HU186304B - Process for producing pename-sulfoxide-derivatives - Google Patents

Abstract

The invention relates to a process for the preparation of penicillanic acid 1,1-dioxide and its esters for use as medicaments. The aim of the invention is an improved process with which the product yield is increased. According to the invention, compounds of formula I, or their pharmaceutically acceptable base salts, wherein R & exp1! Is hydrogen or an ester-forming in vivo readily hydrolyzable group prepared by reacting a compound of formula II or its base salts wherein R is hydrogen, an ester-forming, in vivo readily hydrolyzable group or a conventional penicillin carboxy-protecting group, and X u. Each Y is hydrogen, chlorine, bromine or iodine, with the proviso that when both X and Y are the same, both must be bromine, dehalogenated and, if necessary, the conventional penicillin carboxy protecting group is cleaved off.

Description

The present invention relates to a process for the preparation of penam sulfone.

More particularly, the present invention relates to a novel process for the preparation of intermediates as intermediates in the final product.

The novel process involves oxidizing the 6-halo or -6,6-dihalo derivative of penicillanic acid to the corresponding 1,1-dioxide and dehalogenating the resulting product. The novel compounds useful as intermediates are the 6-halo or 6,6-dihalo derivatives of penicillanic acid.

Penicillanic acid 1,1-dioxide and its readily hydrolysable esters thereof are useful as beta-lactamase inhibitors and as agents that enhance the efficacy of certain antibiotic beta-lactams when used in the treatment of bacterial infections in mammals, in particular people. So far, penicillanic acid 1,1-dioxide and its readily hydrolyzable esters thereof have been prepared from 6-bromopenicillanic acid or its readily hydrolyzable ester thereof by removal of bromine and the resulting penicillanic acid or its readily hydrolyzable ester 1,1-dioxide oxidize. Although the process of the invention is based on 6-halo penicillanic acid and involves the dehydrogenation and oxidation steps, it has surprisingly been found that, if the oxidation step is carried out before the dehalogenation step, the product is obtained in better yield.

Belgian Patent No. 867,859 and German Patent Publication No. 2,824,535 detail the preparation of penicillanic acid 1,1-dioxide and its readily hydrolyzable esters.

6-halo-penicillanic acids are described in Cignarella et al., Journal of Organic Chemistry, 27, 2668 (1962) and U.S. Patent 3,206,469, and the hydrogenolysis of 6-halo-penicillanic acids to penicillanic acid is described in British Patent 1,072,108. .

Harrison et al., Journal of the Chemical Society (London), Perkin I, 1772 (1967), disclose that

(a) oxidation of 6,6-dibromo-penicillanic acid to 3-chloroperbenzoic acid to form a mixture of the corresponding alpha and beta-sulfoxides;

b) oxidizing methyl 6,6-dibromo-penicillanate with 3-chloroperbenzoic acid to form methyl 6,6-dibromo-penicillanate 1,1-dioxide;

c) oxidizing methyl 6-alpha-chloropenylanilate with 3-chloroperbenzoic acid to give a mixture of the corresponding alpha and beta sulfoxides; and

d) Methyl 6-bromo-penicillanate is oxidized with 3-chloroperbenzoic acid to form a mixture of the corresponding alpha and beta sulfoxides.

Clayton, Journal of the Chemical Society (London), (C), 2123, (1969) describes:

a) preparing 6,6-dibromo and 6,6-diiodopenicillanic acid;

b) oxidizing 6,6-dibromo-penicillanic acid with sodium periodate to form a mixture of the corresponding sulfoxides;

c) hydrogenolysis of methyl 6,6-dibromo-penicillanate to form methyl 6-alpha-bromo-penicillanate;

d) hydrogenolysis of 6,6-dibromo-penicillanate and its methyl ester to form penicillanic acid and its methyl ester; and

e) hydrogenolysis of a mixture of methyl 6,6-diiodopenicillanate and methyl 6-alpha-iodo-penicillanate to give pure methyl 6-alpha-iodo-penicillanate.

The present invention therefore relates to a process for the preparation of penamsulfone of formula (I) or salts thereof with pharmaceutically acceptable bases.

which involves dehalogenating and oxidizing a 6-halo-penicillanic acid.

\ z process is characterized by

a) reacting a compound of formula II or a basic salt thereof with an alkali metal permanganate, an alkaline earth metal permanganate or an organic peroxycarboxylic acid ¹ and οJ the resulting compound of formula (IH) or a basic salt thereof, wherein X and Y are each hydrogen; it may be bromine or iodine, with the proviso that when X and Y are the same, both must be bromine, dehalogenated.

Preferably, step b) is carried out by reacting the product of step ej with an inert solvent at a pressure of about 1 to 100 kg / cm ² , at a temperature of 0 ° C to about 60 ° C, at a pH of 4 to 9, and in the presence of a catalyst. Contact with oxygen. The catalyst is usually present in an amount of from about 0.01% to about 2.5% by weight, preferably from about 0.1% to about 1.0% by weight, based on the weight of the compound of formula (III).

The X and Y substituents preferably represent bromine and the preferred reagents for performing step a) are potassium permanganate and 3-chloroperbenzoic acid.

In the case where both X and Y are chlorine, the compound of formula II is difficult to prepare. In the case where X and Y are each iodine, step a) of the process of the invention proceeds very slowly.

In the process of the invention, in the intermediates of formula (III), X and Y are as defined above and R ¹ is hydrogen or a carboxyl protecting group. A preferred intermediate is 6,6-dibromopenicillanic acid 1,1-dioxide, which is a compound of formula III wherein X and Y are both bromine and R ¹ is as defined above.

The compound of formula (I) and the intermediates are referred to herein as derivatives of penicillanic acid of formula (IV). The dashed line indicating the attachment of a substituent to the bicyclic ring in the penicillanic acid derivatives indicates that the substituent; below the plane of the ring. Such a substituent is called an alpha configuration. In contrast, a continuous line indicating the attachment of a substituent to the bicyclic ring means that the substituent is located above the plane of the ring. This configuration is called the beta configuration. Thus, X is in the alpha configuration and Y is in the beta configuration in formula II.

Step (a) of the process of the present invention involves the oxidation of a sulfide group in a compound of formula (II) to a sulfone group to form a compound of general formula (III). A wide variety of known oxidizing agents can be used in this process to oxidize sulfides to sulfones.

-2186304

In practice, alkali metal permanganates such as sodium and potassium permanganate may conveniently be used for this purpose; alkaline earth metal permanganates, such as calcium and barium permanganates, and organic peroxycarboxylic acids, such as peracetic acid and 3-chloroperbenzoic acid.

In the case where the compound of formula II, where X, Y and R ¹ are as defined above, is oxidized with a metal permanganate to the corresponding compound of formula III, the reaction is usually carried out by reacting the compound of formula II. The compound is treated with about 0.5 to about 10 molar equivalents, preferably about 1 to about 4 molar equivalents, of permanganate in a solvent inert reaction system. A solvent system which is inert to the reaction is a system of solvents which does not react with either the starting materials or the product. Preferably such a solvent is water. If desired, an auxiliary solvent may be used which is miscible with water but does not react with the permanganate. An example of such a solvent is tetrahydrofuran. The reaction is carried out at a temperature in the range of -30 ° C to about 50 ° C, preferably at about -10 ° C to 10 ° C. The reaction is substantially complete at about 0 ° C over a short period of time, for example 1 hour. The reaction is carried out under neutral, basic or acidic conditions, preferably in a pH range of about 4-9, in particular 6-8. In any event, conditions must be selected which avoid the degradation of the beta-lactam ring system of the compounds of formula (II) or (III). It is often preferable to adjust the pH of the reaction medium to or about the neutral pH range. The product is recovered by conventional methods. A certain amount of excess permanganate is usually decomposed when sodium bisulfite is used and if the product is not in solution it is isolated by filtration. It is separated from the manganese dioxide by extraction with an organic solvent and evaporation of the solvent. Alternatively, if the product does not precipitate out of solution at the end of the reaction, it can be recovered by conventional solvent extraction.

In the case where the compound of formula (II), wherein X, Y and R ¹ are as defined above, is oxidized with a peroxycarboxylic acid to the corresponding compound of formula (III), the reaction is usually carried out by reacting the compound of formula (II). 1 to 6 molar equivalents, preferably about 1 molar equivalent

2.2 molar equivalents treated with an oxidizing agent in a reaction inert solvent. Such solvents include chlorinated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane. The reaction is usually carried out at a temperature in the range of -30 ° C to 50 ° C, preferably between about 15 ° C and 30 ° C. The reaction is carried out at about 25 ° C, usually for about 2-16 hours. The product is usually isolated by evaporation of the solvent in vacuo. The reaction product may be purified in a manner well known in the art. Alternatively, the product can be used without further purification in step b).

