JPS6145993B2 - - Google Patents

Description

[Detailed description of the invention]

This invention relates to a new chemical method. More specifically, the present invention relates to a method for producing penicillanic acid 1,1-dioxide and its ester that can be easily hydrolyzed in vivo. This novel chemical method oxidizes 6-halo or 6,6-dihalo derivatives of penicillanic acid or their easily hydrolyzable esters in vivo to the corresponding 1,1-dioxides, and the oxidation products are then exposed to water. It consists of dehalogenation by addition decomposition. A novel compound useful as an intermediate is the 6-
These are halo and 6,6-dihalo derivatives and their esters that can be easily hydrolyzed in vivo. Penicillanic acid 1,1-dioxide and its easily hydrolyzable esters in vivo are useful as β-lactamase inhibitors, and certain β-lactamase inhibitors are used to treat bacterial infections in mammals, especially humans. It is useful as a drug that enhances the effects of lactam antibiotics. Previously, penicillanic acid 1.1
- Dioxide and its esters that can be easily hydrolyzed in vivo can be obtained by debrominating 6-bromopenicillanic acid or its esters that can be easily hydrolyzed in vivo. It is prepared by obtaining and oxidizing it to 1,1-oxide. The process of the invention starts from 6-halopenicillanic acid or its readily hydrolyzable ester in vivo and consists of dehalogenation and oxidation steps, but surprisingly if the oxidation step is carried out before the dehalogenation step. It has been found that the yield of product is improved. Details of the method for producing penicillanic acid 1,1-dioxide and its easily hydrolyzable esters in the body are described in Belgian patent no.
See No. 867859 (patent of December 6, 1978) and DE 2824535. 6-halopenicillanic acid was prepared by Cignarella et al.
Journal of Organic Chemistry 27, 2668
(1962) and U.S. Pat. No. 3,206,469;
The hydrogenolysis of 6-halopenicillanic acid to penicillanic acid is disclosed in British Patent Specification No. 1072108. Harrison et al.Journal of the Chemicoal
Society (London), Perkin I, 1772 (1976)
(a) Oxidation of 6,6-dibrompenicillanic acid with 3-chloroperbenzoic acid to produce the corresponding α- and
(b) oxidizing methyl 6,6-dibrompenicillanate with 3-chromium perbenzoic acid to produce methyl 6,6-dibrompenicillanate 1,1-dioxide; (c) oxidation of methyl 6-α-chlorpenicillanate with 3-chloroperbenzoic acid to produce the corresponding mixture of α- and β-sulfoxides; (d) oxidation of methyl 6-brompenicillanate with 3-chloroperbenzoic acid; oxidation to produce the corresponding mixture of α- and β-sulfoxides. Clayton, Journal of the Chemical Society
(London) (C) 2123 (1969) (a) produced 6,6-dibromo- and 6,6-diiodopenicillanic acid; (b) prepared 6,6-dibromo- and 6,6-diiodopenicillanic acid; (c) Hydrogenolysis of methyl 6,6-dibrompenicillanate to form methyl 6-α-brompenicillanate; (d) methyl 6-α-brompenicillanate; Hydrogenolysis of 6-dibromopenicillanic acid and its methyl ester to produce penicillanic acid and its methyl ester, respectively; The hydrogenolysis of the mixture to produce frame-pure methyl 6-α-iodopenicillanate is disclosed. This invention is based on the formula [R ¹ is selected from the group consisting of hydrogen and an ester-forming residue that can be easily hydrolyzed in vivo] or a pharmaceutically suitable base salt thereof, the method comprising the following steps: Provide: (a) formula or a base salt thereof with a reagent selected from the group consisting of alkali metal permanganates, alkaline earth metal permanganates and organic peroxycarboxylic acids to obtain the formula [In the formula, X and Y are each selected from the group consisting of hydrogen, chloro, bromo and iodo;
are the same only in the case of bromine] or its base salt is produced, and the compound of formula (b) is dehalogenated by catalytic hydrogenolysis. A preferred method of carrying out step (b) is to combine the product of step (a) with hydrogen in an inert solvent at a pressure in the range of from about 1 to about 100 Kg/cm ² and at a temperature in the range of from about 0 to about 60°C and a pH of about 4. 9 to about 9 in the presence of a hydrogenolysis catalyst. Hydrogenolysis catalysts are usually about 0.01 of the compound of formula
from about 2.5% by weight, preferably from about 0.1 to about 1.0
Present in an amount of % by weight. The preferred group for X and Y is bromine, and the preferred reagents for carrying out the above-mentioned dioxidedation (formula→formula) (step (a)) are potassium permanganate and 3
- chlorperbenzoic acid. When both X and Y are chloro, compounds of formula are difficult to obtain. If both X and Y are iodine, the above-mentioned dioxide formation (formula→formula) (step (a)) proceeds too slowly. A preferred intermediate is 6,6-dibrompenicillanic acid 1,1-dioxide, i.e. in compounds of formula
and Y is bromine and R ¹ is hydrogen. These compounds are named herein as derivatives of penicillanic acid having the following structural formula. The dotted bond of the substituent of the bicyclic nucleus in the derivatives of penicillanic acid indicates that the substituent is attached below the plane of the nucleus. Such substituents are said to be in the α-configuration. Conversely, substituents bound to the bicyclic nucleus by solid lines indicate attachment above the plane of the nucleus. This configuration is called the β-configuration. Thus, in the formula the group X is α-
and the group Y has a β-configuration. As used herein, when R ¹ is an ester-forming residue that can be easily hydrolyzed in vivo, R ¹ is of the formula
A group conceptually derived from the alcohol of R ¹ --OH, the COOR ¹ portion of such a compound in the formula represents an ester group. Furthermore, R ¹ is the group COOR ¹
is easily cleaved in vivo to form a free carboxy group (COOH). That is, R ¹ indicates that when the compound of the formula (wherein R ¹ is an ester residue that can be easily hydrolyzed in vivo) is exposed to the blood or tissue of a mammal, the compound of the formula where R ¹ is hydrogen is It is a type of group that is easily produced. Such R ¹ is well known in the penicillin art. In most cases, R ¹ improves the absorption properties of penicillin compounds. Furthermore, R ¹ confers pharmaceutically suitable properties to the compound of formula and liberates the pharmaceutically suitable compound when cleaved in vivo. The group R ¹ is well known in the penicillin art and readily identified by those skilled in the art. See, for example, West German Published Application No. 2517361. The group R ¹ is, for example, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolactone-4
-yl and a group of the formula:

[expression] and

[wherein R ² and R ³ are selected from the group consisting of hydrogen and alkyl having 1 to 2 carbon atoms; R ⁴ is alkyl having 1 to 5 carbon atoms]

However, preferred groups for R ¹ are alkanoyloxymethyl having 3 to 7 carbon atoms, 1-(alkanoyloxy)ethyl having 4 to 8 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having 5 to 9 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms,
1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1- having 5 to 8 carbon atoms
(Alkoxycarbonyloxy)ethyl, 3-phthalidyl, 4-crotonolactonyl and gamma-butyrolacton-4-yl. 3-phthalidyl, 4-crotonolactonyl and gamma-butyrolacton-4-yl are represented by the following structural formulas and. The wavy line represents either of the two epimers or a mixture thereof.

【formula】 【formula】

##STR1## Step (a) of the process of this invention consists of oxidizing the sulfide group of the compound of formula to a sulfone group to produce a compound of formula. A variety of oxidizing agents known for oxidizing sulfides to sulfones can be used in this process. However, particularly useful reagents are permanganates of alkali metals such as sodium and potassium; permanganates of alkaline earth metals such as calcium and barium; and peracetic acid and
Organic peroxycarboxylic acids such as chlorperbenzoic acid. When a compound of formula (wherein X, Y and R ¹ are as defined above) is oxidized to the corresponding compound of formula using a metal permanganate, the reaction typically oxidizes the compound of formula from about 0.5 to This is accomplished by treatment with 10 molar equivalents, preferably from about 1 to about 4 molar equivalents, of permanganate in a suitable reaction-inert solvent system. A suitable reaction inert solvent system is one that does not affect the starting compounds or products, and water is usually used. If desired, a co-solvent that is miscible with water and does not affect the permanganate, such as tetrahydrofuran, can be added.
