IE49535B1 - Process and intermediates for penicillanic acid 1,1-dioxide and esters thereof - 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

This invention relates to a new chemical process, and to new chemical compounds useful as intermediates in said process. More particularly, it relates to a new chemical process for the preparation of penicillanic acid 1,1-dioxide and esters thereof readily hydrolyzable in vivo. Said new chemical process comprises dehalogenation of a 6-halo or 6,6-dihalo derivative of penicillanic acid 1.1- dioxide or ester thereof readily hydrolyzable in vivo, or carboxy-protected derivative thereof to the correspond10 ing 1,1-dioxide, followed, if necessary, by deprotection. Said new chemical compounds useful as intermediates are 6-halo and 6,6-dihalo derivatives of penicillanic acid 1.1- dioxides, esters thereof readily hydrolyzable in vivo, and carboxy-protected derivatives thereof.

Penicillanic acid 1,1-dioxide and esters thereof readily hydrolyzable in vivo are useful as beta-lactamase inhibitors and as agents which enhance the effectiveness of certain beta-lactam antibiotics when the latter are used to treat bacterial infections in mammals, particularly humans. Previously, penicillanic acid 1,1-dioxide and esters thereof readily hydrolyzable in vivo have been prepared from 6-bromopenicillanic acid, or ester thereof readily hydrolyzable in vivo, by debromoination to give ; , penicillanic acid, or ester thereof readily hydrolyzable ^5 'in vivo, followed by oxidation to the 1,1-dioxide. It has how bedn found that, if the oxidation step is performed before the dehalogenation step, a better yield of product is obtained. See Belgian Patent No. 867,859, granted December 6, 1978; and West German Offenlegungsschrift No. 2,824,535 for details of methods of preparing penicillanic acid 1,1-dioxide and esters thereof readily hydrolyzable in vivo. 6-Halopenicillanic acids have been disclosed by Cignarella et al., Journal· of. Organic. Chemistry, 27, 2668 (J962£ and in United States Patent No, 3,2067462; hydrogenolysis of 6-halopeni.cillanic acids to penicillanic acid is disclosed in British. Patent Specification No. 1,072,108.

Harrison et al., Journal of the Chemical Society (London), Perkin Γ, 1772 GL276I disclose; O£ the oxidation of 6,6-dibromopenicillanic acid with. 3chloroperbenzoic acid, to give a mixture of the corresponding alpha- and beta-sulfoxides; Cb£ oxidation of methyl 6,6-dibromopenicillanate with. 3-chloroperbenzoic acid to give a methyl 6,6-dibromopenicillanate 1,1dioxide; fc) oxidation of methyl 6-alpha-chloropenicillanate with. 3-chloroperbenzoic acid, to give a mixture of the corresponding alpha- and beta-sulfoxides; and (d) oxidation of methyl 6-bromopenicillanate with. 3chloroperbenzoic acid, to give a mixture of the corresponding alpha- and beta-sulfoxides.

Clayton, Journal of the Chemical Society (London), (C), 2123, (1969), discloses; (a) the preparation of 6,6-dibromo- and 6,6-diiodopenicillanic acid; fb) oxidation of 6,6-dibromopenicillanic acid with sodium periodate, to give a mixture of the corresponding sulfoxides; Cc) hydrogenolysis of methyl 6,6-dibromopenicillanate to give methyl 6-alpha-bromopenicillanate; fdl hydrogenolysis of 6,6-dibromopenicillanxo acid, and its methyl ester, to give penicillanic acid and its methyl ester, respectively; and (a) hydrogenolysis of a mixture of methyl 6,6-diiodopenicillanate and methyl 6-alphaiodopenicillanate to give pure methyl 6-alphaiodopenioillanate.

This invention provides a process for the preparation of a compound of. the formula - 3 or a pharmaceutically acceptable base salt thereof, wherein R1 is hydrogen or an ester-forming residue readily hydrolyzable in vivo, characterised in that a compound of the formula: 'XQ> O'' ''''COOR --- (Ill) or a base salt thereof, wherein R is hydrogen, an esterforming residue readily hydrolyzable in vivo or a conventional penicillin carboxy protecting group; and X and Y are each hydrogen, chloro, bromo or iodo, with the proviso that when X and Y are both the same, they must both be bromo; is dehalogenated, followed, if necessary, by removal of the conventional penicillin carboxy protecting group.

A preferred way of carrying out the invention comprises contacting the compound of formula (III) with hydrogen, in an inert solvent, at a pressure in the range from about 1 to about 100 kg/cm , at a temperature in the range from about 0 to about 60°C, and at a pH in the range from about 4 to about 9, and in the presence of a hydro20 genolysis catalyst. The hydrogenolysis catalyst is usually present in an amount from about 0.01 to about 2.5 weight-percent, and preferably from about 0.1 to about 1.0 weight-percent, based on the compound of formula III. - 4 Preferably X and Y are both bromo or X is bromo and Y is hydrogen.

Preferred values for R and R1 are hydrogen.

Also embraced within the ambit of this invention are 5 the intermediates of formula III, wherein X, Y and R are as defined above. Preferred intermediates are the compounds of the formula (III) wherein X is bromo and Y is hydrogen or X and Y are both bromo, and wherein R is hydrogen, especially 6-o<-bromo and 6,6-dibromopenicillanic acid 1,1-dioxide.

This invention relates to the preparation of compounds of the formula I, and to several intermediates therefor. Throughout this specification, these compounds are named as derivatives of penicillanic acid, which is represented hy the following '5 structural formula: H X CH3 rr,cooa ,CH, -avi In derivatives of penicillanic acid, broken line attachment of a substituent to the bicyclic nucleus indicates that the substituent is- below the plane of lo the nucleus . Such, a substituent is· said to be in the alpha-configuration. Conversely, solid line attachment of a substituent to the Bicyclic nucleus indicates that the substituent is aBove. the plane of the nucleus. This latter configuration is referred to as the Beta2.5 configuration. Thus, the group X has the alphaconfiguration and the group Γ has the Beta-configuration in formula III.

In thia specification, when R1 ia an esterforming residue readily hydrolyzable in vivo, it is a grouping which ia notionally derived from an alcohol of the formula R^-OH, such, that the moiety COOR1 in such, a compound of formula I represents- an ester grouping. Moreover, R1 is of such, a nature that the grouping COOR1 is readily cleaved in vivo to liberate a free carboxy group (CQQHI, That is to say, R1 is a group of the type that when a compound of formula I, wherein R1 is an ester-forming residue readilyhydrolyzed in vivo, is exposed to mammalian blood or tissue, the compound of formula I, wherein R1.is hydrogen, is readily produced. The. groups R1 are well known in the penicillin art. In most instances, they improve the absorption characteristics of the penicillin compound. Additionally, R1 should be of such a nature that it imparts pharmaceuticallyacceptable properties to a compound of formula I, and it liberates pharmaceutically-acceptable fragments when cleaved in vivo. The groups R1 are well known and are readily identified by those skilled in the penicillin art. See, for example, West German Offenlegungsschrift No. 2,517,315. Specific examples of groups for R1 are 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl and groups of the formula R 0 ι ll 4 V VI consisting of hydrogen and alkyl having from 1 to 2 carbon atoms, and R is alkyl having from 1 to 5 carbon atoms. However, preferred groups for R1 are 9 S3 5 alkanoyloxymethyl having from 3 to 7 carhon atoms, 1-(alkanoyloxyLathy1 having from 4 to 5 caxBon atoms, 1-methyl-l-(alkanoyloxyLathyl having from 3 to 2 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 5 carhon atoms, .1- CalkoxycarbonyloxyLetliyl having from 4 to 7 carbon atoms, 1-meth.yl-l-alkoxycarbonyloxylethyl having from 5 to 8 carbon atoms, 3-phthalidyl, 4-crotonolactonyl and gamma-butyrolacton-4-yl.

Id 3-Ph.thalidyl, 4-crotonolactonyl and gammabutyrolacton-4-yl refer to structures VII, VIII and IX. Ihe wavy lines are intended to denote either of the two epimers or a mixture thereof.

VII VIII IX The compounds of formula (III) are obtained by a process which involves oxidation of the sulfide grouping in a compound of the formula: wherein X, Y and R are as previously defined, to a sulphone grouping, thereby producing a compound of the formula III. A wide variety of oxidants known in the art for the oxidation of sulfides to sulfones can be used for this process. However, particularly convenient reagents are alkali metal permanganates such as sodium and potassium permanganate; alkaline earth metal permanganates, such as calcium and barium permanganates ·, and organic peroxycarboxylic acids, such as peracetic acid and 3-chloroperbenzoic acid. -7When a compound oi the formula XI, wherein X, Y and R are as defined previously, is oxidized to the corresponding compound, of the. formula I'll, using a metal permanganate, the reaction is usually carried out by treating the compound of the formula II with from about 0.5 to about ten molar equivalents, and preferably from about one to about four molar equivalents, of the permanganate in an appropriate, reaction-inert solvent system. An appropriate, reaction-inert solvent system is one that does not adversely interact with, either the starting materials or the product, and water is commonly used. If desired, a cosolvent which is miscible with water but. will not interact with the permanganate, such as tetrahydro15 furan, can be added. The reaction can be carried out at a temperature in the range from about -30° to about 50°C,, and it is preferably carried out from about -10 to about 10°C. At about 0,°C. the reaction is normally substantially complete within a short period, e.g. within one hour. Although the reaction can be carried out under neutral, basic or acid conditions, it is preferable to operate at a pH in the range from about 4 to about 9, perferably 6-8. However, it is essential to choose conditions which avoid decomposition of the beta-lactam ring system of the compound of the formulae II or III, Indeed, it is often advantageous to buffer the pH of the reaction medium in the vicinity of neutrality. The product is recovered by conventional techniques·. Any excess permanganate is usually decomposed using sodium bisulfite, and then if the product is out of solution,· it is recovered by filtration. It is separated from manganese dioxide by extracting it into an organic solvent and 4953S -8removing the solvent hy evaporation. Alternatively, if the product is not out of solution a.t the end of the reaction, it is isolated By the usual procedure of solvent extraction.

When a compound of the formula TI wherein X, Y and R are as previously· defined, is oxidized -to the corresponding compound of the formula III using a peroxycarboxylic acid, the reaction is usually carried out by treating the compound of the formula II with from about 1 to about 5 molar equivalents, and preferably about 2.2 molar equivalents of the oxidant in a reaction-inert organic solvent. Typical solvents are chlorinated hydrocarbons, such as dichloromethane, chloroform and 1,2-dichloroethane; and ethers, such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane. The reaction is normally carried out at a temperature of from about -30 to about 50’C,, and preferably from about 15 to about 3Q°C, At about 25°C., reaction times of about 2 to about 16 hours are commonly used. The product is normally isolated by removal of the solvent by evaporation in vacuo. The reaction product can be purified by conventional methods, well known in the art. Alternatively, it can be used directly in the dehalogenation-step without further purification.

