FI81353C - Process for the preparation of novel penicillanic acid 1,1-dioxide derivatives and intermediates useful in the process - Google Patents

Description

1 81353

Process for the preparation of new penicillanic acid 1,1-dioxide derivatives and intermediates useful in the process 5 By division separated from patent application 824409

The invention relates to the preparation of novel chemical compounds which are valuable beta-lactamase inhibitors. More specifically, it relates to the preparation of monoesters of certain 1,1-alkanediol dicarboxylates in which the carboxyl group of certain β-lactamase inhibitors is esterified.

Penicillanic acid 1,1-dioxide (sulbactam) is known from U.S. Patent No. 4,234,579 to be a potent β-lactamase inhibitor and antibacterial agent.

U.S. Patent No. 4,244,951 describes bls esters of formula (IX) in which sulbactam is associated with known antibacterial penicillins R1NH4_ ^ S \ / CH3 ^ CH3 A-N-O 'coo \ (IX)

25 ° / ° 'CH

, _ ^ SV / CH3 / 2 I Xc [i3 / 0 'N //// coo' 30

In the above formula, Rx denotes certain acyl groups of known antibacterial penicillins. For example, Rx may represent 2-amino-2-phenylacetyl or 2-amino-2- (p-hydroxyphenyl) acetyl.

U.S. Patent No. 4,342,772, issued August 3, 1982, describes analogous compounds in which penicillanic 2,81353 silicins and β-lactamase inhibitors such as penicillanic acid 1,1-dioxide, clavulanic acid and 6-β-halopenicillanic acids are attached via 1,1-alkanediol groups.

U.S. Patent Nos. 4,540,687 and 4,582,829 describe compounds of formula (IX) wherein Ra is

R „COO -ft \ y ~ -CHCO

10 I

NH2 and R2 represent certain alkyl or alkoxy groups.

Ampicillin, 6- [D- (2-amino-2-phenylacetamido)] - 15 penicillanic acid, is described in U.S. Patent 2,985,648. Amoxicillin, 6- [D- (2-amino-2- [p-hydroxyphenyl) ] acetamido)] penicillanic acid is known from U.S. Patent 3,192,198 and U.S. Reissue 28,744. Amoxicillin β-acyl derivatives are described in 20 U.S. Patent Nos. 2,985,648, 3,520,876 and 4,053,360.

2-β-Acetoxymethyl-2-α-methyl-penam-3-α-carboxylic acid 1,1-dioxide has been described in the U.S. patent as being useful as an β-lactamase inhibitor.

2-β-Chloromethyl-2-α-methyl-penam-3-α-carboxylic acid 1,1-dioxide is described in GB patent application 2,070,592 as a β-lactamase inhibitor.

Bis-esters of 1,1-alkanediols and 6-β-hydroxymethylpenicillanic acid 1,1-dioxide are described in U.S. Patent 4,342,768. Corresponding derivatives of 6-α-hydroxymethylpenisil-30-danoic acid 1,1-dioxide are described in U.S. Patent Application 338,794.

The invention relates to the preparation of compounds of formula (I) which are β-lactamase inhibitors and to certain intermediates used in their preparation. The compounds of formula (I) are efficiently absorbed from the gastrointestinal tract of a mammal and are thus rapidly altered.

II

3 81353 as a β-lactamase inhibitor, BCOOH or its salts.

The invention relates to a process for the preparation of penicillanic acid 1,1-dioxide derivatives of the formula (I) having beta-lactamase inhibitory activity and to the preparation of their pharmaceutically acceptable cationic and acid addition salts H \ CH3, o "-rf ·» 0 ^ N <C0CH20C ^ = 0

Il Δ \ 0 \

A

/ -13 HOC = O wherein A is) alkylene, - (CH 3) 2 C-, (C 3 -C 7) cycloalkylene or phenylene.

Particularly preferred values for A are (CH2) 2, (CH2) 3, (CH2) 4, (CH2) 8, C (CH3) 2, 1,4-phenylene and trans-1,4-cyclohexylene.