This reaction can be carried out at temperatures ranging from about -30° to about 50°C. Preferred is about -10 to about 10°C. At about 0°C, the reaction is usually short;
For example, it can be completed within an hour. This reaction can be carried out under neutral, basic or acidic conditions, but it is preferably carried out at a pH of about 4 to about 9, preferably 6 to 8. However, it is essential to choose conditions that do not degrade the alpha-lactam ring system of the compound of formula or. In fact, it is often advantageous to buffer the PH of the reaction medium around neutrality. The product is recovered by conventional methods. Excess permanganate is usually destroyed using sodium bisulfite and removed as the product precipitates out of solution. The product is separated from the manganese dioxide by extraction into an organic solvent and evaporation of the solvent; alternatively, if the product does not precipitate out of solution at the end of the reaction, conventional methods of solvent extraction isolated in Formula (wherein X, Y and R ¹ are as described above)
When a compound of formula is oxidized using a peroxycarboxylic acid to the corresponding compound of formula, the compound of formula is treated with about 1 to about 6 molar equivalents of oxidizing agent, preferably about 2.2 molar equivalents, in a reactive inert solvent. to carry out a reaction. Typical solvents are dichloromethane,
chlorinated hydrocarbons such as chloroform and 1,2-dichloroethane; and ethers such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane. This reaction is normally carried out at a temperature of about -30 to about 50°C, preferably about 15 to about 30°C. At about 25°C, reaction times are usually about 2 to about 16 hours. The product is usually isolated by removing the solvent by vacuum evaporation. This reaction product can be purified by conventional methods well known to those skilled in the art. Alternatively, this reaction product can be passed directly to step (b) without further purification.
Can be used in Step (b) of this invention is a dehalogenation reaction.
One convenient way to carry out this transformation is to stir a solution of the compound of formula in the presence of a hydrogenolysis catalyst in an atmosphere of hydrogen or hydrogen mixed with an inert diluent such as nitrogen or argon. It is. A suitable solvent for this hydrogenolysis reaction is one that sufficiently dissolves the starting compound of the formula, but does not have any effect on the hydrogenation or hydrogenolysis. Such solvents are, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane and -1,2-dimethoxyethane; low molecular weight esters such as ethyl acetate and butyl acetate; N·N-dimethylformamide, N·N- tertiary amides such as dimethylacetamide and N·N-dimethylpyrrolidone; water; and mixtures thereof. Additionally, the reaction mixture is usually buffered to operate at a pH of about 4-9, preferably about 6-8. Borate and phosphate buffers are commonly used. Introduction of hydrogen gas into the reaction medium is accomplished by carrying out the reaction in a sealed vessel containing the conventional compound, solvent, catalyst, and hydrogen. The pressure within the reaction vessel may vary from about 1 to about 100 Kg/cm ² . Preferred pressures are from about 2 to about 5 kg/cm ² when the atmosphere within the reaction vessel is substantially pure hydrogen. Hydrogenolysis is generally carried out at a temperature of about 0° to about 60°C, preferably about
It is carried out at a temperature of 25° to about 50°C. Using these suitable temperatures and pressures, hydrogenolysis is typically carried out for several hours, such as from about 2 hours to about 20 hours. The catalyst used in this hydrogenolysis reaction is of a type well known in the art for this type of conversion and includes:
For example, noble metals such as nickel, palladium, platinum and rhodium. The catalyst is typically present from about 0.01 to about 2.5%, preferably from about 0.1 to about 1.0% by weight of the compound of formula. The catalyst is advantageously supported on an inert support; a particularly preferred catalyst is palladium on an inert support such as carbon. Another method is the reductive elimination of the halogen from compounds of formula. For example, X and Y can be removed by well known methods using dissolved metal reducing systems such as zinc dust in acetic acid, formic acid or phosphate buffers.
Tin hydrides; for example, trialkyltin hydrides such as tri-n-butyltin hydride can also be used. In addition, 6-α-chlorpenicillanic acid and 6-α
-Bromopenicillanic acid is prepared by diazotizing 6-aminopenicillanic acid in the presence of hydrochloric acid and hydrobromic acid, respectively. (Journal of Organic
Chemistry, 27, 2668 (1962)). 6-α-iodopenicillanic acid is prepared by diazotization of 6-aminopenicillanic acid in the presence of iodine followed by hydrogenolysis. (Clayton, Journal of the Chemical
Society(C), 2123 [1969]). 6-β-chlorpenicillanic acid, 6-β-brompenicillanic acid and 6
- iodopenicillanic acid is produced by reduction of 6-chloro-6-iodopenicillanic acid, 6,6-dibrompenicillanic acid and 6,6-diiodopenicillanic acid, respectively, with tri-n-butyltin hydride; 6-chloro-6-diiodopenicillanic acid is 6
- produced by diazotization of aminopenicillanic acid in the presence of iodine chloride; 6,6-dibromopenicillanic acid is produced by Clayton, Journal of the
Produced by the method of Chemical Society (London) 2123 (1969); 6,6-diiodopenicillanic acid is produced by diazotization of 6-aminopenicillanic acid in the presence of iodine. Compounds of the formula, and in which R ¹ is hydrogen are acidic and form salts with basic reagents. These salts can be prepared by standard methods, eg, by contacting the acidic and basic components, usually in a 1:1 molar ratio, in a suitably aqueous, non-aqueous or partially aqueous medium. These are then recovered by suitable filtration, precipitation with a non-solvent followed by filtration or evaporation of the solvent, or, in the case of aqueous solutions, by rendering them lyophilic. Basic reagents preferably used for salt formation belong to both organic and inorganic types, such as ammonia, organic amines, alkali metal hydroxides, carbonates, bicarbonates, hydrides, alkoxides as well as alkaline earth metal hydroxides. carbonates, hydrides and alkoxides. Typical examples of such bases are primary amines such as n-propylamine, n-
Butylamine, aniline, dichlorohexylamine, 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 ethoxide and potassium hydroxide ethoxides; hydrides, such as calcium hydride and sodium hydride; carbonates, such as potassium carbonate and sodium carbonate; bicarbonates, such as sodium and potassium bicarbonate and alkali metal salts of long-chain fatty acids, such as sodium chloride;
2-ethylhexanoate. Preferred salts of the compound of formula are the sodium, potassium and triethylamine salts. As mentioned above, compounds in which R ¹ is hydrogen and salts thereof are antibacterial agents with moderate potency in vivo and in vitro. Compounds of the formula in which R ¹ is an ester-forming residue that can be easily hydrolyzed in vivo are antibacterial agents with moderate potency in vivo. Penicillanic acid 1.1 against several types of microorganisms
The MIC values of -dioxide are shown in Table 1. Table 1 In vitro antibacterial activity of penicillanic acid 1,1-dioxide Microorganism MIC (mcg/ml) Staphylococcus aureus 100 Streptococcus faecalis 200 Streptcoccus pyogenes 100 Escherichia coli 50 Pseudomonas aeruginosa 20 Klebsiella pneumoniae 50 Proteus mirabilis 100 Proteus morgani 100 Salmonella ty phimurium) 50 Pasteurella multocida) 50 Serasia marcescens (Serratia marcescens) 100 Enterobacter aerogenes 25 Enterobacter clocae 100 Citrobacter freundii 50 Providencia 100 Staphylococcus epidermis 20 0 Pseudomonas putida 200 Hemophilus influenzae 50 Neisseria gonorrhoeae 0.312 The compound represented by the formula in which R ¹ is hydrogen and its salts have in vitro antibacterial activity and are therefore used as industrial disinfectants, e.g. for water treatment. It is useful in topical applications, as a slime control, paint preserver and wood preserver, and as a disinfectant. When the compound is used for topical applications, it may be convenient to mix the active ingredient with a non-toxic carrier, such as a vegetable or mineral oil, or a emollient cream. Similarly, it can be dissolved or dispersed in liquid diluents or solvents such as water, alkanols, glycols or mixtures thereof. In most cases, it will be appropriate to use an active ingredient concentration of about 0.1 to 10% by weight of the total composition. The compound of the formula and its salts have in vivo antibacterial activity and are therefore suitable for the control of bacterial infections in mammals, including humans, whether administered orally or parenterally. These compounds are useful in the control of infections caused by bacteria that are pathogenic to humans, such as those caused by strains of Neisseria gonorrhoeae. When considering the therapeutic use in mammals, especially humans, of a compound of formula or a salt thereof,
The compounds can be administered alone or mixed with a pharmaceutically suitable carrier or diluent. These can be administered orally or parenterally, i.e., intramuscularly;
