DD149367A5 - PROCESS FOR THE PREPARATION OF PENICILLANIC ACID 1,1-DIOXIDE AND ESTERS - Google Patents

Abstract

The invention relates to a process for the preparation of penicillanic acid 1,1-dioxide and its esters for use as medicaments. The aim of the invention is an improved process with which the product yield is increased. According to the invention, compounds of formula I, or their pharmaceutically acceptable base salts, wherein R & exp1! Is hydrogen or an ester-forming in vivo readily hydrolyzable group prepared by reacting a compound of formula II or its base salts wherein R is hydrogen, an ester-forming, in vivo readily hydrolyzable group or a conventional penicillin carboxy-protecting group, and X u. Each Y is hydrogen, chlorine, bromine or iodine, with the proviso that when both X and Y are the same, both must be bromine, dehalogenated and, if necessary, the conventional penicillin carboxy protecting group is cleaved off.

Description

Berlin, 3 · 9- 1980 AP C 07 D / 219 432 57 108 18

21 94-3 2 - "-

Process for the preparation of penicillanic acid 1,1-dioxide and its esters

Field of application of the invention

The present invention relates to a novel chemical process and to novel chemical compounds useful as intermediates in this process, and more particularly to a novel chemical process for producing penicillanic acid 1,1-dioxide and its in vivo readily hydrolyzable esters.

Penicillanic acid 1,1-dioxide and its in vivo readily hydrolyzable esters are useful as β-lactamase inhibitors and as agents which enhance the efficacy of certain β-lactam antibiotics when the latter are useful for the treatment of bacterial infections in mammals, especially humans, be used·

Characteristic of the known technical solutions

Heretofore, penicillanic acid 1,1-dioxide and its in vivo readily hydrolyzable esters of 6-bromopenicillanic acid or its in vivo readily hydrolyzable esters were prepared by debromination to penicillanic acid or its in vivo readily hydrolyzable esters with subsequent oxidation to 1,1-dioxide. See BE-PS 867 859 and DE-OS 2 824 535 for details of the preparation processes for penicillanic acid 1, 1-dioxide and its in vivo readily hydrolysable esters.

3. 9 "1980

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6-Halpene penicillan acids have been disclosed by Cignarella et al., Journal of Organic Chemistry 2, 2668 (1962) and U.S. Patent 3,206,469. the hydrogenolysis of 6-halo-penicillanic acids to penicillanic acid is disclosed in GB ~ PS 1 072 108 *

Harrison et al., Journal of the Chemical Society (London), Perkin I, 1772 (1976) describe a) the oxidation of 6,6-Dibroinpenicillansäure with 3 ~ chloroperbenzoic acid to a mixture of the corresponding oc- and ß-sulfoxides, b) the Oxidation of methyl 6,6-dibromophenicillanate with 3-chloroperbenzoic acid to give methyl 6,6-dibromophenicillanate 1,1-dioxide; c) oxidation of methyl 6o (chlorobenzicillanate with 3-hydroxybenzolate a mixture of the corresponding (X- and ß-sulfoxides and d) the oxidation of methyl-6 ~ brompenicillanat with 3 ~ chloroperbenzoic acid to a mixture of the corresponding oC ~ and ß-sulfoxides _β

Clayton, Journal of the Chemical Society (London), (C), 2123, (1969), describes a) the preparation of 6,6-dibromo and 6,6-di-3-dodecipic acid, b) the oxidation of 6,6-dibromopenicillanic acid c) the hydrogenolysis of methyl 6,6-dibromopenicillanate to methyl 6-benzophenicillanate; d) the hydrogenolysis of 6,6-dibromopicicanoic acid and its methyl ester to penicillanic acid and its methyl esters and (e) the hydrogenolysis of a mixture of methyl-6,6-dihydro-penicillanate and methyl-6-iodobenzicillanate to give pure methyl 6ci- godpenicillanate _e

Object of the invention

The aim of the invention is to provide an improved process for the production of penicillanic acid Τ, Ι-

3. 9 "1980

AP G 07 D / 219 432

57 108 18

- 3 dioxide, which increases the production yield

Essence3 _t

The object of the invention is to find suitable starting components and suitable reaction conditions,

The new chemical process involves the oxidation of a 6-halogeno or 6,6-dihalogeno derivative of penicillanic acid or its in vivo readily hydrolyzable ester to the corresponding 1,1-dioxide followed by dehalogenation. The novel intermediates useful chemical compounds are 6-halogeno- and 6,6-dihalogen derivatives of penicillanic acid "1,1-dioxides and their easily hydrolysable esters in vivo",

Although the process of the present invention starts from a 6-halogeno-penicillanic acid or its in vivo readily hydrolyzable ester and involves the steps of dehalogenation and oxidation, it is surprisingly found that when the oxidation takes place before dehalogenation, a better product yield is achieved ".

According to the invention, compounds of the formula

5 "~ 'CH

-CH ₃

or a pharmaceutically acceptable base salt thereof, wherein R is selected from hydrogen and ester-forming "in vivo readily hydrolyzable radicals"

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The preparation according to the invention is carried out as follows: a) bringing together a compound of the formula

or a base salt thereof with a reagent selected from the group consisting of alkali metal permanganates, alkaline earth metal permanganates and organic peroxycarboxylic acids to give a compound of the formula

hf

-A-

N L- ^CH 3,

'''COOR ¹

or a base salt thereof, wherein X and Y are each selected from hydrogen, chlorine, bromine and iodine, with the proviso that when X and Y are both the same, they must both be bromine, and

b) Dehalogenating the compound of formula III.

In a preferred embodiment of step b), the product of step a) is reacted with hydrogen in an inert solvent at a pressure in the range of about 0.98 to

about 98 bar (about 1 to about 100 kp / cm) at a temperature in the range of about 0 to about 60 C and a pH in the range of about 4 to about 9 and in the presence of a hydrogenolysis catalyst brought into contact. The hydrogenolysis catalyst is usually present in an amount of about 0.01 to about 2.5 weight percent, preferably about 0.1 to about 1.0 weight percent, based on the compound of formula III.

The preferred meaning for X and Y is bromine, and the preferred reagents for carrying out the step a) are potassium permanganate and 3-chloroperbenzoic acid.

If X and Y are both chlorine, the compound of formula II is difficult to obtain. If X and Y are both iodine, step a) of the process according to the invention is inconveniently slow.

The intermediates of the invention are also covered by the invention

Formula III, wherein X, Y and R are as defined above. A preferred intermediate is 6,6-dibromophenicillanic acid-i, 1-dioxide, the compound of formula III wherein X and Y are bromo

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and R is hydrogen.

The invention relates to the preparation of compounds of the formula I and to various intermediates for this purpose. In the present specification, these compounds are named as derivatives of penicillanic acid represented by the following structural formula:

H _CR

' ^{vV 3} CiV).

NC ^CH 3

'' COOH

For penicillanic acid derivatives, the broken linkage of a substituent to the bicyclic nucleus means that the substituent is below the level of the nucleus. Such a substituent is referred to as α-configured. Conversely, an extended linkage of a substituent to the bicyclic nucleus means that the substituent is above the level of the nucleus. This latter configuration is called the beta configuration. Thus, the group X has α configuration and the group Y β configuration in formula II.

Here, when R is an ester-forming, in vivo readily hydrolyzable radical, it is a moiety which is thought to be derived from an alcohol of the formula R-OH such that the radical COOR in such a compound of formula I represents an ester moiety. Further, R is of such a kind that the COOR moiety is readily cleaved in vivo to release a free carboxyl group COOH). That is, R ¹ is a group of the type that when a compound of formula I, wherein R is a esterbildender easily in vivo hydrolysable radical, mammalian blood or tissue is exposed to ^7, the compound of formula I wherein R ¹ is hydrogen is, easily arises. The R groups are well known on the penicillin region. In most cases they improve the absorption

Properties of the Penicillin Compound In addition, R should be of such type as to confer pharmaceutically acceptable properties on a compound of Formula I and to release pharmaceutically acceptable fragments upon cleavage in vivo. The R groups are well known and are of. Specific to such groups R ¹ are 3-phthalidyl, 4- * crotonolactonyl, T -butyrolactone "= 4-" yl and groups of the formula

R ² 0 R ² 0

"C-O-C-R ^ V and C-O-C-O-R" "VI f ο I 3

R ^J R ^

wherein R and R "are each hydrogen and alkyl of 1 to

2 carbon atoms are selected and R ^{4 is} alkyl of 1 to 5

However, preferred groups R are alkanoyloxymethyl of 3 to 7 carbon atoms, 1 ~ (alkanoyloxy) ethyl of 4 to 8 carbon atoms, 1-methyl-1- (alkanoyloxy) ethyl of 5 to 9 carbon atoms, alkoxycarbonyloxymethyl of 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl of 4 to 7 carbon atoms, 1-methyl-1-alkoxycarbonyloxy) ethyl of 5 to 8 carbon atoms, 3-phthalidyl, 4-crotonolactonyl and T-butyrolactone-4-yl. Particularly preferred R groups are tetrahydropyranyl , Trialkylsilyl having 1 to 3 carbon atoms in each alkyl group, benzyl, 4-methylbenzyl, benzylhydryl, 2,2,2-trichloroethyl, T-butyl or phenacyl.

3-Ph.th.alidyl, 4-orotonolactonyl and T-butyrolactone-4-yl refer to structures VII, VIII and IX * The lines of the figure are intended to designate either one of the two epimers or their mixture »

VIII

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Stage a) of the process of the invention comprises the oxidation of the sulfide moiety in a compound of formula II to a sulfone moiety resulting in a compound of formula III. A large number 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 permanganate, and organic peroxycarboxylic acids such as peracetic acid and 3-chloroperbenzoic acid.