The process of· the present invention is a dehalogenation reaction. One convenient method of carrying out this transformation is to stir or shake a solution of a compound of the formula TH under an atmosphere of hydrogen, or hydrogen mixed with an inert diluent such as nitrogen or argon, in the presence of a hydrogenolysis catalyst. Suitable, solvents for this· hydrogenolysis reaction are those, which substantially dissolve the starting compound qf the formula I'll hut which do not themselves- suffer hydrogenation or hydrogenolysis. Examples of such, solvents include ethers such as diethyl ether, tetrahydrofuran, dioxan and 1,2-dimethoxyethane; low molecular weight esters such, as ethyl acetate and Butyl acetate; tertiary amides such, as N,N^dimethylformamide, dimethylacetamide and Nrqnathylpyrrolidona; water; and mixtures thereof. Additionally, it is usual to Buffer the reaction mixture so as to operate at a pH in the range from about 4 to 9, and preferably from about 6 to 8. Borate and phosphate buffers are commonly used. Introduction of the hydrogen gas into the reaction medium is usually accomplished by carrying out the reaction in a sealed vessel, containing the compound of formula III, the solvent, the catalyst and the hydrogen. The pressure inside the reaction vessel can vary from 2 about 1 to about 100 kg/cm , The preferred pressure range, when the atmosphere inside the reaction vessel is substantially pure hydrogen, is from about 2 to about 5 kg/cm . The hydrogenolysis is generally run at a temperature of from about 0° to about 60°C., and preferably from about 25° to about 50°C. Utilizing the preferred temperature and pressure values, hydrogenolysis generally takes place in a few hours, e.g., from about 2 hours to about 2Q hours.

The catalysts used in this hydrogenolysis reaction are the type of agents known in the art for this kind of transformation, and typical examples are the noble metals, such as nickel, palladium, platinum and rhodium. The catalyst is usually present in an amount from about Q.(J1 to about 2.5 weight-percent, -1Qand preferably from about 1,1 tq about l.Q weightpercent, based on the compound Other methods can he used for reductive removal of the halogen from a compound of formula ΙΙΓ.

For example, X and Y can he removed using a dissolving metal reducing system, such, as zinc dust in acetic acid, formic acid or a phosphate buffer, according to well-known procedures. Alternatively,the processcan he carried out using a tin hydride, for example a trialkyltin hydride such as tri-n-butyltin hydride.

As will be appreciated hy one skilled in the art, when it is desired to prepare a compound of the formula I, wherein R^ is hydrogen, a compound of the formula II, wherein R is hydrogen, can he subjected to the dehalogenation process disclosed herein.

In other words, the process comprises dehalogenation, of a 6-halo or 6,6-dihalo derivative of penicillanic acid with, a free carboxy group at the 3-position. However, in a further aspect of this invention, it is possible to begin with, the carboxy group at the 3-position blocked hy a conventional penicillin carboxy protecting group. The protecting group can he removed during or after the dehalogenation step, with re30 generation of the free, carboxy group. In this regard, a variety of protecting groups conventionally· used in 'the penicillin art to protect the. 3-carhoxy group can Be -11employed. The major requirements for the protecting group are that it must Be attachable to the particular compound of fonnula IT or TTTf and removable from the particular compound of formula I? or TTTf using conditions under which the Beta-lactam ring system remains substantially intact. For each case.preferred typical examples are the tetrahydropyranyl group, trialkylsilyl groups, the benzyl group, substituted benzyl groups (e.g, 4-nitrobenzyl), the Benzhydryl group,-the 2,2,2tri-chloroethyl group, the t-butyl group and the phenacyl group. Although all protecting groups are not operable in all situations a particular group which can be used in a particular situation will be readily selected by one skilled in the art. See further; United States Patents 3,632,850 and 3,197,466; British patent No. 1,041,985, Woodward et at, Journal of the American Chemical Society, 88, 852 (1966); Chauvette, Journal of Organic Chemistry, 36, 1259 (1971): Sheehan et al, Journal of Organic Chemistry, 29, 2006 (1964}; and Cephalosporin and Penicillins, Chemistry and Biology, edited by Η. E. Flynn, Academic Press, Inc., 1972. The penicillin carboxy protecting group is removed in conventional manner, having due regard for the lability of the beta-lactam ring system.

- Ila 6-alpha-Chloropenicillanic acid and 6-alpha-bromopenicillanic acid are prepared by diazotization of 6aminopenicillanic acid in the presence of hydrochloric acid and hydrobromic acid, respectively (Journal of Organic Chemistry, 27, 2668 [1962]). 6-alpha-Iodopenieillanic acid is prepared by diazotization of 5-aminopenicillanic acid in the presence of iodine, followed by hydrogenolysis (Clayton, Journal of the Chemical Society (C), 2123 [1969)). 6-beta-Chioropenicillanic acid, 6-beta-bromopenicillanic acid and 6-iodopenicillanic acid are prepared by reduction of 6-chloro-6-iodopenieillanic acid, 6,6-dibromopenicillanic acid and 6,6-diiodopenicillanic acid, respectively, with tri-n-butyltin hydride. 6-Chloro-6-iodopenicillanic acid is prepared by diazotization of 6-aminopenicillanic acid in the presence of iodine chloride; 6,6-dibromopenicillanic acid is prepared by the method of Clayton, Journal of. the Chemical Society (London) (C) 2123 (1969); and 6,6diiodopenicillanic acid is prepared by diazotization of 6-aminopenicillanic acid in the presence of iodine.

The compounds of formula I, ΪΪ and III, wherein Rand R1 is hydrogen, are acidic and will form salts with basic agents. These salts can be prepared by standard techniques, such as contacting the acidic and basic components, usually in a stoichiometric ratio, in an aqueous, non-aqueous or partially aqueous medium, as appropriate. They are then recovered by filtration, by precipitation with a non-solvent followed By filtration, by evaporation of -12the solvent, or in the case of aqueous solutions, hy lyophilization, as appropriate. Basic agents which, are suitably employed in salt formation belong to both, the organic and inorganic types, and they include ammonia, organic amines, alkali metal hydroxides, carbonates, bicarbonates, hydrides and alkoxides, as well as alkaline earth metal hydroxides, carbonates, hydrides and alkoxides Representative examples of such bases are primary amines, such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine and octylamine; secondary amines, such as diethylamine, morpholine, pyrrolidine and piperidine; tertiary amines, such as triethylamine, N-ethylpiparidine, N-methylmorpholine and 1,5-diazabicyclo[4.3.0]non-5-ene; hydroxides, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and barium hydroxide; alkoxides, such as sodium ethoxide and potassium ethoxide; hydrides, such as calcium hydride and sodium hydride; carbonates, such as potassium carbonate and sodium carbonate; bicarbonates, such as sodium bicarbonate and potassium bicarbonate; and alkali metal salts of long-chain fatty acids, such as sodium 2-ethylhexanoate. Preferred salts of the compound of the formula I are the sodium, potassium and triethylamine salts.

The compound of formula If wherein R^ is hydrogen, and the salts thereof is active as an antibacterial agent of medium potency both in vitro and in vivo, and the compounds of formula I, wherein R1 is an esterforming residue readily hydrolyzable in vivo, are active as antibacterial agents of medium potency in yiyo, Minimum inhibitory concentrations- (MIC'sL· of penicillanic acid 1,1-dioxide against several microorganisms are shown in Table I. -13TABLE I In Vitro Antibacterial Activity of penicillanic Acid 1,1-Dioxlde.

Microorganism_ MIC Cmcg./ml.I Staphylococcus aureus 1QQ Streptococcus faecalis 2QQ Streptococcus pyogenes 1QQ Escherichia coli 50 Pseudomonas aeruginosa 2Q0 10. Klebsiella pneumoniae 5Q Proteus mirabilis 1QQ Proteus morgani 10Q Salmonella typhimurium 50 Pasteurella multocida 50 15 Serratia marcescens 10Q Enterobacter aerogenes 25 Enterobacter clocae' 1QQ Citrobacter freundii 50 Providencia 1QQ 20 Staphylococcus epidermis 2QQ Pseudomonas putida 2Q0 Hemophilus influenzae 50 Neisseria gonorrhoeas 0, -14The in vitro antibacterial activity of the compound of the formula I, wherein R1 is hydrogen, and ita salts, .makes them useful as industrial antimicrobials, for example in water, treatment, slime control, paint preservation and wood preservation, as . well as for topical application as disinfectants. In the case of use of these compounds for topical application, it is often convenient to admix the active ingredient with a non-toxic carrier, such, as vegetable or mineral oil or an emollient cream. Similarly, it can be dissolved or dispersed in liquid diluents or solvents such as water, alkanols, glycols or mixtures thereof. In most instances it is appropriate to employ concentrations of the active ingredient of from about 0.1 percent to about IQ percent by weight, based on total composition.

The in vivo activity of the compounds of formula I wherein R1 is hydrogen or an ester-forming residue readily hydrolyzable in vivo, and the salts thereof, 2o makes them' suitable for the control of bacterial infections in mammals, including man, by both, the oral and parenteral modes of administration. The compounds will find use in the control of infections caused by susceptible bacteria in human subjects, e.g. infections caused by strains of Neisseria gonorrhoeae When considering therapeutic use of a compound of the formula I, or a salt thereof, in a mammal, particularly man, the compound can be administered alone, or it can be mixed with, pharmaceutically acceptable carriers or diluents- It can be administered orally or parenterally, i.e, intramuscularly, subcutaneously or intraperitoneally. The carrier o.r diluent is chosen on the basis of the intended * 48535 -15mode of administration. For example, when considering the oral mode of administration, the compound can be used in the form of tablets, capsules, lozenges, troches, powders, syrups, elixirs, aqueous solutions and suspensions, and the like, in accordance with, standard pharmaceutical practice. The proportional ratio of active ingredient to carrier will depend on the chemical nature, solubility and stability of the active ingredient, as well as the dosage contem10 plated. However, pharmaceutical compositions containing an antibacterial agent of the formula. I will likely contain from about 20% to about 95% of active ingredient. In the case of tablets for oral use, carriers which are commonly used include lactose, sodium citrate and salts of phosphoric acid. Various disintegrants such as starch, and lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc, are commonly used in tablets. For oral administration in capsule form, useful diluents are lactose and high molecular weight polyethylene glycols. When aqueous suspensions are required for oral use, the active ingredient can be combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents can be added. For parenteral administration, which includes intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the. pH of the solutions are suitably adjusted and buffered. For intravenous use, 3Q the total concentration of solutes- should Be controlled to render the preparation isotonic.

