treated with 1.05 ml of tri-n-buitylcínhydridu and a catalytic amount azobisiisobuityrcnitrilu. The mixture is irradiated at about 5 ° C for 1 hour with ultraviolet light and poured into 30 ml of cold 5% sodium bicarbonate. The mixture was stirred for 30 minutes and then 50 mL of ethyl acetate was added. The mixture was acidified to pH 1.5 and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 X 25 mL) and the combined ethyl acetate layers were washed with brine, dried (MgSO 4) and evaporated in vacuo. The residue was dried under high vacuum and then 3Cml of hexane was added. The insoluble material was filtered off to give 0.0315 g of the title compound.

Example 1 a d 1'8

Pivalolyloxymethyl 6,6-dibromopenicillanate

3.80 g of 3-chloroperbenzoic acid are added to a solution of 4.73 g of pivaloyloxymethyl-6,6-dibrompenicilate in 15 ml of dichloromethane and at 0-5 ° C. The reaction mixture was stirred at 0-5 ° C for 1 hour and then at 25 ° C for 24 hours. The filtered reaction mixture was evaporated in vacuo to dryness and the residue partitioned between ethyl acetate and water. The pH of the aqueous phase is adjusted to 7.5 and the layers are separated. The ethyl acetate layer was dried over sodium sulfate and evaporated in vacuo to give the title compound.

Example 19

1.1-Pivaloyloxymethyl-6,6-dibromopentilicilate dioxide

A stirred solution of 3.62 g of 6,6-dibromopenilicilic acid 1,1-dioxide in 20 ml of N, N-dimethylformamide was cooled to 0 ° C and then 1.2 * 9 g of diisopropylethylamine was added. 1.51 g of chloromethyl pivalate are then added. The reaction mixture was stirred at 0 ° C for 3 hours and then at room temperature for 16 hours. The reaction mixture was then diluted with 25 mL of ethyl acetate and 25 mL of water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were washed with cold 5% aqueous sodium bicarbonate solution, water and brine. The ethyl acetate solution was treated with activated carbon (Darco), dried over magnesium sulfate and evaporated in vacuo to a brown oil (2.1 g). This oil was chromatographed on 200 g of silica gel using dichloromethane as eluent. The fractions containing the desired compound were combined and re-chromatographed on silica gel to give 0.025 g of the title compound.

The NMR spectrum (CDCl 3) shows absorption at 6.10 (q, 2H), 5.00 (s, 1H), 4.55 (3, 1H),

1.60 (s, 3H), 1.50 (s, 3H) and 1.15 (s, 9H) ppm.

Example 20

Pivaloyloxymethylpenicilateate 1,1-dioxide

To a stirred solution of 60 mg of 1,1-dioxide beer 10-yl-oxymethyl-6,6-dibromo-nicilate in

5. ml of benzene is added 52 μl tri-n-butyltin hydride and then a catalytic amount of azobisbutyronitrile. The reaction mixture was cooled to about 5 ° C and then irradiated with ultraviolet light for 1 hour. The reaction mixture was poured into 20 ml of cold 5% sodium bicarbonate solution and stirred for 30 minutes. Ethyl acetate was added and the pH of the aqueous phase was adjusted to 7.0. The layers were separated and the aqueous phase was further extracted with ethyl acetate. The combined ethyl acetate solutions were washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was dried under high vacuum for 30 minutes. 70 mg of a yellow oil are obtained which, according to NMR spectroscopy, contains the title compound together with some of the impurities containing n-butyl groups.

Example 21

1.1-Bismyl-6,6-dibromopenillanate dloxide

A mixture of 10.6 g of 6,6-dibromopenilicilic acid 1,1-dioxide, 2.15 g of sodium hydrogencarbonate, 3.06 ml of benzyl bromide and 10 ml of Ν, Ν-dimethylformamide was stirred at room temperature overnight. Most of the solvent was removed by evaporation in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was removed, washed with 1N hydrochloric acid and saturated sodium chloride solution, and dried over sodium sulfate. Evaporation in vacuo afforded 11.5 'g of the title compound.

The NMR spectrum in (CDCl 3) shows absorption at 7.40 (s, 5H), 5.30 (m, 2H), 4.95 (s, 1H), 4.55 (s, 1H), 1.50 [ s, 3H) and 1.20 (s, 3H) ppm.