Step b) of the process of the invention is a dehalogenation reaction. Conventionally, this conversion reaction is carried out by stirring or shaking a solution of the compound of formula (III) in a hydrogen gas atmosphere or in a mixture of an inert gas such as nitrogen or argon as a diluent in the presence of a hydrogenation catalyst. Suitable solvents for the hydrogenolysis are solvents which essentially dissolve the starting compound of formula (III) but do not themselves hydrogenate or are not hydrogenolysed. Examples of such solvents include ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-methoxyethane; low molecular weight esters such as ethyl acetate and butyl acetate, tertiary amides such as N, N-dimethylformamide, Ν, Ν-dimethylacetamide and N-methylpyrrolidone; water and mixtures thereof. In addition, the reaction mixture is usually buffered to a pH of about 4-9, preferably about 6-8. Borate and phosphate buffers are commonly used. Hydrogen gas is introduced into the reaction mixture and the reaction is carried out in four sealed containers. The reactor contains the compound of formula (III), the catalyst and hydrogen. The strain in the reaction vessel may vary from 1 kg / cm ² to 100 kg / cm ² . The preferred pressure range when the atmosphere inside the reaction vessel is substantially pure hydrogen is between 2 kg / cm ² and 5 kg / cm ² . Hydrogenolysis is generally carried out at about 0 ° C to 60 ° C, preferably at about 25 ° C to 50 ° C. Hydrogenolysis is generally carried out within a few hours, for example about 2 to 20 hours, if preferred temperatures and pressures are employed. The catalyst used in the hydrogenolysis reaction for such conversion may be a catalyst of the type known in the art, such as precious metals such as nickel, palladium, platinum and radium. The catalyst is usually present in an amount of from about 0.01% to about 2.5% by weight, preferably from about 0.1% to about 1.0% by weight, based on the weight of the compound of formula (III). It is often advantageous for the catalyst to be applied to an inert support, and it is particularly advantageous to suspend palladium on an inert support such as carbon.

Other methods of reductive removal of the halogen from the compound of formula III in step b) may also be used. The X and Y substituents can be removed, for example, by a soluble metal reduction system such as zinc powder in acetic acid, formic acid or phosphate buffer according to well known methods. Alternatively, step b) is carried out using a tin hydride such as a trialkyl anhydride such as tri-n-butyl anhydride.

Thus, in one embodiment, the 6-halo or 6,6-dihalo-penicillanic acid derivative containing the free carboxyl group in the 3-position is oxidized and subsequently dehalogenated. In another embodiment of the process of the present invention, it is also possible to initiate the reaction by blocking the carboxyl group 3 in either step a) or b) with a conventional penicillin carboxyl protecting group. The protecting group may be removed after either step a) or b) by liberating the carboxyl group. Many conventional protecting groups known in penicillin chemistry can be used to protect the 3-carboxyl group. The main requirements are:

-3186304 to be coupled to and removed from compounds of formula II or III under conditions such that the beta-lactam ring system remains substantially intact. For each of steps a) and b'j, for example, tetrahydropyranyl, trialkylsilyl, benzyl, substituted benzyl (e.g. 4-nitrobenzyl), benzhydryl, 2,2,2-trichloroethyl, tert-butyl and phenacyl groups. Although not all protecting groups can be used in all situations, one skilled in the art can easily select the appropriate group. See, for example, U.S. Patent Nos. 3,632,850 and 3,197,466 and British Patent 1,041,985 and Woodward et al., Journal of the American Chemical Society, 88, 852 (1966); Chauvette, Journal of Organic Chemistry, 36, 1259 (1917); Sheehan et al., Journal of Organic Chemistry, 29, 2006 (1964); and Cephalosporin and Penicillins, Chemistry and Biology, Η. E. Fiynn Publisher, Academic Press, Inc., 1972. The penicillin carboxyl group may be deprotected in the conventional manner, but consideration should be given to the lability of the beta-lactam ring system.

6-alpha-chlorpenicillanic acid and 6-alpha-bromopenicillanic acid are prepared by diazotizing 6-aminopenicillanic acid in the presence of hydrogen chloride and hydrogen bromide (Journal of Organic Chemistry, 27, 2668 (1962)). 6-Alpha-iodopenicillanic acid is prepared by diazotizing 6-aminopenicillanic acid in the presence of iodine and then hydrogenating the diazotized product (Clayton, 1969, Journal of the Chemical Society (C) 2123). 6-Beta-chloro-penicillanic acid, 6-beta-bromo-penicillanic acid and 6-iodo-penicillanic acid are prepared by reducting 6-chloro-6-iodo-penicillanic acid, 6,6-dibromo-penicillanic acid and 6,6-diiodo-penicillanic acid with tri-n-butylone hydrochloride. 6-Chloro-6-iodo-penicillanic acid is prepared by diazotizing 6-aminopenicillanoic acid in the presence of iodine chloride. 6,6-dibromopenicillanic acid was prepared according to Clayton's method as described in the Journal of the Chemical Society (London) (C) 2123 (1969). 6,6-Diiodopenicillanic acid is prepared by diazotizing 6-aminopenicillanic acid in the presence of iodine.

Compounds of formula (I), (II) and (III) wherein R ^{1 is} hydrogen are acidic and form salts with basic agents. These salts may be prepared by conventional techniques such that the acidic and basic components are contacted, usually in stoichiometric proportions, in aqueous, non-aqueous or partially aqueous media. These salts are then isolated by filtration, precipitated with a solvent which does not dissolve the product and subsequently filtered, the solvent evaporated or, in the case of aqueous solutions, lyophilized. Basic salts suitable for salt formation may be of either the organic or inorganic type, such as ammonium hydroxide, organic amines, alkali metal hydroxides, carbonates, bicarbonates, hydrides and alkoxides, as well as alkaline earth metal hydroxides, carbonates, hydrides and alkoxides. Representative such bases include 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-5-ene; hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and barium hydroxide; alkoxides such as sodium oxide and potassium ethoxide; hydrides such as calcium hydride and sodium hydride; carbonates such as potassium carbonate and sodium carbonate; bicarbonates such as triumihydrocarbonate and potassium bicarbonate; and alkali metal salts of long chain fatty acids such as sodium 2-ethylhexanoate. Preferred salts of the compound of formula (I) are sodium, potassium and triethylamine salts.

The compound of formula (és) and its salts are active as active agents of agents that act against bacteria both in vitro and in vivo. The minimum inhibitory concentration (MIC = inhibitory concentration) of penicillanic acid 1,1-dioxide active against certain microorganisms is the lowest. It is given in Table I.

Table I

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

Micro-organism MIC (mcg / ml) Staphylococcus aureus 100 Streptococcus faecalis 200 Streptococcus pyrogenes 100 Escherichia coli 50 Pseudomonas aeruginosa 200 Kletsiella pneumoniae 50 Proteus mirabilis 100 Proteus morgani 100 Salmonella typhimurium 50 Pasteurella multocida 50 Serratia marcescens 100 Self er obacter aerogenes 25 Enlerobacter clocae 100 Cit obacter freundii 50 Providence 100 Staphylococcus epidermis 200 Pseudomonas putida 200 Hemophilus influenza 50 N <isseria gonorrhoeae 0.312

Due to its in vitro antimicrobial activity and the activity of its salts, the compound of formula (I) is useful as an active ingredient in industrial antimicrobial agents such as water treatment, sludge treatment, paint and wood preservation, and topical disinfection. For topical application, the compound is often admixed with suitable non-toxic vehicles such as vegetable or mineral oils or emollient creams. Similarly, the compound may be dissolved or dispersed in liquid diluents or brain solvents. Such diluents or solvents include water, alkanols, glycols or mixtures thereof. In most cases it is appropriate if it is

The active ingredient of formula I is used in a range of about 0.1 to about 10% w / w of the total composition.

The in vivo activity of the compound of formula (I) and its salts makes it useful for the treatment of bacterial infections in mammals both by oral and pa

-4186304 for rental administration. This compound, in the form of pharmaceutical compositions, is well suited for the treatment of infections caused by susceptible bacteria in humans, such as infections caused by strains of Neisseria gonorrhoeae.

For therapeutic use, the compound of formula (I) or salts thereof may be administered to a mammal, particularly a human, in the form of a pharmaceutical composition. These pharmaceutical compositions contain, in addition to the active ingredient, pharmaceutically acceptable carriers or diluents. These compositions may be administered orally or parenterally, for example, intramuscularly, subcutaneously or intraperitoneally. The vehicle or diluent is selected according to the route of administration. For oral administration, the compound of formula (I) is prepared in the form of tablets, capsules, troches, pills, powders, syrups, elixirs, aqueous solutions and suspensions, and the like according to standard pharmaceutical techniques. The ratio of active ingredient to vehicle will depend on the chemical nature, solubility and stability of the active ingredient, and the route of administration. A pharmaceutical composition comprising as active ingredient a compound of formula (I) having an antibacterial property contains from about 20% to about 95% of the active ingredient. In the case of tablets for oral use, the carriers are conventionally used in the form of lactose, sodium citrate and salts of phosphoric acid. Various disintegrants such as starch and lubricants such as magnesium stearate, sodium lauryl sulfate and talc are also included in the tablets. Commonly used diluents for oral administration in capsule form are lactose and high molecular weight polyethylene glycols. When aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring agents may be added. For parenteral administration, which includes intramuscular, intraperitoneal, subcutaneous and intravenous administration, sterile solutions of the active compounds are customarily prepared and the pH of the solutions adjusted and buffered accordingly. For intravenous use, the total concentration of solutes is controlled to produce an isotonic composition.

The amount of active ingredient of formula (I) that can be administered to each patient is readily determined by the attending physician. This amount will vary with the age, weight and response of the individual and the severity of the symptoms and the nature and severity of the disease. The pharmaceutical compositions are administered orally at dosages in the range of about 10 mg to about 200 mg per kilogram of body weight per day. The parenteral dosage is about 10 to 400 mg / kg body weight / day. The amounts given are for information only and may be administered if necessary or desired outside these limits.

