NO800618L - ANALOGY PROCEDURE FOR PREPARATION OF PENICILLANIC ACID-1,1-DIOXYD AND ESTERS OF THEREOF - Google Patents

Description

This invention relates to a new chemical method and

new chemical compounds, which are suitable as intermediates

by the procedure. More particularly, it relates to a new chemical process for the production of penicillanic acid 1,1-dioxide and esters thereof which are readily hydrolyzable in vivo. The new chemical method involves oxidation of a 6-halogen or 6,6-dihalogen derivative of penicillanic acid or an ester thereof, which is easily hydrolyzable in vivo, to the corresponding 1,1-dioxide, followed by dehalogenation. The new chemical compounds useful as intermediates are 6-halo-v and 6,6-dihalo derivatives of penicillanic acid 1,1-dioxides and esters thereof which are readily hydrolyzable in vivo.

Penicillanic acid 1,1-dioxide and esters thereof which are readily hydrolyzable in vivo are useful as 3-lactamase inhibitors, and as agents which increase the effectiveness of certain 3-lactam antibiotics when the latter are used to treat bacterial infections in mammals, particularly humans . Previously, penicillanic acid 1,1-dioxide and esters thereof which are readily hydrolyzable in vivo have been prepared from 6-bromopenicillanic acid or an ester thereof, which is readily hydrolyzable in vivo, by debromination to form penicillanic acid or an ester thereof which is readily hydrolysable in vivo, followed by oxidation to

The 1,1-dioxide. Although the method according to the invention

starting with a 6-halo-penicillanic acid or an ester thereof

which is easily hydrolyzable in vivo, and comprises the steps of dehalogenation and oxidation, it has surprisingly been found that if the oxidation step is carried out before the dehalogenation step,

you get a better yield from the product. Sé(Belgian patent 867,859 and German official publication 2. 824 . 535] for details concerning^' ■ methods for the preparation of penicillanic acid 1,1-dioxide and esters thereof which are readily hydrolysable in vivo. ,\

6-Halopericillanic acids are described by Cignarella et al, Journal of Organic Chemistry, 2-7, 2668 (1962) and in US Patent 3,206,469. Hydrogenolysis of 6-halopenicillanic acids to penicillanic acid is described in British patent 1,072,108.

Harrison et al, Journal of the Chemical Society (London), Perkin I,(1772 (1976) describe: (a) oxidation of 6,6-dibromopenicillanic acid with 3-chloroperbenzoic acid to form a mixture of the corresponding a- and (3 -sulfoxides; (b) oxidation of;

methyl 1-6,6-dibromopenicillanate with 3-chloroperbenzoic acid to form a methyl 6,6-dibromopenicillanate-1,1-dioxide; } J\

(c) oxidation of methyl 6-α-chloropenicillanate with 3-chloroperbenzoic acid to form a mixture of the corresponding α- and α-3-sulfoxides; and (d) oxidation, of methyl 6-bromopenicillanate f with 3-chloroperbenzoic acid to form a mixture of the corresponding α- and 3-sulfoxides. Clayton, Journal of the Chemical Society (London), (C), 2123 (1969) describes: (a) preparation of 6,6-dibromide and 6,6-diiodopenicillanic acid; (b) oxidation of 6,6-dibromopenicillanic acid with sodium periodate to form a mixture of the corresponding sulfoxides; (c) hydrogenolysis of methyl 6,6-dibromopenicillanate to form methyl 6-α-bromopenicillanate; (d) hydrogenolysis of 6,6-dibromopenicillanic acid and its methyl ester to form penicillanic acid and its methyl ester, respectively; and (e) hydrogenolysis of a mixture of methyl 6,6-diiodopenicillanate and methyl 6-α-iodopenicillanate to form pure methyl 6,6-α-iodopenicillanate. This invention relates to a method for the preparation of a compound with the formula

or a pharmaceutically acceptable base salt thereof wherein R^" is hydrogen or an ester-forming residue which is readily hydrolyzable in vivo, comprising the steps of:

(a) a compound of the formula

or a base salt thereof is contacted with a reagent selected from alkali metal permanganates, alkaline earth metal permanganates

and organic peroxycarboxylic acids, to form a compound, of the formula

;or a base salt thereof, where X and Y are each hydrogen, chlorine, bromine or iodine, with the proviso that when X and Y are equal,

they both be bromine; and

(b) the compound of formula III is dehalogenated.

A preferred way of carrying out step (b) comprises bringing the product from step (a) into contact with hydrogen in an inert solvent at a pressure of approx. 1 to approx.

100 kg/cm, at a temperature in the range from approx. 0 to approx. 60°C and at a pH in the range from approx. 4 to approx. 9, and in the presence of a . hydrogenolysis catalyst. The hydrogenolysis catalyst is usually present in an amount from about 0.01 to approx. 2.5% by weight, and preferably from approx. 0.1 to about 1.0% by weight, based on the compound of formula III.

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

When both X and Y are chlorine, the compound of formula II is difficult to obtain. When both X and Y are iodine, step (a) of the method takes place impractically slowly.

The invention also encompasses the intermediates of formula III, where X, Y and R1 are as indicated above. A preferred intermediate is 6,6-dibromopenicillanic acid-1,1-dioxide, the compound , of formula III, where X and Y are bromine and R" is hydrogen.

The invention relates to the production of compounds with

formula I and several intermediates for this purpose. These compounds are here designated as derivatives of penicillanic acid, which are represented by the following structural formula:

In derivatives of penicillanic acid, attachment of a substituent through a broken line to the bicyclic nucleus means that the substituent is below the plane of the nucleus. Such a substituent is said to be in the α-configuration. Conversely, binding a substi- through a full line to the bicyclic nucleus that the substituent is above the plane of the nucleus. This latter configuration is referred to as the (3-configuration. Thus the group X has a-configuration and the group Y has 13-configuration i formula II. When R here is an ester-forming residue that is readily hydrolyzable in vivo, it is a group thought to be derived from an alcohol with the formula R^OH, so that the part COOR1 in a such compound of formula I represents an ester group. Furthermore, R is of such a nature that the group COOR"*" is easily cleaved in vivo to release 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 is an ester-forming residue which is readily hydrolyzed in vivo is exposed to mammalian blood or tissue, the compound of formula I wherein R is readily formed "1" is hydrogen. The groups R^" are well known in penicillin science. In most cases they improve the absorption properties of the penicillin compound. Moreover, R should be of such a nature as to give a compound of formula I pharmaceutically acceptable properties and to liberate pharmaceutically acceptable fragments when it is cleaved in vivo. The groups R^ are well known and can be easily identified by those skilled in the art, see, for example, German Off.Schrift 2,517,316. Particular examples of groups denoted by R are 3-phthalidyl, 4-crotonlactonyl, Y-butyrolactone -4-y1 and group with the formula

2 3

where R and R are each hydrogen or alkyl with 1 or 2 carbon atoms, and R 4 is alkyl with from 1 to 5 carbon atoms. However, preferred values for R are alkanoyloxymethyl having from 3 to 7 carbon atoms, 1-(alkanoyloxy)ethyl having from 4 to 8 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having from

5 to 9 carbon atoms, . alkoxycarbonyloxymethyl with from

3 to 6 carbon atoms, 1-(Alkoxycarbonyloxy)ethyl with from

4 to 7 carbon atoms, 1-methyl 1-1-alkoxycarbonyloxy).ethyl with from 5 to 8 carbon atoms, 3-phthalidyl, 4-crotonolactonyl and Y-butyrolacton-4-yl. 3-phthalidyl, 4-crotonolactonyl and Y-butyrolacton-4-yl denote structures VII, VIII and IX. The wavy lines denote that they include both epimers or a mixture thereof.

Step (a) in the method according to the invention comprises oxidation of the sulphide group in a compound of formula II

to a sulfone group, whereby a compound of formula III is formed. A number of oxidizing agents known for the oxidation of sulfides to sulfones can be used for this method. Particularly suitable reagents, however, are alkali metal permanganates such as sodium and potassium permanganate; alkaline earth metal permanganates, such as calcium and barium permanganates; and organic peroxycarboxylic acids such as peracetic acid and 3-chloroperbenzoic acid.

