SE449103B - SET TO PENICILLANIC ACID-1,1-DIOXIDE AND ESSERS THEREOF - Google Patents

Description

Cyn 40 449 '(05 27, 2668 (1962) and in U.S. Pat. No. 3,206,469). Hydrogenolysis of 6-halopenicillanic acids to penicillanic acid is described in GB-PS 1,072,108. _Harrison et al., Journal of the Chemical Society (London ), Perkin I, 1772 (1976) discloses: (a) oxidation of 6,6-dibromopenicillanic acid with 3-chloroperbenzoic acid, thereby obtaining a mixture of the corresponding α- and β-sulfoxides; (b) oxidation of methyl- 6,6-dibromopenicillanate with 3-chloroperbenzoic acid to a methyl-6,6-dibromopenicillanate-1,1-dioxide; (c) oxidation of methyl 6-d-chloropenicillanate with 3-chloroperbenzoic acid to a mixture of the corresponding d and (d) oxidation of methyl 6-bromopenicillanate with 3-chloroperbenzoic acid to a mixture of the corresponding α- and β-sulfoxides.

Clayton, Journal of the Chemical Society (London), (C), 2123, (1966) describes: (a) preparation of 6,6-dibromo- and 6,6-diiodopenicillanic acid; (b) oxidation of 6,6-dibromopenicillanic acid with sodium periodate to a mixture of the corresponding sulfoxides; (c) hydrogenolysis of methyl 6,6-dibromopenicillanate to methyl 6-d-bromopenicillanate; (d) hydrogenolysis of 6,6-dibromopenicillanic acid and its methyl ester to penicillanic acid and its methyl ester, respectively; and (e) hydrogenolysis of a mixture of methyl 6,6-diiodopenicillanate and methyl 6-d-iodopenicillanate to pure methyl 6-d-iodopenicillanate.

The present invention relates to a process for the preparation of a compound of the formula H o, oi may (vMuCl-I 3 I \ <2H3 <1) __N 0 / 'fcooal or a pharmaceutically acceptable base salt thereof, in which the formula R 1 represents hydrogen or an in vivo easily hydrolyzable ester-forming residue. The process comprises the following steps: (a) contacting a compound of the formula 40 449 105 y \ g / s gene, S to * xww '1 t CH (II) 3 ___N 0 / "mfcoonl or a base salt thereof with a permanganate of an alkali metal or an alkaline earth metal or an organic peroxycarboxylic acid, to give a compound of the formula Y f; o ",, o pen, xf's X" "'"' \ _cH3 (III) \ ___. N (t, I '0 / e' coonl n fl n or a base salt thereof, in which formula each of the symbols X and Y represents a hydrogen, chlorine, bromine or iodine atom, wherein, when X and Y represent mutual substituents, both must be bromine, and (b) dehalogenation of compound III by catalytic hydrogenation in an inert solvent.

A preferred method of carrying out step (b) comprises contacting the product of step (a) with hydrogen in an inert solvent at a pressure between about 100 - 10,000 kPa at a temperature between about 0 - 60 ° C and at a pH between about 4 - 9 and in the presence of a hydrogen oil catalyst. The latter is usually present in an amount corresponding to between about 0.01 - 2.5, preferably between about 0.1 - 1.0% by weight based on compound III.

Preferably X and Y represent bromine and the preferred reactants for carrying out step (a) are potassium permanganate and 3-chloroperbenzoic acid.

When X and Y both represent chlorine, compound II is difficult to produce. When X and Y both represent iodine, step (a) of the process of the present invention is inconveniently slow. The present invention relates to S19 to a process for the preparation of compounds of the general formula I defined above. In the present context, these compounds are referred to as derivatives of penicillanic acid, which is represented by the following formula (I) ___N. 0 / ”coon In penicillanic acid derivatives, a dashed line between a substituent and the bicyclic nucleus indicates that the substituent in question is below the plane of the nucleus. Such a substituent has by definition an α-configuration. On the other hand, solid lines between a substituent and the bicyclic nucleus indicate that the substituent in question is above the plane of the nucleus. This latter configuration is referred to as the B configuration. Accordingly, in the above general formula II, the substituent X has a α-configuration and the substituent Y has a B-configuration.

When R1 in the present context is an in vivo readily hydrolysable ester-forming residue, it is conceivable to be derived from the alcohol of the formula RI-OH, so that the group -COOR1 in such a compound of the formula I represents an ester. In addition, RI is of such a nature that the group -COCR1 is readily cleaved in vivo, so that the free carboxyl group -COOH is released. In other words, R 1 is a group of such a type that when a compound of formula I, in which R 1 is an in vivo readily hydrolyzable ester-forming residue, is exposed to mammalian blood or tissue, the compound of formula I in which R 1 is hydrogen is easily formed. The RI groups are well known in the penicillin field. In most cases, they improve the absorption characteristics of the penicillin compound. In addition, RI should be of such a nature that it gives the compound I pharmaceutically acceptable properties and upon in vivo cleavage gives rise to the release of pharmaceutically acceptable fragments. The groups R1 are well known and can be easily identified by those skilled in the penicillin field. Compare here to, for example, DE-OS 2,517,316. Specific examples of groups represented by R 1 are 3-phthalidyl, 4-crotonolactonyl, Y-butyrolacton--4-yl and groups of the formulas 122 R o I II IH -cocR 'and -coco-lä * åâ ÅS v VI where each and one of R 2 and R a is selected from a group consisting of hydrogen and alkyl of 1 to 2 carbon atoms and R "is alkyl of 1 to 5 carbon atoms. However, preferred groups R 1 are alkanoyloxymethyl having 3 to 7 carbon atoms, 1- (al kanoyloxy) ethyl of 4 to 8 carbon atoms, 1-methyl-1- (alkanoyloxy) ethyl of 5 to 9 carbon atoms, alkoxycarbonyloxymethyl of 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl of 4 to 7 carbon atoms, 1- methyl-1-alkoxycarbonyloxy) ethyl of 5 to 8 carbon atoms, 3-phthalidyl, 4-crotonolactonyl and γ-butyrolacton-4-yl.

The terms 3-phthalidyl, 4-crotonolactonyl and Y-butyrolacton-4-yl refer to the following structures VII, VIII and IX, respectively. The wavy lines indicate either of the two epimers or a mixture thereof: Step V (a) of the process of the invention comprises oxidizing the sulfide group of a compound II to a sulfone group, whereby a compound III is formed.

Alkali metal permanganates, such as sodium and potassium permanganate, are used as oxidizing agents; permanganates of alkaline earth metals, such as calcium and barium permanganate; or organic peroxycarboxylic acids, such as peracetic acid and 3-chloroperbenzoic acid.

When a compound of formula II, in which X, Y and R 1 have the meanings given above, is oxidized to the corresponding compound III using a metal permanganate, the reaction is usually carried out by treating the compound II with between about 0.5 - 10, preferably with between about 1 to 4 molar equivalents of permanganate in a suitable reaction-inert solvent system, i.e. a solvent system which does not react adversely with either the starting material or the product. Usually water was used. If desired, a co-solvent which is miscible with water but which does not react with the permanganate, for example tetrahydrofuran, can also be added. The reaction can be carried out at a temperature between about -30 and about + 50 ° C, and preferably the reaction is carried out at a temperature between about -10 and about + 100 ° C. At about 0 ° C, the reaction is normally substantially completed in a short time, for example within one hour. Although the reaction can be carried out under neutral, basic or acidic conditions, it is preferred to operate at a pH between about 4-9, preferably at pH 6-8. However, it is essential to select conditions so as to avoid decomposition of the β-lactam ring system. in compound II or III. In fact, it is often advantageous to buffer the pH of the reaction medium to the vicinity of the point of neutrality. The product is extracted in a conventional manner. Any excess permanganate is usually decomposed using sodium bisulfite and if the product is not in solution then it can be filtered off. It is separated from the manganese dioxide by extraction into an organic solvent and the solvent is removed by evaporation. If, on the other hand, the product is not in an undissolved state at the end of the reaction, it can be isolated in the usual way by the extraction of the solvent.

When a compound of formula II, in which X, Y and R 1 have the meanings given above, is oxidized to the corresponding compound III using peroxycarboxylic acid, the reaction is usually carried out by treating the compound II with between about 1 to 6, is preferred at about 2.2 molar equivalents of the oxidizing agent in a reaction solvent inert to the reaction. Typical solvents are chlorinated hydrogen chlorides, such as dichloromethane, chloroform and 1,2-dichloroethane; and ethers such as diethyl ether, tetrahydrofuran, and 1,2-dimethoxyethane. The reaction is normally carried out at a temperature between about -30 and about + 50 ° C and preferably between about + 15 and about + 30 ° C. At about + 25 ° C, reaction times between about 2 - 16 hours are usually required. The product is normally isolated by removing the solvent by evaporation in vacuo. The reaction product can be purified by applying conventional methods well known in the art in question. Alternatively, the reaction product can be used directly in step (b) without further purification.

Step (b) of the present process is a dehalogenation reaction. A convenient way to carry out this conversion is to stir or shake a solution of a compound III under an atmosphere of hydrogen or hydrogen mixed with an inert diluent gas, for example nitrogen or argon, in the presence of a hydrogen oil catalyst.

Suitable solvents for this hydrogenolysis reaction are those which substantially dissolve the starting compound III but which do not themselves undergo hydrogenation or hydrogenolysis.

