FI70024B - FOERFARANDE FOER FRAMSTAELLNING AV PENICILLANSYRA-1,1-DIOXID OCH DESS ESTRAR - Google Patents

Description

[7S5F ^ 1 ΓΒ1 ANNOUNCEMENT 70094 J | gj | LBJ (11) UTLÄGGNINGSSKRIFT / U U Z M · C (45) Post-examination awarded

Patent me.1 ·.: Sectors 12 10 1000 (51) Kv.lk. '/ Int.CI.1 C 07 D 499/00 (21) Patent application - Patentansökning 80066 1 (22) Application date - Ansökningsdag 0 4. 0 3 .8 0 (23) Start date - Giltighetsdag 04.03.80 (41) Has become public - Blivit offentlig 06.09.80

Patent and Registration Office ..... .. " . . . .. „, r · m (44) Date of issue of the publication. - 31 Qi 0 £

Patent and registration authorities Ansökan utlagd och uti.skriften publicerad (32) (33) (31) Claim claimed privilege — Begärd priority 05.03.79 Ο5.Ο3.79 USA (US) I78O8, 17810 (71) Pfizer Inc., 235 East 42nd Street, New York, New York, USA (72) Bernard Shields Moore, Waterford, Connecticut,

Ronnie D. Carrol 1, East Lyme, Connecticut,

Robert Alfred Volkmann, Ledyard, Connecticut, USA (74) Oy Koister Ab (54) Process for the preparation of penic acid 1,1-dioxide and its esters - Preparation for the preparation of penic acid 1,1-dioxide and 1,1-dioxide of esters

This invention relates to a novel chemical process for the preparation of penicillanic acid 1,1-dioxide and its esters of formula I

O O

? 'J

Γ ich3 I — n — l j (I)

O 'C OOR

wherein R · * · is hydrogen or an ester-forming, easily hydrolysable group in vivo, which is preferably 3-phthalidyl, 4-crotonylactonyl, gamma-butyrolacton-4-yl or a group of formula V or VI

2 70024

R2 O R2 O

-C-O-i-R 4 -C-O-C-O-R 4 '3 13 R R 3 (V) (VI) 23 wherein R and R represent hydrogen or C 1-2 alkyl and R 4 is C 1-5 alkyl, or pharmaceutically acceptable base salts thereof, wherein

(a) a compound of formula II

X-J_v "S ^ H3 l CH (II) i- N ^ 0 COOR1

or a base salt thereof is contacted with a reagent which is an alkali metal permanganate, an alkaline earth metal permanganate or an organic peroxycarboxylic acid to give a compound of formula III

v _γ s - / 3 'CH3 (III) j- N \ Ί 0 COOR1 or a base salt thereof, wherein R1 is as defined above and X and Y are hydrogen, chlorine, bromine or iodine, provided that when X and Y are the same, they must both be bromine; and (b) performing dehalogenation by catalytic hydrogenolysis in an inert solvent.

Penicillanic acid 1,1-dioxide and its in vivo hydrolysable esters are useful as β-lactamase inhibitors and agents that enhance the efficacy of certain β-lactam antibiotics in the treatment of bacterial infections in mammals, and in particular humans. Previously, penicillanic acid 1,1-dioxide and its in vivo readily hydrolyzable esters have been prepared from 6-bromopenicillanic acid or its in vivo readily hydrolyzable ester by debromination to penicillanic acid or its in vivo readily hydrolyzable ester followed by oxidation to 1,1-dioxide. Although the process of the present invention starts from 6-halopenicillanic acid and includes a dehalogenation and oxidation step, it has surprisingly been found that if the oxidation step is performed before the dehalogenation step, the product yield is improved (see Belgian Patent 867,859, issued December 6, 1978 to West German 824 535 for the preparation of penicillanic acid 1,1-dioxide and its in vivo hydrolysable esters).

6-Halopenicillanic acids have been reported by Cignarella et al., Journal of Organic Chemistry, 27, (1962) 2668 and U.S. Patent 3,206,469. The hydrogenolysis of 6-halopenicillanic acids to penicillanic acid is described in British Patent 1,072,108.

Harrison et al. have reported in the Journal of the Chemical Society (London), Perkin I, 1772 (1976): a) oxidation of 6,6-dibromopenicillanic acid with 3-chloroperbenzoic acid to give a mixture of the corresponding β- and β-sulfoxides, b) oxidation of methyl 6,6-dibromopenicillanate with 3-chloroperbenzoic acid to give methyl 6,6-dibromopenicillanate 1,1-dioxide, c) oxidation of methyl 6 - (4) chloropenicillanate with 3-chloroperbenzoic acid to give the corresponding a mixture of β-sulfoxides, and d) oxidation of methyl 6-bromopenicillanate with 3-chloroperbenzoic acid to give a mixture of ε-sulfoxides and β-sulfoxides, respectively.

Clayton has reported in the Journal of the Chemical Society (London), (C), 2123 (1969): 4,70024 a) Preparation of 6,6-dibromo and 6,6-diiodopenicillanic acid, b) Oxidation of 6,6-dibromopenicillanic acid i) to give a mixture of the corresponding sulfoxides, c) hydrogenolysis of methyl 6,6-dibromopenicillanate to give methyl 6-X-bromopenicillanate, d) hydrogenolysis of 6,6-dibromopenicillanic acid and its methyl ester to give penicillanic acid and its methyl ester, respectively. , and e) hydrogenolysis of a mixture of methyl 6,6-diiodopenicillanate and methyl 6-> X-iodopenicillanate to give pure methyl 6-X-iodopenicillanate.

Details relating to the use and synthesis of the compounds of the formula I are given in West German Application No. 2,824,535.

The novel process according to the invention for the preparation of penicillanic acid 1,1-dioxide of the formula I and its esters and their salts is characterized in that step (a) is carried out first and then the product obtained in step (a) is dehalogenated according to step (b).

The process according to the invention is a new, even better process for the preparation of compounds having antibacterial and beta-lactamase inhibitory activity known from the applicant's previous FI patent application 781800; in the new method the yield is better than that. in a known method.

Both the new process according to the invention and the process known from FI patent application 781800 are shown in the following reaction scheme, in which R, X and Y have the same meaning as above: 5 70024

Reaction scheme Y ^ 1 rCH3 cr N '' 'Coor1 / ,,' l \

V H? / ° H

Γ c tCH o - e, CH_ X ,, / _ X '3 __SX'; '3 ί Γ <^ 3 i! CH3 / N "'COOR1 O'" N _ // '' COOR1 (III) (IIIA) * 0 0 H \ f _: - / S \ 0-CH3 ί rCH3 - N 1, 1

0 'COOR

(I)

In the process of the invention, compound II is converted to compound III, which compound is then converted to compound I. In a known process, compound II is converted to compound IIIA, which compound is converted to compound I.

Looking at the yields obtained by the different methods, it is found that according to Examples 1 and 4, which describe the process according to the invention, where X is bromine and Y and R 1 are hydrogen, the yields are 82% (16% x 66%) (Example 1) and 65% ( Example 4), where the total yield is 53% (82% x 65%).

Accordingly, according to Examples 5 and 6 illustrating the process of the invention, wherein X is bromine, Y is hydrogen and R · * · is an easily hydrolyzable ester-forming group (pivaloyloxymethyl), the yields are 94% and 67%, with a total yield of 63%.

