NO823127L - NEW PENICILLANIC ACID-1,1-DIOXYDE DERIVATIVES. - Google Patents

Description

This invention relates to new chemical compounds which are suitable as intermediate products in a new chemical

method for the production of penicillanic acid 1,1-dioxide and esters thereof which are easily hydrolysable 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 hydrolysable in vivo, to the corresponding 1,1-dioxide, followed by dehalogenation..The new chemical compounds which are useful as intermediates are 6-halo-

and 6,6-dihalogen 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 6-lactam antibiotics when the latter are used in the treatment of bacterial infections in mammals, especially humans. Previously, penicillanic acid-1 ,1-dioxide and esters thereof which are readily hydrolyzable in vivo, 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 hydrolyzable in vivo, followed by oxidation

. 1, l-dioc, boiled. Although the method according to the invention starts with a 6-halo-penicillanic acid or an ester thereof which is easily hydrolysable in vivo, and includes the steps of dehalogenation and oxidation, it has surprisingly been found that

if the oxidation step is carried out before the dehalogenation step t,

you get a better yield from the product. See Belgian patent 867,859 and German official publication 2,824,535 for details regarding methods for the preparation of penicillanic acid 1,1-dioxide and esters thereof which are readily hydrolyzable in vivo.

6-Halopenicillanic 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 α- and (3-sulfoxides; (b) oxidation of methyl 6,6-dibromopenicillanate with 3-chloroperbenzoic acid to form a methyl 6,6-dibromopenicillanate- 1,1-dioxide; (c) , oxidation of .methyl-6-α-chloropenicillanate with 3-chloro-perbenzoic acid to form a mixture of<e>ie corresponding α- and 3-sulfoxides; and (d) oxidation of methyl-6-bromopenicillanate with 3-chloroperbenzoic acid to form a mixture of the corresponding α- and (3-sulphoxides. Clayton, Journal of the Chemical Society (London), (C), 212' 3 (.1969) describes: (a) preparation of 6,6-dibromo- 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, respectively. methyl ester; and (e) hydrogenolysis of a mixture of methyl 6,6-diiodopenicillanate and methyl 1-6-α-iodopenicillanate to form pure methyl 1-6-α-iodopenicillanate. This invention relates to a method for manufacturing, of a compound with the formula

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

(a) a compound of the formula

or a base salt thereof is contacted with a reagent selected from alkali metal permanganates, . jo.rdalkali metal permanganates

and organic' peroxycarboxylic acids,' to form a ■ compound

■with 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 leavening agent at a pressure of approx. 1 to approx.

100 kg/cm2, 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 ten! 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.

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) according to the method takes place impractically slowly.

The invention also encompasses the intermediates of formula III, •where X, Y and R"*" 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 preparation of compounds of 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 . ct configuration. Conversely, attachment of a substituent through a full line to the bicyclic nucleus means that the substituent is above the plane of the nucleus. This latter configuration is referred to as (3-configuration. Thus the group X has ct-configuration and the group Y has 8-configuration in formula II.

When' R"*"- here is an ester-forming residue which is readily hydrolyzable in vivo, it is a group thought to be derived from an alcohol of the formula R"^-OH, so that" the part COQR^ in such a connection with ' 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). It will

say that R^ is a group of such a type that when your compound of formula I where R"'" is an ester-forming residue which is readily hydrolyzed in vivo, is exposed to mammalian blood or tissue, the compound is readily formed of formula I where R 1 is hydrogen. The groups R"<*>" are well known in the penicillin science. In most cases, they improve the absorption properties of the penicillin compound. Moreover, R 2 should be of such a nature as to give a compound of formula I pharmaceutically acceptable properties and to liberate pharmaceutically acceptable fragments when cleaved in vivo'. The groups R"*" are well known and can be easily identified by those skilled in the art, see e.g. German official script

2,517,316. Special examples of groups denoted by R^ are 3-phthalidyl, 4-crotonlactonyl, Y-butyrolactone-4-y1 and groups of 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. Preferred meanings for. 'R' is, however, alkanoyloxymethyl with from 3 to 7 carbon atoms, 1-(alkanoyloxy)ethyl with from 4 to 8 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl with from . 5 to 9 carbon atoms, alkoxycarbonyl l.oxymethyl with from 3 to 6 carbon atoms, 1-(Alkoxycarbonyloxy)ethyl with from 4 to 7 carbon atoms,. 1-Methyl-1-Alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, 3-phthalidyl, 4-crotonolactonyl and Y-butyrolacton-4-yl. 3-phthalidyl, 4-crotonolactonyl and Y-bu.tyrolacton-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 sulphon group, whereby a compound of formula III is formed. A variety of oxidizing agents known for the oxidation of sulfides to sulfones can be used for this process. 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 molecular equivalents, and preferably from approx. 1 to approx. 4 molar equivalents of the permanganate in a suitable, reaction-inert solvent system."A suitable, reaction-inert" solvent system is one that has no harmful

impact on neither the starting materials nor the product,

and water are 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 compound with the formulas II or III. It is often appropriate to buffer the pH value of the reaction medium 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 evaporation. Alternatively, if the product does not fall out of the solution - at the end of the reaction, it is isolated in the usual way with solvent extraction...

