DK166353B - Penicillanic acid 1,1-dioxide DERIVATIVES - Google Patents

Description

DK 166353B

The present invention relates to novel penicillanic acid 1,1-dioxide derivatives which are characterized in that they are derivatives of the general formula

5 Y \? "-CH

* -i (\ i "U'T" T CH, (III) - \

o COOR

or base salts thereof, wherein R is hydrogen, an in vivo easily hydrolyzable ester-forming group selected from 3-phthalidyl, 4-crotonolactonyl, γ-butyrolactonyl or a group of the formula:

2 2 R O R O

I II 4 I II 4 -C-O-C-R or -C-O-C-O-R I 3 I 3

15 RJ RJ

Wherein R and R are each hydrogen or alkyl of 1-2 to 4 C atoms and R is alkyl of 1 to 5 C atoms, or a usual penicillin carboxy protecting group selected from tetrahydropyranyl, trialkylsilyl having 1-3 C atoms in each alkyl group, benzyl, 4-nitrobenzyl, benzhydryl, 2,2,2-trichloroethyl, t-butyl or phenacyl, and X and Y are each hydrogen, chloro, bromo or iodo with the condition that when X and Y are the same, they should both be bran.

These novel penicillanic acid 1,1-dioxide derivatives are useful as intermediates and as such may be particularly included in a particular and advantageous yielding process for the preparation of penicillanic acid 1,1-dioxide and in vivo readily hydrolyzable esters thereof , which is referred to in the case in the case of the Danish Patent Application No. 305,552.

Penicillanic acid 1,1-dioxide and in vivo easily hydrolyzable esters thereof are useful as beta-lactamasein inhibitors and as agents promoting the efficacy of certain beta-lactam antibiotics when the latter is used to treat bacterial infections in mammals, especially humans. .

From Danish Patent Specification No. 155,740 it is known to prepare penicillanic acid 1,1-dioxide and in vivo easily hydrolyzable esters thereof by oxidation of penicillin.

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2 lanoic acid or esters thereof, wherein these starting compounds can be prepared by debromating the corresponding 6-bromo-penicillanic acid derivatives. Compared to this known process, the above-mentioned special advances.

5 positioning method, as documented in the stem case, for better yields of penicillanic acid 1,1-dioxide and in vivo easily hydrolyzable esters thereof.

The difference between said particular process for the purification of penicillanic acid 1,1-dioxide and in vivo readily hydrolyzable esters thereof and the known method of preparation of such penicillanic acid derivatives from the above-mentioned Danish Patent Specification No. 155,740 can be illustrated by the following scheme:

Y H

J_i_I “S

'' / COOR

/ “\

Ϊ S ° \? H

X · ../.-, l ^ Nt'CH3 _ps \ i-'CH3 T p ch3 T P 'ch3

CP - "-" •• COOR <P-8- * * .. COOR

25/111 \ Stm

^ S V

CH3 J-I. Tch3 where R, X and Y are as defined above.

As can be seen, in the known process it is first dehalogenated and then oxidized, while in the said particular process it is first oxidized, whereby

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3 which forms as the intermediate the novel penicillanic acid 1,1-dioxide derivatives of formula III, which are then dehalogenated.

The total yield of the known process II 5 IIIA - ^ I is no more than approx. 27%, while the said special method can expect a total yield IIIII -> I of at least 53%.

Preferred intermediates are 6-bromo- and 6,6-di-brompenicillanic acid 1,1-dioxide, i.e. compounds of formula III wherein X is bromine and Y are hydrogen, X and Y are bromine, respectively; and R is hydrogen.

The compounds of formula III as described herein are referred to as derivatives of penicillanic acid represented by the following structural formula: \ vCH3 (IV)

"'COOH

20 U

In penicillanic acid derivatives, a broken line bond of a substituent to the bicyclic nucleus indicates that the substituent is below the core plane. Such a substituent is said to be in ct configuration. Conversely, full line binding of a substituent to the bicyclic nucleus indicates that the substituent is above the plane of the nucleus. The latter configuration is referred to as the $ configuration.

Thus, group X has α-configuration and group Y has 30 (3-configuration of formula III).

The readily hydrolyzable ester forming groups listed in the main claim are well known in the art of penicillin. In most cases, they improve the absorption properties of the penicillin compounds. See, for example, 35 German Publication Publication No. 2,517,316. However, among such groups for R are alkanoyloxymethyl of 3-7 C atoms, 1- (alkanoyloxy) ethyl of 4-8 C atoms, 1-methyl-1- (alkanoyloxy) ethyl of 5-9 C atoms, alkoxycarbonyl

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4 oxymethyl with 3-6 C atoms, 1- (alkoxycarbonyloxy) ethyl with 4-7 C atoms, 1-methyl-1-alkoxycarbonyloxy) ethyl with 5-8 C atoms, 3-phthalidyl, 4-crotonolactonyl and γ -butyrolacton-4-yl preferred.

5 3-Phthalidyl, 4-crotonolactonyl and γ-butyrolactone-4-yl refer to structures VII, VIII and IX. The wavy lines must indicate each of the two epimers or a mixture thereof.

· <O Φ φ o o o VII VIII ix 15

The usual penicillin carboxy protecting group mentioned in the main claim are protecting groups commonly used in the penicillin field to protect the 3-carboxy group, such protecting groups being particularly able to bind and be removed under conditions under which β-lactam the ring system remains essentially intact. Although not all protecting groups are applicable in all situations, a particular group that can be used in a particular situation can be readily selected by one of ordinary skill in the art. See also U.S. Patent Nos. 3,632,850 and 3,197,466, British Patent No. 1,041,985, Woodward et al., Journal of the American Chemical Society, 88, 852 (1966), Chauvette,

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5

Journal of Organic Chemistry 3 <5, 1259 (1971), Sheedan et al., Journal of Organic Chemistry, 29, 2006, (1964) and "Cephalosporin and Penicillins, Chemistry and Biology", published by H.E. Flynn, Academic Press, Inc., 1972. The penicillin carboxy protecting group may be removed in the usual manner, taking into account the lability of the β-lactam system.

The compounds of formula III can, as already mentioned, be prepared by oxidation of the sulfide group in a compound of formula II wherein R, X and Y are as defined above. For this reaction, for example, alkali metal permanganates such as sodium and potassium permanganate, alkaline earth metal permanganates such as calcium and barium permanganates, and organic peroxycarboxylic acids such as peracetic acid and 3-chloroperbenzoic acid may be used.