It can be administered subcutaneously or intraperitoneally. The carrier or diluent can be determined based on the intended mode of administration. For example, when considering oral dosage forms, the penum compounds of the invention may be prepared in the form of tablets, capsules, lozenges, lozenges, powders, syrups, elixirs, aqueous solutions and suspensions, etc. according to standard pharmaceutical practice. Can be used according to the method. The ratio of active ingredient to carrier will vary depending on the chemical nature, solubility and stability of the active ingredient and the planned dosage. However, in the case of oral tablets containing about 20-95% active ingredient, pharmaceutical compositions containing antimicrobial agents of the formula commonly used carriers include lactose, sodium citrate, and phosphates. be. Various disintegrants such as starch, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are commonly used in tablets. For oral administration in capsule form, useful diluents are lactose and high molecular weight polyethylene glycols. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. Certain sweetening and/or flavoring agents can be added if desired. Parenteral administration includes intramuscular, intraperitoneal, subcutaneous and intravenous administration, in which case a sterile solution of the active ingredient is usually prepared and the pH of the solution suitably adjusted and buffered. For intravenous use, the total concentration of solutes must be adjusted to render the preparation isotonic. The antimicrobial agents of this invention have utility in humans against pathogenic microorganisms. The prescribing physician ultimately determines the appropriate dosage of the compound for a given person, which will depend on the age, weight, and response of each patient and the nature and severity of the patient's symptoms. It is expected that this will change over time. The compounds of this invention are usually administered orally to
It is used in dosages of about 10 to 200 mg per kg of body weight, and parenterally in dosages of about 10 to 400 mg per kg of body weight per day. However, these numbers are exemplary and it may sometimes be necessary to use dosages outside these limits. A compound of formula or a salt thereof enhances the antibacterial effect of β-lactam antibiotics in vivo. Thus, they reduce the amount of the antibiotic needed to protect mice against lethal specific β-lactamase producing bacterial inocula. This ability makes co-administration of these compounds with β-lactam antibiotics effective in the treatment of bacterial infections in mammals, especially humans. For the treatment of bacterial infections, the compound of the formula can be mixed with a beta-lactam antibiotic, so that the two drugs are administered simultaneously.
Alternatively, the compound of formula may be administered as a separate agent during treatment with a β-lactam antibiotic. In some cases, it may be advantageous to pre-administer a compound of the formula to a subject before commencing treatment with a β-lactam antibiotic. Penicillanic acid 1,1-dioxide, its salts, or esters that can be easily hydrolyzed in vivo are
When used to enhance the efficacy of lactam antibiotics, they are preferably administered with standard pharmaceutical carriers or diluents. The formulation method described above when using penicillanic acid 1,1-dioxide or its easily hydrolyzable ester in vivo as a single antibacterial agent can also be applied when co-administering with other β-lactam antibiotics. . Pharmaceutical compositions comprising a pharmaceutical carrier, a β-lactam antibiotic, and penicillanic acid 1,1-dioxide or a readily hydrolyzable ester thereof usually contain about 5
Contains ~80% by weight of pharmaceutical carrier. Penicillanic acid 1,1-dioxide or its easily hydrolyzable ester in vivo with other β-
When administered in combination with lactam antibiotics, the sulfones can be administered orally or parenterally, ie, intramuscularly, subcutaneously, or intraperitoneally. Although the prescribing physician ultimately determines the dosage, the weight ratio of penicillanic acid 1,1-dioxide or its salt or its ester to the daily dosage of the β-lactam antibiotic is usually about 1:3 to about 3. :1. Furthermore, when penicillanic acid 1,1-dioxide, its salts, or its easily biodegradable esters are used in combination with other lactam antibiotics, the daily oral dosage of each component is usually per kilogram of body weight. about 10 to about 200 mg, and 1
The daily parenteral dosage is about 10 to about 400 per kg of body weight.
mg. However, these numbers are stated for illustration purposes and it may be necessary to use dosages outside of this range in some cases. Typical β-lactam antibiotics that can be co-administered with penicillanic acid 1,1-dioxide and its readily hydrolyzable in vivo are: 6-(2-phenylacetamido)penicillanic acid 6- (D-2-amino-2-phenylacetamide)penicillanic acid 6-(2-carboxy-2-phenylacetamide)penicillanic acid and 7-(2-[1-tetrazolyl]acetamide)
-3-(2-[5-methyl-1,3,4-thiadiazolyl]thiomethyl)-3-desacetoxymethylcephalosporanic acid. Typical microorganisms against which the antibacterial activity of the above β-lactam antibiotics is increased are Staphylococcus Aureus, Haemophilus influenzae, Klebsiella, and Klebsiella pneumoniae.
pneumoniae) and Bacteroides fragilis. As is well known to those skilled in the art, some beta-lactam compounds are effective when administered orally or parenterally, while other beta-lactam compounds are effective only when administered parenterally. Penicillanic acid 1,1-
When used simultaneously (i.e., in admixture) with a β-lactam antibiotic that is effective only when administered parenterally, a combination suitable for parenteral use is determined. A prescription will be required. When penicillanic acid 1,1-dioxide or its ester is administered simultaneously (mixed) with a beta-lactam antibiotic that is effective either orally or parenterally, formulation is possible. Furthermore, while the preparation of penicillanic acid 1,1-dioxide or its salt or ester is administered orally, it is possible to further administer the β-lactam antibiotic parenterally at the same time. Alternatively, the ester preparation may be administered parenterally, while at the same time additional β
- It is also possible to administer lactam antibiotics orally. Further details regarding the use and synthesis of compounds of the formula are disclosed in DE-A-2824535. The following examples are only for the purpose of further illustrating the invention. Infrared (IR) spectra were measured as potassium bromide disks (KBr disks) or as nudyol, and characteristic absorption bands were expressed in wavenumbers (cm ^-1 ). Nuclear magnetic resonance spectra (NMR) were measured at 60 MHz on solutions in deuterated chloroform (CDCl3), deuterated dimethylformamide (DMSO- _d6 ) or deuterated water ( _D2O ), and the peak positions were determined from tetramethylsilane [( _CH3 ) ₄ Si] or sodium 2,2-dimethyl-2-silapentane-5-sulfonate, expressed in ppm on the lower magnetic field side. The following abbreviations were used for the peak waveforms. s = singlet, d = doublet, t = triplet, q =
quartet, m = multiple weight. Reference example 1 6-α-brompenicillanic acid 1,1-dioxide 560 ml of water, 300 ml of dichloromethane and 56.0 ml of water
g of 6-α-brompenicillanic acid into a stirred mixture of
Add 4N NaOH solution to stabilize pH 7.2. This required 55ml of 4N NaOH 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 was then quickly poured, with stirring, into the oxidation mixture previously prepared as described below. 63.2 g potassium permanganate, 1000 ml water and 48.0 g acetic acid were mixed in a 3 liter flask. The mixture was stirred for 15 minutes at 20°C and then cooled to 0°C. After adding the 6-α-bromopenicillanic acid solution to the above oxidation mixture, a −15° C. cooling bath was fixed around the reaction mixture. The internal temperature rose to 15°C and then decreased to 5°C over 20 minutes. at this point
30.0 g of sodium metabisulfite was added with stirring at approximately 10° C. over a period of 10 minutes. After another 15 minutes,
The mixture was filtered and the pH of the solution was lowered to 1.2 by adding 170 ml of 6NHCl. The aqueous phase was extracted with chloroform and then with ethyl acetate. The chloroform and ethyl acetate extracts were dried using anhydrous magnesium sulfate and evaporated in vacuo. 10.0 g (yield 16%) of the title compound was obtained from the chloroform solution. 57 g of oil was obtained from the ethyl acetate solution, which was triturated with hexane. A white solid was obtained. This was taken to obtain 41.5 g (yield 66%) of the title compound. It had a melting point of 134°C (decomposed). Elemental analysis values: Calculated values (as C ₈ H ₁₀ BrNO ₅ S): C, 30.78; H, 3.23; Br, 25.60;
4.49; S, 10.27% Actual value: C, 31.05; H, 3.24; Br, 25.54;
N, 4.66; S, 10.21% Reference Example 2 6-α-Chlorpenicillanic acid and 6-α-iodopenicillanic acid were oxidized with potassium permanganate by the method of Reference Example 1 to obtain 6-α-chlorpenicillanic acid 1,1-, respectively. Dioxide and 6-α-iodopenicillanic acid 1,1-dioxide were obtained. Reference example 3 6-β-chlorpenicillanic acid 1,1-dioxide 185 mg of potassium permanganate, 0.063 ml of 85%
An oxidizing solution was prepared from phosphoric acid and 5 ml of water.