The compound of formula (I) or salts thereof enhances the in vivo antibacterial activity of the antibiotic beta-lactam. These substances reduce the amount of antibiotic active ingredient needed to protect mice against the lethal inoculum of certain beta-lactamases produced by bacteria. This ability makes this compound suitable for co-administration with antibiotic beta-lactam in mammals, especially humans, for the treatment of bacterial infections. In the treatment of a bacterial infection, the compound of formula (I) is combined with the antibiotic beta-lactam and the two agents are administered simultaneously. Alternatively, the compound of formula (I) may be administered as a separate agent during treatment with the antibiotic beta-lactam. In some aspects, it is preferred to administer the compound of formula (I) as a pre-dose followed by treatment with the antibiotic beta-lactam.

When penicillanic acid 1,1-dioxide or a salt thereof is used to increase the activity of the antibiotic beta-lactam, it is preferably administered in the form of pharmaceutical preparations prepared with standard pharmaceutical excipients or diluents. The methods described above for the preparation of formulations containing only penicillanic acid 1,1-dioxide, a salt thereof, as the sole antibacterial agent, may also be used for the preparation of formulations which additionally contain antibiotic beta-lactam. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, an antibiotic beta-lactam and penicillanic acid 1,1-dioxide, normally contains from about 5% to about 80% of a pharmaceutically acceptable active ingredient.

When penicillanic acid 1,1-dioxide is used in combination with antibiotic beta-lactam, the sulfone can be administered orally or parenterally, for example, intramuscularly, subcutaneously or intraperitoneally. Although it is ultimately up to the attending physician to determine the amount to be administered to the patient, the ratio of penicillanic acid to 1,1-dioxide, a salt thereof, and antibiotic-beta-lactam in the dosages to be administered is about 1: 3 to 3: 1. In addition, when penicillanic acid 1,1-dioxide or a salt thereof is used in combination with an antibiotic beta-lactam, the daily oral dose for each component will normally be about 10-200 mg / kg body weight / day and for each component, under conditions of 10-400 mg / kg body weight / day. Of course, these amounts are only approximate and other amounts may be added if necessary.

The following are some typical antibiotic beta-lactams that can be administered to the patient along with penicillanic acid ΐ, Ι-dioxide:

6- (2-phenylacetamido) penicillanic acid,

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

6- (2-Carboxy-2-phenylacetamido) penicillanic acid, and a

7- (2- [1-Tetrazolyl] acetamido) -3- (2- [5-methyl-1,3,4-thiadiazolyl] thiomethyl) -3-deacetoxymethyl cephalosporanic acid. The following are some typical microorganisms against which the activity of the aforementioned anbiotic beta-lactams is enhanced by the compound of formula (I):

Staphylococcus aureus,

Haemophilus influenza,

Klebsiella pneumoniae and

Bacteroides fragilis.

It is known in the art that certain beta-lactam compounds are active at both oral and parenteral administration, while others are effective only at parenteral administration. When penicillanic acid 1,1-dioxide or a salt thereof is used concomitantly (for example, as already mentioned) with an antibiotic-acting beta-lactam which acts only by parenteral administration, a combination preparation suitable for parenteral administration must be prepared. Alternatively, when penicillanic acid 1,1-dioxide is used concomitantly with a beta-lactam antibiotic (as mentioned above) that acts orally or parenterally, a combination composition that can be administered orally or parenterally should be prepared. In addition, it is also possible to administer penicillanic acid 1,1-dioxide or a salt thereof orally and antibiotic beta-lactam parenterally, and it is also possible to administer penicillanic acid 1,1-dioxide or a salt thereof parenterally, while the antibiotic beta-lactam is administered orally.

Detailed information on the use and synthesis of the compounds of the formula I can be found in German Patent Publication No. 2 824 535.

The following examples and methods of preparation are for the purpose of better illustrating the invention only and are not limiting. Infrared (IR) spectra were measured in potassium bromide tablets (KBr tablets), and the diagnostic absorption bands in wavelength (cm ^-1 ). Nuclear Magnetic Resonance Spectra (NMR) spectra were measured at 60 MHz in deuterochloroform (CDCl ₃ ), in deuterium acetone (CD ₃ COCD ₃ ), in deuterium dimethylsulfoxide (DMSO-d ₆ ) or in deuterium oxide (D ₂ O) and reported in ppm. (relative to tetramethylsilane or sodium 2,2-dimethyl-2-silapentane-5-sulfonate). The following abbreviations are used for vertex shapes: s (singlet); d (doublet); t (triplet); q (quartet); m (multiplet).

Example 1

6-alpha-bromo-penicillanic acid 1,1-dioxide

To a mixture of 560 ml of water, 300 ml of dichloromethane and 56.0 g of 6-alpha-bromo-penicillanic acid is added 4N sodium hydroxide solution with stirring until the pH of the mixture reaches a constant value of 7.2. This requires 55 ml of sodium hydroxide solution. The mixture was stirred at pH 7.2 for 10 minutes and then filtered. The layers were separated and the organic phase was discarded. The aqueous phase is then poured rapidly with stirring into an oxidizing mixture, which is prepared as follows.

In a 3 liter vessel mix 63.2 g of potassium permanganate, 1000 ml of water and 48.0 g of acetic acid. The mixture was stirred for 15 minutes at 20 ° C and then cooled to 0 ° C.

After the 6-alpha-bromo-penicillanic acid solution was added to the oxidation mixture, a cooling bath of -15 ° C was created around the reaction mixture. The internal temperature rises to 15 ° C and then decreases to 5 ° C in 20 minutes. At this time, 30.0 g of sodium metahydrogensulphite were added with stirring at 10 ° C for 10 minutes. After an additional 15 minutes, the mixture was filtered and the filtrate was brought to pH 1.2 by addition of 170 ml of 6N hydrochloric acid. The aqueous phase is extracted first with chloroform and then with ethyl acetate. Both the chloroform and ethyl acetate extracts were dried over anhydrous magnesium sulfate and then concentrated in vacuo. The chloroform solution provided 10.0 g (16% yield) of the title compound. The ethyl acetate solution gave 57 g of an oil which was triturated under hexane. A white precipitate formed which was collected by filtration to give 41.5 g (66% yield) of the title compound, m.p. 134 DEG C. (dec.).

Analysis for C ₈ H ₁₀ Brno ₅ S Calcd: C, 30.78; H, 3.23; Br, 25.60; N, 4.49;

S 10.27%

Found: C, 31.05; H, 3.24; Br, 25.54; N, 4.66;

S 10.21%

Example 2

6-alpha-chlorpenicillanic acid and 6-alpha-iodo-penicillanic acid are oxidized with potassium permanganate as described in Example 1 to give 6-alpha-chloro-penicillanic acid 1,1-dioxide and 6-alpha-iodo-penicillanic acid 1,1-dioxide.

Example 3

6-beta-chloropenicillanic acid 1,1-dioxide

A cidating solution is prepared from 185 mg of potassium permanganate, 0.063 ml of 85% phosphoric acid and 5 ml of water. This oxidizing solution is added dropwise to a solution of 0-5-5 Con of 150 mg of sodium 6-beta-chloropenicillanate in 5 ml of water. The addition is continued until the purple color of the potassium permanganate is maintained. This requires approximately half of the oxidizing solution. At this point, the color of the potassium permanganate was removed by addition of solid sodium bisulfite and the reaction mixture was filtered. Ethyl acetate was then 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, and the combined ethyl acetate layers were washed with water, dried and evaporated in vacuo to give 118 mg of the title compound. The NMR spectrum (CD ₃ COCD ₃ in) 5.82 (d, IH), 5.24 (d, IH), 4.53 (s. IH), 1.62 (s, 3H) and 1.50 (s, 3H) shows absorption at ppm.

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

Example 4

6-Byt-penicillanic acid 1,1-dioxide

To a solution of 25 mg of sodium 6-beta-bromopenicillanate in 5 ml of water at 0-5 ° C is added a solution of 140 mg of potassium permanganate, 0.11 ml of 85% phosphoric acid and 5 ml of water. The pH is maintained between 6.0 and 6.4 until the addition is complete. The reaction mixture

Stir at pH 6.3 for 15 minutes and then lay the ethyl acetate in a purple solution. The pH was adjusted to 1.7 and

-613

185 304

330 mg of sodium hydrogen sulfate are added to the solution. After 5 minutes, the separated layers were separated and the aqueous layer was further extracted with ethyl acetate. The combined ethyl acetate solutions were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. This gave 216 mg of a compound of cfm as a white crystalline product.

Nuclear Magnetic Resonance Spectrum (in D ₂ O) 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) at ppm.

Example 5

6-beta-iodo-penicillanic acid 1,1-dioxide

6-Beta-iodo-penicillanic acid is oxidized with potassium permanganate as described in Example 4 to give 6-beta-iodo-penicillanic acid 1,1-dioxide.

