DK159852B - PROCESS FOR THE PREPARATION OF PENICILLANIC ACID-1,1-DIOXIDE OR BASIC SALTS OR IN VIVO EASY HYDRAULIZABLE ESTERS - Google Patents

Description

in

DK 159852 B

The present invention relates to a particular process for the preparation of penicillanic acid 1,1-dioxide or esters thereof of the general formula

5 'ί V »% CHJ

0 ·% C00R1 or a pharmaceutically acceptable base salt thereof, wherein 10 is hydrogen or an in vivo readily hydrolyzable ester-forming group, characterized by the characterizing part of claim 1.

Penicillanic acid 1,1-dioxide and in vivo readily hydrolyzable esters thereof are useful as beta-lactamasein inhibitors and as agents promoting the efficacy of certain beta-lactam antibiotics when the latter is used to treat bacterial infections in mammals, especially humans. .

From Danish Patent Specification No. 155,740, it is known to prepare penicillanic acid 1,1-dioxide and in vivo readily hydrolyzable esters thereof by oxidation of penicillanic acid or esters thereof, wherein these starting compounds can be prepared by debromating similar 6-bromo-penicillanic acid derivatives . Compared to this known process, the process of the present invention, which also uses, as starting compounds, 6-halo-penicillanic acid derivatives, leads to better yields of penicillanic acid 1,1-dioxide and in vivo easily hydrolyzable esters thereof, as documented below.

30 6-Halo-penicillanic acids are disclosed by Cignarella et al., Journal of Organic Chemistry, 22, 2668 (1962), and in U.S. Patent No. 3,206,469, and hydrogenolysis of 6-halo-penicillanic acids for penicillanic acid is disclosed in British Patent Specification No. 1,072,108.

Harrison et al., Journal of the Chemical Society

DK 159852 B

(London), Perkin I, 1772 (1976) mentioned (a) oxidation of 6,6-dibrompenicillanic acid with 3-chloroperbenzoic acid to form a mixture of the corresponding α- and β-sulphoxides, (b) oxidation of methyl 6,6-dibrompenicillanate 5 with 3-chloroperbenzoic acid to form a methyl 6,6-dibrompenicillanate-1,1-dioxide; (c) oxidation of methyl 6-a-chlorpenicillanate with 3-chloroperbenzoic acid to form a mixture of and (d) oxidation of methyl 6-brompenicillanate with 3-chloro-perbenzoic acid to form a mixture of the corresponding α- and 8-sulfoxides.

Clayton, Journal of the Chemical Society (London), (C), 2123, (1969) discloses: (a) preparation of 6,6-di-bromo- and 6,6-diiodo-penicillanic acid, (b) oxidation of 6, 6-15 dibrompenicillanic acid with sodium periodate to form a mixture of the corresponding sulfoxides, (c) hydrogenolysis of methyl 6,6-dibrompenicillanate to give methyl 6-a-brompenicillanate, (d) hydrogenolysis of 6.6 dibrompenicillanic acid and its methyl ester for the formation of penicillanic acid and its methyl ester; and (e) hydrogenolysis of a mixture of methyl 6,6-diiodo-penicillanate and methyl 6-a-iodo-penicillanate to form pure methyl-6-a-iodo-penicillanate.

The process of the present invention 25 for the preparation of penicillanic acid 1,1-dioxide and in vivo easily hydrolyzable esters thereof of the above general formula I is characterized in that a) a compound of the general formula 30 Y * vvCH3

“Λ-T P'CBj (ID

35 J-H-

o 'COOR

DK 159852 B

3 or a pharmaceutically acceptable base salt thereof, wherein R is as defined above for R 2 or is a conventional penicillin carboxy protecting group, and X and Y are each selected from hydrogen, chlorine, bromine and iodine with the condition that when X and Y are the same, they must both be bromine, contacted with a reagent selected from alkali metal permanganates, alkaline earth metal permanganates and organic peroxycarboxylic acids, to form a compound of the general formula 10 H H +. / ° _CH, X '' '<U3i ^ CH3 (III)

0 S C OCR

15 or a base salt thereof, wherein X, Y and R are as defined above, and b) the product of step a) is dehalogenated by catalytic hydrogenolysis in an inert solvent, at a pressure 20 in the range of 1 to 100 kg / cm the presence of 0.01 to 2.5 wt. of a hydrogenolysis catalyst, at a temperature in the range of 0 to 60 ° C and at a pH in the range of 4 to 9, wherein a protecting group present at R is removed below or after step a) or step b) and, if desired, an obtained compound of formula (I) wherein R 1 is hydrogen is esterified to a corresponding compound wherein R 1 is an in vivo readily hydrolyzable ester forming group, or a obtained compound of formula (I), wherein R 1 is an in vivo readily hydrolyzable ester forming group, hydrolyzed to a corresponding compound wherein R 1 is hydrogen or a won compound of formula (I) is transferred into a pharmaceutically acceptable base salt thereof.

4

DK 159852 B

In step b), the hydrogenolysis catalyst is preferably present in an amount of from ca. 0.1 to approx. 1.0% by weight based on the compound of formula III.

The preferred meaning of X and Y is bromine and the 5 preferred reagents for carrying out step (a) are potassium permanganate and 3-chloroperbenzoic acid.

In the case where X and Y are both chlorine, the compound of formula II is difficult to obtain. In the case where X and Y are both iodine, step (a) 10 of the process according to the invention proceeds inappropriately slowly.

The difference between the present process for the preparation of penicillanic acid-1,1-dioxide and in vivo readily hydrolyzable esters thereof and the known method of preparation of such penicillanic acid derivatives from the above-mentioned Danish Patent Specification No. 155,740 can be illustrated by the following scheme:

Y H

x '· / -CH3 20 JI CH3 (CN-1, J i 1 nCOOR1 / "\ 25 ϊ 8' y * g * · ../_ V · 'CH3 I ^ S. -CH, JJI CH3 j JTP' CH , 30 111 / ΠΙΑ _CH3 35 JZJ_TCH3! '-. COOR1

DK 159852 B

5 where r \ X and Y are as defined above.

As can be seen, the known process first dehalogenates and then oxidizes, while in the process according to the invention it is first oxidized and then dehalogenated.

In the known manufacturing process, at stage IIIA -> I, the best yield is 78% (Example 1), which relates to the preparation of penicillanic acid 1,1-dioxide by oxidation of the sodium salt of penicillanic acid.

In the disclosure no yield is reported for the preparation of the penicillanic acid starting material at the debromination step II -> IIIA. Therefore, for comparison purposes, the following comparative example has been carried out: Preparation of penicillanic acid:

To a stirred solution of 1095.2 g of 6-α-brompenic-cillanic acid in 2177 ml of methanol was added 622 ml of water.

The resulting solution was cooled to 20 ° C, the pH was adjusted to 7.2 with 4N sodium hydroxide, and then 550 g of 5% palladium-on-carbon catalyst was added. The mixture was then shaken in a hydrogen atmosphere at a pressure of approx. 5 kg / cm until hydrogen uptake ceased. The catalyst was filtered off and washed with a mixture of 2177 ml of methanol and 622 ml of water. The washings and filtrate from the filtration were collected and diluted to a volume of 18 liters with water. The resulting mixture was extracted with dichloromethane and the extracts were washed with water followed by saturated sodium chloride solution. The dichloromethane solution was dried 50 with magnesium sulfate and evaporated in vacuo to give 275.6 g (35% yield) of penicillanic acid.

Thus, the total yield of the known process II -> IIIA -> I is no more than approx. 27%.

For the process of the present invention, based on the Examples below, a total yield II -> III -> I of at least 53% can be expected (cf. Examples 1 + 8, Examples 12 + 13 and Examples 17 + 21).

The method of the present invention 6

DK 159852 B

thus, yields about twice the yields obtained by the known synthetic route.

The intermediate compounds of general formula III and their base salts, wherein X, Y and R are as defined above, are novel compounds.

A preferred intermediate is 6,6-dibrompenicillanic acid 1,1-dioxide, i.e. the compound of formula III wherein X and Y are bromine and R1 is hydrogen.

The final compounds and intermediates referred to in the present specification are referred to as penicillanic acid derivatives represented by the following structural formula:

"'COOH

In penicillanic acid derivatives, a broken line bond of a substituent to the bicyclic nucleus indicates that the substituent is below the core plane. Such a substituent is said to be in o-configuration. Conversely, full line binding of a substituent to the bicyclic nucleus indicates that the substituent is above the plane of the nucleus.

DK 159852 B

7

The latter configuration is referred to as 8 configuration.

Thus, group X has α-configuration and group Y has 8-configuration of formula II.