The prescribing physician will ultimately determine the appropriate dose of a compound of formula I for a given human subject, and this can Be expected to vary according to the age, weight, and response of the individual patient, as well as the nature and the -16severity of the patient’s symptoms, The compound will normally be used orally at dosages- in the range from about IQ to about 2Q.Q mg. per ki.lpgram of hody weight per day, and parenterally at dosages from about IQ to about 4QQ mg. per kilogram Of Body weight per day. These figures are illustrative only, however and in some cases it may he necessary to use dosages outside these limits.

The compounds of the formula If wherein R1 is 10 hydrogen or an ester-forming residue readily hydrolyzable in yiyo, or a salt thereof, enhance the antibacterial effectiveness of Beta-lactam antibiotics in vivo. They lower the amount of the antibiotic which is needed to protect mice against an otherwise lethal inoculum of certain beta-lactamase producing bacteria. This ability makes them valuable for coadministration with beta-lactam antibiotics in the treatment of bacterial infections in mammals, particularly man. In the treatment of a bacterial in20 fection, said compound of the formula I can be comingled with the beta-lactam antibiotic, and the two agents thereby administered simultaneously. Alternatively, said compound of the formula I can be administered as a separate agent during a course of treatment with a beta-lactam antibiotic. In some instances it is advantageous to pre-dose the subject with the compound of the formula 1' before initiating treatment with a beta-lactam antibiotic.

When using penicillanic acid 1,1-dioxide, a salt 3d or an ester thereof readily hydroly2ahle in vivo to enhance the effectiveness- of beta-lactam antibiotic, it is administered preferably in formulation with' standard pharmaceutical carriers- or diluents. The methods of formulation discussed earlier for use of penicillanic acid 1,1-dioxide or an ester thereof readily hydrolyzable in vivo as a single-entity -17antibacterial agent can be used when co-administration with another beta-lactam antibiotic is intended, A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier, a beta-lactam antibiotic and penicillanic acid 1,l-dioxide or a readily hydrolyzable ester thereof will normally contain from about 5 to about 8Q percent of the pharmaceutically acceptable carrier by weight.

When using penicillanic acid 1,l-dioxide or an 10 ester thereof readily hydrolyzable in vivo in combination with another beta-laotam antibiotic, the'sulfone can be administered orally or parenterally, i.e. intramuscularly, subcutaneously or intraperitoneally. Although the prescribing physician will ultimately decide the dosage to be used in a human subject, the ratio of the daily dosages of the penicillanic acid 1,l-dioxide or salt or ester thereof and the betalactam antibiotic will normally be in the range from about 1:3 tc 3:1. Additionally, when using penicil20 lanic acid 1,l-dioxide or salt or ester thereof readily hydrolyzable in vivo in combination with another beta-lactam antibiotic, the daily oral dosage of each component will normally be in the range from about IQ to about 200 mg. per kilogram of body weight and the daily parenteral dosage of each component will normally be about IQ to about 4QQ mg, per kilogram of body weight. These figures are illustrative only, however, and in some cases it may be necessary to use dosages· outside these limits, 3Q Typical beta-lactam antibiotics with which. penicillanic acid 1,l-dioxide and its esters readily hydrolyzable in vivo can be co-administered are; ff- C2-phenylacetamidqI.penicillanic acid, ff- Q)-2-amino-2-phenylacetamideIpenicillanic acid, -186- (2-carboxy-2-phenylaceta.midQl_penicillan.ic acid, and 7- C2-Il-tetrazolylJ acetamido£-3- (2-15-meth.yl1,3,4-thiadiazolyl] thiomethyiy_-3-desacatoxymsthyl5 cephalosporanic acid.

Typical microorganisms against which, the antibacterial activity of the above beta-lactam antibiotics is enhanced are: Staphylococcus aureus, Haemophilus influenzae, Klebsiella pneumoniae and Bacteroides fragllis.

As will be appreciated hy one skilled in the art, some beta-lactam compounds are effective when administered orally or parenterally, while others are effective only when administered hy the parenteral route. When penicillanic acid 1,1-dioxide, a salt or an aster thereof readily hydrolyzable in vivo, is to be used simultaneously (i.e. co-mingled). with a heta20 lactam antibiotic which is effective only on parenteral administration, a combination formulation suitable for parenteral use will be required. When the penicillanic acid 1,1-dioxide or ester thereof is to be used simultaneously (co-mingled). with a beta—lactam antibiotic which is effective orally or parenterally, combinations suitable for either oral or parenteral administration can be prepared. Additionally, it is possible to administer preparations of the penicillanic acid 1,1-dioxide or salt or ester thereof orally·, 3Q while at the same time administering a further betalactam antibiotic parenterally; and it is also possible to administer preparations of the penicillanic acid 1,1-dioxide or salt or ester thereof parenterally, -19while at the same time, administering the further Beta-lactam antibiotic orally.

Further details concerning the use and synthesis of compounds of the formula X are. disclosed in West German Offenlegungsschrift No. 2,824,535, The following examples and preparations 'are provided solely for the purpose of further illustration. infrared (IRl spectra were measured as potassium bromide discs fiKBr discs)., and diagnostic absorption bands are reported in wave numbers (cm”1I, Nuclear magnetic resonance, spectra QWR). were measured at 60 MHz for solutions in deuterochloroform (CDCl^L, perdeutero acetone CCD^COCD^L, perdeutero dimethyl sulfoxide (DMSO-dg) or deuterium oxide (D20l, and peak positions are expressed in parts per million (ppml ..downfield from tetramethylsilane or sodium 2,2-dimethyl2-silapentane-5-sulfonate. The following abbreviations for peak shapes are used: s, singlet; d, doublet; t, triplet; g, quartet; m, multiplet. -20EXAMgLE 1 S-alpha-Bromopenicillanic Acid 1,1-Dioxide To a stirred mixture of 56Q ml of water, 3QQ ml of dichloromethane and 56. Q g of 6-alpha-bromopenicillanic 5 acid was added 4N sodium hydroxide solution until a stable ph of 7.2 was achieved. This required 55 ml of sodium hydroxide. The mixture was stirred at pH 7.2 for 10 minutes and then it was- filtered. The layers were separated and the organic phase was discarded. The aqueous phase was then poured rapidly, with stirring, into an oxidizing mixture which had been prepared as follows.

In a 3 liter flask was mixed 63.2 g of potassium permanganate, 1,000 ml of water and 48.Q g of acetic acid. This mixture was stirred for 15 minutes at 20° C. and then it was cooled to 0’ C.

After the 6-alpha-bromopenicillanic acid solution had been added to the oxidizing mixture, a cooling bath at -15° C. was maintained around the reaction mixture. 2q The internal temperature rose to 15° C. and then fell to 5° C. over a 20 minute period. At this point, 30.0 g of sodium metabisulfite was added with stirring over a 10 minute period at about 10° C, After a further 15 minutes, the mixture was filtered, and the pH of the filtrate was lowered to 1.2 by the addition of 170 ml of 6N hydrochloric acid. The aqueous phase was extracted with chloroform, and then with ethyl acetate. Both the chloroform extracts and the ethyl acetate extracts were dried using anhydrous- magnesium sulfate and then they in were evaporated in vacuo. The chloroform solution .afforded -2110.Q g, (16% yield) of the title compound, The ethyl acetate solution afforded 57 g, of an oil, which, was triturated under hexane. A white solid appeared. It was filtered off, giving 41,5 g. (£6% yield)! of the title compound, mp 134’ C, (dec.I, Analysis;-Calcd for CgH^QBTNOgS: C, 30.-,78+ H, 3.23; BE, 25.60; N, 4,49; S, 10.27%, Found; C, 31.05; H, 3.24; Br, 25.54; N, 4,66; 5, IQ.21%, EXAMPLE 2 Oxidation of 6-alpha-chloropenicillanic acid and 6alpha-iodopenicillanic acid with potassium permanganate, according to the procedure of Example 1, affords 6alpha-chloropenicillanic acid 1,1-dioxide and 6-alphaiodopenicillanic acid 1,1-dioxide, respectively.

EXAMPLE 3 6-beta-Chloropenicillanic Acid 1,1-Dioxlde An oxidizing solution was 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 sodium 6-betachloropenicillanate in 5 ml. of water at 0-5° C., until the purple color of the potassium permanganate persisted. Approximately half of the oxidizing solution was required. At this point, the potassium permanganate color was discharged by the addition of solid sodium bisulfite, and then the reaction mixture was filtered. Ethyl acetate was added to the filtrate and the pH was adjusted to 1.8. The layers were separated and the aqueous layer was further extracted with, ethyl acetate. The . combined ethyl acetate layers were, washed with water, dried and evaporated in vacuo to give 118 mg. of the title compound. The NMB, spectrum Cm CDgCQCDgL showed -22absorption at 5.82 Cd, lffl, 5.24 Cd, IH)., 4,53 Cs, IH) j 1.62 Cs, 3H1 and 1.5Q Ca-, 3H). ppm.

The above product was dissolved in tetrahydrofuran and an equal volume of water was added. The pH was adjusted to 6.8 using dilute sodium hydroxide, the tetrahydrofuran was- removed by evaporation in.vacuo, and the residual aqueous solution was freeze dried. This afforded the sodium salt of the title compound.

EXAMPLE 4 6-beta-Bromopenicillanlc Acid 1,1-Dloxide To a solution of 255 mg, of sodium ff-beta-Bromopenicillanate in 5 ml. of water, at Q to 5° C., was added a solution prepared from 140 mg, of potassium permanganate, 0.11 ml. of 85% phosphoric acid and 5 ml. of water, at 0 to 5° C. The pH was maintained between 6.0. and 6.4 during the addition. The reaction mixture was stirred at pH 6.3 for 15 minutes, and then the purple solution was covered with ethyl acetate. The pH was adjusted to 1.7 and 330 mg. of sodium bisulfite was added. After 5 minutes, the layers were separated and the aqueous layer was further extracted with, ethyl acetate. The combined ethyl acetate solutions were washed with brine, dried (MgSO^). and evaporated in vacuo. This afforded 216 mg. of the title compound as white crystals. The NMR spectrum (in D2O) showed absorptions at 5.78 Cd, 1Ξ, J = 4Hz}., 5.25 Cd, Iff, J =° 4HzL, 4.20 Css, Iff), 1.65 Cs, 3H) and 1,46 (s, 3HJ. ppm, EXAMPLE 5 6-beta-lodopeniclllanic Acid. 1,1-Dioxide Oxidation of 6-beta-iodopenicillanic acid with, potassium permanganate, according to the procedure of Example. 4,. affords 6-Beta-iodopenicillanic acid, 1,1dioxide , -23EXAMPLE 6 Pivaloyloxymethyl g-alpha-BroinQpen.icillan.a-be 1,1-Dioxide To. a solution of 324 mg. of pivaloyloxymethyl 6alpha-bromopenicillanate in IQ ml. of dichloromethane is added 4QQ rag. of 3-chloroperbenzoic acid at Q to 5’ C.