Example 6

Pivaloyloxymethyl 6-alpha-bromo-penicillanate-1,1-dioxide

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

Example 7

The procedure described in Example 6 was followed except that pivaloyloxymethyl-6-beta-bromo-penicillanate was replaced by

3-phthalidyl-6-alpha-chlorpenicillanate,

4-crotonolactonyl-6-beta-chlorpenicillanate, gamma-butyrolacton-4-yl-6-alpha-bromo-penicillanate, acetoxymethyl-6-beta-bromo-penicillanate, pivaloyloxymethyl-6-beta-bromo-penicillanate, hexanoyloxymethyl, (acetoxy) ethyl 6-beta-iodo-penicillanate, 1- (isobutyryloxy) ethyl-6-alpha-chlorpenicillanate, 1-methyl-1- (acetoxy) ethyl-6-beta-chlorpenicillanate,

methyl-1- (hexanoyloxy) ethyl-6-alpha-bromo-penicillanate, methoxycarbonyloxymethyl-6-alpha-bromo-penicillanate, propoxycarbonyloxymethyl-6-beta-bromo-penicillanate, 1- (ethoxycarbonyloxy) ethyl-6-alpha-butyl, ethyl 6-alpha-jódpenicillanátot,

methyl-1- (methoxycarbonyloxy) ethyl-6-beta-iodopenicillanate and 1-methyl-1- (isopropoxycarbonyloxy) ethyl-6-alpha-chlorpenicillanate.

This way

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

4-crotonolactonyl-6-beta-chloropenicillanate-1,1-dioxide, gamma-butyrolacton-4-yl-6-alpha-bromo-penicillanate-1,1-dioxide, acetoxymethyl-6-beta-bromo-penicillanate-1,1-dioxide, pivaloyloxymethyl 6-beta-bromo-penicillanate-1,1-dioxide, hexanoyloxymethyl-6-alpha-iodo-penicillanate-1,1-dioxide,

- (acetoxy) ethyl 6-beta-iodo-penicillanate-1,1-dioxide, 1- (isobutyryloxy) ethyl-6-alpha-chlorpenicillanate-1,1-dioxide, 1-methyl-1- (acetoxy) ethyl-6- beta-chloropenicillanate 1,1-dioxide,

-methyl 1- (hexanoyloxy) ethyl 6-alpha-bromo-penicillanate-1,1-dioxide, methoxycarbonyloxymethyl-6-alpha-bromo-penicillanate-1,1-dioxide, propoxycarbonyloxymethyl-6-beta-bromo-penicillanate-1,1-dioxide, l- (ethoxycarbonyloxy) ethyl-O-alpha-bromopenicillanate l, l-dioxide,

- (butoxycarbonyloxy) ethyl 6-alpha-iodo-penicillanate-1,1-dioxide, 1-methyl-1- (methoxycarbonyloxy) ethyl-6-beta-iodo-penicillanate-1,1-dioxide, and

Methyl 1- (isopropoxycarbonyloxy) ethyl 6-alpha-chlorpenicillanate-1,1-dioxide is obtained.

Example 8

Penicillanic acid 1,1-dioxide

To 100 ml of water was added 9.4 g of 6-alpha-bromo-penicillanic acid 1,1-dioxide at 22 ° C, followed by the addition of 4N sodium hydroxide solution to achieve a constant pH of 7.3. To the resulting solution was added 2.25 g of 5% palladium on carbon, followed by dipotassium phosphate trihydrate. The mixture was then shaken under a hydrogen atmosphere at 3.5-1.8 kg / cm ² , and after removal of hydrogen uptake, the resulting solid was collected by filtration and the aqueous solution was layered with 100 mL of ethyl acetate. The pH is slowly lowered from 5.0 to 1.5 by the addition of 6N hydrochloric acid. The layers were separated and the aqueous layer was extracted with additional ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was triturated under ether and the resulting solid collected by filtration. 4.5 g (65%) of the title compound are obtained.

Analysis for C ₈ H _n NO ₅ S Calcd: 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%

The sodium salt of the compound is prepared in a manner known per se. IR absorption spectrum in potassium bromide tested wavelengths, 1786 and 1608 ^cm-1 can be digested main absorption maxima.

NMR of the compound in deuterium oxide: 1.48 (s, 3H); 1.62 (s, 3H); 3.35 (1H, J1: 16 Hz); L: 2 Hz; 3.70 (1H, J1: 16 Hz, J ₂ : 4 Hz); 4.25 (s, 1H) and 5Ό3 (1H, Jj 4 Hz, _J2 2 Hz) ppm.

Example 9

Penicillanic acid 1,1-dioxide

In the same manner as in Example 8, 6-yl-chloro-penicillanic acid 1,1-dioxide, 6-d-iodo-penicillanic acid 1,1-dioxide, 6-beta-chloro-penicillanic acid 1,1-dioxide, 6- beta-bromo-penicillanic acid 1,1-dioxide and

-7186304

Hydrogenation of 6-beta-iodo-penicillanic acid 1,1-dioxide gives penicillanic acid 1,1-dioxide.

Example 10

Pi valoyloxymethyl penicillanate 1,1-dioxide

To a solution of 1.0 g of pivaloyloxymethyl 6-alpha-bromo-penicillanate in 10 ml of methanol are added 3 ml of a 1 M sodium bicarbonate solution and 200 mg of 10% palladium on carbon. The reaction mixture was shaken vigorously under a hydrogen atmosphere at a pressure of about 5 kg / cm ² until hydrogen uptake ceased. The mixture was filtered and most of the 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 layers were then separated, the organic layer washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. In this way, the title compound is obtained.

Example 11

When the corresponding 6-halo penicillanic acid ester from Example 7 is hydrogenated as described in Example 10, the following compounds are obtained:

3-phthalidyl penicillanate 1,1-dioxide,

4-Crotonolactonyl penicillanate 1,1-dioxide, gamma-butyrol kton-4-yl 1-penicillanate 1,1-dioxide, acetoxymethyl penicillanate 1,1-dioxide, pivaloyloxymethyl penicillanate 1,1-dioxide , hexanoyloxymethyl penicillanate 1,1-dioxide,

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

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

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

-methyl-1- (hexanol loxijet I-penicillanate-1,1-dioxide, methoxycarbonyloxymethyl penicillanate-1,1-dioxide, propoxycarbonyloxymethyl penicillanate-1,1-dioxide, 1- (ethoxycarbonyloxy) ethyl penicillanate- l, l-dioxide,

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

-methyl-1- (methoxycarbonyloxy) ethyl-penicyl lanate-1,1-dioxide and

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

Example 12

Pivaloyloxymethyl 6-alpha-bromo-penicillanate-1,1-dioxide

An oxidizing solution was prepared by combining 4.26 g of potassium permanganate, 2.65 g of 85% phosphoric acid and 40 ml of water. The mixture is stirred for one hour, then slowly added to a solution of 5.32 g of pivaloyloxymethyl-6-alpha-bromo-penicillanate in 70 ml of acetone and 10 ml of water over 20 minutes at 5 to 10 ^° C. The mixture was stirred for 30 minutes at 5 ° C and 100 mL of ethyl acetate was added and the mixture was stirred for another 30 minutes. A solution of sodium bisulfite (3.12 g) in water (30 ml) was then added over a period of 15 minutes at about 10 ° C. Stirring was continued for another 30 minutes at 5 ° C and then the mixture was filtered. The organic layer was separated and washed with brine. The dried organic layer was evaporated to give 5.4 g of the title product as an oil which slowly crystallized.

Nuclear Magnetic Resonance Spectrum (in CDCl ₃ ) 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 t

Pivaloyl ·) ximethyl penicillanate 1,1-dioxide

A solution of 4.4 g of β-valoyloxymethyl-6-alpha-bromo-penicillanate-1,1-dioxide in 60 ml of tetrahydrofuran is added to a solution of 0.84 g of sodium bicarbonate in 12 ml of water. The solution is shaken under a hydrogen atmosphere in the presence of 2.0 g of 5% palladium on carbon at 3.3 to 3.6 atmospheres. The reaction mixture is filtered and the residue is washed with 100 ml of ethyl acetate and 25 ml of water. The combined filtrate and washings were separated. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. This affords the title compound as an oil. This oil was dissolved in ethyl acetate (20 mL), and hexane (100 mL) was added slowly to the solution and the precipitate was collected by filtration. 2.4 g of product are obtained.

The NMR spectrum (in _DMSO-d6) 5.75 (q, 2H), 5.05 (m, 14H), 4.40 (s, IH), 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-alpha-bromo-penicillanilate 1,1-dioxide

The 2,2,2-trichloroethyl 6-alpha-bromo-penicillanate was oxidized with potassium permanganate substantially in the same manner as in Example 12 to give the title product in 79% yield.

The NMR spectrum (in _CDCl3) 5.30 to 4.70 (m, 4H), 4.60 (s, IH ;, 1.70 (s, 3H) and 1.50 (s, 3H) ppm = shows absorption.

Example 14A

Penicillar acid 1,1-dioxide

To a suspension of 6.5 g of zinc powder in 100 ml of glacial acetic acid / tetrahydrofuran (70: 30) is added 4.0 g of 2,2,2-trilloroethyl-6-alpha-bromopenicillanate 1,1 - 1 g over 5 minutes with stirring. dioxide. The mixture was stirred at ambient temperature for 3 hours and then filtered. The filtrate was concentrated in vacuo to a volume of 10 ml and the solution was stirred with water (50 ml) and ethyl acetate (100 ml). The pH is adjusted to 1.3 and the layers are separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate; and then evaporate to dryness in vacuo. The residue was triturated under ether for 20 minutes to give 553 ng of the title compound as a solid.