Particularly preferred carboxylate salt-forming cations are tetrabutylammonium or alkali metal cation. The primary alkali metal cations are sodium 25 and potassium.

The invention also relates to compounds of formula (I) useful as intermediates in the preparation of compounds of formula (I) in the preparation of 0 0 H K s * _> 0CH3 \ __ fcn 3 -N-% cooch2oc = o \

A

, / R 1OC = O 4 81 353 wherein A is (C 1 -C 4 alkylene, - (CH 3) 2 C-, (C 3 -C 7) cycloalkylene or phenylene, and R 1 is benzyl.

Examples of pharmaceutically acceptable acid addition salts are hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, citric acid, malic acid, tartaric acid, maleic acid, fumaric acid, gluconic acid, sugar acid, benzenesulfonic acid po, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid po and 2-naphthalenesulfonic acid salts.

This invention relates to penicillanic acid derivatives represented by the following structural formula:

B

P- 15 ^ CH3

O "N 2" COOH

In penicillanic acid derivatives, the dashed line ('' ') of the substituent to the bicyclic ring indicates that the substituent is below the level of the core. Such a substituent is said to conform to the α-configuration. Conversely, the broad-banded attachment (^) of the substituent to the bicyclic core indicates that the substituent is above the plane of the core. This latter configuration is called the β-configuration.

As used herein, the solid line attachment () of a substituent to a bicyclic core indicates that the substituent may be in either the α-configuration or the fl-configuration.

The compounds of formula (I) are prepared according to the invention in such a way that (a) the compounds of formulas 35

II

5 81 353 H CH XCH 2 OC = 0 H V_ / 3 \

f | "CH3 and A

5 A- N- / COOM / R10C = 0 10 or (b) compounds of the formulas: 0 o \ r

H,, CH, MOC-O

H-i__ / N / 3 \ 15 TH, Da \

-> A

-N- \ f v ^ COOCH2X / R10C = O 20 wherein R1 is benzyl and A is as defined above; M is a carboxylate salt-forming cation, preferably sodium, potassium or tetrabutylammonium, and X is a leaving group, is reacted in the presence of a polar organic solvent at a temperature of 0 to 80 ° C, preferably 25 to 25 ° C, and the benzyl group is removed.

The compounds of formula (I) may be prepared by a variety of ester synthesis methods known in the art. However, the preferred process involves the formation of a salt by condensing a carboxylate salt and a halomethyl ester in which the "halogen" is a leaving group X. The preferred values of X are Cl, Br, J, CH 3 SO 2 O, p-CH 3 C 6 H 4 SO 2 O.

In an effort to form a protected intermediate, the corresponding carboxylate salt and halomethyl ester 35 are contacted with each other in approximately equimolar amounts in the presence of a polar organic solvent at a temperature between about 0-80 ° C and preferably between about 25-50 ° C. as mentioned, the reagents are used in approximately equimolar amounts, either the carboxylate salt or the halomethyl ester 5 can be used in excess, even in moles tenfold.Varely different solvents can be used in this reaction, however, it is usually preferable to use a relatively polar organic solvent to minimize the reaction time. solvents include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, ethyl acetate, dichloromethane, acetone and hexamethylphosphoric triamide. depending on a number of factors, such as the nature of the reagents, the reaction temperature, and the solvent. However, at about 25 ° C, commonly used reaction times range from about 10 minutes to about 24 hours.

The desired protected compound is then isolated by methods well known to those skilled in the art. For example, the reaction mixture is dissolved in a water-immiscible solvent, e.g. ethyl acetate, chloroform or dichloromethane, washed with water, brine and dried. Evaporation of the solvent gives an intermediate which can be purified, if desired, e.g. by chromatography on silica gel.