When a compound of formula II where X, Y and R"*" are as indicated 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 about 0.5 to approx. 10 molar equivalents, and preferably from approx. 1 to approx. 4 molar equivalents of the permanganate in a suitable reaction-initiated solvent system. A suitable reactive solvent system is one which has no deleterious effect on either the starting materials or the product, and water is commonly used. Optionally, one can add a co-solvent which is miscible with water, but which will not react with the permanganate, such as tetrahydrofuran. The reaction can be carried out at a temperature in the range from

about. -30 to approx. 50°C, and it is preferably carried out from approx. -10 to approx. 10°C. At approx. At 0°C, the turnover is normally almost complete within a short time, e.g. within 1 hour. Although the reaction can be carried out under neutral, basic or acidic conditions, it is preferred to work at a pH in the range from approx. 4 to approx. 9, preferably 6-8. However, it is essential to choose conditions which avoid cleavage of the 3-lactam ring system in the connection with the formulas II or III. It is often appropriate to buffer the reaction medium's pH value to around the neutrality point. The product is extracted in the usual way. Any excess of permanganate is usually decomposed using sodium bisulphite, and if the product is then out of solution, it is recovered by filtration. It is separated from manganese dioxide by extraction into an organic solvent and removal of the solvent by de- . steaming. Alternatively, if the product does not fall out of the solution at the end of the reaction, it is isolated in the usual way by solvent extraction.

When a compound of formula II where X, Y and R are as indicated 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 approx. 1 to approx. 6 molar equivalents, and preferably approx. 2.2 molar equivalents of the oxidizing agent 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 conversion is normally carried out at a temperature of approx. -30 to approx. 50°C, and preferably from approx.

15 to approx. 30°C. At approx. 25°C reaction times are usually used

from approx. 2 to approx. 16 hours. The product is normally isolated by removing the solvent by evaporation in a vacuum. The reaction product can be purified by usual methods that are well known in the art. Alternatively, it can be used directly in

step (b) without further purification.

Step (b) according to the present process is a dehalogenation reaction. A convenient method for carrying out this conversion is to stir or shake a solution of a compound of formula III under an atmosphere of hydrogen, or hydrogen mixed with an inert diluent such as nitrogen or argon, in the presence of a hydrogenolysis -catalyst. Suitable solvents for this hydrogenolysis reaction are those which essentially dissolve the starting compound of formula III, but which are not themselves subjected to 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-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone; water and mixtures thereof. In addition, it is common to buffer the reaction mixture so that one works at a pH in the range from approx. 4 to 9, preferably from approx. 6 to 8. Borate and phosphate buffers are usually used. Introduction of the hydrogen gas into the reaction medium is usually achieved by carrying out the reaction in a closed vessel containing the compound of formula III, the solvent, the catalyst and hydrogen. The pressure inside the reaction vessel can vary from approx. 1 to approx. 100 kg/cm . The preferred pressure range, when the atmosphere inside the reaction vessel is almost pure hydrogen, is from approx. 2 to approx. 5 kg/cm 2. The hydrogenolysis is usually carried out at a temperature from approx. 0 to approx. 60°C, and preferably from approx. 25 to approx. 50°C. Using the preferred temperature and pressure values, hydrogenolysis usually takes place within a few hours, e.g. from approx. 2 to approx. 20 hours. The catalysts used in this hydrogenolysis reaction are the type of agents known in the art for this kind of transformation, and typical examples are the noble metals such as nickel, palladium, platinum and rhodium. The catalyst is usually present in an amount from approx. 0.01 to approx. 2.5% by weight, and preferably from approx. 0.1 to about 1.0% by weight, based on the compound of formula III. It is often appropriate to distribute the catalyst on an inert carrier, and a particularly suitable catalyst is palladium distributed on an inert carrier such as coal.

t Other methods can be used for reductive removal of the halogen from a compound of formula III, i.e. step (b). E.g. X and Y can be removed using a dissolving metal reducing system, such as zinc dust in acetic acid, formic acid or a phosphate buffer, according to well known methods. Alternatively, step (b) can be carried out using stannous hydride, e.g. a trialkyltin hydride such as tri-n-butyltin hydride.

As will be understood by those skilled in the art, when it is desired to prepare • a compound of formula I where is hydrogen, a compound of formula II where R"*" is hydrogen can be subjected to steps (a) and (b) of the method according to the invention. In other words, the method comprises oxidation, followed by dehalogenation, of a 6-halogen or 6,6-dihalogen derivative of penicillanic acid with a free carboxy group in the 3-position.

According to a further feature of the invention, however, it is possible to begin one of steps (a) and (b) with the carboxy group in the 3-position blocked with a conventional penicillin carboxy protecting group. The protecting group can be removed during or after step (a) or step (b), with regeneration of the free carboxyl group. A number of protecting groups which are usually used in penicillin science to protect the 3-carboxy group can be used in this context. The main ■ requirements for the protecting group are that it must be capable of being attached to the particular compound of formula II or/III and capable of being removed from the particular compound of formula I or III, using conditions in which the β-lactam ring system remains approx. intact. For each of steps (a) and (b), typical examples are the tetrahydropyranyl group, trialkylsilyl groups, the benzyl group, substituted benzyl groups (e.g. 4-nitrobenzy1), the benzhydryl group, the 2,2,2-trichloroethyl group, the t-butyl group and the phenacyl group. Although not all protective groups can be used in all situations, a particular group will . which can be used in a particular situation, could easily be selected by a person skilled in the art. See also: US Patents 3,632,850 and 3,197,466, British Patent 1,041,985, Woodward et al, Journal of the American Chemical Society, 8_8, 852 (1966); Chauvette, Journal

of Organic Chemistry, _36 , 1259 (1971); Sheehan et al. Journal of Organic Chemistry, 2_9, 2006 (1964).; and "Cephalosporin and

Penicillins, Chemistry and Biology", 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 3-lactam ring system. r 6-a-chloropenicillanic acid and 6-a -bromopenicillanic acid is prepared by diazotization of 6-aminopenicillanic acid in the presence of hydrochloric acid and hydrobromic acid respectively (Journal of Organic Chemistry, 27, 2668 (1962)). 6-a-iodopenicillanic acid is prepared by diazotization of 6-aminopenicillanic acid in the presence of iodine, followed by hydrogenolysis ■

(Clayton, Journal of the Chemical Society (C), 2123 (1969)). 6-3-Chloropenicillanic acid, 6-3-bromopenicillanic acid and 6-iodopenicillanic acid are produced by reducing respectively 6-chloro-6-iodopenicillanic acid, 6,6-dibromopenicillanic acid and 6,6-diiodopenicillanic acid with tri-n-butyltin hydride. 6-Chloro-6-iodopenicillanic acid is prepared by diazotization of 6-aminopenicillanic acid in the presence of iodine chloride; 6,6-dibromopenicillanic acid is prepared by the method of Clayton, Journal of the Chemical Society (London) (C) 2123 (1969); and 6,6-diiodopenicillanic acid is prepared by diazotization of 6-aminopenicillanic acid in the presence of iodine. • The compounds of formula I, II and III, where b}~ is hydrogen,

are acidic and will form salts with basic substances. These salts can be prepared by standard methods, such as bringing the acidic and basic components into contact, usually in a stoichio-j; metric ratio, in an aqueous, non-aqueous or partially aqueous state

medium, depending on what suits. 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 suitably used in salt formation are of both the organic and inorganic types, and they include ammonia, organic amines, alkali metal hydroxides, carbonates, bicarbonates, hydrides and alkoxides, as well as alkaline earth metal hydroxides, carbonates, hydrides and

-alkoxides. Representative examples of such bases are primary amines, such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine and octylamine; secondary amines such as diethylamine, morpholine, pyrrolidine and piperidine; tertiary amines such as triethylamine, N-ethylpiperidine, N-methylmorpholine and 1,5-diazar

bicyclo[4.3.0]non-5-ene, hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and barium hydroxide; alkoxides such as sodium ethoxide and potassium ethoxide; hydrides such as calcium hydride and sodium hydride; carbonates such as potassium carbonate and sodium carbonate; bicarbonates such as sodium bicarbonate and potassium bicarbonate; and alkali metal salts of long chain fatty acids such as sodium 2-ethyl hexanoate. Preferred salts of the compound of formula I are the sodium, potassium and triethylamine salts.

The compound of formula I wherein R is hydrogen and its salts are active as an antibacterial agent of medium potency both in vitro and in vivo, and compounds of formula I wherein R"*" is an ester-forming residue which is readily hydrolyzable in vivo, are active as -antibacterial agents of medium potency in vivo. Minimum inhibitory concentrations (MIC) of penicillanic acid 1,1-dioxide against several microorganisms are shown

.in Table I.