The reaction mixture is stirred at Q to 5’ C. -for 1 hour and then at 25° C. for 24 hours· The. filtered reaction mixture is evaporated to dryness in vacuo to give the title compound.

EXAMPLE 7 The procedure of Example 6 is repeated, except that the pivaloyloxymethyl 6-Beta-brqraopenicillanate acid is replaced hy: 3-phthalidyl 6-alpha-chloropenicillanate, 4-crotonolactonyl 6-beta-chloropenicillanate, gamma-butyrolacton-4-yl 6-alpha-bromopenicillanate, acetoxymethyl 6-beta-bromopenicillanate, pivaloyloxymethyl 6-beta-bromopenicillanate, hexanoyloxymethyl 6-alpha-iodopenicillanate, 2q 1-(acetoxy)ethyl 6-beta-iodopenicillanate, 1-(isobutyryloxy)ethyl 6-alpha-chloropenicillanate, 1-methyl-l- (.acetoxy) ethyl 6-beta-chloropenicillanate, 1-methyl-l-(hexanoyloxylethyl 6-alpha-bromopenicillanate, methoxycarbonyloxymethyl 6-alpha-bromopenicillanate, propoxycarbonyloxymethyl 6-beta-bromopenicillanate, 1-(ethoxycarbonyloxy).ethyl 6-alpha-bromopenicillanate, 1- (butoxycarhonyloxyJ. ethyl 6-alpha-iodopenicillanate, 1-methyl-l- (methoxycarBonyloxyi.ethyl 6-beta-iQdopenicillanate and 3Q 1-methyl-l-CisopropoxycarhonyloxyLethyl 6-alpha-chlorapenicillanate, respectively. This affords? -243- phthalidyl 6-alpha-chloropenicilla.nate 1, l-dioxide, 4- crotonolactonyl 6-beta-chloropenicillanate 1,l-dioxide, gamma-butyrolacton-4-yl S-alpha-bromopenicfllanate 1,1dioxide, acetoxymethyl 6-beta-bromopenicillanate 1, l-dioxide, pivaloyloxymethyl ff-bata-bromopenicillanate 1', l-dioxide, hexanoyloxymethyl 6-alpha-iodopenicillanate 1,l-dioxide, l-(acefcoxylethyl 6-beta-iodopenicillanate 1,l-dioxide, l-fisobutyryloxy).ethyl ff-alpha-chloropenioillanate 1, ΙΙΟ dioxide, 1-methyl-l- (acetoxy)ethyl S-beta-chloropenicillanate 1,l-dioxide, 1-methyl-l- (hexanoyloxy). ethyl 6-alpha-bromopenicillanate 1,l-dioxide, methoxycarbonyloxymethyl 6-alpha-bromopenicillanate 1,1dioxide, propoxycarbonyloxymethyl 6-beta-bromopenicillanate 1,1dioxide, 1-(ethoxycarbonyloxylethyl 6-alpha-bromopenicillanate 20 1,l-dioxide, 1- (butoxycarbonyloxy).ethyl 6-alpha-iodopenicillanate 1,l-dioxide, 1-methyl-l- (methoxycarbonyloxy)ethyl 6-beta-iodopenicillanate 1,l-dioxide and 1-methyl-l-(isopropoxycarbonyloxyj.eth.yl 6-alpha-ohloropen icillanate 1,l-dioxide, respectively.

EXAMPLE 8 Penicillanic Acid 1,1-Dioxide 3Q To 10Q ml. of water was added 9.,4 g, of ff-alphabromopenicillanic acid, 1,1-dioxida, at 22’ C,, followed by sufficient 4N sodium hydroxide solution to achieve a stable pH? of 7.3. To the resulting solution was added 2,25 g, of 5% palladium-on-carbon followed By ff, 9 g. of dipotassium phosphate tri'hydrate. This mixture was then -25shaken under an atmosphere of hydrogen at a pressure varying from 3/5 to 1,8 kg/cm2, When hydrogen uptake ceased, the solids were removed filtration, and the aqueous solution was covered with. 1Q(I ml, of ethyl acetate.

The pH was slowly lowered from 5.Q to 1,5 with SN hydrochloric acid. The layers were separated, and’ the aqueous phase was extracted with further ethyl acetate.

The. combined ethyl acetate layers were washed with brine, dried using anhydrous magnesium sulfate and evaporated in vacuo. The residue was triturated under ether and then the solid material was collected by filtration. This afforded 4.5 g. C.65% yield), of the title compound.

Analysis:-Calcd. for CgE^NQgS: C, 41.2d; H, 4.75; N, 6.0Q; S, 13.75%. Found: C, 41.16, H, 4.81; N, 6.11; S, 13.51%.

EXAMPLE S Penicillanic Acid 1,1-Dioxide Hydrogenolysis of each of; 6-alpha-chloropenicillanic acid 1,1-dioxide, 6-alpha-iodopenicillanic acid 1,1-dioxide, 6-beta-chloropenicillanic acid 1,1-dioxide, 6-beta-bromopenicillanic acid 1,1-dioxide and 6-beta-iodopenicillanic acid 1,1-dioxide, according to the procedure of Example 8, affords penicillanic acid 1,1-dioxide.

EXAMPLE IQ Piyaloyloxymethyl Penicillanate 1,1-Eioxide To a solution of l.Q g. of piyaloyloxymethyl 630 alpha-bromopenicillanate in IQ ml. of methanol is added ml, of 1M sodium bicarbonate, and 2dd mg. of ld% palladium on carbon. The reaction mixture is- shaken vigorously under an atmosphere qf. hydrogen, at a pressure of about /. -265 kg/cm2, until hydrogen, uptake ceases.. The mixture is then filtered and the Bulk of the methanol is removed By evaporation in vacuo, Water and ethyl acetate a-e added to the residue and the pH is adjusted to 8.5, The layers are separated and the organic layer is washed with, water, dried and evaporated' in vacuo.

This affords the title compound.

EXAMPLE 11 Hydrogenolysis of the appropriate 6-halopenicil10 lanic acid ester 1,1-dioxide from Example 7, according to the procedure of Example 10, affords the following compounds: 3- phthalidyl penicillanate 1,1-dioxide, 4- crotonclactonyl penicillanate 1,1-dioxide, gamma-butyrolacton-4-yl penicillanate 1,1-dioxide, acetoxymethyl penicillanate 1,1-dioxide, pivaloyloxymethyl penicillanate 1,1-dioxide, hexanoyloxymethyl penicillanate 1,1-dioxide, 1-(acetoxy)ethyl penicillanate 1,1-dioxide, 2q 1-(isohutyryloxy)ethyl penicillanate 1,1-dioxide, 1-methyl-1- (acetoxylethyl penicillanate 1,1-dioxide, 1-methy1-1-(hexanoyloxyIethyl penicillanates 1,1-dioxide, methoxycarbonyloxymethyl penicillanate 1,1-dioxide, propoxycarbonyloxymethyl penicillanate 1,1-dioxide, 1-(ethoxycarbonyloxy).ethyl penicillanate 1,1-dioxide 1-(butoxycarbonyl)ethyl penicillanate 1,1-dioxide, 1-methyl-1- (methoxycarbonyloxymethyl penicillanate 1,1dioxide and 1-methyl-l-CisopropoxycarbonyloxyLethyl penicillanate 3Q 1,1-dioxide, respectively. -27EXAMPLE 12 Pivaloyloxymethyl 6-Alpha-bromopeniclllanate 1,1-Dloxide An oxidizing solution was.· prepared hy combining 4,26 g, of potassium pentenganate, 2,65 g, of 85% pbos»' phoric acid and 4Q ml. of water. The mixture was stirred far one hour, and then it was added slowly, during 2Q minutes, at 5 to 10° C,, to a stirred solution of .32 g, of pivaloyloxymethyl 6-alpha-bromopenicillanate in 70. ml. of acetone and 10 ml, of water. The mixture was stirred at 5° C, for 3Q minutes, and 1Q0 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 during 15 minutes at about 10° C, Stirring was continued for another 3Q minutes at 5° C,, and then the mixture was filtered. The organic phase was separated and washed, with saturated sodium chloride solution. The dried organic layer was evaporated to give 5.4 g. of the title compound as an oil, which slowly crystallized. The NMR spectrum fin CDClg) showed absorptions at 5.80 Cg, 2H), 5.15 Cd, 1H), 4.75 (.d, 1H), 4.50 Cs, lH), 1.60 Cs, 3Hl, 1.40 Cs, 3H) and 1.20 (s, 9H) ppm.

EXAMPLE 13 Pivaloyloxymethyl Penicillanate lyl-Dioxlda A solution of 4,4 g. qf pivaloyloxymethyl 6-alphahromopenicilianate 1,1-di.qxide in SO. ml, of tetrahydrofuran was added to CL, 84 g. of sodium bicarbonate in 12 ml, of water. The solution was· shaken, under an atmosphere of hydrogen in the presence of 2.0 g. of 5% palladium on carhon at 47 to 51 psig. The reaction mixture was then filtered and the residue was washed with 100 ml. of ethyl acetate and 25 ml. of water.

The combined filtrate and washes were separated. The organic layer was washed, with saturated sodium chloride, and dried (MgSC^)., and evaporated affording the title compound as an oil. This oil was dissolved in ethyl acetate C20 ml.). To the solution was added hexane (100 ml.) slowly, and the precipitate was filtered off. Yield: 2.4 g. The NMR spectrum Cin DMSO-dgl showed absorptions at 5.75 Cq, 2Ξ) , 5.05 Cm, IH), 4.40 Cs, 1Ξ), 3.95 - 2.95 Cm, 2H) , 1.40 Cs, 3Ξ)., 1,25 Cs, 3H1 and 1.10 Cs, 9H) ppm.

EXAMPLE 14 2,2,2-Trichloroethyl 6-alphaBromopenicillanate 1,1-Dioxide 2,2,2-Trichloroethyl 6-alpha-bromopenicillanate was oxidized with potassium permanganate substantially according to the procedure of Example 12 to give the title compound in 79% yield. The NMR spectrum of the product (in CDClg). showed absorptions at 5,30 to 4.70 Cm, 4H), 4.60 Cs, 1H1, 1.70. Cs, 3H1 and 1.50 Cs, 3H) ppm. • 49535 -29EXAMPLE 14A Penicillanic Acid- 1,1-Dloxide To a stirred slurry of S.5 g, of zinc powder in 100. ml. of a 70:30 glacial acetic acid - tetrahydrofuran 5 mixture, was added, portionwise during 5 minutes, 4,0 g. of 2,2,2-trichloroethyl 6-alpha-bromopeniciIlanate 1,1dioxide, The mixture was stirred at ambient temperature for 3 hours, and then it was filtered. The filtrate was concentrated to a volume of IQ ml. and the tan solution was mixed with 50 ml, of water and 100 ml. of ethyl acetate. The pH was adjusted to 1,3 and the layers were separated. The organic phase was washed with, saturated sodium chloride solution, dried using magnesium sulfate, and then concentrated to dryness . in vacuo. The residue was triturated under ether for minutes. This afforded 553 mg. of the title compound as a solid. The NMR spectrum Cin CDCl^/DMSO-dg). showed absorptions at 11.2 (broad s, IHl, 4.65 Qn, IHl, 4.30 (s, IH), 3.40 (m, 2H), 1.65 Cs, 3HJ and 1.50 Cs, 3ΗΪ ppm.