-8186104

Nuclear Magnetic Resonance Spectrum (CDCl ₃ / DMSO-d ₆ ) 11.2 (bs, 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-alpha-bromopenicillanate 1,1-dioxide

Benzyl 6-alpha-bromo-penicillanate is oxidized with potassium permanganate essentially as described in Example 12 to give the title compound in 94% yield.

Nuclear Magnetic Resonance Spectrum (in CDCl ₃ ) 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

To a solution of 4.0 g of benzyl 6-alpha-bromopenicinanate 1,1-dioxide in 50 ml of tetrahydrofuran is added 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% aqueous suspension of 5% palladium on carbon and the mixture was shaken under a hydrogen atmosphere at 3.3 to 3.6 atmospheres for 20 minutes. The catalyst is then filtered off and 30 ml of tetrahydrofuran and 3.0 g of a 5% palladium on carbon 50% suspension are added to the filtrate. The resulting mixture was shaken under a hydrogen atmosphere at a pressure of 2.8 to 3.2 atmospheres for 65 minutes. The reaction mixture was 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 layer was removed and fresh ethyl acetate was added to the remaining aqueous phase. Then adjust the pH

It is reduced to 1.5 and the layers are separated. The aqueous phase was further extracted with ethyl acetate, and the combined ethyl acetate solutions were washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. This gave a gum which was triturated under ether to give 31 mg of penicillanic acid 1,1-dioxide as a yellow solid.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ / DMSO-d ₆ ) 9.45 (bs, 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-dibromo-penicillanic acid 1,1-dioxide

To a solution of 6,6-dibromo-penicillanic acid obtained in Preparation K is added 300 ml of water in dichloromethane, followed by dropwise addition of 105 ml of 3N sodium hydroxide solution over 30 minutes. The pH of the mixture was adjusted to 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 solution of 59.25 g of potassium permanganate, 18 ml of concentrated phosphoric acid and 600 ml of water. The addition is carried out for as long as the purple color of the permanganate persists. The addition takes 50 minutes and requires 550 ml of oxidizing solution. Ethyl acetate (500 mL) was added and the pH was reduced to 1.23 by the addition of 105 mL of 6N hydrochloric acid. Subsequently, 250 ml of 1M sodium hydrogen sulfite solution are added over a period of 10 to 15 minutes at about 10 ° C. During the addition of the sodium bisulfite solution, the pH of the mixture was maintained at 1.25-1.35 with 6N hydrochloric acid. The aqueous phase is saturated with brine and the two phases are separated. The aqueous solution was extracted with additional ethyl acetate (2 x 150 mL) and the combined ethyl acetate solutions were washed with brine and dried over anhydrous magnesium sulfate. A solution of 6,6-dibromo-penicillanic acid 1,1-dioxide in ethyl acetate is thus obtained.

The 6,6-dibromo-penicillanic acid 1,1-dioxide was isolated by removing the solvent in vacuo. A sample of material isolated in this way melts at 201 ° C (with decomposition). Nuclear Magnetic Resonance Spectrum (CDCl ₃ / DMSO-d ₆ ) 9.35 (s, 1H), 5.30 (s, 1H), 4.42 (s, 1H), 1.63 (s, 3H) and It shows absorption at 1.50 (s, 3H) ppm.

The IR spectrum (KBr) 3846-2500, 1818, 1754, 1342 and 1250 showed absorptions at 1110 cm ^_1.

Example 18

6-chloro-6-iodo-penicillanic acid 1,1-dioxide

To a solution of 4.9 g of 6-chloro-6-iodo-penicillanic acid in 50 ml of dichloromethane is added 50 ml of water and then the pH is adjusted to 7.2 with 3N sodium hydroxide solution. The layers were separated and the aqueous layer cooled to 5 ° C. To this solution is then added dropwise over a period of 20 minutes a solution of 2.61 g of potassium permanganate, 1.75 ml of concentrated phosphoric acid and 50 ml of water. The pH is maintained at 6, while the temperature is maintained below 10 ° C during the addition. Ethyl acetate (100 mL) was added and the pH was adjusted to 1.5. 50 ml of 10% sodium bisulfite solution are then added, the temperature is maintained below 10 ° C and the pH is maintained at about 1.5 with 6N hydrochloric acid. The pH was lowered to 1.25 and the layers were separated. The aqueous layer was saturated with sodium chloride and extracted with ethyl acetate. The combined organic solutions were washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. 4.2 g of the title compound are obtained, m.p. 143-145 ° C.

The NMR spectrum (in _CDCl3) showed absorptions at 4.86 ppm (s, IH), 4.38 (s, IH), 1.60 (s, 3H) and 1.43 (s, 3H).

The IR spectrum (KBr disc) showed absorptions at 1800, 1740 and 1110 cm ^_1 at 1250-.

Example 19

6-Bromo-6-iodo-penicillanic acid 1,1-dioxide

To a solution of 6-bromo-6-iodo-penicillanic acid (6.0 g) in dichloromethane (50 mL) was added water (50 mL). The pH is adjusted to 7.3 with 3N sodium hydroxide solution and the aqueous layer is removed and the organic layer is extracted with 10 ml of water. The combined aqueous phases were cooled to 5 ° C and a solution of 2.84 g of potassium permanganate, 2 ml of concentrated phosphoric acid and 50 ml of water was added dropwise at 5 to 10 ° C. Adding takes 20 minutes. Ethyl acetate (50 mL) was added and the pH was reduced to 1.5 by the addition of 6N hydrochloric acid. To this biphasic system is added dropwise 50 ml of 10% sodium hydrogen sulfite solution and the pH is maintained at about 1.5 by addition of 6N hydrochloric acid solution. A further 50 mL of ethyl acetate was added and the pH was reduced to 1.23. The layers were separated and the aqueous layer was saturated with sodium chloride. The saturated solution (3 x 50 mL) was extracted with ethyl acetate, the combined ethyl acetate layers were washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo to give 4.2 g of the title compound, m.p. ° C.

Nuclear Magnetic Resonance Spectrum (in CDCl ₃ ) at 4.90 (s, 1H), 4.30 (s, 1H), 1.60 (s, 3H) and 1.42 (s, 3H) in ppm.

The IR spectrum (KBr tablet) shows absorption at 1800, 1740, 1330 and 1250-11010 cm- ¹ .

Example 20

6-Chloro-6-bromo-penicillanic acid 1,1-dioxide

6-Chloro-6-bromo-penicillanic acid is oxidized with potassium permanganate as described in Example 19 to give 6-chloro-6-bromo-penicillanic acid 1,1-dioxide.

Example 21

Penicillanic acid 1,1-dioxide

A solution of 6,6-dibromo-penicillanic acid 1,1-dioxide prepared in Example 17 in ethyl acetate was mixed with 705 ml of saturated sodium bicarbonate solution and 8.88 g of 5% carbonized catalyst. The mixture was shaken under a hydrogen atmosphere at 5 kg / cm ^{2 for} about 1 hour. The catalyst was then filtered off and the aqueous phase of the filtrate was adjusted to pH 1.2 with 6N hydrochloric acid. The aqueous phase is saturated with sodium chloride. The layers were separated and the aqueous layer was extracted with additional ethyl acetate (3 X 200 mL). The combined ethyl acetate solutions were dried over anhydrous magnesium sulfate and concentrated in vacuo. 33.5 g (58% of 6-aminopenicillanic acid) of penicillanic acid 1,1-dioxide are obtained. This product was dissolved in ethyl acetate (600 mL), decolorized with charcoal and the solvent removed by evaporation in vacuo. The product was washed with hexane to give 31.0 g of pure material.

Example 22

6-Chloro-6-iodo-penicillanic acid 1,1-dioxide, 6-bromo-6-iodo-penicillanic acid 1,1-dioxide and 6-chloro-6-bromo-penicillanic acid 1,1-dioxide were hydrogenated as described in Example 21, and in each case, penicillanic acid 1,1-dioxide is obtained.

Example 23

Penicillar acid 1,1-dioxide

To a suspension of 6-chloro-6-iodo-penicillanic acid 1,1-dioxide (786 mg) in benzene (10 ml) was added triethylamine (0.3 ml) followed by trimethylsilyl chloride (0.25 ml) at about 0 ° C. Stirring is continued for 5 minutes at about 0 ° C and then the mixture is heated at reflux for 30 minutes. The reaction mixture was cooled to 25 ° C and the precipitated material was collected by filtration. The filtrate was cooled to about 0 ° C and 1.16 g of tri-n-butylonitrile and a few milligrams of azobisisobutyronitrile were added. The reaction mixture is then stirred and irradiated with ultraviolet light for 1 hour at about 0 ° C and then heated at reflux temperature of the solvent. A further portion (1.1 ml) of 1-n-butylone hydride and a catalytic amount of azobisisobutyronitrile were then added and the irradiation and stirring continued for an additional 1 hour. The reaction mixture was then poured into 50 ml of 5% cold sodium bicarbonate solution and the biphasic system was stirred for 30 minutes. Ethyl acetate (50 mL) was then added and the pH was adjusted to 1.5 with 6N hydrochloric acid. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate solutions were washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was triturated under hexane and then separated by filtration. 0.075 mg of the title compound is obtained in this manner.