The in vitro antibacterial activity of the compounds of formula I where R"*" is hydrogen and their salts make them useful as industrial antimicrobial agents, e.g. in water treatment, slime control, paint preservation and wood preservation, and also for local use as disinfectants. When these compounds are used topically, it is often appropriate to mix the active ingredient with a non-toxic carrier such as a vegetable oil or mineral oil or an emollient. cream. Likewise, they can be dissolved or dispersed in liquids, diluents or solvents such as water, alkanols, glycols or mixtures thereof. In most cases, it is suitable to use concentrations of the active ingredient from approx. 0.1 to approx. 10% by weight, based on the total mixture. •" V

The in vivo activity of the compounds of formula I wherein

R"*" is hydrogen or an ester-forming residue which is light.

hydrolysable in vivo, and the salts thereof, make them suitable for combating bacterial infections in mammals, including humans, by both oral and parenteral administration. The compounds can be used to combat infections caused by susceptible bacteria in humans, e.g. infections caused by strains of Neisseria gonorrhoeae.

In the therapeutic use of a compound of formula I or a salt thereof, in a mammal, especially humans, the compound may be administered alone or it may 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 on the basis of the form of administration in question. When you e.g. desiring oral administration, the compound can be used in the form of tablets, capsules, pastilles, candy, powders, syrups, elixirs, aqueous solutions and suspensions, etc., in accordance with usual pharmaceutical practice. The ratio between active ingredient and carrier will depend on the chemical nature, solubility and stability of the active ingredient as well as the desired dose. ■ ■ ;' < Pharmaceutical preparations, containing an antibacterial agent with,, formula I will, however, normally contain from approx. 20 to approx. 95%. active ingredient. In the case of tablets for oral use, commonly used carriers are 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 often used in tablets. Suitable diluents for oral administration in capsule form are lactose and high molecular weight polyethylene glycols. When aqueous suspensions are desired for oral use, the active ingredient can be mixed with emulsifiers; or suspending agents. Optionally, various sweeteners and/or flavoring agents can be added.' For parenteral administration, which includes intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions is. appropriately regulated and buffered"..

v

For intravenous use, the total concentration of the dissolved substances should be regulated so that the preparation becomes isotonic. -

The prescribing physician will ultimately determine the appropriate dose of a compound of formula I for a given individual, and this may be expected to vary according to the age, weight and response of the individual patient, as well as the nature and degree of the patient's symptoms. The compound will normally be used orally in doses ranging from approx. 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. These figures are only illustrative, and in some cases it may be necessary to use doses outside these limits.

The compounds of formula I wherein R<3>" is hydrogen or an ester-forming residue which is readily hydrolyzable in vivo, or a salt thereof, enhance the antibacterial effectiveness of 3-lactam antibiotics in vivo. They lower the amount of the antibiotic substance which is necessary to protect mice against an otherwise lethal inoculation of certain 3-lactamase-producing bacteria.. This ability makes them valuable for co-administration with 3-lactam antibiotics in the treatment of bacterial infections in mammals, especially humans.. In the treatment of<1 >, a bacterial infection, the compound of formula I can be formed with the 3-lactam antibiotic substance, and the two agents are thereby administered simultaneously. Alternatively, the compound of formula I can be administered as a separate agent during treatment with a 3-lactam antibiotic substance In some cases it is appropriate to

giving the subject a predose of the compound of formula I prior to initiation of treatment with a 3-lactam antibiotic.

When using penicillanic acid 1,1-dioxide, a salt or ester thereof which is readily hydrolyzable in vivo, to increase the effectiveness of a 3-lactam antibiotic, it is preferably administered in admixture with standard pharmaceutical carriers or diluents. The preparation forms mentioned above in connection with penicillanic acid 1,1-dioxide or an ester thereof which is easily hydrolysable in vivo, as an antibacterial agent with a single active ingredient, can be used when co-administration with another 3 ~lactam antibiotic. A pharmaceutical preparation containing a pharmaceutically acceptable carrier, a 3-lactam antibiotic and penicillanic acid 1,1-dioxide or an easily hydrolyzable ester thereof, will normally contain from approx. 5 to approx. 80% by weight of the ', , pharmaceutically acceptable carrier.

When using penicillanic acid 1,1-dioxide or an ester thereof which is readily hydrolyzable in vivo, in combination with another (3-lactam antibiotic, the sulfone can be administered orally or parenterally, i.e. intramuscularly, subcutaneously, or intraperitoneally. Although the prescribing doctor will ultimately decide the dose to be used for an individual, the ratio: between the daily doses of the penicillanic acid 1,1-dioxide or a salt or an ester thereof and the ft-lactam antibiotic will normally be in the range from about 1:3 to 3:1. Furthermore, when penicillanic acid 1,1-dioxide or a salt or ester thereof which is readily hydrolyzable in vivo is used in combination with another 3-lactam antibiotic, it daily oral dose of each component will normally be in the range of from about 10 to about 200 mg per kg of body weight, and the daily parenteral dose of each component will normally be from about 10 to about 400 mg per kg of body weight. figures are illustrative only, and in some cases may be necessary you to use doses outside these limits.

Typical (3-lactam antibiotics such as penicillanic acid 1,1-dioxide and esters thereof which are readily hydrolyzable in vivo, can be co-administered with, are: • :' V; 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- desacetoxymethylcephalosporanic acid.

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

As will be appreciated by those skilled in the art, some 3-lactam compounds are effective when administered orally or parenterally, while others are effective only when administered parenterally. When penicillanic acid 1,1-dioxide, a salt or ester thereof which is easily hydrolysable in vivo, is to be used simultaneously (ie mixed together) with a 3-lactam antibiotic which is only effective by parenteral administration, it is necessary with a combina- 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 CD 3 COCD 3 ) 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.

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

Example 4

6- 3- bromopenicillanic acid- 1, 1- dioxide

To a solution of 255 mg of sodium 6-|3-bromopenicillanate in 5 ml of water, at 0 to 5°C, was added a solution prepared

from 140 mg of potassium permanganate, 0.11 ml of 85% phosphoric acid and 5 ml of water, at 0 to 5°C. The pH value 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 colored solution was covered with ethyl acetate. The pH was adjusted to 1.7,

and 330 mg of sodium bisulfite was added. After 5 minutes, the layers were separated, and the aqueous layer was further extracted with ethyl acetate. The combined ethyl acetate solutions were washed with brine, dried (MgSO 4 ) and evaporated in vacuo. This gave 216 mg of the title compound as white crystals. The NMR spectrum (xD^O) showed absorptions at 5.78 (d, 1H, J = 4 Hz), 5.25 (d, 1H, J = 4Hz), 4.20 (s, 1H), 1.65 (s, 3H) and 1.46 , (

(s, 3H) ppm./

Example 5

6- 3- iodopenicillanic acid- 1, 1- dioxide

..Oxidation of 6-3-iodopenicillanic acid with potassium permanganate.: the method according to example 4 gives 6-3-iodopechillanoic acid 1,1-dioxide.

1

Example 6

Pivaloyloxymethyl- 6- a- bromopenicillariat- 1, 1- dioxide.

To a solution of 394 mg of pivaloyloxymethyl-6-a-bromopenicillanate in 10 ml of dichloromethane is added 400 mg of 3-chloroperbenzoic acid at .0 to 5°C. The reaction mixture is stirred at 0 to 5°C for 1 hour and then at 25°C for 24 hours. The filtered reaction mixture is evaporated to dryness in vacuo to give the title compound.