6 70024

Examples 11 and 14 illustrate the process of the invention when X and Y are both bromine and are hydrogen. However, the amount of starting material used in Example 11 is not specified, but the product obtained in Preparation H was used as such without isolation. On the other hand, using the amount of 6-aminopenicillanic acid used as a starting material in Preparation H (54.0 g) and the amount of product (of formula I) shown in Example 14 (31.0 g) are obtained for the reaction sequence 6-aminopenicillanic acid-> compound II compound III->

compound I

overall yield 53%. Thus, the reaction sequence

compound II compound III-> compound I

the total yield cannot be less than 53%.

Based on the above, the overall yield of the new process according to the application is at least 53%.

Examining the method presented in FI patent application 781800 (compound II-> compound IIIA—> compound I), it is found that for step

compound II - => compound IIIA

no yield is shown and that the best yield for step compound IIIA -> compound I

is 78% (see Example 1 of FI patent application 781800). To find out the stage

compound II-> compound IIIA

yield, the applicant prepared penicillanic acid according to a known method, wherein the the yield of the phase was 35% (see comparative example below). Based on this, the overall yield of the known method is at best 27% (35% x 78%).

From the above, it can be stated that the new process according to the invention gives a substantially double yield compared to the known process; yields are 53% and 27%, which is of great importance in industry.

A preferred way to carry out process step (b) is to contact the product obtained in step (a) with hydrogen in an inert solvent at a pressure of about 1 to about 100 kg / cm 3, at a temperature of about 0 to 60 ° C and a pH of about 4 to 9 hydrogens. in the presence of a lysis catalyst. Usually the amount of hydrogenolysis 70024 catalyst is about 0.01 to 2.5% by weight and preferably about 0.1 to 1.0% by weight based on the compound of formula III.

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

When X and Y both represent chlorine, it is difficult to obtain a compound of formula II. When X and Y both represent iodine, step (a) of the process of the invention proceeds uncomfortably slowly.

This invention relates to the preparation of compounds of formula I and throughout this patent these compounds are referred to as penicillanic acid derivatives and have the following basic structure:

B

s (^ CH3 (IV) (/ -N-ί

σ COOH

In penicillanic acid derivatives, the dashed line connecting the substituent and the bicyclic ring indicates that the substituent is below the level of the core. Such a substituent is said to have a Ck configuration. The solid line connecting the substituent and the two-ring core indicates that the substituent is above the level of the core. This latter configuration is called the β-configuration. Thus, for example, in formula II, the group X has the <configuration and the group Y has the <configuration.

When this patent has an ester-forming, easily in vivo hydrolysable residue, it is intended to be derived from an alcohol of formula R 2 OH such that part of the compound of formula I is a ester group. In addition, R "* · is such that the group COOR ^ is easily cleaved in vivo to the free carboxyl group (COOH). This means that for the R1-type group, when β 70024 of formula I

a compound having an ester-forming, easily hydrolyzable group in vivo is contacted with mammalian blood or tissue, a compound of formula I wherein R · 1 · is hydrogen is readily formed. The groups R1 are known in the penicillin technique. In most cases, they improve the absorption properties of the penicillin compound. In addition, the group R 1 must be such that it imparts pharmaceutically acceptable properties to the compound of formula I and degrades to pharmaceutically acceptable moieties upon cleavage in vivo. The groups R 1 are known and are readily recognized by those skilled in the art of penicillin technology (see, e.g., West German Application No. 2,517,316). Specific examples of R 1 groups include 3-phthalidyl, 4-crotonylactonyl, gamma-butyrolactone-4-yl and groups of formula V or VI

R2 O R2 O

I II 4 I II 4

-C-O-C-R -C-O-C-O-R

1 3 I 3

R RJ

(V) (VI) 2 3 4 wherein R and R 0 represent hydrogen or C 1-6 alkyl and R 4 is C 1-6 alkyl. However, preferred groups R are 7-alkanoyloxymethyl, (alkanoyloxy) ethyl-7, C5-8-methyl-1- (alkanoyloxy) ethyl, C3-8-alkoxycarbonyloxymethyl, (alkoxycarbonyloxy) ethyl-7, C (-g-1-ethyl) -ethyl. - (alkoxycarbonyloxy) ethyl-1,3-phthalidyl, 4-crotonylactonyl or gamma-butyrolacton-4-yl.

3-Phthalidyl, 4-crotonylactonyl and gamma-butyrolacton-4-yl correspond to formulas VII, VIII and IX, respectively. The wavy lines denote two epimers or a mixture thereof.

.-Vi Λ Λ oi o I o

V V

O 0 0 (VII) (VIII) (IX) 9 70024 In step (a) of the process of this invention, the sulfide group of a compound of formula II is oxidized to a sulfone group to form a compound of formula III. Several oxidants known in the art can be used in this process to oxidize sulfides to sulfones. However, particularly nice reagents are alkali metal permanganates, such as sodium and potassium permanganate, alkaline earth metal permanganates, such as calcium and barium permanganate, and organic peroxycarboxylic acids, such as peracetic acid and 3-chloroperbenzoic acid.

When a compound of formula II wherein X, Y and are as defined above is oxidized with metal permanganate to the corresponding compound of formula III, the reaction is usually carried out by treating a compound of formula II with about 0.5 to 10, preferably about 1 to 4 molar equivalents of permanganate. in a suitable reaction-inert solvent system. A suitable reaction-inert solvent system is such that it does not adversely affect the starting materials or the product, and water is usually used. If desired, a co-solvent which mixes with water but does not react with permanganate may be added. The reaction can be carried out at a temperature of about -30 to + 50 ° C, and preferably at about -10 to + 10 ° C. At a temperature of about 0 ° C, the reaction normally ends in a short time, e.g. an hour. Although the reaction may be carried out under neutral, basic or acidic conditions, it is preferable to operate at a pH of about 4 to 9 and preferably 6 to 8. However, it is necessary to select conditions which avoid degradation of the β-lactam ring system of the compounds of formulas II and III. It is even often advantageous to buffer the pH of the reaction medium close to the neutral point. The product is isolated in the usual way. Usually the excess permanganate is decomposed with sodium bisulfite and if the product has precipitated from solution it is isolated by filtration. It is separated from the manganese dioxide by extraction into an organic solvent and the solvent is removed by evaporation. Alternatively, when the product is dissolved at the end of the reaction, it is isolated in the usual manner by extraction with solvents.

ίο 7 0 0 2 4

When a compound of formula II wherein X, Y and R * are as defined above is oxidized with a peroxycarboxylic acid to the corresponding compound of formula III, the reaction is usually carried out by treating a compound of formula II with about 1-6, preferably about 2.2 molar equivalents of oxidant inert to the reaction. , in an organic solvent. Typical solvents include chlorinated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane and ethers such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane. The reaction is normally carried out at a temperature of about -30 to + 50 ° C, preferably about 15 to 30 ° C. At about 25 ° C, the reaction time is usually about 2 to 16 hours. Normally the product is isolated by removing the solvent by evaporation. The reaction product can be purified by conventional methods well known in the art. Alternatively, it can be used directly in step (b) without further purification.