When a compound of formula II wherein X, Y and R are as previously defined is oxidized to the corresponding compound of formula III using a metal permanganate, the reaction is usually carried out by treating the compound of formula II with from about 0.5 to about 10 Mole equivalents, preferably about 1 to about 4 MoI-A equivalents of permanganate in a suitable reaction inert solvent system. A suitable solvent-inert solvent system is one which does not adversely interact with any of the starting materials or product, and usually water is used. If desired, a cosolvent that is miscible with water but does not interact with the permanganate, such as tetrahydrofuran, may be added. The reaction may be carried out at a temperature in the range of about -30 to about 50 ^° C., preferably at about -10 to about 10 ^° C. At about 0 ^° C., the reaction is normally within a short time, eg within 1 hour , practically finished. Although the reaction may be carried out under neutral, basic or acidic conditions, it is preferred to operate at a pH in the range of about 4 to 9, preferably 6 to 8. It is important, however, to choose conditions that a decomposition of the ß-lactam ring system of the compound of the formulas II or III

avoid. In fact, it is often beneficial to buffer the pH of the reaction medium around the neutral point. The product is obtained by conventional techniques. Any excess permanganate is usually decomposed using sodium bisulfite, and then, when it is no longer in solution, the product is recovered by filtration. From the manganese dioxide, it is separated by extraction into an organic solvent and recovered by evaporation of the solvent. On the other hand, if the product is still in solution at the end of the reaction, it is isolated according to the usual procedure of the solvent reaction.

When a compound of formula II in which X, Y and R are as previously defined is oxidized to the corresponding compound of formula III using a peroxycarboxylic acid, the reaction is usually carried out by treating the compound of formula II with from about 1 to about 6 molar equivalents, preferably about 2.2 molar equivalents of the oxidizing agent in a reaction inert organic solvent. Typical solvents are chlorinated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane _T and ethers such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane. The reaction is carried out usually at a temperature of about -30 to about 50 ⁰ C, preferably at about 15 to about 30 ⁰ C. At about 25 ° C usually reaction times of about 2 to about 16 hours are applied. The product is usually isolated by stripping off the solvent in vacuo. The reaction product can be purified by conventional methods well known in the art. On the other hand, it can be used directly in stage b) without further purification.

Stage b) of the process according to the invention is a dehalogenation reaction. A convenient method of performing this transformation is to react a solution of a compound of formula III under an atmosphere of hydrogen or out

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To stir or shake hydrogen in admixture 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 of formula III, but themselves do not undergo hydrogenation or hydrogenolysis. Examples of such solvents are ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, low molecular weight esters such as ethyl acetate and butyl acetate, tertiary amides such as Ν, Ν-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, water and their mixtures. In addition, it is common to buffer the reaction mixture to operate at a pH in the range of about 4 to 9, preferably about 6 to 8. Usually, borate and phosphate buffer are used. Usually, hydrogen gas is introduced into the reaction medium 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 may vary between about 0.98 and about 98 bar (about 1 and about 100 kp / cm). When the atmosphere in the reaction vessel is virtually pure hydrogen, the preferred pressure range is about 1.96 to about 4.9 bar (about 2 to about 5 kp / cm). The hydrogenolysis is generally carried out at a temperature from about 0 to about 60 ^° C., preferably from about 25 to about 50 ^° C. By employing the preferred temperatures and pressures, the hydrogenolysis generally requires a few hours, eg, about 2 to about 20 hours. The catalysts used in this hydrogenolysis are of the type known in the art for the type of conversion, and typical examples are nickel and the noble metals palladium, platinum and rhodium. The catalyst is usually present in an amount of about 0.01 to about 2.5, preferably about 0.1 to about 1.0 weight percent, based on the compound of formula III. It is often convenient to disperse the catalyst on an inert support, a particularly suitable one

Catalyst is palladium on an inert support, such as carbon.

Other methods can be used to reductively remove the halogen from a compound of formula III, i.e., at step b). For example, X and Y may be removed using a dissolving metal reduction system such as zinc dust in acetic acid, formic acid or a phosphate buffer, according to well-known procedures. On the other hand, step b) can be carried out using a tin hydride, e.g. a trialkyltin hydride, such as tri-n-butyltin hydride.

As one skilled in the art will recognize, when a compound of formula I wherein R is hydrogen is to be prepared, a compound of formula II wherein R is hydrogen may be subjected to steps a) and b) of the process disclosed herein. In other words, the process involves oxidation and subsequent dehalogenation of a 6-halo or 6,6-dihalogeno derivative of penicillanic acid having a 3-position free carboxyl group. However, according to another aspect of the invention, each of steps a) and b) can be started with 3-position carboxyl group blocked by a conventional penicillin carboxy-protecting group. The protecting group may be cleaved during or after step a) or step b) to regenerate the free carboxyl group. In this regard, a variety of protecting groups commonly used in the penicillin field to protect the 3-carboxyl group can be used. The main requirements for the protecting group are that it be attachable to the particular compound of formula II or III and removable from the particular compound of formula I or III using conditions in which the β-lactam ring system remains virtually intact. For the steps a) and b) typical examples are the tetrahydropyranyl group, the trialkylsily groups, the benzyl group, substituted

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benzyl groups (eg 4-nitrobenzyl), the benzhydryl group, the 2,2,2-trichloroethyl group, the t-butyl group and the phenacyl group. Although all. Protective groups are not applicable in all situations, a particular group that is applicable in a particular situation is easy to select by those skilled in the art. See also U.S. Patent Nos. 3,632,850 and 3,197,466, British Patent 1,041,985, Woodward et al., Journal of the American Chemical Society, 8, 852 (1966), Chauvette, Journal of Organic Chemistry 3j5 / 1259 (1971): Sheehan et al., Journal of Organic Chemistry 29_, 2006 (1964) and "Cephalosporin and Penicillins, Chemistry and Biology" by HEFlynn, Academic Press, Inc., 1972. The penicillin carboxy-protecting group is described in U.S. Patent Nos. 4,135,199; cleaved in a conventional manner, with due regard to the lability of the .beta.-lactam ring system.

The compounds of formula I, II and III, wherein R is hydrogen, are acidic and form salts with bases. These salts can be prepared by standard techniques, e.g. by contacting the acidic and basic components, usually in stoichiometric ratio in an aqueous, non-aqueous or partially aqueous medium, as appropriate. They are then recovered by filtration, precipitation with a nonsolvent followed by filtration, by evaporation of the solvent or in the case of aqueous solution by lyophilization as appropriate. Salts suitably used for salt formation include both the organic and the inorganic and include ammonia, organic amines, alkali metal hydroxides, carbonates, bicarbonates, hydrides and alkoxides, and alkaline earth hydroxides, carbonates, hydrides and alkoxides. Representative examples of such bases are primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine and octylamine, see. Amines such as diethylamine, morpholine, pyrrolidine and piperidine, tertiary amines such as triethylamine, N- Ethylpiperidine, 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 ethylate and potassium ethylate, 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 formula I are the sodium, potassium and triethylamine salts.

The compound of formula I wherein R is hydrogen and its salts are effective as medium strength antibacterial agents both in vitro and in vivo, and the compounds of formula I wherein R is an ester-forming in vivo readily hydrolyzable group effective as medium strength antibacterial agents in vivo. The minimum inhibitory concentrations (MIC values) of penicillanic acid 1,1-dioxide over various microorganisms are listed in Table I.

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Table I

Antibacterial in vitro activity of penicillan

acid 1,1-dioxide

Microorganism MIC

Staphylococcus aureus 1OQ

Streptococcus faecalis 2OQ

Streptococcus pyogenes IQQ

Escherichia coli 5Q

Pseudomonas aeruginosa 2QQ

Klebsiella pneumonias 50

Proteus mirabilis 100

Proteus morgani 1OQ

Salmonella typhimurium 50

Pasteurella multocida 50

Serratia marcescens 1OQ

Enterobacter aerogenes 25

Enterobacter clocae 100

Citrobacter freundii 50

Providencia 1OQ

Staphylococcus epidermis 2OQ

Pseudcir.onas putida 2QQ

Hemophilus influenzae 50.

Neisseria gonorrhoeae Q «

The in vitro antibacterial activity of the compound of formula I wherein R is hydrogen and its salts makes them useful as industrial antimicrobials, e.g. in the treatment of water, silt or mud control, color and wood preservation as well as for local application as a disinfectant useful. In the case of using these compounds for topical application, it is often convenient to mix the active ingredient with a non-toxic carrier, such as vegetable or mineral oil, or a softening cream. Similarly, it may be dissolved or dispersed in liquid diluents or solvents such as water, alkanols, glycols or mixtures thereof. In most instances, concentrations of the active ingredient are from about 0.1 to about 10 weight percent, based on the total agent.

The in vivo activity of the compounds of formula I wherein R is hydrogen or an ester-forming in vivo readily hydrolyzable group and their salts makes them suitable for controlling bacterial infections in mammals, including humans, in both oral and pareneteral routes of administration. The compounds find use in the control of infections caused by susceptible bacteria in human patients, e.g. of infections caused by strains of Neisseria gonorrhoeae.

In therapeutic use of a compound of formula I or its salt in a mammal, particularly in humans, the compound can be administered alone or it can be mixed with pharmaceutically acceptable carriers or diluents. It can be oral or parenteral, i. be administered intramuscularly, subcutaneously or intraperitoneally. The carrier or diluent is selected based on the intended route of administration. at

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oral administration e.g. For example, the compound may be employed in the form of tablets, capsules, lozenges, round pastilles, powders, syrups, elixirs, aqueous solutions and suspensions, and the like, in standard pharmaceutical practice. The proportion of active ingredient to carrier depends on the chemical nature, solubility and stability of the active ingredient as well as the dosage in question. However, drugs containing an antibacterial agent of Formula I contain from about 20% to about 95% of active ingredient. For tablets for oral ingestion, commonly used carriers are e.g. Lactose, sodium citrate and salts of phosphoric acid. Various disintegrating agents, such as starch, and lubricants, 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 may be combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring agents may be added. For parenteral administration, including intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions is suitably adjusted and buffered. For intravenous use, the total solute concentration should be controlled so that the preparation becomes isotonic.