Example 7

The procedure according to example 6' is repeated, except

that the pivaloyloxymethyl-6-3-bromopenicillanate is replaced with: 3- phthalidyl-6-a-chloropenicillanate,

4-crotonolactonyl-6-(3-chloropenicillanate,

Y-butyrolacton-4-yl-6-a-bromopenicillanate, acetoxymethyl-6-3-bromopenicillanate, pivaloyloxymethyl 1-6-3-bromopenicillanate,

hexanoyloxymethyl 1-6-a-iodopenicillanate,

1-(acetoxy)ethyl-6-3-iodopenicillanate, 1-(isobutyryloxy)ethyl-6-a-chloropenicillanate,

1-methyl-l-(acetoxy)ethyl-6-3~chloropenicillanate, 1-methyl-l-(hexanoyloxy) ethyl-6-a-bromopenicillanate, ■■"„)'■*■ , methoxycarbonyloxymethyl-6-a- bromopenicillanate, propoxycarbonyloxymethyl-6-3-bromopenicillanate, 1-(ethoxycarbonyloxy)ethyl-6-ct-bromopenicillanate, 1-(butoxycarbonyloxy)ethyl-6-a-iodopenicillanate, 1-methyl-1-(methoxycarbonyloxy)ethyl-6-3 ~iodopenicillanate and 1-methyl-1-(isopropoxycarbonyloxy)ethyl 1-6-a-chloropenicillanate This gives respectively: 3-phthalidyl-6-a-chloropenicillanate-1,1-dioxide, ,

4-crotonolactonyl-6~3~chloropenicillanate-1,1-dioxide, Y-butyrolactone-4-y1-6-a-bromopenicillanate-1,1-dioxide, acetoxymethyl-6-3-bromopenicillanate-1,1-dioxide, pivaloyloxymethyl 1-6-3-bromopenicillanate-1,1-dioxide, hexanoyloxymethyl-6-a-iodopenicillanate-1,1-dioxide, 1-(acetoxy)'ethyl-6-3-iodopenicillanate-1,1-dioxide, 1- (isobutyryloxy)ethyl 1-6-α-chloropenicillanate-1,1-dioxide, 1-methyl-1-(acetoxy)ethyl-6-3-chloropenicillanate-1,1-dioxide,

1-methyl-1-(hexanoyloxy)ethyl-6-a-bromopenicillanate-1,1-dioxide, methoxycarbonyloxymethyl-6-a-bromopenicillanate-1,1-dioxide, propoxycarbonyloxymethyl-6-3-bromopenicillanate-1,1-dioxide , 1-(ethoxycarbonyloxy)ethyl-6-a-bromopenicillanate-1,1-dioxide, 1-(butoxycarbonyloxy)ethyl-6-a-iodopenicillanate-1,1-dioxide,

1-methyl-1-1-(methoxycarbonyloxy)ethyl-6-(3-iodopenicillanate-1,1-dioxide and 1-methyl-1-(isopropoxycarbonyloxy)ethyl-6-a-chloropenicillanate-1,1-dioxide.

Example 8

Penicillanic acid- 1, 1- dioxide

To 100 ml of water was added 9.4 g of 6-α-bromohecylic acid 1,1-dioxide at 22°C, followed by sufficient 4N sodium hydroxide solution to give 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 dipotassium phosphate trihydrate. This mixture was then shaken under an atmosphere of hydrogen at a pressure varying from 3.5 to 1.8 kg/cm 2 . When the hydrogen uptake ceased, the solids were removed by filtration, and the aqueous solution was covered with 100 ml of ethyl acetate. The pH value 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; solution, dried using anhydrous magnesium sulfate and evaporated in vacuo. The residue was triturated under ether, and then the solid was collected by filtration. This gave 4.5 g (65% yield) of the title compound.

Analysis : Calculated for CgH^NO^: C 41.20, H. 4.75, N 6.00, S 13.75% Found: C 41.16, H 4.81,.N 6.11, S 13 .51%. _

Example 9

Penicillanic acid- 1, 1- dioxide

Hydrogenolysis of each of: 6-ct-chloropenicillanic acid!-1, 1-dioxide,

6-a-iodopechillanic acid-1,1-dioxide, 6-3-chloropenicillanic acid-1,1-dioxide, 6-3-bromopenicillanic acid-1,1-dioxide, and

6-3-iodopenicillanic acid-1,1-dioxide,

by the method according to example 8, gives penicillanic acid 1,1-dioxide.

■ Example 10

Pivaloyloxymethyl- penicyl Thanat- 1, 1- dioxide

To a solution of 1.0 g of pivaloyloxymethyl-6-a-bromopenicillanate in 10 ml of methanol, add 3 ml of IM sodium bicarbonate

and 200 mg of 10% palladium on charcoal. The reaction mixture is vigorously shaken under an atmosphere of hydrogen at a pressure of approx.

5 kg/cm 2 until hydrogen absorption ceases. The mixture

is filtered, and most of the methanol is removed by evaporation in a vacuum. Water and ethyl acetate are added to the residue, and the pH value is adjusted to 8.5. The layers are separated, and the organic layer is washed with water, dried (Na 2 SO 4 ) and evaporated in vacuo. This ^ :.provides the title compound. ■ n i

Example 11

Hydrogenolysis of the appropriate 6-halopenicillane methyl ester 1,1-dioxide from example 7 by the method according to example 10 gives respectively 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-1-penicillanate-1,1-dioxide,

1-(acetoxy)ethyl penicillanate-1,1-dioxide,

1-(isobutyryloxy)ethyl-1-penicillanate-1,1-dioxide,

1-methyl-1-(acetoxy)ethyl penicillanate-1,1-dioxide,

1-methyl-1-(hexanoyloxy)ethyl-1-penicillanate-1,1-dioxide, methoxycarbonyloxymethyl-penicillanate-1,1-dioxide,

propoxy.arbony loxymethyl-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-dioxide. ,.

Example 12'

Pivaloyloxymethyl-6-g-bromopenicillanate-1,1-dioxide

An oxidizing solution was prepared by mixing 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 over 20 minutes at 5 to 10° C., to a stirred solution of 5.32 g pivaloyloxymethyl-6-α-bromopenicillanate in 70 ml acetone and 10 ml water. The mixture was stirred at 5° C. in

30 minutes, and 100 ml of ethyl acetate was added. After further

.30 minutes, a solution of 3.12 g of sodium bisulphite i

30 ml of water added over 15 minutes at approx. 10°C.

Stirring was continued for a further 30 minutes at 5°C, 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. the compound as an oil which crystallized slowly. The NMR spectrum (iCDCl^) showed absorptions at 5.80 (q, 2H), 5.15 (d, 1H), 4.75 (d, 1H), 4.50 (s, 1H), 1.60 ( p, 3H), 1.40

(p, 3H). and 1.20 (s, 9H) ppm.

Example 13

Pivaloyloxyrnety1-penicillanate-1,1-dioxide.

A solution of 4.4 g of pyaloyloxymethyl-6-a-bromopenicillanate-1,1-dioxide in .60 ml of tetrahydrofuran was added to 0.84 g of sodium bicarbonate in 12 ml of water. The solution was shaken under an atmosphere of hydrogen in the presence of 2.0 g of 5% palladium-on-charcoal at 3.3 to 3.6 kg/cm 2 . The reaction mixture was then filtered, and the residue was washed with 100 ml of ethyl acetate and 25 ml of water. The combined filtrates and washing liquids were separated. The organic layer was washed with saturated sodium chloride solution and dried (MgSO 4 ) and evaporated to give the title compound as an oil. This oil was dissolved in ethyl acetate (20 mL). Hexane (100 ml) was slowly added to the solution, and the precipitate was filtered off. Yield: 2.4 g. The NMR spectrum (in DMS0-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-bro<mp>eni<c>i<i>ranate-<l>, 1- d<i>bksyd

2,2,2-trichloroethyl-6-a-bromopenicillanate was oxidized with potassium permanganate essentially by the method of Example 12 to give the title compound in 79% yield. The NMR spectrum of the product (in CDCl3) showed absorptions at

5.30 to 4.70 (m, 4H), .4.60 (s, 1H), 1.70 (s, 3H) and 1.50 r-(s, 3H) ppm... - j

< ■ ..<_i>' Example 14 A

Penicillanic acid- 1, 1- dioxide

For a stirred slurry of 6.5 g zinc powder in 100 ml

of a 70:30 glacial acetic acid-tetrahydrofuran mixture was added portionwise over 5 minutes 4.0 g of 2,2,2-trichloroethyl-6-ct-bromopenicillanate-1,1-dioxide. The mixture was stirred at ambient temperature for 3 hours and then filtered. The filtrate was concentrated to a volume of 10 ml, bg the light brown solution was mixed with 50 ml of water and 100 ml of ethyl acetate. The pH value was adjusted to 1.3, and the layers were separated.' The organic phase was washed with saturated sodium chloride solution, dried using magnesium sulfate, and then concentrated to dryness in vacuo. The residue was triturated with ether for 20 minutes... • : This gave 553 mg of the title compound as a solid. The NMR spectrum (in CDCl3/DMSO-dg) showed absorptions at 11.2

(wide s, 1H),.4.65 (m, 1H), 4.30 (s, 1H), 3.40 (m, 2H), 1.6 5

(s, 3H) and 1.50 (s, 3H) ppm.