Selective removal of the benzyl group is accomplished by treating intermediate (VIII) under conditions commonly used in catalytic hydrogenolysis. The intermediate is stirred or shaken under a hydrogen atmosphere, or with hydrogen, optionally mixed with a neutral diluent such as nitrogen or argon, in the presence of a catalytic amount of catalytic hydrogenolysis catalyst. Suitable solvents for this hydrogenolysis include lower alkanols such as methanol and isopropanol; ethers such as tetrahydrofuran and dioxane; low molecular weight esters such as ethyl acetate and butyl acetate; chlorinated hydrocarbons such as dichloromethane and chloroform; water, and mixtures of these solvents. Usually, however, the conditions under which the starting material is in solution are selected. The hydrogenolysis is usually carried out at a temperature in the range of 0 to 60 ° C and a pressure in the range of 1 to 10 atmospheres, preferably about 3 to 4 atmospheres. The catalysts used in this hydrogenolysis reaction are of the type of substances known to be used in such a conversion reaction, and typical examples are nickel and precious metals such as palladium, platinum and rhodium. The catalyst is usually used in an amount of 0.5 to 5.0 times and preferably about 1.0 times the weight of the intermediate. It is often convenient to suspend the catalyst on a neutral support, a particularly suitable catalyst being palladium suspended on a neutral support such as carbon.

Intermediates can be obtained, for example, as follows: 20

-MX

CgH5CH2OCO-A-COOM + BC02CH2X -► 25

CcHeCHo0CO HOOC M + M00C

o 5 2 \ H, \ M \ / catalyst / * / BC0OCH20CO BCOOCH2OCO BC00CH20CO (II, R1 = C5H5CH2) (II, R1 = H) (II) '30

XCH 2X

XCH-OCO.

/

35 BCOOCEjOCO

UI) "8 81353 wherein A, M and X are as defined above, B is a beta-lactamase inhibitor group and X2 is X or a better leaving group than X, e.g. when X is Cl, X2 may be Cl, Br , J, OSO 2 Cl, O 2 SO 2 CH 3 or 2-CH 3 Cl 6 H 4 SO 2 O. Particularly preferred values for 5 X 2 are Br and J.

The first step described above, in which the benzyl half-ester salt is reacted with a halomethyl ester of 1,1-dioxopenicillanic acid to form intermediates of formula (II) wherein R 1 is Bent-10 wart, is performed as described above.

Selective removal of the benzyl group is typically performed by catalytic hydrogenolysis by the same methods and under the same conditions described above. In a particularly preferred process for removing the benzyl group, a palladium-carbon catalyst at 3-4 atmospheric pressure and tetrahydrofuran or ethyl acetate are used as the solvent. The carboxylic acid of formula II (R 1 is H) may then be isolated by standard methods or the acid may be conveniently reacted with a suitable base 20 to form the corresponding salt of formula (II ') wherein M is the carboxylate salt forming cation as defined above. In the preferred process for obtaining the sodium and potassium salts of formula (II '), the sodium or potassium salt of 2-ethylhexanoic acid is used as the base. As a typical example, the carboxylic acid of formula (II) is dissolved in ethyl acetate, an equimolar amount of sodium (or potassium) -2-ethylhexanoate is added with stirring, and the precipitated salt of formula (II ') is collected by filtration and washed.

Salts of formula (II ') wherein M is tetrabutylammonium can be obtained from the corresponding acid, sodium or potassium salt. For example, when a carboxylic acid of formula (II) is used, it is typically reacted with an equimolar amount of tetrabutylammonium hydroxide in the presence of a water-immiscible organic solvent, preferably chloroform. Solvent 9 81353 is separated and the product is isolated by evaporation of the solvent.

Intermediates of formula (II ") are obtained by eliminating MX2 elements in the reaction between the corresponding compounds of formula (II") and XCH2X2, wherein M, X and X2 are as defined above. The reaction is carried out using the same methods and conditions as above.

Acid addition salts are prepared by standard methods for the preparation of penicillin compounds, for example by combining a solution of a compound of formula (I) in a suitable solvent (e.g. water, ethyl acetate, acetone, methanol, ethanol or butanol) with a stoichiometrically equivalent amount of a suitable acid. If the salt precipitates, it is recovered by filtration. Alternatively, it can be recovered by evaporating the solvent or, in the case of aqueous solutions, by freeze-drying. Particularly valuable are the sulfate, hydrochloride, hydrobromide, nitrate, phosphate, citrate, tartrate, pamoate, perchlorate, sulfosalicylate, benzenesulfonate, 4-toluenesulfonate and 2-naphthylenesulfonate salts.