This oxidizing solution was mixed with 150 mg of 6 ml in 5 ml of water at 0-5°C.
It was added dropwise to a solution of sodium -β-chlorpenicillanate so that the purple color of potassium permanganate remained. This required about half of the oxidizing solution. At this point, solid sodium bisulfite was added and the potassium permanganate color disappeared and the reaction mixture was filtered. Add ethyl acetate to the solution and adjust the pH.
Adjusted to 1.8. The layers were separated and the aqueous layer was further extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried and evaporated in vacuo to give 118 mg of the title compound. The NMR spectrum (in CD ₃ COCD ₃ ) showed the following absorption. 5.82 (d, 1H), 5.24 (d, 1H) 4.53 (s,
1H), 1.62 (s, 3H) and 1.50 (s, 3H)
ppm. The above product was dissolved in tetrahydrofuran and an equal amount of water was added. PH with dilute sodium hydroxide solution
Adjusted to 6.8. Tetrahydrofuran was removed by vacuum evaporation and the remaining aqueous solution was lyophilized.
This gave the sodium salt of the title compound. Reference example 4 6-β-bromopenicillanic acid 1,1-dioxide A solution of 255 mg of sodium 6-β-bromopenicillanate in 5 ml of water was added with 140 mg of potassium permanganate, 0.11 ml of 85% phosphoric acid and 5
A solution prepared from ml of water at 0-5°C was added. The PH was maintained at 6.0-6.4 during this addition. The reaction mixture was stirred for 15 minutes at PH 6.3 and the purple solution was covered with ethyl acetate. The PH was adjusted to 1.7 and 330 mg of sodium bisulfite was added. After 5 minutes, the layers were separated and the aqueous layer was further extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried over MgSO ₄ and evaporated in vacuo. 216 mg of the title compound as white crystals were obtained. NMR spectrum (in D ₂ O) is 5.78 (d, 1H, J = 4 Hz),
5.25 (d, 1H, J=4Hz), 4.20 (s, 1H), 1.65
(s, 3H) and 1.46 (s, 3H) ppm. Reference Example 5 6-β-iodopenicillanic acid 1,1-dioxide 6-β-iodopenicillanic acid 1,1-dioxide was oxidized with potassium permanganate according to the method of Reference Example 4 to obtain 6-β-iodopenicillanic acid 1,1-dioxide. Reference Example 6 Pivaloyloxymethyl 6-α-brompenicillanate 1,1-dioxide To a solution of 394 mg pivaloyloxymethyl 6-α-brompenicillanate in 10 ml dichloromethane was added 400 mg of 3-chlorofiltrate at 0 to 5°C. Benzoic acid was added. The reaction mixture was stirred at 0-5°C for 1 hour,
Stirred at 25°C for 24 hours. The reaction mixture was filtered and evaporated in vacuo to give the title compound. Example 1 Penicillanic acid 1,1-dioxide 9.4 g of 6-α-bromopenicillanic acid 1,1-dioxide was added to 100 ml of water at 22°C, followed by enough 4N NaOH solution to give a stable pH of 7.3.
To the resulting solution was added 2.25 g of 5% palladium on charcoal followed by 6.9 g of dipotassium phosphate trihydrate. Then this mixture is 3.5-1.8Kg/cm ²
The mixture was shaken under a hydrogen atmosphere at a pressure of . When hydrogen consumption ceased, the solid was removed, the aqueous solution was covered with 100 ml of ethyl acetate, and the pH was adjusted to 5.0 to 1.5 with 6NHCl.
decreased to The layers were separated and the aqueous phase was further extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried using anhydrous magnesium sulfate, and evaporated in vacuo. The residue was triturated with ether and the solid was collected, 4.5g (yield 65%)
The title compound was obtained. Elemental analysis value: Calculated value as C ₈ H ₁₁ NO ₅ S:
C, 41.20; H, 4.75; N, 6.00; S, 13.75% Actual value:
C, 41.16; H, 4.81; N, 6.11; S, 13.51% Example 2 Pivaloyloxymethyl penicillanate 1.1-
Dioxide 3 ml to a solution of 1.0 g pivaloyloxymethyl 6-α-bromopenicillanate in 10 ml methanol
1M sodium bicarbonate and 200mg charcoal loading 10%
of palladium was added. The reaction mixture was shaken vigorously under a hydrogen atmosphere at a pressure of about 5 Kg/cm ² until hydrogen consumption ceased. The mixture was then filtered and most of the methanol was removed by vacuum evaporation. Ice and ethyl acetate were added to the residue to adjust the pH to 8.5. Separate each layer, wash the organic layer with water,
Dry over Na ₂ SO ₄ and evaporate in vacuo to give the title compound. Reference example 7 6-α-brompenicillanate pivaloyloxymethyl 1,1-dioxide 4.26 g potassium permanganate, 2.65 g 85%
An oxidizing solution was prepared by combining phosphoric acid and 40 ml of water. This mixture was stirred for 1 hour and slowly added to a stirred solution of 5.32 g of pivaloylmethyl 6-α-brompenicillanate in 70 ml of acetone and 10 ml of water at 5-10° C. over 20 minutes. The mixture was stirred at 5°C for 30 minutes and 100ml of ethyl acetate was added. After a further 30 minutes, a solution of 3.12 g of sodium bisulfite in 30 ml of water was added over 15 minutes at approximately 10°C. Stirred for an additional 30 minutes at 5°C and filtered the mixture. The organic phase was separated and washed with saturated sodium chloride solution. The dried organic phase was evaporated to give 5.4 g of the title compound as an oil. This slowly crystallized. NMR spectra (in CDCl ₃ ) are 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
showed blotting. Example 3 Pivaloyloxymethyl penicillanate 1,1-
Dioxide 4.4 g 6-α- in 60 ml tetrahydrofuran
Pivaloyloxymethyl brompenicillanate 1.
A solution of 1-dioxide was added to 0.84 g of sodium bicarbonate in 12 ml of water. This solution was mixed in the presence of 2.0 g of 5% palladium on charcoal under a hydrogen atmosphere.