When a metal permanganate is used for the oxidation, the reaction is usually carried out by treating the compound of formula II with from ca. 0.5 to approx. 10 molar equivalents, preferably from ca. 1 to approx.

20 4 molar equivalents of the permanganate in an appropriate inert solvent system reaction.

A suitable solvent inert to the reaction is one which does not adversely interact neither with the starting materials nor with the product, and water is commonly used. If desired, a water-miscible co-solvent may be added but will not interact with the permanganate such as tetrahydrofuran. The reaction can be carried out at a temperature within the range of from ca. -30 ° C to approx. 50 ° C, and preferably it is carried out from ca. -10 ° to approx. 10 ° C.

At about. 0 ° C, the reaction is generally completed in a short time, e.g. within an hour. Although the reaction may be carried out under neutral, basic or acidic conditions, it is preferred to use a pH within the range of from ca. 4 to approx. 9, preferably 6-8. However, it is important to select conditions under which decomposition of the β-lactam ring system by the compound with 35

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6 formula II or III is avoided. It is often advantageous to buffer the pH of the reaction medium in the vicinity of neutrality. The product is recovered by conventional techniques. Any excess permanganate is generally decomposed using sodium bisulfite, and if the product is not in solution, it is then recovered by filtration. It is separated from manganese dioxide by extracting it into an organic solvent and removing the solvent by evaporation. If the product is in solution at the end of the reaction, it is isolated by usual solvent extraction.

When a peroxycarboxylic acid is used for the oxidation reaction, the reaction is usually carried out by treating the compound of formula II with from about 1 to approx. 6 molar equivalents, and preferably approx. 2.2 molar equivalents of the oxidant in a reaction-inert organic solvent. Typical solvents are chlorinated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, and ethers such as diethyl ether; tetrahydrofuran and 1,2-dimethoxyethane. The reaction is usually carried out at a temperature of from ca. -30 ° to approx.

50 ° C, preferably from ca. 15 ° to approx. 30 ° C. At about. Reaction times of about 25 ° C are generally used. 2 to approx.

16 hours. The product is usually isolated by removing the solvent by evaporation in vacuo. The reaction product 25 can be purified by conventional methods well known in the art.

A preferred use of the compounds of formula III is, as mentioned, for the preparation of pharmacologically active compounds of formula I, wherein R, X and Y are as defined above, in a dehalogenation reaction.

An appropriate method for carrying out this conversion is to stir or shake a solution of a compound of formula III under a hydrogen atmosphere, or hydrogen mixed with an inert diluent such as nitrogen or argon, in the presence of a hydrogenolysis catalyst. Suitable solvents for this hydrogen oleic reaction are those which essentially dissolve the starting compound with

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7, but which does not itself undergo hydrogenation or hydrogenolysis. Examples of such solvents include ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, low molecular weight esters such as 5ethyl acetate and butyl acetate, tertiary amides such as N, N-dimethylformamide, Ν, Ν-dimethylacetamide and N-methylpyrro-amide. lidon, water and mixtures thereof. Further, it is common to buffer the reaction mixture so that it is operated at a pH within the range of approx. 4 to about 9, 10 preferably from about 6 to about 8. Borate and phosphate buffers are commonly used. The introduction of the gaseous hydrogen into the reaction medium is usually carried out by carrying out the reaction in a sealed container containing the compound of formula III, the solvent, the catalyst and the hydrogen. The pressure within the reaction vessel may range from 1 to 100 kg / cm. The preferred pressure range when the atmosphere within the reaction vessel is substantially pure hydrogen is from 2 to 5 kg / cm. The hydrogenolysis is carried out at a temperature of · from 200 ° C to. & 0 ° C, preferably from 25 ° C to 50 ° C. When the preferred temperature and pressure values are used, the hydrogenolysis generally proceeds within a few hours, e.g. from 2 hours to 20 hours. The catalysts used in this hydrogenolysis reaction are of the type well known in the art for this type of conversion, and typical examples are the precious metals such as nickel, palladium, platinum and rhodium. The catalyst is present in an amount of from 0.01 to 2.5% by weight, preferably from 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 carrier. A particularly suitable catalyst is palladium suspended on an inert carrier such as coal.

Other methods may be used in the reductive removal of the halogen from a compound of formula III.

For example, X and Y can be removed using a dissolution metal reduction system such as zinc dust i

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s acetic acid, formic acid or a phosphate buffer, according to well known methods. Alternatively, a tin hydride may be used, for example a trialkyltin hydride such as tri-n-butyltin hydride.

The compounds of formula 'III # wherein R

are salts, are acidic and will form salts with basic agents. These salts can be prepared by standard techniques, such as by contacting the acidic and basic components, usually in a stoichiometric ratio # in an aqueous, non-aqueous or partially aqueous medium, as appropriate. They are then recovered by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent or, in the case of aqueous solutions, by lyophilization, as appropriate. Basic agents which can be suitably used in salt formation belong to both the organic and inorganic types, and they include ammonia, organic amines, alkali metal hydroxides, carbonates, bicarbonates, hydrides and alkoxides, as well as alkaline earth metal hydroxides, - carbonates, hydrides and alkoxides. Representative examples of such bases are primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine and octylamine, secondary amines such as diethylamine, morpholine, pyrrolidine and piperidine, tertiary amines such as triethylamine, N-ethylamine. 25 piperidine, 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 methoxide and potassium ethoxide, hydrides such as sodium anhydride and sodium hydride. , carbonates such as potassium carbonate and sodium carbonate, bicarbonates such as sodium bicarbonate and potassium bicarbonate, and alkali metal salts of long chain fatty acids such as sodium 2-ethyl hexanoate. Preferred salts are the sodium, potassium and triethylamine salts.

The invention is further described by the following examples which illustrate, in part, the preparation of the subject compounds of formula III and in part the conversion of the compounds of formula III into pharmacologically active compounds of formula I by a dehalogenation agent.