The compounds of formula (I), and their salts, may be purified by conventional methods for purifying penicillin compounds, e.g. by recrystallization or chromatography, while taking into account the lability and ester bonds of β-lactam ring systems.

In planning the therapeutic use of a salt of an antibacterial compound of the invention, a pharmaceutically acceptable salt must be used; however, salts other than those mentioned may be used for various purposes. Such purposes include the isolation and purification of certain compounds, and the exchange of pharmaceutically acceptable salts for each other and their unsalted counterparts.

The compounds of formula (I) of the invention all have in vivo antibacterial activity in mammals.

10 81 353 This effect can be demonstrated by the standard methods used for penicillin compounds. For example, the above-mentioned compound of formula (I) is administered to mice infected with acute infections by intramuscular injection of a standardized culture of a pathogenic bacterium. The severity of the infection is standardized so that the mice receive one to ten times the dose of LD100 (LD100: the minimum dose of vaccine required to kill 100 percent of the control-10 mice evenly). At the end of the experiment, the effect of the compound is evaluated by counting the number of surviving animals that have been exposed to the bacterium and have also received the compound of the invention. The carboxylic acids and alkali metal salts of formula (I) can be administered both orally (po) and subcutaneously (it).

The in vivo activity of the antibacterial compounds of the invention makes them suitable for controlling bacterial infections in mammals, including humans, using both oral and parenteral routes of administration. The compounds are useful in controlling infections caused by susceptible bacteria in humans.

Carboxylic acids of formula (I), and in particular compounds of formula 25 0 0 t-rVi

o N '"' CO-XH-OC-A-COOH

. . U / Z n

30 O

their alkali metal salts, especially the sodium and potassium salts, are useful as oral or parenteral prodrug forms of sulbactam and as such have therapeutic potential as β-lactamase inhibitors, for example in applications;

II

11,81353 described for sulbactam in U.S. Patent 4,234,479.

Examples of pharmaceutically acceptable cationic salts of the carboxylic acid compounds of formula (I) include alkali metal salts such as sodium and potassium salts; as well as the ammonium salt and salts of pharmaceutically acceptable amines such as N-methylglucamine, N, N-dibenzylethylenediamine, ethanolamine and procaine.

10 In determining whether a particular Escherichia coli or

A staphylococcus aureus strain sensitive to a particular therapeutic compound or mixture can be used in the previously described in vivo assay. Alternatively, for example, the minimum inhibitory concentration (MIC) of amoxicillin and sulbactam or a 1: 1 mixture of ampicillin and sulbactam can be determined. MIC values can be determined by the method recommended by the International Collaborative Stydy on Antibiotic Sensitivity Testing (Ericcson and Sherris, Acta. Pathologica et Microbiologia Scandinav, Supp. 217, 20 Section B: 64-68 [1971]) using brain-heart - injection (BHI) agar and a vaccine applicator. Tubes grown overnight are diluted 100-fold for use as a standard vaccine (20,000-10,000 cells in approximately 0.002 ml are plated on agar; 20 ml BHI agar / plate). Twelve 2-fold dilutions of test compound are used, with an initial concentration of 200 mcg / ml. Private bacterial clusters are disregarded when performing plate counts 18 hours after exposure to 37 ° C. The lowest concentration of a compound that can cause complete growth inhibition in the naked eye is accepted as the sensitivity (MIC) of the test organism.

When a compound of the invention, or a salt thereof, is used when administered to a mammal, especially a human, the compound may be administered alone or may be mixed with other antibiotic agents and / or pharmaceutically acceptable carriers or diluents. Said carrier or diluent is selected on the basis of the intended mode of administration. For example, when considering an oral dosage form, the compound of this invention may be used in the form of tablets, capsules, lozenges, troches, powders, syrups, elixirs, aqueous solutions and suspensions, and the like, in accordance with normal pharmaceutical practice. depending on the chemical nature, solubility and stability of the naturally active ingredient, as well as the intended dosage. In the case of tablets for oral use, carriers which are commonly used include lactose, sodium citrate and salts of phosphoric acid. In Table 15, various disintegrants such as starch and glidants such as magnesium stearate, sodium lauryl sulfate and talc are commonly used. Diluents useful for oral administration in capsule form include lactose and high molecular weight polyethylene glycols, e.g., polyethylene glycols having molecular weights in the range of 2000-4000. If aqueous suspensions for oral use are required, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring agents may be added. For parenteral administration, which are intramuscular, intraperitoneal, subcutaneous, and intravenous, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions is adjusted and buffered. For intravenous use, the total concentration of the solutions should be adjusted to make the preparation isotonic.