The prescriber will ultimately determine the appropriate dose of Formula I compound for a particular human patient, and this will vary with the age, weight, and response of the individual patient as well as the nature and severity of the patient's symptoms. The compounds will normally be administered orally at dosages ranging from about 10 to about 200 mg / kg of body weight per day

_ 1 C. _

- I -

and parenterally at dosages of from about 10 to about 4,000 mg / kg of body weight per day. However, these figures are for illustrative purposes only and in some cases it may be necessary to use cans outside these limits.

The compounds of the formula I in which R is hydrogen or an ester-forming, in vivo readily hydrolyzable radical or salts thereof enhance the antibacterial activity of β-lactam antibiotics in vivo. They lower the amount of antibiotic needed to protect mice against otherwise lethal inoculum of certain β-lactamase-producing bacteria. This ability makes them valuable for coadministration with β-lactam antibiotics in the treatment of bacterial infections in mammals, particularly humans. In the treatment of a bacterial infection, the compound of formula I may be mixed with the β-lactam antibiotic and the two agents thereby administered simultaneously. On the other hand, the compound of formula I may be administered as a separate agent in the course of treatment with a β-lactam antibiotic. In some cases, it is advantageous to pre-dose the patient with the compound of formula I before starting treatment with a β-lactam antibiotic.

When penicillanic acid 1,1-dioxide, a salt or an in vivo readily hydrolyzable ester of this compound is used to enhance the efficacy of a β-lactam antibiotic it is preferably administered in formulation with standard pharmaceutical carriers or diluents. The compilation methods previously discussed for the use of penicillanic acid 1,1-dioxide or an in vivo readily hydrolyzed ester as the sole antibacterial agent may be used when co-administration with another β-lactam antibiotic is contemplated. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, a

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β-lactam antibiotic and penicillanic acid 1,1-dioxide or its readily hydrolyzable ester normally contains from about 5 to about 80% by weight of the pharmaceutically acceptable carrier.

When using penicillanic acid 1,1-dioxide or one of its in vivo readily hydrolyzable esters in combination with another β-lactam antibiotic, the sulphone may be administered orally or parenterally, i. intramuscularly, subcutaneously or intraperitoneally. Although the prescribing physician will ultimately determine the dose to be used in a patient, the ratio of the daily doses of penicillanic acid 1,1-dioxide or its salt or ester and β-lactam antibiotic will normally be in the range of about 1: 3 to 3: 1 , In addition, when penicillanic acid 1,1-dioxide or its salt or in vivo readily hydrolyzable ester is used in combination with another β-lactam antibiotic, the daily oral dose of each component is usually in the range of about 10 to about 200 mg / kg body weight and daily parenteral dose of each component normally at about 10 to about 400 mg / kg of body weight. However, these figures are for illustrative purposes only, and sometimes it may be necessary to use doses outside these limits.

Typical β-lactam antibiotics in which penicillanic acid 1,1-dioxide and its in vivo readily hydrolyzable esters can be coadministered are 6- (2-phenylacetamido) penicillanic acid, 6- (D-2-amino-2-phenylacetamido) penicillanic acid, 6- (2-carboxy-2-phenylacetamido) penicillanic acid and 7- (2- [1-tetrazolyl] acetamido) -3- (2- [5-methyl-1,3,4-thiadiazolyl] thiomethyl) -J- desacetoxymethylcephalosporic acid.

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Typical microorganisms which are used to enhance the antibacterial activity of the above β-lactam antibiotics are the following: Staphylococcus aureus, Haemophilus influenzae, Klebsiell pneumoniae and Bacteroides fragilis.

As one skilled in the art knows, some β-lactam compounds are effective when administered orally or parenterally while others are effective only when administered parenterally. When penicillanic acid is 1,1-dioxia, a salt or an in vivo readily hydrolyzable ester of which it is intended to be used simultaneously (d, h in admixture) with a β-lactam antibiotic which is active only on parenteral administration, a combination suitable for parenteral use is required. When the penicillanic acid 1,1-dioxide or its ester is to be used simultaneously (in admixture) with a β-lactam antibiotic which is orally or parenterally effective, combinations suitable for oral or parenteral administration can be prepared Preparations of the penicillanic acid 1,1-dioxide or its salt or ester can be administered orally, while at the same time another β-lactam antibiotic is administered parenterally, and "preparations of penicillanic acid 1,1-dioxide or its salt or ester can also be administered parenterally while at the same time the other β-lactam antibiotic is administered orally «

Y / eitere, the use and synthesis of compounds of the formula I concerning details are disclosed in DE-OS 2,824,535 *

embodiment

   »! IIH I il - I IH IM III ΠIH I lllll I I Il I Il '' -Il-l

The invention is explained in more detail below with reference to some exemplary embodiments. The following examples and preparations serve exclusively to illustrate the following: Infra red (IR) spectra

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measured as potassium bromide compacts (KBr briquettes) and detection absorption bands are reported in wavenumbers (cm). Nuclear magnetic (NMR) spectra were measured at 60 MHz for solutions in deuterochloroform (CDCl ₃ ), perdeuteroacetone (CD ₃ COCD ₃ ), perdeuterodimethylsulfoxide (DMSO-dg) or deuterium oxide (D 2 O), and the peak levels are in parts per million (ppm) ) to the lower field of tetramethylsilane or sodium 2,2-dimethyl-2-silapentane-5-sulfonate indicated. The following abbreviations for peak shapes are used: s for singlet, d for doublet, t for triplet, g for quadruplet and m for multiplet.

Example 1 6-cx bromopenicillanic acid i, 1-dioxide

To a stirred mixture of 560 ml of water, 300 ml of methylene chloride and 56.0 g of 6-a-Brompenicillansäure 4 η sodium hydroxide solution was added until a stable pH of 7.2 was reached. This required 55 ml of sodium hydroxide. The mixture was stirred at pH 7.2 for 10 minutes and then filtered. The layers were separated and the organic phase discarded. The aqueous phase was then poured rapidly into an oxidizing mixture with stirring, which was prepared as follows:

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

After the 6-a-bromopenicillanic acid solution was added to the oxidizing solution, a cooling bath of -15 ° C was kept around the reaction mixture. The internal temperature rose to 15 ° C and then dropped to 5 ° C over 20 min. Then 30.0 g of sodium metabisulfite was added under stirring in 10 minutes at about 10 ⁰ C. After a further 15 minutes, the mixture became

filtered and the pH of the filtrate by adding 170 ml of 6 η hydrochloric acid to 1.2. The aqueous phase was extracted with chloroform and then with ethyl acetate. Both the chloroform extract and the ethyl acetate extract were dried with anhydrous magnesium sulfate and then concentrated in vacuo. The chloroform solution provided 10.0 g (16% yield) of the title compound. The ethyl acetate solution provided 57 g of an oil which was triturated under hexane. A white solid appeared. It was filtered off to yield 41.5 g (66% yield) of the title compound, m.p. 134 ° C (dec.).

Analysis,%:

Calc. for CgH ₁₀ BrNO ₅ S: C 30.78, H 3.23, Br 25.60, N 4.49, S 10.27

Found: C 31.05, H 3.24, Br 25.54, N 4.66, S 10.21

Example 2

Oxidation of 6-a-chlorpenicillanic acid and 6-a-iodopenicillanic acid with potassium permanganate according to the procedure of Example 1 gives 6-a-chlorpenicillanic acid-i, 1-dioxide and 6-a-iodopenicillanic acid-1,1-dioxide, respectively.

Example 3 δ-β-chlorpenicillanic acid-i, 1-dioxide

An oxidizing solution was prepared from 185 mg of potassium permanganate, 0.063 ml of 85% phosphoric acid and 5 ml of water. This oxidation solution was added dropwise to a solution of 150 mg of sodium 6-.beta.-chloro-penicillanate in 5 ml of water at 0 to 5 C until the purple color of the potassium permanganate remained. About half of the oxidation solution was needed. At this point, the potassium permanganate color was removed by the addition of solid sodium bisulfite, and then the reaction mixture was filtered. The filtrate was ethyl

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acetate added and the pH adjusted to 1.8. The layers were separated and the aqueous layer further extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, dried and concentrated in vacuo to 118 mg of the title compound. The NMR spectrum (in CD ₃ COCD ₃ ) showed absorption at 5; 82 (d, 1 H), 5.24 (d, 1 H), 4.53 (s, 1 H), 1.62 (s, 3 H) and 1.50 (s, 3 H) ppm.

The above product was dissolved in tetrahydrofuran and an equal volume of water added. The pH was adjusted to 6.8 with dilute sodium hydroxide solution, the tetrahydrofuran was stripped off in vacuo and the remaining aqueous solution was freeze-dried. This provided the sodium salt of the title compound.

Example 4 6-β-bromopenicillanic acid-i, 1-dioxide

To a solution of 255 mg of sodium 6-β-bromopenicillanate in 5 ml of water at 0 to 5 C was added a solution consisting of 140 mg of potassium permanganate, 0.11 ml of 85% phosphoric acid and 5 ml of water at 0 to 5 ° C, had been produced. The pH was maintained between 6.0 and 6.4 during the addition. The reaction mixture was stirred for 15 min at pH 6.3 and then the purple solution was overlaid 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 over MgSO 4, and concentrated in vacuo. This provided 216 mg of the title compound as white crystals. The NMR spectrum (in D ₃ O) showed absorptions at 5.78 (d, 1 H, J = 4 Hz), 5.25 (d, 1 H, J = 4 Hz), 4.20 (s, 1 H), 1.65 (s, 3H) and 1.46 (s, 3H) ppm.

Example 5 6-3-iodopenicillanic acid i, 1-dioxide

Oxidation of 6-β-iodopenicillanic acid with potassium permanganate following the procedure of Example 4 yielded 6-β-iodopenicillanic acid 1,1-dioxide.

