CH644608A5 - METHOD FOR PRODUCING PENICILLANIC ACID 1,1-DIOXIDE AND ITS ESTERS AND INTERCONNECTING COMPOUNDS FOR CARRYING OUT THE METHOD. - Google Patents

Description

The invention relates to a new chemical process and new chemical compounds which can be used as intermediates in this process, in particular to a new chemical process for the preparation of penicillanic acid 1,1-dioxide and its in vivo hydrolysable esters. The new chemical process involves the dehalogenation of corresponding new 1,1-dioxides. The new chemical compounds that can be used as intermediates are 6-halogen and 6,6-dihalo derivatives of penicillanic acid l, l-dioxide and their in vivo hydrolysable esters.

Penicillanic acid 1,1-dioxide and its in vivo hydrolysable esters can be used as β-lactamase inhibitors and as agents which increase the effectiveness of certain β-lactam antibiotics when the latter are used to treat bacterial infections in mammals, especially in humans, 35 can be used. So far, penicillanic acid 1,1-dioxide and its in vivo hydrolysable ester from 6-brompenicillanic acid or its in vivo easily hydrolyzable esters have been produced by debromination to penicillanic acid or its in vivo hydrolysable esters with subsequent oxidation to 40 1,1-dioxide. Although the process according to the invention starts from a 6-halogenopenicillanic acid or its ester which can be hydrolyzed in vivo and comprises the step of dehalogenation, it has surprisingly been found that if the new intermediates were obtained by oxidation 45, a better product yield is achieved in dehalogenation. See BE-PS 867 859 and DE-OS 2 824 535 for details of the production processes for penicillanic acid 1, 1-dioxide and its esters which are easily hydrolyzed in vivo.

so 6-halogenopenicillanic acids have been disclosed by Cignarella et al., Journal of Organic Chemistry 27, 2668 (1962) and in U.S. Patent 3,206,469; the hydrogenolysis of 6-halogenopenicillanic acids to penicillanic acid is disclosed in GB-PS 1 072 108.

55 Harrison et al., Journal of the Chemical Society (London), Perkin 1,1772 (1976), describe a) the oxidation of 6,6-dibromophenicillanic acid with 3-chloroperbenzoic acid to a mixture of the corresponding α- and β-sulfoxides, b) the oxidation of methyl 6,6-dibrompenicillanate with 60 3-chloroperbenzoic acid to give a methyl 6,6-dibrompenicil-lanate-1,1-dioxide, c) the oxidation of methyl 6a-chlorpeni-cillanate with 3- Chloroperbenzoic acid to a mixture of the corresponding a- and ß-sulfoxides and d) the oxidation of methyl 6-bromophenicillanate with 3-chloroperbenzoic acid to a mixture of the corresponding a- and ß-sulfoxides.

Clayton, Journal of the Chemical Society (London), (C), 2123 (1969), describes a) the production of 6,6-dibromo and 6,6-diiodpenicillanic acid, b) the oxidation of

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6,6-dibromophenicillanic acid with sodium periodate to a mixture of the corresponding sulfoxides, c) the hydrogenolysis of methyl 6,6-dibromophenicillanate to methyl 6cc-bromopenicillanate, d) the hydrogenolysis of 6,6-dibrompenicillanic acid and its methyl ester to penicillanic acid and its methyl esters and e) the hydrogenolysis of a mixture of methyl 6,6-diiodopenicillanate and methyl 6a-iodpenicil-lanate to give pure methyl 6a-iodpenicillanate.

The invention relates to a new process for the preparation of compounds of the formula

H Q.0

- V. \ CH.

(X)

'f COOR1

or a pharmaceutically acceptable base salt thereof, wherein R1 is selected from hydrogen and ester-forming, in vivo hydrolysable residues, which is characterized in that a compound of the formula

* IV .'CH3

V "\ \ (. V * - 3 A <CU <, ^>

L

r

N.

tr,

ÇH, COOR]

Cxii)

or a base salt thereof, wherein X and Y are each selected from hydrogen, chlorine, bromine and iodine, provided that if X and Y both have the same meaning, they must both be bromine, dehydrohalogenate.

The present invention also relates to the new intermediates of the formula III defined above.

These new compounds of formula III can be prepared by using a compound of formula

CID

it. J

m COOR

or a base salt thereof is oxidized with a reagent from the group of the alkali metal permanganates, alkaline earth metal permanganates and organic peroxycarboxylic acids to give the compound of the formula III, which is then dehydrohalogenated according to the invention to give the compounds of the formula I.

In a preferred embodiment of the process according to the invention, the compound of the formula III is reacted with hydrogen in an inert solvent at a pressure in the range from 1 × 105 Pabis 100-105 Pa at a temperature in the range from 0 to 60 ° C. and a pH in Range from 4 to 9 and in the presence of a hydrogenolysis catalyst. The hydrogenolysis catalyst is usually present in an amount of 0.01 to 2.5% by weight, preferably 0.1 to 1.0% by weight, based on the compound of the formula III.

The preferred meaning for X and Y is bromine, and the preferred reagents for performing the oxidation are potassium permanganate and 3-chloroperbenzoic acid.

If X and Y are both chlorine, the compound of formula 11 is difficult to obtain. If X and Y are both iodine, the oxidation stage is uncomfortably slow.

The invention also covers the intermediates of the formula III in which X, Y and R1 are as defined above. A preferred intermediate is 6,6-dibromophenicillanic acid-1,1-dioxide, the compound of Formula III, where X and Y are bromine and R1 is hydrogen.

In the present description, the compounds of the formula I which can be prepared according to the invention are referred to as derivatives of penicillanic acid, which are represented by the following structural formula:

10th

h wCH3

0

r> s — k

UV)

CH3 COOH

In penicillanic acid derivatives, the interrupted linkage of a substituent to the bicyclic core means that the substituent is below the level of the core. Such a substituent is called an a-configuration. Conversely, an extended link between a substituent and the bicyclic core means that the substituent lies above the level of the core. This latter configuration is called the β configuration. For example, the group X has a configuration and the group Y has the β configuration in formula II.

If R1 here is an ester-forming, in vivo hydrolysable residue, it is a group which is derived from an alcohol of the formula R'-OH, so that the residue COOR1 in such a compound of the formula I means an ester group. Furthermore R1 is of such a kind

that the COOR1 group can be cleaved in vivo to release a free carboxyl group (COOH). That is, R1 is a group such that when a compound of Formula I, wherein R1 is an ester-forming, in vivo hydrolysable residue, is exposed to mammalian blood or tissue, the compound of Formula I, wherein R1 is hydrogen, easily arises. Groups R1 are well known in the penicillin field. In most cases, they improve the absorption properties of the penicillin compound. In addition, R1 should be of a type such that it imparts pharmaceutically acceptable properties to a compound of formula I and releases pharmaceutically acceptable fragments when cleaved in vivo. Groups R1 are well known and easily identified by those skilled in the penicillin field. See e.g. DE-OS 2 517 316. Specific examples of such groups R1 are 3-phthalidyl, 4-crotonolactonyl, Y-butyrolacton-4-yl and groups of the formula

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55

R2 O

I II

-C-O-C-R4

I.

R3

(V)

and

R2 O

I II

-C-O-C-O-R4

I.

R3

(VI)

wherein R2 and R3 are each selected from hydrogen and alkyl having 1 to 2 carbon atoms and R4 is alkyl having 1 to 60 5 carbon atoms. However, preferred groups R1 are alkanoyloxymethyl with 3 to 7 carbon atoms, 1- (alkanoyloxy) ethyl with 4 to 8 carbon atoms, 1-methyl-1- (alkanoyloxy) ethyl with 5 to 9 carbon atoms, alkoxy-carbonyloxymethyl with 3 to 6 carbon atoms , l- (Alko-65 xycarbonyloxy) ethyl with 4 to 7 carbon atoms,

1-methyl-l-alkoxycarbonyloxy) ethyl with 5 to 8 carbon atoms, 3-phthalidyl, 4-crotonolactonyl and y-butyro-lacton-4-yI.