When a compound of formula II where X, Y and R are as indicated above, is oxidized to the corresponding compound with. formula III using a peroxycarboxylic acid, the reaction is usually carried out by treating the compound of formula II with from about 1 to approx. 6 molar equivalents, and. preferably approx. 2.2 mole equivalents of the oxidizing agent in a react ionized, 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 carried out. normally at a temperature from approx. -30 to approx. 5oPc, 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 reactive ion product can be purified by conventional 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 method 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; lowmolecular esters such as ethyl acetate" and

butyl acetate; tertiary amides such as N,N-dimethylformamide, N,N-dimethyllacetami.d - and N-methylpyrrolidone; water and mixtures thereof...Furthermore, 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. Borate7 and phosphate buffers are commonly 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 reax ion vessel can vary - from approx. 1 to approx. 100 kg/cm 2 . The preferred pressure range, •' when the atmosphere inside. in the reaction vessel is almost pure hydrogen,

2

is from approx. 2 to approx. 5 kg/cm. The hydrogenolysis is usually carried out at a temperature of 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 operation are the type of agents known in the art for this kind of conversion, and typical examples are the noble metals such as nickel, palladium, platinum and rhodium. The catalyst is usually present in an amount from about 0.01 to about 2.5% by weight, and preferably from about 0.1 to about 1.0% by weight, based on the compound of formula III. It is often convenient to distribute the catalyst on an inert carrier, and one particularly suitable catalyst is palladium dispersed on an inert carrier such as coal.

Other methods can be used for reductive removal of the halogen from a compound of formula III, i.e. step (b). For example, 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 tin- . hydride, e.g. a trialkyltin hydride such as tri-n-butyltin hydride

As will be appreciated by those skilled in the art, 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 (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 an additional<r>e. 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 normal 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 able to bind to the special compound of formula II or III and could be removed from the particular compound of formula I or III, using conditions in which the β-lactam ring chain remains substantially 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-nitrobenzyl), 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 that can be used in a particular situation will be easily selected by one skilled in the art. See further: US patents. 3.6 32,850 and 3 . 19 7,466 , British patent 1. 041. 9 85 , . 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..

6-ct-chloropenicillanic acid and 6-a-bromopenicillanic acid are prepared by diazotization of 6-aminopenicillanic acid i; presence of hydrochloric acid and hydrobromic acid respectively (Journal of Organic Chemistry, 2 7, 2668 (1962)). 6-α-Iodopenicillanic acid is prepared by the 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-brqmpenicillanic 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 sodium chloride; 6,6-dibromopenicillanic acid is prepared by the method according to Clayton, Journal of the Chemical Society. (London) (C) '2123 (1969); and 6,6-diiodopenicillanic acid is produced by diazotization of 6-aminopenicillanic acid in the presence of iodine..

The compounds of formula I, II and III, where 'R^" is hydrogen, are acidic and will form salts with basic substances. These salts can be prepared by standard methods', such that the acidic and basic components are brought into contact, usually in a stoichiometric ratio, in an aqueous, non-aqueous or semi-aqueous medium, as appropriate. They are then recovered by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent, or for aqueous in the case of 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 such 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-diaza-

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 then

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 with medium; strength in vivo. The 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 convenient 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 liquid 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.

The activity in vivo of the compounds of formula I wherein R"'" is hydrogen or an ester-forming residue which is readily hydrolyzable 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 can be administered alone or it can be mixed with pharmaceutically acceptable carriers or diluents. It can be administered orally or parenterally, i.e. intramuscularly, subcutaneously or intraperitoneally .■ The carrier or diluent is selected on the basis of the relevant form of administration. When you e.g. if oral administration is desired, the compound can be used in the form of tablets, capsules, lozenges, candies, powders, syrups, elixirs, aqueous solutions and suspensions, etc., in accordance with usual pharmaceutical practice. The ratio between active ingredient and carrier will be of- ■

depending on the chemical nature, solubility and stability of the active ingredient as well as the desired dose,

Pharmaceutical preparations containing an antibacterial agent of formula I will, however, normally contain from approx. 20 to approx. 95% active ingredient...When it comes to tablets for oral use, commonly used carriers are lactose, sodium citrate and salts of phosphoric acid. Different explosives 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 emulsifying 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 suitably adjusted and buffered. For intravenous use, the total concentration of the dissolved substances should be regulated so that the preparation becomes isotonic.

It. 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 in the range 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 numbers are illustrative only,

and in some cases it may be necessary to apply doses outside these limits.