In the present specification, when 5 is an in vivo readily hydrolyzable ester-forming group, this is a group which is intended to be derived from an alcohol of the formula 11 of R-OH, so that the part COOR in such a compound of the formula You represent an ester group. Furthermore, R 1 is such that the COOR 3 group is readily cleaved in vivo with the release of a free carboxy group (COOH). That is, R 1 is a group of such a type that when a compound of formula I wherein R 1 is an in vivo readily hydrolyzable ester-forming group is exposed to mammalian blood or tissue, the compound of formula I wherein R is hydrogen, easily formed. The groups R are well known in the art of penicillin. In most cases, they improve the absorption properties of the penicillin compound. In addition, R1 must be of such a nature that it provides a compound of formula I with pharmaceutically acceptable properties and releases pharmaceutically acceptable fragments when cleaved in vivo. The groups R 1 are well known and readily identified by one of skill in the art of penicillin. See, for example, German Publication No. 2,517,316. Specific examples of groups for R 1 are 3-phthalidyl, 4-crotonolactonyl, γ-butyrolacton-4-yl and groups of the formulas:

R2 O R2 O

in II 4 I II 4 -C-O-C-R and -C-O-C-O-R '

30 r3 P

V VI

Wherein R and R are each hydrogen or alkyl of 1-2 C atoms and R 1 is alkyl of 1-5 C atoms. However, preferred groups for R are alkanoyloxymethyl of 3-7 C atoms, 1- (alkanoyloxy) ethyl of 4-8 C atoms, 1-methyl-1- (alkanoyloxy) ethyl of 5-9 C atoms, alkoxycarbonyl -oxymethyl with 3-6 C atoms, 1- (alkoxycarbonyloxy) ethyl with 4-7 C atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl 8

DK 159852 B

with 5-8 C atoms, 3-phthalidyl, 4-crotonolactonyl and γ-butyrolacton-4-yl.

3-Phthalidyl, 4-crotonolactonyl and γ-butyrolactone-4-yl refer to structures VII, VIII and IX. The wave-5 lines must indicate each of the two epimers or a mixture thereof.

- y> 'Φ o o 0

will VIII IX

Step (a) of the process of the invention injects oxidation of the sulfide group of a compound of formula II to a sulfone group, thereby forming a compound of formula III. As mentioned, for this reaction, alkali metal permanganates such as sodium and potassium permanganate, alkaline earth metal permanganates such as calcium and barium permanganates, and organic peroxycarboxylic acids such as peracetic acid and 3-chloroperbenzoic acid may be used.

When a compound of formula II wherein X, Y and R * are as defined above 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 0.5 to 30 approx. 10 molar equivalents, preferably from ca. 1 to approx.

4 molar equivalents of the permanganate in an appropriate inert solvent system reaction.

A suitable solvent inert to the reaction is one which does not adversely interact neither with the starting materials nor with the product, and water is commonly used. If desired, a water-miscible co-solvent may be added but will not interact with the permanganate such as

DK 159852 B

9 tetrahydrofuran. The reaction can be carried out at a temperature within the range of from ca. -30 ° C to approx. 50 ° C, and it is preferably carried out from ca. -10 ° to approx. 10 ° C.

At about. 0 ° C, the reaction is generally completed in a short period of time, e.g. within an hour. Although the reaction may be carried out under neutral, basic or acidic conditions, it is preferred to use a pH within the range of from ca. 4 to approx. 9, preferably 6-8. However, it is essential to select conditions under which de-composing the β-lactam ring system of the compound of formula II or III is avoided. It is often advantageous to buffer the pH of the reaction medium in the vicinity of neutrality. The product is recovered by conventional techniques. Any excess permanganate is generally decomposed using sodium bisulfite, and if the product is not in solution, it is then recovered by filtration. It is separated from manganese dioxide by extracting it into an organic solvent and removing the solvent by evaporation. If the product is in solution at the end of the reaction, it is isolated by usual solvent extraction.

When a compound of formula II wherein X, Y and R * 10 are as defined above 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 1 to approx. 6 molar equivalents, and preferably approx. 2.2 molar equivalents of the oxidant in a reaction-inert organic solvent. Typical solvents are chlorinated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, and ethers such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane. The reaction is usually carried out at a temperature of from ca. -30 ° to approx.

50 ° C, preferably from ca. 15 ° to approx. 30 ° C. At about. Reaction times of about 25 ° C are generally used. 2 to approx.

10

DK 159852 B

16 hours. The product is usually isolated by removing the solvent by evaporation in vacuo. The reaction product can be purified by conventional methods well known in the art. Alternatively, it can be used directly in step (b) without further purification.

Step (b) of the process of the invention is a dehalogenation reaction. An appropriate method for carrying out this conversion is to stir or shake a solution of a compound of formula III under a hydrogen atmosphere, or hydrogen mixed with an inert diluent such as nitrogen or argon, in the presence of a hydrogenolysis catalyst. Suitable solvents for this hydrogenolysis reaction are those which essentially dissolve the starting compound of formula III but which do not themselves undergo hydrogenation or hydrogenolysis. Examples of such solvents include 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-20-dimethylformamide, Ν, dim-dimethylacetamide and N -methylpyrro-lidone, water and mixtures thereof. Further, it is common to buffer the reaction mixture so that it is operated at a pH within the range of approx. 4 to approx. 9, preferably from ca. 6 to approx. 8. Borate and phosphate buffers are commonly used. The introduction of the gaseous hydrogen into the reaction medium is usually carried out by carrying out the reaction in a sealed container containing the compound of formula III, the solvent, the catalyst and the hydrogen. The pressure within the reaction vessel may range from 1 to 100 kg / cm. The preferred pressure range when the atmosphere inside the reaction vessel is 2 substantially pure hydrogen is from 2 to 5 kg / cm. The hydrogenolysis is carried out at a temperature of from 0 ° C to 6 ° C, preferably from 25 ° C to 50 ° C. When the preferred temperature and pressure values are used, the hydrogenolysis generally proceeds within a few minutes.

DK 159852 B

11 hours, e.g. from 2 hours to 20 hours. The catalysts used in this hydrogenolysis reaction are of the type well known in the art for this type of conversion, and typical examples are the precious metals such as nickel, palladium, platinum and rhodium. The catalyst is present in an amount of from 0.01 to 2.5% by weight, preferably from 0.1 to 1.0% by weight, based on the compound of formula III. It is often convenient to suspend the catalyst on an inert carrier. A particularly suitable catalyst is palladium suspended on an inert carrier such as coal.

When it is desired to prepare a compound of formula I wherein R is hydrogen, a compound of formula II wherein R 1 is hydrogen may be subjected to steps (a) and 15 (b) of the present process. In other words, the process of oxidation followed by dehalogenation of a 6-halogen or 6,6-dihalogen derivative of penicillanic acid with a free carboxy group at the 3-position. According to a further aspect of the invention, however, it is possible to begin each of steps (a) and (b) with the carboxy group at the 3-position blocked by a conventional penicillin carboxy protecting group. The protective group may be removed during or after step (a) or step (b) during regeneration of the free carboxy group. In this regard, various protecting groups commonly used in the penicillin field can be used to protect the 3-carboxy group. The essential requirements of the protecting group are that it must be capable of being bound to the particular compound of formula II or III and be removable from that compound of formula I or III using conditions under which the β-lac taming system remains in it. essentially intact. For each of steps (a) and (b), typical examples are the tetrahydropyranyl group, trialkylsilyl groups, the benzyl group, substituting benzyl groups (e.g. 4-nitrobenzyl), the benzhydryl group, 2,2,2-trichloroethyl group, t.- butyl group and phenacyl group. Although all protective 12

DK 159852 B

groups not applicable in all situations, a particular group that can be used in a particular situation can be readily selected by one of ordinary skill in the art. See also U.S. Patent Nos. 3,632,850 and 3,197,466, British Patent No. 1,041,985, Woodward et al., Journal of the American Chemical Society, 88, 852 (1966), Chauvette , Journal of Organic Chemistry 36, 1259 (1971), Sheedan et al., Journal of Organic Chemistry, £ 2, 2006, (1964) and "Cephalosporin and Penicillins, Chemistry and Biology", 10 published by H.E. Flynn, Academic Press, Inc., 1972. The penicillin carboxy protecting group is removed in the usual manner, taking into account the lability of the β-lactam ring system.

6-α-Chlorpenicillanic acid and 6-α-bromo-penicillanic acid are prepared by diazotizing 6-aminopenicillanic acid in the presence of hydrochloric acid and hydrobromic acid, respectively (Journal of Organic Chemistry, 21, 2668 (1962)). 6-α-Iodine penicillanic acid is prepared by diazotizing 6-aminopenicillanic acid in the presence of iodine, followed by hydrogenolysis (Clayton, Journal of the Chemical Society (C), 21,223 (1969)). 6-p-Chlorpenicillanic acid, 6- (3-brompenicillanic acid and 6-iodopenicillanic acid are prepared by reduction of 6-chloro-6-iodopenicillanic acid, 6,6-dibromepicillanic acid and 6,6-diiodpenicillanic acid with tri-n-butyl 6-Chloro-6-iodopenicillanic acid is prepared by diazotizing 6-aminopenicillanic acid in the presence of iodine chloride, 6,6-dibrompenicillanic acid is prepared by the method of Clayton, Journal of the Chemical Society (London) (C) 2123 (1969 ), and 6,6-diiodo-penicillanic acid is prepared by diazotizing 6-aminopenicillanic acid in the presence of iodine.

The compounds of formula I, II and III which are hydrogen are acidic and will form salts with basic agents. These salts can be prepared by standard techniques, such as by contacting the acidic and basic components, usually in a stoichiometric ratio, in an aqueous, non-aqueous or partially aqueous medium, such as a grid. They are then recovered by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent or, in the case of aqueous solutions, by lyophilization, as appropriate. Basic agents which can be suitably used in salt formation are both organic and inorganic, and include ammonia, organic amines, alkali metal hydroxides, carbonates, bicarbonates, hydrides and alkoxides, as well as alkaline earth metal hydroxides, carbonates, hydrides and alkoxides. Representative examples of such bases are primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine and octylamine, secondary amines such as diethylamine, morpholine, pyrrolidine and piperidine, tertiary amines such as triethylamine, N-ethylpiperidine , N-methylmorpholine and 1,5-diazabicyclo [4.3.0] -15 non-5ene, hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and barium hydroxide, alkoxides such as sodium methoxide and potassium ethoxide, hydrides such as calcium hydride and sodium hydride carbonates such as potassium carbonate and sodium carbonate, bicarbonates such as sodium bicarbonate and potassium bicarbonate, and alkali metal salts of long chain fatty acids such as sodium 2-ethyl hexanoate. Preferred salts of the compound of formula I are the sodium, potassium and triethylamine salts.