Step (b) of the present process is a dehalogenation reaction. A convenient procedure for doing this is to stir or shake a solution of a compound of formula III in a hydrogen atmosphere or a hydrogen ring mixed with an inert diluent such as nitrogen or argon in the presence of a hydrogenolysis catalyst. Suitable solvents for this hydrogenolysis reaction are those which almost completely dissolve the starting compound of formula III, but which do not themselves hydrogenate or hydrogenolyze. Examples of such solvents are ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, low molecular weight esters such as ethyl acetate and butyl acetate, tertiary amides such as Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide and N-dimethylacetamide. and mixtures thereof. In addition, the reaction mixture is usually buffered at a pH of about 4 to 9, and preferably about 6 to 8. Borate and phosphate buffers are generally used. Typically, the reaction is carried out by introducing hydrogen gas into the reaction medium in a sealed vessel containing a compound of formula III, a solvent and hydrogen. The pressure in the reaction vessel can range from about 1 to about 100 kg / cm 2. When the atmosphere in the reaction vessel is formed from nearly pure hydrogen, the recommended pressure range is about 2 to 2 5 kg / cm. Generally, the hydrogenolysis is performed at a temperature of about 0 to 60 ° C, and preferably about 25 to 50 ° C. When using the recommended temperature and pressure values, hydrogenolysis usually takes place within a few hours, e.g. about 2-20 hours. The catalysts used in this hydrogenolysis reaction are of the type known in the art for such conversion. Typical examples are precious metals such as nickel, palladium, platinum and rhodium. The amount of catalyst is usually about 0.01 to 2.5%, preferably about 0.1 to 1.0% by weight based on the compound of formula III. It is often convenient to suspend the catalyst on an inert support, and a particularly suitable catalyst is on an inert support such as palladium suspended on carbon.

Other methods can be used to remove halogen from the reducing compound of formula III, i.e. to carry out step (b). For example, X and Y can be removed using a soluble metal reduction system, such as zinc dust in acetic acid or formic acid or phosphate buffer, according to known methods. Alternatively, step (b) may be performed with stannous hydride, e.g. trialkyltin hydride such as tri-n-butyltin hydride.

If it is desired to prepare a compound of formula I wherein R * is hydrogen, one skilled in the art will recognize that a compound of formula II containing hydrogen may be treated according to the process of the invention in steps (a) and (b). That is, in this case, the 6-halogen or 6,6-dihalogen derivative of the penicillanic acid having a free carboxy group in the 3-position is oxidized and then dehalogenated. In this case, it is also possible to use in step (a) or in step (b) a starting material whose carboxy group in the 3-position is protected by a conventional penicillin carboxy-protecting group. The protecting group may be removed during or after step (a) or step (b) when the free carboxy group is recovered. In this case, various protecting groups commonly used in penicillin technology can be used to protect the 3-carboxy group. The main requirements for a protecting group are that it be associated with said compound of formula II or III and be removable from said compound of formula I or III under conditions in which the β-lactam ring system remains virtually intact. Typical protecting groups include, for example, a tetrahydropyranyl group, a trialkylsilyl group, a benzyl group, substituted benzyl groups (e.g., 4-nitrobenzyl), a benzhydryl group, a 2,2,2-trichloroethyl group, a tert-butyl group, and a phenacyl group. Although not all protecting groups work in all situations, one skilled in the art will readily be able to select a particular group that is useful in a particular situation (see also U.S. Patent Nos. 3,632,850 and 3,197,466, GB 1,041,985, and Woodward et al., Journal of the American Chemical Society 88 (1966) 852, Chauvette, Journal of Organic Chemistry 36 (1971) 1259, Sheehan et al., Journal of Organic Chemistry 29 (1964) 2006 and "Cephalosporin and Penicillins, Chemistry and Biology", edited by HE Flynn, Academic Press, Inc., 1972). The carboxy-protecting group of penicillin is removed in the usual manner, taking into account the instability of the β-lactam ring system.

6β-Chloropenicillanic acid and 6α-bromopenicillanic acid are prepared by diazotizing 6-aminopenicillanic acid in the presence of hydrochloric acid and hydrobromic acid, respectively / Journal of Organic Chemistry 27 (1962) 2668.7. 6 β-Iodopenicillanic acid is prepared by diazotizing 6-aminopenicillanic acid in the presence of iodine followed by hydrogenation / Clayton, Journal of the Chemical Society (C), 2123 -penicillanic acid is prepared by reduction with 6-chloro-6-iodopenicillanic acid, 6,6-dibromopenicillanic acid and 6,6-diiodopenicillanic acid with tri-n-butyltin hydride, respectively.

6-Chloro-6-iodopenicillanic acid is prepared by diazotizing 6-aminopenicillanic acid in the presence of iodine chloride. 6,6-Dibromopenicillanic acid is prepared by the method described in Clayton / Journal of the Chemical Society, London (C), 2123 (1969-7) and 6,6-diiodopenicillanic acid is prepared by diazotizing 6-aminopenicillanic acid in the presence of iodine.

The compounds of formulas I, II and III with 13,70024 hydrogen are acidic and form salts with basic substances. These salts can be prepared by standard methods, e.g. by contacting the acidic and basic components, usually in a stoichiometric ratio, under conditions, in an aqueous, non-aqueous or partially aqueous medium. The salts are then isolated, depending on the conditions, by filtration, precipitation with a non-solvent and then filtration, evaporation of the solvent or, in the case of aqueous solutions, freeze-drying. Suitable basic substances for salt formation include both organic and inorganic types and include ammonia, organic amines, alkali metal hydroxides, carbonates, hydrides and alkoxides, and alkaline earth metal hydroxides, carbonates, hydrides and alkoxides. Representative examples of 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 amine such as tertiary amines, , N-methylmorpholine and 1,5-diazabicyclo / 1.3. Q7non-5-ene, hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and barium hydroxide, alkoxides such as sodium ethoxide and potassium ethoxide, hydrides such as calcium hydrate and sodium carbonate and sodium carbonate, carbonates such as potassium carbonate and sodium carbonate alkali metal salts of fatty acids such as sodium 2-ethylhexanoate. Preferred salts of the compound of formula I are the sodium, potassium and triethylamine salts.

The compound of formula I wherein R 1 is hydrogen and its salts act as a moderate antibacterial agent both in vitro and in vivo. The compounds of formula I having an ester-forming group which is easily hydrolysable in vivo act as moderate antibacterial agents in vivo. The minimum inhibitory concentrations (MEK) of penicillanic acid 1,1-dioxide against various microorganisms are shown in Table I.

i4 7 0024

Table I

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

Small MEK (micrograms / ml)

Staphylococcus aureus 10Q

Streptococcus faecalis 20Q

Streptococcus pyogenes 100

Escherichia coli 50

Pseudomonas aeruginosa 200

Klebsiella pneumoniae 50

Proteus mirabilis 100

Proteus morgani 10Q

Salmonella typhimurium 50

Pasteurella multocida 50

Serratia marcescens, 100

Enterobacter aerogenes 25

Enterobacter clocae 100

Citrobacter freundii 50

Providence 10Q

Staphylococcus epidermis 20Q

Pseudomonas putida 200

Hemophilus influenzae 50_

Neisseria gonorrhoeae 0.312 is 70024

The in vitro antibacterial activity of the compound of formula I wherein κ is hydrogen and its salts makes them useful as industrial antimicrobials, e.g. in water treatment, slime control, paint preservation and wood preservation, as well as for topical use as disinfectants. When these compounds are applied topically, it is often convenient to mix the active ingredient with a non-toxic carrier such as a vegetable or mineral oil or a skin softening cream. Accordingly, the active ingredient may 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 active ingredient concentrations of about 0.1 to 10% by weight of the total composition.

The in vivo potency of the compounds of formula I having a hydrogen or ester-forming, readily hydrolysable group and their salts makes them suitable for controlling bacterial infections in mammals, including humans, when administered both orally and parenterally. The compounds have utility in controlling infections in humans caused by susceptible bacteria, e.g., Neisseria gonorrhoeae strains.