Examples of such solvents are ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane; low molecular weight ethers 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 and carry out the reaction at a pH between about 4-9, preferably between 6-8. Borate and phosphate buffers are commonly used. Introduction of hydrogen gas into the reaction medium is usually accomplished by carrying out the reaction in a closed vessel containing the compound III, the solvent, the catalyst and hydrogen.

The pressure inside the reaction vessel can vary between about 449103 “8- 100 - 10,000 kPa. When the atmosphere inside the reaction vessel is composed of substantially pure hydrogen, the preferred pressure is between about 200 - 500 kPa. The hydrogenolysis is usually carried out at a temperature between about 0 - + 60 ° C, preferably between about + 25 - + 50PC. When applying preferred temperature and pressure values, the hydrogenolysis generally takes place in a few hours, for example between about 2 hours. The catalyst used in this hydrogenolysis reaction is of the type used in the field in question for the conversions in question and as typical examples may be mentioned noble metals, such as nickel, palladium, platinum and rhodium. The catalyst is usually included in the reaction mixture in an amount corresponding to between about 0.01 - 2.5% by weight, preferably between about 0.1 - 1.0% by weight based on compound III. It is often convenient to suspend the catalyst in an inert medium, in particular it is convenient to suspend palladium in an inert medium, for example carbon.

It will be apparent to those skilled in the art that when it is desired to prepare a compound of formula T in which R1 is hydrogen, one may subject a compound of formula II in which R1 is hydrogen to the reactions set forth in steps (a ) and (b) above. In other words, the process involves oxidation followed by dehalogenation of a 6-halogen or 6,6-dihalogen derivative of penicillanic acid with a free carboxyl group in the 3-position. According to another embodiment of the present invention, step (a) or (b) is started with the carboxyl group in the 3-position blocked with a conventional penicillin carboxyl protecting group. The protecting group can be removed during or after step (a) or step (b) during regeneration of the free carboxyl group. For this purpose, one can use a number of protecting groups conventionally used in penicillin chemistry to protect the 3-carboxyl group. The main requirement of the protecting group is that it must be able to bind to the special compound II or III and be able to be removed from the special compound I or III under the application of such conditions, under which the β-lactam ring system remains substantially intact. For each of steps (a) and (b), typical examples are the tetrahydropyranyl group, the trialkylsilyl groups and the benzyl group, substituted benzyl groups (for example 4-nitrobenzyl), the benzhydryl group, the 2,2,2-trichloroethyl group, t the butyl group and the phenacyl group. Although not every one of the protecting groups can be used in all cases, the person skilled in the art can easily select one which is suitable for a particular situation.

Compare here to US-Ps 3,632,850 Qch 3,197,466, GB-Ps 1,041,985, Woodward et al., Journal of the American Chemical Society, 88, 852 (1966); Chauvette, Journal of Organic Chemistry, 36, 1259 (1971): Sheehan et al., Journal of Organic Chemicstry, 29, 2006 (1964); and "Cephalosporins and Penicillins, Chemistry and Biology" ed. by H.E. Flynn, Academic Press, Inc., 1972.

The penicillin carboxyl protecting group is removed in a conventional manner taking into account the lability of the β-lactam ring system. Compounds I, II and III, where R1 is hydrogen, are acidic and form salts with basic agents. These salts can be prepared according to standard techniques, for example by contacting the acidic and basic components with each other usually in a stoichiometric ratio and, as appropriate, in an aqueous, non-aqueous or partially aqueous medium.

They can then be recovered, as appropriate, 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. Basic agents which are suitably used as salt formers belong to both the organic and the inorganic types and may be mentioned, for example, ammonia, organic amines, alkali metal hydroxides, carbonate, bicarbonate, hydrides and alkoxides as well as hydroxides, carbonate, hydrides and alkoxides. _ 10 _ 449 10 LN of alkaline earth metals. Representative examples of such bases are primary amines, such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine and octylamine; secondary amines such as diethylamine, morpholine, pyrrolidine and piperidine; tertiary amines such as triethylamine, N-ethylpiperidine, N-methylmorpholine and 1,5-diazabicyclo (4.3.0) non-S-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; carbonate such as potassium carbonate and sodium carbonate; bicarbonate such as sodium bicarbonate and potassium bicarbonate; and alkali metal salts of long chain fatty acids, such as sodium 2-ethylhexanoate. Preferred salts of compounds I are sodium, potassium and triethylamine salts. The compound of formula I, in which R 1 is hydrogen, and salts thereof are active as antibacterial agents of medium potency both in vitro and in vivo, and the compounds of formula I, wherein R 1 is an in vivo easily hydrolyzable ester-forming residue, are active as antibacterial agents that have medium potency in vivo. The minimum inhibitory concentrations (MIC) of penicillanic acid-1,1-dioxide against a number of microorganisms are summarized in Table 1.

Table 1 'Penicillanic acid 1,1-dioxide. In vitro antibacterial activity.

Microorganism MIC (mcg / ml) Stapnylococcus aureus 100 Streptococcus faecalis 200 Streptococcus pyogenes 100 Escherichia coli 50 Pseudomonas aeruginosa 200 Klebsiella pneumoniae 50 Proteus mirabilis 100 Proteus morgani 100 Salmonella typhimurium marellia 50 Pasteurella 50 Pasteurella 44 Pasteurella cont.) Microorganism MIC (mcg / ml) Enterobacter clocae 100 Citrobacter freundii 50 Providencia 100 Staphylococcus epidermis 200 Pseudomonas putida 200 Hemophilus influenzae 50 Neisseria gonorrhoeae 0.312 The in vitro antibacterial activity of the compound of formula I, wherein R 1 is hydrogen, These compounds are useful as industrial antimicrobials, for example for water treatment, as sludge control agents, as preservatives for paints and wood and as disinfectants for topical application. When using these compounds for topical application, it is often convenient to mix the active ingredient with a non-toxic carrier, for example a vegetable oil or a mineral oil or also with an emollient cream. Likewise, it can be dissolved or dispersed in liquid diluents or solvents, such as water, alkanols, glycols or mixtures thereof. In most cases, it is advisable to use concentrations of the active ingredient between about 0.1 - 10% by weight, based on the whole mixture.

The in vivo activity of the compounds of formula I, wherein RI is hydrogen or an in vivo readily hydrolyzable ester-forming group and 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 control infections caused by susceptible bacteria in humans, for example infections caused by Neisseria gonorrhoeae.

In the therapeutic use of a compound I or a salt thereof for the treatment of mammals, in particular humans, the compound may be administered alone, but it may also be mixed with pharmaceutically acceptable carriers or diluents. It can be administered orally or parenterally, for example intramuscularly, sub-. ._ 449 105,. cutaneous or intraperitoneally. The carrier or diluent is selected according to the intended mode of administration. For example, for oral administration, the compound may be used in the form of tablets, capsules, powders, syrups, elixirs, aqueous solutions and suspensions, etc., all in accordance with standard pharmaceutical practice. The quantity ratio of active ingredient carrier depends on the chemical nature, solubility and stability of the active ingredient as well as on the intended dosage. However, it is convenient that pharmaceutical preparations contain between about 20-95% of active antibacterial agent (Formula IL Tablets for oral use are generally included as carriers of lactose, sodium citrate and salts of phosphoric acid. Various disintegrants are usually used in tablets). such as starch and lubricants such as magnesium stearate, sodium lauryl sulphate and lime Capsules for oral administration may contain lactose and high molecular weight polyethylene glycol as useful diluents.When aqueous suspensions are required for oral use the active ingredient may be with emulsifiers and suspending agents, if desired, certain sweetening and / or flavoring agents may be added.For parenteral administration which includes intramuscular, intraperitoneal, subcutaneous and intravenous injection, sterile solutions of the active ingredient are usually prepared and the pH of the solutions is suitably adjusted and buff For intravenous use, it should tota The concentration of dissolved constituents is regulated so that the preparation is isotonic.

The doctor ultimately determines the appropriate dose of compound I and this can be expected to vary according to the patient's age, body weight and sensitivity as well as depending on the nature and severity of the symptoms. The compounds are normally used for oral administration in doses between about 10 - 200 mg / kg body weight and day and for parenteral administration the doses are between about 10 - 400 mg / kg body weight and day. These figures are given by way of example only and in some cases it may be necessary to apply dosing outside these limits.

The compounds I in which R 1 is hydrogen or an in vivo readily hydrolyzable ester-forming residue, or a salt thereof, improve the antibacterial efficacy of β-lactam antibiotics in vivo. The amount of antibiotic required is reduced in protecting mice against an otherwise lethal inoculation of certain ß-1-lactamase-producing bacteria. This makes them valuable for co-administration of β-lactam antibiotics in the treatment of bacterial infections in mammals, especially humans.

In the treatment of a bacterial infection, said compound I may be mixed with the β-lactam antibiotic used and the two agents administered simultaneously. Alternatively, said compound I may be administered as a separate mg portion during treatment with a β-lactam antibiotic. In some cases, it is advantageous to administer the compound I to the patient before starting treatment with a β-lactam antibiotic. When using penicillanic acid ~ 1,1-dioxide, a salt or an in vivo readily hydrolysable ester thereof to improve efficacy of β-lactam antibiotic, the dioxide is preferably administered in mixture W with standard pharmaceutical carriers or diluents.

The above-discussed formulation for the use of penicillanic acid 1,1-dioxide or an in vivo readily hydrolyzable ester thereof as a simple antibacterial agent can be used for co-administration with another 6-lactam antibiotic. A pharmaceutical preparation containing a pharmaceutically acceptable carrier, a β-lactam antibiotic and penicillanic acid 1,1-dioxide or an easily hydrolyzable ester thereof normally contains between about 5 to 80% by weight of the pharmaceutically acceptable carrier.