The compound of formula I wherein R 1 is hydrogen and its salts are active as medium-strength antibacterial agents both in vitro and in vivo, and compounds of formula I wherein R 1 is an in vivo readily hydrolyzable ester-forming group are active as antibacterial agents. medium strength agents in vivo. Minimum inhibition concentrations 30 (MIC values) for penicillanic acid 1,1-dioxide against several microorganisms are shown in Table I.

14

DK 159852 B

Table I

In vitro antibacterial activity of penicillanic acid 1,1-dioxide.

Microorganism MIC (mcg / ml)

Staphylococcus aureus 100

Streptococcus faecalis 200

Streptocuccus pyogenes 100

Escherichia coli 50 10 Pseudomonas aeruginosa 200

Klebsiella pneumoniae 50

Proteus mirabilis 100

Proteus morgani 100

Salmonella typhimurium 50 15 Pasteurella multocida 50

Serratia marcescens 100

Enterobacter aerogenes 25

Enterobacter clocae 100

Citrobacter freundii 50 20 Providencia 100

Staphylococcus epidermis 200

Pseudomonas putida 200

Hemophilus influenzae 50

Neisseria gonorrhoeae 0.312 25

The in vitro antibacterial activity of the compound of formula I, wherein hydrogen is and its salts, makes them useful as industrial antimicrobial agents, for example in water treatment, slime control, paint preservation and wood preservation, and for local use as disinfectants. When these compounds are used for topical application, it is often convenient to mix the active ingredient with a non-toxic carrier such as vegetable oil or mineral oil or an emollient cream. It may also be dissolved or dispersed in liquid diluents or solvents such as water, alkanols, glycols or mixtures thereof. In most cases, it is appropriate to use concentrations of the active ingredient of from approx. 0.1 to approx. 10% by weight based on the total composition.

The in vivo activity of the compounds of formula I wherein R 1 is hydrogen or an in vivo readily hydrolyzable ester forming group, and salts thereof, make them suitable for controlling bacterial infections in mammals, including humans, both by oral and parenteral use. The compounds will be used to control infections caused by susceptible bacteria in 10 people, e.g. infections caused by strains of Neisseria gonorrhoeae.

In the therapeutic application of a compound of formula I or a salt thereof to a mammal, in particular humans, the compound may be used alone or it may be mixed with pharmaceutically acceptable carriers or diluents. It can be used orally or parenterally, ie. intramuscularly, subcutaneously or intraperitoneally. The carrier or diluent is selected based on the intended application. In the case of, for example, oral use, the compound can be used in the form of e.g. tablets, capsules, bolches, lozenges, powders, syrups, elixirs, aqueous solutions and suspensions, in accordance with standard pharmaceutical practice. The amount ratio of active ingredient to carrier will depend on the chemical nature, solubility and stability of the active ingredient as well as the intended dose. However, pharmaceutical compositions containing an antibacterial agent of formula I will generally contain from 20% to approx. 95% active ingredient. In the case of tablets for oral use, commonly used carriers include lactose, sodium citrate and phosphoric acid salts. Various disintegrating agents such as starch and lubricants such as magnesium stearate, sodium lauryl sulfate and talc are commonly used in tablets. For oral use in capsule form, useful diluents are lactose and high molecular weight polyethylene glycols. When aqueous 16 is required

DK 159852 B

suspensions for oral use, the active ingredient may be combined with emulsifying and suspending agents. If desired, certain sweeteners and / or flavors / fragrances can be added. For parenteral use comprising intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared and the pH of the solutions adjusted and buffered appropriately. For intravenous use, the total concentration of solutes 10 must be controlled so that the preparation is made isotonic.

The physician will ultimately determine the appropriate dose of a compound of formula I for a given patient, and this dose may be expected to vary by age, weight and response for that patient as well as the nature and degree of the patient's symptoms. The compound will normally be used orally in doses in the range of about 10 to approx. 200 mg per kg body weight per day and parenterally in doses from approx. 10 to approx. 400 mg per kg body weight per day. However, these figures are illustrative only and in some cases doses outside the above limits may be required.

in

The compounds of formula I wherein R is hydrogen or an in vivo easily hydrolyzable ester forming group, or a salt thereof, enhance the antibacterial efficacy of β-lactam antibiotics in vivo. They lower the amount of antibiotic needed to protect mice against an otherwise lethal inoculum of certain β-lactamase-producing bacteria. This ability makes them valuable for co-use with β-lactam antibiotics in the treatment of bacterial infections in mammals, especially humans. In the treatment of a bacterial infection, said compound of formula I may be admixed with said β-lactam antibiotic and the two agents are thus used simultaneously. Alternatively, said compound of formula I can be used as a separate agent during a course of treatment with a β-lactam antibiotic. In some cases, it is advantageous to give the patient a pre-dose of the compound of formula I before initiating treatment with a β-lac-tam antibiotic.

DK 159852 B

When penicillanic acid 1,1-dioxide, a salt or an in vivo readily hydrolyzable ester thereof is used to enhance the efficacy of β-lactam antibiotic, it is preferably used in composition with standard pharmaceutical carriers and -fortyndingsmidler. The compositional methods discussed above for the use of penicillanic acid 1,1-dioxide or an in vivo readily hydrolyzable ester thereof as a single unit antibacterial agent may be used when co-use is contemplated with another β-lactam antibiotic. . A pharmaceutical composition comprising a pharmaceutically acceptable carrier, a β-lactam antibiotic and penicillanic acid-1,1-dioxide or an in vivo readily hydrolyzable ester thereof will normally contain from ca. 5 to approx. 80% of the 15 pharmaceutically acceptable carrier by weight.

When penicillanic acid 1,1-dioxide or an in vivo readily hydrolyzable ester thereof is used in combination with another β-lactam antibiotic, the sulfone may be used orally or parenterally, i.e. intramuscularly, subcutaneously or intraperitoneally. Although the 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 salt or ester thereof to the β-lactam antibiotic will usually be within the range of about 5%. 1: 3 to approx.

25 3: 1. When penicillanic acid-1, l-dioxide or salt or in vivo readily hydrolyzable ester thereof is used in combination with another β-lactam antibiotic, the daily oral dose of each component will usually be in the range of about 5%. 10 to approx. 200 mg per kg body weight, and the daily parenteral dose of each component will usually range from approx. 10 to approx. 400 mg per kg body weight.

However, these figures are illustrative only and in some cases doses outside these limits may be required.

Typical β-lactam antibiotics, along with which penicillanic acid-1,1-dioxide and its in vivo easily hydrolyzable esters can be used, are:

DK 159852B

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) -3-desacetoxymethylcephalosporanoic acid.

Typical microorganisms against which the anti-bacterial activity of the above β-lactam antibiotics are enhanced are: 10 Staphylococcus aureus,

Haemophilus influenzae,

Klebsiella pneumoniae and

Bacteroides fragilis.

As is known to those skilled in the art, some (3-15 lactam compounds are effective when used orally or parenterally, while others are effective only when used parenterally. When penicillanic acid 1,1-dioxide, a salt thereof or In vivo readily hydrolyzable ester thereof should be used simultaneously (i.e. co-blended) with a (3-20 lactam antibiotic effective only in parenteral use), it will be required with a combination composition suitable for parenteral use. the picicillanic acid 1,1-dioxide or an ester thereof should be used simultaneously (co-mixed) with a β-lactam antibiotic effective either orally or parenterally, combinations suitable for either oral or Furthermore, it is possible to use preparations of penicillanic acid 1, 1-dioxide or salt or ester thereof orally, while administering additional β-lactam antibiotics parenterally, and it is also possible to use preparations. rates of penicillanic acid 1,1-dioxide or salt or ester thereof parenterally, while the additional (3-lactam antibiotic) is used orally.

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

DK 159852 B

19

The invention is further described by the following examples. Infrared (IR) spectra are measured as potassium bromide plates (KBr plates) and diagnostic absorption bands are indicated in wavelengths (cm. Nuclear magnetic resonance spectra (NMR) are measured at 60 MHz for solutions in deuterochloroform (CDCl , perdeuteroacetone (CD2 COCDj), perdeuterodimethylsulfoxide (DMSO-dg) or deuterium oxide (DjO), and peak positions are expressed in parts per million (ppm) downward from tetramethylsilane or sodium 2,2-dimethyl-2-10 silapentane. The following abbreviations for tip forms are used: s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet.

Example 1 6-α-Brompenicillanic acid 1,1-dioxide.

To a stirred mixture of 560 ml of water, 300 ml of dichloromethane and 56.0 g of 6-a-brompenicillanic acid was added 4N sodium hydroxide solution 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 was discarded. The aqueous phase was then rapidly poured with stirring into an oxidizing mixture prepared as follows: In a 3 liter container, 63.2 g of potassium permanganate, 1,000 ml of water and 48.0 g of acetic acid were mixed. This mixture was stirred for 15 minutes at 20 ° C and then cooled to 0 ° C.