For the therapeutic use of a compound of formula I or a salt thereof in a mammal, and in particular a human, they may be administered alone or in admixture with pharmaceutically acceptable carriers or diluents. The compound or a salt thereof can be administered orally or parenterally, e.g., intramuscularly, subcutaneously, or intraperitoneally. The choice of carrier or diluent depends on the intended route of administration.

Compounds of formula I wherein R 1 is hydrogen or an ester-forming, easily hydrolysable group in vivo, or a salt thereof, enhance the antibacterial activity of β-lactam antibiotics in vivo. They reduce the amount of antibiotic needed to protect mice against an otherwise lethal inoculum of certain β-lactamase-forming bacteria.

This ability makes them valuable to be administered with β-lactam antibiotics in the treatment of bacterial infections in mammals, and in particular in humans. In the treatment of a bacterial infection, said compound of formula I can be mixed with a β-lactam antibiotic and thus both substances can be administered simultaneously. Alternatively, said compound of formula I may be administered separately during β-lactam antibiotic treatment. In some cases, it is preferred to first administer a compound of formula I to a subject prior to initiating β-lactam antibiotic therapy.

When penicillanic acid 1,1-dioxide, a salt thereof or a readily hydrolysable ester thereof is used to enhance the efficacy of a lactam antibiotic, it is preferably administered formulated with standard pharmaceutical carriers or diluents. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, a β-lactam antibiotic and penicillanic acid 1,1-dioxide or a readily hydrolysable ester thereof will normally contain from about 5% to about 80% by weight of a pharmaceutically acceptable carrier.

When penicillanic acid 1,1-dioxide or its in vivo readily hydrolysable ester is used in combination with another β-lactam antibiotic, the sulfone can be administered orally or parenterally, i.e., intramuscularly, subcutaneously or intraperitoneally. Although the prescribing physician will ultimately decide on the dosage to be used in humans, the ratio of the daily doses of penicillanic acid-1,1-dioxide or a salt or ester thereof to the β-lactam antibiotic is normally about 1: 3 to 3: 1. In addition, when a combination of penicillanic acid 1,1-dioxide or a salt thereof or an in vivo readily hydrolyzable ester and another β-lactam antibiotic is used, the daily oral dose of each component is normally about 10 to 400 mg / kg body weight.

Typical β-lactam antibiotics with which penicillanic acid 1,1-dioxide and its in vivo hydrolysable esters can be administered include: 6- (2-phenylacetamido) penicillanic acid, 6- (D-2-amino-2-phenylacetamido) - penicillanic acid, 6- (2-carboxy-2-phenylacetamido) penicillanic acid and 7- [2- (1-tetrazolyl) acetamido] -3- [2- (5-methyl-1,3,4-thiadiazolyl) - thiomethyl / -3-desasetoksimetyylikefalosporaanihappo.

i7 70024

Typical microorganisms against which the antibacterial activity of the above-mentioned β-lactam antibiotics is improved are:

Staphylococcus aureus,

Haemophilus influenzae,

Klebsiella pneumoniae and Bacteroides fragilis.

Comparative Example Preparation of Penicillanic Acid

To a stirred solution of 1095.2 g of 6-alpha-bromopenicillanic acid in 2177 ml of methanol was added 622 ml of

of water. The solution was allowed to cool to 20 ° C, its pH

was adjusted to 7.2 with 4N sodium hydroxide and then 550 g of 5% palladium on carbon catalyst was added. The mixture was shaken under a hydrogen pressure of 520 kN / m (75 psi) until hydrogen uptake ceased. The catalyst was removed by filtration and washed with a mixture of 2177 ml of methanol and 622 ml of water. The washings and the filtrate from the filtration were combined and the resulting solution was diluted with water to a volume of 18 L. The resulting mixture was extracted with dichloromethane, and the extracts were washed with water, then saturated sodium chloride solution. The dichloromethane solution was dried over magnesium sulfate and evaporated in vacuo to give 275.6 g (35% yield) of penicillanic acid.

The following examples and preparations are provided to further illustrate the invention. Infrared (IR) spectra were run as potassium bromide tablets (KBr tablet) and characteristic absorption peaks are reported as wavenumber (cm). Nuclear magnetic resonance (NMR) spectra were run at 60 MHz as solutions in deuterochloroform (CDCl 3), perdeuteroacetone (CD 2 CO 2 3), perdeuterodimethylsulfoxide (DMSO-d 6) or deuterium oxide (D 2 O) and the position of the peaks is reported in ppm sodium 2,2-dimethyl-2-silaanipentaani-5-sulfonate. The following abbreviations were used for the shape of the peak: s = Singlet, d = doublet, t = triplet, q = quartet, and m = multiplet.

18 70024

Example 1 6-tX-Bromopenicillanic acid 1,1-dioxide

To a stirred mixture of 560 ml of water, 300 ml of dichloromethane and 56.0 g of 6-C 1-4 bromopenicillanic acid was added 4N sodium hydroxide solution until a constant pH of 7.2 was reached. This required 55 ml of sodium hydroxide solution. The mixture was stirred for 10 minutes at pH 7.2 and then filtered. The layers were separated and the organic phase was discarded. The aqueous phase was poured rapidly and with stirring into the oxidation mixture prepared in the following manner.

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

After the 6-CX bromopenicillanic acid solution was added to the oxidation mixture, a cooling bath maintained at -15 ° C was placed around it. The internal temperature rose to 15 ° C and then dropped to 5 ° C over 20 minutes. At this point, 30.0 g of sodium metabisulfite was added with stirring for 10 minutes at about 10 ° C. After a further 15 minutes, the mixture was filtered and the pH of the filtrate was lowered to 1.2 by adding 170 ml of 6N hydrochloric acid. The aqueous phase was extracted with chloroform and then ethyl acetate. Both the chloroform extracts and the ethyl acetate extracts were dried over magnesium sulfate and then evaporated in vacuo. 10.0 g (16% yield) of the title compound were obtained from the chloroform solution. 57 g of an oil were obtained from the ethyl acetate solution, which was triturated in hexane. A white solid formed. It was isolated by filtration to give 41.5 g (yield 66%) of the title compound, m.p. 134 ° C (decomposes).

Analysis for C8H10BrNO5S

Calculated: 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- (α-Chloropenicillanic acid 1,1-dioxide)

An oxidation solution containing 185 mg of potassium permanganate, 0.063 ml of 85% phosphoric acid and 5 ml of water was prepared. This oxidation solution was added dropwise at 0-5 ° C to a solution of 150 mg of sodium β-chloropenicillanate in 5 ml of water until the purple color of the potassium permanganate remained. Approximately half of the oxidation solution was consumed. At this point, the color of the potassium permanganate was destroyed by the addition of solid sodium bisulfite and then the reaction mixture was filtered. Ethyl acetate was added to the filtrate, and the pH was adjusted to 1.8. The layers were separated and the aqueous layer was further extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, dried, evaporated in vacuo to give 118 mg of the title compound. The NMR spectrum (CD 2 in COCD 2) showed absorbances at 5.82 (d, 1H), 5.24 (d, 1H), 4.53 (s, 1H), 1.62 (s, 3H) and 1.50 (s, 3 H) ppm.