The compounds of formula I wherein. R"*" is hydrogen or a

• ester-forming residue which. is readily hydrolyzable in vivo, or, a salt thereof, enhances the antibacterial efficacy of 3-lactam antibiotics in vivo. They lower the amount of the antibiotic needed to protect mice from an otherwise lethal inoculation of certain β-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. When treating a bacterial infection, the compound of formula I can be formed with the 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 an β-lactam antibiotic. In some cases, it is appropriate to give the individual a pre-dose of the compound of formula I before starting the 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-actam antibiotic, it is preferably administered in admixture with standard pharmaceutical carriers or diluents/ means...The' preparations for forms that are discussed

above in connection with penicillanic acid 1,1-dioxide or an ester thereof which is. easily hydrolyze bar wine vivo,. as an antibacterial agent with a single active ingredient, curry is used when co-administration with another 3-lactam antibiotic is desired. A pharmaceutical preparation containing a pharmaceutically acceptable carrier, a 3-lactam antibiotic and

Penicillanic acid 1,1-dioxide or an easily hydrolysable 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 physician 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 ester thereof and the 3-lactam antibiotic will normally .be in the area from approx. 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, the daily oral dose of each component will normally be in the range from approx. 10 to approx. 200 mg per kg body weight, and the daily parenteral dose of each component will normally be approx. 10 to approx. 400 mg per kg body weight.. These figures are only illustrative, and in some cases it may be necessary to use doses outside these limits..

Typical 3~lactam antibiotics such as penicillanic acid-1,1-dioxide and. esters thereof which are easily hydrolysable in vivo, Jcåfi. administered together with, are: 6-(2-phenylacetamido)penicillanic acid,

6-(D^-2-amino-2-phenylacetamido)penicillanic acid,

6-(2-carboxy-2-phenylacetamido)penicillanic acid and 7-(2-[1-tetrazolyl]acetamido)-3-(2-[5-methyl-1,3,4-thiadiazolyl]tholomethyl)-3- desacetoxymethylcephalosporanic acid.

Typical microorganisms against which the antibacterial activity of the above-mentioned 3-lactam antibiotics is enhanced are: Staphylococcus aureus, Haemophilus influenzae, Klebsiella pneuimoniae 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, must be used simultaneously (i.e. mixed together) with a 3-lactam antibiotic which is only effective when administered parenterally, a combination

After the 6-α-bromopenicillanic acid solution had been added

■ an oxidizing■mixture, a cooling bath of -15°C was kept around the reaction mixture. The internal temperature rose to 15°C and then fell to 5°C over a period of 20 minutes. On

at this point, 30.0 g of sodium metabisulphite was added with stirring over a 10 minute period at approx. 1<0>°C. After a further 15 minutes, the mixture was filtered, and the pH of the filtrate was lowered to 1.2 by adding 170 ml of 6N hydrochloric acid.

The aqueous phase was extracted with chloroform, and then with ethyl acetate. Both the chloroform and 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 gave 57 g of an oil which was triturated under hexane.

A white, solid substance was obtained. It was filtered off to give

41.5 g (66% yield) of the title compound, m.p. 134°C (dec.) .

Analysis:

Calculated for CgH^BrNO^: C 30.78, H 3.2-3, 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-α-chloropenicillanic acid and 6-α-iodopenicillanic acid with. potassium permanganate in the method according to example 1 gives 6-α-chloropenicillanic acid-1,1-dioxide and 6-α-iodo-penicillanic acid-1,1-dioxide, respectively.

Example 3

6- 3- Chlorpehic. illanic acid- i, 1- dioxy. d

An oxidizing solution was prepared from 185 mg of potassium permanganate, 0.063 ml of 85% phosphoric acid and 5 ml of water. This oxidizing solution was added dropwise to a solution of 150 mg of sodium 6-[3-chloropenicillanate in 5 ml of water at 0-5°C until the purple-red color of potassium permanganate remained. Approximately half of the oxidation solution was required. At this point the potassium permanganate color was removed by addition of solid sodium bisulfite, and then the reaction mixture was filtered. Ethyl acetate was added to the filtrate and the pH was adjusted to .1.8. The layers were separated and the aqueous layer was further extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, dried and evaporated. in-vacuum to

yield 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, a solution prepared from 140 mg of potassium permanganate was added. 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 value 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 (in. D20^ vi.st absorptions ' at 5.78 (d, 1H, J = 4 Hz), 5.25.(d,lH, J=4Hz), 4.20 (s,"lH ), 1.65 (s,.3H) and 1.46

(s, 3H) ppm.

Example 5

6~ 3~ iodopenicillanoic acid- 1, 1- dioxide

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

Example 6

Pi valoylok synrety1- 6 - a - the bromine in ci 1 lan- a t- 1, 1- diok syd

-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. Stir the reaction mixture 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 connection.