After the 6-a-brompenicillanic acid solution was added to the oxidizing mixture, a cooling bath was maintained at -15 ° around the reaction mixture. The internal temperature rose to 15 ° C and then dropped to 5 ° C over a period of 20 minutes. At this point, stirring was performed at ca. 10.0 C added 30.0 g of sodium 33 bisulfite. After a further 15 minutes, the mixture was filtered and the pH of the filtrate was lowered to 1.2 by the addition of 170 ml of 6N hydrochloric acid. The aqueous phase became

DK 159852 B

20 extracted with chloroform and then with ethyl acetate.

Both the chloroform extracts and the ethyl acetate extracts were dried using anhydrous magnesium sulfate and then evaporated in vacuo. The chloroform solution gave 10.0 g (16% yield) of the title compound. The ethyl acetate solution yielded 57 g of an oil which was triturated under hexane. A white solid appeared. It was filtered off to give 41.5 g (66% yield) of the title compound, m.p. 134 ° C (dec.).

Analysis: Calculated for C 8 H 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-alpha-chlorpenicillanic acid and 6-alpha-iodopicillanic acid with potassium permanganate by the procedure of Example 1 gave 6-alpha-chlorpenicillanic acid -1,1-dioxide and 6-alpha-iodopenicillanic acid -1,1-dioxide, respectively.

20

Example 3 6-8-Chlorpenicillanic acid 1,1-dioxide.

An oxidizing solution was prepared from 185 mg of potassium permanganate, 0.063 ml of 85% phosphoric acid and 25 ml of water. This oxidizing solution was added dropwise to a solution of 150 mg of sodium 6-3-chlorpenicillanate in 5 ml of water at 0-5 ° C until the purple color of the potassium permanganate was softened. About half of the oxidizing solution was needed. At this point, the potassium permanganate color was removed by the addition of solid sodium bisulfite and the reaction mixture was then filtered and the pH was adjusted to 1.8. The layers were separated and the aqueous layer was further extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, dried and evaporated in vacuo to give 118 mg of the title compound. The NMR spectrum (in CD2 COCD2) showed absorption at 5.82 (d, 1H), 5.24 (d, 1H), 4.53 (s, 1H), 1.62 (s, 3H) and 1 , 50 (s, 3H) ppm.

DK 159852 B

21

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, the tetrahydrofuran was removed by evaporation 5 in vacuo and the remaining aqueous solution was freeze-dried. Thereby the sodium salt of the title compound was won.

Example 4 6- {i-Brompenicillanic acid 1,1-dioxide.

To a solution of 255 mg of sodium 6-3-brompenic-cillanate in 5 ml of water was added at 0-5 ° C a solution prepared from 140 mg of potassium permanganate, 0.11 ml of 85% phosphoric acid and 5 ml of water at 0 -5 ° C. The pH was maintained between 6.0 and 6.4 during the addition. The reaction mixture was stirred at pH 6.3 for 15 minutes and then the purple solution was covered with ethyl acetate. The pH was adjusted to 1.7 and 330 mg of sodium bisulfite was added. After 5 minutes, the layers 20 were separated and the aqueous layer was further extracted with brine, dried (MgSO 4) and evaporated in vacuo. Thereby, 216 mg of the title compound were obtained as white crystals. The NMR spectrum (in D 2 O) showed absorptions at 5.78 (d, 1H, J = 4Hz), 5.25 (d, 1H, J = 4Hz), 4.20 (s, 1H), 1.65 ( s, 3H) and 1.46 (s, 3H) ppm.

Example 5 6-3-Iodpenicillanic acid 1,1-dioxide.

Oxidation of 6-3-iodo-penicillanic acid with potassium per-O Λ manganate in the procedure of Example 4 gave 6-3-iodo-penicillanic acid 1,1-dioxide.

Example 6

Pivaloyloxymethyl 6-alpha-bromopenicillanate-l, 1-dioxide.

To a solution of 394 mg of pivaloyloxymethyl-6-α-brompenicillanate in 10 ml of dichloromethane was added 400 mg of 3-chloroperbenzoic acid at 0-5 ° C. The reaction mixture was stirred at 0-5 ° C for 1 hour and then at 25 ° C for 24 hours

DK 159 852 B

hours. The filtered reaction mixture was evaporated to dryness in vacuo to give the title compound.

Example 7 The procedure of Example 6 was repeated except that the pivaloyloxymethyl-6- (3-brompenicillanate was replaced by: 3-phthalidyl-6-α-chloropenicillanate, 4-crotonolactolyl-6-3-chloropenicillanate, 10 Y -butyrolacton-4-yl-6-a-brompenicillanate, acetoxymethyl 6- [3-brompenicillanate, pivaloyloxymethyl 1-6-β-brompenic illanate, hexanoyloxymethyl-6-a-iodopenicillanate, 1- (acetoxy) ethyl-6-β iodo-penicillanate, 1- (isobutyryloxy) ethyl-6-a-chloropenicillanate, 1-methyl-1- (acetoxy) ethyl-6- (3-chloropenicillanate, 1-methyl-1- (hexanoyloxy) ethyl-6-a-brompenicillanate , methoxycarbonyloxymethyl 6-a-brompenicillanate, propoxyc arbonyloxymethyl 1-6-β-brompenicilianate, 1- (ethoxycarbonyloxy) ethyl 6-a-brompenicillanate, 1- (butoxycarbonyloxy) ethyl 6-a-iodopenicillanate - (methoxycarbonyloxy) ethyl 6-3-iodo-penicillanate and 1-methyl-1- (isopropoxycarbonyloxy) ethyl-6-a-chloro-penicillanate.

There were thus obtained: 3-phthalidyl-6-a-chloropenicillanate-1,1-dioxide, 4-crotonolactonyl-6-β-chloropenicillanate-1,1-dioxide, Y-butyrolacton-4-yl-6-a-brompenicillanate-1 , 1-dioxide, acetoxymethyl-6-3-brompenicillanate-1,1-dioxide, pivaloyloxymethyl-6 - & - brompenicillanate-1,1-dioxide, hexanoyloxymethyl-6-a-iodophenicillanate-1,1-dioxide, 1- (acetoxy) ethyl 6-3-iodopenicillanate-1,1-dioxide, 1- (isobutyryloxy) ethyl-6-a-chloropenicillanate-1,1-dioxide, 1-methyl-1- (acetoxy) ethyl-6- 3-Chloro -penicillanate-1,1-dioxide, 1-methyl-1- (hexanoyloxy) ethyl-6-a-brompenicillanate-1,1-dioxide,

DK 159852 B

23 methoxycarbonyloxymethyl-6-a-brompenicillanate-1,1-dioxide, propoxycarbonyloxymethyl-6-, 3-brompenicillanate-1,1-dioxide, 1- (ethoxycarbonyloxy) ethyl-6-a-brompenicillanate-1,1-dioxide (1-Butoxycarbonyloxy) ethyl 6-a-iodopenicillanate-1,1-dioxide, 1-methyl-1- (methoxycarbonyloxy) ethyl-6-p-iodopenicillanate-1,1-dioxide and 1-methyl-1- isopropoxycarbonyloxy) ethyl 6-a-chlorpenicilanate-1,1-dioxide.

10

Example 8

Penicillanic acid 1,1-dioxide.

To 100 ml of water was added 9.4 g of 6-a-brompenicil-lanoic acid 1,1-dioxide at 22 ° C followed by sufficient 15 4N sodium hydroxide solution to reach a stable pH of 7.3. To the resulting solution was added 2.25 g of 5% palladium on charcoal followed by 6.9 g of dicalcium phosphate trihydrate. This mixture was then shaken under an atmosphere of hydrogen at a pressure ranging from 3.5 to 20 1.8 kg / cm 2. When hydrogen uptake ceased, 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 was extracted with additional ethyl acetate. The combined ethyl acetate layers were washed with brine, dried using anhydrous magnesium sulfate and evaporated in vacuo. The residue was triturated under ether and the solid was then collected by filtration. This gave 4.5 g (65% 50 yield) of the title compound.

Analysis: Calculated for C 18 H 25 O: C: 41.20; H: 4.75; N: 6.00; S: 13.751 Found: C: 41.16; H: 4.81; N: 6.11; S: 13 , 51%.

DK 159852 B

24

Example 9

Penicillanic acid 1,1-dioxide.

Hydrogenolysis of each of: β-α-chlorpenicillanic acid-1,1-dioxide, 5-β-α-iodopenicillanic acid-1,1-dioxide, 6-3-chlorpenicillanic acid-1,1-dioxide, 6 - & - brompenicillanic acid-1, 1-dioxide and 6-3-iodo-penicillanic acid-1,1-dioxide by the method of Example 8 gave penicillanic acid-1,1-dioxide.

Example 10

Pivaloyloxymethyl penicillanate 1,1-dioxide.

To a solution of 1.0 g of pivaloyloxymethyl-6-α-15-bromopanicillanate-1,1-dioxide in 10 ml of methanol was added 3 ml of 1M sodium bicarbonate and 200 mg of 10% palladium-on-charcoal. The reaction mixture was shaken vigorously under an atmosphere o of hydrogen at a pressure of ca. 5 kg / cm until hydrogen uptake ceased. The mixture was then filtered, and the majority of methanol was removed by evaporation in vacuo. Water and ethyl acetate were added to the evaporation residue and the pH was adjusted to 8.5. The layers were separated and the organic layer was washed with water, dried (Na 2 SO 4) and evaporated in vacuo. The title compound was thus won.