EXAMPLE 15 Benzyl 6-alpha-Bromopenicillanate 1,1-Dloxide Benzyl 6-alpha-bromopenieillanate was oxidized with potassium permanganate substantially according to the procedure of Example 12, to give the title compound in 94% yield. The NMR spectrum Cin CDCl^l showed absorptions at 7.35 Cs, 5h), 5.10 Cm, 3Hl, 4,85 Cm, IH), 4.40 (s, IHl, 1.50 fe, 3H1 and 1,25 Cs, 3HJ ppm. -30EXAMPLE 16 penicillanic Acjd. 1,1-Dipxlde A solution of 4,0 g. of Benzyl 6-alpha-bromopenicillanate 1,1-dioxide in 50. ml. of tetrahydrofuran 5 was combined with, a solution of 1,06 g, of sodium bicarbonate in 50 ml. of water- To the mixture was added 2.Q g. of a 50% suspension of 5% palladium-oncarbon in water, then this mixture was shaken tinder an atmosphere of hydrogen, at a pressure of 46.5 to 50 psig. for 20 minutes. The catalyst was removed by filtration, and then 30 ml. of tetrahydrofuran and 3.0 g. of a 50% suspension of 5% palladium-on-carbon were added.

The resulting mixture was shaken under an atmosphere of hydrogen, at pressure of from 42 to 45 psig., for 65 minutes. The reaction mixture was then filtered and the tetrahydrofuran was removed by evaporation. 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 was further extracted with ethyl acetate, and the combined ethyl acetate solutions were washed with saturated sodium chloride solution and dried (MgSO^L, Evaporation in vacuo gave a gum which was triturated under ether. This afforded 31 mg. of penicillanic acid 1,1-dioxide as a yellow solid. The nmr spectrum C.in CDClg/EMSOrdgl showed absorption at 9.45 (broad s, IK)., 4,60l Ct, 1H1, 4.25 (s, 1HJ, 3.40 Cd, 2ΗΣ, 1.65 Cs, 3Κί and 1.3α &, 3HJ. ppm. 9 5 3 5 —31— EXAMPLE 17 6,6-DibromQpen.icfllanxc Acid 1,1-Dioxlde To the dichloromethane solution of 6,6dihronopenicxllanic acid from Preparation K was added 300. ml of water, followed by the dropwise addition over a period of 30 minutes of 1Q5 ml of 3n sodium hydroxide. The pH stabilized at 7.(1. The aqueous layer was removed and the organic layer was extracted with water (2 x 10Q mil, To the combined aqueous solutions was added, at -5°C, a premixed solution prepared from 59.25g of potassium permanganate, 18 ml of concentrated phosphoric acid and 600 ml of water, until the pink color of the permanganate persisted. The addition took 50 minutes and 550 ml of oxidant were required. At this point 500 ml of ethyl acetate was added and then the pH was lowered to 1.23 by the addition of 105 ml of 6N hydrochloric acid. Then 250 ml of 1M sodium bisulfite was added during 10-15 minutes at ca. 10°C, During the addition of the 2q sodium bisulfite solution the pH was maintained at 1.25-1.35 using 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 C2 x 150 ml) and the combined ethyl acetate solutions were washed with brine and dried (MgSO^L. This afforded an ethyl acetate solution of 6,6-dibromopenicillanic acid 1,1dioxide.

The 6,6-dibromopencilla.nic acid 1,1-dioxide 3Q can be isolated by removal of the solvent in vacuo, A sample so isolated from an analogous preparation had a melting point of 2Q1°C Cdec.L. The NMR -32spectrum C£DC13/ DMSQ~d&). showed absorptions ftt 2.35 Cs,lHi, 5.30. 4,42 feflHlf 1.53· fe,3EL and 1.50 Cs,3H3.ppm. The IR spectrum (KBr discL showed absorptions at 3946-2500., 1813, 1754,. 1342 and 125Q5 111Q απ’1.

EXAMPLE 18 g-Chloro-6-lodopeniclllanlc Acid 1,1-Dioxide To a solution of 4.9g of 6-ehloro-Siodopencillanic acid in 50 ml of dichloromethane was added 50 ml of water and then the pH. was raised to 7.2 using 3N sodium hydroxide. The layers were separated and the aqueous layer was cooled to 5°C. To this solution was then added, dropwise, over a 20 minute period, a premixed solution prepared from 2.61g of potassium permanganate, 1.75 ml of concentrated phosphoric acid and 50 ml of water. The pE was maintained at S, and the temperature was maintained below 10°C, during the addition. At this point, 100 ml of ethyl acetate was added and the pH was adjusted to 1.5. To the mixture was then added 50 ml of 10% sodium bisulfite, keeping the temperature below 10°C and the pH at ca 1.5 by the addition of 6N hydrochloric acid. The pH was 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 (MgSOdI and evaporated in vacuo to give 4.2g of the title compound, mp 143-145°C, The NMR spectrum CCDClgl showed absorptions at 4,85 Cs.lHl, 4,38 fS, 1HI., 1.50 Cs, 3HI and 1,43 Cs,3Hlppm. The IR spectrum (KBr disci showed absorptions- at 1800, 174Q and 1250-1110. cm'1'. -33EXAMPLE 13 6-Bromo-6-iodopenlcillanic Acid. l/l-Dipxide To a solution of 6 ,0. g, of 6-bromo-6iodopenicillanic acid in 5Q ml Qf dichloromathan® was added 5Q ml of water. The pH.wha raised to 7,3 using 3N sodium hydroxide and the agueous layer was removed. The organic layer was extracted with, IQ ml of water. The combined, agueous phases were cooled to 5°C, and a premixed solution of 284g of potassium permanganate in 2 ml of concentrated phosphoric acid and 5Q ml of water was added dropwise, between 5 and 10’C. The addition took 20 minutes. At this point, 50. ml of ethyl acetate was added and the pH of the mixture was lowered to 1.5 using 6N hydrochloric acid. To this two-phase system was added, dropwise, 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 added, and then the pH was lowered to 1.23. The layers were separated and the agueous layer was saturated with sodium chloride. The saturated solution was extracted with ethyl acetate Ο x 5() ml) and the combined ethyl acetate layers were washed with brine, dried OigSO^L and evaporated in vacuo. The residue was dried under high vacuum, leaving 4,2g of the title compound, mp 145-147.

The NMR spectrum (CDClgI showed absorptions at 4.SQ Cs,lH), 4,30 Cs,lH), 1,60. Cs,3Hl and 1,42 Cs,3H)ppm.

The IR spectrum (EBr disci showed absorptions at 3Q 18Q0, 1740, 133Q and 1250-1110. cm1, -34EXAMPLE 2a 6-Chloro-6-bromopenicillanic Acid. 1,1-Dioxide Oxidation of £-chlQro-6-hramapenicillanic acid with, potassium permanganate, according to the procedure of Example 12, affords 6-chloro-6-bromopen± cillanic acid 1,1-dioxide.

EXAMPLE 21 Penicillanic Acid 1,1-Dloxide .

The ethyl acetate solution of 6,6-dibromo10 penicillanic acid 1,1-dioxide from Example 17 was combined with 7Q5 ml of saturated sodium bicarbonate solution and 8.88g of 5% palladium-on-carhon catalyst. The mixture was shaken under an atmosphere of hydrogen, at a pressure of about.5 kg/cm for about 1 hour. The catalyst was removed hy filtration, and the pH of the aqueous phase of the filtrate was adjusted to 1.2 with 6N hydrochloric acid. The aqueous phase was saturated with sodium chloride.

The layers were separated and the aqueous phase was 2q extracted with further ethyl acetate C.3 x 20Q ml)..

The combined ethyl acetate solutions were dried (MgSO4) and evaporated in vacuo to afford 33. 5g C58% yield from 6-aminopenicillanic acid), of penicillanic acid 1,1-dioxide. This product was dissolved, in 600 ml of ethyl acetate, the solution was decolorized using activated carbon and the solvent was removed hy evaporation in vacuo. The product wee washed with hexane. This afforded 31. Qg of pure product. -35EXAMPLE 22 Hydrogenolysis; of each, of 6-chloro-6iodopenicillanic acid 1, l-dioxide, ST'&romo-ff-r iodopenicillanic acid and 6-chloro—6-bromopeni5 cillanic acid, respectively, according to the procedure of Example 21, affasds, in each, case, penicillanic acid 1,l-dioxide.

EXAMPLE 23 Penicillanic Acid 1,1-Dioxlde 10 To a stirred suspension of 786 mg of 6chloro-6-iodopenicillanic acid 1,l-dioxide in .10 ml of benzene was added 0.3 ml of triethylamine followed by Q.25 ml of trimethylsilyl chloride, at ca Q°C, Stirring was continued for 5 minutes at ca Q°C and then at the reflux temperature of the solvent for 3Q minutes. The reaction mixture was cooled to 25°C and the precipitated material was removed by filtration.

The filtrate was cooled to ca 0°C and 1.16g of tri-nbutyltin hydride and a few milligrams of azobisiso2Q butyronitrile were added. The reaction mixture was stirred and irradiated with ultraviolet light for 1 hour at ca 0°C and then for 3.5 hours at the reflux temperature of the solvent. A further quantity of tri-n-butyltin hydride (1,1 ml) and a catalytic 25 amount of azobisisobutyronitrile were added and stirring and irradiation at the reflux temperature were continued for an additional 1 hour. The reaction mixture was then poured into 5Q ml of cold 5% sodium bicarbonate and the two-phasa system was 3Q stirred for 30. minutes. Ethyl acetate (50 mil wasadded and the pH; was adjusted to 1.5 with 6N hydrochloric acid. The layers- were separated and the -36aqueous layer was extracted with, ethyl acetate. The combined ethyl acetate solutions? were washed with, brine, dried G4g5©4I and evaporated in vacuo. The residue was triturated under hexane and then recovered by filtration. This afforded a,075 mg of the title EXAMPLE 24 Penicillanio Acid 1,1-Dloxjde To a stirred suspension of 0,874g of 6bromo-6-iodopenicillanic acid 1,1-dioxide in IQ ml of benzene at ca 5aC, was added 0..3 ml of triethylamine followed by 0.25 ml of trimethylsilyl chloride. Stirring was continued at ca 5°C for 5 minutes and then for 3Q minutes at the reflux temperature of the solvent. The reaction mixture was cooled to room temperature and the solids were removed by filtration. The filtrate was cooled to ca 5°C, and 1.Q5 ml of tri-n-butyltin hydride and a catalytic amount of azobisisobutyronitrile were added. The mixture was irradiated with ultraviolet light for 1 hour at ca 5°C, and then it was poured into 30 ml of cold 5% sodium bicarbonate. The mixture was stirred for 30 minutes and then 50 ml of ethyl acetate were 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 mil and the combined ethyl acetate layers were washed with, brine, dried (MgSO^l and evaporated in vacuo, The residue was dried under high vacuum and the 30 ml of hexane was- added. The insoluble material was recovered by filtration, affording 0..035g of the title compound. -37EXAMPLE 25 Piyaloyloxymethyl 6,g-DiBromopentcillanate 1,1-Ploxide To a solution of 4,73g of pivaloyoxymethyl 6,6-dibromopenic±llanate in 15 ml of dichloromethane is added 3.8Qg of 3-chlOEQperBenzoic acid at <1 to 5°C, The reaction mixture is stirred at 0. to 5°C for 1 hour and then at 25BC for 24 hours. The filtered reaction mixture is evaporated to dryness in vacuo and the residue is 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 phase is dried Q^SO^J and evaporated in vacuo to give the title compound.