Example 22

1.1- Penicillanic acid dioxide

To a solution of 2.0 g of benzyl 6,6-dibromopenicenilate 1,1-dioxide in 50 ml of tetrahydrofuran is added a solution of 0.699 g of sodium bicarbonate in 50 ml of water, and then 2.0 g of 5% palladium on carbon are added. The mixture is then shaken under an atmosphere of hydrogen for 70 minutes at about 50 mbar. The tetrahydrofuran was evaporated and the residue was partitioned between ethyl acetate and passed at pH 7.37. The aqueous layer was removed and fresh ethyl acetate was added. The pH was lowered to 1.17, the ethyl acetate was removed and washed with saturated sodium chloride solution. Evaporation in vacuo afforded 423 mg of the title compound.

Example 23

2,2,2-trichloroethyl 6,6-dibromopenicilate 1,1-dioxide

The title compound was prepared from 6,6-dibromopenicillanic acid 1,1-dioxide and 2,2,2-trichloroethyl chloroformate as described in Preparation J. The product was purified by silica gel chromatography. NMR spek215130 of the product in (CDCl3) showed absorption at 4.85 (m, 2H), 1.65 (s, 3H) and 1.45 (s, 3H) ppm.

Example 1 and O 24

1- (ethoxycarbenyloxy) ethyl penicillanate 1,1-oxide

230 mg of 1,1-dimethoxy-1-tethoxycarbonyloxy) ethyl-.beta.-dibromicnicilate are dissolved in 10 ml of toluene. To the solution was added 0.4 mL of tri-butyltin hydrochloride followed by 0.164 g of azobisisobutyrophenitrile. The solvent was removed by evaporation in vacuo and the residue was dissolved in 25 ml of acetonitrile. The acetonitrile solution was washed several times with hexane and then evaporated in vacuo. The residue was chromatographed on silica gel to afford 0.043 g of the title compound. NMR (CDCl 3) absorption at 6.75 (m, 4.60 (m), 4.30 (m), 4.15 (s), 4.00 (s), 3.30 (m) and 1.75-1.00 [mu ppm].

Preparation

O-Chloo - (- (-) - iodo-peiliciic acid)

To 3.38 g in 30 ml of dichloromethane is added at 0-5 ° C with stirring 11.1 ml of 2.5 N sulfuric acid and then 1.92 g of sodium nitrite. Then all at once, 3.00 g of O-aminopenicllanové acid and stirring was continued for 30 minutes at 0 ^up to 5 ° C. 22.8 ml of 1M sodium sulfite solution are then added portionwise to the reaction mixture and the layers are separated. The aqueous layer was washed with additional dichloromethane and then all organic phases were washed with saturated sodium chloride solution. The dichloromethane solution was dried over sodium sulfate and evaporated in vacuo to give 3.48 g of the title compound.

The above product is dissolved in 30 ml of tetrahydrofuran and then 30 ml of water are added. The pH is adjusted to 6.8 with dilute sodium hydroxide solution and the 1611X10Frofuran is evaporated in vacuo. The remaining aqueous phase was frozen and the residue was washed with diethyl ether. 3.67 g of the title compound are obtained as the sodium salt.

Preparation

6 - / ^ - C ^ CLll ^ π. P] ppe ^ ii ^ iil ^^^^ ´ ^ ‘acid

A sample of 2.95 g of 6-chloro-6-iodopenicillanic acid sodium salt was converted to the free acid and then dissolved in 125 ml of benzene under nitrogen. To the solution was added 1.08 mL of triethylamine and the mixture was cooled to 0-5 ° C.

Trimethylsilylchloride (0.977 ml) was then added to the cooled mixture, and the reaction mixture was stirred at 0-5 ° C for 5 minutes, at 25 ° C for 60 minutes, and at 50 ° C for 30 minutes. The reaction mixture was cooled to 25 ° C and the triethylamine (OH) and (CH 2) 2 were filtered off. To the filtrate was added 15 mg of azobisisobutyromotriol followed by 2 x C2 mL of tri-n-butyltin tetrahydrofuran. The reaction mixture was then irradiated with ultraviolet light for 15 minutes under cooling so as to maintain the temperature at about ^20: C. The solvent was then evaporated in vacuo and the residue was dissolved in tetrahydrofuran / water 1: 1. The pH was adjusted to 7.0 and evaporated in vacuo with tetrahydrofuran. The aqueous phase was washed with ether and then a stepped volume of ethyl acetate was added. The pH was adjusted to 1.8 and the ethyl acetate layer was removed. The aqueous phase was extracted with additional ethyl acetate and then the combined ethyl acetate solutions were dried and evaporated in vacuo. SC10 mg of 6-chloropropenic acid was obtained.