When using penicillanic acid 1,1-dioxide or an in vivo readily hydrolysable ester thereof in combination with another β-lactam antibiotic, the sulfone can be administered orally or parenterally, i.e. intramuscularly, subcutaneously or intraperetoneally. Although the physician in each case ultimately determines the dosage, the ratio between on the one hand the daily dose of penicillanic acid 1,1-dioxide or the salt or ester thereof and on the other hand β-lactam antibiotic is usually between about 1: 3 and about 3: 1. Furthermore, when penicillanic acid ~ 1,1-dioxide or salt or in vivo readily hydrolyzable ester thereof in combination with another β-lactam antibiotic is used, the daily oral dose of each of the components is normally between about 10 - 200 mg / kg body weight and day and the daily parenteral dosage of each of the components is normally between about 10 - 400 mg / kg body weight. These figures are only examples and in some cases it may be necessary to choose doses outside these limits.

Typical β-lactam antibiotics by which penicillanic acid 1,1-dioxide and its in vivo readily hydrolyzable esters can be co-administered are: 6- (2-phenylacetamido) penicillanic acid, 6- (D-2-amino-2-phenylacetamido) penicillanic acid, 6- (2-carboxy-2-phenylacetamido) penicillanic acid, and 7- (2-E1-tetrazolyllacetamido) -3- (2-E5-methyl-1,2,4-thiadiazolylthiomethyl) -3- desacetoxymethylcephalosporanic acid.

Typical microorganisms against which the antibacterial activity of the above-mentioned β-lactam antibiotics is increased are; staphylococcus aureus hacmophilus influenzae klebsiella pneumoniae and bacteroides fragilis. It will be apparent to those skilled in the art that some β-lactam compounds are effective in oral or parenteral administration, whereas others are effective only in parenteral administration. When penicillanic acid 1,1-dioxide, a salt or an in vivo readily hydrolysable ester thereof is used simultaneously, i.e. in admixture with a β-lactam antibiotic, which is effective only in parenteral administration, a combined preparation suitable for paracetamol is required. renteral use. When penicillanic acid 1,1-dioxide or its ester is used concomitantly, ie in admixture with a β-lactam antibiotic which is effective only in oral or parenteral administration, combinations suitable for oral or parenteral administration may be prepared. In addition, it is possible to administer formulations of penicillanic acid 1,1-dioxide or a salt or ester thereof orally, while administering an additional β-lactam antibiotic parenterally. It is also possible to administer preparations of the penicillanic acid-1,1-dioxide or salt or ester thereof parenterally, while administering additional β-lactam antibiotic orally.

Further details regarding the use and synthesis of compounds of formula I are described in DE-OS 2,824,535.

The following examples are given only to further illustrate the invention. The indicated IR spectra have been determined as potassium bromide disks (KBr disks) and diagnostic absorption bands are given as weight (cmnI).

NMR spectra have been determined at 60 MHz for solutions in deuterochloroform (CDCl3), perdeuteroacetone (CDSCOCD3), perdeuterodimethylsulfoxide (DMSO-de) or deuterium oxide (D20) and the positions of the peaks are given in parts per million (ppm) below tetramethylsilane sodium 2,2-dimethyl-2-silapentane-5-sulfonate. The following abbreviations for the shape of the peaks were used: s = singlet, d = doublet, t = n triplet, q = quartet, m = multiplet.

Example 1 6-d-bromopenicillanic acid 1,1-dioxide.

To a stirred mixture of 560 ml of water, 300 ml of dichloromethane and 56.0 grams of 6-d-bromopenicillanic acid was added 4N-NaOH, until a stable pH of 7.2 was reached. For this purpose, 55 ml of the sodium hydroxide solution were required. The mixture was stirred at pH 7.2 for 10 minutes and then filtered. The phases were separated and the organic phase was discarded. The aqueous phase was then poured rapidly and with stirring into an oxidizing mixture, which had been prepared as follows: In a 3-liter flask, 63.2 grams of potassium permanganate, 1,000 ml of water and 48.0 grams of acetic acid were mixed.

This mixture was stirred for 15 minutes at 0 ° C, then cooled to 0 ° C.

After adding the 6-α-bromopenicillanic acid solution to the oxidizing mixture, a cooling bath with a temperature of -15 ° C was maintained around the reaction mixture. The internal temperature rose to + 15 ° C, then + 5 ° C over the course of 20 minutes. At this point, 30.0 grams of sodium metabisulfite was added with stirring and for 10 minutes at about + 10 ° 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-HCl.

The aqueous phase was extracted with chloroform and then with ethyl acetate. Both the chloroform extracts and the ethyl acetate extracts were dried using anhydrous magnesium sulphate and evaporated in vacuo. The chloroform solution gave 10.0 grams (16% yield) of the title compound (the title compound in the present context means the compound indicated in the title of the section in question).

The ethyl acetate solution gave 57 grams of an oil. This was triturated under hexane and a white solid appeared. This was filtered off to give 41.5 grams (66% yield) of the title compound, m.p. 134 ° C (dec.). of Analysis:% C% H% Br% N% S calculated for C8H1 ° BrNo5S: 30.78 3.23 25.60 4.49 10.27 found: 31.05 3.24 25.54 4.66 10, Example 2 By oxidation of 6-d-chloropenicillanic acid and 6-d-iodopenicillanic acid with potassium permanganate in the manner set forth in Example 1, 6-α-chloropenicillanic acid 1,1- -dioxide and 6-u-iodopenicillanic acid-1,1- dioxide.

Example 3 6-β-Chloropenicillanic acid 1,1-dioxide.

An oxidizing solution was prepared from 185 mg of potassium permanganate, 0.063 ml of an 85% phosphoric acid and ml of water. This oxidizing solution was added dropwise to a solution of 150 mg of sodium 66-β-chloropenicillanate in ml of water at 0-5 ° C, until the purple color of the potassium permanganate remained. About half of the oxidizing solution was required for this purpose. The potassium permanganate dye was now eliminated by the addition of solid sodium bisulfite, after which the reaction mixture was filtered.

Ethyl acetate was added to the filtrate and the pH was adjusted to 40 - 17 - 449 1035 1.8. The phases were separated and the aqueous phase was further extracted with ethyl acetate. The combined ethyl acetate phases were washed with water, dried and evaporated in vacuo to give 118 mg of the title compound. 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 products were dissolved in tetrahydrofuran and an equal volume of water was added. The pH was adjusted to 6.8 using a dilute sodium hydroxide solution, the tetrahydrofuran was evaporated in vacuo and the remaining aqueous solution was lyophilized. This gave the sodium salt of the title compound.

Example 4 6-β-Bromopenicillanic acid 1,1-dioxide.

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

Example 5 6-β-Iodopenicillanic acid 1,1-dioxide.

By oxidation of 6-β-iodopenicillanic acid with potassium permanganate in the manner set forth in Example 4, 6-β-iodopenicillanic acid 1,1-dioxide was obtained.

Example 6 Pivaloyloxymethyl-6-α-bromopenicillanate-1,1-dioxide.

To a solution of 394 mg of pivaloyloxymethyl- 40 _. 449 103 -6-α-bromopenicillanate in 10 ml of dichloromethane was added 400 mg of 3-chloroperbenzoic acid at 0- SOC. The reaction mixture was stirred at 0-SCC for one hour and then at 25 ° C for 24 hours. The filtered reaction mixture was evaporated to dryness in vacuo to give the title compound.

Example 7 The procedure described in Example 6 was repeated but pivaloyloxymethyl 6-α-bromopenicillanate was exchanged for: 3-phthalidyl-6-α-chloropenicillanate, γ 4-crotonolactonyl-6-β-chloropenicillanate, γ-butyrolactone-4 -yl-6-α-bromopenicillanate, acetoxymethyl-6-β-bromopenicillanate, pivaloyloxymethyl-6-β-bromopenicillanate, hexanoyloxymethyl-6-α-iodopenicillanate, 1- (acetoxy) ethyl 6-β-iodopenicobutylate ) ethyl 6-α-chloropenicillanate, 1-methyl-1- (acetoxy) ethyl 6-β-chloropenicillanate, 1-methyl-T- (hexanoyloxy) ethyl-6-α-bromopenicillanate, methoxycarbonyloxymethyl-6 -α-bromopenicillanate, propoxycarbonyloxymethyl-6-β-bromopenicillanate, 1- (ethoxycarbonyloxy) ethyl-6-α-bromopenicillanate, 1- (butoxycarbonyloxy) ethyl ~ 6-α-iodopenicillanate, 1-methyl -1- (methoxycarbonyloxy) ethyl 6-β-iodopenicillanate and 1-methyl-1- (isopropoxycarbonyloxy) ethyl 6-α-chloropenicillanate.