EXAMPLE 26 Oxidation of each, of the 6,6-dihalopeni-7cillanic acid esters of Preparation P using 3-chloroperbenzoic acid, according to the procedure of Example 25, affords the following compounds: 3- phthalidyl 6,6-dibromopenicillanate 1,1-dioxide, 4- crotonolactonyl 6-chloro-6-iodopenicillanate, 1,1dioxide, γ-butyrolactonyl 6-bromo-6-iodopencillanate 1,1dioxide, acetoxymethyl 6-chloro-S-bromopenicillanate 1,1dioxide, piyaloyloxymethyl S-chloro-ff-iodopenicillanate 1,1dioxide, -38hexanoyloxymethyl 6,6-dibramQpeni.cillanate 1,1-dioxide 1- (acetoxy)ethyl 6, 6-dibromopenicillanate 1,1-dioxide, 1-(isohutyryloxy).ethyl S-Bromo-S-iodopenicillanate 1,1-dioxide, 1-methyl-l-(acetoxylethyl 6, 6-di.bromopenicillanate 1,1-dioxide, 1-methyl-l-(hexanoyloxy)ethyl 6-chloro-6-hromo_penicillanate, methoxycarbonyloxymethyl 6,6-dibromopenicillanate 10 1,1-dioxide, propoxycarbonyloxymethyl 6-chloro-6-iodopenicilianate 1,1-dioxide, 1-(ethoxycarbonyloxy]ethyl 6,6-dibromopenicillanate 1,1-dioxide, 1-(butoxycarbonyloxy[ethyl 6-bromo-6-iodopenicillanate 1,1-dioxide, 1-methyl-l- (methoxycarbonyloxy)ethyl 6,6-dibromopenicillante 1,1-dioxide and 1-methyl-l-CisopropoxycarbonyloxyLethyl 6,5-dibromo2q penicillanate 1,1-dioxide, respectively. -32EXAMPLE 27 piyaloyloxymethyl Penicillanate 1,l-Dloxlde To. a solution of l.Og of piyaloyloxymethyl 6,6-dibromopenicillanate 1,1-dioxi.de in Id ml of methanol is added 3 ml of IX sodium bicarbonate and 2(M mg of 10% palladium on carbon. The reaction mixture is. shaken vigorously under an atmosphere of hydrogen, at a 2 pressure of about 5 kg/cm , until hydrogen uptake ceases. The mixture is then filtered and the Bulk of the methanol is removed by evaporation in vacuo.

Water and ethyl acetate are added to the residue and the pH is adjusted to 8.5. The layers are separated and the organic layer is washed with, water, dried G^SO^l and evaporated in vacuo. This affords piyaloyloxymethyl penicillanate 1,1-dioxide.

EXAMPLE 28 Hydrogenolysis of each, of the 6,6-dxhalopenicillanic acid ester 1,1-dioxides from Example 26, according to the procedure of Example 27, affords the following compounds; 3- phthalidyl penicillanate 1,1-dioxide, 4- crotonolactonyl penicillanate 1,1-dioxide, gamma-butyrolacton-4-yl penicillanate 1,1-dioxide, acetoxymethyl penicillanate 1,1-dioxide, piyaloyloxymethyl penicillanate 1,1-dioxide, hexanoyloxymethyl penicillanate 1,1-dioxide, 1-(acetoxylethyl penicillanate 1,1-di.oxide, 1- (isobutyrylcxylethyl penicillanate 1,1-dioxide, -401-methyl- (acetoxy).ethyl penicillanate 1,1-dioxide, 1-methyl-1-(hexanoyloxyLathyl penicillanate 1,1dioxide, methoxycarbonyloxymethyl penicillanate 1,1-dioxides, propoxycarbonyloxymethyl penicillanate 1,1-dioxide, 1-(ethoxycarbonyloxy)ethyl penicillanate 1,1-dioxide, 1-(butoxycarbonyl)ethyl penicillanate 1,1-dioxide, 1-methyl-l-(methoxycarBonyloxy). ethyl penicillanate 1.1- dioxide and 1-methyl-l-(isopropoxycarbonyloxylethyl penicillanate 1.1- dioxide, respectively.

EXAMPLE 29, Pivaloylcxymethyl S/r-DlBromopeniclllanate 1,1-Dioxlde A stirred solution of 3.92g of 6,5-dibromo15 penicillanic acid 1,1-dioxide in 20 ml of N,Ndimethylformamide was cooled to 0°C and then 1.29g of diisopropylethylamine was added. This was followed by I.51g of chloromethyl pivalate. This 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 % sodium bicarbonate solution, water and Brine. The ethyl acetate solution was then treated with (SarcS /an activated charcoal/, dried (MgSO^) and evaporated in vacuo to a brown oil weighing 2.1g. This oil was chromatographed or. 2QQg of silica gel, using dichloro30 methane as eluant. The fractions containing the desired -41product were combined and rechrowatographed on silica gel to give. a. Q25g of the title compound. TBs NMR spectrum CCDCl3l showed absorptions at 5,10. (q, 2H1, .QQ Cfj·, IK), 4.55 O,1H1, 1.5Q fe,3Hl, 1.50 &,3Hl, and 1,15 fe,9Klppm, EXAMPLE 30 Pivaloyloxymethyl Penicillanate 1,1-Dioxlde To a stirred solution of 6Q mg. of pivaloyloxymathyl 6,6-dihroraopenici.llanate 1, l-dioxide in 5 ml IQ of benzene was added 52 ul of tri-n-butyltin hydride followed by a catalytic amount of azobisisobutytronitrile. The reaction mixture was cooled to ca'5°C, and then it was irradiated with ultraviolet light for 1 hour. The reaction mixture was poured into 20 ml 3.5 of cold 5% sodium bicarbonate and stirred for 3Q minutes. Ethyl acetate was added and the pH of the aqueous phase was adjusted to 7.Q. The layers were separated, and the aqueous phase was further extracted with ethyl acetate. The combined ethyl acetate solutions were washed with brine, dried Q4gS0^). and evaporated in vacuo. The residue was dried under high vacuum for 30 minutes. This afforded 70 mg of a yellow oil which was shown by NMR spectroscopy to contain the title compound, together with some impurities contain25 ing n-butyl groups. -4249535 EXAMPLE 31.

S, 6-Dibrojcopenlcjllanlc· Acid 1,l-Pioxida To a solution of 359 mg of 5,S-diBromopenicillanic acid in 30 ml of dichloromethane is added 380 mg of 3chloroperhenzoic acid at 0-5eC, The. reaction mixture is stirred at Q-5°C, for 30 minutes and then at '25eC for 24 hours. The filtered reaction mixture is evaporated in vacuo to give the title compound. -43EXAMPLE 32 Benzyl 6,6-DiEromopenicillanata 1,1-Lloxida ft mixture of lQ.Qg, of S,G-diBromopenicillanic acid 1,1-dioxide, 2.15 g, of sodium Bicarbonate,. 3.06 ml. of benzyl bromide and 1(IG ml. of NfN-dimethylformamide, was stirred at ambient temperature overnight.' Most of the solvent was removed by evaporation in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was removed, washed with IN hydrochloric acid and with saturated sodium chloride, and dried (NagSO^l, Evaporation in vacuo afforded 11.55 g. of the title compound. The NMR spectrum Cin CDClg) showed absorptions at 7.40 Cs, 5H), 5.3Q On, 2H1, 4.95 {.s, 1H), 4.55 Cs, IE), 1.50 Cs, 3H) and 1.20 (s, 3H) ppm.

EXAMPLE 33 Penicillanic Acid 1,1-Dioxide To a solution of 2.Q g. of benzyl 6,5-dibromopenicillanate 1,1-dioxide in 50 ml. of tetrahydrofuran was added a solution of 0.699 g. of sodium bicarbonate in 50 ml. of water, followed by 2.0 g. of 5% palladium-oncarbon. This mixture was then shaken under an atmosphere of hydrogen, at about 50 psig., for 7Q minutes. The tetrahydrofuran was removed by evaporation, and the residue was partitioned Between ethyl acetate and water at pH 7.37. The aqueous layer was removed and fresh ethyl acetate was added. The pH was lowered to 1,17 and the ethyl acetate was removed and washed with, saturated sodium chloride solution. Evaporation In vacuo gave 423 mg. of the title product. 4S535 -44EXAMPLE 34 2,2,2-TricM.oroathyl S, 6-DiBromopeniclllanats 1,1-Djoxide The title compound was prepared from 6, S-diBromopenicillanic acid 1,1-dioxide and 2,2,2-trichloroethyl chloroformate, substantially according to the procedure of Preparation J, The product was purified By chromatography on silica gel. The NMR spectrum of the product (in CDCl^I showed absorptions at 4.85 On, 2HL, 1.65 (s, 3H) and 1.45 (s, 3 Hl ppm.

EXAMPLE 35 Penicillanic Acid 1,1-Dloxide 2,2,2-Trichloroethyl 6,6-dibromopenicillanate 1,1dioxide was reduced with zinc dust in a mixture of glacial acetic acid and tetrahydrofuran, substantially according to Example 14A, The yield was 27¾.