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3-phthalidyl, 4-crotonolactonyl and y-butyrolacton-4-yl refer to structures VII, VIII and IX. The wavy lines should either designate one of the two epimers or their mixture.

II

0 0 0

(VII) (VIII) I IX I

The preferred method of making the compounds of Formula III involves oxidation of the sulfide moiety in a compound of Formula II to a sulfone moiety, resulting in the new compound of Formula III. A large number of oxidizing agents 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.

If e.g. a compound of formula II, wherein X, Y and R1 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 about 0.5 to about 10 moles -Equivalents, preferably about 1 to about 4 mole equivalents of permanganate in a suitable solvent system inert to the reaction. A suitable reaction system inert solvent system is one that does not adversely interact with any of the starting materials or the product, and water is commonly used. If desired, a cosolvent that is miscible with water but does not interact with the permanganate, such as tetrahydrofuran, can be added. The reaction can be carried out at a temperature in the range from about -30 to about 50 ° C, preferably at about -10 to about 10 ° C. At about 0 ° C the reaction is usually within a short time, e.g. within 1 h, practically finished. Although the reaction can take place under neutral, basic or acidic conditions, the pH is preferably in the range from about 4 to 9, preferably at 6 to 8. However, it is important to choose conditions which avoid decomposition of the β-lactam ring system of the compound of the formulas II or III. Indeed, it is often advantageous to buffer the pH of the reaction medium around the neutral point. The product can be obtained using conventional techniques. Any excess permanganate is usually decomposed using sodium bisulfite and then when the product is no longer in solution it is typically recovered by filtration. It can be separated from the manganese dioxide by extraction into an organic solvent and obtained by evaporating off the solvent. On the other hand, if the product is still in solution at the end of the reaction, it is usually isolated according to the usual procedure of the solvent reaction.

If e.g. a compound of formula II, wherein X, Y and R1 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 about 1 to about 6

Molar equivalents, preferably about 2.2 molar equivalents, of the oxidizing agent in an organic solvent inert to the reaction. Typical solvents are chlorinated hydrocarbons, such as methylene chloride, chloroform and 1,2-dichloroethane, and ethers, such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane. The reaction is usually carried out at a temperature of about -30 to about 50 ° C, preferably at about 15 to about 30 ° C. At about 25 ° C, reaction times of about 2 to about 16 hours are usually used. The product is usually isolated by removing the solvent in vacuo. The reaction product can be purified by conventional methods that are well known in the art. On the other hand, it can be used directly in the process according to the invention without further purification.

The process according to the invention represents a dehalogenation reaction. A convenient method of carrying out this conversion is to dissolve a compound of the formula III under an atmosphere of hydrogen or of hydrogen in a mixture with an inert diluent, such as nitrogen or argon, in the presence of a Stir or shake hydrogenolysis catalyst. Suitable solvents for this hydrogenolysis reaction are those which essentially dissolve the starting compound of the formula III but do not themselves 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 N, N-dimethylformamide, N, N-dimethylacetamide and N- Methylpyrro-lidon, water and their mixtures. In addition, it is customary to buffer the reaction mixture in such a way that a pH in the range from 4 to 9, preferably 6 to 8, is employed. Borate and phosphate buffers are commonly used. Usually hydrogen gas is introduced into the reaction medium by carrying out the reaction in a sealed container containing the compound of formula III, the solvent, the catalyst and the hydrogen. The pressure inside the reaction vessel can vary between 1 • 105 Pa to 100-105 Pa. If the atmosphere in the reaction vessel consists practically of pure hydrogen, the preferred pressure range is 2 • 105 Pa to 5 • 105 Pa. The hydrogenolysis is generally carried out at a temperature of 0 to 60 ° C, preferably 25 to 50 ° C. Hydrogenolysis generally takes a few hours, e.g. about 2 to about 20 hours. The catalysts preferably 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 0.01 to 2.5, preferably 0.1 to 1.0% by weight, based on the compound of the formula III. It is often appropriate to distribute the catalyst on an inert support; a particularly suitable catalyst is palladium on an inert support, such as carbon.

Further methods can be used for the reductive removal of the halogen from a compound of the formula III according to the invention. For example, X and Y can 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, the process 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, if a Ver4

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444608

bond of the formula I, in which R1 is hydrogen, is to be prepared from a compound of the formula II in which R1 is hydrogen. In other words, a 6-halogen or 6,6-dihalogen derivative of penicillanic acid with a free carboxyl group in the 3-position can first be subjected to oxidation and then to dehalogenation.

6-Alpha-chlorpenicillanic acid and 6-alpha-bromopenicillanic acid can be obtained by diazotization of 6-aminopenicillanic acid in the presence of hydrochloric acid or hydrobromic acid [Journal of Organic Chemistry, 27.2668 (1962)]. 6-alpha-iodpenicillanic acid is obtained e.g. by diazotization of 6-aminopenicillanic acid in the presence of iodine, followed by hydrogenolysis [Clayton, Journal of the Chemical Society (C), 2123 (1969)]. 6-beta-chlorpenicillanic acid, 6-beta-bromopenicillanic acid and 6-beta-iodpenicillanic acid are preferably obtained by reducing 6-chloro-6-iodpenicillanic acid, 6,6-dibrompenicillanic acid or 6,6-diiodpenicillanic acid with tri- n-butyltin hydride; 6-chloro-6-iodpenicillanic acid can be obtained by diazotizing 6-aminopenicillanic acid in the presence of iodine chloride; 6,6-dibromophenicillanic acid is obtained e.g. by the method of Clayton, Journal of the Chemical Society (London), (C), 2123 (1969); and 6,6-diiodpenicillanic acid are usually obtained by diazotizing 6-aminopenicillanic acid in the presence of iodine.

The compounds of formula I, II and III, wherein R1 is hydrogen, are acidic and form salts with bases. These salts can be prepared using standard techniques, e.g. by bringing the acidic and basic components together, usually in a stoichiometric ratio in an aqueous, non-aqueous or partially aqueous medium, as appropriate. They can then be obtained by filtering, precipitating with a non-solvent and then filtering, by evaporating the solvent or, in the case of aqueous solution, by lyophilizing, as appropriate. Bases suitably used for salt formation belong to 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, sec.-amines, such as diethylamine, morpholine, pyrrolidine and piperidine, tert.-amines, such as triethylamine, N- Ethyl piperidine, N-methylmorpholine and 1,5-diazabi-cycIo [4.3.0] non-5-enes, 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 R1 is hydrogen, and its salts are effective as medium strength antibacterial agents both in vitro and in vivo, and the compounds of formula I, in which R1 is an ester-forming, in vivo hydrolysable residue, are as medium strength antibacterial agent effective in vivo. The minimum inhibitory concentrations (MIC values) of penicillanic acid-1,1-dioxide against various microorganisms are listed in Table I.

Table I

Antibacterial in vitro activity of penicillanic acid 1,1-dioxide

Microorganism

MIC (jxg / ml)

Staphylococcus aureus

100

Streptococcus faecalis

200

Streptococcus pyogenes

100

Escherichia coli

50

Pseudomonas aeruginosa

200

Klebsiella pneumoniae

50

Proteus mirabilis

100

Proteus morgani

100

Salmonella typhimurium

50

Pasteurella multocida

50

Serratia marcescens

100

Enterobacter aerogenes

25th

Enterobacter cloacae

100

Citrobacter freundii

50

Providencia

100

Staphylococcus epidermis

200

Pseudomonas putida

200

Hemophilus influenzae

50

Neisseria gonorrhoeae

0.312

The in vitro antibacterial activity of the compound of formula I, wherein R1 is hydrogen, and its salts renders them commercial antimicrobial agents, e.g. usable in the treatment of water, silt or sludge control, paint and wood preservation and for local use as a disinfectant. In the case of using these compounds for topical application, it is often appropriate to mix the active ingredient with a non-toxic carrier such as vegetable or mineral oil or a softening cream. Similarly, it can be dissolved or dispersed in liquid diluents or solvents such as water, alkanols, glycols or their mixtures. In most cases, concentrations of the active ingredient from about 0.1 to about 10% by weight, based on the total agent, are suitable.