Example. 7•

The procedure according to example 6 is repeated, except that the pivaloyloxymethyl 1-6-(3-bromopenicillanate) is replaced by:

■4-crotonolactony1-6~3-chloropenicillanate, Y-butyrolactone-4-y1-6-a-bromopenicillanate, -

acetoxyméty1^6-3-bromopenicillanate, pivaloyloxymethyl-6-3-bromopenicillanate, hexanoyloxymethyl-6-a-iodopenicillanate, 1-(acetoxy)ethyl-6-3-iodopenicillanate, "

1-(isobutyryloxy) ethyl 6-α-chloropenicillanate, 1-methyl-1-(acetoxy) ethyl 6-3-chloropenicillanate,''.-...'-1-methyl-1-(hexanoyloxy) ethyl- 6-α-bromopenicillanate, methoxycarbonyloxymethyl 1-6-α-bromopenicillanate,

propoxycarbonyloxymethyl 1-6-3-bromopenicillanate, 1-(ethoxycarbonyloxy)ethyl 1-6-a-bromopenicillanate,

1-(butoxycarbonyloxy.)ethy 1-6-α-iodopenicillanate,

1-methyl-1-(methoxycarbonyloxy)ethyl-6-3-iodopenicillanate and 1-methyl-1-(isopropoxycarbonyloxy)ethyl-6-a-chloropenicillanate. This gives respectively: 3-fthalidyl.-6-a-chloropenicillanate-1,1-dioxide',

4-crotonolac tony 1-6-,8-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 1-6-a-iodopenicillanate-1,1-dioxide, 1-(acetoxy!)'ethyl I-6-3-iodopenicillanate -1,1-dioxide , 1^-(isobutyryloxy)ethyl 1-6-a-chloropenicillanate-1,l^dioxide, 1-methyl-1-(acetoxy)ethyl 1-6~3-chloropenicillanate-1,1-dioxide ,

1-Methyl-1-(hexanoyloxy)ethyl-6-a-bromopenicillanate-1,1-dioxide, me toxycarbohyloxymethyl 1-6-a-bromopenicillanate-1,1-dioxide, propoxycarbonyloxymethyl 1-6-(3-bromopenicillanate -1, 1-dipoxyd, 1-(ethoxycarbonyloxy)ethyl 1-6-a-bromopenicillanate-1,1-dioxide,

1-(butoxycarbonyloxy)ethyl-6-a-jppenicillanate-1,1-dioxide, 1-methyl-:1-(methoxycarbonyloxy)ethyl-6-6-iodopenicillanate-1,1-dioxide and ,

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

Example 8

P. e n ici He acid- 1, 1- dioxide

To 100 ral of water was added 9.4 g of 6-α-bromopenicillanic acid 1,1-dioxide at 22°C, followed by sufficient 4N sodium hydroxide solution to give a stable pH of 7.3. To it

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 hydrogen uptake ceased, the solids were removed by filtration, 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 then the solid material was collected by filtration. 4.5' g (65%' yield) of the title compound.. Analysis: •.'Calculated for. e8'Hi:LN05S: 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-α-chloropenicillanoic acid 1,1-dioxide,

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

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

6-O^-iodopenicinic acid 1,1-dioxide,

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

Example 10

P ivaloyloxymethyl- penicillanate- 1, 1- dipoxyd

To a solution of 1.0 g of pivaloyloxymethyl-6-a-bromo-penicillanate in 10 ml of methanol, 3 ml of IM sodium bicarbonate and 200 mg of 10% palladium on charcoal are added. The reaction mixture is shaken vigorously under an atmosphere of hydrogen at a pressure of approx. 5-kg/cm 2 until h<y>dro<g>enop<p>ta'<g>else<en>ceases. The mixture

. is filtered, and most of the methanol is removed by evaporation

in 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 the title compound.

Example 11

Hydrogenolysis of the appropriate 6-halogenopenicillanic acid ester-1,1-dioxide from example 7 by the method according to example 10 gives respectively the following compounds:

3-ft alidyl-penicillanate-1,1-dioxide, 4-crotonolactonyl-penicillanate-1,1,dioxide, Y-butyroiacton-4-yl-penicillanate-1,1-dioxide,

acetoxymethyl 1-penicillanate-1,1-dioxide, pivaloyloxymethyl-penicillanate-1,1-dioxide, hexanoyloxymethyl-penicillanate-1,1-dioxide,

1-(acetoxy) ethyl penicill'a'nate-1,1-dioxide,

1-(isobutyryloxy.)ethyl penicillanate-1,1-dioxide, 1-methyl-l-(acetoxy)ethyl penicillanate-1,1-dioxide, 1-methyl-l-(hexanoyloxy)ethyl 1-penicillanate-l . -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-α-bromopenicillanate-1,1-dioxide

An oxidizing solution was prepared by mixing

4.26 g potassium permanganate, 2.65 g 85% phosphoric acid and 40 ml water. - The mixture" was stirred for 1 hour, and it was then added slowly over 20 minutes at 5 to 10°C, to a stirred solution of 5.32 g of pivaloyloxymethyl-6-a-bromopenicillanate in 70 ml of acetone and 10 ml of water. The mixture was stirred at 5°C for 30 minutes, and 100 ml of ethyl acetate was added. After a further 3.0 minutes, a solution of 3.12 g of sodium bisulfite in 30 ml of water was added during 15 minutes at about 10° C. Stirring was continued for a further 30 minutes at 5° C, then the mixture was filtered. The organic phase was

r 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 crystallized slowly. The NMR spectrum (.in CDCl 3 ) 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, 911) ppm.