EXAMPLE 36 1- (EthoxycarbonyloxyIethyl 6,6-Dibromopenicillanate 1,1-Dloxide A mixture of 2.26 g. of 6,6-dibromopenicillanic 20 acid 1,1-dioxide, 1.02 ml. of 1-(ethoxycarbonyloxy)ethyl chloride, 1.32 ml. of diisopropylethylamine and' ml. of Ν,Ν-dimethylformamide was stirred at room temperature for 28 hours. The reaction mixture was diluted with 100 ml. of ethyl acetate, and then it was washed sequentially with water, dilute hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride. The dried ethyl acetate solution was evaporated in vacuo to give 1.50 g. of an oil which was chromatographed on silica gel. This afforded 353 mg, of the title compound contaminated with some 1-(etiioxycarbonyloxy).ethyl 6-bromopenicillanate. -45EXAMPLE 37 1-(Ethoxycarbonyloxy). ethyl Penicillanate 1,1-Dioxlde A portion (230 mg,I of the product of Example 35 was dissolved in IQ ml. of toluene. To thi® was added 5 0.4 ml. of tri-n-butyltin hydride, followed by 0,164 g.. of azobisisobutyronitrile, and. the mixture was heated to 70-80° C, for 3.5 hour®. The solvent was removed by evaporation in vacuo, and the residue was dissolved in 25 ml. of acetonitrile. The acetonitrile solution was 10 washed with, hexane several times, and then it was evaporated in vacuo. The residue was dissolved in ether, and the ether solution was washed with. 5% potassium fluoride and followed by saturated sodium chloride. The dried Qfe^SO^l ether solution was evaporated in vacuo, and the residue was chromatographed on silica gel, to give 0.Q43 g. of the title product. The NMR spectrum Cin GDCl^l showed absorptions at 6.75 (ml, 4.60 Cml, 4.30 (ml, 4.15 Csl, 4.00 Csl, 3.30 (d) and 1.75-1.00 (ml ppm. -46PREPARATIQN A e-Chloro-e-iodopenjclllanic Acid To 3.38 g, of iodine monochloride in 30 ml, of dichloromethane was added, .with stirring, at 0-5® C., 11.1 ml. of 2.5N sulfuric acid, followed By 1.22 g. of . sodium nitrite. At this point, 3,QQ g. of 6-drainopenicillanic acid was added all at once, and stirring was continued for 3Q minutes at 0—5° C. To the reaction mixture was then added 22.8 ml. of 1M sodium sulfite IQ solution in portions, and the layers were separated.

The aqueous layer was washed with, further dichloromethane, and then all the organic phases were washed with saturated sodium chloride. The dichloromethane solution was dried (NagSO^J. and evaporated in vacuo giving 3,48 g. of the title compound.

The above product was dissolved in 30 ml. of tetrahydrofuran, and then 30 ml. of water were added. The pH was adjusted to 6.8 with dilute sodium hydroxide and the tetrahydrofuran was removed in vacuo. The remaining aqueous phase was freeze-dried and the residue was washed with diethyl ether. This afforded 3.67 g. of the title compound as its sodium salt.

PREPARATION B 6-beta-Chloropenicillanic Acid A 2.95—g. sample of sodium 6-chloro-6-iodopenicillanic acid was converted to the free acid, and then it was dissolved in 125 ml. of benzene under nitrogen. To the solution was added 1.Q8 ml. of triethylamine, and the mixture was cooled to 0—5° C, To the cooled mixture 3Q was then added Q.277 ml. of trfmethylsi.lyl chloride, and the reaction mixture was stirred at (1-5° C, for 5 minutes, at 25° C. for 6Q minutes and at 56a C, for 36 minutes.

The reaction mixture was cooled to 25® C, and the -47triethylaminu hydrochloride was removed hy filtration.

To the. filtrate was added 15 mg. of azobisisobutyronitrile, followed By 2.02 ml, of tri-nybutyltin hydride. The mixture was then irradiated with, ultraviolet light for minutes with, cooling to maintain at temperature of ca. 2Q° C. The solvent was then removed By evaporation in yaouo, and the residue was dissolved in a ljl mixture of tetrahydrofuran-water. The pH was adjusted to 7.0 and the tetrahydrofuran was removed By evaporation in vacuo The aqueous phase was washed with ether, and then an equal 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 further ethyl acetate, and then the combined ethyl acetate 15 solutions were dried and evaporated in vacuo. This afforded 980 mg. of 5-beta-chlorpenicillanic acid.

The above product was dissolved in tetrahydrofuran, and an equal volume of water was added. The pH was adjusted to 6.8, and the tetrahydrofuran was removed by evaporation in vacuo. The aqueous phase remaining was freeze-dried to give 850 mg. of sodium 6-beta-chloropenicillanate. The NMR spectrum showed absorption at 5.70 (d, IH, J = 4Hz)., 5.50 td, IH, J = 4Hz), 4.36 Ls, 1H1, 1.60 (ja, 3H1 and 1,53 Cs, 3H). ppm.

PREPARATION C 6-beta-Bromopenlclllanic Acid A mixture of 5,0 g, of 6,S-dibromopenicillanic acid, 1.54 ml. of triethylamine and 1QQ. ml. of benzene was stirred under nitrogen until a solution was obtained.

The solution was cooled to CL-5’ C,, and 1,78 ml. of trimethylsilyl chloride wag added. The reaction mixture was stirred at 0-5’ C. for 2-3 minutes, and then at 50.’ C, for 35 minutes. The cooled reaction mixture was filtered and the filtrate was cooled 0-5’ C. A small quantity 9535 -48of azohisisobutyronitrile was added followed by 3.68 ml. of tri-n-butyltin hydride,. The reaction flash was irradiated with ultraviolet light for 15 minutes-, and then the reaction was- stirred a.t' ca, 25° C, for 1,75 hours.

The reaction mixture was irradiated again fop 15 minutes and then stirring was continued 2.5 hours. At this point a further small quantity of azobisisobutyronitrile was added, followed by Q.6 ml· of tri-n-butyltin hydride CQ.6 ml, I, added and the mixture was again irradiated iQ for 30 minutes. The solvent was then removed by evaporation in vacuo, and to the residue was added 5%.sodium bicarbonate solution and diethyl ether. The two-phase system was shaken vigorously for IQ minutes and then the pH was adjusted to 2.Q. The ether layer was removed, dried and evaporated in vacuo to give 2.33 g. of an oil.

The oil was converted into a sodium salt by adding water containing 1 equivalent of sodium bicarbonate followed by freeze drying the solution thus obtained.. The afforded sodium 6-beta-bromopenicillanate, contaminated with a- small amount of the alpha-isomer.

The sodium salt was purified by chromotography on Sephadex LH-20, combined with some further material of the same quality and re-chromatographed. The NMR spectrum CP20) °£ the product thus obtained showed absorptions at .56 (s, 2H), 4.25 Cs, IH), 1.6Q (s, 3H) and 1.5Q Cs, 3H). ppm.

PREPARATION D 6-beta-Iodopeniclllanlc Acid The title compound is- prepared by reduction of 6,630 diiodopenicillanic acid, with, tri-n-butyltin hydride, according to the procedure of Preparation B. -49PREPARATION Ε P j-'/a.loyloxymethyl 6-alpha-BroinQpen.icillanate To a solution of 280 mg, of ff-alpha-Bromopenicillanic acid in 2 ml. of NfNrdimethylfoxmamide is added 26Q mg, of diisopropylethylamine followed By 155 mg. of chloromethyl pivalate and 15 mg. of sodium iodide. The reaction mixture is stirred at room temperature for 24 hours, and then it is diluted with, ethyl acetate and water. The pH is adjusted to 7.5, and then the ethyl ]_q acetate layer is separated and washed three times with water and once with, saturated sodium chloride-solution.

The ethyl acetate solution is then dried using anhydrous sodium sulfate, and evaporated in vacuo to give the title compound.

PREPARATION P Reaction of the appropriate S-halopenicillanic acid with'3-phthalidyl chloride, 4-crotonolactonyl chloride, gamma-fautyrolacton-4-yl chloride or the requisite alkanoyloxymethyl chloride, 1-(alkanoyl oxy).ethyl chloride, 2Q 1-methyl-1-(alkanoyloxy1ethyl chloride, alkoxycarhonyloxymethyl chloride, 1-(alkoxycarbonyloxy)ethyl chloride or 1-methyl-l-(alkoxycarbonyloxylethy1 chloride, according to the procedure of Preparation E, affords the following compounds; 3-phthalidyl 6-alpha-chloropenicillanate, 4-crotonolactonyl 6-beta-chloropenicillanate, gamma-butyrolacton-4-yl 6-alpha-bromopeni.ci'llanate, acetoxymethyl 6-beta-bromopenicillanate, pivaloyloxymethyl 6-beta-bcomopenicillanate, 3Q hexanoyloxymethyl 6-alpha-iodopenicillanate, 1-fecetoxylethyl 6-beta-iodopenicillanate, 1- Cisobutyryloxylethyl 6-alpha-chloropenicillanate, 1-methyl-l-(acetoxylethyl 6-beta-chloropenicillanate, 1-methyl-l-(hexanoyloxyLethyl 6-alpha-bromopenicillanate, methoxycarbonyloxymethyl 6-alpha-bromopenicillanate, -50propcxycarbonyloxymethyl 6—Bata,—hxomopsnicillanate, 1- CethoxycarbqnyloxyLathyl 6-alpha-Bromopenicillanate, 1-butoxycar Bo nyloxy-J. ethyl S-alpha-iodopenicillanate, 1-methyl-l- QnethoxycarBanyloxyLethyl 6-Beta,-ie>dopenicil5 lanate, and 1-methyl-l- Cisopropcxycar-BonyloxyLathyl 5-alpKa-chloropenicillanates, respectively.

PREPARATION G IQ g, g-Dilodopeniclllanic Acid A mixture of 15.23 g. of iodine, IQ ml, of 2.5N sulfuric acid, 2.7ff g. of sodium nitrite and 75 ml. of dichloromethane was stirred at 5° C,, and 4.32 g. of 6aminopenicillanic acid were added over a period of minutes. Stirring was continued at 5-10° C, for minutes after the addition was complete, and then 100 ml. of 10% sodium bisulfite was added dropwise. The layers were separated, and the agueous layer was further extracted with dichloromethane. The combined dichloro20 methane layers were washed with brine, dried QigSO^l and evaporated in vacuo. This afforded 1.4 g. of the title compound, contaminated with some 6-iodopenicillanic acid. The product had a melting point of 58-64° C. The NMR spectrum CCDClgl showed'absorptions at 5,77 Cs, IH), 4.60 (s, IH) , 1.71 Cs, 3Ξ) and 1.54 Cs, 3Hl ppm. -51PREPARATIQN Η.

Pivaloyloxymethyl 6~alpha,~Bramopenicilianata To a stirred mixture of 11.2 g. of 6-alphabromopeni.cillanic acid, .3.7 g. of sodium hicarBonate and 44 ml. of N,N-dimethylformamide was added 6.16 g. of chloromethyl pivalate, dropwise, during 5 minutes, at ambient temperature. Stirring was continued for 66 hours and then the reaction mixture was diluted with 1QQ ml. of ethyl acetate and 1Q0 ml. of water. The layers were separated, and the ethyl acetate layer was washed sequentially with water, saturated sodium chloride, saturated sodium bicarbonate, water and saturated sodium chloride. The decolorized ethyl acetate solution was dried (MgSO^l and evaporated to dryness in vacuo. This afforded. 12.8 g. f8Q% yield), of the title compound.