Example 24

Penicillanic acid 1,1-dioxide

To a suspension of 0.874 g of 6-bromo-6-iodo-penicillanic acid 1,1-dioxide in 10 ml of benzene at about 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 at the reflux temperature of the solvent for 30 minutes. The reaction mixture was then cooled to room temperature and the solid was collected by filtration. The filtrate was cooled to 5 ° C and 1.05 mL of tri-n-butylone hydride and a catalytic amount of azobisisobutyronitrile were added. The mixture was then irradiated with ultraviolet light for 1 hour at about 5 ° C and then poured into 30 ml of 5% cold sodium bicarbonate solution. The mixture was stirred for 30 minutes and then ethyl acetate (50 mL) was added. The mixture was then acidified to pH 1.5 and the layers were separated. The aqueous layer (2 x 25 mL) was extracted with ethyl acetate, and the combined ethyl acetate layers were washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was dried under high vacuum and then 30 ml of hexane were added. The insoluble material was isolated by filtration to give O, C 35 g of the title compound.

-10186304

Example 25

Pivaloyloxymethyl 6,6-dibrómpenicillanát-l, l-dioxide

To a solution of 4.73 g of pivaloyloxymethyl-6,6-dibromo-penicillanate in 15 ml of dichloromethane is added 3.80 g of 3-chloroperbenzoic acid at 0-5 ° C. The reaction mixture was stirred at 0-5 ° C for 1 hour and then at 24 ° C for 24 hours, then filtered and the filtrate evaporated to dryness in vacuo. The residue was partitioned between ethyl acetate and water. The aqueous phase was adjusted to pH 7.5 and the layers were separated. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound.

Example 26

The 6,6-dihalo-penicillanic acid esters obtained according to Preparation P are oxidized with 3-chloroperbenzoic acid as described in Example 25 to give the following compounds:

3-phthalidyl-6,6-dibromopenicillanate 1,1-dioxide,

4-Crotonolactonyl-6-chloro-6-iodo-penicillanate-1,1-dioxide, Y-butyrolactonyl-6-bromo-6-iodo-penicillanate-1,1-dioxide, acetoxymethyl-6-chloro-6-bromo-penicillanate-1,1 - dioxide, pivaloyloxymethyl 6-chloro-6-iodpenicillanate-1,1-dioxide, hexanol oxymethyl-6,6-dibromo-penicillanate 1,1-dioxide,

- (acetoxy) ethyl 6,6-dibromo-penicillanate-1,1-dioxide, 1- (isobutyryloxy) ethyl-6-bromo-6-iodopenicillanate-1,1-dioxide, 1-methyl-1 '(acetoxy) ethyl- 6,6-dibromo-penicillanilate 1,1-dioxide, 1-methyl-1- (hexanoyloxy) ethyl-6-chloro-6-bromo-penicillanate-1,1-dioxide, propoxycarbonyloxymethyl-6-chloro-6-iodo-penicillanate-1,1 -dioxide,

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

- (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-dibrómpenicillanát-l, l-dioxide.

Example 27

Pivaloyloxymethyl penicillanate 1,1-dioxide

To a solution of 1.0 g of pivaloyloxymethyl-6,6-dibromo-penicillanate-1,1-dioxide in 10 ml of methanol was added 3 ml of 1 molar sodium bicarbonate solution and 200 mg of 10% palladium on carbon. The reaction mixture is shaken vigorously under a hydrogen atmosphere at 5 kg / cm ² until hydrogen uptake ceases. The mixture was then filtered and most of the methanol was evaporated in vacuo. Water and ethyl acetate were added to the residue and the pH of the mixture was adjusted to 8.5. The layers were separated, the organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. This gives pivaloyloxymethyl penicillanate 1,1-dioxide.

Example 28

The 6,6-dihalo-penicillanic acid 1,1-dioxide listed in Example 26 was hydrogenated as described in Example 27 to give the following compounds:

S-f talid 1-penicyl lanate-1,1-dioxide,

4-crotonolactonyl penicillanate 1,1-dioxide, gamma-butyrolacton-4-yl penicillanate 1,1-dioxide, acetoxymethyl penicillanate 1,1-dioxide, pivaloyloxymethyl penicillanate 1,1-dioxide, hexanoyloxymethyl- penicillanate 1,1-dioxide,

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

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

-methyl 1- (hexanoyloxy) ethyl penicillanate 1,1-dioxide, methoxycarbonyloxymethyl penicillanate 1,1-dioxide, propoxycarbonyloxymethyl penicillanate 1,1-dioxide, 1- (ethoxycarbonyloxy) ethyl penicillanate-1, l-dioxide,

- (butoxycarbonyl) ethyl penicillanate 1,1-dioxide, 1-methyl-1- (methoxycarbonyloxy) ethyl penicillanate 1,1-dioxide, and

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

Example 29

Pivaloyloxymethyl 6,6-dibromo-penicillanate 1,1-dioxide

A solution of 3.92 g of 6,6-dibromo-penicillanic acid 1,1-dioxide in 20 ml of N, N-dimethylformamide is cooled to 0 ° C and 1.29 g of diisopropylethylamine are added with stirring followed by 1.51 g of chloromethyl pivalate. The reaction mixture was stirred for 3 hours at 0 ° C and for 16 hours at room temperature. 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 5% cold sodium bicarbonate solution, water, and brine. The ethyl acetate solution was then treated with Darco (activated charcoal), dried over anhydrous magnesium sulfate and concentrated in vacuo to give 2.1 g of a brown oil. This oil was chromatographed on 200 g silica gel eluting with dichloromethane. The fractions containing the desired product were combined and chromatographed again on silica gel to give 0.025 g of the title compound.

Nuclear Magnetic Resonance Spectrum (in CDCl3) 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

To a solution of pivaloyloxymethyl penicillanate-1,1-dioxide mg pivaloyloxymethyl-6,6-dibromo-penicillanate 1,1-dioxide in 5 ml benzene was added 52 ml tri-n-butylone hydride followed by a catalytic amount of azobisisobutyronitrile. The reaction mixture was cooled to about 5 ° C and then irradiated with ultraviolet light for 1 hour. The reaction mixture was poured into 20 ml of 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 stripped and the aqueous layer was further extracted with ethyl acetate. The combined ethyl acetate solutions were washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was dried under high vacuum for 30 minutes to give 70 mg of a yellow oil which by NMR spectroscopy showed the title compound to be present together with impurities containing n-butyl groups.

31.példa

6,6-dibromo-penicillanic acid 1,1-dioxide

To a solution of 359 mg of 6,6-dibromopenicillanic acid in 30 ml of dichloromethane is added 380 mg of 3-chloroperbenzoic acid at 0-5 ° C. The reaction mixture was stirred at 0-5 ° C for 30 minutes, then at 25 ° C for 24 hours, then filtered and the filtrate 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 Ν, Ν-dimethylformamide is stirred overnight at room temperature. Most of the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was separated, washed with 1 N hydrochloric acid, then brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. 11.5 g of the title compound are obtained.

Nuclear Magnetic Resonance Spectrum (in CDCl ₃ ) 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

Penicillanate I, I-dioxide

To a solution of 2.0 g of benzyl 6,6-dibromopenicylanate-1,1-dioxide in 50 ml of tetrahydrofuran is added a solution of 0.699 g of sodium bicarbonate in 50 ml of water followed by 2.0 g of 5% palladium on carbon. The mixture was shaken under a hydrogen atmosphere at about 2 atmospheres for 70 minutes. The tetrahydrofuran was removed by evaporation and the residue partitioned between ethyl acetate and water at pH 7.37. The aqueous layer was separated and fresh ethyl acetate was added. The pH of the mixture was lowered to 1.17 and the ethyl acetate removed, washed with brine and concentrated in vacuo to give 423 mg of the title compound.

Example 34

2,2,2-Trichloroethyl-6,6-dibromo-penicillanate-1,1-dioxide

The title compound is prepared from 6,6-dibromo-penicillanic acid 1,1-dioxide and 2,2,2-trichloroethylchloroformate essentially according to Preparation J. The product was purified by chromatography on silica gel.

The NMR spectrum (in _CDCl3) 4.85 (m, 2H), 1.65 (s, 3H) and 1.45 (3H, s) showed absorptions at ppm.

Example 35

Penicillan-lanoic acid 1,1-dioxide

2,2,2-t-Chloroethyl-6,6-dibromo-penicillanate-1,1-dioxide in a mixture of glacial acetic acid and tetrahydrofuran is substantially reduced as described in Example 14A. The product was obtained in a yield of 27%.

Example 36

- (E xxycarbonyloxy) ethyl 6,6-dibromo-penicillanilate 1,1-dioxide

A mixture of 2.26 g of 6,6-dibromopenicillanic acid 1,1-dioxide, 1.02 ml of 1- (ethoxycarbonyloxy) ethyl chloride, 1.32 ml of diisopropylethylamine and 10 ml of Ν, Ν-dimethylformamide was stirred at room temperature for 28 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water, dilute hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride, and dried. The dry ethyl acetate solution was concentrated in vacuo to give 1.50 g of an oil which was chromatographed on silica gel. This gives 353 mg of the title compound contaminated with a small amount of 1- (ethoxycarbonyloxy) ethyl-6-bromophenic acid.