Example 11

Hydrogenolysis of the respective 6-halo-penicillanoic acid ester-1,1-dioxide from Example 7 by the procedure of Example 10 gave the following compounds: 3-phthalidyl-penicillanate-1,1-dioxide, 4-crotonolactonyl-penicillanate-1,1 -dioxide, Y-butyrolacton-4-yl-penicillanate-1,1-dioxide, acetoxymethyl-penicillanate-1,1-dioxide, pivaloyloxymethyl-penicillanate-1,1-dioxide, hexanoyloxymethyl-penicillanate-1,1-dioxide , 1- (acetoxy) ethyl-penicillanate-1,1-dioxide, 1- (isobutyryloxy) ethyl-penicillanate-1,1-dioxide,

DK 159852 B

1-methyl-1- (acetoxy) ethyl-penicillanate-1,1-dioxide, 1-methyl-1- (hexanoyloxy) ethyl-penicillanate-1,1-dioxide, methoxycarbonyloxymethyl-penicillanate-1,1-dioxide, propoxycarbonyloxymethyl -penicillanate-1,1-dioxide, 1- (ethoxycarbonyloxy) ethyl-penicillanate-1,1-dioxide, 1- (butoxycarbonyl) ethyl-penicillanate-1,1-dioxide, 1-methyl-1- (methoxycarbonyloxy) ethyl -penicillanate-1,1-dioxide and 1-methyl-1- (isopropoxycarbonyloxy) ethyl-penicillanate-1,1-ΙΟ dioxide.

Example 12

Pivaloyloxymethyl 6-alpha-bromopenicillanate-l, 1-dioxide.

An oxidizing solution was prepared by combining 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, over 5 minutes at 5-10 ° C, was added to a stirred solution of 5.32 g of pivaloyloxy-methyl-6-a-brompenicillanate in 70 ml of acetone and 10 ml. water. The mixture was stirred at 5 ° C for 30 minutes and 100 ml of ethyl acetate was added. After a further 30 minutes, a solution of 3.12 g of sodium bisulfite in 30 ml of water was added over 15 minutes at ca. 10 ° C. Stirring was continued for an additional 30 minutes at 5 ° C and then the mixture was filtered. The organic phase was separated and washed with saturated sodium chloride solution. The dried organic layer was evaporated to give 5.4 g of the title compound as an oil which slowly crystallized. The NMR spectrum (in CDCl3) showed absorptions at 5.80 (q, 2H), 5.15 (d, 1H), 4.75 (d, 1H), 4.50 (s, 1H), 1.60 (s, 3H), 1.40 (s, 3H) and 1.20 (s, 9H) ppm.

Example 13 Pivaloyloxymethyl penicillanate-1,1-dioxide.

A solution of 4.4 g of pivaloyloxymethyl-6-a-bromo-penicillanate-1,1-dioxide in 60 ml of tetrahydrofuran was added to 0.84 g of sodium bicarbonate in 12 ml of water. The solution

DK 159852 B

26 was shaken under an atmosphere of hydrogen in the presence of 2.0 g of 5% palladium on charcoal at 47-51 psig. The reaction mixture was then filtered and the filter residue was washed with 100 ml of ethyl acetate and 25 ml of water. The combination of filtrate and washings was separated. The organic layer was washed with saturated sodium chloride, dried (MgSO 4) and evaporated to give the title compound as an oil. This oil was dissolved in ethyl acetate (20 ml).

To the solution was added hexane (100 ml) slowly and the precipitate was 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-a-brompenicillanate-1,1-dioxide.

2,2,2-Trichloroethyl 6-a-brompenicillanate was oxidized with potassium permanganate substantially by the procedure of Example 12, thereby winning the title compound ice in 79% yield. The NMR spectrum of the product (in CDCl3) showed absorbances at 5.30 to 4.70 (m, 4H), 4.60 (s, 1H), 1.70 (s, 3H) and 1.50 (s). , 3H) ppm.

Example 15 Benzyl-6-α-brompenicillanate-1,1-dioxide.

Benzyl 6-α-brompenicillanate was oxidized with potassium permanganate substantially as in the procedure of Example 12, thereby gaining the title compound in 94% yield. The NMR spectrum (in CDCl3) showed absorptions at 7.35 (s, 5H), 5.10 (m, 3H), 4.85 (m, 1H), 4.40 (s, 1H), 1, 50 (s, 3H) and 1.25 (s, 3H) ppm.

Example 16

Penicillanic acid 1,1-dioxide.

33 A solution of 4.0 g of benzyl-6-a-brompenicillanate-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.

27

DK 1S9852 B

To the mixture was added 2.0 g of a 50% suspension of 5% palladium-on-charcoal in water, after which this mixture was shaken under an atmosphere of hydrogen at a pressure of 46.5 -50 psig. for 20 minutes. The catalyst was filtered off, then 30 ml of tetrahydrofuran and 3.0 g of a 50% suspension of 5% palladium-on-charcoal were added. The resulting mixture was shaken under an atmosphere of hydrogen at pressures from 42 to 45 psig. for 65 minutes. The reaction mixture was then filtered and the tetrahydrofuran was evaporated. Ethyl acetate was added to the aqueous evaporation 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 separated. The aqueous phase 15 was further extracted with ethyl acetate and the combined ethyl acetate solutions were washed with saturated sodium chloride solution and dried (MgSO4). Evaporation in vacuo gave a gum which was triturated under ether. There was thus obtained 31 mg of penicillanic acid 1,1-dioxide as a yellow solid. The NMR spectrum (in CDCl3 / DMSO-dg) showed absorption at 9.45 (broad s, 1H), 4.60 (t, 1H), 4.25 (s, 1H), 3.40 (d, 2H) ), 1.65 (s, 3H) and 1.30 (s, 3H) ppm.

Example 17 6,6-Dibrompenicillanic acid 1,1-dioxide.

To the dichloromethane solution of 6,6-dibrompenicilanoic acid from Preparation K, 300 ml of water was added after * i followed by dropwise addition over a period of 30 minutes of 105 ml of 3N sodium hydroxide. The pH value stabilized at 7.0. The aqueous layer was removed and the organic layer was extracted with water (2 x 100 ml). To the combined aqueous solutions, at -5 ° C a pre-mixed solution was 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 oxidizer was needed. At this time, 500 mL of ethyl acetate was added, and then the pH was lowered to 1.23 by the addition of 105 mL of 6N hydrochloric acid. Then, during the course of 23

DK 159852 B

of 10-15 minutes at approx. 10 ml of 250 ml of 1M sodium bisulfite. During the addition of the sodium bisulfite solution, the pH was maintained at 1.25-1.35 using 6N hydrochloric acid. The aqueous phase was saturated with sodium chloride, and the two phases were separated. The aqueous solution was extracted with additional ethyl acetate (2 x 150 mL) and the combined ethyl acetate solutions were washed with brine and dried (MgSO 4). This gave an ethyl acetate solution of 6,6-dibrompenicillanic acid 1,1-dioxide.

The two 6,6-dibrompenicillanic acid 1,1-dioxide could be isolated by removing the solvent in vacuo. A sample isolated in this way from an analog preparation had m.p. 201 ° C (dec.). The NMR spectrum (CDCl3 / DMSO-dg) showed absorptions at 9.35 (s, 1H), 5.30 (s, 1H), 4.42 (s, 1HV, 1.63 (s, 3H), and 1 , 50 (s, 3H) ppm. The IR spectrum (KBr plate) showed absorptions at 3846-2500, 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-iodo-penicillanic acid in 50 ml of dichloromethane was added 50 ml of water and then the pH was raised to 7.2 using 3N sodium hydroxide. The layers were separated and the aqueous layer 25 was cooled to 5 ° C. To this solution was then added dropwise over a period of 20 minutes a premixed solution prepared from 2.61 g of potassium permanganate, 1.75 ml of concentrated phosphoric acid and 50 ml of water. The pH was maintained at 6 and the temperature kept below 10 ° C during the addition. At this point, 100 ml of ethyl acetate was added and the pH was adjusted to 1.5.

To the mixture was then added 50 ml of 10% sodium bisulfite, keeping the temperature below 10 ° C and the pH at ca. 1.5 by the addition of 6N hydrochloric acid. The pH 35 was lowered to 1.25 and the layers separated. The aqueous layer was saturated with sodium chloride and extracted with ethyl acetate. The combined organic solutions were washed with brine, dried (MgSO 4) and evaporated in vacuo to give 4.2 g of the title compound, m.p.

DK 159852 B

29 143-145 ° C. The NMR spectrum (CDCl3) showed absorptions at 4.86 (s, 1H), 4.38 (s, 1H), 1.60 (s, 3H) and 1.43 (s, 3H) ppm. The IR spectrum (KBr plate) showed absorptions at 1800, 1740 and 1250-1110 cm -1.

5

Example 19 6-Bromo-6-iodopenicillanic acid 1,1-dioxide.