Shake at 51 psig. The reaction mixture was then filtered and the residue was washed with 100ml ethyl acetate and 25ml water. The liquid and washing liquid were separated at any time. The organic phase was washed with saturated brine, dried (MgSO ₄ ) and evaporated to give the title compound as an oil. 100 ml of hexane was slowly added to this solution to collect the precipitate. Yield 2.4g. NMR spectrum (in DMSO-d ₆ ) is 5.75 (q, 2H),
5.05 (m, 1H), 4.40 (s, 1H), 3.95−2.95
(m, 2H), 1.40 (s, 3H), 1.25 (s, 3H) and 1.10 (s, 9H) ppm. Reference Example 8 6,6-Dibrompenicillanic acid 1,1-dioxide 300 ml of water was added to the dichloromethane solution of 6,6-dibrompenicillanic acid obtained from Production Example K, and then 105 ml of 3N sodium hydroxide was added. was added dropwise over 30 minutes. PH stabilized at 7.0. The aqueous phase was removed and the organic phase was extracted twice with 100 ml each of water. Add 59.25 g of potassium permanganate, 18 ml of concentrated phosphoric acid and
A solution consisting of 600 ml of water was added until the pink color of the permanganate no longer disappeared. This includes
It took 50 minutes and required 550 ml of the above permanganate solution. At this point 500ml of ethyl acetate was added and the PH was lowered to 1.23 by addition of 105ml of 6NHCl. Then add 250ml of 1M sodium bisulfite solution.
Addition was made over 10-15 minutes at approximately 10°C. The PH was maintained at 1.25-1.35 using 6NHCl during the addition of the sodium bisulfite solution. The aqueous phase was saturated with sodium chloride and the two phases were separated. This aqueous solution was further extracted with two 150 ml portions of ethyl acetate, and the ethyl acetate solution was washed with brine and dried over MgSO ₄ . As a result, 6.6-
An ethyl acetate solution of dibrompenicillanic acid 1,1-dioxide was obtained. 6,6-Dibrompenicillanic acid 1,1-dioxide could be isolated by vacuum evaporation of the solvent. The melting point of a sample obtained by a similar method was 201°C (decomposed). NMR spectrum (CDCl ₃ /
DMSO−d ₆ ) is 9.35 (s, 1H), 5.30 (s, 1H),
4.42 (s, 1H), 1.63 (s, 3H) and 1.50
It showed absorption at (s, 3H) ppm. IR spectrum (KBr tablet) is 3846−2500, 1818, 1754, 1342
and showed absorption at 1250-1110 cm ^-1 . Reference example 9 6-chloro-6-iodopenicillanic acid 1,1-
Dioxide To a solution of 4.9 g of 6-chloro-6-iodopenicillanic acid in 50 ml of dichloromethane was added 50 ml of water and the PH was raised to 7.2 using 3N sodium hydroxide. The layers were separated and the aqueous phase was cooled to 5°C. To this solution was added dropwise over 20 minutes a premixed solution made from 2.61 g potassium permanganate, 1.75 ml concentrated phosphoric acid and 50 ml water. The pH was maintained at 6 and the temperature below 10° C. during this addition. At this point the pH was adjusted to 1.5 by adding 100 ml of ethyl acetate. 50ml of this mixture
10% sodium bisulfite was added. The temperature was kept below 10° C. during this addition and the pH was maintained at about 1.5 by addition of 6NHCl. The pH was lowered to 1.25 and the layers were separated. The aqueous phase was saturated with sodium chloride and extracted with ethyl acetate. The organic solution was then washed with brine, dried over MgSO ₄ and evaporated in vacuo to give 4.2 g of the title compound, mp 143-145°C. NMR spectrum (CDCl ₃ ) is 4.86 (s,
1H), 4.38 (s, 1H), 1.60 (s, 3H) and
Absorption was observed at 1.43 (s, 3H) ppm. IR spectrum (KBr tablet) is 1800, 1740 and 1250−1110 cm
^-1 showed absorption. Reference example 10 6-bromo-6-iodopenicillanic acid 1,1-
Dioxide To a solution of 6.0 g of 6-bromo-6-iodopenicillanic acid in 50 ml of dichloromethane was added 50 ml of water. PH 7.3 using 3N sodium hydroxide solution
The aqueous phase was removed. The aqueous phase was cooled to 5°C and a premixed solution of 284 g of potassium permanganate in 2 ml of concentrated phosphoric acid and 50 ml of water was added dropwise at 5-10°C. This addition took 20 minutes. At this point 50ml of ethyl acetate was added and the PH of the mixture was lowered to 1.5 using 6NHCl. To this two-phase system was added 50 ml of 10% sodium bisulfite while maintaining the pH at approximately 1.5 by addition of 6NHCl. A further 50ml of ethyl acetate was added to reduce the pH to 1.23. The layers were separated and the aqueous phase was saturated with sodium chloride. The saturated solution was extracted three times with 50 ml portions of ethyl acetate, and the ethyl acetate layer was washed with brine.
Dry with _MgSO4 and evaporate in vacuo. The residue was dried under high vacuum to give the title compound with a melting point of 145-147°C.
4.2g was obtained. MNR spectrum (CDCl ₃ ) is 4.90 (s, 1H),
4.30 (s, 1H), 1.60 (s, 3H) and 1.42
It showed absorption at (s, 3H) ppm. IR spectrum (KBr tablets) is 1800, 1740, 1330 and 1250−
It showed absorption at 1110 cm ^-1 . Example 4 Penicillanic acid 1,1-dioxide The ethyl acetate solution of 6,6-dibromopenicillanic acid 1,1-dioxide obtained in Reference Example 8 was
ml of saturated sodium bicarbonate solution and 8.88 g of 5% palladium on charcoal catalyst. The mixture was shaken under an atmosphere of hydrogen at a pressure of about 5 Kg/cm ² for about 1 hour. The catalyst is removed and the aqueous phase of the liquid
The pH was adjusted to 1.2 with 6NHCl. The aqueous phase was saturated with sodium chloride. The layers were separated and the aqueous phase was further extracted with three 200 ml portions of ethyl acetate. The ethyl acetate solution was cooled, dried over MgSO ₄ and evaporated in vacuo to yield 33.5 g of penicillanic acid 1,1-dioxide (calculated from 6-aminopenicillanic acid).
% yield) was obtained. This product was dissolved in 600 ml of ethyl acetate, the solution was decolorized using activated carbon,
The solvent was removed by vacuum evaporation. The product was washed with hexane. This gave 31.0 g of pure product. Example 5 Penicillanic acid 1,1-dioxide To a stirred suspension of 786 mg of 6-chloro-6-iodopenicillanic acid 1,1-dioxide in 10 ml of benzene was added 0.3 ml of triethylamine, followed by
0.25 ml of trimethylsilyl chloride was added at approximately 0°C. Stirring was continued for 5 minutes at about 0°C and then for 30 minutes at the reflux temperature of the solvent. The reaction mixture was cooled to 25°C, the precipitate was removed, and the liquid was cooled to about 0°C.
1.16 g of tri-n-butyltin hydride and a few mg of azobisisobutyronitrile were added. The reaction mixture was stirred and irradiated with UV light for 1 hour at about 0° C. and then stirred for 3.5 hours at the reflux temperature of the solvent. Further tri-n-butyltin hydride (1.1 ml) and a catalytic amount of azobisisobutyronitrile were added and stirring at reflux temperature and irradiation continued for a further 1 hour. The reaction mixture was then diluted with 50 ml of cold
% sodium bicarbonate and the two-phase system was stirred for 30 minutes. Add ethyl acetate (50ml) and adjust the pH.