Example 13

' Pivaloyloxymethyl- penicillanate- 1, 1- dioxide

A solution of 4.4 g of pivaloyloxymethyl-6-a-bromopenicillanate-1,1-dioxide in 60 ml of tetrahydrofuran was added to

*.0>.8-4 '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.5% palladium-on-carbon at .3.3 to 3.6 kg/cm . 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 suspension, and the precipitate was first filtered off. Yield: 2.4 g. The NMR spectrum (in DMSO-d^) showed absorptions at 5.75 (q, 2H), 5.05. (m, 1H), 4.40 (s, 1H) , ■ 3.,'95-2-.95 (m, 2H) , 1.40, (s, 3H>, 1.25 (s, 3H) and 1.10 (s, 9H) ppm'.

Example 14

2, 2, 2-trichloroethyl-6-α-bromo, enicillanate-1, 1-dioxide 2,2,2-trichloroethyl-6-α-bromopenicillanate was oxidized with potassium permanganate 1 essentially by the method according to example 12, to give the title compound.in 79% yield. The NMR spectrum of the product, (in CDCl^) showed absorptions at 5.30 to 4.70 (m, 4H), 4.60 (s, 1H), 1.70 (s, 3H) and 1.50

(s, 3H) ppm. "

' Example 14A.

Penicillanic acid- 1, l.- di. oxide

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

of eh70:30 glacial acetic acid-tetrahydrofuran mixture was added portionwise over 5 minutes 4.0 g-2,2,2-trichloro<y>1-6-a-bromo-penicilla'nat-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, and the pale brown solution was mixed with 50 ml of water and 100 ml of ethyl acetate. The pH was adjusted to 1.3' and the layers were separated. The organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate, 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 CDCl o/DMS0-d,) showed absorptions at 11.2

' . < . j fa

.(wide s, 1H) , 4.65 (m, 1H) , 4 30 (s, 1H) , 3.40 (m, 2H) , 1.65 .(;s,. 3H) and 1.50 ( s, 3H) ppm.

Example 15'

Benzy1- 6- g- bromopenicillanate- 1, 1- dioxide

Benzy 1-6-α-bromoenicillanate was oxidized with potassium permanganate essentially by the method according to example 12,

.fpr to give the title compound in 94% yield. The NMR spectrum

(i, CDC13). 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

Penicianic acid- 1, l'-* di ok syd

..A solution of 4.0 g of benzyl 6-a-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 2 for 20 minutes. The catalyst was removed by filtration, and then 30 ml of tetrahydrofuran and 3.0 g of a 50% suspension of 5% palladium-on-charcoal were added. The resulting mixture was shaken under 2 atmospheres 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 was adjusted to 7.1 .' The ethyl acetate layer was removed, and fresh ethyl acetate was added to the remaining aqueous phase. The pH was lowered to 1.5, and the layers were separated. The aqueous phase was further extracted with ethyl acetate, and the combined ethyl acetate solutions were washed with saturated sodium chloride solution' and dried (MgSO 4 ). Evaporation in vacuo gave a gum -which was triturated under ether. This gave 31 mg of penicillanic acid 1", 1-dioxide as a yellow solid. The NMR spectrum (in CDCl 3 /DMSO-d 6 ) 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 - dib. rompenici llanic acid- 1, j- dioxide

To the dichloromethane solution of 6,6-dibromopeiricillanic acid from Preparation K was added 300 ml of water, 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 premixed solution prepared from -59.25 g of potassium permanganate, 18 ml of concentrated phosphoric acid and 6.00 ml of water, until the pink color of the permanganate remained. The addition took 50 minutes, and 550 ml. of the oxidizing agent was required. At this point, 500 ml of ethyl acetate was added and then the pH was lowered to 1.23 by the addition of 105 ml of 6N hydrochloric acid. Then 250 ml 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 ). This gave 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 in the same way from an analogous preparation had a melting point of . at 201°C (decomposition). The NMR spectrum (CDCl 3 /DMSO-d 6 ) showed

absorptions at 9.35 (s, 1H), 5.30 (s, 1H), 4.42 (s, 1H), 1.6 3 (s, 3H) and 1.50 (s, 3H) ppm. The IR spectrum (KBr disc) showed absorptions at 3846-2500, 1818, 1754, 1342 and 1250-'11-10 cm"<1.>

Example 18

6- chloro- 6- j odpenici 11 an sy re- 1, 1- dioxide

To a solution, of 4.9 g of 6-chloro-6-iodopenicillanic acid i

50 ml. dichloromethane was added to 50 ml of water, and then the pH value

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 hand-mixed solution prepared from 2.61 g

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, 100 ml of ethyl acetate was added and the pH was adjusted to 1.5. To