To a solution of 6.0 g of 6-bromo-6-iodo-penicillanic acid in 50 ml of dichloromethane was added 50 ml of water. The pH-value diene 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 ° C. The addition took 20 minutes. At this point, 50 ml of ethyl acetate was added and the pH of the mixture was lowered to 1.5 with 6N hydrochloric acid. To this two-phase system was added dropwise 50 ml of 10% sodium bisulfite, keeping the pH at about 1.5 20 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 x 50 ml) and the combined ethyl acetate layers 25 washed with brine, dried (MgSO 4) and evaporated in vacuo. The residue was dried in high vacuum to give 4.2 g of the title compound, m.p. 145-147 ° C. The NMR spectrum (CDCl3) showed absorptions at 4.90 (s, 1H), 4.30 (s, 1H), 1.60 (s, 3H) and 1.42 (s, 3H) ppm. The IR spectra (KBr plate) showed absorptions at 1800, 1740, 1330 and 1250-1110 cm

Example 20 6-Chloro-6-brompenicillanic acid 1,1-dioxide.

Oxidation of 6-chloro-6-brompenicillanic acid with potassium permanganate by the procedure of Example 19 gave 6-chloro-6-brompenicillanic acid 1,1-dioxide.

DK 159852B

30

Example 21

Penicillanic acid 1,1-dioxide.

The ethyl acetate solution of 6,6-dibrompenicillanic acid 1,1-dioxide from Example 17 was combined with 705 ml of 5 saturated sodium bicarbonate solution and 8.88 g of 5% palladium-on-carbon catalyst. The mixture was shaken under an atmosphere of hydrogen at a pressure of approx. 5 kg / cm for approx. 1 hour. The catalyst was filtered off and the pH of the aqueous phase of the filtrate was adjusted to 1.2 with 6N 10 hydrochloric acid. The aqueous phase was saturated with sodium chloride. The layers were separated and the aqueous phase was extracted with additional ethyl acetate (3 x 200 mL). The combined ethyl acetate solutions were dried (MgSO4) and evaporated in vacuo to give 33.5 g (58% yield 15 based on 6-aminopenicillanic acid) of penicillanic acid 1,1-dioxide. This product was dissolved in 600 ml of ethyl acetate, the solution was decolorized with activated charcoal and the solvent was evaporated in vacuo. The product was washed with hexane. There was thus obtained 31.0 g of pure product.

Example 22

Hydrogenolysis of each of 6-chloro-6-iodo-penicillanic acid-1,1-dioxide, 6-bromo-6-iodo-penicillanic acid and 6-chloro-6-bromo-penicillanic acid by the procedure of Example 21 in each case gave penicillanic acid-1 , 1-dioxide.

25

Example 23

Pivaloyloxymethyl 6,6-dibromopenicillanate-l, 1-dioxide.

To a solution of 4.73 g of pivaloyloxymethyl-6,6-dibrompenicillanate in 15 ml of dichloromethane was added 3.80 g of 3-chloroperbenzoic acid at 0-5 ° C. The reaction mixture was stirred at 0-5 ° C for 1 hour and then at 25 ° C for 24 hours. The filtered reaction mixture was evaporated to dryness in vacuo and the residue was partitioned between ethyl acetate and water. The pH of the 35 aqueous phase was adjusted to 7.5 and the layers were ad 31

DK 159G52B

sign. The ethyl acetate phase was dried (Na 2 SO 4) and evaporated in vacuo to give the title compound.

Example 24 Oxidation of each of the 6,6-dihalogenpenicillanic acid esters of Preparation P using 3-chloro-perbenzoic acid by the procedure of Example 23 gave the following compounds: 3-phthalidyl-6,6-dibrompenicillanate-1,1-dioxide 4-Crotonolactonyl-6-chloro-6-iodo-penicillanate-1,1-dioxide, Y-butyrolactonyl-6-bromo-6-iodo-penicillanate-1,1-dioxide, acetoxymethyl-6-chloro-6-brompenicillanate-1, 1-dioxide, pivaloyloxymethyl-6-chloro-6-iodopenicillanate-1,1-dioxide, hexanoyloxymethyl-6,6-dibrompenicillanate-1,1-dioxide, 1- (acetoxy) ethyl-6,6-dibrompenicillanate-1, 1-dioxide, 1- (isobutyryloxy) ethyl-6-bromo-6-iodopenicillanate-1,1-dioxide, 1-methyl-1- (acetoxy) ethyl-6,6-dibrompenicillanate-1,1-dioxide, 1 -methyl-1- (hexanoyloxy) ethyl-6-chloro-6-brompenicillanate, methoxycarbonyloxymethyl-6,6-dibrompenicillanate-1,1-dioxide, propoxycarbonyloxymethyl-6-chloro-6-iodopenicillanate-1,1-dioxide, 1 - (ethoxycarbonyloxy) ethyl 6,6-dibrompenicillanate-1,1-dioxide, 1- (butoxycarbonyloxy) ethyl-6-bromo -6-iodopenicillanate-1,1-dioxide, 1-methyl-1- (methoxycarbonyloxy) ethyl-6,6-dibrompenicillanate-1,1-dioxide and 1-methyl-1- (isopropoxycarbonyloxy) ethyl-6, 6-dibrompeni cillanat-1,1-dioxide.

Example 25 33 Pivaloyloxymethyl penicillanate-1,1-dioxide.

To a solution of 1.0 g of pivaloyloxymethyl-6,6-dibrompenicillanate-1,1-dioxide in 10 ml of methanol was added 3 ml of 1M sodium bicarbonate and 200 ml of 10% palladium

DK 159852 B

32 cool. The reaction mixture was shaken vigorously under a 2 atmosphere of hydrogen at a pressure of ca. 5 kg / cm until hydrogen uptake ceased. The mixture was then filtered and the majority of the methanol removed by evaporation in vacuo. Water and ethyl acetate were added to the evaporation residue and the pH was adjusted to 8.5. The layers were separated and the organic layer was washed with water, dried (Na 2 SO 4) and evaporated in vacuo. Pivaloyloxymethylpenicillanate-1,1-dioxide was thereby obtained.

10

Example 26

Hydrogenolysis of each of the 6,6-dihalo-penicillanic acid ester-1,1-dioxides of Example 24 by the procedure of Example 25 gave the following compounds: 3-phthalidyl-penicillanate-1,1-dioxide, 4-crotonolactonyl-penicillanate -1,1-dioxide, Y-butyrolacton-4-yl-penicillanate-1,1-dioxide, acetoxymethyl-penicillanate-1,1-dioxide, pivaloyloxymethyl-penicillanate-1,1-dioxide, hexanoyloxymethyl-penicillanate-1, 1-dioxide, 1- (acetoxy) ethyl-penicillanate-1,1-dioxide, 1- (isobutyryloxy) ethyl-penicillanate-1,1-dioxide, 1-methyl (acetoxy) ethyl-penicillanate-1,1-dioxide , 1-methyl-1- (hexanoyloxy) ethyl-penicillanate-1,1-dioxide, methoxycarbonyloxymethyl-penicillanate-1,1-dioxides, propoxycarbonyloxymethyl-penicillanate-1,1-dioxide, 1- (ethoxycarbonyloxy) ethyl-penicillanate 1,1-dioxide, 1- (butoxycarbonyl) ethyl-penicillanate-1,1-dioxide, 1-methyl-1- (methoxycarbonyloxy) ethyl-penicillanate-1,1-30-dioxide and 1-methyl-1- (isopropoxycarbonyloxy) ethyl penicillanate 1,1-dioxide.

Example 27 Pivaloyloxymethyl 6,6-dibrompenicillanate-1,1-dioxide.

A stirred solution of 3.92 g of 6,6-dibrompenicillanic acid 1,1-dioxide in 20 ml of Ν, Ν-dimethylformamide was cooled to 0 ° C and then 1.29 g of diisopropylene was added.

DK 159852 B

33 pylethylamine. Then 1.51 g of chloromethyl pivalate was added. This reaction mixture was stirred at 0 ° C for 3 hours and then at room temperature for 16 hours. The reaction mixture was then diluted with 25 ml of ethyl acetate and 25 ml of water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were washed with cold 5% sodium bicarbonate solution, water and brine. The ethyl acetate solution was then treated with Darco (an activated charcoal), dried (MgSO 4) and evaporated in vacuo to a brown oil weighing 2.1 g. This oil was chromatographed on 200 g of silica gel using dichloromethane as eluent. agent. The fractions containing the desired product were pooled and re-chromatographed on silica gel to give 0.025 g of the title compound. The NMR spectrum (CDCl3) 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.

Example 28 20 6,6-Dibrompenicillanic acid 1,1-dioxide.

To a solution of 359 mg of 6,6-dibrompenicillanic acid in 30 ml of dichloromethane was added 380 mg of 3-chloroperbenzoic acid at 0-5 ° C. The reaction mixture was stirred at 0-5 ° C for 30 minutes and then at 25 ° C for 24 hours.

The filtered reaction mixture was evaporated in vacuo to give the title compound.

Example 29

Benzyl 6,6-dibromopenicillanate-l, 1-dioxide.

A mixture of 10.0 g of 6,6-dibrompenicillanic acid-1,1-dioxide, 2.15 g of sodium bicarbonate, 3.06 ml of benzyl bromide and 100 ml of Ν, Ν-dimethylformamide was stirred at room temperature overnight. Most of the solvent was removed by evaporation in vacuo and the residue 35 was partitioned between ethyl acetate and water. The organic layer was removed, washed with 1N hydrochloric acid and with saturated sodium chloride and dried (Na 2 SO 4). Evaporation in vacuo afforded 11.55 g of the title compound. NMR spectrum (in CDCl3) 34

DK 159852 B

showed absorbances 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 30 Penicillanic Acid-1,1-Dioxide.