The in vivo activity of the compounds of formula I, wherein R1 is hydrogen or an ester-forming, in vivo hydrolysable residue, and their salts make them suitable for controlling bacterial infections in mammals, including humans, by both oral and parenteral routes. The compounds find use in the control of infections caused by susceptible bacteria in human patients, e.g. infections caused by strains of Neisseria gonorrhoeae.

When a compound of formula I or its salt is used therapeutically 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 administered orally or parenterally, i.e. intramuscularly, subcutaneously or intraperitoneally. The carrier or diluent is selected based on the intended route of administration. When administered orally e.g. the compound can be used in the form of tablets, capsules, lozenges, round pastilles, powders, syrups, elixirs, aqueous solutions and suspensions and the like according to standard pharmaceutical practice. The proportion of active ingredient to carrier depends on the chemical nature, the solubility and stability of the active ingredient and the dosage in question. Medicament containing an antibacterial agent of formula I.

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644608

6

however, contain about 20 to about 95% active ingredient. For oral tablets, commonly used carriers are e.g. Lactose, sodium citrate and salts of phosphoric acid. Various disintegrants 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. If 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, including intramuscular, intraperitoneal, subcutaneous, and intravenous use, sterile solutions of the active ingredient are usually prepared and the pH of the solutions is adjusted and buffered appropriately. For intravenous use, the total concentration of solutes should be controlled so that the preparation becomes isotonic.

The prescriber will ultimately determine the appropriate dose of a compound of Formula I for a particular human patient and this will vary with the age, weight and response of the individual patient as well as the type and severity of the patient's symptoms. The compounds are normally used orally in doses ranging from about 10 to about 200 mg / kg body weight per day and parenterally in doses ranging from about 10 to about 400 mg / kg body weight per day. However, these values are for illustration only and in some cases it may be necessary to use doses outside these limits.

The compounds of the formula I in which R1 is hydrogen or an ester-forming radical which can be hydrolyzed in vivo, or their salts, increase the antibacterial activity of β-lactam antibiotics in vivo. They reduce the amount of antibiotic that is necessary to protect mice against an otherwise lethal inoculum of certain ß-lactamase-producing bacteria. This ability makes them valuable for co-administration with β-lactam antibiotics in the treatment of bacterial infections in mammals, particularly humans. In the treatment of a bacterial infection, the compound of the formula I can be mixed with the β-lactam antibiotic and the two agents can thereby be administered simultaneously. On the other hand, the compound of formula I can 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.

E.g. Penicillanic acid-1,1-dioxide, a salt or an in vivo hydrolysable ester of this compound used to increase the effectiveness of a ß-lactam antibiotic, it is preferably administered in a formulation with standard pharmaceutical carriers or diluents. The methods of composition previously discussed for the use of penicillanic acid 1,1-dioxide or an easily hydrolyzable ester in vivo as the only antibacterial agent can be used when co-administration with another β-lactam antibiotic is intended. A pharmaceutical composition having a pharmaceutically acceptable carrier, a β-lactam antibiotic and penicillanic acid 1,1-dioxide or its easily 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 easily hydrolysable in vivo esters in combination with another β-lactam antibiotic, the sulfone can be administered orally or parenterally, i.e. intramuscularly, subcutaneously or intraperitoneally. Although the prescriber will ultimately determine the dose to be used on a patient, the ratio of the daily doses of penicillanic acid 1,1-dioxide or its salt or ester and the beta-lactam antibiotic is usually in the range of about 1: 3 to 3: 1 . In addition, when using penicillanic acid 1,1-dioxide or its salt or in vivo easily hydrolyzable ester in combination with a further β-lactam antibiotic, the daily oral dose of each component is normally in the range from about 10 to about 200 mg / kg body weight and daily parenteral dose of each component is usually about 10 to about 400 mg / kg body weight. However, these values are for illustration purposes only, and it may sometimes be necessary to use doses outside of these limits.

Typical ß-lactam antibiotics with which penicillanic acid 1,1-dioxide and its in vivo hydrolysable esters can be administered together are 6- (2-phenylacetamido) penicilanoic acid, 6- (D-2-amino-2-phenylacetamido) penicillanic acid,

6- (2-carboxy-2-phenylacetamido) penicillanic acid and

7- [2- (l-tetrazolyl) acetamido) -3- (2- (5-methyl-l, 3,4-thiadiazolyl) thiomethyl] -3-deacetoxymethylcephalosporanoic acid.

Typical microorganisms against which the antibacterial activity of the above β-lactam antibiotics are increased are the following:

Staphylococcus aureus,

Haemophilus influenzae,

Klebsiella pneumoniae and Bacteroides fragilis.

As those skilled in the art know, some beta-lactam compounds are effective when administered orally or parenterally, while others are effective only when administered parenterally. If penicillanic acid-1,1-dioxide, a salt or an in vivo hydrolysable ester thereof is to be used simultaneously (ie in a mixture) with a β-lactam antibiotic which is only effective when administered parenterally, a combined combination is suitable for parenteral use required. If the penicillanic acid 1,1-dioxide or its ester is to be used simultaneously (in a mixture) with a β-lactam antibiotic which is active orally or parenterally, combinations which are suitable for oral or parenteral administration can be prepared. In addition, preparations of 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 be administered parenterally administer while the other ß-lactam antibiotic is administered orally.

Further details relating to the use and synthesis of compounds of the formula I are disclosed in DE-OS 2 824 535.

The following examples and preparations serve exclusively for further illustration. Infrared (IR) spectra were measured as potassium bromide pellets (KBr pellets) and recognition absorption bands are given in wavenumbers (cm-1). Nuclear magnetic (NMR) spectra were measured at 60 MHz for solutions in deuterochloroform (CDCb), perdeuteroacetone (CD3COCD3), perdeuterodimethyl sulfoxide (DMSO-dr>) or deuterium oxide (D2O), and the peak levels are in parts per million (tpm) Field out of tetra

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specified methylsilane or sodium 2,2-dimethyl-2-silapentane-5-sul-fonate. The following abbreviations for peak shapes are used: s for singlet, d for doublet, t for tri-plett, q for quadruple «and m for multiplet.

Preparation 1

6-a-Brompenicillic acid-1,1-dioxide

4N sodium hydroxide solution was added to a stirred mixture of 560 ml of water, 300 ml of methylene chloride and 56.0 g of 6-oc-bromopenicillanic acid 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 min and then filtered. The layers were separated and the organic phase was discarded. The aqueous phase was then quickly poured into an oxidizing mixture, which was prepared as follows:

63.2 g of potassium permanganate, 1000 ml of water and 48.0 g of acetic acid were mixed in a 3-1 flask. The mixture was stirred at 20 ° C for 15 minutes and then cooled to 0 ° C.

After the 6-a-bromophenicillanic acid solution was added to the oxidation solution, a -15 ° C cooling bath was kept around the reaction mixture. The internal temperature rose to 15 ° C and then fell to 5 ° C over 20 min. Then 30.0 g of sodium metabisulfite were added with stirring in about 10 ° C. in 10 minutes. After a further 15 min the mixture was filtered and the pH of the filtrate was reduced to 1.2 by adding 170 ml of 6N hydrochloric acid. 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 and yielded 41.5 g (66% yield) of the title compound, mp. 134 ° C. (dec.).

Analysis,% for CsHioBrNOsS:

Calc .: 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

Preparation 2

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

Preparation 3

6-ß-chlorpenicillanic acid-1,1-dioxide

An oxidation solution was prepared from 185 mg potassium permanganate, 0.063 ml 85% phosphoric acid and 5 ml water. This oxidation solution was added dropwise to a solution of 150 mg of sodium 6-β-chloro-penicillanate in 5 ml of water at 0 to 5 ° C. until the purple color of the potassium permanganate persisted. 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. 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 concentrated in vacuo to 118 mg of the title compound. The NMR spectrum (in CD3COCD3) 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, 3H) ppm.