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

Example 3 6-R-Bromopenicillanic acid 1,1-dioxide

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

Example 4

Of penicillanic acid 1,1-dioxide

At 22 [deg.] C., 9.4 g of 6-[(bromo-7-bromo-penicillanic acid 1,1-dioxide) were added to 100 ml of water at 22 [deg.] C. and then enough sodium hydroxide solution to give a constant pH of 7. 3. To the resulting solution were added 2.25 g of 5% palladium on carbon and then 6.9 g of dipotassium phosphate trihydrate.This mixture 2 was shaken under a hydrogen atmosphere at a pressure of 3.5 to 1.8 kg / cm. the solution was covered with 100 ml of ethyl acetate, the pH was slowly lowered from 5.0 to 1.5 with 6N hydrochloric acid, the layers were separated and the aqueous phase was further extracted with ethyl acetate. and the solid was isolated by filtration to give 4.5 g (65% yield) of the title compound.

Analysis for C 9 H 18 NO 2 S

Calculated: C 41.20, H 4.75, N 6.00, S 13.75%

Found: C 41.16, H 4.81, N 6.11, S 13.51%

Example 5

Pivaloyloxymethyl-6-cX-bromopene Isane 1,1-dioxide

An oxidation solution of 4.26 g of potassium permanganate, 2.65 g of 85% phosphoric acid and 40 ml of water was prepared. The mixture was stirred for one hour and then added slowly over 20 minutes at 5-10 ° C to a stirred solution of 5.32 g of pivaloyloxymethyl 6- [X-bromopenicillanate in 70 ml of acetone and 10 ml of water. The mixture was stirred for 30 minutes at 5 ° C and 100 ml of ethyl acetate were added.

After a further 30 minutes, a solution of 3.12 g of sodium bisulphite in 30 ml of water was added over 15 minutes at about 10 ° C. Stirring was continued for another 30 minutes at 5 ° C and then the mixture was filtered. The organic phase was isolated and washed with saturated sodium chloride solution. The dried organic layer was evaporated to give 5.4 g of the title compound as an oil which crystallized slowly. The NMR spectrum (in CDCl 3) showed absorbances at 5.80 (q, 2H), 5.15 (d, 1H), 4.75 (d, 1H), 4.50 (s, 1H), 1.60 (s, 3H), 1.40 (s, 3H) and 1.20 (s, 9H) ppm.

21,700 24

Example 6

Pivaloyylioksimetyylipenisillanaatti-1,1-dioxide

A solution of 4.4 g of pivaloyloxymethyl-6-CX-bromopenicillanate-1,1-dioxide in 60 ml of tetrahydrofuran was added to a solution of 0.84 g of sodium bicarbonate in 12 ml of water. The solution was shaken under a hydrogen atmosphere at a pressure of 3.3 to 3.6 kg / cm with 2.0 g of 5% palladium on carbon. The reaction mixture was then filtered and the residue was washed with 100 ml of ethyl acetate and 25 ml of water. The combined filtrate and washings were isolated. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate, evaporated to give the title compound as an oil. This was dissolved in 20 ml of ethyl acetate. To the solution was slowly added 100 ml of hexane and the precipitate was isolated by filtration, yield 2.4 g. The NMR spectrum (in DMSO-d 6) showed absorbances at 5.75 (q, 2H), 5.05 (m, 1H), 4.40 (s, 1H), 3.95 to 2.05 (m, 2H), 1.40 (s, 3H), 1.25 (s, 3H) and 1.10 (s, 9H) ppm.

Example 7 2.2.2-Trichloroethyl 6-O-bromopenicillanate-1,1-dioxide 2.2.2-Trichloroethyl 6- (X-bromopenicillanate) was oxidized with potassium permanganate mainly according to the method of Example 5 to give the title compound in 79% yield. The NMR spectrum of the product (in CDCl 3) showed absorbances at 5.30-4.70 (m, 4H), 4.60 (s, 1H), 1.70 (s, 3H) and 1.50 (s, 3H). ) ppm.

Example 8

Of penicillanic acid 1,1-dioxide

To a stirred suspension of 6.5 g of zinc powder in 100 ml of a 70:30 mixture of glacial acetic acid and tetrahydrofuran was added portionwise over 5 minutes 4.0 g of 2,2,2-trichloroethyl 6-cis-bromopenicillanate-1 , 1-dioxide. The mixture was stirred for 3 hours at ambient temperature and then filtered. The filtrate was concentrated to a volume of 10 ml, and the brown-brown solution was mixed with 50 ml of water and 100 ml of ethyl acetate. The pH was adjusted to 1.3 and the layers were separated. The organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was triturated with ether for 20 minutes. There was thus obtained 553 g of the title compound as a solid. The NMR spectrum (in CDCl 3 -DMSO-d 6) showed absorbances at 11.2 (broad s, 1H), 4.65 (m, 1H), 4.30 (s, 1H), 3.40 (m, 2H), 1.65 (s, 3H) and 1.50 (s, 3H) ppm.

Example 9

Benzyl 6-CX bromopenicillanate 1,1-dioxide

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

Example 10

Of penicillanic acid 1,1-dioxide

A solution of 4.0 g of benzyl 6-oC-bromopenicillanate-1,1-dioxide in 50 ml of tetrahydrofuran was combined with a solution of 1.06 g of sodium bicarbonate in 50 ml of water. To the mixture was added 2.0 g of a 50% suspension of 5% palladium on carbon in water, and then this mixture was shaken under a hydrogen atmosphere for 20 minutes at a pressure of 3.26 to 3.50 2 kg / cm 3. The catalyst was removed by filtration and 30 ml of tetrahydrofuran and 3.0 g of a 50% suspension of 5% palladium on carbon were added. The resulting mixture was shaken under a hydrogen atmosphere for 65 minutes at a pressure of 2.9 to 3.2 kg / cm 3. The reaction mixture was then filtered and the tetrahydrofuran was removed by evaporation. Ethyl acetate was added to the remaining aqueous solution, and the pH was adjusted to 7.1. The ethyl acetate layer was removed and new ethyl acetate was added to the remaining aqueous phase. The pH was lowered to 1.5 and the layers were separated. The aqueous phase was further extracted with ethyl acetate, the combined ethyl acetate solutions were washed with saturated sodium chloride solution and dried over magnesium sulfate. Evaporation in vacuo gave a resin which was triturated with ether. There was thus obtained 31 mg of penicillanic acid 1,1-dioxide as a yellow solid. The NMR spectrum (CDCl 3 - 23 7 0 0 2 4 in DMSO-d 6) showed absorbances at 9.45 (broad s, 1H), 4.60 (t, 1H), 4.25 (s, 1H), 3.40 (d, 2H), 1.65 (s, 3H) and 1.30 (s, 3H) ppm.

Example 11 6.6-Dibromopenicillanic acid 1,1-dioxide

To a solution of 6,6-dibromopenicillanic acid from Preparation H in dichloromethane was added 300 ml of water, followed by dropwise addition of 105 ml of 3N sodium hydroxide solution over 30 minutes. The pH stabilized at 7.0. The aqueous layer was removed and the organic layer was extracted twice with 100 ml of water. To the combined aqueous solutions was added at -5 ° C a premixed solution of 59.25 g of potassium permanganate, 18 ml of concentrated phosphoric acid and 600 ml of water until the pink color of the permanganate remained. The addition took 50 minutes and 550 ml was consumed without oxygen. At this point, 500 mL of ethyl acetate was added and the pH was lowered to 1.23 by the addition of 105 mL of 6N hydrochloric acid. 250 ml of 1 M sodium bisulfite solution were then added over a period of 10 to 15 minutes at about 10 ° C. During this addition, the pH was maintained at 1.25 to 1.35 with 6-N hydrochloric acid. The aqueous phase was saturated with sodium chloride and both phases were separated. The aqueous solution was extracted twice more with 150 ml of ethyl acetate, the combined ethyl acetate solutions were washed with brine and dried over magnesium sulfate. There was thus obtained an ethyl acetate solution of 6,6-dibromopenicillanic acid-1,1-dioxide.