To a solution of 2.0 g of benzyl-6,6-dibrompenicilanate-1,1-dioxide in 50 ml of tetrahydrofuran was added a solution of 0.699 g of sodium bicarbonate in 50 ml of water followed by 2.0 g of 5% palladium. on-carbon. This mixture TO was then shaken under an atmosphere of hydrogen at ca. 50 psig. for 70 minutes. The tetrahydrofuran was removed by evaporation and the residue was partitioned between ethyl acetate and water at pH 7.37. The aqueous layer was removed and fresh ethyl acetate was added. The pH-Weather-T5 diene was lowered to 1.17 and the ethyl acetate was removed and washed with saturated sodium chloride solution. Evaporation in vacuo afforded 423 mg of the title compound.

2 0 Preparation A

6-Chloro-6-iodopenicillanic acid.

To 3.38 g of iodine monochloride in 30 ml of dichloromethane was added with stirring at 0-5 ° C 11.1 ml of 2.5N sulfuric acid followed by 1.92 g of sodium nitrite. At this time, 3.00 g of 6-aminopenicilanoic acid was added at one time and stirring was continued for 30 minutes at 0-5 ° C.

To the reaction mixture was then added 22.8 ml of 1M

DK 159852 B

35 sodium bisulfite solution in portions and the layers were separated. The aqueous layer was washed with additional dichloromethane and then all the organic phases were washed with saturated sodium chloride. The dichloromethane solution was dried (Na 2 SO 4) and evaporated 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 and the tetrahydrofuran was removed in vacuo. The remaining aqueous phase was freeze-dried and the residue was washed with diethyl ether. There was thus obtained 3.67 g of the title compound as its sodium salt.

Preparation B

6-8-Chlorpenicillanic acid.

A sample of 2.95 g of sodium 6-chloro-6-iodo-penicilanoic acid was converted to the free acid and then dissolved in 125 ml of benzene under nitrogen. To the solution was added 1.08 ml of triethylamine and the mixture was cooled to 0-5 ° C. To the cooled mixture was then added 0.977 ml of trimethylsilyl chloride and the reaction mixture was stirred at 0-5 ° C for 5 minutes, at 25 ° C for 60 minutes and at 50 ° C for 30 minutes. The reaction mixture was cooled to 25 ° C and the triethylamine hydrochloride was filtered off. To the filtrate was added 15 mg of azobisisobutyronitrile followed by 2.02 ml of tri-n-butyltin hydride. The mixture was then irradiated with ultraviolet light for 15 minutes under cooling to maintain a temperature of ca. 20 ° C. The solvent was then removed by evaporation in vacuo and the residue was dissolved in a 1: 1 tetrahydrofuran / water mixture. The pH was adjusted to 7.0 and the tetrahydrofuran was removed by evaporation in vacuo. The aqueous phase was washed with ether and then an equal volume of ethyl acetate was added. The pH was adjusted to 1.8 and the ethyl acetate layer was removed. The aqueous phase was extracted with additional ethyl acetate, and then

DK 159852 B

36, the combined ethyl acetate solutions were dried and evaporated in vacuo. 980 mg of 6β-chlorpenicillanic acid were thereby obtained.

The above product was dissolved in tetrahydrofuran and an equal volume of water was added. The pH was adjusted to 6.8 and the tetrahydrofuran was removed by evaporation in vacuo. The remaining aqueous phase was lyophilized to give 850 mg of sodium 6-D-chlorpenicillanate. The NMR spectrum (0) showed absorption at 5.70 Cd, 1H, J = 4Hz), 5.50 (d, 1H, J = 4Hz), 4.36 (s, 1H), 1.60 ( s, 3H) and 1.53 (s, 3H) ppm.

Preparation C

6-3-bromopenicillanic acid.

A mixture of 5.0 g of 6,6-dibrompenicillanic acid, 154 ml of triethylamine and 100 ml of benzene was stirred under nitrogen until a solution was obtained. The solution was cooled to 0-5 ° C and 1.78 ml of trimethylsilyl chloride was added. The reaction mixture was stirred at 0-5 ° C for 2-3 minutes and then at 50 ° C for 35 minutes. The cooled reaction mixture was filtered and the filtrate was cooled to 0-5 ° C. A small amount of azobisisobutyronitrile was added followed by 3.68 ml of tri-n-butyltin hydride. The reaction vessel was irradiated with ultraviolet light for 15 minutes, and then the reaction mixture was stirred at ca. 25 ° C for 1.75 hours. The reaction mixture was again irradiated for 15 minutes, and then stirring was continued for 2.5 hours. At this time, a further small amount of azobisisobutyronitrile was added followed by 0.6 ml of tri-n-butyltin hydride and the mixture was again irradiated for 30 minutes. The solvent was then removed by evaporation in vacuo and to the evaporation residue was added 5% sodium bicarbonate solution and diethyl ether. The two-phase system was shaken vigorously for 10 minutes and then the pH was adjusted to 2.0. The ether layer 35 was removed, dried and evaporated in vacuo to give 2.33 g of an oil. The oil was converted to a sodium salt by the addition of water containing 1 equivalent

DK 159852 B

37 sodium bicarbonate followed by freeze-drying of the solution thus obtained. Thereby, sodium 6-β-bromo-nicillanate was obtained contaminated with a small amount of the isomer.

The sodium salt was purified by chromatography on Sepadex LH-20, combined with some additional material of the same quality, and re-chromatographed. The NMR spectrum (D 2 O) of the product thus obtained showed absorbances at 5.56 (s, 2H), 4.25 (s, 1H), 1.60 (s, 3H) and 1.50 (s, 10H) ppm.

Preparation D

6-3-iodopenicillanic acid.

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

Preparation E

Pivaloyloxymethyl 6-alpha-bromopenicillanate.

To a solution of 280 mg of 6-α-brompenicillanic acid in 2 ml of Ν, Ν-dimethylformamide was added 260 mg of diisopropylethylamine followed by 155 mg of chloromethyl pivalate and 15 mg of sodium iodide. The reaction mixture was stirred at room temperature for 24 hours and then diluted with ethyl acetate and water. The pH was adjusted to 7.5 and then the ethyl acetate layer was separated and washed three times with water and once with saturated sodium chloride solution. The ethyl acetate solution was then dried using anhydrous sodium sulfate and evaporated in vacuo to give the title compound.

Preparation F

Reaction of the appropriate 6-halo-penicillanic acid with 3-phthalidyl chloride, 4-crotonolactonyl chloride, γ-butyrolacton-4-yl chloride or the required alkanoyloxy methyl chloride, 1- (alkanoyloxy) ethyl chloride, 1-methyl-1- (alkanoyloxy) ethyl chloride, alkoxycarbonyloxymethyl chloride, 1- (alkoxycarbonyloxy) ethyl chloride or 1-methyl-1-

DK 159852 B

38 (alkoxycarbonyloxy) ethyl chloride in the process of Preparation E gave the following compounds: 3-phthalidyl-6-a-chloropenicillanate, 4-crotonolactonyl-6-3-chloropenicillanate, 5-y-butyrolacton-4-yl-6-a-brompenicillanate, acetoxymethyl -6-3-brompenicillanate, pivaloyloxymethyl 1-6-β-brompenicillanate, hexanoyloxymethyl-6-a-iodopenicillanate, 1- (acetoxy) ethyl 6-3-iodopenicillanate, 1- (isobutyryloxy) ethyl 6-a-chloropenicillanate, 1-methyl-1- (acetoxy) ethyl 6-3-chloropenicillanate, 1-methyl-1- (hexanoyloxy) ethyl-6-a-brompenicillanate, methoxycarbonyloxymethyl 1-6-α-brompenicilianate, propoxycarbonyloxymethyl 1-6-β-brompenicilianate, 1- (ethoxycarbonyloxy) ethyl 6-a-brompenicillanate, 1-butoxycarbonyloxy) ethyl 6-cc-iodopenicillanate, 1-methyl-1- (methoxycarbonyloxy) ethyl 6- (3-iodopenicillanate and 1-methyl-1- (isopropoxycarbonyloxy) ethyl 6-α-chlorpenicilanates.

Preparation G

6,6-diiodopenicillanic acid.

A mixture of 15.23 g of iodine, 10 ml of 2.5N sulfuric acid, 276 g of sodium nitrite and 75 ml of dichloromethane was stirred at 5 ° C and 4.32 g of 6-aminopenicillanic acid was added over a period of 15 minutes. Stirring was continued at 5-10 ° C for 45 minutes after completion of addition and then 100 ml of 10% sodium bisulfite was added dropwise. The layers were separated and the aqueous layer was further extracted with dichloromethane. The combined dichloromethane layers were washed with brine, dried (MgSO4) and evaporated in vacuo. 1.4 g of the title compound were contaminated with some 6-iodo-penicillanic acid. The product had m.p. 58-64 ° C. The NMR spectrum (CDCl 3) showed absorptions at 5.77 (s, 1H), 4.60 (s, 1H), 1.71 (s, 3H) and 1.54 (s, 3H) ppm.

DK 159852 B

39

Preparation H

Pivaloyloxymethyl 6-alpha-bromopenicillanate.

To a stirred mixture of 11.2 g of 6-a-brompenicilanoic acid, 3.7 g of sodium bicarbonate and 44 ml of N, N-dimethylformamide, 6.16 g of chloromethyl pivalate was added dropwise over 5 minutes at room temperature. 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, saturated sodium bicarbonate, water and saturated sodium chloride. The stained ethyl acetate solution was dried (MgSO4) and evaporated to dryness in vacuo. This gave 12.8 g (80% yield) of the title compound.