There were thus obtained: 3-phthalidyl-6-u-chloropenicillanate-1,1-dioxide, 4-crotonolactonyl-6-β-chloropenicillanate-1,1-dioxide, γ-butyrolacton-4-yl-6-α-bromopenicillanate -1,1-dioxide, 40 -19 .. 449 103 acetoxymethyl-ε-β-bromopenicillanate-1,1- -dioxide, pivaloyloxymethyl-6-β-bromopenicillanate--1,1-dioxide, hexanoyloxymethyl-6-α-iodopenicillanate -1,1--dioxide, 1- (acetoxy) ethyl 6-β-iodopenicillanate-1,1-dioxide, 1- (isobutyryloxy) ethyl-6-α-chloropenicillanate-1,1-dioxide, 1-methyl -1- (acetoxy) ethyl 6-β-chloropenicillanate-1,1-dioxide, 1-methyl-1- (hexanoyloxy) ethyl 6-α-bromopenicillanate-1,1-dioxide, methoxycarbonyloxymethyl-6 -u-bromopenicillanate-1,1-dioxide, propoxycarbonyloxymethyl-6β-bromopenicillanate-1,1-dioxide, 1- (ethoxycarbonyloxy) ethyl-6-α-bromopenicillanate-1,1-dioxide, 1- (butoxycarbonylxlo) ethyl 6-α-iodopenicillanate-1,1-dioxide, 1-methyl-1- (methoxycarbonyloxy) ethyl 6-β-iodine-penicillanate-1,1-dioxide and 1-methyl- 1- (isopropoxycarbonyloxy) ethyl 6-u-chloropenicillanate-1,1-dioxide.

Example Gel 8 Penicillanic acid 1,1-dioxide.

To 100 ml of water was added 9.4 grams of 6-α-bromopenicillanic acid 1,1-dioxide at 22 ° C and then a sufficient amount of 4N-NaOH to achieve a stable pH of 7.3.

To the solution thus obtained was added 2.25 grams of 5% palladium-on-carbon and then 6.9 grams of dipotassium phosphate trihydrate. This mixture was then shaken under an atmosphere of hydrogen at a pressure ranging from 345 to 175 kPa.

When hydrogen uptake ceased, the solids were filtered off and the aqueous solution was covered with 100 ml of ethyl acetate. The pH was slowly lowered from 5.0 to 1.5 with GN-HCl. The phases were separated and the aqueous phase was extracted with additional ethyl acetate. The combined ethyl acetate phases were washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was triturated under ether, after which the solid was filtered off. 4.5 grams (65% yield) of the title compound were thus obtained.

Analysis: É_§% H §_§ §_§ calculated for CgH11NO5S: 41.20 4.75 6.00 13.75 found 41.16 4.81 6.11 13.51 _ Example 9 Penicillanic acid-1.1- dioxide. By hydrogenolysis of each of the following compounds, namely 6-α-chloropenicillanic acid 1,1-dioxide, 6-α-iodopenicillanic acid-1,1-dioxide, 6-β-chloropenicillanic acid-1,1-dioxide, 6- β-bromopenicillanic acid 1,1-dioxide and 6-β-iodopenicillanic acid 1,1-dioxide, as given in Example 8, penicillanic acid -1,1-dioxide was obtained.

Example 10 Pivaloyloxymethyl penicillanate 1,1-dioxide.

To a solution of 1.0 gram of pivaloyloxymethyl fl6-α-bromopenicillanate in 10 ml of methanol was added 3 ml of 1M-NaHCO 3 and 200 mg of 10% palladium-on-carbon. The reaction mixture was shaken vigorously under an atmosphere of hydrogen and at a pressure of about 490 kPa, until the hydrogen uptake ceased. The mixture was then filtered and the major amount of methanol was removed by evaporation in vacuo. Water and ethyl acetate were added to the residue and the pH was adjusted to 8.5. The phases were separated and the organic phase was washed with water, dried over Na 2 SO 4 and evaporated in vacuo. This gave the title association.

Example 11 By hydrogenolysis in the manner set forth in Example 10 of the appropriate 6-halopenicillanic acid ester 1,1-dioxide from Example 7, the following compounds were obtained: 3-phthalidylpenicillanate-1,1-dioxide, 4-crontonolactonylpenicillanate-1,1-dioxide, 40 -21 449 105 v Y-Butyrolactone-4-yl-penicillanate-1,1-dioxide, acetoxymethylpenicillanate-1,1-dioxide, pivaloyloxymethylpenicillanate-1,1-dioxide, hexanoyloxymethylpenicillanate-1,1-dioxide, 1- (acetoxy ) ethyl penicillanate 1,1-dioxide, 1- (isobutyryloxy) ethyl penicillanate 1,1-dioxide, 1-methyl-1- (acetoxy) ethyl penicillanate 1,1-dioxide, 1-methyl-1- ( hexanoyloxy) ethyl penicillanate-1,1-dioxide, methoxycarbonyloxymethylpenicillanate-1,1- -dioxide, propoxycarbonyloxymethylpenicillanate-1,1-dioxide, 1- (ethoxycarbonyloxy) ethylpenicillanate-1,1-dioxyl, 1- (butoxylate); -1,1-dioxide, 1-methyl-1- (methoxycarbonyloxy) ethyl penicillanate-1,1-dioxide and 1-methyl-1- (isopropoxycarbonyloxy) ethyl penicillanate-1,1-dioxide, respectively.

Example 12 Pivaloyloxymethyl-6-α-bromopenicillanate-1,1-dioxide.

An oxidizing solution was prepared by combining 4.26 grams of potassium permanganate, 2.65 grams of an 85% phosphoric acid and 40 ml of water. The mixture was stirred for one hour, then slowly, for 20 minutes and at -10 ° C, was added to a stirred solution of 5.32 grams of pivaloyloxymethyl-6-α-bromopenicillanate in 70 ml of acetone and 10 ml of water. The mixture was stirred at 500 for 30 minutes and 100 ml of ethyl acetate was added. After an additional 30 minutes, a solution of 3.12 grams of sodium bisulfite in 30 ml of water was added over 15 minutes at about 10 ° C. Stirring was continued for another 30 minutes at SOC, after which the mixture was filtered. The organic phase was separated and washed with a saturated sodium chloride solution. The dried organic phase was evaporated to give 5.4 grams of the title compound as an oil.

This crystallized slowly. 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, 9H) ppm.

Example 13 Pivaloyloxymethylpenicillanate 1,1-dioxide.

A solution of 4.4 grams of pivaloyloxymethyl-6-u-bromopenicillanate-1,1-dioxide in 60 ml of tetrahydrofuran was added to 0.84 grams of sodium bicarbonate in 12 ml of water.

The solution was shaken under a hydrogen atmosphere in the presence of 2.0 grams of 5% palladium-on-carbon at 325-350 kPa gauge.

The reaction mixture was then filtered and the residue was washed with 100 ml of ethyl acetate and 25 ml of water. The filtrate combined with the washing liquids was separated. The organic phase was washed with a saturated sodium chloride solution, dried over MgSO 4 and evaporated to give the title compound as an oil. This was dissolved in ethyl acetate (20 ml) and to the solution was slowly added 100 ml of hexane. The precipitate was filtered off and 2.4 grams were obtained as a yield. NMR spectrum (in DMSO-d 6) showed absorptions at 5.75 (q, 2H), 5.05 (m, 1H), 4.40 (s, 1H), 3.95 - 2.95 (m , ZH), 1.40 (s, 3H), 1.25 (s, 3H) and 1.10 (s, 9H) ppm. Example 14 2,2,2-Trichlorethyl-6-d-bromopenicilanate-1,1-dioxide. 2,2,2-Trichloroethyl-6-u-bromopenicillanate was oxidized with potassium permanganate essentially as in Example 12 to give the title compound in 79% yield. NMR spectrum of the product (in CDCl 3) showed absorptions at 5.30 - 4.70 (m, 4H), 4.60 (s, 1H), 1.70 (s, 3H) and 1.50 (s , 3H) Ppm.

Example 14A Penicillanic acid 1,1-dioxide.

To a stirred slurry of 6.5 grams of zinc powder in 100 ml of a 70:30 mixture of glacial acetic acid and tetrahydrofuran was added portionwise over 5 minutes 4.0 grams of 2,2,2-trichloroethyl-6-α-bromopenicillanate. .. 449 105 -1,1-dioxide. The mixture was stirred at room temperature for 3 hours, then filtered. The filtrate was evaporated to a volume of 10 ml and the yellowish brown solution was mixed with 50 ml of water and 100 ml of ethyl acetate. The pH was adjusted to 1.3 and the phases were separated. The organic phase was washed with a saturated sodium chloride solution, dried over magnesium sulfate and then evaporated to dryness in vacuo. The residue was triturated under ether for minutes. 553 mg of the title compound were thus obtained in the form of a solid. NMR spectrum (in CDCl 3 / DMSO-d 6) showed absorptions at 11.2 (broad 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 Benzyl 6-d-bromopenicillanate-1,1-dioxide.

Benzyl 6-d-bromopenicillanate was oxidized with potassium permanganate essentially as in Example 12 to give the title compound in 94% yield. NMR spectrum (in CDCl 3) showed absorptions at 7.35 (s, 5H), 5.10 (m, 3H), 4.85 (m, 1H), 4.40 (s, 1H), 1.50 ( s, 3H) and 1.25 (s, 3H) ppm.

Example 16 Penicillanic acid 1,1-dioxide.