37.)> live

- (E Toxycarbonyloxyethyl penicillanate 1,1-dioxide

A portion (230 mg) of the product of Example 36 was dissolved in 10 mL of toluene. To the solution was added 0.4 ml of tri-n-butylone hydride followed by 0.164 g of azobis-butyronitrile, and the mixture was heated at 70-80 ° C for 3.5 hours. The solvent was evaporated in vacuo and the residue was dissolved in acetonitrile (25 mL). The etonitrile solution was washed several times with hexane and then concentrated in vacuo. The residue was dissolved in ether and the ether solution was washed with 5% potassium fluoride followed by washing with saturated sodium chloride solution. The ethereal solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel to give 0.043 g of the expected product.

The NMR spectrum (in _CDCl3) 6.75 (m), 4.60 (m). 4.30 (m), 4.15 (s), 4.00 (s), 3.30 (d) and 1.75-1.00 (m) ppm.

Example 38

Comparative Example (Penicillanic Acid) To a solution of 95.2 g of 6-alpha-bromo-penenillanic acid in 2177 ml of methanol and stirred, 622 ml of vi13

-1 225

18 (304) was added. The resulting solution was cooled to 20 ° C, adjusted to pH 7.2 with 2N sodium hydroxide solution, and 550 g of 5% palladium on carbon was added. shaken at 5.1 kg / cm ² pressure to atmosphere until hydrogen uptake was observed. the catalyst was removed by filtration, and washed with 2177 ml of methanol and 622 mL of water. the wash solution and filtrate from the filtration were combined and diluted with 18 1 volume of water. the resulting The mixture was extracted with dichloromethane, the extracts washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give penicillanic acid (275.6 g, 35% yield).

The method of production

6-chloro-6-iodopenicillanic

To 3.38 g of iodine monochloride in 30 ml of dichloromethane are added with stirring at 0-5 ° C, 11.1 ml of 2.5N sulfuric acid followed by 1.92 g of sodium nitrite. At this point, 3.00 g of 6-aminopenicillanic acid are added all at once and stirring is continued for 30 minutes at 0-5 ° C. To the reaction mixture was then added 22.8 mL of 1 M sodium sulfite solution in portions and the layers were separated. The aqueous layer was washed with additional dichloromethane, while the organic layers were washed with brine. The dichloromethane solution was dried over anhydrous sodium sulfate and concentrated in vacuo to give 3.48 g of the title compound.

The above product was dissolved in THF (30 mL) and water (30 mL) was added. The pH of the solution was adjusted to 6.8 with dilute sodium hydroxide solution and the tetrahydrofuran was removed in vacuo. The remaining aqueous phase was freeze-dried and the residue was washed with diethyl ether. 3.67 g of the title compound are obtained in the form of the sodium salt.

Production Method B

6-beta-klórpenicillánsav

Sodium 6-chloro-6-iodopenicillanate (2.95 g) was converted to the free acid and dissolved in 125 ml benzene under a nitrogen atmosphere. Triethylamine (1.08 mL) was added to the solution and the mixture was cooled to 0-5 ° C. To the cooled mixture was then added 0.977 ml of trimethylsilyl chloride and the reaction mixture was stirred at 0-5 ° C for 5 minutes, 25 ° C for 60 minutes and 50 ° C for 30 minutes. The reaction mixture was then cooled to 25 ° C and the triethylamine hydrochloride was collected by filtration. To the filtrate was first added 15 mg of azobisisobutyronitrile followed by 2.02 ml of tri-n-butylic anhydride. The mixture is then irradiated with ultraviolet light for 15 minutes and the temperature is maintained at about 20 ° C by cooling. The solvent was then removed by evaporation in vacuo and the residue dissolved in 1: 1 tetrahydrofuran / vfz. The solution was adjusted to pH 7.0 and the tetrahydrofuran was evaporated in vacuo. The aqueous phase was washed with ether and then an equal volume of ethyl acetate was added. The pH of the mixture was adjusted to 1.8 and the ethyl acetate layer was separated. The aqueous phase was extracted with additional ethyl acetate, the combined ethyl acetate solutions were dried and evaporated in vacuo. This gives 980 mg of 6-beta-chloro penicillanic acid.

The above product is dissolved in tetrahydrofuran and an equal volume of water is added. The pH of the mixture was adjusted to 6.8 and the tetrahydrofuran was removed in vacuo. The residual aqueous phase was freeze-dried to give 850 mg of sodium 6-beta-chloropenicillanate.

Nuclear Magnetic Resonance Spectrum (D ₂ O) 5.70 (d, 1H, J = 4Hz), 5.50 (d, 1H, J = 4Hz), 4.36 (s, 1H), It exhibits absorption at 60 (s, 3H) and 1.53 (s, 3H) ppm.

Production mode C

6-beta-bromopenicillanic

A mixture of 5.0 g of 6,6-dibromo-penicillanic acid, 1.54 ml of triethanolamine and 100 ml of benzene is stirred under nitrogen until a solution is obtained. The solution was cooled to 0-5 ° C and 1.78 mL of trimethylsilyl chloride was added. The reaction mixture is stirred at 0-5 ° C for 2-3 minutes and then stirred at 50 ° C for 35 minutes. The cooled reaction mixture was filtered and the filtrate was cooled to 0-5 ° C. To the cooled solution was added a small amount of azobisisobutoronitrile followed by 3.58 ml of tri-n-butylone hydride. The reaction vessel was irradiated with ultraviolet light for 15 minutes and 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. Additional azobisisobutyronitrile was added, mixed with 0.6 mL of tri-n-butylic anhydride (0.6 mL) and irradiated again for 30 minutes. The solvent was evaporated in vacuo and to the residue was added 5% sodium bicarbonate solution and diethyl ether. The biphasic system was shaken vigorously for 10 minutes and the pH was adjusted to 2.0. The ether layer was separated, dried and concentrated in vacuo to give 2.33 g of an oil. This oil was converted to the sodium salt by addition of water containing 1 equivalent of sodium bicarbonate and the resulting solution was freeze-dried. The resulting sodium 6-beta-bromopenicillanate is contaminated with a small amount of alpha isomer.

The sodium salt was purified by chromatography on Sephadex LH-20, combined with additional material of similar quality and rechromatographed.

Nuclear Magnetic Resonance Spectrum (in D ₂ O) at 5.56 (s, 2H), 4.25 fs, 1H), 1.60 (s, 3H) and 1.50 (s, 3H) in ppm .

Production mode D

6-beta-iodopenicillanic

The title compound is prepared by reduction of 6,6-diiodopenicillanic acid with tri-n-butylic anhydride as described in Preparation B.

This method of production

Of pivaloyloxymethyl 6-alpha-Bromopenicillanate

To a solution of 280 mg of 6-alpha-bromo-penicillanic acid in 2 ml of N, N-dimethylformamide was added 260 mg of diisopropylethylamine followed by 155 mg of chloromethyl pivalate and 15 mg of sodium iodide. The reaction mixture was stirred at sat-13186304 for 24 hours, then diluted with ethyl acetate and water. The mixture was adjusted to pH 7.5, and the ethyl acetate layer was removed and washed three times with water and once with brine. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound.

Production Method F

The corresponding 6-halo-penicillanic acid with 3-phthalidyl chloride, 4-crotonolactonyl chloride, gamma-butyrolacton-4-yl chloride or the desired alkanoyloxymethyl chloride, 1- (alkanoyloxy) ethyl chloride, 1-methyl-1- (alkanoyloxy) ethylchloride, - Reaction with (alkoxycarbonyloxy) ethyl chloride or 1-methyl-1- (alkoxycarbonyloxy) ethyl chloride according to Preparation E to give the following compounds:

3-phthalidyl 6-alpha-chlorpenicillanate,

4-crotonolactonyl-6-beta-chlorpenicillanate, gamma-butyrolacton-4-yl-6-alpha-bromo-penicillanate, acetoxymethyl-6-beta-bromo-penicillanate, pivaloyloxymethyl-6-beta-bromo-penicillanate, hexanoyloxymethyl-6-beta-bromo-penicillanate, (acetoxy) ethyl 6-beta-iodopenicillanate, 1- (isobutyryloxy) ethyl 6-alpha-chlorpenicillanate,

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

1-Methyl-1- (hexanoyloxy) ethyl'-6-alpha-bromo-penicillanate, methoxycarbonyloxymethyl-6-alpha-bromo-penicillanate, propoxycarbonyloxymethyl-6-beta-bromo-penicillanate, 1- (ethoxycarbonyloxy) -ethyl-6-alpha-bromo-penicillanate, butoxycarbonyloxy) ethyl 6-alpha-iodo-penicillanate, 1-methyl-1- (methoxycarbonyloxy) ethyl-6-beta-iodo-penicillanate, and

methyl-1- (isopropoxycarbonyloxy) ethyl-6-chlorpenicylanate.

Production Method G

6,6-dijódpenicilIánsav

A mixture of 15.23 g of iodine, 10 ml of 2.5N sulfuric acid, 2.76 g of sodium nitrite and 75 ml of dichloromethane is stirred at 5 ° C and 4.32 g of 6-aminopenicillanic acid are added over 15 minutes. Stirring is continued for 5 minutes at 5 to 10 [deg.] C., during which time 100 ml of 10% sodium hydrogen sulphite are added dropwise. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined dichloromethane layers were washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. This gives 1.4 g of the title compound which is contaminated with a certain amount of 6-iodopenicillanic acid. Melting point 58-64 ° C.