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

Preparation 4

6-ß-Brompenicillanoic acid-1,1-dioxide

To a solution of 255 mg of sodium 6-ß-brompenicil lanate in 5 ml of water at 0 to 5 ° C, a solution was added, consisting of 140 mg of potassium permanganate, 0.11 ml of 85% phosphoric acid and 5 ml of water 0 to 5 ° C, had been prepared. 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 overlaid with ethyl acetate. The pH was adjusted to 1.7 and 330 mg 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 MgSO4) and concentrated in vacuo. This provided 216 mg of the title compound as white crystals. The NMR spectrum (in D2O) 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.

Preparation 5

6-ß-iodpenicillanic acid-1,1-dioxide

Oxidation of 6-β-iodopenicillanic acid with potassium permanganate according to the procedure of preparation 4 gave 6-β-iodopenicillanic acid-1,1-dioxide.

Preparation 6

Pivaloyloxymethyl-6-a-bromophenicillanate-1,1-dioxide

400 mg of 3-chloroperbenzoic acid are added at 0 to 5 ° C. to a solution of 394 mg of pivaloyloxymethyl-6-a-bromo-penicillanate in 10 ml of methylene chloride. 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 evaporated to dryness in vacuo to provide the title compound.

Preparation 7

The procedure of preparation 6 is repeated, with the exception that the pivaloyloxymethyl-6-ß-brompenicil-lanate is replaced by:

3-phthalidyl-6-ct-chlorpenicillanate,

4-crotonolactonyl-6-ß-chlorpenicillanate, y-butyrolacton-4-yl-6-oc-bromopenicillanate, acetoxymethyl-6-ß-bromopenicillanate, pivaloyloxymethyl-6-ß-bromopenicillanate, hexanoyloxymod-6-i-ai-iodo-6-i (Acetoxy) ethyl 6-ß-iodpenicillanate, l- (isobutyryloxy) ethyl 6-a-chlorpenicillanate,

1-methyl-1 - (acetoxy) ethyl 6-ß-chlorpenicillanate,

1-methyl-1 - (hexanoyloxy) ethyl-6-a-bromopenicilanate, methoxycarbonyloxymethyl-6-a-bromopenicillanate, propoxycarbonyloxymethyl-6-ß-bromopenicillanate, l- (ethoxycarbonyloxy) ethyl-6-a-bromopenicillanate

1 - (Butoxy carbonyloxy) ethyl 6-a-iodpenicillanate, 1-methyl-l- (methoxycarbonyloxy) ethyl 6-ß-iodpenicillanate or

1-Methyl-1 - (isopropoxycarbonyloxy) ethyl 6-a-chlorpenicil lanate

This provides:

3-phthalidyl-6-a-chlorpenicillanate-1,1-dioxide,

4-crotonolactonyl-6-ß-chlorpenicillanate-1,1-dioxide,

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y-butyrolactone-4-y] -6-a-bromopenicillanate-1,1-dioxide, acetoxymethyl-6-ß-bromopenicillanate-l, l-dioxide, pi-valoyloxymethyl-6-ß-bromopenicillanate-1,1-dioxide, Hexanoyloxymethyl-6-a-iodpenicillanate-l, l-dioxide, 1- (acetoxy) ethyl-6-ß-iodpenicillanate-1,1-dioxide, 1 - (isobutyryIoxy) ethyl-6-a-chlorpenicillanate-1,1 - dioxide, 1-methyl-1 - (acetoxy) ethyl-6-ß-chlorpenicillanate-1,1-dioxide, 1-methyl-1 - (hexanoyloxy) ethyl-6-a-bromopenicillanate-1,1-dioxide,

Methoxycarbonyloxymethyl-6-a-bromophenicillanate-1,1-dioxide,

Propoxycarbonyloxymethyl-6-β-bromophenicillanate-1,1-dioxide,

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

1 - (butoxycarbonyloxy) ethyl 6-a-iodpenicillanate-1,1-dioxide, 1-methyl-1 - (methoxycarbonyloxy) ethyl-6-β-iodpenicillanate-1,1-dioxide,

1-Methyl-1 - (isopropoxycarbonyloxy) ethyl-6-a-chlorpenicil-lanate-1,1-dioxide.

Example 1 Penicillanic Acid 1,1 Dioxide

9.4 g of 6-a-bromopenicillanic acid-1,1-dioxide were added to 100 ml of water at 22 ° C., then sufficient 4 N sodium hydroxide solution to establish a stable pH of 7.3. 2.25 g of 5% Pd / C were added to the resulting solution, followed by 6.9 g of dicalium phosphate trihydrate. This mixture was then shaken under a hydrogen atmosphere at a pressure between 3.5 • 105 Pa and 1.8 • 105 Pa. After the end of the hydrogen uptake, the solids were filtered off and the aqueous solution was covered with a layer of 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 further 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,% for CsHuNOsS:

Calculated: 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 2 Penicillanic Acid-1.1 Dioxide The Hydrogenolysis of

6-a-chlorpenicillanic acid-1.1-dioxide, 6-a-iodopenicillanic acid-1.1-dioxide, 6-ß-chlorpenicillanic acid-1.1-dioxide, 6-ß-bromopenicillanic acid-l, 1-dioxide and 6- ß-I odpenicillanic acid 1,1-dioxide according to the procedure of Example 1 provides penicillanic acid-1,1-dioxide.

Example 3

Pivaloyloxymethylpenicillanate-1,1-dioxide 3 ml of 1 M sodium bicarbonate and 200 mg of 10% Pd / C are added to a solution of 1.0 g of pivaloyloxymethyl-6-a-bromo-penicillanate in 10 ml of methanol. The reaction mixture is shaken vigorously under a hydrogen atmosphere at a pressure of about 5 · 105 Pa until the hydrogen uptake ceases. The mixture is then filtered and the bulk of the methanol is removed by vacuum stripping. 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 NaCl) and concentrated in vacuo. This provides the title link.

Example 4

Hydrogenolysis of the suitable 6-halopenicillanoic acid ester-1,1-dioxide from preparation 7 according to the procedure of example 3 provides the following compounds:

3-phthalidylpenicillanate-1,1-dioxide,

4-crotonolactonylpenicillanate-1,1-dioxide, y-butyrolacton-4-y-ipenicillanate-1,1-dioxide, acetoxymethylpenicillanate-1,1-dioxide, pivaloyloxymethylpenicillanate-1,1-dioxide, hexanoyloxymethylpenicillanate-1,1-dioxide, 1 - (Acetoxy) ethylpenicillanate-1,1-dioxide,

1 - (isobutyryloxy) ethylpenicillanate-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 ) ethylpenicillanate-1,1-dioxide,

1-methyl-1 - (methoxycarbonyloxy) ethylpenicillanate-1,1-dioxide or

1-Methyl-1 - (isopropoxycarbonyloxy) ethyl penicillanate-1,1-dioxide.

Preparation 8

Pivaloyloxymethyl-6-a-bromophenicillanate-1,1-dioxide

An oxidizing solution was prepared by bringing together 4.26 g of potassium permanganate, 2.65 g of 85% phosphoric acid and 40 ml of water. The mixture was stirred for 1 hour and then slowly added to a stirred solution of 5.32 g of pivaloyloxymethyl-6-a-bromo-penicillanate in 70 ml of acetone and 10 ml of water at 5 to 10 ° C. in 20 minutes. The mixture was stirred at 5 ° C for 30 minutes and 100 ml of ethyl acetate was added. After a further 30 minutes, a solution of 3.12 g of sodium bisulfite in 30 ml of water was added over 15 minutes at about 10 ° C. The mixture was stirred at 5 ° C. for a further 30 minutes 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 CDCb) showed absorptions at 5.80 (q, 2 H), 5.15 (d, 1H), 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 5

Pivaloyloxymethylpenicillanate-1,1-dioxide

A solution of 4.4 g of pivaloyloxymethyl-6-a-brompeni-cillanate-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 shaken under a hydrogen atmosphere in the presence of 2.0 g 5% Pd / C at about 3.24-105 Pa to 3.52 · 105 Pa gauge pressure. The reaction mixture was then filtered and the residue washed with 100 ml of ethyl acetate and 25 ml of water. The filtrate and the washing liquids were separated after their union. 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 slowly added to (100 ml) hexane and the precipitate was filtered off. Yield 2.4 g. The NMR spectrum (in DMSO-ds) showed absorptions at 5.75

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(q, 2 H), 5.05 (m, 1 H), 4.40 (s, 1 H), 3.95-2.95 (m, 2 H), 1.40 (s, 3 H) , 1.25 (s, 3H) and 1.10 (s, 9H) ppm.