A solution of 4.0 grams of benzyl 6-α-bromopenicillanate-1,1-dioxide in 50 ml of tetrahydrofuran was combined with a solution of 1.06 grams of sodium bicarbonate in 50 ml of water. To the mixture was added 2.0 grams of a 50% suspension of 5% palladium-on-carbon in water, after which this mixture was shaken in a hydrogen atmosphere at a pressure of 320-345 kPa overpressure for 20 minutes. The catalyst was filtered off and then 30 ml of tetrahydrofuran and 3.0 grams of a 50% suspension of 5% palladium-on-carbon were added. The mixture thus obtained was shaken under a hydrogen atmosphere at 290-310 kPa overpressure for 65 minutes. The reaction mixture was then filtered and the tetrahydrofuran was removed by evaporation. Ethyl acetate was added to the aqueous residue and the pH was adjusted to 7.1. The ethyl acetate phase was removed and new ethyl acetate was added to the remaining aqueous phase. The pH was lowered to 1.5 and the phases were separated. The aqueous phase was further extracted with ethyl acetate and the combined ethyl acetate solutions were washed with a saturated sodium chloride solution and dried over 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. NMR spectrum (in CDCl 3 / DMSO-d 6) showed absorptions at 9.45 (broad s, 1H), 4.60 (t, 1H), 4.25 (s, 1H), 3.40 (d, ZH), 1.65 (s, 3H) and 1.30 (s, 3H) PPW - Example 17 6,6-Dibromopenicillanic acid 1,1-dioxide.

To a dichloromethane solution of 6,6-dibromopenicillanic acid prepared according to Example K was added 300 ml of water and then 105 ml of 3N- -NaOH dropwise over 30 minutes. The pH of the solution was stabilized at 7.0. The aqueous phase was removed and the organic phase 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 grams of potassium permanganate, 18 ml of concentrated phosphoric acid and 600 ml of water, until the bright color of the permanganate remained. The addition took 50 minutes and 550 ml of oxidizing agent was required. At this point, 500 ml of ethyl acetate was added and then the pH was lowered to 1.23 by adding 105 ml of 6N-HCl. Then 250 ml of a 1 molar sodium bisulfite solution was added over the course of 10-15 minutes at about 10 ° C. During the addition of the sodium bisulfite solution, the pH was maintained at 1.25 - 1.35 using 6N-HCl. The aqueous phase was saturated with sodium chloride and the two races were separated. The aqueous solution was extracted with an additional amount of ethyl acetate (2 x 150 mL) and the combined ethyl acetate solutions were washed with brine and dried over MgSO 4. This gave an ethyl acetate solution of 6,6-dibromopenicillanic acid 1,1-dioxide. This can be isolated by removing the solvent in vacuo. Such an isolated sample from an analogous production process had a melting point of 201 ° C (decomposition). NMR spectrum (CDCl 3 / DMSO- -de) showed absorptions at 9.35 (s, 1H), 5.30 (s, 1H), 4.42 (s, 1H), 1.63 (s, an) and 1.50 (s, an) ppm. IR spectra (KBr disk) showed absorptions at 3846 - 2500, 40 _ 25 _ 1818, 1754, 1342 and 1250 - 1110 cm_l.

Example 18 6-Chloro-6-iodopenicillanic acid 1,1-dioxide.

To a solution of 4.9 grams of 6-chloro-6-iodo-penicillanic acid in 50 ml of dichloromethane was added 50 ml of water and then the pH was raised to 7.2 using 3N-NaOH.

The phases were separated and the aqueous phase was cooled to SCC. To this solution was added dropwise over 20 minutes a premixed solution prepared from 2.61 grams of potassium permanganate, 1.75 ml of concentrated phosphoric acid and 50 ml of water. During the addition, the pH was kept at 6 and the temperature below 10 ° C. At this point, 100 ml of ethyl acetate was added and the pH was adjusted to 1.5. To the mixture was then added 50 ml of 10% sodium bisulfite, the temperature was kept below 10 ° C and the pH at about 1.5 by the addition of 6N-HCl. The pH was lowered to 1.25 and the phases were separated. The aqueous phase was saturated with sodium chloride and extracted with ethyl acetate. The combined organic solutions were then washed with brine, dried over MgSO 4 and evaporated in vacuo to give 4.2 grams of the title compound, mp 143-14500. NMR spectrum (CDCl 3) showed absorptions at 4.86 (s, 1H). 4.38 (S, 1H), 1.60 (s, 3H) and 1.43 (s, 3H) ppm. IR spectra (KBr disk) showed absorptions at 1800, 1740 and 1250 - 1110 cnfl.

Example 1-2 6-Bromo-6-iodo-penicillanic acid 1,1-dioxide.

To a solution of 6.0 grams of 6-bromo-6-iodo-penicillanic acid in 50 ml of dichloromethane was added 50 ml of water. The pH was raised to 7.3 using 3N-NaOH and the aqueous phase was removed. The organic phase was extracted with 10 ml of water. The combined aqueous phases were cooled to 5 ° C and a premixed solution of 284 grams of potassium permanganate in 2 ml of concentrated phosphoric acid and 50 ml of water were added dropwise at a temperature between -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-HCl. To the two-phase system thus obtained was added dropwise 50 ml of 10% sodium bisulfite, the pH was maintained at about 1.5 by the addition of 6N-HCl and 40 ml of additional 50 ml of ethyl acetate were added, then the pH was lowered to 1 The phases were separated and the aqueous phase was saturated with sodium chloride, the saturated solution was extracted with ethyl acetate (3 x 50 ml) and the combined ethyl acetate phases were washed with brine, dried over MgSOr and evaporated in vacuo, the residue was dried under high vacuum and dried. remaining 4.2 grams of the title compound, mp 145-147%, una spectrum (CDCl 3) showed absorptions at 4.90 (s, 1H), 4.30 (s, 10H), 1.60 (s, 3H) and 1.42 (s, 3H) ppm. IR spectrum (KBr disk) showed absorptions at 1800, 1740, 1330 and 1250 - 1110 crfl.

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

By oxidizing 6-chloro-6-bromopenicillanic acid with potassium permanganate in the manner set forth in Example 19, 6-chloro-6-bromopenicillanic acid 1,1-dioxide was obtained.

Example 21 Penicillanic acid 1,1-dioxide.

An ethyl acetate solution of 6,6-dibromopenicillanic acid 1,1-dioxide prepared in the manner set forth in Example 17 was combined with 705 ml of saturated sodium bicarbonate solution and 8.88 grams of 5% palladium-on-carbon as catalyst.

The mixture was shaken under an atmosphere of hydrogen at a pressure of about 490 kPa for about one hour. The catalyst was filtered off and the aqueous phase was adjusted to 1.2 with 6N-HCl. The aqueous phase was saturated with sodium chloride. The phases were separated and the aqueous phase was extracted with an additional amount of ethyl acetate (3 x 200 ml). The combined ethyl acetate solutions were dried over MgSO 4 and evaporated in vacuo to give 33.5 grams of penicillanic acid 1,1-dioxide (58% yield) based on the amount of 6-aminopenicillanic acid. This product was dissolved in 600 ml of ethyl acetate, the solution was decolorized using activated carbon and the solvent was removed by evaporation in vacuo. The product was washed with hexane. This gave 31.0 grams of pure product.

Example 22 by hydrogenolysis of each of the following compounds, namely 6-chloro-6-iodopenicillanic acid-1,1-40 - 27 - 449 103 -dioxide, 6-bromo-6-iodopenicillanic acid and 6-chloro-6- bromopenicillanic acid in the manner set forth in Example 21 was obtained in each case of penicillanic acid 1,1-dioxide.

Example gel 23 Penicillanic acid 1,1-dioxide.

To a stirred suspension of 786 mg of 6-chloro-6-iodopenicillanic acid 1,1-dioxide in ml of benzene was added 0.3 ml of triethylamine and then 0.25 ml of trimethylsilyl chloride at about 0 ° C. Stirring was continued for 5 minutes at about 0 ° C and then at the reflux temperature of the solvent for 30 minutes. The reaction mixture was cooled to ZSQC and the precipitated material was filtered off. The filtrate was cooled to about 0 ° C and 1.16 grams of tri-n-butyltin hydride and a few milligrams of azobisisobutyronitrile were added. The reaction mixture was stirred and subjected to UV irradiation for one hour at about 0 ° C and then for 3.5 hours at the reflux temperature of the solvent. An additional amount of tri-n-butyltin hydride (1.1 ml) and a catalytic amount of azobis-isobutyronitrile were added and stirring and irradiation at reflux temperature were continued for a further hour. The reaction mixture was then poured into 50 ml of cold 5% sodium bicarbonate 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-HCl. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined ethyl acetate solutions were washed with brine, dried over MgSO 4 and evaporated in vacuo. The residue was triturated under hexane and filtered to give 0.075 mg of the title compound.

Example 24 Penicillanic acid 1,1-dioxide.

To a stirred suspension of 0.874 grams of 6-bromo-6-iodopenicillanic acid 1,1-dioxide in 10 ml of benzene at a temperature of about 5 ° C was added 0.3 ml of triethylamine and then 0.25 ml of trimethylsilyl chloride. Stirring was continued at about 5 ° C for 5 minutes and then for 30 minutes at the reflux temperature of the solvent. The reaction mixture was cooled to room temperature and the solids were filtered off. The filtrate 40 - 28 ... 449 10 CN 1. was cooled to about SOC and 1.05 ml of tri-n-butyltin hydride and a catalytic amount of azobisisobutyronitrile was added.

The mixture was subjected to UV irradiation for one hour at about 5 ° C and then poured into 30 ml of cold, 5% sodium bicarbonate solution. The mixture was stirred for 30 minutes and then 50 ml of ethyl acetate was added. The mixture was acidified to pH 1.5 and the phases were separated. The aqueous phase was extracted with ethyl acetate (2 x 25 ml) and the combined ethyl acetate phases were washed with brine, dried over MgSOr and evaporated in vacuo. The residue was dried in high vacuum and 30 ml of hexane was added. The insoluble material was filtered off to give 0.035 grams of the title compound.