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9 procss. Infrared (IR) spectra are measured as potassium bromide plates (KBr plates), and diagnostic absorption bands are -1 indicated in wavelengths (cm). Nuclear magnetic resonance spectra (NMR) were measured at 60 MHz for solutions in deuterochloroform (CDCl CD), perdeuteroacetone (CD ^COCD ^), perdeuterodimethylsulfoxide (DMSO-dg) or deuterium oxide (D20), and peak positions are expressed in parts. per. million (ppm) down from tetramethylsilane or sodium 2,2-dimethyl-2-silapentane-5-sulfonate. The following abbreviations for 10 tip forms are used: s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet.

Example 1 6-α-Brompenicillanic acid 1,1-dioxide.

To a stirred mixture of 560 ml of water, 300 ml of dichloromethane and 56.0 g of 6-a-brompenicillanic acid, 4N sodium hydroxide solution was added until a stable pH of 7.2 was obtained. This required 55 ml of sodium hydroxide. 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 an oxidizing mixture prepared as follows: In a 3 liter container, 63.2 g of potassium permanganate, 1,000 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-a-brompenicillanic acid solution was added to the oxidizing mixture, a cooling bath was maintained at -15 ° 30 around the reaction mixture. The internal temperature increased. 15 ° C and then dropped to 5 ° C over a period of 20 minutes. At this point, stirring was performed at ca. 10.0 C added 30.0 g of sodium bisulfite. After a further 15 minutes, the mixture was filtered 55 and the pH of the filtrate was lowered to 1.2 by the addition of 170 ml of 6N hydrochloric acid. The aqueous phase was extracted with chloroform and then with ethyl acetate.

Both the chloroform extracts and the ethyl acetate extracts

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10 was dried using anhydrous magnesium sulfate and then evaporated in vacuo. The chloroform solution afforded 10.0 g (16% yield) of the title compound. The ethyl acetate solution gave 57 g of an oil which was triturated with hexane. A white solid appeared. It was filtered off to give 41.5 g (66% yield) of the title compound, m.p. 134 ° C (dec.).

Analysis: Calculated for C 8 H 10 BrNO 5 S: 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

Oxidation of 6-alpha-chlorpenicillanic acid and 6-alpha-iodopicillanic acid with potassium permanganate by the procedure of Example 1 gave 6-alpha-chlorpenicillanic acid 1,1-dioxide and 6-alpha-iodopenicillanic acid, respectively, 1,1-dioxide .

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

An oxidizing solution was prepared from 185 mg of potassium permanganate, 0.063 ml of 85% phosphoric acid and 5 ml of water. This oxidizing solution was added dropwise to a solution of 150 mg of sodium 6-chlorophenicillanate 25 in 5 ml of water at 0-5 ° C until the purple color of the potassium permanganate was softened. About half of the oxidizing solution was needed. At this point, the potassium permanganate color was removed by the addition of solid sodium bisulfite, and the reaction mixture was then filtered and the pH was adjusted to 1.8. The layers were separated and the aqueous layer was further extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, dried and evaporated in vacuo to give 118 mg of the title compound. The NMR spectrum (in CDgCOCDg) 35 showed absorption at 5.82 (d, 1H), 5.24 (d, 1H), 4.53 (s, 1H), 1.62 (s, 3H) and 1.50 (s, 3H) ppm.

The above product was dissolved in tetrahydrofuran and an equal volume of water was added. '

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The pH was adjusted to 6.8 with dilute sodium hydroxide, the tetrahydrofuran was removed by evaporation in vacuo and the residual aqueous solution was lyophilized. Thereby the sodium salt of the title compound was won.

Example 4 δ-β-Brompenicillanic acid -1,1-dioxide.

To a solution of 255 mg of sodium 6-f} brompeni-cillanate in 5 ml of water was added at 0-5 ° C a solution prepared from 140 mg of potassium permanganate, 0.11 ml of 85% phosphoric acid and 5 ml of water. at 0-5 ° C. The pH was maintained between 6.0 and 6.4 during the addition. The reaction mixture was stirred at pH 6.3 for 15 minutes 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 brine, dried (MgSO4) and evaporated in vacuo.

Thereby 216 mg of the title compound were obtained as white crystals. The NMR spectrum (in D 2 O) showed absorptions at 5.78 (d, 1H, J = 4Hz), 5.25 (d, 1H, J * 4Hz), 4.20 (s, 1H), 1.65 (s , 3H) and 1.46 (s, 3H) ppm.

Example 5 6-3-Iodpenicillanic acid 1,1-dioxide.

Oxidation of β-β-iodine penicillanic acid with potassium permanganate by the procedure of Example 4 gave 6-p-iodo-penicillanic acid 1,1-dioxide.

30

Example 6

Pivaloyloxymethyl 6-alpha-bromopenicillanate-l, 1-dioxide.

To a solution of 394 mg of pivaloyloxymethyl-6-α-brompenicillanate in 10 ml of dichloromethane was added 400 35 mg of 3-chloroperbenzoic acid at 0-5 ° C. The reaction mixture was stirred at 0-5 ° C for 1 hour and then at 25 ° C for 24 hours. The filtered reaction mixture was evaporated to dryness in vacuo to give the title compound.

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12

Example 7

The procedure of Example 6 was repeated except that the pivaloyloxymethyl 6-3 brompenicillanate was replaced by: 3-phthalidyl-6-a-chloropenicillanate, 4-crotonolactolyl-6-ph3-chloropenicillanate, Y-butyrolactone-4 -yl-6-a-brompenicillanate, acetoxymethyl-6β-brompenicillanate, pivaloyloxymethyl-6-p-brompenicillanate, hexanoyloxymethyl-6-a-iodopenicillanate, 1- (acetoxy) ethyl 6-3-iodopenicillanate, 1- ) ethyl 6-a-chloropenicillanate, 1-methyl-1- (acetoxy) ethyl-6-1-chloropenicillanate, 1-methyl-1- (hexanoyloxy) ethyl 6-a-brompenicillanate, methoxycarbonyloxymethyl-6-a brompenicillanate, propoxycarbonyloxymethyl 6-p-brompenicillanate, 1- (ethoxycarbonyloxy) ethyl 6-a-brompenicillanate, 1- (butoxycarbonyloxy) ethyl 6-a-iodopenicillanate, 1-methyl-1- (methoxycarbonyloxy) ethyl β-β -iodopedicillanate 20 and 1-methyl-1- (isopropoxycarbonyloxy) ethyl 6-a-chlorpenicillanate.