Example 6

A. 2,2,2-Trichloroethyl-6-a-bromopenicillanate-l, l-dioxide

2,2,2-TrichloräthyI-6-a-brompenicillanat was oxidized with potassium permanganate practically according to the procedure of preparation 8 to the title compound in 79% yield. The NMR spectrum of the product (in CDCb) showed absorption at 5.30 to 4.70 (m, 4 H), 4.60 (s, 1 H), 1.70 (s, 3 H) and 1.50 (s, 3H) ppm.

B. Penicillanic acid 1,1-dioxide

4.0 g of 2,2,2-trichloroethyl-6-a-bromophenicillanate-1,1-dioxide were added in portions to a stirred suspension of 6.5 g of zinc powder in 100 ml of a 70:30 glacial acetic acid / tetrahydrofuran mixture in 5 minutes given. The mixture was stirred at room temperature for 3 hours 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 evaporated to dryness in vacuo. The residue was triturated under ether for 20 minutes. This provided 553 mg of the title compound as a solid. The NMR spectrum (in CDCb / DMSO-dö) 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.

Preparation 9

Benzyl-6-a-bromophenicillanate-1,1-dioxide

Benzyl 6-a-bromophenicillanate was oxidized with potassium permanganate practically according to the procedure of preparation 8 to give the title compound in 94% yield. The NMR spectrum (in CDCb) showed absorptions at 7.35 (s, 5 H), 5.10 (m, 3 H), 4.85 (m, 1 H), 4.40 (s, 1 H) , 1.50 (s, 3H) and 1.25 (s, 3H) ppm.

Example 7

Penicillanic acid 1,1-dioxide

A solution of 4.0 g of benzyl 6-a-bromophenicillanate-l, l-dioxide in 50 ml of tetrahydrofuran was combined with a solution of 1.06 g of sodium bicarbonate in 50 ml of water. 2.0 g of a 50% suspension of 5% Pd / C in water were added to the mixture, then this mixture was added under a hydrogen atmosphere at an overpressure of approx. 3.21 · 105 Pa to 3.45-105 Pa 20 min shaken. The catalyst was then filtered off and 30 ml of tetrahydrofuran and 3.0 g of a 50% suspension of 5% Pd / C were added. The resulting mixture was shaken under a hydrogen atmosphere at a 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-O. 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 CDCI3 / DMSO-df.) showed absorption at 9.45 (broad, s, 1 H), 4.60 (t, 1 H), 4.25 (s, 1 H) ), 3.40 (d, 2 H), 1.65 (s, 3 H) and 1.30 (s, 3 H) ppm.

Preparation 10

6,6-dibromophenicillanic acid 1,1-dioxide

300 ml of water were added to the dichloromethane solution of 6,6-dibromophenicillanic acid from preparation K, followed by the dropwise addition of 105 ml of 3N sodium hydroxide over 30 min. The pH stabilized at 7.0. The aqueous layer was removed and the organic layer extracted with (2x 100 ml) water. To the combined aqueous solutions, a premix solution was added at -5 ° C, 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 took 50 minutes and 550 ml of oxidant was required. 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. 250 ml of 1 M sodium bisulfite were then added over 10 to 15 minutes at about 10 ° C. During the addition of the sodium bisulfite solution, the pH was maintained at 1.25 to 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 (2 x 150 ml) and the combined ethyl acetate solutions were washed with brine and dried (over Mg S CU). 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 removing the solvent in vacuo. A sample isolated in this way from an analog production had a melting point of 201 ° C. (dec.). The NMR spectrum (CDCb / DMSO-dó) showed absorptions at 9.35 (s, 1 H), 5.30 (s, 1 H), 4.42 (s, 1 H), 1.63 (s, 3 H) and 1.50 (s, 3 H) ppm. The IR spectrum (KBr pellet) showed absorptions at 3846 to 2500, 1818, 1754, 1342 and 1250-1110 cm "1.

Preparation 11

6-chloro-6-iodpenicillanic acid 1,1-dioxide

To a solution of 4.9 g of 6-chloro-6-iodpenicillanic 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. A premix solution was then added dropwise to this solution over 20 minutes, prepared from 2.61 g of potassium permanganate, 1.75 ml of concentrated phosphoric acid and 50 ml of water. The pH was kept at 6 during the addition and the temperature below 10 ° C. At this point 100 ml of ethyl acetate was added and the pH adjusted to 1.5. 50 ml of 10% sodium bisulfite were then added to this mixture, the temperature being kept below 10 ° C. and the pH kept at about 1.5 by adding 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 (over MgSCh) and concentrated in vacuo to 4.2 g of the title compound, mp. 143-145 ° C. The NMR spectrum (CDCb) 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-1.

Preparation 12

6-bromo-6-iodpenicillanoic acid 1,1-dioxide

50 ml of water was added to a solution of 6.0 g of 6-bromo-6-iodpenicillanic acid in 50 ml of methylene chloride. 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

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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 ° 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. 50 ml of 10% sodium bisulfite were added dropwise to this two-phase system, the pH being maintained at about 1.5 by adding 6N hydrochloric acid. Another 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 x 50 ml) 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 gave 4.2 g of the title compound, mp. 145-147 ° C. The NMR spectrum (CDCb) 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.

Preparation 13

6-chloro-6-bromophenicillanic acid, l, l-dioxide

The oxidation of 6-chloro-6-bromopenicillanic acid with potassium permanganate according to the procedure of preparation 12 gave 6-chloro-6-bromopenicillic acid-1,1-dioxide.

Example 8

Penicillanic acid 1,1-dioxide

The ethyl acetate solution of 6,6-dibromophenicillanic acid-1,1-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 shaken under a hydrogen atmosphere at a pressure of about 5 · 105 Pa 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 further ethyl acetate (3 x 200 ml). The combined ethyl acetate solutions were (dried over MgSO <0 and concentrated in vacuo to 33.5 g (58% yield of 6-aminopenicillanic acid) penicillanic acid-1,1-dioxide. This product was dissolved in 600 ml of ethyl acetate, the solution was decolorized with activated carbon and the solvent was removed in vacuo and the product was washed with hexane to give 31.0 g of pure product.

Example 9

Hydrogenolysis of 6-chloro-6-iodpenicillanic acid 1, l -dioxide, 6-bromo-6-iodpenicillanic acid and 6-chloro-6-bromopenicillanic acid according to the procedure of Example 8 in each case gave penicillanic acid-1,1-dioxide .

Example 10

Penicillanic acid 1,1-dioxide

0.3 ml of triethylamine and then 0.25 ml of trimethylsilyl chloride at about 0 ° C. were added to a stirred suspension of 786 mg of 6-chloro-6-iodo-penicillanic acid-1,1-dioxide in 10 ml of benzene. The mixture was stirred for a further 5 minutes at about 0 ° C. and then at the reflux temperature of the solvent for 30 minutes. 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 hour at about 0 ° C. and then for 3.5 hours at the 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 the mixture was stirred and irradiated for another hour at the reflux temperature. 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 was added and the pH was adjusted to 1.5 with 6N hydrochloric acid. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate solutions were washed with brine, dried (over MgSO4) and concentrated in vacuo. The residue was triturated under hexane and then collected by filtration. This provided 0.075 mg of the title compound.

Example 11

Penicillanic acid 1,1-dioxide

0.3 ml of triethylamine and then 0.25 ml of trimethylsilyl chloride were added to a stirred suspension of 0.874 g of 6-bromo-6-iodo-penicillanic acid-1,1-dioxide in 10 ml of benzene at approx. 5 ° C. The mixture was stirred at about 5 ° C. for a further 5 min, then for 30 min at the reflux temperature of the solvent. The reaction mixture was cooled to room temperature and the solids were filtered off. The filtrate was cooled to about 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 at about 5 ° C for 1 h, 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 (2x25 ml) ethyl acetate and the combined ethyl acetate layers were washed with brine, dried (over MgSO4) 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.