50 ml of 10% 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 teams were 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,

sm.p. 1'43-145°C. The NMR spectrum (CDCl 2 ) showed absorptions at 4.86 (s, 1B)/4.38 (s, 1H), 1.60 (s, 3H) and 1.43 (s, 3H) ppm. The IR spectrum (KBr disk )■ shows te abo.srps ions at 1800, 1740 and 1250-1110 cm"<1>;

Example 19

6 - bromo- 6 r j odpenici llan' acid- 1, 1- dioxide

50 ml of water was added to a solution of 6.6 g of 6-bromo-6-iodopenicillanic acid in 50 ml of dichloromethane. 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 6-N hydrochloric acid. 50 ml of 10% sodium bisulphite was added dropwise to this two-phase system, 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 value lowered to 1.23. The layers were ..separated, and the aqueous layer remained. 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 4 ) 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'f 3H) ppm. the IR spectrum

(KBr disk) 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 permannate by the method according to example 19 gives 6-chloro-6-bromopenicillanic acid 1,1-dioxide.

Example 21

Pen i ci H ån sy re - 1, 1- dioxy 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% palladium-on-charcoal catalyst. The mixture was shaken under an atmosphere of hydrogen, at a pressure of about 5 kg/cm for about 1 hour. The catalyst was removed by filtration, and the pH of the aqueous phase of the filtrate was adjusted to 1.2 with 6N hydrochloric acid. The aqueous phase was saturated with sodium chloride The layers were separated and the aqueous phase was 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 charcoal, and the solvent was removed by evaporation in vacuo. 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.e-1, 1-dioxide, 6--bromo-6-iodopenicillanic acid and 6-chloro-6-bromo-penicillanic acid by the method according to Example 21 gives in each case penicillanic acid—1,1 -dioxide.

Example 23

Penicillanic acid- 1, 1- dioxide

To a stirred suspension of 7.86 mg of 6-chloro-6-iodopenicillanic 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•tri-n-butyltin hydride and some 'few. milligrams of azobisisobutyronitrile were added. The reaction mixture was stirred and irradiated with ultraviolet light for one hour at approx. 0°C and then for 3.5 hours at the solvent reflux temperature. A further amount of tri-n-butyltin hydride (1.1 ml) and a catalytic amount of azobisisobutyronitrile were added and stirring and irradiation at reflux continued for a further 1 hour. The reaction mixture was then poured into 50 mL of cold 5% sodium bicarbonate solution, and the biphasic 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 brine, dried (MgSO 4 ) and evaporated in vacuo. The residue was triturated under hexart and then recovered by filtration. This gave 0.075 mg of the title compound.

Example 2 4

Penicillanic acid- 1, 1- dioxide

To a stirred suspension of 6.874 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 about 5°C, and 1.05 mL of tri-n-butyltin hydride and a catalytic amount of azobisisobutyronitrile were added. The mixture was irradiated. with ultraviolet light for 1 hour at about 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

Pi valoyloxymethyl- 6 , 6- dibromopeniciHanat- 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 partitioned 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^SO^)' and evaporated' in vacuo to give the title compound.

Example 26

Oxidation of each 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-dibromopenieyl lanate-1,1-dioxide,

4-crotonolactony 1-6-chloro-6-iodopenicillanate-1,1-dioxide, Y-butyrolactony 1-6'-bromo-6-iodpenicillanate-1,1-dioxide, acetoxyrnety 1-6-chloro-6-bromopenicillanate- 1,1-dioxide, pivaloyloxymethyl-6-chloro-6-iodopenicillanate-1,1-dioxide,

■Hexanoyloxymethyl-6,6-dibromophenylanatate-1,1-dioxide, 1-(acetoxy)ethyl-6,6-dibromophenylanatate-1,1-dioxide,

1-(isobutyryloxy)ethyl-6-bromo-6-iodopenicillanate-1,1-dioxide, 1-methyl-1-(acetoxy)ethyl-6,6-dibromopeneyl llanat-1',1-dioxide, 1-methyl- 1-(Hexanoyloxy)ethyl 6-chloro-6-bromopenicillanate, Methoxycarbonyloxymethyl-6,6-dibromopenicillanate-1,1-dioxide, Propoxycarbonyloxymethyl-6-chloro-6-iodopenicillaneate-1,1-dioxide, 1-( e took sycarbohyloxy) ethyl-6 , 6-dibromopenii Hana t-1', i-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 2 7

Pivaloyloxymethyl- penicillanate- 1, 1- dioxide

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 vacuo. 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-dloxide.