This product was dissolved in tetrachloride and an equal volume of water was added. The pH is adjusted to 6.8 and the pH is evaporated in vacuo. The remaining aqueous phase was freeze-dried to give 850 mg of the salt of B-O-chloropenic acid. The NMR spectrum (D 2 O) shows absorption at 5.70 (d, 1H, J = 4 Hz), 5.15 (d, 1Η, 1 = 4 Hz), 4.36 [s, 1H], 1.60 (s, 3H) and 1.53 (s, 3H) ppm.

C ou and C a

6- 0 Brenepenilic acid

A mixture of 5.0 g, 6-O-bromophenicillanic acid, 1.54 ml of triethylamine and 100 ml of benzene was stirred under nitrogen until a solution was obtained. The solution was cooled to 0-5 ° C and 1.78 mL of tert-butylmethyl chloride was added. The reaction mixture was stirred at 0-5 ° C and 2-3 minutes and then at 50 ° C for 35 minutes. The cooled reaction mixture was filtered and the filtrate was cooled to 0-5 ^° C. A small amount of azobisisobutyroinitrile was added followed by 3.68 mL of tri-n-butyltin hydride. The reaction flask was irradiated with ultraviolet light for 15 minutes and then stirred at about 25 ° C for 1.75 hours. The reaction mixture is irradiated again for 15 minutes and then stirring is continued for 2.5 hours. Then was added a small amount of azobisisobutyronitrile, and then 0.6 ml · · tri-n-butýlhínhýOriOu · and the mixture was again irradiated for 30 minutes ^with. The solvent was evaporated in vacuo and a 5% sodium bicarbonate solution and ethyl ether were added to the residue. The biphasic system was shaken vigorously for 1G minutes and then adjusted to pH 2.0. The ether layer was removed, dried and evaporated in vacuo to give 2.33 g of an oil. This oil was converted to the sodium salt by adding water containing 1 equivalent of sodium bicarbonate and freezing the solution. The obtained 6-ObPomp6: n -chlanic acid sodium salt is contaminated with a small amount of the α-isomer.

The sodium salt is purified by chromatography on Sep215130 hadex LH-2D together with another material of the same quality and then chromatographed again. The NMR (D2O) spectrum of the product thus obtained shows absorption at 5.56 (s, 2H),

4.25 (s, 1H), 1.60 (s, 3Ή) and 1.50 · (s, 3H) ppm.

Preparation D

6- (hoopenic acid. Thioic acid

The title compound was prepared by reduction of 6,6-diiodo-penicillanic acid with tri-n-butyltin hydride as described in Preparation B.

Preparation

Pivaloyloxymethyl-.beta

To a solution of 280 mg of 6-α-bompenicillanic acid in 2 ml of N, N-dimethylformamide was added mg of diisopropylethylamine and then 165 mg of chloromethyl pivalate and 15 mg of sodium iodide. The reaction mixture was stirred at room temperature for 24 hours and then diluted with eithylation with water and water. The pH is adjusted to

7.5 and then the ethyl acetate layer was washed three times with water and once with saturated sodium chloride solution. The ethyl acetate solution was then dried over anhydrous sodium sulfate and evaporated in vacuo to give the title compound.