Preparation 14

Pivaloyloxymethyl-6,6-dibromophenicillanate-1,1-dioxide

3.80 g of 3-chloroperbenzoic acid are added at 0 to 5 ° C. to a solution of 4.73 g of pivaloyloxymethyl-6,6-dibromophenicillanate in 15 ml of methylene chloride. 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 evaporated 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 dried (over Na2S04) and concentrated in vacuo to give the title compound.

Preparation 15

Oxidation of each of the 6,6-dihalophenicillanic acid esters of Preparation P using 3-chloroperbenzoic acid following the procedure of Preparation 14 provides the following compounds:

3-phthalidyl-6,6-dibromophenicillanate-1,1-dioxide,

4-crotonolactonyl-6-chloro-6-iodpenicillanate-1,1-dioxide, y-butyrolactonyl-6-bromo-6-iodpenicillanate-1,1-dioxide, acetoxymethyl-6-chloro-6-bromopenicillanate-1,1 - dioxide, pivaloyloxymethyl-6-chloro-6-iodpenicillanate-l, l-dioxide, hexanoyloxymethyl-6-, 6-dibrompenicillanate-1,1-dioxide, 1 - (acetoxy) ethyl-6,6-dibrompenicillanate-1,1 - dioxide,

1 - (isobutyryloxy) ethyl 6-bromo-6-iodpenicillanate-1,1-dioxide, 1-methyl-1 - (acetoxy) ethyl-6,6-dibrompenicillanate-1,1-dioxide,

l-methyl-l- (hexanoyloxy) ethyl 6-chloro-6-bromo-penicillanate,

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MethoxycarbonyloxymethyI-6,6-dibromophenicillanate-1,1-dioxide,

Propoxycarbonyloxymethyl-6-chloro-6-iodpenicillanate-1,1-dioxide,

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

1 - (butoxycarbonyloxy) ethyl-6-bromo-6-iodpenicillanate-1,1-dioxide,

1-methyl-1 - (methoxycarbonyloxy) ethyl-6,6-dibromo-penicil-lanate-1,1-dioxide or

1-Methyl-1 - (isopropoxycarbonyloxy) ethyl-6,6-dibromo-peni-cillanate-l, l-dioxide.

Example 12

Pivaloyloxymethylpenicillanate-1,1-dioxide 3 ml of 1 M sodium bicarbonate and 200 mg of 10% Pd / C are added to a solution of 1.0 g of pivaloyloxymethyl-6,6-dibromo-penicillanate-1,1-dioxide in 10 ml of methanol. The reaction mixture is shaken vigorously under a hydrogen atmosphere at a pressure of about 4.9 bar (5 kp / cm2) until the hydrogen uptake ceases. The mixture is then filtered and the bulk of the methanol is 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 NanSCU) and concentrated in vacuo. This provides pivaloyloxymethylpenicillanate-1,1-dioxide.

Example 13

Hydrogenolysis of the 6,6-dihalpenicillanoic acid ester-1,1-dioxide from preparation 15 according to the procedure of example 12 provides the following compounds:

3-phthalidyl-penicillanate-1,1-dioxide,

4-crotonolactonyIpenicillanate-1,1-dioxide, y-butyrolactone-4-ylpenicillanate-1,1-dioxide, acetoxymethylpenicillanate-1,1-dioxide, pivaloyloxymethylpenicillanate-1,1-dioxide, hexanoyloxymethylpenicillanate-1,1-dioxide, 1 - (Acetoxy) ethylpenicillanate-1,1-dioxide,

1 - (isobutyryloxy) ethylpenicillanate-1,1-dioxide, 1-methyl- (acetoxy) ethylpenicilanate-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 ) ethylpenicillanate-1,1-dioxide,

1-methyl-1 - (methoxycarbonyloxy) ethylpenicillanate-1,1-dioxide or

1-Methyl-1 - (isopropoxycarbonyloxy) ethyl penicillanate-1,1-dioxide.

Preparation 16

Pivaloyloxymethyl-6,6-dibromophenicillanate-1,1-dioxide A stirred solution of 3.92 g of 6,6-dibromophenicillanic acid-1,1-dioxide in 20 ml of N, N-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 0 ° C. 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 activated carbon (Darco), dried (over MgSO4) 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 the eluent. The fractions containing the desired product were combined and again chromatographed on silica gel to give 0.025 g of the title compound s. The NMR spectrum (CDCb) showed absorptions at 6.10 (q, 2 H), 5.00 (s, 1 H), 4.55 (s, 1 H), 1.60 (s, 3 H), 1.50 (s, 3H) and 1.15 (s, 9H) ppm.

Example 14

io Pivaloyloxymethylpenicillanat-1,1-dioxide

To a stirred solution of 60 mg of pivaloyloxymethyl-6,6-dibrompenicillanate-1,1-dioxide in 5 ml of benzene was added 52 (ig 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 min, ethyl acetate was added and the pH of the aqueous phase was adjusted to 7.0, the layers were separated and the aqueous phase was further extracted with ethyl acetate, the combined ethyl acetate solutions were washed with brine, dried (over MgSCU) and concentrated in vacuo, the residue was dried under high vacuum for 30 minutes to give 70 mg of a yellow oil, which according to NMR spectroscopy 25 the title compound, along with some impurities, contained n-butyl groups.

Preparation 17

6,6-Dibromophenicillanic acid 1,1-dioxide 30 380 mg of 3-chloroperbenzoic acid are added at 0 to 5 ° C to a solution of 359 mg of 6,6-dibromophenicillanic acid in 30 ml of methylene chloride. The reaction mixture is stirred at 0 to 5 ° C for 30 min and then at 25 ° C for 24 h. The filtered reaction mixture is concentrated in vacuo to give the title compound.

Preparation 18

Benzyl-6,6-dibromophenicillanate-1,1-dioxide

A mixture of 10.0 g of 6,6-dibromophenicillanic acid 1.1-40 dioxide, 2.15 g of sodium bicarbonate, 3.06 ml of benzyl bromide and 100 ml of N, N-dimethylformamide was 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 NaSO4). Concentration in vacuo gave 11.55 g of the title compound. The NMR spectrum (in CDCb) showed absorptions at 7.40 (s, 5 H), 5.30 (m, 2 H), 4.95 (s, 1 H), so 4.55 (s, 1 H) ), 1.50 (s, 3 H) and 1.20 (s, 3 H) ppm.

Example 15

Penicillanic acid 1,1-dioxide

A solution of 0.699 g of sodium bicarbonate in 50 ml of water, then 2.0 g of 5% Pd / C was added to a solution of 2.0 g of benzyl 6,6-dibromophenicillanate 55 1,1-dioxide in 50 ml of tetrahydrofuran. This mixture was shaken under a hydrogen atmosphere at about 3.45 • 105 Pa overpressure for 70 min. The tetrahydrofuran was evaporated 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 provided 423 mg of the title compound.

Preparation 19

2,2,2-trichloroethyl-6,6-dibromophenicillanate-1,1-dioxide

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The title compound was prepared from 6,6-dibromophenicillanic acid-1,1-dioxide and 2,2,2-T richloroethylchloroformate, essentially according to the procedure of Preparation J. The product was purified by chromatography on silica gel. The NMR spectrum of the product (in CDCb) showed absorptions at 4.85 (m, 2 H), 1.65 (s, 3 H) and 1.45 (s, 3 H) ppm.

Example 16

Penicillanic acid 1,1-dioxide

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

Preparation 20

1 - (Ethoxycarbonyloxy) ethyl 6,6-dibromophenicillanate-1,1-dioxide

A mixture of 2.26 g of 6,6-dibromophenicillanic acid-1,1-dioxide, 1.02 ml of l- (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 a little l- (ethoxycarbonyl-oxy) ethyl 6-bromophenicillanate.