As previously mentioned, the compounds of the invention can be administered to humans and the daily dose used does not differ significantly from other clinically useful doses of penicillin antibiotics. The prescribing physician will ultimately determine the appropriate dose for the particular patient, and this can be expected to vary depending on the age, weight, and response of the individual patient to the drug, as well as the nature and severity of the patient's symptoms. The compounds of the invention are normally used in oral doses in the range of 20 to about 100 mg per kilogram of body weight per day, and parenterally in doses of about 10 to about 100 mg per kilogram of body weight per day, usually in divided doses. . In some cases, it may be necessary to use doses outside these limits.

The following examples and preparations are provided for illustrative purposes only. Nuclear magnetic resonance (NMR) spectra were determined from solutions in deuterated chloroform (CDCl 3) or deuterated dimethyl sulfoxide (DMSO-d 6), and peak positions are reported in parts per million downfield from tetramethylsilane. The following abbreviations have been used for the forms of peaks: bs, broad singlet; s, singlets; d, doublets; t, triplets; q, 20 quartets; m, multiplets.

Example 1 (intermediate)

Monobenzyl esters of dicarboxylic acids A. trans-1,4-cyclohexanedicarboxylic acid monobenzyl ester To a solution of 1.0 g (2.8 mmol) of dibenzyl trans-1,4-cyclohexanedicarboxylate in 20 ml of tert-butanol (warm), a solution of 1.9 g of potassium hydroxide in 10 ml of tert-butanol is added. After stirring overnight at room temperature, the cloudy mixture is evaporated to dryness to remove the solvent, dissolved in water and acidified to pH 5.3; then after 30 minutes the pH of the solution is acidified to pH

5.25 with dilute hydrochloric acid. The precipitated solid is collected on a filter, redissolved in dilute sodium bicarbonate solution and the pH is again adjusted to 5.25 to precipitate the purified monoester, 1H-NMR

I * 81353 (DMSO-d 6) ppm (delta): 1.1-2.3 (m, 10H), 5.1 (s, 1H), 7.35 (S, 5H).

B. Monobenzyl terephthalate To a warm solution of 10 g of dibenzyl terephthalate in 200 ml of t-butanol is added a solution of 1.9 g of potassium hydroxide in 100 ml of t-butanol and 10 ml of water. The resulting mixture is stirred at room temperature for 60 hours. The solvent is evaporated off in vacuo, the residue is dissolved in water and acidified to pH 5.3 and further treated as in Part A above to give the desired monoester in 56% yield, m.p.

178 ° C.

1 H-NMR (DMSO) ppm (delta): 5.3 (s, 2H), 7.4 (s, 5H), 8.1 (s, 4H); infrared absorption peaks at 1690 cm'1 and 15 1710 cm'1.

Saponification of dibenzyl terephthalate (15 g) in benzyl alcohol (225 ml) with an equimolar amount of potassium hydroxide with stirring overnight at room temperature and trituration with ethyl ether gives the potassium salt of monobenzyl terephthalate in 75% yield.