Preparation · F

Reaction of the appropriate B-haaloenpemcianoic acid with 3-phthaldyichloride, 4-crotonolactoyl chloride, p-butyrolacton-4-yl chloride or with the corresponding alkanoyloxymethyl chloride, 1- (alikanoyloxy) ethyl chloride,

1-Methyl-4- (alkanoyloxy) ethyl-4-carboxylic acid, alkoxycarboinyloxymethyl chloride, 1- (alkoxycarhoinyloxy) ethyl chloride or 1-methyl-1- (alkoxycarbinyloxy) ethyl chloride according to the procedure of Preparation E, gives the following compounds:

3 · -ft a li dy 1 -6 - · - c h lor of warblers and lances,

4-krctonolakt ON y - 6 - J -chloropenicillanate, y bu.tyI ^ C ^; ^ la lttOi ^^ 4 ^. ^ L ^ · ^ .. 6-a: l ^] ro _I warbler: ^ Coating divided ^ ^ _л acetoxymethyh6-3-brompenicilainát, pivaloyloxymethyl 6 + · BBR ompeniciaa NAT, • hexane oylo ^^ ^ -yl ^ xymeth -b-jc ^ d ^ p ^ SAC-C ^^ ^ anal,

1- (acetoxy ethyl B-4-iodopenicilaneate)

1- (isobutyryloxyethyl-6-α-chloropentililate),

1-Methyl-1- (acetoxyethyl-6-β-chloro-oenopenic acid),

1-methyl-1- (hexanoyloxy) ethyl 6-α-bromopeniltilanoate, methoxycarbonyloxymethyl β-α-bromopenicilanate, propoxycarbonyloxy and methyl-6-β-biphenylcilane,

1- (ethoxycarbonyloxy) ethyl -6-.alpha.-bromophenicilane,

1- (butoxycarbonyloxy) ethyl-6-α-iodopenicilane,

1-Methyl-1- (methoxycarbonyloxy) ethyl-6-

- ^ - jнj ^ d ^ l ^ p ^ τ ^ ií ^ ilž ^ α ^ ί ^! t · a

1-methyl-1- (isopropoxycarbonyloxy) ethyl-

-6 - -a c h Ippenicillanate.

Preparation G

6,6 - Diode Transition Manic acid

A mixture of 15.23 g of iodine, 10 ml of 2N sulfuric acid, 2.76 g of sodium nitrite and 75 ml of dichloromethane is stirred at 5 ° C, and then 4.32 g of 6-aminopenicillanic acid is added over 16 minutes. Stirring is continued at 5-10 ° C for 45 minutes after the addition is complete, and then 10 6 ml of 10% sodium bisulfite solution are added dropwise. The layers were separated and the aqueous layer was further extracted with pichloromethane. The combined dichloromethane layers were washed with brine, dried (MgSO 4) and evaporated in vacuo. 1.4 g of the title compound are obtained, which is contaminated with a little 6-iodoquinicillanic acid. Mp 58-64 ° C.

The NMR spectrum (CDCl 3) shows absorption at 5.77 (s, 1H), 4.60 (s, 1H), 1.71 (s, 3H) and 1.54 (s, 3H) ppm.

Preparation H

Pivaloxymethyl-6-a-bromopeniicilate

To a stirred mixture of 11.2 g of 6-.alpha.-bromopenicillanic acid, 3.7 g of sodium bicarbonate and 44 ml of Ν, Ν-dimethylformamide was added dropwise over 5 minutes 6.16 g of chloromethyl pivalate at room temperature. Stirring was continued for 66 hours and then the reaction mixture was diluted with 100 mL ethyl acetate and 100 mL.

m. l of water. The layers were separated and the ethyl acetate layer was washed sequentially with water, saturated sodium chloride solution, saturated sodium bicarbonate solution, water and saturated sodium chloride solution. The decolorized ethyl acetate solution was dried over magnesium sulfate and evaporated to dryness in vacuo. Yield: 12.8 g (80% yield) of the title compound.

I and I

Benzyl-6-α-broinpenicilana't

The title compound was prepared by esterification of 6-.alpha.-pyrazenicilanic acid with benzyl bromide according to Preparation H (83% yield). The NMR spectrum in (CDCl3) shows absorption at 7.35 (s, 5H), 5.35 (m, 1H), 5.15 (s, 2H), 4.70 (m, 1H, 4.60 · (s) 1 H, 1.55 (s, 3H) and 1.35 (s, 3H) ppm.