PREPARATION I Benzyl 6-alpha-Bromopenicillanate The title compound was prepared by esterification of 6-alpha-bromopenicillanic acid with benzyl bromide, 2q substantially according to the procedure of Preparation H (Yield 83%). The NMR spectrum Cin CDClg). showed absorptions at 7.35 (.s, 5H), 5.35 (jn, 1H), 5.15 Cs, 2H) , 4.7Q (m, 1H), 4.60 Cs, 1H), 1.55 Cs, 3H) and 1.35 Cs, 3K1 ppm. -524953K PREPARATION J 2,2,2-Trxchloyoeta.yl Penicillanate To a stirred solution of 11,2 g, of e-alpha,hromopenicillanic acid, in 5Q jql, of. tatraBydrofuran, at 0° C,, was added 3.48 g. of pyridine oyer a oneminute period. To the hazy solution so oBtained was added, over a IQ minute period, 8.47 g. of 2,2,2-trichloroethyl chloroformate, maintaining the temperature Between 0 and 2° C, Stirring was- continued for IO 30 minutes, and then the cooling hath was removed.

Stirring was continued at ambient temperature ^overnight. The reaction mixture was then warmed to 35° C, for five minutes and then it was filtered. The filtrate was evaporated and the residue was dissolved in 10.Q ml. of ethyl acetate. The ethyl aceta.te solution was washed sequentially with saturated sodium bicarbonate, water and saturated sodium chloride. The ethyl acetate solution was then decolorized, and dried, and then it was concentrated to small volume. To the resulting 2Q mixture was added 100 ml. of hexane, and the solids were removed by filtration, giving 10.5 g. of the title compound, m.p. 105-110° C. The NMR spectrum Cin CDClgl showed absorptions at 5.50 Cd, 1H), 4.95 (d, iHl, 4.90 Cs, 2H), 4.65 Cs, IHl, 1.7Q Cs, 3H1 and 1,55 fe, 3H) ppm -53preparation k g, 6-Dlhromopeni,cillanlc Acid To- 5Q.Q ml of dichloromethane cooled, to 5°C was added 112.9g of bromine, .200 ml of 2,5N sulfuric acid and 34.5g of sodium nitrite.. Ta this stirred mixture was then added 54, Qg of g-ajninopenicillanic acid, portionwise over 30 minutes, with the temperature maintained from 4 to 10°C, stirring was continued for 30 minutes at 5aC, and then 41Q ml of a l.QM solution of sodium bisulfite was added dropwise at 5 to lQaC during 2Q minutes. The layers were separated and the aqueous layer was extracted twice with 15Q ml of dichloromethane. The original dichloromethane layer was combined with the two extracts to give a solution of 6,6-dibromopenicillanic acid. This solution was used directly in Example 17.

PREPARATION L 6-Chloro-6-iodopenicillanic Acid To 100 ml of dichloromethane cooled to 3°C was added 4.87g of iodine chloride, 10 ml of 2.5N sulfuric acid and 2.76g of sodium nitrite. To this stirred mixture was then added 4.32g of 6-aminopenicillanic acid portionwise during a 15 minute period. Stirring was continued for 2Q minutes at Q 5°C, and then 10Q ml of 10% sodium bisulfite solution was added dropwise at ca 4aC, Stirring was continued for 5 minutes and then the layers were separated. The aqueous layer was.· extracted with dichloromethane -54(2 x 5Q ml) and the combined dichloromethane solutions were washed with, brine,, dried ®gSQ4L and evaporated in yaouo to give the title compound as a tan solid, mp 148-152’C, The NMR spectrum of the product CCDClgl showed absorptions-at 5.4Q Cs, iHl, 4,5ff Cs,lB3, 1.67 Cs,3K) and 1,50 Cs, 3Blppm, The IR, spectrum GCBr disci showed absorptions at 178 Q and 1715 cm1.

PREPARATION M IQ 6-Bromo-6-iodopeniclilanic Acid To 1Q0 ml of dichloromethane, cooled, to °C, was added IQ ml of 2.5N sulfuric acid, 6,21g of iodine bromide and 2.76g of sodium nitrite. To this mixture was added, with vigorous stirring, at 0 15 5°C, over 15 minutes, 4.32g of 6-am±nopen±.cillanic acid. Stirring was continued for a further 20 minutes at 0 - 5°C, and then 100 ml of 10% sodium bisulfite was added dropwise between Q and 1Q°C. At this point, the layers were separated and the aqueous 2q layer was extracted with dichloromethane Q x 50 ml). The combined dichloromethane layers were washed with brine, dried (MgSO4l and evaporated in vacuo.

The residue was dried under high vacuum for 30 minutes to give 6.Qg (72% yield! of the title compound mp 144-147°C. The NMR spectrum CCDCl^l showed absorptions at 5.50. Cs,lHl, 4.53 Cs,lEl, 1.7Q Cs,3Hl and 1.53 C_s,3H)ppm. The SR spectrum QOBr disci showed absorptions at 1785 and 1710 cm1, The mass spectrum showed a prominent ion at m/e - 406. 535 -55PRSPARATjON N 6-Chloro-6-5rqmopeniclllanio. Acid 6-Chloro-6-Bromopenicillanic acid is prepared from 6-aminopenicillanic acid' via diazot5 zation followed By reaction with- Bromine chloride, according to the procedure, of Preparation Μ, , PREPARATION 0 Pivaloyloxymethyl 6,S-diBromopenjcjllanate To a stirred solution of 3.59g of 6,61Q diBromopenicillanic acid in 2Q ml of N,Nrdimethylformamide is added l,3Qg of diisopropylethylamine followed by 1.50g of chloromethyl pivalate at ca 0°C. The reaction mixture is stirred at' ca tt°C for 30 minutes and then at room temperature for 24 hours. The reaction mixture is then diluted with ethyl acetate and water and the pH of the aqueous phase is adjusted to 7.5. The ethyl acetate layer is separated and washed three times with water and once with saturated sodium chloride solution. The ethyl acetate solution is then dried using anhydrous sodium sulfate, and evaporated in vacuo to give the title compound. -56PREPARATION Ρ Reaction of the appropriate ff,6-dihalopenicillanic acid with 3-phthalidyl chloride, 4-crotonlactonly chloride, gamma-butyrclaction-4-yl chloride or the requisite alkanoyloxymethyl chloride, 1-CalRany— loxyl.eth.yl chloride, 1-methyl-l- (alkanoyloxyLethyl chloride, alkoxycarbonyloxymethyl chloride, 1-Calkoxycarbonyloxylethyl chloride or l-methyl-l-felkonycarbonyloxy). ethyl chloride, according to the procedure Preparation 0, affords the following compounds; 3- phthalidyl 6,6-dibromopenicillanate, 4- crotonola ctony1 6-chloro-6-iodopenicillanate, γ-butyrolactonyl 6-bromo-6-iodopenicillanate, acetoxymethyl 6-chloro-6-bromopenicillanate, pivaloyoxymethyl 6-chloro-6-iodopenicillanate, hexanoyloxymethyl 6,6-dibromopenicillanate, 1- (acetoxy) ethy J. 6, 6-dibromopen.icillanate, 1-(isobutyryloxy). ethyl 6-bromo-6-iodopenicillante, 1-methyl-l- (acetoxyJ.ethyl 6, 6-dibromopenici.llanate, 1-methyl-l-(hexanoyloxylethyl S-chloro-6-bromopenicillante, methoxycarbonyloxymethyl ff,ff-dihromopenicillanate, propoxycarbonyloxymethyl 6-chloro-6-iodopenicillanate -571- (ethoxycarbonyloxy)ethyl 6, 6-dihromopeni;ci(llalna,ta, 1-Cbutoxycarbonyloxylethyl S-bromo-Sriodopenicillanate, 1-methyl-l-(mathoxycarbanyloxylethyl 6,6-dibromopenicillanate and 1-methyl-l-(isopropoxycarhanyloxy£ethyl 6,6-diBromopenicillanate.

Claims (10)

1. A process for the preparation of a compound of the formula — (I) ' 'COOR 1 or a pharmaceutically-acceptahle base salt thereof, 5 wherein R 1 is hydrogen or an ester-forming residue readily hydrolyzable in yiyo; characterized in that a compound of the formula Z CH 3 ? CH 3 %CQQR (III) or a base salt thereof, wherein R is hydrogen, an to ester-forming residue readily hydrolyzable in vivo or a conventional penicillin carboxy protecting group; and X and Y are each hydrogen, chloro, bromo or iodo, with the proviso that when X and Y are both the same, they must both be bromo; 15 is dehalogenated, followed, if necessary, by removal of the conventional penicillin carboxy protecting group.

2. The process according to claim 1, characterized in that the dehalogenation is carried out by catalytic hydrogenolysis.

3. The process according to claim 2, characterized in that the catalytic hydrogenolysis is carried out in an inert solvent. 49 535

4. The process according to either of claims 2 and 3, characterized in that the catalytic hydrogenolysis is carried out at a pressure in the range from 1 to 2 10Q kg/cm and in the presence of ¢,01 to 2.5 weight5 percent of a hydrogenolysis catalyst,

5. The process according to any 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. and at a pH in the range from 4 to 9. lb

6. The process according to any of claims 2 to 5, characterized in that X is bromo and y is hydrogen.

7. The process according to any of claims 2 to 5, characterized in that X and Y are both bromo.

8. The process according to any of claims 2 to '5 7, characterized in that R and R^ are both hydrogen.

9. A compound of the formula and the base salts thereof, characterized in that R is hydrogen, an ester-forming residue readily hydrolyzable 2/ in vivo or a conventional penicillin carboxy protecting group; - 60 - 4S535 |ϋ- A compound according to claim 9, characterised in that R is 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolactonyl or a group of the formula: ? R“ 0 ι II a -C-O-C-R or R 2 0 I II -C-O-CrO-R k 3 2 3 5 wherein R and R are each hydrogen or alkyl having from 1 4 to 2 carbon atoms, and R is alkyl having from 1 to 5 carbon atoms. JJ . A compound according to claim 9, characterised in that R is tetrahydropyranyl, trialkylsilyl having 1 to 3

10. Carbons in each alkyl group, benzyl, 4-nitro-benzyl, benzhydryl, 2,2,2-trichloroethyl, t-butyl or phenacyl. l/i- 6,6-Dibromopenicillanic acid 1,1-dioxide. β. A process as claimed in claim 1 wherein the compound of formula (III) is prepared by contacting a compound of 20 the formula : CH 3 ι COOR ,CH, (ID or a base salt thereof, wherein X, Y and R are as defined in claim 1, with an alkali metal permanganate, an alkaline earth metal permanganate or an organic peroxvcarboxylic acid.