Example 25 Pivaloyloxymethyl 6,6-dibromopenicillanate-1,1-dioxide.

To a solution of 4.73 grams of pivaloyloxymethyl 6,6-dibromopenicillanate in 15 ml of dichloromethane was added 3.80 grams of 3-chloroperbenzoic acid at 0-5 ° C. The reaction mixture was stirred at 0 ° C for one hour and then at 2500 for 24 hours. The filtered reaction mixture was evaporated to dryness in vacuo and the residue partitioned between ethyl acetate and water. The pH of the aqueous phase was adjusted to 7.5 and the phases were separated. The ethyl acetate phase was dried over Na 2 SO 4 and evaporated in vacuo to give the title compound.

Example 26 By oxidizing each of the 6,6-dihalogenpenicillanic acid esters prepared according to Example P using 3-chloroperbenzoic acid in the manner of Example 25, the following compounds were obtained: 3-Phthalidyl-6,6-dibromopenicillanate 1,1-dioxide, 4-crotonolactonyl-6-chloro-6-iodopenicillanate-1,1-dioxide, γ-butyrolactonyl-6-bromo-6-iodopenicillanate--1,1-dioxide, acetoxymethyl-6-chloro- 6-bromopenicillanate-1,1-aioxime, pivaloyloxymethyl-6-chloro-6-iodopenicillanate-1,1-dioxide, 40 - 29 ... hexanoyloxymethyl-6,6-dibromopenicillanate-1,1-dioxide, 1- (acetoxy) ethyl 6,6-dibromopenicillanate-1,1-dioxide, 1- (isobutyryloxy) ethyl 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-6,6-dibromopenicil-1anate-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-iodobenicillanate-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 gel 27 Pivaloyloxymethyl penicillanate 1,1-dioxide.

To a solution of 1.0 gram of pivaloyloxymethyl-6,6-dibromopenicillanate-1,1-dioxide in 10 ml of methanol was added 3 ml of 1M-NaHCO 3 and 200 mg of 10% palladium-on-carbon. The reaction mixture was shaken vigorously under an atmosphere of hydrogen at a pressure of about 490 kPa until hydrogen uptake ceased. The mixture was then filtered and the bulk methanol was removed by evaporation in vacuo. Water and ethyl acetate were added to the residue and the pH was adjusted to 8.5. The phases were separated and the organic phase was washed with water, dried over Na 2 SO 4 and evaporated in vacuo. There was thus obtained pivaloyloxymethyl penicillanate-1,1-dioxide.

Example 28 By hydrogenolysis in the manner set forth in Example 27 of each of the 6,6-dihalogenpenicillanic acid ester 1,1-dioxides prepared according to Example 26, the following compounds were obtained: 3-phthalidylpenicillanate -1,1-dioxide, 4-crotonolactonylpenicillanate-1,1-dioxide, γ-butyrolacton-4-yl-penicillanate-1,1-dioxide, acetomethylpenicillanate-1,1-dioxide, pivaloyloxymethylpenicillanate-1,1-dioxide, hexanoyloxymethylpenicillanate -1,1-dioxide, 1- (acetoxy) ethylpenicillanate-1,1-dioxide, 1- (isobutyryloxy) ethylpenicillanate-1,1-dioxide, 1-methyl- (acetoxy) ethylpenicillanate-1,1 -__ dioxide, 1 -methyl-1- (hexanoyloxy) ethylpenicillanate-1,1-dioxide, methoxycarbonyloxymethylpenicillanate-1,1- -dioxide, propoxycarbonyloxymethylpenicillanate-1,1--dioxide, 1- (ethoxycarbonyloxy) ethylpenicillanoxide-1,1- -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, respectively.

Example Gel 29 Pivaloyloxymethyl 6-dibromopenicillanate-1,1-dioxide.

A stirred solution of 3.92 grams of 6,6-dibromopenicillanic acid 1,1-dioxide in 20 ml of N, N-dimethylformamide was cooled to 0 ° C and then 1.29 grams of diisopropylethylamine was added. Then 1.51 grams of chloromethyl pivalate was added. The 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, after which the phases were separated.

The aqueous phase was extracted with ethyl acetate and the combined ethyl acetate phases were washed with a cold solution of sodium bicarbonate, then with water and finally with brine. The ethyl acetate solution was then treated with Darco (activated carbon), dried over MgSO 4 and evaporated in vacuo to give a brown oil (2.1 grams) which was chromatographed on 200 grams of silica gel using dichloromethane as eluting The fractions containing the desired product were combined and chromatographed again on silica gel to give 0.025 grams of the title compound. NMR spectrum (CDCl 3) showed absorptions at 6.10 (q, ZH), .00 (s, 1H) , 4.55 (s, 1H), 1.60 (s, 3H), 1.50 (s, 3HL and 1.15 (s, 9H) ppm.

Example gel Pivaloyloxymethyl penicillanate 1,1-dioxide.

To a stirred solution of 60 grams of pivaloyloxymethyl-6,6-dibromopenicillanate-1,1-dioxide in 5 ml of benzene was added 52 μl of tri-n-butyltin hydride and then a catalytic amount of azobisisobutyronitrile. The reaction mixture was cooled to about SOC and then subjected to UV irradiation for one 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 of the aqueous phase was adjusted to 7.0. The phases were separated and the aqueous phase was extracted with an additional amount of ethyl acetate. The combined ethyl acetate solutions were washed with brine, dried over MgSO 4 and evaporated in vacuo. The residue was dried in high vacuum for 30 minutes to give 70 mg of a yellow oil. NMR spectrometry showed that this oil contained the rubric compound together with some impurities containing n-butyl groups.

Example Gel 31 6,6-Dibromopenicillanic acid 1,1-dioxide.

To a solution of 359 mg of 6,6-dibromopenicillanic acid in 30 ml of dichloromethane was added 380 mg of 3-chloroperbenzoic acid at 0-5 ° C. The reaction mixture was stirred at 0 DEG-50 DEG C. for 20 minutes and then at 25 DEG C. for 24 hours. The frozen reaction mixture was evaporated in vacuo to give the title compound. 40 _32 ..

Jb. _13.

\ D CZ * Qr.

Example 32 Benzyl 6,6-dibromopenicillanate-1,1-dioxide.

A mixture of 10.0 grams of 6,6-dibromopenicillanic acid 1,1-dioxide, 2.15 grams of sodium bicarbonate, 3.06 ml of benzyl bromide and 100 ml of N, N-dimethylformamide was stirred at room temperature overnight. Most of the solvent was removed by evaporation in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was removed, washed with 1N-CH 1 and with a saturated sodium chloride solution, then dried over Na 2 SO 4. Evaporation in vacuo gave 11.55 grams of the title compound. NMR spectrum (in CDCl 3) showed absorptions at 7.40 ( s, SH), 5.30 (m, 2H), 4.95 (s, 1H), 4.55 (s, 1H), 1.50 (s, 3H) and 1.20 (s, 3H) Ppm .

Example 33 Penicillanic acid 1,1-dioxide.

To a solution of 2.0 grams of benzyl 6,6-dibromopenicillanate-1,1-dioxide in 50 ml of tetrahydrofuran was added a solution of 0.699 grams of sodium bicarbonate in 50 ml of water and then 2.0 grams of 5% palladium. on-coal. This mixture was shaken under an atmosphere of hydrogen at about 345 kPa gauge for 70 minutes. The tetrahydrofuran was removed by evaporation and the residue was partitioned between ethyl acetate and water at pH 7.37. The aqueous phase was removed and new ethyl acetate was added. The pH was lowered to 1.17 and the ethyl acetate was removed and washed with a saturated sodium chloride solution. Evaporation in vacuo gave 423 mg of the title compound.

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 in the manner set forth in Example J.

The product was purified by chromatography on silica gel. 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. 40 _33- 449 103 Exemgel 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 as indicated in Example 14A. The yield was 27%.

Example Gel 36 1- (ethoxycarbonyloxy) ethyl 6,6-dibromopenicillanate-1,1-dioxide.

A mixture of 2.26 grams of 6,6-dibromopenicillanic acid 1,1-dioxide, 1.02 ml of 1- (ethoxycarbonyloxy) -ethylchioria, 1.32 ml of isopropylethylamine and 10 ml of Nm-aminethylformamide was stirred at room temperature for 28 hours.

The reaction mixture was diluted with 100 ml of ethyl acetate and then washed first with water, then with dilute hydrochloric acid, then with a saturated sodium bicarbonate solution and finally with a saturated sodium chloride solution. The dried ethyl acetate solution was evaporated in vacuo to give 1.50 grams of an oil. This was chromatographed on silica gel to give 353 mg of the title compound contaminated with a small amount of 1- (ethoxycarbonyloxy) ethyl 6-- bromopenicillanate.

Example gel 37 1- (ethoxycarbonyloxy) ethyl penicillanate 1,1-dioxide.

A 230 mg portion of the product obtained in Example 36 was dissolved in 10 ml of toluene. To the solution was added 0.4 ml of tri-n-butyltin hydride and then 0.164 grams of azobisisobutyronitrile, and the mixture was heated at 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 evaporation residue was dissolved in ether and the ether solution was washed with a 5% potassium fluoride solution and then with a saturated sodium chloride solution. The ether solution was dried over Na 2 SO 4 and evaporated in vacuo. The evaporation residue was chromatographed on silica gel to give 0.043 grams of the title compound. NMR spectrum (in CDCl 3) showed absorptions at 6.75 (m), 4.60 (m), 4.30 (m), 4.15 (s), 40 - 34 - 449 105 4.00 ( s), 3.30 (d) and 1.75 - Example A 6-chloro-6-iodopenicillanic acid.