Example 2 (intermediate)

Cis-1,2-cyclohexane-monobent-benzyl ester

To a mixture of 15.4 g (0.10 mol) of cis-1,2-25 cyclohexanedicarboxylic anhydride in 200 ml of toluene is added dropwise a solution of 10.8 g (0.10 mol) of benzyl alcohol in 50 ml of: toluene. The mixture is stirred at room temperature for 1 hour, then warmed to 60 ° C and kept at this temperature for 30 hours. The solvent is evaporated off until the volume of the mixture is small and the monoester product is recovered by cooling and filtering off the precipitated solid. Sp. 69-71 ° C. 1 H-NMR (CDCl 3) ppm (delta): 1.3-2.0 (m, 8H), 2.4 (m, 2H), 5.1 (s, 2H), 7.3 (s, 5H) . 35 IR spectrum (CHCl 3) cm -1: 1700, 1720, 2400-3700.

li is 81353

Alternatively, the reaction mixture in toluene is treated with an equimolar amount of an ethanolic solution of potassium hydroxide to give the potassium salt of the monobenzyl ester. The sodium salt is obtained in a similar manner using a methanolic solution of sodium hydroxide.

The corresponding monobenzyl esters or their sodium or potassium salts are obtained by the method described above from the following dicarboxylic acid anhydrides: succinic anhydride 10 glutaric anhydride (boiling in toluene overnight).

Example 3 (intermediate)

Benzyl 1,1-dioxopenicillanoyloxymethyl succinate To a mixture of 9.2 g (0.044 mol) of benzyl succinate half ester in 200 ml of chloroform and 25 ml of water was added with vigorous stirring a 40% aqueous solution of tetrabutylammonium hydroxide to pH 8.5 until . The chloroform layer was separated and the aqueous layer was extracted (1 x 100 mL) with chloroform. The combined chloroform extracts were dried (Na 2 SO 4) and concentrated in vacuo to an oil. The oil was combined with 200 ml of toluene and 16.5 g (0.044 mol) of iodomethylpenicillanate 1,1-dioxide were added. The mixture was stirred for 30 minutes, diluted with ethyl acetate to 400 ml and the precipitated tetrabutylammonium iodide was removed by filtration. The filter cake was washed with 100 mL of ethyl acetate and the combined filtrates were washed with saturated NaHCO 3 (1 x 100 mL), water (1 x 100 mL), brine (1 x 100 mL), dried (Na 2 SO 4) and concentrated in vacuo to an oil. Chromatography on silica gel (1 kg) eluting with ethyl acetate-hexane (1: 1 v / v) gave 8.5 g (43%) of a white solid.

1 H-NMR (CDCl 3) ppm (delta): 1.45 (s, 3H), 1.63 (s, 3H), 2.77 (s, 4H), 3.47 (d, 2H), 4, 43 (S, 1H), 4.62 (t, 1H), 5.17 (s, 1681353 2H), 5.84 (AB quartet, 2H), 7.4 (s, 5H).

The following compounds were also prepared from the appropriate monobenzyl ester in the same manner: a. Benzyl 1,1-dioxopenicillanoyloxymethyl-5-glutarate (Yield 61%) - 1 H-NMR (CDCl 3) ppm (delta): 1.42 (s, 3H), 1.6 (s , 3H), 1.8-2.2 (m, 2H), 2.28-2.68 (m, 4H), 3.45 (d, 2H), 4.4 (s, 1H), 4, Δ (t, 1H), 5.14 (s, 1H), 5.8 (AB quartet, 2H), 7.37 (s, 5H).

10 b. Benzyl 1,1-dioxopenicillanoyloxymethyl adipate (Yield 47%) - 1 H-NMR (CDCl 3) ppm (delta) 1.46 (s, 3H), 1.63 (s, 3H), 1.53- 1.86 (m, 4H), 2.22-2.6 (m, 4H), 3.46 (d, 2H), 4.42 (s, 1H), 4.6 (t, 1H), , 13 (s, 2H), 5.82 (AB-15 quartet, 2H), 7.33 (s, 5H).

c. Benzyl 1,1-dioxopenicillanoyloxymethyl dimethyl malonate (Yield 73.8%) - 1 H-NMR (CDCl 3) ppm (delta): 1.4 (s, 3H), 1.53 (s, 9H), 3.45 ( d, 2H), 4.4 (s, 1H), 4.56 (t, 1H), 5.22 (s, 2H), 5.78 (AB quartet, 2H), 7.35 (s, 5H).