Nuclear Magnetic Resonance Spectrum (in CDCl ₃ ) at 5.77 (s, 1H), 4.60 (s, 1H), 1.71 (s, 3H) and 1.54 (s, 3H) in ppm .

Production of H

Of pivaloyloxymethyl 6-alpha-Bromopenicillanate

To a mixture of 11.2 g of 6-alpha-bromo-penicillanic acid, 3.7 g of sodium bicarbonate and 44 ml of Ν, Ν-dimethylformamide is added 6.16 g of chloromethyl pivalate under stirring over a minute and at ambient temperature. The stirring is continued for 66 hours and then the reaction mixture was diluted with ethyl acetate (100 mL) and water (100 mL). The layers were separated and the ethyl acetate layer was washed with water, saturated sodium chloride solution, saturated sodium bicarbonate solution, water, and saturated sodium chloride solution. The colorless ethyl acetate solution was dried over anhydrous magnesium sulfate and dried in vacuo. Yield: 12.8 g (80% yield) of compound.

eőállításmód

Be isyl-6-alpha-bromo-penicillanate

The title compound was prepared by esterification of 6-alpha-bromo-penicillanic acid with benzyl bromide as described in Preparation H (83% yield).

Nuclear Magnetic Resonance Spectrum (in CDCl3) 7.35 (s, 5H), 5.35 (m, 1H), 5.15 (s, 2H), 4.70 (m, 1H), 4.60 (s) , 1H), 1.55 (s, 3H) and 1.35 (s, 3H) ppm.

Preparation J

2,2-trichloroethyl penicillanate

To a solution of 11.2 g of 6-alpha-bromopenicillanate in 50 ml of tetrahydrofuran at 0 ° C is added 3.48 g of pyridine over a minute. To the resulting cloudy solution was added 8.47 g of 2,2,2-trichloroethyl chloroformate over 10 minutes and the temperature was maintained at 0-2 ° C. Stirring was continued for 30 minutes, then the cooling bath was removed and the mixture was stirred 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 successively with saturated sodium bicarbonate solution, water, and brine. The ethyl acetate solution was then desalted, dried and concentrated to a small volume. To the resulting mixture was added 100 mL of hexane and the solid was collected by filtration to give 10.5 g of the title compound, m.p. 105-110 ° C.

Nuclear Magnetic Resonance Spectrum (in CDCl ₃ ) 5.50 (d, 1H), 4.95 (d, 1H), 4.90 (s, 2H), 4.65 (s, 1H), 1.70 ( s, 3H) and 1.55 (s 3H) ppm.

K Production Method

6,6-dibromopenicillanic

To 500 ml of cooled dichloromethane was added 119.9 g of bromine, 200 ml of 2.5 N sulfuric acid and 34.5 g of sodium nitrite at 5 ° C. To the mixture was added, with stirring, 54.0 g of 6-aminopenicillanic acid in portions over 30 minutes while maintaining the temperature at 4-10 ° C. Stirring was continued for 30 minutes at 5 ° C and then 410 ml of 1.0 M sodium hydrogen sulfite solution was added over 20 minutes at 5 to 10 ° C. The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 150 mL). The original dichloromethane layer was combined with the two extracts to give a solution of 6,6-dibromo-penicillanic acid. This solution was used directly in Example 17.

-1 429

185 304

Production method L

6-Chloro-6-iodopenicillanic

To 100 ml of dichloromethane cooled to 3 ° C are added 4.87 g of iodine chloride, 10 ml of 2.5 N sulfuric acid and 2.6 g of sodium nitrite. 4.32 g of 6-aminopenicillanic acid are added with stirring over a period of 15 minutes. After stirring for 20 minutes at 0-5 ° C, 100 ml of 10% sodium bisulfite solution is added dropwise at 4 ° C. Stirring is continued for 5 minutes and then the layers are separated. The aqueous layer was extracted with dichloromethane (2 x 50 mL) and the combined dichloromethane solutions were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound as a brown solid (148-152 ° C). are.

Nuclear Magnetic Resonance Spectrum (in CDCl ₃ ) at 5.40 (s, 1H), 4.56 (s, 1H), 1.67 (s, 3H) and 1.50 (s, 3H) ppm

The IR spectrum (KBr tablet) shows absorption at 1780 and 1715 cm ^-1 .

M production mode

6-Bromo-6-iodopenicillanic

To 100 ml of dichloromethane cooled to 5 ° C are added 10 ml of 2.5 N sulfuric acid, 6.21 g of iodine bromide and 2.76 g of sodium nitrite. 4.32 g of 6-aminopenicillanic acid are added under vigorous stirring at 0-5 ° C over a period of 15 minutes. Stirring was continued for another 20 minutes at 0-5 ° C and 100 ml of 10% sodium hydrogen sulfite solution was added dropwise at 0 ° C to 10 ° C. The layers were separated and the aqueous layer (3 x 50 mL) was extracted with dichloromethane. The combined dichloromethane layers were washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was dried under high vacuum for 30 minutes to give 6.0 g (72% yield) of the title compound. 144-147 ° C.

Nuclear Magnetic Resonance Spectrum (in CDCl ₃ ) at 5.50 (s, 1H), 4.53 (s, 1H), 1.70 (s, 3H) and 1.53 (s, 3H) in ppm .

The IR spectrum (KBr disc) showed absorptions at 1785 and 1710 cm ^_1. Mass spectrum shows prominent ion at m / e = 406.

N Preparation

6-Chloro-6-bromopenicillanic

6-Chloro-6-bromo-penicillanic acid is prepared from 6-aminopenicillanic acid by diazotization followed by reaction with bromine chloride according to Preparation M.

O production method

Pivaloyloxymethyl 6,6-dibrómpenicillanát

To a solution of 3.59 g of 6,6-dibromo-penicillanic acid in 20 ml of N, N-dimethylformamide is added 1.30 g of diisopropylethylamine followed by 1.50 g 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 layer 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 concentrated in vacuo to give the title compound.

Preparation of P

The corresponding 6,6-dihalogenpenicillanic acid is treated with 3-phthalidyl chloride, 4-crotonlactonyl chloride, gamma-butyrolaction-4-yl chloride or the required alkanoyloxymethyl chloride, 1- (alkanyloxy) ethyl chloride, 1-methyl-1- (alkanoyloxy) alkyloxyl, by reaction with 1- (alkoxycarbonyloxy) ethyl chloride or 1-methyl-1- (alkoxycarbonyloxy) ethyl chloride as described in Preparation O to give the following compounds:

3-phthalidyl-6,6-dibromo-penicillanate,

4-Crotonolactonyl-6-chloro-6-iodo-penicillanate, gamma-butyrolactonyl-6-bromo-6-iodo-penicillanate, acetoxymethyl-6-chloro-6-bromo-penicillanate, pivaloyloxymethyl-6-chloro-6-iodo-penicillanate, hexanoyloxymethyl dibromo-penicillanate, 1- (acetoxy) ethyl-6,6-dibromo-penicillanate, 1- (isobutyryloxy) ethyl-6-bromo-6-iodo-penicillanate, 1-methyl-1- (acetoxy) ethyl-6,6-dibromo-penicillanate, ^5- methyl -1- (hexanoyloxy) ethyl-6-chloro-6-bromenepenicyl lanate, raethoxycarbonyloxymethyl-6,6-dibromo-penicillanate, propoxycarbonyloxymethyl-6-chloro-6-iodo-penicillanate, 1- (ethoxycarbonyloxy) -ethyl-6,6-dibromo-vinylate, (butoxycarbonyloxy) ethyl 6-bromo-6-jódpenicillanát,

methyl 1 - (methoxycarbonyloxy) ethyl 6,6-dibromo-penicillanate, and methyl 1- (isopropoxycarbonyloxy) ethyl-6,6-dibromo-penicillanate.

Claims (4)

A process for the preparation of a penam sulfoxide of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises dehalogenating and oxidizing a 6-halo penicillanic acid comprising reacting a compound of formula (II) or a basic salt thereof, wherein R ^{1 is} hydrogen or carboxylic a benzyl, trichloroethyl or pivaloyloxymethyl group, an alkali metal permanganate, an alkaline earth metal permanganate or an organic peroxycarboxylic acid, and the resulting compound of formula (III) wherein X and Y are each hydrogen, chloro, bromine or iodine, with the proviso that when X and Y are the same, both represent a bromine atom, R ¹ is as defined above, with hydrogen, in an inert solvent, at a pressure of 1-100 kg / cm ² at 0-60 ° C, pH 4-9 , in the presence of a hydrogenation catalyst, and optionally the penicillin-carboxyl protecting group removing and, if desired, converting the resulting compound into a pharmaceutically acceptable basic salt in a known manner. -15186304 2. The process according to claim 1, wherein the catalytic dehalogenation is carried out in the presence of 0.01 to 2.5% by weight of a catalyst. 3. A process according to claim 1 or 2 wherein X is a bromine and Y is a hydrogen atom. The process of claim 1 or 2 wherein the starting compound of formula (III) is wherein X and Y are both bromine. 1 sheet with formulas Responsible for publishing: Director of Economic and Legal Publishing House 87.2493.66-4 Alföldi Nyomda, Debrecen Chief Executive Officer: István Benkő Chief Executive Officer