Example 17

1 - (Ethoxycarbonyloxy) ethylpenicillanate-1,1-dioxide

A portion (230 mg) of the product of preparation 20 was dissolved in 10 ml of toluene. To this was added 0.4 ml of tri-n-butyltin hydride, then 0.164 g of azobisisobutyronitrile, and the mixture was heated at 70 to 80 ° C. for 3.5 hours. 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 was washed with 5% potassium fluoride and then with saturated sodium chloride solution. The ether solution (dried over Na: SO 4) was concentrated in vacuo and the residue was chromatographed on silica gel to give 0.043 g of the title compound. The NMR spectrum (in CDCb) 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-chloro-6-iodpenicillanic acid

To 3.38 g of iodine monochloride in 30 ml of methylene chloride, 11.1 ml of 2.5N sulfuric acid, then 1.92 g of sodium nitrite were added with stirring at 0 to 5 ° C. Then 3.00 g of 6-aminopenicillanic acid were added all at once and stirring was continued at 0 to 5 ° C. for 30 min. Then 22.8 ml of 1 M sodium sulfite solution was added in portions to the reaction mixture, and the layers were separated. The aqueous layer was washed with additional methylene chloride and then all organic phases were washed with saturated sodium chloride solution. The methylene chloride solution was dried (over NanSOi) and concentrated in vacuo to 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 stripped off 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 a sodium salt.

Manufacturing B

6-ß-chlorpenicillanic acid

A 2.95 g sample of sodium 6-chloro-6-iodpenicillanate was converted to the free acid and then dissolved in 125 ml of benzene under nitrogen. 1.08 ml of triethylamine was added to this solution and the mixture was cooled to 0 to 5 ° C. 0.977 ml of trimethylsilyl chloride was then added to the cooled mixture, and the reaction mixture was stirred at 0 to 5 ° C. for 5 minutes, at 25 ° C. for 60 minutes and at 50 ° C. for 30 minutes. The reaction mixture was cooled to 25 ° C. and the triethylamine hydrochloride was filtered off. The filtrate was treated with 15 mg of azobisisobutyronitrile, then with 2.02 ml of tri-n-butyltin hydride. The mixture was then irradiated with UV light under cooling for 15 minutes to maintain a temperature of about 20 ° C. The solvent was then removed in vacuo and the residue was 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 and concentrated in vacuo. This provided 980 mg of 6-ß-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 provide 850 mg of sodium 6-ß-chlorpenicillanate. The NMR spectrum (D2O) 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.

Manufacturing C

6-ß-bromopenicillanic acid

A mixture of 5.0 g of 6,6-dibromophenicillanic acid, 1.54 ml of triethylamine and 100 ml of benzene was stirred under nitrogen until a solution was obtained. The solution was cooled to 0-5 ° C and 1.78 ml 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 min and then stirred for a further 2.5 h. A small amount of azobisisobutyronitrile was then added, then 0.6 ml of tri-n-butyltin hydride (0.6 ml) was added and the mixture was again irradiated for 30 minutes. The solvent was then removed in vacuo and 5% sodium bicarbonate solution and diethyl ether were added to the residue. The two phase system was shaken vigorously for 10 minutes 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 into the sodium salt by adding water with 1 equivalent of sodium bicarbonate and then freeze-drying the solution thus obtained. This provided sodium 6-ß-bromophenicillanate contaminated with a small amount of the a 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, chromatographed and s

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644608

then chromatographed again. The NMR spectrum (D2O) of the product thus obtained showed absorptions at 5.56 (s, 2 H), 4.25 (s, 1 H), 1.60 (s, 3 H) and 1.50 (s 3 H) tpm.

Manufacturing D

6-ß-iodpenicillanic acid

The title compound is prepared by reducing 6,6-diiodopenicillanic acid with tri-n-butyltin hydride following the procedure of Preparation B.

Manufacturing E

Pivaloyloxymethyl-6-a-bromophenicillanate

To a solution of 280 mg of 6-a-bromophenicillanic 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.

Manufacturing F

The reaction of the suitable 6-halopenicillanic acid with 3-phthalidyl chloride, 4-crotonolactonyl chloride, y-butyro-lacton-4-yl chloride or the required alkanoyloxy-methyl chloride, l- (alkanoyloxy) ethyl chloride, 1-methyl-1- (alkanoyloxy) ethyl chloride, Alkoxycarbonyloxymethyl chloride, l- (alkoxycarbonyloxy) ethyl chloride or 1-methyl-1- (alkoxycarbonyloxy) ethyl chloride according to the procedure of preparation E provides the following compounds:

3-phthalidyl-6-a-chlorpenicillanate,

4-crotonolactonyl-6-ß-chlorpenicillanate, y-butyrolacton-4-yl-6-a-bromopenicillanate, acetoxymethyl-6-ß-bromopenicillanate, pivaloyloxymethyl-6-ß-bromopenicillanate, hexanoyloxymod-6-a-a-6-a-aan (Acetoxy) ethyl 6-ß-iodpenicillanate, l- (isobutyryloxy) ethyl 6-a-chlorpenicillanate,

1-methyl-1 - (acetoxy) ethyl 6-ß-chlorpenicillanate,

1-methyl-1 - (hexanoyloxy) ethyl-6-a-bromopenicillanate, methoxycarbonyloxymethyl-6-a-bromopenicillanate, propoxycarbonyloxymethyl-6-ß-bromopenicillanate, l- (ethoxycarbonyloxy) ethyl-6-a-bromopenicillanate, 1 ) ethyl 6-a-iodpenicillanate, 1-methyl-l- (methoxycarbonyloxy) ethyl 6-ß-iodpenicillanate or

1-Methyl-1 - (isopropoxycarbonyloxy) ethyl 6-a-chlorpenicil lanate.

Manufacturing G

6,6-diiodopenicillanic acid

A mixture of 15.23 g iodine, 10 ml 2.5 N sulfuric acid,

2.76 g of sodium nitrite and 75 ml of methylene chloride were stirred at 5 ° C and 4.32 g of 6-aminopenicillanic acid were added over 15 minutes. At 5 to 10 ° C, stirring was continued for 45 minutes after the addition was complete, and then 100 ml of 10% sodium bisulfite solution was 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 MgSO4) and concentrated in vacuo. This provided 1.4 g of the title compound contaminated with some 6-iodopenicillanic acid. The product had a melting point of 58 to 64 ° C. The NMR spectrum (CDCb) showed absorptions

5.77 (s, 1H), 4.60 (s, 1H), 1.71 (s, 3H) and 1.54 (s, 3H) ppm.

Manufacturing H

Pivaloyloxymethyl-6-a-bromophenicillanate

6.16 g of chloromethyl pivalate were added dropwise over 5 minutes at room temperature to a stirred mixture of 11.2 g of 6-a-bromopenicillanic acid, 3.7 g of sodium bicarbonate and 44 ml of N, N-dimeth-s ylformamide. The 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 decolorized ethyl acetate solution was dried (over MgSO-t) and evaporated to dryness in vacuo. This provided 12.8 g (80% yield) of the 15 title compound.

Manufacturing I

Benzyl 6-a-bromophenicillanate

The title compound was prepared by esterifying 20 6-a-bromopenicillanic acid with benzyl bromide following the procedure of Preparation H (yield 83%). The NMR spectrum (in CDCb) showed absorptions at 7.35 (s, 5 H), 5.35 (m, 1 H), 5.15 (s, 2 H), 4.70 (m, 1 H) , 4.60 (s, 1H), 1.55 (s, 3H) and 1.35 (s, 3H) ppm.

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Manufacturing J

2,2,2-trichloroethyl penicillanate

To a stirred solution of 11.2 g of 6-a-bromopenicillanic acid in 50 ml of tetrahydrofuran at 0 ° C., 3.48 g of 30 pyridine were added over 1 hour. 8.47 g of 2,2,2-trichloroethyl chloroformate were added to the cloudy solution thus obtained in 10 min, the temperature being kept between 0 and 2 ° C. The mixture was stirred for a further 30 minutes and then the cooling bath was removed. Stirring was continued at room temperature overnight. 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 40 saturated sodium chloride solution. The ethyl acetate solution was then decolorized and dried and concentrated to a small volume. To the resulting mixture was added 100 ml of hexane and the solids were filtered off to yield 10.5 g of the title compound, mp 45 105-110 ° C. The NMR spectrum (in CDCb) showed absorptions at 5.50 (d, 1 H), 4.95 (d, 1 H), 4.90 (s, 2 H), 4.65 (s, 1 H) , 1.70 (s, 3 H) and 1.55 (s, 3 H) ppm.