Example 6 Pivaloyloxymethyl-e-a-bromophenicillanate-i, 1-dioxide

To a solution of 394 mg of pivaloyloxymethyl-6-a-bromopenicillanate in 10 ml of methylene chloride is added 400 mg of 3-chloroperbenzoic acid at 0 to 5 ° C. The reaction mixture is stirred at 0 to 5 ° C for 1 h and then at 25 ° C for 24 h. The filtered reaction mixture is concentrated to dryness in vacuo / to afford the title compound.

Example 7

The procedure of Example 6 is repeated except that the pivaloyloxymethyl-6-β-bromopenicillanate is replaced with:

3-phthalidyl-6α-chloropenicillanate, 4-crotonolactonyl-6-β-chloropenicillanate, Y-butyrolactone-4-yl-6-α-bromopenicillanate, acetoxymethyl-6-β-bromopenicillanate, pivaloyloxymethyl-6-β-bromopenicillanate, Hexanoyloxymethyl-6-α-iodopenicillanate, 1- (acetoxy) ethyl-6-β-iodopentanecanate, 1- (isobutyryloxy) ethyl-6-α-chloropentanillanate, 1-methyl-1- (acetoxy) ethyl-6-β-chloropenicillanate , 1-methyl-1 - (hexanoyloxy) ethyl-6-a-bromophenicillanate, methoxycarbonyloxymethyl-6-a-brompenicillanate,

- 23 -

21 9432

Propoxycarbonyloxymethyl-e-.beta.-bromopenicillanate, 1- (ethoxycarbonyloxy) ethyl-6-a-bromopenicillanate, 1- (butoxycarbonyloxy) ethyl-6-.alpha.-iodopentanillanate, 1-methyl-1- (methoxycarbonyloxy) ethyl-6-3-iodopicillanate

1-Methyl-1- (isopropoxycarbonyloxy) ethyl-6-a-chlorpenicillanate This provides:

S-phthalidyl-α-a-chlorpenicillanate-i, 1-dioxide, 4-crotonolactonyl-6-β-chlorpenicillanate-1,1-dioxide, Y-butyrolactone-4-yl-6-a-bromopenicillanate-1,1- dioxide, acetoxymethyl-6-β-bromopenicillanate-i, 1-dioxide, pivaloyloxymethyl-6-β-bromophenicillanate-i, 1-dioxide, hexanoyloxymethyl-6-α-iodopenicillanate-1,1-dioxide, 1- (acetoxy) ethyl 6-.beta.-iodopicillanate 1,1-dioxide, 1- (isobutyryloxy) ethyl-6-a-chlorpenicillanate 1,1-dioxide, 1-methyl-1- (acetoxy) ethyl-6-.beta.-chlorpenicillanate-1 ,1-

dioxide, 1-methyl-1- (hexanoyloxy) ethyl-6-a-bromopenicillanate-1,1-

dioxide, methoxycarbonyloxymethyl-e-a-bromophenicillanate-i, 1-

dioxide, propoxycarbonyloxymethyl-6-β-bromophenicillanate-i, 1-

dioxide, 1- (ethoxycarbonyloxy) ethyl-6-a-bromopenicillanate-1,1-

dioxide, 1- (butoxycarbonyloxy) ethyl-6-α-iodopenicillanate-1,1-

dioxide, 1-methyl-1- (methoxycarbonyloxy) ethyl-6-β-iodopentanilanate

1,1-dioxide or 1-methyl-1- (isopropoxycarbonyloxy) ethyl-6-a-chlorpenicillanate-1,1-dioxide.

Example 8

Penicillanic acid 1,1-dioxide

To 100 ml of water was added 9.4 g of 6-a-bromopenicillanic acid i, 1

dioxide at 22 ° C, then enough 4 η sodium hydroxide solution to set a stable pH of 7.3. The solution obtained was admixed with 2.25 g of 5% Pd / C, then with 6.9 g of dipotassium phosphate trihydrate. This mixture was then shaken under a hydrogen atmosphere at a pressure between 3.43 and 1.76 bar (3.5 and 1.8 kp / cm). After the end of the hydrogen uptake, the solids were filtered off and the aqueous solution was covered with 100 ml of ethyl acetate. The pH was slowly lowered from 5.0 to 1.5 with 6N hydrochloric acid. The layers were separated and the aqueous phase extracted with more ethyl acetate. The combined ethyl acetate layers were washed with brine, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was triturated under ether and then the solid material was filtered off. This provided 4.5 g (65% yield) of the title compound.

Analysis,%:

calc. for CgH ₁₁ NO ₅ S: C 41.20, H 4.75, N 6.00, S 13.75

Found: C, 41.16, H, 4.81, N, 6.11, S, 13.51.

Example 9 Penicillanic Acid 1,1-dioxide

Hydrogenolysis of 6-a-chlorpenicillanic acid 1,1-dioxide, 6-a-iodopenicillanic acid 1,1-dioxide, 6-.beta.-chloropenicillanic acid-i, 1-dioxide, 6-.beta.-bromopenicillanic acid-i, 1-dioxide and 6-β-iodopenicillanic acid 1,1-dioxide

according to the procedure of Example 8 provides penicillanic acid 1,1-dioxide.

-25- 21943

Example 10 Pivaloyloxymethylpenicillanate 1,1-dioxide

To a solution of 1.0 g of pivaloyloxymethyl-6-a-bromopenicillanate in 10 ml of methanol is added 3 ml of 1M sodium bicarbonate and 200 mg of 10% Pd / C. The reaction mixture is shaken vigorously under a hydrogen atmosphere at a pressure of about 4.9 bar (5 kp / cm) until the hydrogen uptake ceases. The mixture is then filtered and the bulk of the methanol removed by stripping 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 over Na 2 SO 4 and concentrated in vacuo. This provides the title link.

Example 11

Hydrogenolysis of the appropriate 6-halo-penicillate ester 1,1-dioxide from Example 7 following the procedure of Example 10 provides the following compounds: 3-phthalidylpenicillanate 1,1-dioxide, 4-crotonolactonylpenicillanate 1,1-dioxide, Y-butyrolactone 4-ylpenicillanate 1,1-dioxide, acetoxymethylpenicillanate 1,1-dioxide, pivaloyloxymethylpenicillanate-I, 1-dioxide, hexanoyloxymethylpenicillanate-I, 1-dioxide, 1- (acetoxy) ethylpenicillanate 1,1-dioxide, 1- ( Isobutyryloxy) ethylenedicillanate 1,1-dioxide, 1-methyl-1- (acetoxy) ethylpenicillanate 1,1-dioxide, 1-methyl-1- (hexanoyloxy) ethylpenicillanate 1,1-dioxide, methoxycarbonyloxymethylpenicillanate 1,1- dioxide, propoxycarbonyloxymethylpenicillanate 1,1-dioxide, 1- (ethoxycarbonyloxy) ethylpenicillanate 1,1-dioxide, 1- (butoxycarbonyl) ethylenicillanate 1,1-dioxide,

1-methyl-1- (methoxycarbonyloxy) äthylpenicillanat-1,1-

dioxide or

 1-methyl-1- (isopropoxycarbonyloxy) äthylpenicillanat-1,1-dioxide.

Example 12 Pivaloyloxymethyl-e-a-bromophenicillanate-i, 1-dioxide

By combining 4.26 g of potassium permanganate, 2.65 g of 85% phosphoric acid and 40 ml of water, an oxidizing solution was prepared. The mixture was stirred for 1 h and then added slowly in 20 min at 5 to 10 ⁰ C to a stirred solution of 5.32 g of pivaloyloxymethyl ea-bromopenicillanate in 70 ml of acetone and 10 ml water. The mixture was stirred at 5 ° C for 30 min and 100 ml of ethyl acetate added. After a further 30 minutes, a solution of 3.12 g of sodium bisulfite in 30 ml of water was added at about 10 ^° C. for 15 minutes. Stirring was continued for 5 more 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 concentrated to 5.4 g of the title compound as an oil which slowly crystallized. The NMR spectrum (in _CDCl3) showed absorptions at 5.80 (q, 2 H), 5.15 (d, 1 H), 4.75 (d, 1 H), 4.50 (s, 1 H ), 1.60 (s, 3H), 1.40 (s, 3H), and 1.20 (s, 9H) ppm.

Example 13 Pivaloyloxymethylpenicillanate 1,1-dioxide

A solution of 4.4 g of pivaloyloxymethyl-6-cx-bromopenicillanate-1,1-dioxide in 60 ml of tetrahydrofuran was added to 0.84 g of sodium bicarbonate in 12 ml of water. The solution was placed under a hydrogen atmosphere in the presence of 2.0 g of 5% Pd / C

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shaken at 3.24 to 3.52 bar (47 to 51 psig) overpressure. The reaction mixture was then filtered and the residue washed with 100 ml of ethyl acetate and 25 ml of water. The filtrate and washings were separated after their combination. The organic layer was washed with saturated sodium chloride solution and dried (over MgSCK) and concentrated to give the title compound as an oil. This oil was dissolved in (20 ml) ethyl acetate. The solution was added slowly to (100 ml) hexane and the precipitate filtered off. Yield 2.4 g. The NMR spectrum (in DMSO-dg) showed absorptions at 5.75 (q, 2H), 5.05 (m, 1H), 4.40 (s, 1H), 3.95-2.95 (m, 2H), 1.40 (s, 3H), 1.25 (s, 3H), and 1.10 (s, 9H) ppm.

Example 14

2,2,2-trichloroethyl-6-α-bromopenicillanate 1,1-dioxide

2,2,2-Trichloroethyl-6-a-bromophenicillanate was oxidized with potassium permanganate in virtually the manner of the title compound in 79% yield. The NMR spectrum of the product (in CDCl ₃ ) showed absorbances at 5.30 to 4.70 (m, 4 H), 4.60 (s, 1 H), 1.70 (s, 3 H) and 1, 50 (s, 3 H) ppm.