6,6-Dibromopenicillanic acid 1,1-dioxide can be isolated by removing the solvent in vacuo. The melting point of the sample thus isolated from the corresponding preparation was 201 ° C (decomposes). The NMR spectrum (in CDCl 3 -DMSO-d 6) showed absorbances at 9.35 (s, 1H), 5.30 (s, 1H), 4.42 (s, 1H), 1.63 (s, 3H). ) and 1.50 (s, 3H) ppm. The IR spectrum (KBr tablet) showed absorbances at 3846-2500, 1818, 1754, 1342 and 1250-1110 cm-1.

Example 12 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 then the pH was raised to 7.2 with 3N sodium hydroxide solution. The layers were separated and the aqueous layer was cooled to 5 ° C. To this solution was added dropwise over 20 minutes a premixed solution of 2.61 g of potassium permanganate, 1.75 ml of concentrated phosphoric acid and 50 ml of water. During the addition, the pH was maintained at 6 and the temperature below 10 ° C. At this point, 100 mL of ethyl acetate was added and the pH was adjusted to 1.5. Then, 50 ml of 10% sodium bisulfite solution was added to the mixture, keeping the temperature below 10 ° C and the pH about 1.5 by adding 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 layers were washed with brine, dried over magnesium sulfate, evaporated in vacuo to give 4.2 g of the title compound, m.p. 143-145 ° C. The NMR spectrum (CDCl 3) showed absorbances at 4.86 (s, 1H), 4.38 (s, 1H), 1.60 (s, 3H) and 1.43 (s, 3H) ppm. The IR spectrum (KBr tablet) showed absorbances at 1800, 1740 and 1250-11110 cm

Example 13 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. The pH was raised to 7.3 with 3N sodium hydroxide solution and the aqueous layer was removed. The organic layer was extracted with 10 ml of water. The combined aqueous phases were cooled to 5 ° C and a premixed solution of 2.84 g of potassium permanganate in 2 ml of concentrated phosphoric acid and 50 ml of water was added dropwise at 5-10 ° C. The addition took 20 minutes. At this point, 50 ml of ethyl acetate was added and the pH of the mixture was lowered to 1.5 with 6 N hydrochloric acid. To this two-phase system was added dropwise 50 ml of 10% sodium bisulfite solution and the pH was maintained at about 1.5 by the addition of 6N hydrochloric acid. An additional 50 mL of ethyl acetate was added and then the pH was lowered to 1.23. The layers were separated and the aqueous layer was saturated with sodium chloride. The saturated solution was extracted three times with 50 ml of ethyl acetate, the combined ethyl acetate layers were washed with brine, dried over magnesium sulfate and evaporated in vacuo.

25 7 0 0 2 4 The residue was dried under high vacuum to give 4.2 g of the title compound, m.p. 145-147 ° C. The NMR spectrum (CDCl 3) showed absorbances at 4.90 (s, 1H), 4.30 (s, 1H), 1.60 (s, 3H) and 1.42 (s, 3H) ppm. The IR spectrum (KBr tablet) showed absorbances at 1800, 1740, 1330 and 1250-1110 cm -1.

Example 14

Of penicillanic acid 1,1-dioxide

An ethyl acetate solution of 6,6-dibromopenicillanic acid 1,1-dioxide obtained in Example 11, 705 ml of saturated sodium bicarbonate solution and 8.88 g of 5% palladium-on-carbon catalyst were combined. The mixture was shaken under a hydrogen atmosphere for about 2 hours at a pressure of about 5 kg / cm 3. The catalyst was removed by filtration and the pH of the aqueous phase of the filtrate was adjusted to 1.2 with 6N hydrochloric acid. The aqueous phase was saturated with sodium chloride. The layers were separated and the aqueous phase was extracted three more times with 200 ml of ethyl acetate. The combined ethyl acetate solutions were dried over magnesium sulfate, evaporated in vacuo to give 33.5 g (58% yield based on 6-aminopenicillanic acid) of penicillanic acid 1,1-dioxide. This product was dissolved in 600 ml of ethyl acetate, the color was removed from the solution with activated carbon and the solvent was removed by evaporation in vacuo. The product was washed with hexane. There was thus obtained 31.0 g of pure product, the physicochemical parameters of which are shown in Example 8.

Example 15

Pivaloyloxymethyl 6,6-dibromopenicillanate-1,1-dioxide

A stirred solution of 3.92 g of 6,6-bromopenicillanic acid 1,1-dioxide in 20 ml of Ν, Ν-dimethylformamide was cooled to 0 ° C and then 1.29 g of diisopropylethylamine was added. . Then 1.51 g of chloromethyl lipivalate was added. The reaction mixture was stirred for three hours at 0 ° C and 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 cold 5% sodium bicarbonate solution, water and brine. The ethyl acetate solution was treated with Darco (activated charcoal), dried over magnesium sulfate, evaporated in vacuo to give 2.1 g of a brown oil. This was chromatographed on 200 g of silica gel eluting with dichloromethane. The fractions containing the desired product were combined, rechromatographed on silica gel to give 0.025 g of the title compound. The NMR spectrum (CDCl 3) showed absorbances at 6.10 (q, 2H), 5.00 (s, 1H), 4.55 (s, 1H), 1.60 (s, 3H), 1.50 ( s, 3H) and 1.15 (s, 9H) ppm.

Example 16

Benzyl 6,6-dibromopenicillanate-l, 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 was stirred overnight at ambient temperature. Most of the solvent was removed by evaporation in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was isolated, washed with 1N hydrochloric acid and saturated sodium chloride solution, and dried over sodium sulfate. Evaporation in vacuo gave 11.55 g of the title compound. The NMR spectrum (in CDCl 3) showed absorbances at 7.40 (s, 5H), 5.30 (m, 2H), 4.95 (s, 1H), 4.55 (s, 1H), 1.50 (s, 3H) and 1.20 (s, 3H) ppm.

Example 17

Of penicillanic acid 1,1-dioxide

To a solution of 2.0 g of benzyl 6,6-dibromopenicillanate-1,1-dioxide in 50 ml of tetrahydrofuran was added a solution of 0.699 g of sodium bicarbonate in 50 ml of water and then 2.0 g of 5% palladium on carbon. Mixture 2 was then shaken under a hydrogen atmosphere for 70 minutes at a pressure of about 3.5 kg / cm 3. The tetrahydrofuran was removed by evaporation and the residue was partitioned between ethyl acetate and water at pH 7.37. The aqueous layer was removed and new ethyl acetate was added. The pH was lowered to 1.17 and the ethyl acetate was isolated and washed with saturated sodium chloride solution. Evaporation in vacuo gave 423 mg of the title compound, the physicochemical parameters of which are shown in Example 8.

27 7 0024

Example 18 2,2,2-Trichloroethyl 6,6-dibromopenicillanate 1,1-dioxide

The title compound was prepared from 6,6-dibromopenicillanic acid 1,1-dioxide and 2,2,2-trichloroethyl chloroformate mainly according to the method of Preparation J. The product was purified by chromatography on silica gel. The NMR spectrum of the product (in CDCl 3) showed absorbances at 4.85 (m, 2H), 1.65 (s, 3H) and 1.45 (s, 3H) ppm.