To 3.38 grams of iodine monochloride in 30 ml of dichloromethane was added with stirring and at 0-5 ° C 11.1 ml of 1.00 (m) ppm. 2.5N-HZSOR and then 1.92 grams of sodium nitrite. At this point, 3.00 grams of 6-aminopenicillanic acid was added all at once and stirring was continued for 30 minutes at 0 ° C. To the reaction mixture was then added 22.8 ml of a 1 molar sodium sulfite solution in portions and the phases were separated. The aqueous phase was washed with an additional amount of dichloromethane and then all the organic phases were washed with saturated sodium chloride solution.

The dichloromethane solution was dried over Na 2 SO 4 and evaporated in vacuo to give 3.48 grams of the title compound. V - The above product was dissolved in 30 ml of tetrahydrofuran and 30 ml of water was added to the solution. With dilute sodium hydroxide solution, the pH was adjusted to 6.8 and the tetrahydrofuran was removed in vacuo. The remaining aqueous phase was lyophilized and the residue was washed with diethyl ether. This gave 3.67 grams of the title compound as the sodium salt.

Example B 6-8-Chloropenicillanic acid.

A sample of 2.95 grams 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 a nitrogen atmosphere. To the solution was added 1.08 ml of triethylamine and the mixture was cooled to 0-5 ° C. To the cooled mixture was then added 0.977 ml of trimethylsilyl chloride and the reaction mixture was stirred at 0-5 ° C for 5 minutes, via 25 ° C for 10 minutes and at 50 ° C for 30 minutes. The reaction mixture was cooled to 2500 and triethylamine hydrochloride was filtered off.

To the filtrate was added 15 mg of azobisisobutyronitrile and then 2.02 ml of tri-n-butyltin hydride. The mixture was subjected to UV irradiation for 15 minutes while cooling so that the temperature was maintained at about 20 ° C. The solvent was then removed by evaporation in vacuo and the residue was dissolved in a mixture of tetrahydrofuran and water (1: 1). The pH was adjusted to 7.0 and the tetrahydrofuran was removed by evaporation in vacuo. The aqueous phase was washed with ether, and an equal volume of ethyl acetate was added. The pH was adjusted to 1.8 and the ethyl acetate phase was removed. The aqueous phase was extracted with an additional amount of ethyl acetate, then the combined ethyl acetate solutions were dried and evaporated in vacuo. This gave 980 mg of 6-β-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 lyophilized to give 850 mg of sodium 6-β-chloropenicillanate. NMR spectrum (D 2 O) showed absorptions at 5.70 (d, 1H, J = 4Hz), 5.50 (d , 1H, J = 4112), 4.36 (s, m), 1.60 (s, an) and 1.53 (s, an) ppm.

Example C 6-B-bromopenicillanic acid.

A mixture of 5.0 grams of 6,6-dibromopenicillanic acid, 1.54 ml of triethylamine and 100 ml of benzene was stirred under nitrogen until a solution was obtained. This was cooled to 0-5 ° C and 1.78 ml of trimethylsilyl chloride was added. The reaction mixture was stirred at 0-5 ° C for 2-3 minutes and then at 50 ° C for 35 minutes. The cooled reaction mixture was filtered and the filtrate was cooled to 0 ° C. A small amount of azobisisobutyronitrile and then 3.68 ml of tri-n-butyltin hydride was added. The reaction flask was subjected to UV irradiation for 15 minutes, after which the reaction mixture was stirred at about 25 ° C for 1.75 hours. The reaction mixture was irradiated again for 15 minutes and stirring was continued for 2.5 hours. At this point, a further small amount of azobisisobutyronitrile and then 0.6 ml of tri-n-butyltin hydride (0.6 ml) were added, whereupon the mixture was again irradiated and more specifically 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 phase was removed, dried and evaporated in vacuo to give 2.33 grams of an oil. This was converted to a sodium salt by adding water containing one equivalent of sodium bicarbonate, after which the solution thus obtained was lyophilized. Sodium-6-β-bromopenicillanate was obtained contaminated with a small amount of the u-isomer.

The sodium salt was purified by chromatography on Sephadex ® LH-20, combined with a small amount of additional materials of the same quality and chromatographed again. NMR spectrum (D 2 O) of the product thus obtained showed absorptions at 5 56 (s, 2H), 4.25 (s, 1H), 1.60 (s, 3H) and 1.50 (S, 3H) ppm.

Example D 6-β-Iodopenicillanic acid.

The title compound was prepared by reduction of 6,6-diiodpenicillanic acid with tri-n-butyltin hydride in the manner set forth in Example B.

Example E Pivaloyloxymethyl 6-α-bromopenicillanate.

To a solution of 280 mg of 6-d-bromopenicillanic acid in 2 ml of N, N-dimethylformamide was added 260 mg of diisopropylethylamine, then 155 mg of chloromethyl pivalate and 15 mg of sodium iodide. The reaction mixture was stirred at room temperature for 24 hours and then diluted with ethyl acetate and water. The pH was adjusted to 7.5 and then the ethyl acetate phase was separated and washed three times with water and once with a saturated sodium chloride solution.

The ethyl acetate solution was then dried over anhydrous sodium sulfate and evaporated in vacuo to give the title compound.

Example F By reacting the appropriate 6-halopenicillanic acid with 3-phthalidyl chloride, 4-crotonolactonyl chloride, γ-butyrolacton-4-yl chloride or required alkanoyloxymethyl chloride, 1- (alkanolyoxy) ethyl chloride, 1-methyl-1- (alka noyloxy) ethyl chloride, alkoxycarbonyloxymethyl chloride, 1- (alkoxycarbonyloxy) ethyl chloride or 1-methyl-1- (alkoxycarbonyloxy) ethyl chloride in the manner set forth in Example E, the following compounds were prepared: 3-phthalidyl-6-d-chloropenic , 4-crotonolactonyl-6-β-chloropenicillanate, 40 -β1-449,105-γ-butyrolactone-4-yl-6-α-bromopenicillanate, acetoxymethyl-6-β-bromopenicillanate, pivaloyloxymethyl-6-β-bromopenicillanate, hexanoyloxymethylimethanoyl -d-iodopenicillanate, 1- (acetoxy) ethyl 6-β-iodopenicillanate, 1- (isobutyryloxy) ethyl 6-α-chloropenicillanate, 1-methyl-1- (acetoxy) ethyl 6-β-chloropenicillanate, 1-methyl-1- (hexanoyloxy) ethyl 6-α-bromopenicillanate,. methoxycarbonyloxymethyl-6-d-bromopenicillanate, m propoxycarbonyloxymethyl-6-β-bromopenicillanate, 1- (ethoxycarbonyloxy) ethyl-6-u-bromopenicillanate, 1- (butoxycarbonyloxy) ethyl-6-α-iodopenicillaate , 1-methyl-1- (methoxycarbonyloxy) ethyl 6-β-iodopenicillanate, and 1-methyl-1- (isopropoxycarbonyloxy) ethyl 6-d-chloropenicillanate, respectively.

Example G 6.6-Diiodopenicillanic acid.

A mixture of 15.23 grams of iodine, 10 ml of 2,5N-H 2 SO 4 (2.76 grams of sodium nitrite and 75 ml of dichloromethane was stirred at 500 and 4.32 grams of 6-aminopenicillanic acid was added over 15 minutes. was continued at 5-10 ° C for 45 minutes after completion of the addition, to which 100 ml of 10% sodium bisulfite solution was added dropwise.

The phases were separated and the aqueous phase was extracted with an additional amount of dichloromethane. The combined dichloromethane phases were washed with brine, dried over MgSO 4 and evaporated in vacuo. This gave 1.4 grams of the title compound contaminated with a small amount of .6-iodopenicillanic acid. The product had a melting point of 58-64 ° C. NMR spectrum (CDCl 3) showed absorptions at .77 (s, 1H), 4.60 (s, 1H), 1.71 (s, 3H) and 1.54 (s, 3H) Ppm - 40 ... 38_ 449 193 Exemgel H Pivaloyloxymethyl-6-α-bromopenicillanate.

To a stirred mixture of 11.2 grams of 6-d-bromopenicillanic acid, 3.7 grams of sodium bicarbonate and 44 ml of N, N-dimethylformamide was added dropwise over 5 minutes and at room temperature 6.16 grams of chloromethyl pivalate. Stirring was continued for 66 hours, after which the reaction mixture was diluted with 100 ml of ethyl acetate and 100 ml of water. The phases were separated and the ethyl acetate phase was washed first with water, then with a saturated sodium chloride solution, then with a saturated sodium bicarbonate solution, with water and finally with a saturated sodium chloride solution. The decolorized ethyl acetate solution was dried over MgSO 4 and evaporated to dryness in vacuo. 12.8 grams (yield 80%) of the title compound were obtained in this way.

Example Gel I Benzyl 6-α-bromopenicillanate.

The title compound was prepared by esterification of 6-d-bromopenicillanic acid with benzyl bromide essentially as described in Example H (yield 83%).

NMR spectrum (in CDCl 3) showed absorptions at 7.35 (s, SH), 5.35 (m, 1H), 5.15 (s, ZH), 4.70 (m, 1H), 4.60 ( s, 1H), 1.55 (s, 3H) and 1.35 (s, 3H) ppm.