Example 14A penicillanic acid 1,1-dioxide

To a stirred suspension of 6.5 g of zinc powder in 100 ml of a 70:30 glacial acetic acid / tetrahydrofuran mixture was added in portions 4.0 g of 2,2,2-trichloroethyl-6-a-bromopenicillanate-1,1- given dioxide. The mixture was

stirred for 3 h and then filtered. The filtrate was concentrated to a volume of 10 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 with magnesium sulfate and then concentrated to dryness in vacuo. The residue was triturated under ether for 20 min. This provided 553 mg of the title compound as a solid. The NMR spectrum (in CDCl ₃ / DMSO-dg) showed absorptions at 11.2 (broad, s, 1 H), 4.65 (m, 1 H), 4.30 (s, 1 H), 3, 40 (m, 2H), 1.65 (s, 3H) and 1.50 (s, 3H) ppm.

Example 15

Benzyl-6-a-bromopenicillanate 1,1-dioxide

Benzyl 6-a-bromophenicillanate was oxidized with potassium permanganate in 94% yield, practically according to the procedure of Example 12, to give the title compound. The NMR spectrum (in CDCl ₃ ) showed absorptions at 7.35 (s, 5H), 5.10 (m, 3H), 4.85 (m, 1H), 4.40 (s, 1H ), J, 50 (s, 3H) and 1.25 (s, 3H) ppm.

Example 16 Penicillanic Acid 1,1-dioxide

A solution of 4.0 g of benzyl 6-a-bromopenicillanate-1,1-dioxide in 50 ml of tetrahydrofuran was combined with a solution of 1.06 g of sodium bicarbonate in 50 ml of water. To the mixture was added 2.0 g of a 50% suspension of 5% Pd / C in water, then this mixture was added under a hydrogen atmosphere at a pressure of 3.21 to 3.45 bar (46.5 to 50 psig). Shaken for 20 minutes. The catalyst was then filtered off and 30 ml of tetrahydrofuran was added thereto.

- 29 - 21 943 2

furan and 3.0 g of a 50% suspension of 5% Pd / C added. The resulting mixture was shaken under a hydrogen atmosphere at a gauge pressure of 2.90 to 3.10 bar (42 to 45 psig) for 65 minutes. The reaction mixture was then filtered and the tetrahydrofuran 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 was further extracted with ethyl acetate, and the combined ethyl acetate solutions were washed with saturated sodium chloride solution and dried (over MgSO 4). Concentration in vacuo provided a resin which was triturated under ether. This provided 31 mg of penicillanic acid 1,1-dioxide as a yellow solid. The NMR spectrum (in _CDCl3 / DMSO-d _B) showed absorption at 9.45 (broad, s, 1 H), 4.60 (t, 1 H), 4.25 (s, 1 H), 3 , 40 (d, 2H), 1.65 (s, 3H) and 1.30 (s, 3H) ppm.

Example 17 6,6-Dibromopenicillanic Acid 1,1-dioxide

To the dichloromethane solution of 6,6-dibromopenicillanic acid from Preparation K was added 300 ml of water, followed by dropwise addition of 105 ml of 3N sodium hydroxide over 30 minutes. The pH stabilized at 7.0. The aqueous layer was removed and the organic layer extracted with (2 x 100 ml) water. To the combined aqueous solutions at -5 ° C was added a premix solution prepared from 59.25 g of potassium permanganate, 18 ml of concentrated phosphoric acid and 600 ml of water until the pink color of the permanganate remained. The addition required 50 minutes and 550 ml of oxidizer was needed. At this point, 500 ml of ethyl acetate was added, and

then the pH was lowered to 1.23 by adding 105 ml of 6N hydrochloric acid. Then 250 ml of 1 M sodium bisulfite were added over 10 to 15 minutes at about 10 ^° C. During the addition of the sodium bisulfite solution, the pH was kept at 1.25 to 1.35 using 6 η 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 × 150 ml) and the combined ethyl acetate solutions were washed with brine and dried (over MgSO 4). This provided an ethyl acetate solution of 6,6-dibromophenicillanic acid 1,1-dioxide.

The 6,6-dibromophenicillanic acid, 1,1-dioxide can be isolated by stripping off the solvent in vacuo. Such a sample isolated from an analogous preparation had a mp. Of 201 ⁰ C (dec.). The NMR spectrum (CDClj / DMSO-dg) showed absorptions at 9.35 (s, 1H), 5.30 (s, 1H), 4.42 (s, 1H), 1.63 (s, 3 H) and 1.50 (s, 3 H) ppm. The IR spectrum (KBr compact) showed absorptions at 3846 to 2500, 1818, 1754, 1342 and 1250-1110 cm ^-1 .

Example 18

6-chloro-6-iodopenicillanic acid 1,1-dioxide

To a solution of 4.9 g of 6-chloro-6-iodopicillanic acid in 50 ml of methylene chloride was added 50 ml of water, and then the pH was raised to 7.2 with 3N sodium hydroxide. The layers were separated and the aqueous layer cooled to 5 ° C. To this solution was then dropped, over 20 minutes, a premix solution prepared from 2.61 g of potassium permanganate, 1.75 ml of concentrated phosphoric acid and 50 ml of water. The pH at the addition was kept at 6 and the temperature below 10 ⁰ C. At this point, 100 ml of ethyl acetate was added and the pH was adjusted to 1.5. To this mixture was then added 50 ml of 10% sodium bisulfite,

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wherein the temperature below 10 ⁰ C and the pH was maintained by the addition of 6 η hydrochloric acid at about 1.5. 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 (over MgSO ₄ ) and concentrated in vacuo to 4.2 g of the title compound, mp 143-145 ° C. The NMR spectrum (CDCl ₃ ) showed absorptions at 4.86 (s, 1 H), 4.38 (s, 1 H), 1.60 (s, 3 H), and 1.43 (s, 3 H). ppm. The IR spectrum (KBr pellet) showed absorptions at 1800, 1740 and 1250-1110 cm

Example 19

6-bromo-6-iodopenicillanic acid 1,1-dioxide

To a solution of 6.0 g of 6-bromo-6-iodopicillanic acid in 50 ml of methylene chloride was added 50 ml of water. The pH was raised to 7.3 with 3N sodium hydroxide and the aqueous layer removed. The organic layer was extracted with 10 ml of water. The combined aqueous phases were cooled to 5 ° C, and a premixed solution of 284 g of potassium permanganate in 2 ml of concentrated phosphoric acid and 50 ml of water was added dropwise between 5 and 10 ⁰ C. The addition took 20 minutes. Then, 50 ml of ethyl acetate was added, and the pH of the mixture was lowered to 1.5 with 6N hydrochloric acid. To this two-phase system, 50 ml of 10% sodium bisulfite was added dropwise, 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 aqueous layer was saturated with sodium chloride. The saturated solution was extracted with ethyl acetate (3 × 50 ml) and the combined ethyl acetate layers were washed with brine, dried over MgSO ₄ and concentrated in vacuo.

The residue was dried under high vacuum to yield 4.2 g of the title compound, mp 145-147 ° C. The NMR spectrum (CDCl ₃ ) showed absorptions at 4.90 (s, 1 H), 4.30 (s, 1 H), 1.60 (s, 3 H), and 1.42 (s, 3 H). ppm. The IR spectrum (KBr pellet) showed absorptions at 1800, 1740, 1330 and 1250-1110 cm ^-1 .

Example 20

ö-chloro-ö-bromopenicillanate-i, 1-dioxide

Oxidation of 6-chloro-6-bromopenicillanic acid with potassium permanganate following the procedure of Example 19 yielded e-bromo-1-enhenicillanic acid 1,1-dioxide.

Example 21 Penicillanic Acid 1,1-dioxide

The ethyl acetate solution of 6,6-dibromophenicillanic acid-i, 1-dioxide from Example 17 was combined with 705 ml of saturated sodium bicarbonate solution and 8.88 g of 5% Pd / C catalyst. The mixture was added under a hydrogen atmosphere

2 a pressure of about 4.9 bar (about 5 kgf / cm) shaken for about 1 h. 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 was saturated with sodium chloride. The layers were separated and the aqueous phase extracted with more ethyl acetate (3 × 200 ml). The combined ethyl acetate solutions were dried (over MgSO 4) and concentrated in vacuo to 33.5 g (58% yield of 6-aminopenicillanic acid) penicillanic acid 1,1-dioxide. This product was dissolved in 6 00 ml of ethyl acetate, the solution was decolorized with charcoal and the solvent removed in vacuo. The product was washed with hexane. This yielded 31.0 g of pure product. >

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Example 22

Hydrogenolysis of G-chloro-δ-iodopicillanic acid-i, 1-dioxide, 6-bromo-6-iodopicillanic acid and 6-chloro-6-bromopenicillanic acid following the procedure of Example 21 provided penicillanic acid 1,1-dioxide in each case.

Example 23 Penicillanic Acid 1,1-dioxide

To a stirred suspension of 786 mg of 6-chloro-6-iodopicillanic acid 1,1-dioxide in 10 ml of benzene was added 0.3 ml of triethylamine, then 0.25 ml of trimethylsilyl chloride at about 0 ^° C. It was stirred for a further 5 min at about 0 ⁰ C and then at reflux temperature of the solvent for 30 min. The reaction mixture was cooled to 25 ° C and the precipitated material was filtered off. The filtrate was cooled to about 0 C and 1.16 g of tri-n-butyltin hydride and a few mg of azobisisobutyronitrile were added. The reaction mixture was stirred and irradiated with UV light for 1 h at about 0 ⁰ C and then 3.5 h at reflux temperature of the solvent. An additional amount (1.1 ml) of tri-n-butyltin hydride and a catalytic amount of azobisisobutyronitrile were added and stirred for a further hour at reflux temperature and irradiated. The reaction mixture was then poured into 50 ml of cold, 5% sodium bicarbonate solution and the two-phase system was stirred for 30 minutes. 50 ml of ethyl acetate were 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 over MgSO ₄ and concentrated in vacuo. The residue was triturated under hexane and then recovered by filtration. This provided 0.075 mg of the title compound.