Example 2 8

Hydrogenolysis of each of the 6,6-dihalo-penicillanic acid ester-1,1-dioxides from example 26 by the method according to example 21 gives respectively the following compounds: 3-phthalidyl-penicillanate-1,1-dioxide, 4-crotonolak tony 1-penicillanate-r, 1-dioxide, Y-butyrolacton-4-yl-penicillanate-1,1-dioxide, acetoxymethyl-penicillanat-1,1-dioxide, pivaloy oxymethyl-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-dioxide,-. propoxycarboryloxymethyl-1-penicillanate-1,1-dioxide, 1-(ethoxycarbonyloxy)ethyl-penicillanate-1,1-dioxide, 1-(butoxycarbonyl)ethyl 1-penicillaiiate-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 1- 6, 6- dibromopenieillanate- 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 brine. The ethyl acetate solution was then treated with Darco (activated charcoal), dried (MgSO 4 ) and evaporated. in

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 collected and chromatographed again 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 30

P i valoy loxymety 1- pehici Hana t- 1, 1- dioxide

To a stirred solution of 60 mg of pivaloyloxymethyl-6,6-dibromopenyl 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 aqueous 5% sodium bicarbonate solution and stirred for 30 minutes. Ethyl acetate was added and the pH of the aqueous phase was adjusted to 7.0. The layers were separated, and the aqueous phase was further extracted with ethyl acetate. The combined ethyl acetate solutions were washed with saline, 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

Benzyl-6,6-dibromopenicillanate-1,,1-dioxide

A mixture of 10.0 g of 6,6-dibromopenicillanic acid 1,1-dioxide, 2.15 g of sodium bicarbonate, 3.06 ml of benzyl bromide and 100 ml of 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 CDCl 3 ) showed absorptions at .7.40 (s,'5H), 5.30 (m, 2H),

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

Example . 33

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 about 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 aqueous layer was removed and fresh 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- trichloroethy1- 6, 6- dibromopeniellanoate- 1, 1- dioxide

>

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

in all - 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 2 ) showed absorptions, at 4.85 (m, 2H) ,'

1.65 .(s , 3H)'and 1.45 (s., 3H) ppm..

Exem<pe>l 35

Penicillanic acid- 1, 1- di' oxide

■ 2,2,2-trichloroethy1-6,6-dibromopenieyl 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 27%.

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

Example 37

1-(Ethoxycarbonyloxy)ethylpenicillanate-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. 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 1/7.5-1.00 (m) ppm.

Preparation A

6-chloro-6-iodo-penicillanic acid

To 3.38 g of iodine monochloride. in 30 ml of dichloromethane was placed under stirring at 6-5°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 sulphite 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^O^) and evaporated in vacuo to give 3.4 8 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 1.25 ml of benzene under nitrogen. Until the resolution was set

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 removed by filtration. 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 value 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 value was adjusted. to 6.8, and the tetrahydrofuran was removed by evaporation i

vacuum. The remaining aqueous phase was freeze-dried to

give 850 mg -sodium 6-Ø-chloropenicillanate. The NMR spectrum (D^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- brompenici llansy r é

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 0-5°C, and 1.7 8 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 azobis-: isobutyronitrile was added, followed by 3.68 ml of tri-n-butyltin hydride. The reaction flask was irradiated with ultraviolet light in

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 to the 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 was removed. dried and evaporated in vacuo to give 2.33. g of one 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

resolution 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 additional material of the same quality and chromatographed again. The NMR spectrum (D26) of 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 - 0- j odpenicillansy re-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 1- 6-a- bromopenicillanate

To a solution of 280 mg of 6-α-bromopenicillanic 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 regulated 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 the title compound.

the connection.'

Production F

Reaction of the appropriate 6-halogenopenicillanic acid with 3-phthalidyl chloride, 4-crotonolactonyl chloride, Y-butyrdlacton-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- kro tono lak tony 1-6-(3-k lor penicillanate,

y-butyrolactone-4-y1-6-a-bromopenicillanate,

ace toks ynre ty 1-6-(3-brompenici 11 ana t,

pivaloyloxymethyl-6-(3-bromopenicillanate, hexanoyloxymethyl-6-a-iodopenicillanate,

1-(a<c>ethoxy)et<y>1'-6-(3-iodo<p>enicillanate,

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- diiodopenici! lanic acid

• A mixture of 15.23 g of iodine, 1.0 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 (CDCl 2 ) showed absorptions at 5.77 (s, 1H), 4.60 (s, 1H), 1.71 (s, 3H) and 1.54' (s, 3H) ppm.

Production H

PivalOyloxyrnety1- 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 was added 6.16 g of chloromethylpivalate dropwise over 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 decolorized 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 (i-- CDCl^) 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

2, 2, 2-trichloroethyl penicillanate

To a stirred solution of 11.2 g of 6-α-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°G. Stirring was continued for 30 minutes, and then 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.

•v The NMR spectrum (in CDCl^) showed absorptions at 5.50 (d, 1H), 4.95 (d, 1H), 4.90 (s > 2H), 4.65 (s,'lH), 1.70 (s, 3H)' and 1.55. (p, 3H) . ppm.

Manufacturing. K

6, 6-dibromopenicillanic acid

To 500 ml of dichloromethane cooled to 5°C were added 119.9 g of bromine, ZOO ml of 2.5N sulfuric acid and 34.5 g of sodium nitrite. To this stirred mixture was then added 54.0 g of 6-amino'-penicillanic acid in portions during 30 minutes, while the temperature was maintained 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 20 times with 3.50 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.