There were thus obtained: 3-phthalidyl-6-a-chloropenicillanate-1,1-dioxide, 4-crotonolactonyl-6-p-chloropenicillanate-1,1-dioxide, Y-butyrolacton-4-yl-6-a-brompenicillanate. 1,1-dioxide, acetoxymethyl-6-O-brompenicillanate-1,1-dioxide, pivaloyloxymethyl-6-, 3-brompenicillanate-1,1-dioxide, hexanoyloxymethyl-6-a-iodpenic illanate-1,1-dioxide, 1- (acetoxy) ethyl-6-3-iodo-penicillanate-1,1-dioxide, 1- (isobutyryloxy) ethyl-6-a-chloro-penicillanate-1,1-dioxide, 1-methyl-1- (acetoxy) -ethyl 6-3-chlorpenicillanate-1,1-dioxide, 1-methyl-1- (hexanoyloxy) ethyl-6-a-brompenicillanate-1,135 dioxide, methoxycarbonyloxymethyl-6-a-brompenicillanate-1,1-dioxide, . propoxycarbonyloxymethyl 6-β-brompenicillanate-1,1-dioxide, 13

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1- (ethoxycarbonyloxy) ethyl-6-α-brompenicillanate-1,1-dioxide, 1-butoxycarbonyloxy) ethyl-6-α-iodopenicillanate-1,1-dioxide, 1-methyl-1- (methoxycarbonyloxy) ethyl 6-B-iodo-penicillanate-5, 1,1-dioxide and 1-methyl-1- (isopropoxycarbonyloxy) ethyl-6-a-chloro-penicillanate-1,1-dioxide.

Example 8 Penicillanic Acid-1,1-Dioxide.

To 100 ml of water was added 9.4 g of 6-α-brompenicillanic acid 1,1-dioxide at 22 ° C followed by sufficient 4N sodium hydroxide solution to reach 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 dicalcium phosphate trihydrate. This mixture was then shaken under an atmosphere of hydrogen at a pressure ranging from 3.5 to 2 1.8 kg / cm. When hydrogen uptake ceased, the solids were filtered off and the aqueous solution was covered with 100 ml of ethyl acetate. The pH was slowly lowered from 5.0 to 1.5 with 6N hydrochloric acid. The layers were separated and the aqueous phase was extracted with additional ethyl acetate. The combined ethyl acetate layers were washed with brine, dried using anhydrous magnesium sulfate and evaporated in vacuo. The residue was triturated under ether and the solid was then collected by filtration. This gave 4.5 g (65% yield) of the title compound.

Found: C: 41.20; H: 4.75; N: 6.00; S: 13.75% Found: C: 41.16; H: 4.81; N: 6 , 11, S: 13.51%.

Example 9

Penicillanic acid 1,1-dioxide.

Hydrogenolysis of each of: 6-α-chlorpenicillanic acid-1,1-dioxide, 6-α-iodophenicillanic acid-1,1-dioxide, 14

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β-β-chlorpenicillanic acid-1,1-dioxide, 6- β -br ompenicillanic acid-1,1-dioxide, and 6β-iodophenicillanic acid-1,1-dioxide by the method of Example 8 gave penicillanic acid-5 dioxide.

Example 10

Pivaloyloxymethyl penicillanate 1,1-dioxide.

To a solution of 1.0 g of pivaloyloxymethyl-6-α-10 brompenicillanate-1,1-dioxide in 10 ml of methanol was added 3 ml of 1M sodium bicarbonate and 200 mg of 10% palladium on charcoal. The reaction mixture was shaken vigorously under an atmosphere 2 of hydrogen at a pressure of approx. 5 kg / cm until hydrogen uptake ceased. The mixture was then filtered, and the majority of methanol was removed by evaporation in vacuo. Water and ethyl acetate were added to the evaporation residue and the pH was adjusted to 8.5. The layers were separated and the organic layer was washed with water, dried (Na 2 SO 4) and evaporated in vacuo. The title compound was thus won.

Example 11

Hydrogenolysis of the respective 6-halo-penicillanoic acid ester-1,1-dioxide from Example 7 by the method of Example 10 gave the following compounds: 3-phthalidyl-penicillanate-1,1-dioxide, 4-crotonolactonyl-penicillanate-1 -dioxide, Y-butyrolacton-4-yl-penicillanate-1,1-dioxide, acetoxymethyl-penicillanate-1,1-dioxide, pivaloyloxymethyl-penicillanate-1,1-dioxide, hexanoyloxymethyl-penicillanate-1,1-dioxide, 1- (acetoxy) ethyl-penicillanate-1,1-dioxide, 1- (isobutyryloxy) ethyl-penicillanate-1,1-dioxide, 1-methyl-1- (acetoxy) ethyl-penicillanate-1,1-dioxide, 35 1-methyl-1- (hexanoyloxy) ethyl-penicillanate-1,1-dioxide, methoxycarbonyloxymethyl-penicillanate-1,1-dioxide, propoxycarbonyloxymethyl-penicillanate-1,1-dioxide, 1- (ethoxycarbonyloxy) ethyl-penicillanate-1, 1-dioxide,

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1- (butoxycarbonyl) ethyl penicillanate-1,1-dioxide, 1-methyl-1- (methoxycarbonyloxy) ethyl-penicillanate-1,1-dioxide and 1-methyl-1- (isopropoxycarbonyloxy) ethyl-penicillanate-1, 1-5 dioxide.

Example 12

Pivaloyloxymethyl 6-alpha-bromopenicillanate-l, 1-dioxide.

An oxidizing solution was prepared by combining 4.26 g of potassium permanganate, 2.65 g of 85% phosphoric acid and 40 ml of water. The mixture was stirred for 1 hour and then slowly, over 20 minutes at 5-10 ° C, was added to a stirred solution of 5.32 g of pivaloyloxy-methyl-6-α-brompenicillanate in 70 ml of acetone and 10 ml. water. The mixture was stirred at 5 ° C for 30 minutes and 100 ml 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 ca. 10 ° C. Stirring was continued for an additional 30 minutes at 5 ° C and then the mixture was filtered. The organic phase was separated and washed with saturated sodium chloride solution. The dried organic layer was evaporated to give 5.4 g of the title compound as an oil which slowly crystallized. The NMR spectrum (in CDCl3) showed absorptions at 5.80 (q, 2H), 5.15 (d, 1H), 4.75 (d, 1H), 4.50 (s, 1H), 1.60 (s, 3H), 1/40 (s, 3H) and 1.20 (s, 9H) ppm.