- 34 Example 24 Penicillanic acid 1,1-dioxide

To a stirred suspension of 0.874 g of 6-bromo-6-iodopenicillanic acid 1,1-dioxide in 10 ml of benzene at about 5 ° C was added 0.3 ml of triethylamine, then 0.25 ml of trimethylsilyl chloride. At about 5 C was stirred for a further 5 min, then 30 min at reflux temperature of the solvent. The reaction mixture was cooled to room temperature and the solids were filtered off. The filtrate was cooled to ca. 5 C and 1.05 ml of tri-n-butyltin hydride and a catalytic amount of azobisisobutyronitrile were added. The mixture was irradiated with UV light for 1 h at about 5 ° C, and then poured into 30 ml of cold, 5% sodium bicarbonate solution. 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 (2 × 25 ml) ethyl acetate, and the combined ethyl acetate layers were washed with brine, dried over MgSCK, and concentrated in vacuo. The residue was dried under high vacuum and 30 ml of hexane was added. The insoluble material was filtered off to give 0.035 g of the title compound.

Example 25

Pivaloyloxymethyl-6,6-dibrompenicillanat-i, 1-dioxide

To a solution of 4.73 g of pivaloyloxymethyl-6,6-dibromophenicillanate in 15 ml of methylene chloride is added 3.80 g of 3-chloroperbenzoic acid at 0 to 5 ° C. The reaction mixture is stirred at 0 to 5 ° C for 1 h and then at 25 ° C for 24 h. The filtered reaction mixture was concentrated to dryness in vacuo and the residue was 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

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dried over Na ₃ SO ₄ ) and concentrated in vacuo to the title compound.

example

Oxidation of each of the 6,6-dihalo-penicillanic acid esters of Preparation P using 3-chloroperbenzoic acid following the procedure of Example 25 provides the following compounds:

3-Phthalidyl-6,6-dibromophenicillanate-1,1-dioxide, 4-crotonolactonyl-6-chloro-6-iodopenicillanate-1,1-dioxide, Y-butyrolactonyl-e-bromo-e-iodopicillanate-i, 1 dioxide, acetoxymethyl-o-chloro-e-bromophenicillanate-i, 1-dioxide, pivaloyloxymethyl-o-chloro-e-iodopicillanate-i, 1-dioxide, hexanoyloxymethyl-6,6-dibromophenicillanate-i, 1-dioxide, 1 (Acetoxy) ethyl-6,6-dibromophenicillanate-i, 1-dioxide, 1- (isobutyryloxy-ethyl-e-bromo-o-iodopicillanate-i, 1

dioxide, 1-methyl-1- (acetoxy) ethyl-6,6-dibromophenicillanate-i, 1-dioxide,

1-methyl-1- (hexanoyloxy) ethyl-o-chloro-o-bromo-penicillanate, methoxycarbonyloxymethyl-6,6-dibropenicillanate-1,1-

dioxide, propoxycarbonyloxymethyl-e-chloro-δ-iodopenicillanate

1,1-dioxide, 1- (ethoxycarbonyloxy) ethyl-6,6-dibromophenicillanate-i, 1-

dioxide, 1- (butoxycarbonyloxy-ethyl-e-bromo-e-iodopicillanate

1,1-dioxide, 1-methyl-1- (methoxycarbonyloxy) ethyl-ei-dibromo-penicillanate

1,1-dioxide or 1-methyl-i- (isopropoxycarbonyloxy) ethyl-6,6-dibromo-penicillanate-1,1-dioxide.

- 36 - 'Example 27 Pivaloyloxymethylpenicillanate 1,1-dioxide

To a solution of 1.0 g of pivaloyloxymethyl-1,6,6-dibromophenicillanate-1,1-dioxide in 10 ml of methanol are added 3 ml of 1 M t-sodium bicarbonate and 200 mg of 10% Pd / C. The reaction mixture is shaken vigorously under a hydrogen atmosphere at a pressure of about 4.9 bar (5 kp / cm) until the hydrogen uptake ceases. The mixture is then filtered and the bulk of the methanol removed 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 washed with water, dried (over Na ₂ SO ₄ ) and concentrated in vacuo. This provides pivaloyloxymethylpenicillanate-1,1-dioxxd.

Example 28

Hydrogenolysis of the 6,6-dihalo-penicillanic acid ester 1,1-dioxides from Example 26 by the procedure of Example 27 provides the following compounds:

3-phthalidyl penicillanate 1,1-dioxide, 4-crotonolactonylpenicillanate 1,1-dioxide, Y-butyrolactone-4-ylpenicillanate 1,1-dioxide, acefcoxymethylpenicillanate 1,1-dioxide, pivaloyloxymethylpenicillanate 1,1- dioxide, Hexaixoy loxymethyl lypicillanate-1, 1-dioxide, 1- (ethoxy) ethylenicillanate 1,1-dioxide, 1- (isobutyryloxy) ethylenedicillanate 1,1-dioxide, 1-methyl- (acetoxy) ethylpenicillanate-1,1 dioxide, 1-methyl-1- (hexanoyloxy) ethylpenicillanate 1,1-dioxide, methoxycarbonyloxymethylpenicillanate 1,1-dioxide,

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Propoxycarbonyloxymethylpenicillanate-I, 1-dioxide, 1- (ethoxycarbonyloxy) ethylpenicillanate 1,1-dioxide, 1- (butoxycarbonyl) ethylpenicillanate 1,1-dioxide, 1-methyl-1- (methoxycarbonyloxy) ethylpenicillanate 1,1-

dioxide or

 1-methyl-1- (isopropoxycarbonyloxy) äthylpenicillanat-1,1-dioxide.

Example 29 Pivaloyloxymethyl-ejodibrompenicillanate-i, 1-dioxide

A stirred solution of 3.92 g of 6,6-dibromopenicillanic acid 1,1-dioxide in 20 ml of Ν, Ν-dimethylformamide was cooled to 0 ° C and then 1.29 g of diisopropylethylamine was added. This was followed by 1.51 g of chloromethyl pivalate. This reaction mixture was stirred at OC for 3 h, then at room temperature for 16 h. 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 extracted with ethyl acetate. The combined ethyl acetate layers were washed with cold 5% sodium bicarbonate solution, water and brine. The ethyl acetate solution was then treated with charcoal (Darco), dried (over MgSO ₄ ) and concentrated in vacuo to 2.1 g of a brown oil. This oil was chromatographed on 200 g of silica gel using methylene chloride as eluent. The fractions containing the desired product were combined and rechromatographed on silica gel to give 0.025 g of the title compound. The NMR spectrum (CDCl ₃ ) showed absorptions at 6.10 (q, 2H), 5.00 (s, 1H), 4.55 (s, 1H), 1.60 (s, 3H) , 1.50 (s, 3H) and 1.15 (s, 9H) ppm.

- 38 - £ Example 30 Pivaloyloxymethylpenicillanate 1,1-dioxide

To a stirred solution of 6 0 mg of pivaloyloxymethyl-6,6-dibromophenicillanate-i, 1-dioxide in 5 ml of benzene was added 52 μg of tri-n-butyltin hydride, then a catalytic amount of azobisisobutyronitrile. The reaction mixture was cooled to 5 ° C and then irradiated with UV light for 1 h. 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 further extracted with ethyl acetate. The combined ethyl acetate solutions were washed with brine, dried (over MgSO 4) and concentrated in vacuo. The residue was dried under high vacuum for 30 min. This afforded 70 mg of a yellow oil which by NMR spectroscopy contained the title compound along with some impurities having n-butyl groups.

Example 31 ^

6.6-dibromopenicillanic 1,1-dioxide

To a solution of 359 mg of 6,6-dibromopenicillanic acid in 30 ml of methylene chloride is added 380 mg of 3-chloroperbenzoic acid at 0 to 5 ° C. The reaction mixture is stirred at 0 to 5 ° C for 30 minutes and then at 25 ° C for 24 hours. The filtered reaction mixture is concentrated in vacuo to the title compound.

Example 32

Benzyl-6,6-dibrompenicillanat-i, 1-dioxide

A mixture of 10.0 g of 6,6-dibromophenicillanic acid 1,1-dioxide,

2.15 g of sodium bicarbonate, 3.06 ml of benzylbromide and 100 ml of Ν, Ν-dimethylformamide were stirred at room temperature overnight. Most of the solvent was removed by vacuum stripping and the residue was partitioned between ethyl acetate and water. The organic layer was removed, washed with 1N hydrochloric acid and with saturated sodium chloride solution and dried (over Na 2 SO 4). Concentration in vacuo afforded 11.55 g of the title compound. The NMR spectrum (in CDCl ₃ ) showed absorptions 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 33 Penicillanic Acid 1,1-dioxide

To a solution of 2.0 g of benzyl-6,6-dibromophenicillanate-1,1-dioxide in 50 ml of tetrahydrofuran was added a solution of 0.699 g of sodium bicarbonate in 50 ml of water, then 2.0 g of 5% Pd / C. This mixture was shaken under a hydrogen atmosphere at about 3.45 bar (50 psig) pressure for 70 minutes. The tetrahydrofuran was evaporated and the residue partitioned between ethyl acetate and water at pH 7.37. The aqueous layer was removed and fresh ethyl acetate added. The pH was lowered to 1.17 and the ethyl acetate removed and washed with saturated sodium chloride solution. Evaporation in vacuo provided 423 mg of the title compound.

Example 34

2,2,2-trichloroethyl 6,6 dibrompenicillanat 1,1-dioxide

The title compound was prepared from 6,6-dibromopenicillanic acid-1,1-

dioxide and 2,2,2-trichloroethyl chloroformate, essentially according to the procedure of Preparation J, produced *. The product was purified by chromatography on silica gel. The NMR spectrum of the product (in CDCl ₃ ) showed absorptions at 4.85 (m, 2H), 1.65 (s, 3H), and 1.45 (s, 3H) TpM.