Production of K 50 6,6-dibromophenicillanic acid

To 500 ml of methylene chloride, cooled to 5 ° C., 119.9 g of bromine, 200 ml of 2.5N sulfuric acid and 34.5 g of sodium nitrite were added. 54.0 g of 6-aminopenicillanic acid were then added to this stirred mixture in portions over 30 min 55, the temperature being kept at 4 to 10 ° C. The stirring was continued at 5 ° C for 30 minutes, and then 410 ml of a 1.0 M sodium bisulfite solution was added dropwise at 5-10 ° C over 20 minutes. The layers were separated and the aqueous layer was extracted twice with 150 ml of methylene chloride 60. The original methylene chloride layer was combined with the two extracts to a solution of 6,6-dibromophenicillanic acid. This solution was used directly in Example 17.

65 Manufacturing L

6-chloro-6-iodpenicillanic acid

To 100 ml of methylene chloride, cooled to 3 ° C., 4.87 g of iodine chloride, 10 ml of 2.5N sulfuric acid and 2.76 g were added

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Given sodium nitrite. 4.32 g of 6-aminopenicillanic acid were then added to this stirred mixture in portions over 15 minutes. The mixture was stirred for a further 20 min at 0 to 5 ° C., and then 100 ml of 10% sodium bisulfite solution were added dropwise at approx. 4 ° C. The mixture was stirred for a further 5 minutes and then the layers were separated. The aqueous layer was extracted with methylene chloride (2x50 ml) and the combined methylene chloride solutions were washed with brine, dried (over MgSO4) and concentrated in vacuo to the title compound as a tan solid, mp 148-152 ° C. The NMR spectrum of the product (CDCb) 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 pellet) showed absorptions at 1780 and 1715 cm-1.

Manufacturing M

6-bromo-6-iodpenicillanic acid

To 100 ml of methylene chloride, cooled to 5 ° C., 10 ml of 2.5N sulfuric acid, 6.21 g of iodobromide and 2.76 g of sodium nitrite were added. This mixture was mixed with vigorous stirring at 0 to 5 ° C in 15 min with 4.32 g of 6-aminopenicillanic acid. The mixture was stirred at 0 to 5 ° C for a further 20 min, then 100 ml of 10% sodium bisulfite solution between 0 and 10 ° C was added dropwise. The layers were then separated and the aqueous layer was extracted with (3 x 50 ml) methylene chloride. The combined methylene chloride layers were washed with brine, dried (over MgSO4) and concentrated in vacuo. The residue was dried under high vacuum for 30 min and gave 6.0 g (72% yield) of the title compound, mp. 144-147 ° C. The NMR spectrum (CDCb) 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 1710cm-1. The mass spectrum showed an outstanding ion at m / e = 406.

Manufacturing N

6-chloro-6-bromophenicillanic acid

6-chloro-6-bromophenicillanic acid is prepared from 6-aminopenicillanic acid by diazotization and subsequent reaction with bromine chloride according to the procedure of preparation M.

Manufacturing O

Pivaloyloxymethyl-6,6-dibromophenicillanate

To a stirred solution of 3.59 g of 6,6-dibromophenicillanic acid in 20 ml of N, N-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 approx. 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 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.

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Manufacturing P

Reaction of the suitable 6,6-dihalogenpenicillanic acid with 3-phthalidyl chloride, 4-crotonolactonyl chloride, y-butyrolacton-4-yl chloride or the required alkanoyloxy-20 methyl chloride, l- (alkanoyloxy) ethyl chloride, 1-methyl-1- (alkanoyloxy) ethyl chloride, alkoxycarbonyloxymethyl chloride, l- (alkoxycarbonyloxy) ethyl chloride or 1-methyl-l- (alkoxycarbonyloxy) ethyl chloride according to the procedure of preparation O provides the following compounds:

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3-phthalidyl-6,6-dibromophenicillanate,

4-crotonolactonyl-6-chloro-6-iodpenicillanate, y-butyrolactonyl-6-bromo-6-iodpenicillanate, acetoxymethyl-6-chloro-6-bromopenicillanate,

30 pivaloyloxymethyl-6-chloro-6-iodpenicillanate, hexanoyloxymethyl-6,6-dibromophenicillanate, l- (acetoxy) ethyl-6,6-dibromophenicillanate, l- (isobutyryloxy) ethyl-6-bromo-6-iodophenicillanate, l- -l- (acetoxy) ethyl-6,6-dibromophenicillanate, 35 l-methyl-l- (hexanoyloxy) ethyl-6-chloro-6-bromopenicillanate, methoxycarbonylmethyl-6,6-dibrompenicillanate, propoxycarbonyloxymethyl-6-chloro-6- iodpenicillanate, l- (ethoxycarbonyloxy) ethyl-6,6-dibromophenicillanate, l- (butoxycarbonyloxy) ethyl-6-bromo-6-iodpenicillanate, 40 1 -methyl-1 - (methoxycarbonyloxy) ethyl-6,6-dibrompenicillanate and l- Methyl l- (isopropoxycarbonyloxy) ethyl 6,6-dibromophenicillanate.

B

Claims (15)

644608 2nd PATENT CLAIMS 1. Process for the preparation of a compound of the formula * (I) N "'"' COOK1 or their pharmaceutically acceptable base salt, wherein R1 is hydrogen or an ester-forming, in vivo hydrolysable residue, characterized in that a compound of the formula X {((,,. H O 0 N. > vCH3 CI ^ (III) '' '"' COOR1 or their base salt, wherein R1 is hydrogen or an ester-forming, in vivo hydrolysable residue and X and Y are each hydrogen, chlorine, bromine or iodine, provided that when X and Y both have the same meaning, they are both bromine must be dehalogenated. 2. The method according to claim 1, characterized in that the dehalogenation is carried out by catalytic hydrogenolysis. 3. The method according to claim 2, characterized in that the catalytic hydrogenolysis is carried out in an inert solvent. 4. The method according to claim 2 or 3, characterized in that the catalytic hydrogenolysis at a pressure in the range of 1 • 10s Pa to 100 * 105 Pa and in the presence of 0.01 to 2.5 wt .-% of a hydrogenolysis catalyst is carried out. 5. The method according to any one of claims 2 to 4, characterized in that the catalytic hydrogenolysis is carried out at a temperature in the range from 0 to 60 ° C and at a pH in the range from 4 to 9. 6. The method according to any one of claims 2 to 5, characterized in that X is bromine and Y is hydrogen. 7. The method according to any one of claims 2 to 5, characterized in that X and Y are both bromine. 8. The method according to any one of claims 2 to 7, characterized in that R1 is hydrogen. 9. Compound of the formula H Q p X. y (III) COOR and their base salts, characterized in that R1 is hydrogen or an ester-forming, in vivo hydrolysable radical and X and Y are each hydrogen, chlorine, bromine or iodine, with the proviso that when X and Y both have the same meaning, they both must be bromine. 10. A compound according to claim 9, characterized in that R1 is hydrogen. 11. A compound according to claim 9, characterized in that R13-phthalidyl, 4-crotonolactonyl, y-butyro-lactonyl or a group of the formula R2 O I I! -C-O-C-R4 I. R3 R2 I. O or -C-O-C-O-R4 R3 (V) (VI) wherein R2 and R3 are each hydrogen or alkyl of 1 to 2 carbon atoms and R4 is alkyl of 1 to 5 carbon atoms. 12. A compound according to any one of claims 10 or 11, characterized in that X is bromine and Y is hydrogen. 13. A compound according to any one of claims 10 or 11, characterized in that X and Y are both bromine. 15