Example 13 Pivaloyloxymethyl penicillanate-1,1-dioxide.

A solution of 4.4 g of pivaloyloxymethyl-6-a-bromo-penicillanate-1,1-dioxide in 60 ml of tetrahydrofuran was added to 0.84 g of sodium bicarbonate in 12 ml of water. The solution was shaken under an atmosphere of hydrogen in the presence of 2.0 g of 5% palladium on charcoal at 47-51 psig. The reaction mixture was then filtered and the filter residue was washed with 100 ml of ethyl acetate and 25 ml of water. The combination of filtrate and washings was separated. The organic

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16 layers were washed with saturated sodium chloride, dried (MgSO4) and evaporated to give the title compound as an oil. This oil was dissolved in - ethyl acetate (20 ml).

To the solution was added hexane (100 ml) slowly and the precipitate was filtered off. Yield: 2.4 g. The NMR spectrum (in DMSO-dg) showed absorptions at 5.75 (q, 2H), 5.05 (m, 1H), 4.40 (s, 1H), 3, 95 - 2.95 (m, 2H), 1.40 (s, 3H), 1.25 (s, 3H) and 1.10 (s, 9H) ppm.

Example 14 2,2,2-Trichloroethyl-6-a-brompenicillanate-1,1-dioxide.

2,2,2-Trichloroethyl 6-a-brompenicillanate was oxidized with potassium permanganate substantially by the procedure of Example 12, whereby the title compound was obtained in a yield of 79%. The NMR spectrum of the product (in CDCl 3) showed absorbances at 5.30 to 4.70 (m, 4H), 4.60 (s, 1H), 1.70 (s, 3H) and 1.50 (s, 3H) ) ppm.

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Example 15 • Penicillanic acid 1,1-dioxide.

To a stirred slurry of 6.5 g of zinc powder in 100 ml of a 70:30 glacial acetic acid / tetrahydrofuran mixture, 5 g of 2,2,2-trichloroethyl 6-a-brompenicillanate was added portionwise over 5 minutes. -l, 1-dioxide. The mixture was stirred at room temperature for 3 hours and then filtered. The filtrate was concentrated to a volume of 10 ml and the tan solution was mixed with 50 ml of water 10 and 100 ml of ethyl acetate. The pH was set to 1.3 and the layers separated. The organic phase was washed with saturated sodium chloride solution, dried using magnesium sulfate and then concentrated to dryness in vacuo. The residue was triturated under 15 ether for 20 minutes. Thereby 553 mg of the title compound was obtained as a solid. The NMR spectrum (in CDCl3 / DMSO-dg) showed absorptions at 11.2 (broad s, 1H), 4.65 (m, 1H), 4.30 (s, 1H), 3.40 (m, 2H ), 1.65 (s, 3H) and 1.50 (s, 3H) ppm.

Example 16

Benzyl 6-alpha-bromopenicillanate 1,1-dioxide.

Benzyl 6-α-brompenicillanate was oxidized with potassium permanganate substantially as in the procedure of Example 12, thereby obtaining the title compound in 94% yield. The NMR spectrum (in CDCl3) showed absorptions at 7.35 (s, 5H), 5.10 (m, 3H), 4.85 (m, 1H), 4.40 (s, 1H), 1.50 (s, 3H) and 1.25 (s, 3H) ppm.

Example 17

Penicillanic acid 1,1-dioxide.

A solution of 4.0 g of benzyl-6-a-brompenicillanate-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-charcoal in water, after which this mixture was shaken under an atmosphere of hydrogen at a pressure of 46.5

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-50 psig. for 20 minutes. The catalyst was filtered off and then 30 ml of tetrahydrofuran and 3.0 g of a 50% suspension of 5% palladium-on-charcoal were added. The resulting mixture was shaken under an atmosphere of the hydrogen at pressures from 42 to 45 psig. for 65 minutes. The reaction mixture was then filtered and the tetrahydrofuran was evaporated. Ethyl acetate was added to the aqueous evaporation residue and the pH was adjusted to 7.1. The ethyl acetate layer was removed and fresh ethyl acetate was added to the remaining aqueous phase. The pH was lowered to 1.5 and the layers separated. The aqueous phase was further extracted with ethyl acetate and the combined ethyl acetate solutions were washed with saturated sodium chloride solution and dried (MgSO 4). Evaporation in vacuo gave a gum which was triturated under ether. This gave 31 mg of penicillanic acid 1,1-dioxide as a yellow solid. The NMR spectrum (in CDCl3 / DMSO-dg) showed absorption at 9.45 (broad s, 1H), 4.60 (t, 1H), 4.25 (s, 1H), 3.40 (d, 2H) ), 1.65 (s, 3H) and 1.30 (s, 3H) ppm.

Example 18 6,6-Dibrompenicillanic acid 1,1-dioxide.

To the dichloromethane solution of 6,6-dibrompenicil lanoic acid from Preparation K, 300 ml of water was added after *. Af followed by dropwise addition over a period of 30 minutes of 25 ml of 105 ml of 3N sodium hydroxide. The pH stabilized at 7.0. The aqueous layer was removed and the organic layer was extracted with water (2 x 100 ml). To the total aqueous solutions was added at -5 ° C a premixed solution prepared from 59.25 g of potassium permanganate, 18 ml of concentrated phosphoric acid and 600 ml of water until the pink color of the permanganate remained. The addition took 50 minutes and 550 ml of oxidizer was needed. At this point, 500 mL of ethyl acetate was added, and then the pH was lowered to 1.23 by the addition of 105 mL of 6N hydrochloric acid. Then, within 10-15 minutes, at ca. 10 ml of 250 ml of 1M sodium bisulfite. During the addition of sodium bisulfite solution 19

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gene was maintained at pH 1.25-1.35 using 6N hydrochloric acid. The aqueous phase was saturated with sodium chloride and the two phases were separated. The aqueous solution was extracted with additional ethyl acetate (2 x 150 mL) and the combined ethyl acetate solutions were washed with brine and dried (MgSO4). This gave an ethyl acetate solution of 6,6-dibrompenicillanic acid 1,1-dioxide.