Adjusted to 1.5 with 6NHCl. The layers were separated and the aqueous phase was extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried over NgSO ₄ and evaporated in vacuo. The residue was triturated with hexane and taken to give 0.075 mg of the title compound. Example 6 Penicillanic acid 1,1-dioxide 0.874 g of 6 in 10 ml of benzene at approximately 5°C
To the stirred suspension of -bromo-6-iodopenicillanic acid was added 0.3 ml of triethylamine followed by 0.25 ml of trimethylsilyl chloride. 5 at about 5℃
minutes, and stirring was continued for an additional 30 minutes at the reflux temperature of the solvent. The reaction mixture was cooled to room temperature and the solids were removed. The liquid was cooled to about 5 DEG C. and 1.05 ml of tri-n-butyltin hydride and a catalytic amount of azobisisobutyronitrile were added. The mixture was irradiated with UV light for 1 hour at about 5° C. and then 30 ml of cold 5% sodium bicarbonate was added. Stir this mixture for 30 minutes,
Then 50ml of ethyl acetate was added. this mixture
Acidified to pH 1.5 and separated layers. The aqueous layer was extracted twice with 25 ml each of ethyl acetate, and the ethyl acetate layer was washed with brine.
Dry with _MgSO4 and evaporate in vacuo. The residue was dried under high vacuum and 30 ml of hexane was added. The insoluble product was removed to give 0.035 g of the title compound. Reference example 11 Pivaloyloxymethyl 6,6-dibrompenicillanate 1,1-dioxide To a solution of 4.73 g pivaloyloxymethyl 6,6-dibrompenicillanate in 15 ml dichloromethane, 3.80 g 3-Chlorperbenzoic acid was added at 0-5°C. The reaction mixture was heated at 0-5°C for 1 hour, then
Stirred at 25°C for 24 hours. The filtered reaction mixture was evaporated to dryness in vacuo and the residue was partitioned between ethyl acetate and water, the pH of the aqueous phase was adjusted to 7.5 and the phases were separated. The ethyl acetate layer was dried over Na ₂ SO ₄ and evaporated in vacuo to give the title compound. Example 7 Pivaloyloxymethyl penicillanate 1,1-
Dioxide To a solution of 1.0 g pivaloyloxymethyl 6,6-dibrompenicillanate 1,1-dioxide in 10 ml methanol was added 3 ml 1M sodium bicarbonate and 200 mg 10% palladium on charcoal. The reaction mixture was vigorously shaken under a hydrogen atmosphere at a pressure of about 5 Kg/cm ² until hydrogen consumption ceased. The mixture was then filtered and most of the methanol was removed by vacuum evaporation. Water and ethyl acetate were added to the residue to adjust the pH to 8.5. The layers were separated and the organic phase was washed with water, dried over Na ₂ SO ₄ and evaporated in vacuo. This gave pivaloyloxymethyl penicillanate 1,1-dioxide. Reference example 12 Pivaloyloxymethyl 6-dibrompenicillanate 1,1-dioxide
6-Dibrompenicillanic acid 1,1-dioxide
A stirred solution of 3.92 g was cooled to 0° C. and then 1.29 g of diisopropylethylamine was added. Then 1.5 g of chloromethyl pivalate was added. The reaction mixture was diluted with 25ml ethyl acetate and 25ml water. The layers were separated and the aqueous phase was extracted with ethyl acetate. The ethyl acetate layer was always washed sequentially with cold 5% sodium bicarbonate, water, and brine. The ethyl acetate solution was then treated with Darco (activated carbon), dried over MgSO ₄ and evaporated in vacuo to give 21 g of a brown oil. This oil was chromatographed on 200 g of silica gel using dichloroethane as eluent. The fractions containing the desired compound were then chromatographed again on silica gel to yield 0.025 g of the title compound. NMR spectrum (CDl ₃ ) is 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)
It showed absorption at ppm. Example 8 Pivaloyloxymethyl penicillanate 1,1-
Dioxide To a stirred solution of 60 mg of pivaloyloxymethyl 6,6-dibrompenicillanate 1,1-dioxide in 5 ml of benzene was added 25 μ of tri-n-butyltin hydride, then A catalytic amount of azobisbutyronitrile was added. The reaction mixture was cooled to about 5°C and then subjected to UV irradiation for 1 hour. The reaction mixture was poured into 20 ml of cold 5% sodium bicarbonate and stirred for 30 minutes. Ethyl acetate was added to adjust the pH of the aqueous phase to 7.0. The layers were separated and the aqueous phase was further extracted with ethyl acetate. Remove the ethyl acetate solution, wash with brine,
Dry with _MgSO4 and evaporate in vacuo. The residue was dried under high vacuum for 3 minutes. This gave 70 mg of a yellow oil, which was found by NMR spectroscopy to contain the title compound as well as some impurities with n-butyl groups. Reference example 13 6,6-dibrompenicillanic acid 1-(ethoxycarbonyloxy)ethyl 1,1-dioxide 2.26 g of 6,6-dibrompenicillanic acid 1,1
-dioxide, 1.02 ml of 1-(ethoxycarbonyloxy)ethyl chloride, 1.32 ml of diisopropylethylamine and 10 ml of N.N-dimethylformamide was stirred at room temperature for 28 hours.
The reaction mixture was diluted with 100 ml of ethyl acetate and
Washed successively with water, dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The ethyl acetate solution was dried and evaporated in vacuo to give 1.50 g of an oil which was chromatographed on silica gel to give 353 mg of the title compound. Some 1-(ethoxycarbonyloxy)ethyl 6-brompenicillanate was present. Example 9 Penicillanic acid 1-(ethoxycarbonyloxy) 1,1-dioxide A 230 mg portion of the title compound of Reference Example 13 was dissolved in 10 ml of toluene. Add 0.4ml of hydrogenated trichloride to this.
n-Butyltin was added followed by 0.164g of azobisisobutyronitrile and the mixture was heated at 70-80°C for 3.5 hours. The solvent was removed by vacuum evaporation and the residue was dissolved in 25ml acetonitrile. The acetonitrile solution was washed several times with hexane and evaporated in vacuo. The residue was dissolved in ether and washed with 5% potassium fluoride solution and saturated sodium chloride solution. The ether solution was dried over Na ₂ SO ₄ , evaporated in vacuo and the residue was chromatographed on silica gel to give 0.043 g of the title compound. NMR spectra (in CDCl ₃ ) are 6.75 (m), 4.60 (m), 4.30
(m), 4.15 (s), 4.00 (s), 3.30 (d) and
It showed absorption at 1.75-1.00 (m) ppm. Preparation Example A 6-Chloro-6-iodopenicillanic acid To 3.38 g of mium monochloride in 30 ml of dichloromethane was added 11.1 ml of 2.5N sulfuric acid and then 1.92 g of sodium nitrite with stirring at 0-5°C. At this point, add 3.00 g of 6-aminopenicillanic acid in one portion and continue stirring at 0-5°C for 30 minutes. 22.8 ml of 1M sodium sulfite solution was added portionwise to the reaction mixture and the layers were separated. The aqueous layer was further washed with dichloromethane and then all organic phases were washed with saturated sodium chloride solution. This dichloromethane solution was dried with Na ₂ SO ₄ and evaporated in vacuo.
3.48g of the title compound was obtained. The above product was dissolved in 30ml of tetrahydrofuran and then 30ml of water was added. The pH was adjusted to 6.8 with dilute sodium hydroxide and the tetrahydrofuran was removed in vacuo. Lyophilize the remaining aqueous phase and
The residue was washed with diethyl ether. This results in
3.67 g of the title compound was obtained as the sodium salt. Preparation Example B 6-β-Chlorpenicillanic acid 2.95 g of 6-chloro-6-iodopenicillanic acid sodium salt was converted to the free acid and 125
Dissolve in ml of benzene. 1.08 ml of triethylamine was added to this solution and the mixture was cooled to 0-5°C. 0.977 ml of trimethylsilyl chloride was added to the cooled mixture and the reaction mixture was stirred at 0-5°C for 5 hours, 25°C for 62 minutes, and 50°C for 30 minutes.