Preparation I

Benzyl 6-alpha-bromopenicillanate.

The title compound was prepared by esterification of 6-α-brompenicillanic acid with benzyl bromide essentially by the method of Preparation H (yield 83%). The NMR spectrum (in CDCl3) showed absorptions at 7.35 (s, 5H), 5.35 (m, 1H), 5.15 (s, 2H), 4.70 (m, 1H), 4.60 (s, 1H), 1.55 (s, 3H) and 1.35 (s, 3H) ppm.

Preparation J

2,2,2-Trichloroethyl-6-α-brbm penicillanate.

To a stirred solution of 11.2 g of 6-α-brompenicillanic acid in 50 ml of tetrahydrofuran was added at 0. ° C 3.48 g of pyridine over a period of 1 minute. To the resulting cloudy solution, 8.47 g of 2,2,2-trichloroethyl chloroformate were added over a period of 10 minutes, keeping the temperature between 0 ° and 2 ° C. Stirring was continued for 30 minutes and then the cooling bath was removed. Stirring was continued at room temperature overnight. The reaction mixture was then heated to 35 ° C for 5 minutes and then filtered. The filtrate was evaporated and the residue was dissolved in 100 ml of ethyl acetate.

DK 159852 B

40 acetate. The ethyl acetate solution was washed successively with saturated sodium bicarbonate, water and saturated sodium chloride. The ethyl acetate solution was then decolorized and dried and then concentrated to small volume.

To the resulting mixture was added 100 ml of hexane and the solids were filtered off to give 10.5 g of the title compound, m.p. 105-110 ° C. The NMR spectrum (in CDCl3) showed absorptions at 5.50 (d, 1H), 4.95 (d, 1H), 4.90 (s, 2H), 4.65 (s, 1H), 1 , 70 (s, 3H), 1.55 (s, 3H) ppm.

Preparation K

6,6-dibromopenicillanic acid.

To 500 ml of dichloromethane cooled to 5 ° C was added 119.9 g of bromine, 200 ml of 2.5N sulfuric acid and 34.5 g of sodium nitrite. To this stirred mixture was then added portionwise 54.0 g of 6-aminopenicillanic acid over 30 minutes keeping the temperature from 4 ° to 10 ° C. Stirring was continued for 30 minutes at 5 ° C, and then 410 ml of a 1.0M solution of sodium bisulfite 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 dichloromethane. The original dichloromethane layer was combined with the two extracts to give a solution of 6,6-dibrompenicillanic acid. This solution was used directly in Example 17.

Preparation L

6-Chloro-6-iodopenicillanic acid.

To 100 ml of dichloromethane cooled to 3 ° C was added 4.87 g of iodine chloride, 10 ml of 2.5N sulfuric acid and 2.76 g of sodium nitrite. To this stirred mixture was then added portionwise 4.32 g of 6-aminopenicillanic acid over a period of 15 minutes. Stirring was continued for 20 minutes at 0-5 ° C and then 100 ml of 10% sodium bisulfite solution was added dropwise at ca. 4 ° C. Stirring was continued for 5 minutes and then the layers were separated. The aqueous layer was extracted with dichloromethane (2 x 50 mlV)

DK 159852 B

41 and the combined dichloromethane solutions were washed with brine, dried (MgSO 4) and evaporated in vacuo to give the title compound as a tan solid, m.p. 148-152 ° C. The NMR spectrum of the product (CDCl3) δ showed absorbances at 5.40 (s, 1H), 4.56 (s, 1H), 1.67 (s, 3H) and 1.50 (s, 3H) ppm. The IR spectrum (KBr plate) showed absorptions at 1780 and 1715 cm 2

Preparation M

6-Bromo-6-iodopenicillanic acid.

To 100 ml of dichloromethane cooled to 5 ° C was added 10 ml of 2.5N sulfuric acid, 6.21 g of iodine bromide and 2.76 g of sodium nitrite. To this mixture, vigorous stirring at 0-5 ° C and 4.32 g of 6-aminopenicillanic acid was added over 15 minutes. Stirring was continued for another 15 minutes at 0-5 ° C and then 100 ml of 10% sodium bisulfite between 0 ° and 10 ° C was added dropwise. At this time, the layers were separated and the aqueous layer was extracted with dichloromethane (3 x 50 ml). The combined dichloromethane layers were washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was dried under high vacuum for 30 minutes to afford 6.0 g (72% yield) of the title compound, m.p. 144-147 ° C. The NMR spectrum (CDCl3) showed absorptions at 5.50 (s, 1H), 4.53 (s, 1H), 1.70 (s, 3H) and 1.53 (s, 3H) ppm. The IR spectrum (KBr plate) showed absorptions at 1785 and 1710 cm 2. The mass spectrum showed a prominent ion at m / e = 406.

Preparation N

6-Chloro-6-bromopenicillanic acid.

6-Chloro-6-brompenicillanic acid was prepared from 30-6-aminopenicillanic acid via diazotation followed by reaction with bromochloride, by the method of Preparation M.

DK 159852 B

42

Preparation O

Pivaloyloxymethyl 6,6-dibromopenicillanate.

To a stirred solution of 3.59 g of 6,6-dibrompenicillanic acid in 20 ml of Ν, Ν-dimethylformamide was added 1.30 g of diisopropylethylamine followed by 1.50 g of chloromethyl pivalate at ca. 0 ° C. The reaction mixture was stirred at ca. 0 ° C for 30 minutes and then at room temperature for 24 hours. The reaction mixture was then diluted with ethyl acetate and water and the pH of the aqueous phase was adjusted to 7.5. The ethyl acetate layer was separated and washed three times with water and once with saturated sodium chloride solution. The ethyl acetate solution was then dried using anhydrous sodium sulfate and evaporated in vacuo to give the title compound.

Preparation P

Reaction of the relevant 6,6-dihalogenpenicilanoic acid with 3-phthalidyl chloride, 4-crotonolactonyl chloride, Y-butyrolacton-4-yl chloride or the required al-canoyloxymethyl chloride, 1-alkoanoyloxyethyl chloride, 1-20 methyl-1- ( alkanoyloxy) ethyl chloride, alkoxycarbonyloxymethyl chloride, 1- (alkoxycarbonyloxy) ethyl chloride or 1-methyl-1- (alkoxycarbonyloxy) ethyl chloride in the process of Preparation O gave the following compounds: 3-phthalidyl-6,6-dibrompenicillanate, -chloro-6-iodo-penicillanate, γ-butyrolactonyl-6-bromo-6-iodo-penicillanate, acetoxymethyl-6-chloro-6-brompenicillanate, pivaloyloxymethyl-6-chloro-6-iodo-penicillanate, hexanoyloxymethyl-6,6-dibrompenicillanate (acetoxy) ethyl 6,6-dibrompenicillanate, 1- (isobutyryloxy) ethyl 6-bromo-6-iodopenicillanate, 1-methyl-1- (acetoxy) ethyl 6,6-dibrompenicillanate, 1-methyl-1- hexanoyloxy) ethyl 6-chloro-6-brompenicillanate, methoxycarbonyloxymethyl-6,6-dibrompenicillanate, propoxycarbonyloxymethyl-6-chloro-6-iodopenicil lanate, 1- (ethoxycarbonyloxy) ethyl 6,6-dibrompenicillanate,

Claims (4)

A process for the preparation of penicillanic acid-1,1,1-dioxide or esters thereof of the general formula 10 CH 0 O 3 in COOR1 15 or a pharmaceutically acceptable base salt thereof, wherein R 1 is hydrogen or an in vivo readily hydrolyzable ester forming group, characterized in that a) a compound of the general formula YH CH 2 O - e * pOH ^ (II) 2 COOR or a pharmaceutically acceptable base salt thereof, wherein R is as above - 2- i for defined for R or is a usual penicillin carboxy protecting group, and X and Y are each selected from hydrogen, chlorine, bromine and iodine with the condition that when X and Y are the same, they must both be bromine, is contacted with a reagent selected from alkali metal permanganates, alkaline earth metal permanganates and organic peroxycarboxylic acids to form a compound of the general formula Ί 1 ° / ° v-ch 3 35 X, V v itUvvpT p * ch3 (iii) 0. COOR DK 159852 B or a base salt thereof, wherein X, Y and R are as defined above, and b) the product of step a) is dehalogenated by catalytic hydrogenolysis in an inert solvent, at a pressure ranging from 1 to 100 kg / cm, in the presence of 0.01 to 2.5% by weight of a hydrogenolysis catalyst, at a temperature in the range of 0 to 60 ° C and at a pH in the range of 4 to 9, wherein one optionally present at R protecting group is removed during or after step a) or step b) and, if desired, an obtained compound of formula (I) wherein R 1 is hydrogen esterified to a corresponding compound wherein R hydrolyzable ester-forming group, or an obtained compound of formula (I), wherein R 1 is an in vivo readily hydrolyzable ester-forming group, hydrolyzed to a corresponding compound where R 1 is hydrogen, or a won compound of formula (I) is transferred into a pharmaceutically acceptable base salt thereof. Process according to claim 1, characterized in that X is bromine and Y is hydrogen. Process according to claim 1, characterized in that X and Y are both bromine. Process according to any one of claims 1 to 3, characterized in that R and R are both hydrogen.