The 6,6-dibrompenicillanic acid 1,1-dioxide could be isolated by removing the solvent in vacuo. A sample 10 isolated in this way from an analog preparation had m.p. 201 ° C (dec.). The NMR spectrum (CDCl3 / DMSO-dg) showed absorptions at 9.35 (s, 1H), 5.30 (s, 1H), 4.42 (s, 1¾ 1.63 (s, 3H), and 1, 50 (s, 3H) ppm. The IR spectrum (KBr plate) showed absorptions at 3846-2500, 1818, 1754, 1342 and 15 1250-1110 cm -1.

Example .19 6-Chloro-6-iodopenicillanic acid 1,1-dioxide.

To a solution of 4.9 g of 6-chloro-6-iodo-penicillanic acid in 50 ml of dichloromethane was added 50 ml of water and then the pH was raised to 7.2 using 3N sodium hydroxide. The layers were separated and the aqueous layer was cooled to 5 ° C. To this solution was then added dropwise over a period of 20 minutes a premixed solution prepared from 2.61 g of potassium permanganate, 1.75 ml of concentrated phosphoric acid and 50 ml of water. The pH was maintained at 6 and the temperature kept below 10 ° C during the addition. At this point, 100 ml of ethyl acetate was added and the pH was adjusted to 1.5.

To the mixture was then added 50 ml of 10% sodium bisulfite, keeping the temperature below 10 ° C and the pH at ca. 1.5 by the addition of 6N hydrochloric acid. The pH was lowered to 1.25 and the layers separated. The aqueous layer was saturated with sodium chloride and extracted with ethyl acetate. The combined organic solutions were washed with brine, dried (MgSO4) and evaporated in vacuo to give 4.2 g of the title compound, m.p. 143-145 ° C. The NMR spectrum (CDCl3) showed absorptions at

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4.86 (s, 1H), 4.38 (s, 1H), 1.60 (s, 3H) and 1.43 (s, 3H) ppm. The IR spectrum (KBr plate) showed absorptions at 1800, 1740 and 1250-1110 cm -1.

Example 20 6-Bromo-6-iodopenicillanic acid 1,1-dioxide.

To a solution of 6.0 g of 6-bromo-6-iodo-penicillanic acid in 50 ml of dichloromethane was added 50 ml of water. The pH was raised to 7.3 with 3N sodium hydroxide and the aqueous layer removed. The organic layer was extracted with 10 ml of water. The combined aqueous phases were cooled to 5 ° C and a premixed solution of 284 g of potassium permanganate in 2 ml of concentrated phosphoric acid and 50 ml of water was added dropwise between 5 ° and 10 ° C. The addition took 20 minutes. At this point, 50 ml of ethyl acetate was added and the pH of the mixture was lowered to 1.5 with 6N hydrochloric acid. To this two-phase system, 50 ml was added dropwise. 10% sodium bisulfite, keeping the pH 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 with ethyl acetate (3 x 50 ml) and the combined ethyl acetate layers were washed with brine, dried (MgSO 4) and evaporated in vacuo. The residue was dried under high vacuum to give 4.2 g of the title compound, m.p. 145-147 ° C. The NMR spectrum (CDCl3) showed absorptions at 4.90 (s, 1H), 4.30 (s, 1H), 1.60 (s, 3H) and 1.42 (s, 3H) ppm. The IR spectrum (KBr plate) showed absorptions at 1800, 1740, 1330 and 1250-1110 cm -1.

Example 21 6-Chloro-6-brompenic illansyrene-1,1-dioxide.

Oxidation of 6-chloro-6-brompenicillanic acid with potassium permanganate by the procedure of Example 20 gave 6-chloro-6-brompenicillanic acid 1,1-dioxide.

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21

Example 22

Penicillanic acid 1,1-dioxide.

The ethyl acetate solution of 6,6-dibrompenicillanic acid 1,1-dioxide from Example 18 was combined with 705 ml of 5 saturated sodium bicarbonate solution and 8.88 g of 5% palladium-on-carbon catalyst. The mixture was shaken under an atmosphere of hydrogen at a pressure of about 5 kg / cm for about 1 hour The catalyst was filtered off and the pH of the aqueous phase of the filtrate was adjusted to 1.2 with 6N 10 hydrochloric acid. The aqueous phase was saturated with sodium chloride. separated and the aqueous phase was extracted with additional ethyl acetate (3 x 200 ml) The combined ethyl acetate solutions were dried (MgSO 4) and evaporated in vacuo to give 33.5 g (58% yield 15 based on 6-aminopenicillanic acid) of penicillanic acid This product was dissolved in 600 ml of ethyl acetate, the solution was decolorized with activated charcoal and the solvent was evaporated in vacuo, the product was washed with hexane to give 31.0 g of pure product.

Example 23

Hydrogenolysis of each of 6-chloro-6-iodo-penicillanic acid-1,1-dioxide, 6-bromo-6-iodo-penicillanic acid and 6-chloro-6-bromo-penicillanic acid by the procedure of Example 22 in each case gave penicillanic acid-1 , 1-dioxide.

Example 24

Penicillanic acid 1,1-dioxide.

To a stirred suspension of 786 mg of 6-chloro-6-iodo-penicillanic acid 1,1-dioxide in 10 ml of benzene was added 0.3 ml of triethylamine followed by 0.25 ml of trimethylsilyl chloride at ca. 0 ° C. Stirring was continued for 5 minutes at ca. 0 ° C and then at the reflux temperature of the solvent for 30 minutes. The reaction mixture was cooled to 25 ° C and the precipitated material was filtered off. The filtrate was cooled to ca. 0 ° C and 1.16 g of tri-n-butyltin hydride and a few milligrams of azobic acid

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22 isobutyronitrile was added. The reaction mixture was stirred and irradiated with ultraviolet light for 1 hour at ca.

0 ° C and then for 3.5 hours at the reflux temperature of the solvent. An additional amount of tri-n-butyltin hydride (1.1 ml) and a catalytic amount of azobis-isobutyronitrile were added and stirring and irradiation at the reflux temperature were continued for an additional 1 hour. The reaction mixture was then poured into 50 ml of cold 5% sodium bicarbonate and the two-phase system was stirred for 30 minutes. Ethyl acetate (50 ml) was added and the pH was adjusted to 1.5 with 6N hydrochloric acid. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate solutions were washed with brine, dried (MgSO4) and evaporated in vacuo. The evaporation residue was triturated under hexane and subsequently recovered by filtration. There was thus obtained 0.075 mg of the title compound.