Example 19 1- (Ethoxycarbonyloxy) ethyl 6,6-dibromopenicillanate 1,1-dioxide

A mixture of 2.26 g of 6,6-dibromopenicillanic acid 1,1-dioxide, 1.02 ml of 1- (ethoxycarbonyloxy) ethyl chloride, 1.32 ml of diisopropylethylamine and 10 ml of N, N-dimethyl style formamide, was stirred for 28 hours at room temperature. The reaction mixture was diluted with 100 ml of ethyl acetate and then washed successively with water, dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The dried ethyl acetate solution was evaporated in vacuo to give 1.50 g of an oil which was chromatographed on silica gel. There was thus obtained 353 mg of the title compound with a slight impurity of 1- (ethoxycarbonyloxy) ethyl 6-bromopenicillanate.

Example 20 1- (Ethoxycarbonyloxy) ethyl penicillanate 1,1-dioxide

A portion, i.e. 230 mg, of the product of Example 19 was dissolved in 10 ml of toluene. To this was added 0.4 ml of tri-n-butyltin hydride and then 0.164 g of azobisisobutyronitrile, and the mixture was heated at 70-80 ° C for 3.5 hours. The solvent was removed by evaporation in vacuo and the residue was dissolved in 25 ml of acetonitrile. The acetonitrile solution was washed several times with hexane and then evaporated in vacuo. The residue was dissolved in ether and the ether solution was washed with 5% potassium fluoride solution and saturated sodium chloride solution. The ether solution was dried over sodium sulfate, evaporated in vacuo, and the residue chromatographed on silica gel to give 0.043 g of the title compound. The NMR spectrum (in CDCl 3) showed absorbances at 6.75 (m), 4.60 (m), 4.30 (m), 4.15 (s), 4.00 (s), 3.30 ( d) and 1.75 - 1.00 (m) ppm.

Preparation A

6-chloro-6-jodipenisillaanihappo

To a stirred solution of 3.38 g of iodine monochloride in 30 ml of dichloromethane at 0-5 ° C was added 11.1 ml of 2.5 N sulfuric acid and then 1.92 g of sodium nitrite. At this point, 3.00 g of 6-aminopenicillanic acid was added in one portion and stirring was continued for 30 minutes at 0-5 ° C. To the reaction mixture was added portionwise 22.8 ml of 1 M sodium sulfite solution, and the layers were separated. The aqueous layer was further washed with dichloromethane and all organic phases were washed with saturated sodium chloride solution. The dichloromethane solution was dried over sodium sulfate, evaporated in vacuo to give 3.48 g of the title compound. The product obtained above was dissolved in 30 ml of tetrahydrofuran and 30 ml of water were added. The pH was adjusted to 6.8 with dilute sodium hydroxide solution and the tetrahydrofuran was removed in vacuo. The remaining aqueous phase was lyophilized and the residue was washed with diethyl ether. There was thus obtained 3.67 g of the title compound as a sodium salt.

Preparation B

6-ft-chloropenicillanic acid

A 2.05 g sample was converted to sodium 6-chloro-6-iodopenicillanic acid into the free acid, which was dissolved in 125 ml of benzene under nitrogen. To the solution was added 1.08 ml of triethylamine, and the mixture was cooled to 0-5 ° C. To the cooled solution was added 0.977 ml of trimethylsilyl chloride, and the reaction mixture was stirred for 5 minutes at 0-5 ° C, 60 minutes at 25 ° C, and 30 minutes at 50 ° C. The reaction mixture was cooled to 25 ° C and the triethylamine hydrochloride was removed by filtration. To the filtrate was added 15 mg of azobisisobutyronitrile and then 2.02 ml of tri-n-butyltin hydride. The mixture was then irradiated with ultraviolet light for 15 minutes, maintaining the temperature at about 20 ° C. The 29 7 0 0 2 4 solution was then removed by evaporation in vacuo and the residue was dissolved in a 1: 1 mixture of tetrahydrofuran and water. The pH was adjusted to 7.0 and the tetrahydrofuran was removed by evaporation in vacuo. The aqueous phase was washed with ether and the same 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, the combined ethyl acetate solutions dried and evaporated in vacuo. There was thus obtained 980 mg of 6- / 3-chloro-penicillanic acid.

The product obtained above was dissolved in tetrahydrofuran and the same volume of water was added. The pH was adjusted to 6.8 and the tetrahydrofuran was removed by evaporation in vacuo. The remaining aqueous phase was lyophilized to give 850 mg of sodium β-chloropenicillanate. The NMR spectrum (D 2 O) showed absorbances at 5.70 (d, 1H, J = 4 Hz), 5.50 (d, 1H, J = 4 Hz), 4.36 (s, 1H), 1.60 ( s, 3H) and 1.53 (s, 3H) ppm.

Preparation C

6-β-bromopenicillanic

A mixture of 5.0 g of 6,6-dibromopenicillanic acid, 1.54 ml of triethylamine and 100 ml of benzene was stirred under a nitrogen blanket until a solution formed. The solution was cooled to 0-5 ° C and 1.78 mL of trimethylsilyl chloride was added. The reaction mixture was stirred at 0-5 ° C for 2-3 minutes and then at 50 ° C for 35 minutes. The cooled reaction mixture was filtered and cooled to 0-5 ° C. A small amount of azobisisobutyronitrile and 3.68 ml of tri-n-butyltin hydride were added. The reaction flask was irradiated with ultraviolet light for 15 minutes and then the reaction mixture was stirred for 1.75 hours at about 25 ° C. The reaction mixture was re-irradiated and stirring was continued for 2.5 hours. At this point, a further small amount of azobisisobutyronitrile and 0.6 ml of tri-n-butyltin hydride were added and the mixture was irradiated again for 30 minutes. The solvent was then removed by evaporation in vacuo and 5% sodium bicarbonate solution and diethyl ether were added to the residue. The two-phase system was shaken vigorously for 10 minutes and the pH was adjusted to 2.0. The ether layer was isolated, dried, evaporated in vacuo to give 2.33 g of an oil. This was converted to the sodium salt by adding one equivalent of water containing 30,70024 sodium bicarbonate, and then the solution thus obtained was lyophilized. There was thus obtained sodium 6- [3-bromopenicillanate] which contained a small amount of the <X isomer as an impurity.

The sodium salt was purified by chromatography on Sephadex LH-20, combined with another batch of the same material and rechromatographed. The NMR spectrum (D 2 O) of the product showed absorbances at 5.56 (s, 2H), 4.25 (s, 1H), 1.60 (s, 3H) and 1.50 (s, 3H) ppm.

Preparation D

6,6-dijodipenisillaanihappo

A mixture of 15.23 g of iodine, 10 ml of 2.5 N sulfuric acid, 2.76 g of sodium nitrite and 75 ml of dichloromethane was stirred at 5 ° C and 4.32 g of 6-aminopenicillanic acid was added over 15 minutes. Stirring was continued for 45 minutes at 5-10 ° C after the addition was complete and then 100 ml of 10% sodium bisulfite solution was added dropwise. The layers were separated and the aqueous layer was further extracted with dichloromethane. The combined dichloromethane layers were washed with brine, dried over magnesium sulfate and evaporated in vacuo. There was thus obtained 1.4 g of the title compound with a slight impurity of 6-iodopenicillanic acid. The melting point of the product was 58-64 ° C. The NMR spectrum (CDCl 3) showed absorbances at 5.77 (s, 1H), 4.60 (s, 1H), 1.71 (s, 3H) and 1.54 (s, 3H) ppm.