Example 15

Benzyl- 6- g- bromopenicillanate- l, l-. dioxide

, Benzyl-6-a-bromopenicillanate was oxidized with potassium permanganate in total. substantially by the method of Example 12, to give the title compound in 94% yield. The NMR spectrum

(in CDCl3) showed absorptions at 7.35 (s, 5H), 5.10.(m, 3H),

4.85 (rn, 1H), 4.40 (s, 1H), 1.50 (s,'3H) and 1.25 (s, 3H) ppm.

l

Example 16

, Penicillanic acid- 1/ 1- dibxyd

• »■•■■.

■ ■»"

A solution of 4.0 g of benzyl 6-α-bromopenicillanate-1,1-dioxide in 50 ml of tetrahydrofuran was mixed with a solution of 1.06 g of sodium bicarbonate in 50 ml of water. To the mixture was added 2.0 g of a 50% suspension of 5% palladium-on-charcoal in water, then this mixture was shaken under an atmosphere

of hydrogen at a pressure of 3.3 to 3.5 kg/cm for 20 minutes...

.The catalyst was removed at . filtration, and 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

2 an atmosphere of hydrogen at a pressure of 2.95 to 3.15 kg/cm for 65 minutes. The reaction mixture was then filtered, and the tetrahydrofuran was removed by evaporation.- The ethyl acetate.

was added to the aqueous residue, and the pH value was regulated. to 7.1. The ethyl acetate layer was removed and fresh ethyl acetate was added to the remaining aqueous phase. The pH was lowered to 1.5 and the layers were separated. The aqueous phase was further extracted with ethyl acetate, and the combined ethyl acetate solutions were washed with saturated sodium chloride solution and

■dried (MgSO^). Evaporation in vacuo gave a gum which remained. rubbed under ether. This gave ^3Ju_mg__penicillanic acid-1,1-dioxide as a yellow solid. The NMR spectrum (in CDCl3/DMSO-dg) showed absorption at 9.45. (wide 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- dibromopenicillanic acid- 1, 1- dioxide

To the dichloromethane solution of 6,6-dibromopenicillanic acid

from Preparation K, 300 ml of water was added, followed by the dropwise addition over a period of 30 minutes of .105 ml of 3N sodium hydroxide. The pH 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 was added,

at -5°C, a precooled solution prepared from 59.25 g of potassium permanganate, 18 ml of concentrated phosphoric acid and 600 ml of water, until the pink color of the permanganate remained. The addition took .50 minutes, and 550 ml of the oxidizing agent was

necessary. At this point, 500 ml of ethyl acetate was added, and then the pH was lowered to 1.23 by the addition of 105 ml of 6N hydrochloric acid. Then 250 ml IM sodium bisulphite was added over 10-15 minutes at approx. 10°C. 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 ) to give an ethyl acetate solution of 6,6-dibromopenicillanic acid 1,1-dioxide.

The 6,6-dibromopenicillanic acid 1,1-dioxide can be isolated by removing the solvent in vacuo. A sample isolated on . this way from an analogous preparation, had a melting point of 201°C (split.). The NMR spectrum (CDC13/DMS0-dg) showed absorptions at 9.35 (s, 1H), 5.30 (s, 1H), 4.42 (s, 1H), 1.63 (s, 3H) and 1.50 (s, 3H) ppm. The IR spectrum (KBr disc)

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-iodopenicillanic acid i

50 ml of dichloromethane was added to 50 ml of water, and then the pH was raised to 7.2 using 3N sodium hydroxide. The layers were separated and the aqueous layer was cooled to 5°C. To this solution was then added dropwise over a 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 was maintained below 10°C during the addition. At this point was 100 ml of ethyl acetate added, and the pH was adjusted to 1.5. 50 ml of 10% i.g sodium bisulphite was then added to the mixture.

while the temperature was kept below 10°C and the pH value at approx. 1.5 by adding 6N hydrochloric acid. The pH value was lowered to 1.25,

and the layers were separated.<1>The aqueous layer was saturated with sodium chloride and extracted with ethyl acetate. The combined organic solutions were washed with saline/dried (MgSO 4 ). and evaporated in vacuo to give 4.2 g of the title compound,

sm.p. 143-145°C. The NMR spectrum (CDCl 2 ) showed absorptions at 4.8.6 (s, 1H), 4.38 (s, 1H), . 1.60 (s/. 3H) and 1.43 (s, 3H) ppm. The IR spectrum (KBr disk) showed absorptions at 1800, 1740 and 1250-1110 cm"1. ■ ' 1 •

Example 19

6- bromo- 6- iodoperiicillanic acid- 1, 1- dioxide

To a solution of 6.0 g of 6-bromo-6-iodopenicillanic acid i

50 ml of dichloromethane was added to 50 ml of water. The pH was raised to 7.3 using 3N sodium hydroxide and the aqueous layer was 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 using 6N hydrochloric acid. To this two-phase system, 50 ml of 10% sodium bisulphite was added dropwise, while the pH value was kept at approx. 1.5 by adding 6N hydrochloric acid. A further 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

(MgSO^) and evaporated in vacuo. The residue was dried under high vacuum to . give 4.2 g of the title compound, m.p. 145-147 C. The NMR spectrum (CDCl 3 ) showed absorptions at 4.90 (s, 1H),

4.30 (s, 1H), 1.60 (s, 3H) and 1.42 (s, 3H) ppm. The IR spectrum (KBr disc) showed absorptions at 1800, 1740, 1330 and 1250-1110 cm"1.

Example 20

6- chloro- 6- bromopenicillanic acid- 1, 1- dioxide •

Oxidation of 6-chloro-6-bromopenicillanic acid with potassium permanganate by the method according to example 19 gives 6-chloro-6-bromopenicillanic acid 1,1-dioxide.

Example 21

P e n i c i 11 an sy re - 1, 1 - di ok s y d.

The ethyl acetate solution of 6,6-dibromopenicillanic acid-1,1-dioxide- from Example 17 was mixed with 705 ml of saturated sodium bicarbonate solution and 8.88 g of 5% pa elladium-on-charcoal 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 removed by filtration, and the pH value of the aqueous phase of the filtrate was adjusted to 1.2 with 6N hydrochloric acid. The aqueous phase was saturated with sodium chloride. The layers were separated and the aqueous phase was extracted with additional ethyl acetate (3 x 200 mL). The combined ethyl acetate solutions were dried (MgSO 4 ) and evaporated in vacuo to give 33.5 g (58% yield from 6-aminopenicillanic acid) of penicillanic acid 1,1-dioxide. This product was dissolved in 600 ml of ..^ ethyl acetate, the solution was decolorized using .. activated carbon, and the solvent was removed at . evaporation in vacuum. The product was washed with hexane. This gave 31.0 g of pure product.

Example 22

Hydrogenolysis of each of 6-chloro-6-iodopenicillanic acid 1,1-dioxide, 6-bromo-6-iodopenicillanic acid and 6-chloro-6-bromopenicillanic acid. the method according to example 21 gives in each case penicillanic acid 1,1-dioxide.

Example 2 3

Penicillanic acid- 1, 1- dioxide

To a stirred suspension of 786 mg of 6-chloro-6-iodo-penicillanic acid-1,1-dioxide in 10 ml of benzene was added 0.3 ml of triethylamine followed by 0.25 ml of trimethylsilyl chloride, at approx. 0°C.. Stirring was continued for 5 minutes at approx. 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 removed by filtration. The filtrate was cooled to approx. 0°C, and 1.16 g of tri-n-butyltin hydride and a few milligrams of azobisisobutyronitrile were added. The reactive ion mixture was stirred and irradiated with ultraviolet light for 1 hour at approx. 0°C and then for 3.5 hours at the solvent reflux temperature.

An additional amount of tri-n-butyltin hydride (1.1 ml) and one

catalytic amount, azobisisobutyronitrile was added, and stirring, and irradiation, at reflux temperature was continued for an additional 1 hour. 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. Ethyl acetate (50 mL) was added and the pH was adjusted to 1.5 with 6N hydrochloric acid. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate solutions were washed with saline, dried (MgSO 4 ) and concentrated in vacuo. The residue ''•••"•' was triturated under hexane and then recovered by filtration. This gave 0.075 mg of the title compound.

Example 24

Penicillanic acid- 1, 1- dioxide

To a stirred suspension of 0.874 g of 6-bromo-6-iodopenicillanic acid 1,1-dioxide in 10 ml of benzene at approx. 5°C was added 0.3 ml of triethylamine followed by 0.25 ml of trimethylsilyl chloride. Stirring was continued at about... 5°C for 5 minutes and then for 30 minutes at the solvent reflux temperature.