Example 25

Penicillanic acid 1,1-dioxide.

To a stirred suspension of 0.874 g of 6-bromo-6-iodo-penicillanic acid 1,1-dioxide in 10 ml of benzene was added at ca.

At 5 ° C, 0.3 ml of triethylamine was added followed by 0.25 ml of trimethylsilyl chloride. Stirring was continued at ca. 5 ° C for 5 minutes and then for 30 minutes at the reflux temperature of the solvent. The reaction mixture was cooled to room temperature and the solids were filtered off. The filtrate was cooled to ca. 5 ° C and 1.05 ml of tri-n-butyltin hydride and a catalytic amount of azo-bisisobutyronitrile were added. The mixture was irradiated with ultraviolet light for 1 hour at ca. 5 ° C and was then poured into 30 ml of cold 5% sodium bicarbonate. The mixture was stirred for 30 minutes and then 50 ml of ethyl acetate was added. The mixture was acidified to pH 1.5 and the layers separated. The aqueous layer was extracted with ethyl acetate (2 x 25 mL) and the combined ethyl acetate layers were washed with brine, dried (MgSO 4) and evaporated in vacuo. The evaporation residue was dried in high vacuum, and 23

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ml of hexane was added. The insoluble material was filtered off to give 0.035 g of the title compound.

Example 26 Pivaloyloxymethyl-6,6-dibrompenicillanate-1,1-dioxide.

To a solution of 4.73 g of pivaloyloxymethyl-; 6,6-dibrompenicillanate in 15 ml of dichloromethane was added 3.80 g of 3-chloroperbenzoic acid at 0-5 ° C. The reaction mixture was stirred at 0-5 ° C for 1 hour and then at 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 layers separated. The ethyl acetate phase was dried (Na 2 SO 4) and evaporated in vacuo to give the title compound.

Example 27

Oxidation of each of the corresponding 6,6-dihalogenepicillanic acid esters using 3-chloro-20-perbenzoic acid by the procedure of Example 26 gave the following compounds: 3- phthalidyl-6,6-dibrompenicillanate-1,1-dioxide, 4- crotonolactonyl-6-chloro-6-iodopenicillanate-1,1-dioxide, Y-butyrolactonyl-6-bromo-6-iodopenicillanate-1,1-dioxide, acetoxymethyl-6-chloro-6-brompenicillanate-1,1-dioxide , pivaloyloxymethyl-6-chloro-6-iodopenicillanate-1,1-dioxide, hexanoyloxymethyl-6,6-dibrompenicillanate-1,1-dioxide, 1- (acetoxy) ethyl-6,6-dibrompenicillanate-1,1-dioxide, 1- (isobutyryloxy) ethyl-6-bromo-6-iodopenicillanate-1,1-dioxide, 1-methyl-1- (acetoxy) ethyl-6,6-dibrompenicillanate-1,1-dioxide, 1- methyl 1- (hexanoyloxy) ethyl-6-chloro-6-brompenicillanate, methoxycarbortyloxymethyl-6,6-dibrompenicillanate-1,1-dio-.

Oxide, propoxycarbonyloxymethyl-6-chloro-6-iodopenicillanate-1,1-dioxide, 24

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1- (ethoxycarbonyloxy) ethyl 6,6-dibrompenicillanate-1,1-dioxide, 1- (butoxycarbonyloxy) ethyl-6-bromo-6-iodopenicillanate-1,1-dioxide, 1-methyl-1- (methoxycarbonyloxy) ethyl 6,6-dibrompenicillanate-1,1-dioxide and 1-methyl-1- (isopropoxycarbonyloxy) ethyl 6,6-dibrompenicillanate-1,1-dioxide.

Example 28 Pivaloyloxymethyl penicillanate-1,1-dioxide.

To a solution of 1.0 g of pivaloyloxymethyl-6,6-dibrompenicillanate-1,1-dioxide in 10 ml of methanol was added 3 ml of 1M sodium bicarbonate and 200 ml of 10% palladium-on-charcoal. The reaction mixture was shaken vigorously under an atmosphere of hydrogen at a pressure of ca. 5 kg / cm until hydrogen uptake ceased. The mixture was then filtered and the majority of the methanol removed by evaporation in vacuo. Water and ethyl acetate were added to the evaporation residue and the pH was adjusted to 8.5. The layers 20 were separated and the organic layer was washed with water, dried (Na2804) and evaporated in vacuo. Pivaloyloxymethylpenicillanate-1,1-dioxide was thereby obtained.

Example 29

Hydrogenolysis of each of the 6,6-dihalo-penicillanic acid ester-1,1-dioxides of Example 27 by the procedure of Example 28 gave the following compounds: 3-phthalidyl-penicillanate-1,1-dioxide, 4-crotonolactonyl-penicillanate -1,1-dioxide, Y-butyrolacton-4-yl-penicillanate-1,1-dioxide, acetoxymethyl-penicillanate-1,1-dioxide, pivaloyloxymethyl-penicillanate-1,1-dioxide, hexanoyloxymethyl-penicillanate-1 , 1-dioxide, 1- (acetoxy) ethyl-penicillanate-1,1-dioxide, 1- (isobutyryloxy) ethyl-penicillanate-1,1-dioxide, 1-methyl (acetoxy) ethyl-penicillanate-1.1 -dioxide, 1-methyl-1- (hexanoyloxy) ethyl-penicillanate-1,1-dioxide, 25

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methoxycarbonyloxymethyl-penicillanate-1,1-dioxides # propoxycarbonyloxymethyl-penicillanate-1,1-dioxide, 1- (ethoxycarbonyloxy) ethyl-penicillanate-1,1-dioxide, 1- (butoxycarbonyl) ethyl-penicillanate-1,1-dioxide, 5 1-methyl-1- (inethoxycarbonyloxy) ethyl penicillanate-1,1-dioxide and 1-methyl-1- (isopropoxycarbonyloxy) ethyl 1-penicilliana t-1,1-dioxide.

Example 30 Pivaloyloxymethyl-6,6-dibrompenicillanate-1,1-dioxide.