Example J

2,2,2-Trichloroethylpenicilate

To a stirred solution of 11.2 g of O-.alpha.-bromopenicillanic acid in 50 ml of tetrahydrofuran at 0 DEG C. was added 3.48 g of pyridine over 1 minute. 8.47 g of 2,2,2-trichloroethyl chloroformate were added to the turbid solution thus obtained, maintaining the temperature between 0 and 2 ° C over 10 minutes. Stirring was continued for 30 minutes and then the cooling bath was removed. Stirring was continued at room temperature overnight. The reaction mixture was then heated to 35 ° C for 5 minutes and then filtered. The filtrate was evaporated and the residue was dissolved in 100 ml of ethyl acetate. The ethyl acetate solution was washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution. The ethyl acetate solution is then decolorized and dried and then concentrated to a small volume. Hexane (1.00 ml) was added and the solids were filtered to give the title compound (10.5 g), mp 1015-110 ° C.

The NMR spectrum in (CDCl3) shows absorption at 5.50 (d, 1H), 4.95 (d, 1H), 4.90 (s, 2H), 4.65 (s, 1H), 1.70 ( s, 3Ή) and 1.55 (s, 3H) ppm.

C o ck

6,6 - D i b r cm fo r c y y y y y y

To 500 ml of dichloromethane cooled to 5 ° C were added 119.9 g of bromine, 2010 ml of 2.5 N sulfuric acid and 34.5 g of sodium nitrite. To this stirred mixture was added 54.0 g of 6'-aminopenicillanic acid portionwise over 30 minutes, maintaining the temperature at 4 to 10 ° C. Stirring is continued for 30 minutes at 5 ° C and then 410 ml of sodium bisulfite solution are added dropwise at 5 to 10 ° C over 20 minutes. The layers were separated and the aqueous layer was extracted twice with 150 mL of dichloromethane. The original dichloromethane layer was combined with the two extracts to give a solution of 6,6-dibroimpenicilinoic acid. This solution was used directly in Example 17.

Preparation L

To 10C mL of dichloromethane cooled to 3 T was added 4.87 g of joid chloride, 1.0 mL of 2.5N sulfuric acid, and 2.76 g of sodium nitrite. To this stirred mixture was then added portionwise 4.32 g of 6-aminopenic manic acid over 15 minutes. Stirring is continued for 20 minutes at 0-5 ° C and then 100 ml of 10% sodium bisulfite solution is added dropwise at about 4 ° C. Stirring was continued for 5 minutes and then the layers were separated. The aqueous layer was extracted with dichloromethane (2 X 50 mL) and the combined dichloromethane solutions were washed with brine, dried over magnesium sulfate and evaporated in vacuo to give the title compound as a tan solid, mp 148-152 ° C.

The NMR spectrum of the product (CDCl 3) showed absorption at 5.40 (-s, 1H), 4.56 (s, 1H), 1.67 (s, 3H) and 1.50 (s, 3H) ppm.

The IC spectrum (KBr) shows absorption at 1780 and 1715 cm ^-1 .

Preparation Mα-Вгзт-6-iodopenicilanic acid

To 100 ml of dichloromethane cooled to 5 ° C was added 10 ml of 2.5N sulfuric acid, 6.2.1 g of iodomethane and 2.76 g of sodium nitrite. To this mixture was added 4.32 g. Stirring is continued for a further 20 minutes at 0-5 ° C and then 100 ml of a 10% sodium hydrogen sulfite solution are added dropwise at a temperature between 0 and 10 ° C. The layers were separated and the aqueous layer was extracted with dichloromethane (3X50 mL). The combined dichloromethane layers were washed with brine, dried (MgSO 4) and evaporated in vacuo. The residue was dried under high vacuum for 30 minutes to give 6.0 g (72% yield) of the title compound, mp 144-147 ° C.

The NMR spectrum (CDCl 3) shows absorption at

5.50 (s, 1H),

4.53 (s, 1H).

1.70 (s, 3H);

1.53 (s, 3H) ppm.

The IC spectrum (KBr) shows absorption at 1785 and 1710 cm ^-1 . The mass spectrum predominantly shows an ion at m / e = 406.

Preparation N

- C 1 H 6 -Bromo-p-cilicanoic acid

Chloro-6-benzoic acid is prepared from 6-aminopenicillanic acid by diazoitation followed by reaction with briomchloride according to Preparation M.