The reaction mixture. was cooled to room temperature, and the solids were removed by filtration. The filtrate was cooled to approx. 5°C, and 1.05 ml of tri-n-butyltin hydride and a catalytic ',''

'■' '; ' ■V,

amount of azobisisobutyronitrile was added. The mixture was irradiated with ultraviolet light for 1 hour at approx. 5°C, and then

it was poured into 30 ml of cold 5% sodium bicarbonate. The mixture was stirred for 30 minutes, and then 50 ml of ethyl acetate was added. The mixture was acidified to pH 1.5, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 25 ml), and the combined ethyl acetate layers were washed with brine, dried (MgSO 4 ) and evaporated in vacuo. The residue was dried under high vacuum and 30 ml of hexane was added. The indissoluble

material was recovered by filtration to give 0.035 g of the title compound..

Example 25 ■

Pivaloyloxymethyl- 6, 6- dibromopenicyl Tanate- 1, 1- dioxide

To a solution of 4.73 g of pivaloyloxymethyl-6,6-dibromopenicillanate in 15 ml of dichloromethane is added 3.80 g of 3-chloroperbenzoic acid at 0 to 5°C. The reaction mixture is stirred at 0 to 5°C for 1 hour and then at 25°C for 24 hours. The filtered reaction mixture is evaporated to dryness in vacuo, and the residue is distributed between ethyl acetate and water. The pH value of the aqueous phase is adjusted to 7.5, and the layers are separated. The ethyl acetate phase is dried (Na 2 SO 4 ) and evaporated in vacuo to give the title compound.

Example 26

Oxidation of h<y>er of the 6,6-dihalopenicillanic acid esters according to Preparation P using 3-chloro-perbenzoic acid using the method according to example 25 gives respectively the following compounds: 3-phthalidyl -6,6-dibromopenicillanate-1,1-dioxide,

4- crotonolactonyl-6-chloro-6-iodopenicillanate-1,1-dioxide, Y-but<y>rolactonyl-6-bromo-6-iodopenicillanate-1,1-dioxide, ; acetoxymethyl-6-chloro-6-bromopenicillanate-1, 1-dioxide, ■■ >. pi valoyloxyme tyl-6-chloro-6-iodopenici Hana t-1,1-dioxide, hexanoyloxymethyl 1-6,6-dibromopenicillanate-1,1-dioxide, 1-(acetoxy)ethyl-6,6-dibromopenicillanate-1,1 -dioxide, 1-(isobutyryloxy)ethyl 1-6-bromo-6-iodopenicillanate-1,1-dioxide,

1-methyl-1-(acetoxy)ethyl-6,6-dibromopenicillanate-1,1-dioxide, 1-methyl-1-(hexanoyloxy)ethyl-6-chloro-6-bromopenicillanate, methoxycarbonyloxymethyl-1-6,6- dibromopenicillanate-1,1-dioxide, propoxycarbonyloxymethyl-6-chloro-6-iodopenicillanate-1,1-dioxide, 1-(ethoxycarbonyloxy)ethyl-6,6-dibromopenicillanate-1,1-dioxide,. 1-(butoxycarbonyloxy)ethyl-6-bromo-6-iodopenicillanate-1,1-dioxide, 1-methyl-1-(methoxycarbonyloxy)ethyl-6,6-dibromopenicillanate-1,1-dioxide and

1-Methyl-1-(isopropoxycarbonyloxy)ethyl-6,6-dibromopenicillanate-1,1-dioxide.

Example 27

Pjvaloyloxymethyl- penicillanate- 1, 1- dioxide

r' To a solution of 1.0 g of pivaloyloxymethyl-6,6-dibromopenicillanate-1,1-dioxide in 10 ml of methanol is added 3 ml of IM sodium bicarbonate and 200 mg of 10% palladium-on-charcoal. The reaction mixture is shaken vigorously under an atmosphere of hydrogen at a pressure of approx. 5 kg/cm 2 until hydrogen absorption ceases. The mixture

is then filtered, and most of the methanol is removed by evaporation in a vacuum. Water and ethyl acetate are added to the residue, and the pH value is adjusted to 8.5. The layers are separated, and the organic layer is washed with water, dried (Na 2 SO 4 ) and evaporated in vacuo. This gives pivaloyloxymethyl-penicillanate-1,1-dioxide.

Example 2 8

.'v Hydrogenolysis of each a-y 6,6-dihalogen-penicillanic acid-■'' ester-1,1-dloxides from example 26. by the method according to example 27, gives respectively the following compounds: 3-phthalidyl-penicillanate-1, 1-dioxide, 4-crotonolactonyl-penicillanate-1,1-dioxide,

Y-butyrolacton-4-yl-penicillanate-1', 1-dioxide,

acetoxymethylpenicillanate-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-1-penicillanate-1,1-dioxide,

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

Example 29

Pivaloyloxymethyl-6,6-dibromo. nicillanate-1,1-dioxide

A stirred solution of 3.92 g of 6,6-dibromopenicillanic 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 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

saline solution. The ethyl acetate solution was then treated

with "Darco" (activated charcoal), dried (MgSO4) and evapd.i.

vacuum to a brown oil weighing 2.1. g. This oil was chromatographed on 200 g of silica gel using dichloromethane as eluent. The fractions containing the desired product were pooled and chromatographed again on silica gel to give 0.025 g of the title compound. The NMR spectrum. (CDCl 3 ) showed absorptions at 6.10 (q, 2H), 5.00 (s, 1H), 4.55 (s, 1H), 1.60 (s, 3H), 1.50 (s, 3H) .and 1.15 (s, 9H) ppm.

Example 30

Pivaloyloxymethyl- penicillanate- 1, 1- dioxide

To a stirred solution of 60 mg of pivaloyloxymethyl-6,6-dibromopenicillanate-1,1-dioxide in 5 ml of benzene was added 52 µl of tri-n-butyltin hydride followed by a catalytic amount of azobisisobutyronitrile. The reaction mixture was cooled to approx. 5°C, and it was irradiated with ultraviolet light for 1 hour. The reaction mixture was poured into 20 ml of cold 5% sodium bicarbonate solution and stirred for 30 minutes. Ethyl acetate was added, and the pH value of the aqueous phase was adjusted to 7.0. The layers were separated and the aqueous phase was further extracted with ethyl acetate. v' The combined ethyl acetate solutions were washed with brine, dried (MgSO 4 ) and evaporated in vacuo. The residue' was dried under high vacuum for 30 minutes. This gave 70 mg of a yellow oil which by NMR spectroscopy was shown to contain the title compound, together with some impurities containing n-butyl groups.

Example 31

6, 6- dibromopenicillanic acid- 1, 1- dioxide

To a solution of 359 mg of 6,6-dibromopenicillanic acid i

30 ml of dichloromethane is added to 380 mg of 3-chloroperbenzoic acid at 0-5°C. The reaction mixture is stirred at 0-5°C for 30 minutes and then at 25°C for 24 hours. The filtered reaction mixture is evaporated in vacuo.to give the title compound.

Example 32

Benzy 1- 6 , 6 - dibromopenicillanate- 1, 1- dioxide -m!?'

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

(in CDCl3) showed absorptions at 7.40 (s, 5H), 5.30 (m,..2H),

4.95 (s, 1H) , 4.55 (s, 1H) ,. 1.50 (s', 3H) and 1.20 (s, 3H) ppm.

Example 33

Pencillanic acid- 1, 1- dioxide

To a solution of 2.0 g of benzyl-6,6-dibromopenicillanate-1,1-dioxide in 50 ml of tetrahydrofuran was added a solution of 0.699 g of sodium bicarbonate in 50 ml of water, followed by 2.0 g of 5% palladium-on-coal. This mixture was shaken under a hydrogen atmosphere at approx. 3.5 kg/cm<2> for 70 minutes. Tetrahydrofuran was removed by evaporation, and the residue was partitioned between ethyl acetate and. water at pH 7.37. The watery layer was removed, and healthy.,' ? ethyl acetate was added. The pH was lowered to 1.17, and ethyl acetate was removed and washed with saturated sodium chloride solution. Evaporation in vacuo gave 423 mg of the title product.