A stirred solution of 3.92 g of 6,6-dibrompenicillanic acid 1,1-dioxide in 20 ml of Ν, Ν-dimethyl fomamide was cooled to 0 ° Cr and then 1.29 g of diisopropylethylamine was added. Then 1.51 g of chloromethyl pivalate was added. This reaction mixture was stirred at 0 ° C for 3 hours and then at room temperature for 16 hours. The reaction mixture was then diluted with 25 ml of ethyl acetate and 25 ml of water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl-acetate layers were washed with cold 5% sodium bicarbonate solution, water and brine. The ethyl acetate solution was then treated with Darco (an activated charcoal), dried (MgSO4) and evaporated in vacuo to give a brown oil weighing 2.1 g. This oil was chromatographed on 200 g of silica gel using dichloromethane as eluent. . The fractions containing the desired product were pooled and re-chromatographed on silica gel to give 0.025 g of the title compound. The NMR spectrum (GDCl ^) showed absorptions at 6.10 (q, 2H), 5.00 (s, 1H), 4.55 (s, 1H), 1.60 (s, 3H), 1.50 (s, 3H) and 1.15 (s, 9H) ppm.

Example 31

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 52 μΐ of tri-n-butyltin anhydride followed by a catalytic amount of azobisisobutyronitrile. Reaction mixture 26

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gene was cooled to ca. 5 ° C and then irradiated with ultraviolet light 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 and the pH of the aqueous phase was adjusted to 7.0. The layers were separated and the aqueous phase was further extracted with ethyl acetate.

The combined ethyl acetate solutions were washed with brine, dried (MgSO4) and evaporated in vacuo. The evaporation residue was dried in high vacuum for 30 minutes. Thereby, 10 mg of a yellow oil was obtained which, by NMR spectroscopy, was found to contain the title compound along with some impurities containing n-butyl groups.

Example 32 6,6-Dibrompenicillanic acid 1,1-dioxide.

To a solution of 359 mg of 6,6-dibrompenicillanic acid in 30 ml of dichloromethane was added 380 mg of 3-chloroperbenzoic acid at 0-5 ° C. The reaction mixture was stirred at 0-5 ° C for 30 minutes and then at 25 ° C for 24 hours.

The filtered reaction mixture was evaporated in vacuo to give the title compound.

Example 33

Benzyl 6,6-dibromopenicillanate-l, 1-dioxide.

A mixture of 10.0 g of 6,6-dibrompenicillanic acid-1,1-dioxide, 2.15 g of sodium bicarbonate, 3.06 ml of benzyl bromide 25 and 100 ml of Ν, Ν-dimethylformamide was stirred at room temperature overnight. Most of the solvent was removed by evaporation in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was removed, washed with 1N hydrochloric acid and with saturated sodium chloride and dried (Na 2 SO 4). Evaporation in vacuo afforded 11.55 g of the title compound. The NMR spectrum (in CDCl3) showed absorptions at 7.40 (s, 5H), 5.30 (m, 2H), 4.95 (s, 1H), 4.55 (s, 1H), 1.50 (s, 3H) and 1.20 (s, 3H) ppm.

27

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Example 34

Penicillanic acid 1,1-dioxide.

To a solution of 2.0 g of benzyl 6,6-dibrompenicil lanate-1,1-dioxide in 50 ml of tetrahydrofuran was added a solution of 0.699 g of sodium bicarbonate in 50 ml of water followed by 2.0 g of 5% palladium. -on-carbon. This mixture was then shaken under an atmosphere of hydrogen at ca. 50 psig. for 70 minutes. The tetrahydrofuran was removed by evaporation and the residue was partitioned between ethyl acetate and water at pH 7.37. The aqueous layer was removed and fresh ethyl acetate was added. The pH was lowered to 1.17 and the ethyl acetate was removed and washed with saturated sodium chloride solution. Evaporation in vacuo afforded 423 mg of the title compound.

15

Example 35

Penicillanic acid 1,1-dioxide.

2,2,2-Trichloroethyl 6,6-dibrompenicillanate-1,1-dioxide was reduced with zinc dust in a mixture of glacial acetic acid and tetrahydrofuran, essentially according to Example 15. The yield was 27%.

Example 36 1- (Ethoxycarbonyloxy) ethyl 6,6-dibrompenicillanate -1,225 dioxide.

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

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Example 37 1- (Ethoxycarbonyloxy) ethyl penicillanate-1,1-dioxide.

An aliquot (230 mg) of the product of Example 36 was dissolved in 10 ml of toluene. To this was added 0.4 ml of 5-tri-n-butyltin hydride, followed by 0164 g of azobisisobutyronitrile, and the mixture was heated to 70-80 ° C for 3.5 hours. The solvent was removed by evaporation in vacuo and the residue was dissolved in 25 ml of acetonitrile. The acetonitrile solution was washed with hexane 10 several times and then evaporated in vacuo. The residue was dissolved in ether and the ether solution was washed with 5% potassium fluoride followed by saturated sodium chloride. The dried (Na 2 SO 4) ether solution was evaporated in vacuo and the residue was chromatographed 15 p | silica gel to give 0.043 g of the title compound. The NMR spectrum (in CDCl3) showed absorptions 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.

Claims (4)

1. Penicillanic acid 1,1-dioxide derivatives, characterized in that they are derivatives of the general formula V H 0 0 5 Ϊ; '/ CH - x ά \ ch3 -L 3 (III) of', C (X) R 10 or base salts thereof, wherein R is hydrogen, an in vivo readily hydrolyzable ester forming group selected from 3-phthalidyl, 4-crotonolactonyl, γ -butyrolactonyl or a group of the formula: R 2 is R 2 is -COCR * or -COCOR * in 3 * 3 R where and R 1 is each hydrogen or alkyl of 1 to 2 C-20 atoms and R 2 is alkyl of 1 to 5 C atoms, or a usual penicillin carboxy protecting group selected from tetrahydropyranyl, trialkylsilyl having 1-3 C atoms in each alkyl group, benzyl, 4-nitrobenzyl, benzhydryl, 2,2,2-trichloroethyl, t-butyl or phenacyl, and X 25 and Y each is hydrogen, chlorine, bromine or iodine with the condition that when X and Y are the same, they must both be bromine. A compound according to claim 1, characterized in that R is hydrogen. A compound according to claim 2, characterized in that X is bromine and Y is hydrogen. A compound according to claim 2, characterized in that X and Y are both bromine.