6-Chloro-6-iodopenicilanic acid

Preparation О

Pivoyloxy / methyl-6 _? 6-dlbrompeinicilane

To a stirred solution of 3.59 g of 6,6-dibirompenicillanic acid in 2Ό ml of N, N-dimethylformamide was added 1.30 'at about 0 ° C. g of diisopropyethylamine and then 1.50 g of chloromethyl pivalate. The reaction mixture was stirred at about C for 30 minutes and then for 24 hours at room temperature. The reaction mixture was then diluted with ethyl acetate and water and the pH of the aqueous phase adjusted to 7.5. The ethyl acetate layer was separated and washed three times with water and once with saturated sodium chloride solution; The ethyl acetate solution was then dried over anhydrous sodium sulfate and evaporated in vacuo to give the title compound.

P r a v a P

Responses appropriate

6,6-dihalo-genetic acid: s

3-phthalidyl chloride, 4'-crotonolactonylchloiride, X-buityrol) acton-4-ylchloride or with the corresponding alcononyloxymethyl chloride,

1- (alkanoyloxy) ethyl chloride, 1-methyl-1- (alkanoyloxy) ethyl chloride, alkoxycarbonyloxymethyl chloride, 1- (alkoxycarbonyloxy) ethyl chloride according to Preparation O yield the following compounds:

- phenylethyl 1, 6, 6-di-bromophenyl anate, γ-buityrolactcinyl-ε-bromo-ε-iodopenicilanoate, acetoxymethyl-6-chloro-6-bromopenitianate, pi va lioxyl ymeth-1 - 6-chloro-6-piperazinate, hexanoyloxymethyl-6,6-dibromopenillanate,

1- (acetoxy) ethyl-6,6-dibiophenilicinate, 1- (isobutyryloxy) ethyl-6-bromo-6-iodopenicilane,

1-methyl-1- (acetoxy) ethyl 1-6,6-dibromo-penicillanate,

1-methyl-1- (hexanoyloxy) ethyl-6-chloro-ε-bromopenicilanoate, methoxycarbonyloxymethyl-6,6-dibrompenicilate, propoxycarbonyloxymothyl-6-chloro-6-iodopenicillate,

1- (ethoxycarbonyloxy) ethyl 1, 6,6-dibromopenicillanate,

1- (butoxycarbonyloxy) ethyl 6-bromo-6-iodopenicilane,

1-methyl-1- (methoxycarbonyloxy) ethyl 1-6,6-dibrompenicilianate, and

methyl 1- (isopropoxycarbonyloxy) ethyl 6,6-dibromopentilianate.

4-Croitono-lactonyl-6-chloro-6-iodo-dpenicilate,

Claims (8)

SUBJECT OF THE INVENTION A process for the preparation of a penicillanic acid 1,1-dioxide derivative of the general formula I by carbonyloxyethyl, characterized in that the compound of the general formula III COOR 4) or a pharmaceutically acceptable base salt thereof, wherein R ¹ is a hydrogen atom or an ester-forming moiety readily hydrolysable in vivo, such as pivaloyloxymethyl or ethoxy or the corresponding base salt, wherein R is a hydrogen atom, an ester-forming moiety readily hydrolysable in vivo, or a conventional penicitane carboxyl protecting group and X and Y are hydrogen, chlorine, bromine or iodine, and if X and Y are the same, both bromine atoms must be dehalogenated and optionally removed the penicillin carboxyl protecting group and converted to a salt. 2. Process according to claim 1, characterized in that the dehalogenation is carried out by catalytic hydrogenolysis. 3. A process according to claim 2 wherein the catalytic hydrogenolysis is carried out in an inert solvent. 4. The process according to claim 2, wherein the catalytic hydrogenolysis is carried out at a pressure of 0.018 to 9.8 MPa in the presence of 0.01 to 2.5% by weight of the hydrogenolytic catalyst. 5. Process according to any one of claims 2 to 4, characterized in that the catalytic hydrogenolysis is carried out at a temperature in the range from 0 to 60 ° C, at a pH in the range from 4 to 9. 6. A process according to any one of claims 2 to 5, wherein X is bromine, Y is hydrogen and R is as defined in 1. 7. A process as claimed in any one of claims 2 to 5, wherein the starting compound is a general compound. of formula III uses compounds wherein X and Y are bromine atoms and R is as defined in point 1. 8. A process according to any one of claims 2 to 7, wherein ‘is a starting compound of formula III wherein R is hydrogen and X and Y are as defined in