The reaction mixture was cooled to 25°C and triethylamine hydrochloride was removed. To this solution was added 15 mg of azobisisobutyronitrile and 2.02 ml of tri-n-butyltin hydride. The mixture was cooled and maintained at approximately 20°C while being UV irradiated for 15 minutes. The solvent was then evaporated in vacuo and the residue was dissolved in a 1:1 mixture of tetrahydrofuran and water. PH
7.0 and evaporate the tetrahydrofuran 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 layer was removed. The aqueous phase was further extracted with ethyl acetate and the ethyl acetate solution was kept dry and evaporated in vacuo. This gave 980 mg of 6-β-chlorpenicillanic acid. The above product was dissolved in tetrahydrofuran and an equal volume of water was added. The pH was adjusted to 6.8 and tetrahydrofuran was removed by vacuum evaporation. The remaining aqueous phase was freeze-dried to obtain 850 mg of sodium 6-β-chlorpenicillanate. NMR spectrum ( _D2O ) is 5.70 (d, 1H, J
= 4Hz), 5.50 (d, 1H, J = 4Hz), 4.36 (s,
1H), 1.60 (s, 3H), and 1.53 (s, 3H)
It showed absorption at ppm. Production example C 6-β-bromopenicillanic acid 5.0g of 6,6-dibromopenicillanic acid, 1.54
A mixture of ml triethylamine and 100 ml benzene was stirred under nitrogen until a solution was obtained. Cool the solution to 0-5°C and add 1.78 ml of trimethylsilyl chloride. This reaction mixture was
Stirred at 50°C for 2-3 minutes and then 35 minutes at 50°C. Filter the cooled reaction mixture and remove the liquid from 0 to 0.
Cooled to 5°C. A small amount of azobisisobutyronitrile was added and 3.68 ml of tri-n-butyltin hydride was added. The reaction flask was irradiated with UV light for 15 minutes and the reaction was stirred at approximately 25° C. for 1.75 hours. The reaction mixture was again UV irradiated for 15 minutes and stirring continued for 2.5 hours. At this point a further small amount of azobisisobutyronitrile was added followed by 0.6 ml of tri-n-butyltin hydride (0.6 ml) and the mixture was irradiated again for 30 minutes. The solvent was removed by vacuum evaporation and 5% sodium bicarbonate and diethyl ether were added to the residue. The two-phase system was shaken vigorously for 10 minutes and then the pH was adjusted to 2.0. The ether layer was removed, dried and evaporated in vacuo to give 2.33g of oil. This oil was converted to the sodium salt by adding 1 equivalent of sodium bicarbonate in water and freezing the resulting solution. The obtained sodium 6-β-brompenicillanic acid salt was contaminated with a small amount of α isomer. The sodium salt was purified by chromatography on Sephadex LH-20 and rechromatographed with homogeneous product. NMR of the product thus obtained
Spectrum (D ₂ O) is 5.56 (s, 2H), 4.25
(s, 1H), 1.60 (s, 3H) and 1.50 (s,
3H) showed absorption at ppm. Preparation D 6-β-iodopenicillanic acid The title compound was obtained by reducing 6,6-diiodopenicillanic acid with tri-n-butyltin hydride according to the method of Preparation B. Preparation Example E 6-α-Pivaloyloxymethyl 6-α-brompenicillanate 6-α in 2 ml of N·N-dimethylformamide
−260 mg of brompenicillanic acid dissolved in a solution of 280 mg
ml of diisopropylethylamine followed by 155 mg
of chloromethyl pivalate and 15 mg of sodium iodide were added. The reaction mixture was stirred at room temperature for 24 hours and diluted with ethyl acetate and water. PH
7.5, separate the ethyl acetate layer and dilute with water 3.
twice and once with saturated sodium chloride solution. The ether acetate solution was dried using aqueous sodium sulfate and evaporated in vacuo to give the title compound. Production Example F 6-halopenicilanic acid was prepared by the method of Production Example E into 3-phthalidyl chloride, 4-crotonolactonyl chloride, γ-butyrolactone-4-yl chloride or the necessary alkanoyloxymethyl chloride, 1-(alkanoyloxy ) Ethyl chloride, 1-methyl-1-(alkanoyloxy)
The following compounds were obtained by reacting with ethyl chloride, alkoxycarbonyloxymethyl chloride, 1-(alkoxycarbonyloxy)ethyl chloride, or 1-methyl-1-(alkoxycarbonyloxy)ethyl chloride. 3-phthalidyl 6-α-chlorpenicillanate 4-crotonolactonyl 6-β-chlorpenicillanate γ-brarolactone-4-yl 6-α-bromopenicillanate Acetoxymethyl 6-β-bromopenicillanate Pivalo 6-β-bromopenicillanate hexanoyloxymethyl 6-α-iodopenicillanate 1-(acetoxy)ethyl 6-β-iodopenicillanate 1-(isobutyryloxy)ethyl 6-α-chlorpenicillanate 1-methyl- 6-β-chlorpenicillanate 1-
(acetoxy)ethyl 6-α-brompenicillanate 1-methyl-1-
(hexanoyloxy)ethyl 6-α-brompenicillanic acid methoxycarbonyloxymethyl 6-α-brompenicillanic acid 1-(ethoxycarbonyloxy)ethyl 6-α-iodopenicillanic acid 1-(butoxycarbonyloxy)ethyl 6-β-iodopenicillanic acid 1-methyl-1-
(methoxycarbonyloxy)ethyl and 1-methyl-1-6-α-chlorpenicillanate
(isopropoxycarbonyloxy)ethyl. Production example G 6,6-diiodopenicillanic acid A mixture of 15.23 g of iodine, 10 ml of 2.5N sulfuric acid, 2.76 g of sodium nitrate and 75 ml of dichloromethane was stirred at 5°C, and 4.32 g of 6-aminopenicillanic acid was added over 15 minutes. 5-10℃ after completion of addition
Stirring was continued for 45 minutes. Then 100ml of 10% sodium bicarbonate was added dropwise. The layers were separated and the aqueous phase was further extracted with dichloromethane. Remove the dichloromethane layer, wash with brine,
Dry with _MgSO4 and vacuum dry. This results in
1.4 g of the title compound was obtained. How much is this6-
It was contaminated with iodopenicillanic acid. The product has a melting point of 58-64°C and its NMR spectrum ( _CDCl3 ) is 5.77 (s, 1H), 4.60 (s, 1H) 1.71
(s, 3H) and 1.54 (s, 3H) ppm. Production Example H Pivaloyloxymethyl 6-α-brompenicillanate 11.2 g of 6-α-brompenicillanic acid, 3.7 g
To a stirred mixture of sodium bicarbonate and 44 ml of N.N-dimethylformamide was added 6.16 g of chloromethyl pivalate dropwise at room temperature for 5 minutes.
Stirring was continued for 66 hours and the reaction mixture was diluted with 100ml ethyl acetate and 100ml water. The layers were separated and the ethyl acetate layer was washed successively with water, saturated brine, saturated sodium bicarbonate solution, water, and saturated brine. The decolorized ethyl acetate solution was dried with MgSO ₄ and evaporated to dryness in vacuo to give 12.8 g (80% yield) of the title compound. Preparation Example I Benzyl 6-α-bromopenicillanate 6-α-bromopenicillanic acid was esterified with benzyl chloride according to the method of Preparation Example H to give the title compound. Yield 83%. NMR spectra (in CDCl ₃ ) are 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
showed absorption. Preparation Example J 2,2,2-Trichloroethyl penicillanate 11.2 g of 6-α in 50 ml of tetrahydrofuran
3.48 g of pyridyl was added over 1 minute to a solution obtained by stirring -bromopenicillanic acid at 0°C. 8.47 g of 2,2,2-trichloroethyl chloroformate was added to the resulting cloudy solution over a period of 10 minutes at a temperature of 0 to 2.