Example gel J 2,2,2-trichloroethylpenicillanate.

To a stirred solution of 11.2 grams of 6-α-bromopenicillanic acid in 50 ml of tetrahydrofuran was added at 0 DEG C. 3.48 grams of pyridine over the course of one minute.

The cloudy solution thus obtained was charged with 10.47 grams of 2,2,2-trichlorethylchloroformate over 10 minutes, keeping the temperature between 0 DEG-0 DEG C. Stirring was continued for 30 minutes and then the cooling bath was removed. Stirring was continued at room temperature all night. The reaction mixture was then heated and kept at 35 ° C for 5 minutes, after which it was filtered. The filtrate was evaporated and the residue was dissolved in 100 ml of ethyl acetate. The ethyl acetate solution was washed first with a saturated sodium bicarbonate solution, then with water and finally with a saturated sodium chloride solution. The ethyl acetate solution of 40 - 39 - 449 105 was then colored and dried, after which it was evaporated to a small volume. To the mixture thus obtained was added 100 ml of hexane and the solids were filtered off. 10.5 grams of the title compound were obtained in this way, m.p. 105-110 ° C. NMR spectrum (in CDCl 3) showed absorptions at 5.50 (d, 1H), 4.95 (d, 1H), 4.90 (s, ZH), 4.65 (s, 1H), 1.70 ( s, βH) and 1.55 (s, 3H) ppm.

Example K 6,6-Dibromopenicillanic acid.

To 500 ml of dichloromethane cooled to SOC was added 119.9 grams of bromine, 200 ml of 2.5N-H 2 SO 4 and 34.5 grams of N sodium nitrite. The mixture was stirred and then added portionwise and over 30 minutes with 54.0 grams of 6-aminopenicillanic acid, keeping the temperature between 4-10 ° C. Stirring was continued for 30 minutes at 5 ° C and then 410 ml of a 1.0 molar solution of sodium bisulfite was added dropwise at 5-10 ° C over 20 minutes. The phases were separated and the aqueous phase was extracted twice with 150 ml of dichloromethane. The original dichloromethane phase was combined with the two extracts to give a solution of 6,6-dibromopenicillanic acid. This solution was used directly in Example 17.

Example L 6-Chloro-6-iodopenicillanic acid.

To 100 ml of chloromethane cooled to 3 ° C was added 4.87 grams of iodine chloride, 10 ml of 2,5N-H 2 SO 4 and 2.76 grams of sodium nitrite. The mixture was stirred and added portionwise over 15 minutes with 4.32 grams of 6-aminopenicillanic acid. Stirring was continued for 20 minutes at 0 DEG-5 DEG C. and then 100 ml of a 10% sodium bisulfite solution were added dropwise at about 400 ml. Stirring was continued for 5 minutes, after which the phases were separated. The aqueous phase was extracted with dichloromethane (2 x 50 ml) and the combined dichloromethane solutions were washed with brine, dried over MgSO 4 and evaporated in vacuo to give the title compound as a yellowish brown solid, mp 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 40.40. 449 103 v (s , 3H) ppm. IR spectrum (KBr disk) showed absorptions at 1780 and 1715 cm -1.

Example M 6-bromo-6-iodopenicillanic acid.

To 100 ml of chloromethane cooled to 5 ° C was added 10 ml of 2,5N-H2SOr, 6.21 grams of iodine bromide and 2.76 grams of sodium nitrite. To the mixture was added with vigorous stirring at 0-5 ° C and in the course of 15 minutes 4.32 grams of 6-aminopenicillanic acid. Stirring was continued for a further 20 minutes at 0 DEG-0 DEG C. and then 100 ml of sodium bisulfite solution were added dropwise at a temperature between 0 DEG-10 DEG C. At this point, the phases were separated and the aqueous phase was extracted with dichloromethane (3 x 50 ml). The combined dichloromethane phases were washed with brine, dried over MgSO 4 and evaporated in vacuo. The residue was dried in high vacuum for 30 minutes to give 6.0 grams (72% yield) of the title compound, mp 144-147 ° C. 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. IR spectrum (KBr disk) showed absorptions at 1785 and 1710 cm -1. Mass spectrum showed an eye-catching ion at m / e = 406.

Example N 6-chloro-6-bromopenicillanic acid. 6-Chloro-6-bromopenicillanic acid was prepared from 6-aminopenicillanic acid via diazotization followed by reaction with bromine chloride in the manner set forth in Example M.

Example O Pivaloyloxymethyl 6,6-dibromopenicillanate.

To a stirred solution of 3.59 grams of 6,6-dibromopenicillanic acid in 20 ml of N, N-dimethylformamide was added 1.30 grams of diisopropylethylamine and then 1.50 grams of chloromethyl pivalate at about 0 ° C. The reaction mixture was stirred at about 0 ° C for 30 minutes and then at room temperature for 24 hours. The reaction mixture was then diluted with ethyl acetate and water and the pH of the aqueous phase was adjusted to 7.5.

The ethyl acetate phase was separated and washed three times with water and then once with a saturated sodium chloride solution. The ethyl acetate solution was then dried using anhydrous sodium sulfate and evaporated in vacuo to give the title compound.

Example P By reacting the appropriate 6,6-dihalo-penicillanic acid with 3-phthalidyl chloride, 4-crotonolactonyl chloride, V-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 in the manner set forth in Example 0, the following compounds were prepared: N 3-Phthalidylene-6,6-dibranyl , 4-Chronolactonyl-6-chloro-6-iodopenicillanate, γ-butyrolactonyl-6-bromo-6-iodopenicillanate, acetoxymethyl-6-chloro-6-bromopenicillanate, pivaloyloxymethyl-6-chloro-6-iodopenicillanimeth, hexanoylox6 -dibromopenicillanate, 1- (acetoxy) ethyl-6,6-dibromopenicillanate, 1- (isobutyryloxy) ethyl 6-bromo-6-iodopenicil-14: lanate, 1-methyl-1- (acetoxy) ethyl-6,6 -dibromopenicillanate, 1-methyl-1- (hexanoyloxy) ethyl 6-chloro-6-bromopenicillanate, methoxycarbonyloxymethyl-6,6-dibromopenicillanate, propoxycarbonyloxymethyl-6-chloro-6-iodopenicillanate, 1- (ethoxycarbonyloxy) et yl 6,6-dibromopenicillanate, 1- (butoxycarbonyloxy) ethyl 6-bromo-6-iodopenicillanate, 1-methyl-1- (methoxycarbonyloxy) ethyl 6,6-dibromopenicillanate and 1-methyl, respectively -1- (isopropoxycarbonyloxy) ethyl 6,6-dibromopenicillanate. 6-α-Chloropenicillanic acid and 6-α-bromopenicillanic acid were prepared by diazotizing 6-aminopenicillanic acid in the presence of hydrochloric acid and hydrobromic acid, respectively (Journal of Organic Chemistry, 27, 2668, E1962]). 6-u-42-449 105-iodine penicillanic acid was prepared by diazotizing 6-aminopenicillanic acid in the presence of iodine followed by hydrogenolysis (Clayton, Journal of the Chemical Society, ECJ, 2123 C1969J). 6-6-Chloropenicillanic acid, 6-β-bromopenicillanic acid and 6-iodopenicillanic acid were prepared by reduction of 6-chloro-6-iodopenicillanic acid, 6,6-dibromopenicillanic acid and 6,6-diiodopenicillanic acid, respectively, with tri- -n- butyltin hydride. 6-Chloro-6-iodopenicillanic acid was prepared by diazotizing 6-aminopenicillanic acid in the presence of iodine chloride; 6,6-Dibromopenicillanic acid was prepared according to Clayton, Journal of the Chemical Society (London) (C) 2123 (1969): and 6,6-diiodopenicillanic acid was prepared by diazotization of 6-aminopenicillanic acid in the presence of iodine .

Claims (7)

10 15 20 25 30 35 M 449 1Ü3 PATENTKRAV An improved process for the preparation of compounds of the formula such as E PCH3 (I) '| CH3 Å çcoonl or a pharmaceutically acceptable base salt thereof, in which the formula R1 is hydrogen or an in vivo readily hydrolysable ester-forming group, characterized in that (a) contacting a compound of the group consisting of a compound of the formula "'HY" _ x, / - ï Sega (II) / 7 "" "NQ, I °, cooR or a base salt thereof alkali metal permanganates, alkaline earth metal permanganates and organic peroxycarboxylic acids, to give a compound of formula qo Y É 9 / en xj - ° J H3 (III) .a- N "" '”I, o' 1 çooR or a base salt thereof, X and Y are each hydrogen, chlorine, bromine or iodine, with the proviso that, if X and Y both have the same meaning, they must be bromine and the product from step (a) by catalytic hydrogenation in an inert solvent. A method according to claim 1, that step (a) is carried out using an alkali metal permanganate thereof. 3. A method according to claim 2, characterized in that step (a) is performed using potassium permanganate. characterized in that step (b) is carried out at a pressure of 1-100 kg / cm 2 and in the presence of 0.01-2.5% by weight of a hydrogenation A process according to any one of claims 1-3, n a t catalyst at a temperature in the range 0-GOOC and at a pH in the range 4-9. 5. A method according to any one of claims 2-4, characterized in that X is bromine and Y is hydrogen. 6. A method according to any one of claims 1-4, characterized in that X and Y are both bromine. 7. A process according to any one of claims 1-3, characterized in that R1 is hydrogen.