Example 35 ·

Penicillanic acid 1,1-dioxide

2,2,2-Trichloroethyl-6,6-dibromophenicillanate-1,1-dioxide was prepared with zinc dust in a mixture of glacial acetic acid and tetrahydrofuran, practically according to Example 14A. The yield was 27%.

Example 36

1- (ethoxycarbonyloxy) ethyl 6,6-dibromophenicillanate 1, 1-dioxide.

A mixture of 2.26 g of 6,6-dibromophenicillanic acid-i, 1-dioxide, 1.02 ml of 1- (ethoxycarbonyloxy) ethyl chloride, 1.32 ml of diisopropylethylamine and 10 ml of N, N-dimethylformamide was stirred at room temperature for 28 hours. The reaction mixture was diluted with 100 ml of ethyl acetate, and then washed successively with water, dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The dried ethyl acetate solution was concentrated in vacuo to 1.50 g of an oil which was chromatographed on silica gel. This provided 353 mg of the title compound contaminated with some 1- (ethoxycarbonyloxy) ethyl-6-bromopenicillanate.

2 t 943 2

Example 37

1- (ethoxycarbonyloxy) äthylpenicillanat-1,1-dioxide

A portion (230 mg) of the product of Example 36 was dissolved in 10 ml of toluene. To this was added 0.4 ml of tri-n-butyltin hydride, then added 0.164 g of azobisisobutyronitrile, and the mixture was heated 3.5 hours at 70 to 80 ⁰ C. The solvent was removed in vacuo and the residue was dissolved in 25 ml of acetonitrile. The acetonitrile solution was washed several times with hexane and then concentrated in vacuo. The residue was dissolved in ether and the ether solution washed with 5% potassium fluoride and then with saturated sodium chloride solution. The (over Na-SO.) Dried ether solution was concentrated in vacuo and the residue chromatographed on silica gel to 0.043 g of the title compound. The NMR spectrum (in CDCl ₃ ) showed absorptions at 6.75 (m), 4.60 (m), 4.30 (m), 4.15 (s), 4.00 (s), 3.30 (d) and 1.75-1.00 (m) ppm.

Production A

6- ¹ chloro-6-iodopenicillanic acid

To 3.38 g of iodine monochloride in 30 ml of methylene chloride were added with stirring at 0 to 5 ° C 11.1 ml of 2.5 η sulfuric acid, then 1.92 g of sodium nitrite. Then, 3.00 g of 6-aminopenicillanic acid was added all at once, and stirring was continued at 0 to 5 ° C for 30 minutes. To the reaction mixture was then added 22.8 ml of 1 M sodium sulfite solution in portions, and the layers were separated. The aqueous layer was washed with more methylene chloride and then all organic phases were washed with saturated sodium chloride solution. The methylene chloride solution was dried (over Na ₃ SO ₄ ) and concentrated in vacuo to give 3.48 g of the title compound.

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

Production B '.

6-beta-chloropenicillanate

A 2.95 g sample of sodium 6-chloro-6-iodopenicillanate was transferred to the free acid and then dissolved in 125 ml of benzene under nitrogen. This solution was added with 1.08 ml of triethylamine, and the mixture was cooled to 0 to 5 ° C. 0.977 ml of trimethylsilyl chloride were then added to the cooled mixture, and the reaction mixture was stirred for 5 min at 0 to 5 ° C, 60 min at 25 ° C and 30 min at 50 ⁰ C. The reaction mixture was cooled to 25 ° C and filtered off the triethylamine hydrochloride. The filtrate was mixed with 15 mg of azobisisobutyronitrile, then with 2.02 ml of tri-n-butyltin hydride. The mixture was then irradiated with UV light for 15 minutes with cooling to keep at a temperature of about 20 ^° C. The solvent was then removed in vacuo and the residue dissolved in a 1: 1 mixture of tetrahydrofuran and water. The pH was adjusted to 7.0 and the tetrahydrofuran was removed 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 more ethyl acetate, and then the combined ethyl acetate solutions were dried

- 43 - 21 9432

and concentrated in vacuo. This provided 980 mg of 6-β-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 in vacuo. The remaining aqueous phase was freeze-dried to yield 850 mg of sodium .beta.-.beta.-chlorpenicillanate. The NMR spectrum (DO) showed absorption at 5.70 (d, 1 H, J = 4 Hz), 5.50 (d, 1 H, J = 4 Hz), 4.36 (s, 1 H), 1.60 (s, 3H) and 1.53 (s, 3H) ppm.

Preparation C 6-β-bromopenicillanic acid

A mixture of 5.0 g of 6,6-dibromopenicillanic acid, 1.54 ml of triethylamine and 100 ml of benzene was stirred under nitrogen until solution was obtained. The solution was cooled to 0 to 5 ° C and 1.78 ml of trimethylsilyl chloride was added. The reaction mixture was stirred at 0 to 5 ° C for 2 to 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 azobisisobutyronitrile was added, then 3.68 ml of tri-n-butyltin hydride. The reaction flask was irradiated with UV light for 15 minutes, and then the reaction mixture was stirred at about 25 ° C for 1.75 hours. The reaction mixture was irradiated again for 15 minutes and then stirred for a further 2.5 hours. Then a small amount of azobisisobutyronitrile was added, then 0.6 ml of tri-n-butyltin hydride (0.6 ml) was added and the mixture was irradiated again for 30 minutes. The solvent was then removed in vacuo and to the residue was added 5% sodium bicarbonate solution and diethyl ether. The two-phase system was vigorous for 10 min

shaken and then the pH was adjusted to 2.0. The ether layer was removed, dried and concentrated in vacuo to 2.33 g of an oil. The oil was converted to the sodium salt by adding water with 1 equivalent of sodium bicarbonate and then freeze-drying the resulting solution. This provided sodium 6-β-bromophenicillanate contaminated with a small amount of the α-isomer.

The sodium salt was chromatographed on a cross-linked dextran gel (Sephadex LH-20), combined with a little more material of the same quality, and then rechromatographed. The NMR spectrum (D ₂ O) of the product thus obtained showed absorptions at 5.56 (s, 2H), 4.25 (s, 1H), 1.60 (s, 3H) and 1.50 ( s, 3 H) TpM.

Preparation D 6-.beta.-iodopenicillanic acid

The title compound is prepared by reduction of 6,6-diiodopicillanic acid with tri-n-butyltin hydride according to the procedure of Preparation B.

Preparation E Pivaloyloxymethyl-e-a-bromopenicillanate

To a solution of 280 mg of 6-a-bromopenicillanic acid in 2 ml of N, N-dimethylformamide are added 260 mg of diisopropylethylamine, then 155 mg of chloromethyl pivalate and 15 mg of sodium iodide. The reaction mixture is stirred at room temperature for 24 h and then diluted with ethyl acetate and water. The pH is adjusted to 7.5 and then 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 with anhydrous sodium sulfate and concentrated in vacuo to the title compound.

Production F

The reaction of the appropriate 6-halo-penicillanic acid with 3-phthalidyl chloride / 4-crotonolactonyl chloride, γ-butyrolactone-4-yl chloride or the requisite alkanoyloxymethyl chloride, 1- (alkanoyloxy) ethyl chloride, 1-methyl-1- (alkanoyloxy) ethyl chloride, alkoxycarbonyloxymethyl chloride, 1- (Alkoxycarbonyloxy) ethyl chloride or 1-methyl-1- (alkoxycarbonyloxy) ethyl chloride according to the procedure of Preparation E provides the following compounds:

S-phthalidyl-α-a-chlorpenicillanate, 4-crotonolactonyl-6-β-chloropenicillanate, Y-butyrolactone-4-yl-6-a-bromopenicillanate, acetoxymethyl-G-β-bromopenicillanate / pivaloyloxymethyl-6-β-bromopenicillanate, Hexanoyloxymethyl-1-6-α-iodopentanillanate, 1- (acetoxy) ethyl-6-β-iodopenicillanate, 1- (isobutyryloxy) ethyl-α-α-chloropenicillanate, 1-methyl-1- (acetoxy) ethyl-6-β-chloropenicillanate , 1-methyl-1- (hexanoyloxy) ethyl-6-a-bromopenicillanate, methoxycarbonyloxymethyl-o-a-bromopenicillanate, propoxycarbonyloxymethyl-6-β-bromopenicillanate, 1- (ethoxycarbonyloxy) ethyl-6-a-bromophenicillanate, 1-butoxycarbonyloxy ) ethyl 6-a-iodopicillanate, 1-methyl-1- (methoxycarbonyloxy) ethyl-6-β-iodopentanilanate

1-methyl-1- (isopropoxycarbonyloxy) ethyl-ö-a-chloropenicillanate.

Production G

6.6-Dijodpenicillansäure

A mixture of 15.23 g of iodine, 10 ml of 2.5 N sulfuric acid, 2.76 g of sodium nitrite and 75 ml of methylene chloride was stirred at 5 ° C and 4.32 g of 6-aminopenicillanic acid were added over 15 min.

  - 46 - /

puts. At 5 to 10 ⁰ C was stirred for a further 45 minutes after the addition was complete, and then 100 ml of 10% sodium bisulfite solution were added dropwise. The layers were separated and the aqueous layer was further extracted with methylene chloride. The combined methylene chloride layers were washed with brine, dried over MgSO ₄ and concentrated in vacuo. This provided 1.4 g of the title compound contaminated with some 6-iodopicillanic acid. The product had a melting point of 58 to 64 ° C. The NMR spectrum (CDCl ₃ ) showed absorptions at 5.77 (s, 1 H), 4.60 (s, 1 H), 1.71 (s, 3 H), and 1.54 (s, 3 H). ppm.