Preparation E

Pivaloyloxymethyl 6- (X-bromipenisill permanganate ·

To a stirred mixture of 11.2 g of 6-CK-bromopenicillanic acid, 3.7 g of sodium bicarbonate and 44 ml of N, N-dimethylformamide were added dropwise over five minutes at ambient temperature 6.16 g of chloromethyl pivalate. Stirring was continued for 66 hours and then the reaction mixture was diluted with 100 ml of ethyl acetate and 100 ml of water. The layers were separated and the ethyl acetate layer was washed successively with water, saturated sodium chloride solution, saturated sodium bicarbonate solution, water and saturated sodium chloride solution. The ethyl acetate solution was decolorized, dried over magnesium sulfate 31 70024 and evaporated to dryness in vacuo. There was thus obtained 12.8 g (yield 80%) of the title compound.

Preparation F

Benzyl 6-ol bromopenicillanate

The title compound was prepared by esterification of 6-t-bromopenicillanic acid with benzyl bromide mainly according to the method of Preparation H (yield 83%). The NMR spectrum (in CDCl 3) showed absorbances at 7.35 (s, 5H), 5.35 (m, 1H), 5.15 (s, 2H), 4.70 (m, 1H), 4.60 (s, 1H), 1.55 (s, 3H) and 1.35 (s, 3H) ppm.

Preparation G

2,2,2-trikloorietyylipenisillanaatti

To a stirred solution of 11.2 g of 6-o-bromopenicillanic acid in 50 ml of tetrahydrofuran at 0 ° C was added 3.48 g of pyridine per minute. To the cloudy solution thus obtained was added 8.47 g of 2,2,2-trichloroethyl chloroformate over 10 minutes, maintaining the temperature at 0-2 ° C. Stirring was continued for 10 minutes and the cooling bath was removed. Stirring was continued overnight at ambient temperature. The reaction mixture was then heated to 35 ° C for five minutes and 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 saturated sodium chloride solution. The ethyl acetate solution was then decolorized, dried and concentrated to a small volume. To the resulting mixture was added 100 ml of hexane, the solid was removed by filtration to give 10.5 g of the title compound, m.p. 105-110 ° C. The NMR spectrum (CDCl 3) showed absorbances at 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.

Preparation H

6,6-Dibromopenicillanic acid To 500 ml of dichloromethane cooled to 5 ° C were added 119.9 g of bromine, 200 ml of 2.5 N sulfuric acid and 34.5 g of sodium nitrite. To this stirred mixture was added portionwise over 30 minutes 54.0 g of 6-aminopenicillanic acid 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 bisulfite solution was added dropwise over 20 minutes at 5-10 ° C. The layers were separated and the aqueous layer 32 7 00 2 4 was extracted twice with 150 ml of dichloromethane. The original dichloromethane layer was combined with the two extracts to give a solution of 6,6-dibromopenicillanic acid. This was used directly in Example 11.

Preparation I

6-Chloro-6-iodopenicillanic acid To 100 ml of dichloromethane cooled to 3 ° C were added 4.87 g of iodine chloride, 10 ml of 2.5 N sulfuric acid and 2.76 g of sodium nitrite. To this stirred mixture was then added portionwise over 15 minutes 4.32 g of 6-aminopenicillanic acid. Stirring was continued for 20 minutes at 0-5 ° C and then 100 ml of 10% sodium bisulfite solution was added dropwise at about 4 ° C. Stirring was continued for five minutes and then the layers were separated. The aqueous layer was extracted twice with 50 ml of dichloromethane, the combined dichloromethane solutions were washed with brine, dried over magnesium sulphate, evaporated in vacuo to give the title compound as a tan solid, m.p. 148-152 ° C. The NMR spectrum of the product (CDCl 3) showed absorbances at 5.40 (s, 1H), 4.56 (s, 1H), 1.67 (s, 3H) and 1.50 (s, 3H) ppm. The IR spectrum (KBr tablet) showed absorbances at 1780 and 1715 cm -1.

Preparation J

6-Bromo-6-iodopenicillanic acid To 100 ml of dichloromethane cooled to 5 ° C were added 10 ml of 2.5 N sulfuric acid, 6.21 g of iodine bromide and 2.76 g of sodium nitrite. To this mixture was added, with vigorous stirring over 15 minutes at 0-5 ° C, 4.32 g of 6-aminopenicillanic acid. Stirring was continued for 20 minutes at 0-5 ° C and then 100 ml of 10% sodium bisulfite solution was added dropwise at 0-10 ° C. At this point, the layers were separated and the aqueous layer was extracted three times with 50 mL of dichloromethane. The combined dichloromethane layers were washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was dried under high vacuum for 30 minutes to give 6.0 g (72% yield) of the title compound, m.p. 144-147 ° C. The NMR spectrum (CDCl 3) showed absorbances at 5.50 (s, 1H), 4.53 (s, 1H), 1.70 (s, 3H) and 1.53 (s, 3H) ppm. The IR spectrum (KBr tablet) showed absorbances at 1785 and 1710 cm. The mass spectrum showed the main ion at m / e = 406.

Claims (4)

A process for the preparation of penicillanic acid 1,1-dioxide and its esters of the formula I 0 0? / -T> H3 (I) i-N -% i 'COOR wherein R1 is hydrogen or an ester-forming, easily hydrolysable group in vivo which is preferably 3-phthalidyl, 4-crotonylactonyl, gamma-butyrolactone- 4-yl or a group of formula V or VI R2 0 R2 0 I II 4 1 II 4 -COCR -OO-COR 1. I 3 RR (V) (VI) 2 3 4 wherein R and R represent hydrogen or C 1-2 alkyl and R is C 1-5 alkyl, or pharmaceutically acceptable base salts thereof, wherein (a) a compound having Formula II HXY: S Λ \ t - fCH I (II) L - N- * ^ ^ COOR1 or a base salt thereof is contacted with a reagent which is an alkali metal permanganate, an alkaline earth metal permanganate or an organic peroxycarboxylic acid to give a compound having of formula III 70024 34 cr H - / * J_ ^ s ^ ch3 I CH3 (III) ti- N "j COOR or a base salt thereof, wherein R is as defined above and X and Y are hydrogen, chlorine, bromine or iodine, provided that when X and Y are the same, they must each be bromine; and (b) carrying out the dehalogenation by catalytic hydrogenolysis in an inert solvent, characterized in that step (a) is carried out first and then the product obtained in step (a) is dehalogenated according to step (b). 35 7 0 0 2 4 For the production of penicillans-sulfur-1,1-dioxide and esters of formula I 0? ? = / „^ S ^ CH3 I CH3 (I) j-N - \, COOR1 color R · * "is derived from an ester form, in vivo from a hydrolyser bar group, in which case 3-phthalidyl, 4-crotonylactonyl, gamma-butyrolacton-4-yl or a group of formulas V or VI R2 O R2 OI II 4 1 II 4 -COCR -COCOR> 3 l3 R R3 (V) (VI) 2 3 4 is R and R is a bond or C 1-6 alkyl and R is C 1-6 alkyl, or a pharmaceutical product bassalter, varvid man (a) bikar en förening med formuleln II HY; c PH3 xs_-xs 1 3 (II)) N ^ 1 o COOR eller dess bassalt i contact med ett reagent, som är et alkalimetallermermanganat, jordalkalimetallpermanganat eller organic organic peroxycarboxylic acid, varvid erhälls en förening med formeln III