Example 34 2,2,2-trichloroethyl-6,6-dibromopenicillanate-1,1-dioxide The title compound was prepared from 6,6-dibromopenicillanic acid 1,1-dioxide and 2,2,2-trichloroethyl chloroformate,

essentially by the method according to Preparation J. The product was purified by chromatography on silica gel. The NMR spectrum of the product (in CDCl 3 ) showed absorptions at 4.85 (m, 2H), 1.65 (s, 3H) and 1.45 (s, 3H) ppm. - Oh

Example 35

Penicillanic acid'- 1, 1 - dioxide

2,2,2-trichloroethyl-6,6-dibromopenicillanate-1,1-dioxide.

was reduced with zinc dust in a mixture of glacial acetic acid and tetrahydrofuran, essentially according to Example 14A. The yield was 2 7%.

Example 36

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

A mixture of 2.26 g of 6,6-dibromopenicillanic acid-1,1-'

dioxide, 1.02 ml of 1-(ethoxycarbonyloxy)ethyl chloride, 1.32 ml of diisopropylethylamine and 10 ml of N,N-dimethylformamide were stirred at room temperature for 28 hours. The reaction mixture was diluted with 100 ml of ethyl acetate, and it was then washed successively with water, dilute hydrochloric acid, saturated sodium bicarbonate and

saturated sodium chloride. The dried ethyl acetate solution was evaporated in vacuo to give 1.50 g of an oil which was chromatographed on silica gel. This gave 353 mg of the title compound contaminated with some 1-(ethoxycarbonyloxy)ethyl-6- bromopenicillanate..

Example 37

1-(Ethoxycarbonyloxy)ethyl penicillanate-1,1-dioxide..

Some of the product (230 mg) from Example 36 was dissolved in

10 ml of toluene. To this was added 0.4 ml of tri-n-butyltin hydride, followed by 0.164 g of azobisisobutyronitrile, and the mixture was heated to 70-80°C for 3.5 hours. The solvent was removed by evaporation in vacuo, and the residue was dissolved in 25 ml of acetonitrile. The acetonitrile solution was washed with hexane several times and then evaporated in vacuo. The residue was dissolved in ether, and the ether solution was washed with 5% potassium fluoride and then with saturated sodium chloride. The dried (Na 2 SO 4 ) ether solution was evaporated in vacuo and the residue chromatographed on silica gel to give 0.043 g of the title product. The NMR spectrum (in CDCl^) 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.

Preparation A

6-chloro-6-iodo-penicillanic 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 point 3.00 g of 6-aminopenicillanic acid was added all at once and stirring was continued for 30 minutes at 0-5°C. To the reaction mixture was then added 22.8 ml of 1M sodium sulfite solution in portions, and the layers were separated. The aqueous layer was washed with additional dichloromethane, and then all of 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. This gave 3.67 g of the title compound as the sodium salt.

Production B

6- 3- Chlorpenicillanic acid

A 2.95 g sample of sodium-6-chloro-6-iodo-penicillanic acid

was converted to the free acid, and this was then dissolved in 125 ml of benzene under nitrogen. 1.08 ml of triethylamine was added to the solution, 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 removed by filtration. 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 with cooling to maintain the temperature

about. 20°C. The solvent was then removed by evaporation in vacuo, and the residue was dissolved in a 1:1 mixture of tetrahydrofuran-water. The pH was adjusted to 7.0, and the tetrahydrofuran was removed by evaporation in vacuo. The aqueous phase was washed with ether, and then an equal volume of ethyl acetate

added. The pH was adjusted to 1.8. and the ethyl acetate layer was removed. The aqueous phase was extracted with additional ethyl acetate, and then the combined ethyl acetate solutions were dried and evaporated in vacuo. This gave 980 mg of 6-3-chloropenicillanic acid.

The above product was dissolved in tetrahydrofuran,

and an equal volume of water was added. The pH was adjusted to 6.8, and the tetrahydrofuran was removed by evaporation in vacuo. The remaining aqueous phase was freeze-dried to

give 850 mg of sodium 6-3"~chloropenicillanate. The NMR spectrum (D 2 O) showed absorption at 5.70 (d, 1H, J = 4 Hz), 5.50 (d, 1H,

J = 4 Hz), 4.36 (s, 1H), 1.60 (s, 3H) and 1.53 (s, 3H) ppm.

■ Production C

6- 3- bromopenicillar acid

A mixture of 5.0 g of 6,6-dibromopenicillanic acid, 1.54 ml of triethylamine and 100 ml of benzene was stirred under nitrogen until a solution was obtained. The solution was cooled to 6-5°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 flask was irradiated with ultraviolet light for 15 minutes, and then the reaction mixture was stirred at about 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 point, a further small amount of azobisisobutyronitrile was added, followed by 0.6 ml of tri-n-butyltin hydride (0.6 ml), and the mixture was again irradiated for 30 minutes. The solvent was then removed by evaporation 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 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 of sodium bicarbonate followed by freeze drying of the solution thus obtained. This gave sodium 6-3-bromopenicillanate, contaminated with a small amount of the α-isomer.

The sodium salt was purified by chromatography on "Sephadex LH-20", (ion exchange resin), was mixed with further material of the same quality and chromatographed again. The NMR spectrum (D2CO) for the product thus obtained showed absorptions at 5.56 (s, 2H), 4.25 (s, 1H), 1.60 (s, 3H) and 1.50 (s, 3H ) ppm...

Manufacturing D

6~ 3~ iodopenicillanic acid ' ■

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

Manufacturing E

Pivaloyloxymethyl- 6-a- bromopenicillanate

To a solution of 280 mg of 6-a-brompenicIllanic acid i

2 ml of N,N-dimethylformamide is added to 260 mg of diisopropylethylamine followed by 155 mg of chloromethylpivalate and 15 mg of sodium iodide. The reaction mixture is stirred at room temperature for 24 hours 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 using anhydrous sodium sulfate and evaporated in vacuo to give title the connection.

Production F.

Reaction of the appropriate 6-halogenopenicillanic acid with 3-phthalidyl chloride, 4-crotonolactonyl chloride, γ-butyrolacton-4-yl chloride or the required alkanoyloxymethyl chloride, 1-(alkanoyloxy)ethyl chloride, 1-methyl-1-(alkanoyloxy)ethyl chloride, alkoxycarbonyloxymethyl chloride, 1- (Alkoxycarbonyloxy)ethyl chloride or 1-methyl-1-(Alkoxycarbonyloxy)ethyl chloride by the method according to Preparation E gives respectively the following compounds: 3-phthalidyl-6-a-chloropenicillanate,

4-crotonolactonyl-6-3-chloropenicillanate, Y-butyrolacton-4-yl-6-a-brdmpenicillanate,

acetoxymethyl-6-3_bromopenicillanate,

pivaloyloxymethyl!-6-3-bromopenicillanate,

hexanoyloxymethyl 1-6-a-iodopenicillanate,

1-(acetoxy)ethyl 6-3-iodopenicillanate,

1-(isobutyryloxy)ethyl 1-6-a-chloropenicillanate,

1-methyl-1-(acetoxy)ethyl-6-3-chloropenicillanate,

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

propoxycarbonyloxymethyl-6-3-bromopenicillanate, 1-(ethoxycarbonyloxy)ethyl-6-a-bromopenicillanate, .1-butoxycarbonyloxy)ethyl-6-a-iodopenicillanate, 1-methyl-1-(methoxycarbonyloxy)ethyl-6-3-iodopenicillanate and 1-methyl-1-(isopropoxycarbonyloxy)ethyl-6-α-chloropenicillanate.

Production G

6, 6-diiodopenicillanic acid

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

2.76 g of sodium nitrite and 75 ml of dichloromethane were 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 the addition was complete, 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 (MgSO 4 ) and evaporated in vacuo. This gave 1.4 g of the title compound, contaminated with some 6-iodopenicillanic acid. The product had a melting point of 58-64°C. The NMR spectrum (CDC!2) showed absorptions at 5.77 (s, 1H), 4.60 (s, 1H), 1.71 (s, 3H) and 1.54 (s, 3H) ppm.

Production H

Pivaloyloxymethyl- 6-a-bromopenicillanate

To a stirred mixture of 11.2 g of 6-α-bromopenicillanic acid, 3.7 g of sodium bicarbonate and 44 ml of N,N-dimethylformamide, 6.16 g of chloromethylpivalate was added dropwise over the course of 5 minutes at ambient 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 sequentially with water, saturated sodium chloride, saturated sodium bicarbonate, water and saturated sodium chloride. The of-

colored ethyl acetate solution was dried (MgSO 4 ) and evaporated to dryness in vacuo. This gave 12.8 g (80% yield) of the title compound.