Preparation H Pivaloyloxymethyl-α-a-bromopenicillanate

To a stirred mixture of 11.2 g of 6-a-bromopenicillanic acid, 3.7 g of sodium bicarbonate and 4 ml of N, N-dimethylformamide was added dropwise at room temperature over a period of 5 minutes to 6.16 g of chloromethyl pivalate. Stirring was continued for 66 hours and then the reaction mixture was diluted with 100 ml of ethyl acetate and 100 ml of water. The layers were separated and the ethyl acetate layer was washed successively with water, saturated sodium chloride solution, saturated sodium bicarbonate solution, water and saturated sodium chloride solution. The discolored ethyl acetate solution was dried (over MgSO 4) and concentrated to dryness in vacuo. This provided 12.8 g (80% yield) of the title compound.

Production I

Benzyl-6-a-bromopenicillanate

The title compound was prepared by esterification of 6-a-bromopenicillanic acid with benzyl bromide practically according to the procedure of Preparation H (Yield 83%).

The NMR spectrum (in _CDCl3) showed absorptions at 1 7/35 (s, 5 H), 5.35 (m, 1 H), 5.15 (s, 2 H), 4.70 (m, H ), 4.60 (s, 1H), 1.55 (s, 3H), and 1.35 (s, 3H) ppm.

Production J

2,2,2-Trichloräthylpenicillanat

To a stirred solution of 11.2 g of 6-cx-bromopenicillanate in 50 ml of tetrahydrofuran at 0 ⁰ C were added 3.48 g of pyridine h for 1 hour. 8.45 g of 2,2,2-trichloroethyl chloroformate were added over 10 minutes to the cloudy solution so obtained, the temperature being kept between 0 and 2 ° C. Stirring was continued for a further 30 minutes and then the cooling bath was removed. Stirring was continued overnight at room temperature. The reaction mixture was then warmed to 35 ° C for 5 minutes and then filtered. The filtrate was concentrated and the residue was dissolved in 100 ml of ethyl acetate. The ethyl acetate solution was then washed successively with saturated sodium bicarbonate solution, water and saturated sodium chloride solution. The ethyl acetate solution was then decolorized and dried and concentrated to a small volume. To the resulting mixture wurclen 100 ml of hexane was added and the solids were filtered and yielded 10.5 g of the title compound, mp. 105-110 ⁰ C. The nmr spectrum showed (in CDCl ₃₎ absorptions at 5.50 (d, 1H), 4.95 (d, 1H), 4.90 (s, 2H), 4.65 (s, 1H), 1.70 (s, 3H) and 1.55 (s, 3 H) TpM.

Production K

6.6-dibromopenicillanic

To 500 ml of methylene chloride, cooled to 5 ° C, 119.9 g of bromine, 200 ml of 2.5 η sulfuric acid and 34.5 g of sodium nitrite were added. This stirred mixture was then treated with 54.0 g of 6-aminopenicillanic acid in portions over 30 minutes,

wherein the temperature was maintained at 4 to 10 ⁰ C. The mixture was further stirred for 30 minutes at 5 ° C, and then 410 ml of a 1.0 M sodium bisulfite solution were added dropwise at 5-10 ⁰ C over 20 min. The layers were separated and the aqueous layer was extracted twice with 150 ml of methylene chloride. The original methylene chloride layer was combined with the two extracts to a solution of 6,6-dibromopicicanoic acid. This solution was used directly in Example 17.

Production L

6-chloro-6-iodopenicillanic acid

To 100 ml of methylene chloride, cooled to 3 ° C, were added 4.87 g of iodine chloride, 10 ml of 2.5 N sulfuric acid and 2.76 g of sodium nitrite. This stirred mixture was then added with 4.32 g of 6-aminopenicillanic acid in portions over 15 minutes. The mixture was further stirred for 20 minutes at 0 to 5 ° C, and then 100 ml of 10% sodium bisulfite solution were added dropwise at about 4 ° C. Stirring was continued for a further 5 minutes and then the layers were separated. The aqueous layer was extracted with methylene chloride (2 × 50 ml) and the combined methylene chloride solutions were washed with brine, dried over MgSO 4, and concentrated in vacuo to give the title compound as a tan solid, mp 148-152 ° C NMR spectrum of the product (CDCl ₃ ) showed absorptions at 5.40 (s, 1 H), 4.56 (s, 1 H), 1.67 (s, 3 H), and 1.50 (s, 3 H ) TpM The IR spectrum (KBr compact)

_1 showed absorptions at 1780 and 1715 cm.

Production M

6-bromo-6-iodopenicillanic acid

To 100 ml of methylene chloride, cooled to 5 ° C, 10 ml of 2.5 η

219432

Sulfuric acid, 6.21 g of iodobromide and 2.76 g of sodium nitrite. This mixture was added with vigorous stirring

0 to 5 ° C in 15 min with 4.32 g of 6-aminopenicillanic acid. The mixture was stirred for a further 20 min'bei 0 to 5 ° C, then 100 ml of 10% sodium bisulfite solution were added dropwise between 0 and 10 ⁰ C. Then the layers were separated and the aqueous layer was extracted with (3 × 50 ml) methylene chloride. The combined methylene chloride layers were washed with brine, dried over MgSO 4, and concentrated in vacuo. The residue was dried under high vacuum for 30 minutes to yield 6.0 g (72% yield) of the title compound, mp 144-147 ° C. The NMR spectrum (CDCl ₃ ) showed absorptions at 5.50 (s, 1 H), 4.53 (s,

1 H), 1.70 (s, 3 H) and 1.53 (s, 3 H) ppm. The IR spectrum (KBr pellet) showed absorptions at 1785 and 1710 cm. The mass spectrum showed a prominent ion at m / e = 406.

Preparation of N-chloro-e-bromopenicillanic acid

G-chloro-o-bromophenicillanic acid is prepared from 6-aminopenicillanic acid via the diazotization and subsequent reaction with bromine chloride according to the procedure of Preparation M.

Production 0

Pivaloyloxymethyl-6,6-dibrompenicillanat

To a stirred solution of 3.59 g of 6,6-dibromopenicillanic acid in 20 ml of Ν, Ν-dimethylformamide are added 1.30 g of diisopropylethylamine, then 1.50 g of chloromethyl pivalate at about 0 ° C. The reaction mixture is stirred at about 0 ^° 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

- so - 2 1 ^ 43 2

acetate layer is separated and washed three times with water and once with saturated sodium chloride solution. The ethyl acetate solution is then dried with anhydrous sodium sulfate and concentrated in vacuo to the title compound.

Production P

Reacting the appropriate 6,6-dihalopenicillanic acid with 3-phthalidyl chloride, 4-crotonolactonyl chloride, γ-butyrolactone-4-yl chloride or the required alkanoyloxymethyl chloride, 1- (alkanoyloxy) ethyl chloride, 1-methyl-1- (alkanoyloxy) ethyl chloride, alkoxycarbonyloxymethyl chloride, 1 - (Alkoxycarbonyloxy) ethyl chloride or 1-methyl-1- (alkoxycarbonyloxy) ethyl chloride according to the procedure of preparation O provides the following compounds:

3-Phthalidyl-1,6-dibromophenicillanate, 4-crotonolactonyl-6-chloro-6-iodopenecanate, Y-butyrolactonyl-6-bromo-6-iodopentanecanate, acetoxymethyl-e-chloro-e-bromopenicillanate, pivaloyloxymethyl-e-chloro ö-iodopicillanate, hexanoyloxymethyl-6,6-dibromophenicillanate, 1- (acetoxy) ethyl-6,6-dibromophenicillanate, 1- (isobutyryloxy) ethyl-6-bromo-6-iodopentanecanate, 1-methyl-1- (acetoxy) ethyl -6,6-dibromophenicillanate, 1-methyl-1- (hexanoyloxy) ethyl-e-chloro-o-bromophenicillanate, methoxycarbonylmethy1-6,6-dibromophenicillanate, propoxycarbonyloxymethyl-6-chloro-6-iodopentanecanate, 1- (ethoxycarbonyloxy) ethyl -6,6-dibromophenicillanate, 1- (butoxycarbonyloxy) ethyl-6-bromo-6-iodopenicillanate, 1-methyl-1 ~ (methoxycarbonyloxy) ethyl-6,6-dibromophenicillanate and

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

Claims (1)

3. 9. 1980 AP C 07 D / 219 432 57 108 18 21943 2 invention claim 1 · Process for the preparation of a compound of the formula HOO
* S "'COOR ¹ or their pharmaceutically acceptable base salts, wherein R is hydrogen or an ester-forming, in vivo readily hydrolyzable radical, characterized in that a compound of the formula HOO or their base salt, wherein R is hydrogen, an ester-forming in vivo easily hydrolyzable group or a conventional penicillin carboxy-protecting group, and X and Y are each hydrogen, chlorine, bromine or iodine, with the proviso that when X and Y are both the same They all have to be bromine, dehalogenated and, if necessary, the conventional penicillin carboxy protective group is split off · - 52 - £ I 3 2β Process according to item 1, characterized in that the dehalogenation was carried out by catalytic hydrogenolysis 3ö method according to item 2, characterized in that the catalytic hydrogenolysis is carried out in an inert solvent * 4 "Process according to item 2 or 3", characterized in that the catalytic hydrogenolysis is carried out at a pressure in the range from about 0.98 to 98 bar (1 to 100 kp / cm ² ) and in the presence of from 0.01 to 2.5 Gew _e -% of a hydrogenolysis catalyst is performed. Method according to one of the items 2 to 4 »characterized in that the catalytic hydrogenolysis is carried out at a temperature in the range of 0 to 60 ° C and at a pH in the range of 4 to 9« 6e process according to one of the items 2 to 5, characterized in that X is bromine and Y is hydrogen · 7 · A method according to any one of items 2 to 5, characterized _s that X and Y are both bromine, " Method according to one of the items 2 to 7j, characterized in that R and R are both hydrogen.