The mixture was added while maintaining the temperature at °C. Stirring was continued for 30 minutes and the cooling bath was removed. Stirring was continued overnight at room temperature. The reaction mixture was heated to 35°C for 5 minutes.
The liquid was evaporated and the residue was dissolved in 100ml ethyl acetate. The ethyl acetate solution was washed successively with saturated sodium bicarbonate, water and saturated brine. The ether acetate solution was then decolorized, dried and concentrated to a small volume. 100 ml of hexane was added to the resulting mixture to remove the solid, yielding 10.5 g of the title compound with a melting point of 105-110°C. NMR spectrum ( _CDCl3 )
are 5.50 (d, 1H), 4.95 (d, 1H), 4.90 (s,
2H), 4.65 (s, 1H), 1.170 (s, 3H) and
It showed absorption at 1.55 (s, 3H) ppm. Production example K 6,6-dibromopenicillanic acid 500ml of dichloromethane was cooled to 5°C, and 119.9
g of bromine, 200 ml of 2.5N sulfuric acid and 34.5 g of sodium sulfate were added. Stir this and add 54.0g of 6
-Aminopenicillanic acid 54.0 g of 6-aminopenicillanic acid was added in portions over 30 minutes while maintaining the temperature at 4-10°C. Stir at 5℃ for 60 minutes, then add 410ml.
of 1.0 M sodium bisulfite was added dropwise over 20 minutes at 5-10°C. The layers were separated and the aqueous phase was extracted twice with 150 ml of dichloromethane. Combine the original dichloromethane layer with the above two extracts and add 6.
A solution of 6-dibrompenicillanic acid was obtained. This solution was used as is in Example 17. Production example L 6-chloro-6-iodopenicillanic acid 4.87 in 100 ml of dichloromethane cooled to 3°C
g of iodine chloride, 10 ml of 2.5N sulfuric acid and 2.76 g of sodium nitrate were added. Stir this and make 4.32g
of 6-aminopenicillanic acid was added portionwise over 15 minutes. Continue stirring for 20 minutes at 0-5℃,
ml of 10% sodium bisulfite solution was added dropwise at about 4°C. Stirring was continued for 5 minutes and the layers were separated. The aqueous phase was extracted with two 50 ml portions of dichloromethane, the dichloromethane solution was washed with brine, dried over NgSO ₄ and evaporated to dryness in vacuo to give the title compound as a tan solid with a melting point of 148-152 °C. Ta.
The NMR spectrum of this product ( _CDCl3 ) is 5.40
(s, 1H), 4.56 (s, 1H), 1.67 (s, 3H) and 1.50 (s, 3H) ppm.
IR spectrum (KBr tablet) showed absorption at 1780 and 1715 cm ^-1 . Production example M 6-bromo-6-iodopenicillanic acid 10ml in 100ml dichloromethane cooled to 5°C
of 2.5N sulfuric acid, 6.21 g of iodine bromide and 2.76 g of sodium sulfate were added. To this mixture was added 4.32 g of 6-aminopenicillanic acid over 15 minutes at 0-5° C. with vigorous stirring. 0-5℃ for another 20 minutes
Stirring was continued at , and 100 ml of 10% sodium bisulfite was added dropwise at 0-10°C, at which point the layers were separated and the aqueous phase was extracted with three 50 ml portions of dichloromethane. The dichloromethane layer was washed with brine, dried over MgSO ₄ and evaporated in vacuo. The residue was dried under high vacuum for 30 minutes to yield 6.0 g of the title compound. Yield 72%, melting point 144-147°C. NMR
Spectrum (CDCl ₃ ) is 5.50 (s, 1H), 4.53
(s, 1H), 1.70 (s, 3H) and 1.53 (s,
3H) showed absorption at ppm. IR spectrum (KBr
tablet) showed absorption at 1785 and 1710 cm ^-1 . The mass spectrum showed a prominent ion at m/e=406. Production Example N 6-Chromium-6-brompenicillanic acid 6-aminopenicillanic acid was diazotized by the method of Production Example M, and reacted with bromine chloride to produce 6-chloro-6-brompenicillanic acid. Production example O pivaloyloxymethyl 6,6-dibrompenicillanate 3.59 g in 20 ml of N.N-dimethylformamide
1.30 g of diisopropylethylamine followed by 1.50 g of chloromethyl pivalate are added to the stirred solution of 6,6-dibromopenicillanic acid 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 diluted with ethyl acetate and water and the PH of the aqueous phase was adjusted to 7.5. The ethyl acetate layer was separated and washed three times with water and once with saturated brine. The ethyl acetate solution was dried over anhydrous sodium sulfate and evaporated in vacuo to give the title compound. Production example P Production example O
3-phthalidyl chloride, 4-crotonolactonyl chloride, γ-butyrolactone-
4-yl chloride or the required alkanoyloxymethyl chloride, 1-(alkanoyloxy)
Reacting with ethyl chloride, 1-methyl-1-(alkanoyloxy)ethyl chloride, alkoxycarbonyloxymethyl chloride, 1-(alkoxycarbonyloxy)ethyl chloride or 1-methyl-1-(alkoxycarbonyloxy)ethyl chloride The following compounds were obtained. 3-phthalidyl 6,6-dibromopenicillanate 4-crotonolactonyl 6-chromium-iodopenicillanate γ-butyrolactonyl 6-brom-6-iodopenicillanate 6-chloro-6-brompenicillanate acetoxymethyl 6-chloro-6 -Pivaloyloxymethyl iodopenicillanate Hexanoyloxymethyl 6,6-dibrompenicillanate 1-(acetoxy)ethyl 6,6-dibrompenicillanate 1-(isobutyryl 6-brom-6-iodopenicillanate) oxy)ethyl 1-methyl-1 6,6-dibrompenicillanate
-(acetoxy)ethyl 1-methyl-1-(hexanoyloxy)ethyl 6-chloro-6-brompenicillanate 6,6-dibrompenicillanate methoxycarbonyloxymethyl 6-chloro-6-iodopenicillanate propoxycarbonyloxymethyl 1-(ethoxycarbonyloxy)ethyl 6,6-dibrompenicillanate 1-(butoxycarbonyloxy)ethyl 6-brom-6-iodopenicillanate 1-methyl-1 6,6-dibrompenicillanate
-(methoxycarbonyloxy)ethyl and 1-methyl-1 6,6-dibrompenicillanate
-(isopropoxycarbonyloxy)ethyl.

Claims (1)

[Claims] 1 formula [In the formula, R ¹ is hydrogen or an ester-forming residue that can be easily hydrolyzed in vivo] In a method for producing a compound of the formula or a pharmaceutically suitable base salt thereof; contacting a compound of formula or a base salt thereof with a reagent selected from the group consisting of alkali metal permanganates, alkaline earth metal permanganates and peroxycarboxylic acids to obtain a compound of formula or a base salt thereof; [Formula and R ¹ are the same as defined above;
X and Y are each hydrogen, chloro, bromine, or iodo; however, X and Y are the same only when they are brome.] (b) The compound produced in step (a) above or its base salt is A process characterized in that dehalogenation is carried out by catalytic hydrogenolysis in an active solvent. 2. Process according to claim 1, characterized in that step (a) is carried out using an alkali metal permanganate. 3. Process according to claim 1, characterized in that step (a) is carried out using potassium permanganate. 4 Step (b) at a pressure in the range of 1 to 100Kg/ ^cm2 , 0.01
0 to 2.5% by weight of a hydrogenolysis catalyst.
4. A method according to any one of claims 1 to 3, characterized in that it is carried out at a temperature in the range of 60 DEG C. and at a pH of 4 to 9. 5. The method according to any one of claims 1 to 4, characterized in that X is bromine and Y is hydrogen. 6. A method according to any one of claims 1 to 4, characterized in that X and Y are both bromine. 7. The method according to any one of claims 1 to 6, wherein R ¹ is hydrogen.