Production I

Benzyl-6-a-bromopenicillanate

The title compound was prepared by esterification of 6-a-bromopenicillanic acid with benzyl bromide, essentially by the method according to Preparation H (yield 83%). The NMR spectrum (in CDCl 2 ) 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. ,

Production J / „ — gc^,—iw>—

2 , 2 , 2-trichloroethylpenicillanate

To a stirred solution of 11.2 g of 6-a-bromopenicillanic acid in 50 ml of tetrahydrofuran at 0°C was added 3.48 g of pyridine over a period of 1 minute. To the cloudy solution thus obtained, 8.47 g of 2,2,2-trichloroethyl-1-chloroformate were added over a period of 10 minutes, while the temperature was kept between 0 and 2°C. Stirring was continued for 30 minutes, after which the cooling bath was removed. Stirring was continued at ambient temperature overnight. The reaction mixture was then heated to 35°C for 5 minutes and then filtered. The filtrate was evaporated,

and the residue was dissolved in 100 ml of ethyl acetate. The ethyl acetate solution was washed sequentially with saturated sodium bicarbonate, water and saturated sodium chloride. The ethyl acetate solution was then decolorized and dried, and then it was concentrated to a small volume. To the resulting mixture was added 100 ml of hexane, and the solids were removed by filtration to

give 10.5 g of the title compound, m.p. 105-110°C.

The NMR spectrum (in CDCl^) showed absorptions at 5.50 (d, 1H), 4.95 (d, 1H), 4.90 (s, 2H), 4.65 (s, 1H), 1.70 (p, 3H) and

1.55 (s, 3H) ppm.

Production K

6, 6-dibromopenicillanic acid.

119.9 g of bromine, 200 ml of 2.5N sulfuric acid and 34.5 g of sodium nitrite were added to 500 ml of dichloromethane cooled to 5°C. To this stirred mixture, 54.0 g of 6-aminopenicillanic acid was then added, in portions over the course of 30 minutes, while the temperature was kept from 4 to 10°C. Stirring was continued for 30 minutes at 5°C, and then 410ml 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 mixed with the two extracts to give a solution of 6,6-dibromopenicillanic acid. This

solution was used directly in Example 17.

Production L

6- chloro- 6- iodopenicillanic acid

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

To this stirred blajide was then added 4.32 g of 6-aminopenicillanic acid in portions over a 15 minute period. Stirring was continued for 20 minutes at 0-5°C, and then. 100 ml of 10% sodium bisulphite solution was added dropwise

about. 4°C. Stirring was continued for 5 minutes, after which the layers were separated. The aqueous layer was extracted with dichloromethane (2 x 50 mL), and the combined dichloromethane solutions were washed with brine, dried (MgSO 4 ) and evaporated in vacuo to

give the title compound as a light brown solid, m.p. 148-152°C. The NMR spectrum of the product (CDCl 3 ) showed absorptions at 5.40 (s, 1H), 4.56 (s, 1H), 1.67 (s, 3H) and 1.50 (s, 3H) ppm. The IR spectrum (KBr disk) showed absorptions at 1780 and 1715 cm^.

Production M

6- bromo- 6- iodopenicillanic acid

To 100 ml of dichloromethane, cooled to 5°C, was added 10 ml

. 2.5N sulfuric acid, 6.21 g of iodobromide and 2.76 g of sodium nitrite.

4.32 g of 6-aminopenicillanic acid was added to this mixture, with vigorous stirring, at 0-5°C, over the course of 15 minutes. Stirring was continued for a further 20 minutes at 0-5°C, and then 100 ml of 10% sodium bisulfite was added dropwise between 0 and 10°C. At this point 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 give 6.0 g (72% yield) of the title compound, m.p. 144-147°C. The NMR spectrum (CDCl 3 ) 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 disc) showed absorptions at 1785 and 1710 cm^. The mass spectrum showed a dominant ion at m/e = 406.

Production N

6-chloro-6-bromopenicillanic acid

6-chloro-6-bromopenicillanic acid is prepared from 6-aminopenicillanic acid via diazotization followed by reaction with bromo-

chloride according to the procedure in Preparation M.

Production 0

Pivaloyloxymethyl- 6, 6- dibromopenicillanate

1.30 g of diisopropyl- • .; ethylamine followed by 1.50 g of chloromethyl pivalate at approx. 0°C. The reactive ion 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 aqueous phase

The pH value is adjusted to 7.5. The ethyl acetate layer is separated and.

washed three times with water and once with saturated sodium chloride solution. Ethyl acetate solutions; then dried using anhydrous sodium sulfate and evaporated in vacuo to give the title compound.

• Production P

Conversion of the appropriate 6,6-dihalopenicillanic acid

with 3-phthalidyl chloride, 14-crotonlactonyl chloride, Y-butyrolacton-4-yl chloride or the necessary alkanoyloxymethyl chloride, 1-(alkanyloxy)ethyl chloride, 1-methyl-1-(alkanoyloxy)ethyl chloride, alkoxycarbonyloxymethyl chloride, 1-(alkoxycarbonyloxy)ethyl-

chloride or 1-methyl-1-(Alkoxycarbonyloxy)ethyl chloride,

according to the procedure of Preparation 0, they give the following. compounds: 3- f tal idy 1-6 ,6-dibrompenici Hana t, 4- crotonolactony 1-6-chloro-6-iodopenicillanate,

Y-butyroiactonyl-6-bromo-6-iodopenicillanate,

acetoxymethyl-6-chloro-6-bromopenicillanate,

pivaloyloxymethyl 1-6-chloro-6-iodopenicillanate,

hexanoyloxymethyl-6,6-dibromopenicilanate,

1-(acetoxy)ethyl-6,6-dibromopenicillanate, , 1-(isobutyryloxy)ethyl-6-bromo-6-iodopenicillanate, 1-methyl-1-(acetoxy)ethyl-6,6-dibromopenicillanate, 1-methyl- l-(Hexanoyloxy)ethyl 6-chloro-6-bromopenicillanate, Methoxycarbonyloxymethyl-6,6-dibromopenicillanate, Propoxycarbonyloxymethyl-6-chloro-6-iodopenicillanate, 1-(Ethoxycarbonyloxy)ethyl 6,6-dibromopenicillanate, 1-(Butoxycarbonyloxy) )ethyl-6-bromo-6-iodopenicillanate, 1-methyl-1-(methoxycarbonyloxy)ethyl-6,6-dibromopenicillanate and 1-methyl-1-(isopropoxycarbonyloxy)ethyl-6,6-dibromopenicillanate.

Claims (10)

1. Procedure for preparing a compound of the formula or a pharmaceutically acceptable base salt thereof, wherein R"*" is hydrogen or an ester-forming residue which is readily hydrolyzable in vivo, characterized .' in that a connection with the formula or a base salt thereof, wherein R is hydrogen; an ester-forming residue which is readily hydrolyzable in vivo, or a common penicillin carboxy protecting group, and X and Y are each hydrogen, chlorine, bromine or iodine, with the proviso that when X and Y are equal, are they both bromine, dehalogenated, followed optionally by removal of the usual penicillin carboxy-protecting group. 2.. Method as stated in claim 1, characterized in that X is bromine and Y is hydrogen. 3. Method as stated in claim 1, characterized in that X and Y are both bromine. 4. Method as stated in one of claims 1 to 3, characterized in that R and R1 are both hydrogen. 5. A compound with the formula and base salts thereof, characterized in that ■ R' is hydrogen, an ester-forming residue readily hydrolyzable in .vivo, or a common penicillin carboxy-protecting group, and X and Y are each hydrogen, chlorine, bromine, or iodine, with the proviso that when X and Y are alike, they are both bromine. 6. Connection as stated in claim 5, characterized in that R is hydrogen. 7. Connection as stated in claim 5, characterized in that R is 3-phthalidyl, 4-crotonolactonyl, Yjbutyrolactonyl or a group with the formula where R 2 and R 3 are each hydrogen or alkyl with from 1 to 2 carbon atoms, and R 4 is alkyl with from 1 to 5 carbon atoms. 8. Compound as stated in claim 5, characterized in that R is tetrahydropyranyl, trialkylsilyl with 1 to 3 carbon atoms in each alkyl group, benzyl, 4-nitrobenzyl, benzhydryl, 2,2,2-trichloroethyl, t-butyl or phenacyl. 9. Connection as specified in one of claims 6 to 8, . characterized in that X is bromine and Y is hydrogen. 10. Compound as stated in one of claims 6 to 8, characterized in that X and Y are both bromine.