Forward ten 1, 1 ing L

6- chloro- 6- iodopenicillaic acid

4.87 g of iodine chloride were added to 100 ml of dichloromethane cooled to 3°C. 10 ml of 2.5N sulfuric acid and 2.76 g of sodium nitrite'. •To this stirred mixture, 4 > 32 g of 6'-amino-'penicillanic acid were then added 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 at approx. 4°C. Stirring was. continued for 5 minutes, after which the teams were separated. The aqueous layer was extracted with dichloromethane (2 x 50 ml), and the combined dichloromethane solutions were washed with brine. dried, (MgSO^) 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 (CDCl3) 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<1.>

Production M

6- b room- 6- j odpenici lian sy re

10 ml of 2.5'N' sulfuric acid, 6.21 g of iodine bromide and 2.76 g of sodium nitrite were added to 100 ml of dichloromethane, cooled to .5°C. To this mixture was added, under vigorous stirring, at 0-5°C,

in the course of 15 minutes, 4.32 g of 6-aminopenicillanic acid'. Stirring

was continued for a further 20 minutes at 0-5°C, and then 100 ml of 10% sodium bisulphite 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 vacuum. The residue was dried under high vacuum for 30 minutes to give 6.0 g (72% yield) of the title compound, mp<.>'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- bromopenicillin. an acid

6-chloro-6-bromopenicillanic acid is produced from 6-aminopenicillanic acid via diazotization followed by reaction with bromine chloride according to the procedure in Preparation M.

Production 0

Pi valoy lok syrne ty 1- 6 , 6 - dibrompeniei llanat

To a stirred solution of 3.59 g of 6,6-dibromopenicillanic acid in 20 ml of N,N-dimethylformamide is added 1.30 g of diisopropyl 1-ethylamine followed by 1.50 g of chloromethylpivalate 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 pH value of the aqueous phase is adjusted to 7.5. The ethyl acetate layer is separated and washed three times with water and once with saturated sodium chloride solution. The ethyl acetate solution is then dried using anhydrous sodium sulfate and evaporated in vacuo to give the title compound.

Production P

Conversion of the appropriate 6,6-dihalopenicillanic acid

with 3-phthalidyl chloride, 4-crotonlactonyl chloride, Y-butyrolacton-4-yl chloride or the required alkanoyloxymethyl chloride, 1-(aikanyloxy)ethyl chloride, 1-methyl-1-(alkanoyloxy)ethyl chloride, alkyloxycarbonyloxymethyl chloride, 1-(alkoxycarbonyloxy)ethyl chloride, 1-

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

according to the procedure in Preparation 0, they give the following compounds:

3- Phthalidyl-6,6-dibromopenicillanate, 4-Chro.tonolactonyl-6-chloro-:-6-iodopenicillanate, • "Y-Butyrolactony 1-6-bromo-6-iodopenicillanate, Acetoxymethyl-6-chloro-6 -bromopenicillanate, pivaloyloxyméty1-6-chloro-6 -j odpenicillanate, hexanoyloxymethyl-6,6-dibrpmpenieillanate, 1-(acetoxy )■ ety 1-6 ,6 -dibromopenieillanate, 1-(isobutyryloxy)ethy1-6-bromo-6- iodopenicillanate, .1-methyl-1-(acetoxy)ethyl-6,6-dibromopechyllate, 1-methyl-1-(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.

S common equation example

Penleillanic acid

To a. stirred solution of 1095.2 g of 6-a-bromo-penicillanic acid in 2177 ml of methanol was added 622 ml of water. The obtained 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-charcoal catalyst was added. The mixture was then shaken under an atmosphere of hydrogen at ca. 5.3 kg./cm until the hydrogen absorption. ceased-. The catalyst was removed by filtration and washed with a mixture of 2177 ml of methanol and 622 ml of water. Washing liquids and filtrate from the filtration were collected and diluted to a volume of 18 liters with water. The mixture thus obtained was extracted with dichloromethane, and the extracts were washed with water, followed by saturated sodium chloride solution. The dichloromethane solution was dried with magnesium sulfate and evaporated in vacuo to give 27 5 .6 g (35%•yield) of penicillanic acid,

Reaks jons skjerna

R1 is hydrogen or an ester-forming residue that is readily hydrolyzable in vivo.

X and Y are each hydrogen, chlorine, bromine or iodine, with the proviso that when X And Y are equal, are. they both brom.

Claims (5)

1. New penicillinic acid-1,,1-dioxide derivatives, characterized by the formula and the base salts. thereof, wherein R 1 is hydrogen or an ester-forming residue readily hydrolyzable in vivo, and X and Y are each hydrogen, chlorine, bromine or iodine, with the proviso that when X and Y are the same, they are both bromine. 2. Compound as stated in claim 1, characterized in that R is hydrogen. 3. Compound as stated in claim 1, characterized in that R1 is pivaloyloxymethyl1. 4. Compound as stated in claim 2 or 3, • characterized in that X is bromine and Y is hydrogen. 5. Compound as stated in claim 2 or 3, characterized in that X and Y are both bromine.