d. Benzyl 1,1-dioxopenicillanoyloxomethyl malonate (Yield 45%) - 1 H-NMR (CDCl 3) ppm (delta): 1.43 (s, 3H), 1.6 (s, 3H), 3.46 (d, 2H) , 3.53 (s, 2H), 4.42 (s, 1H), 4.6 (t, 1H), 5.2 (s, 2H), 5.85 (AB quartet, 2H), 739 (s, 5H); infrared spectrum (nujol) cm -1: 1795, 1790.

e. Benzyl 1,1-dioxopenicillanoyloxymethyl sebacate (Yield 54%), oil, 1 H-NMR (CDCl 3) ppm (delta): 1.2-1.9 δ (m, 18H), 2.1-2, Δ (m, 4H), 3.4 (d, 2H), 4.4 (s, 1H), 4.6 (t, 1H), 5.1 (s, 2H), 5.8 (q, 2H) ), 7.3 (s. 5H).

f. Similarly, the remaining monobenzyl esters mentioned in Examples 1 and 2 are converted to the corresponding compounds of formula 35 ii 17 81 353 0? \ / ΓΗ - ^ CE3 q * N / y // C0C ^ 00 = 0 5 \

A

/

C 9 H 5 CH 2 OC = 0 10

Where A is the same as defined for the monobenzyl ester used as starting material.

g. Alternatively, the aforementioned benzyl-1,1-dioxopenicillanoyloxymethyl diesters are prepared as described below for the adipate diester.

A mixture of 17.0 g (0.0665 moles) of sodium 1,1-dioxopenicillanate, 18.0 g (0.0634 moles) of benzyl 20-chloromethyl adipate, 6.7 g (0.020 moles) of tetrabutylammonium bromide and 300 ml of acetone , heated under nitrogen, boiling overnight. The acetone is evaporated off and the remaining gel is dissolved in 300 ml of ethyl acetate. Water (150 ml) is added, the organic layer is separated and the aqueous layer is extracted with fresh ethyl acetate (150 ml). The combined organic extracts were washed with water (3 x 250 mL), brine (2 x 150 mL), dried (Na 2 SO 4) and concentrated in vacuo to an oil (31.8 g). The oil is chromatographed on 700 grams of silica gel, eluting with hexane / ethyl acetate 2: 1 to remove more non-polar impurities, then ethyl acetate / hexane 1: 1 to remove product. Evaporation of the solvent from the product fractions gives 27.3 g (89.5%) of product.

Using the corresponding methyl half-ester or other alkyl half-ester in which alkyl is ethyl, n-propyl, isopropyl, n-butyl or isobutyl instead of benzyl half-ester in the above process in the same manner, the corresponding alkyl-1 , 1-dioxopenicillan-5-noyloxymethyl dicarboxylate.

Example 4 (final product)

Sodium 1,1-carbonate-dioksopenisillanoyylioksimetyylisukki

A solution of 8.4 g (0.019 mol) of benzyl 10,1-dioxopenicillanoyloxymethyl succinate in 75 ml of tetrahydrofuran was added to a suspension of 4 g of 10% (w / w) palladium-on-carbon in tetrahydrofuran (THF). and shaken at 50 psi (3.52 kg / cm 2) hydrogen pressure in a hydrogenator. After 15 minutes, the catalyst was removed by filtration through a filter aid and the filter cake was washed with 75 mL of THF, the combined filtrates were concentrated in vacuo and dissolved in 75 mL of ethyl acetate. To this solution was added 3.07 g (0.019 mol) of sodium 2-ethylhexanoate with stirring. After 20 minutes, the precipitate was filtered off, washed with diethyl ether and dried under nitrogen to give 6.8 g (95%) of a white solid.

In a similar manner, the following sodium salts were prepared, except that in cases where no precipitate formed upon addition of sodium 2-ethylhexanoate, ethyl ether was added to cause precipitation.

a. Sodium 1,1-dioxopenicillanoyloxymethyl glutarate (Yield 93%) - 1 H-NMR (D 2 O) ppm (delta): 1.48 (s, 3H), 1.63 (s, 3H), 1.6 -2.7 (m, 6H), 3.22-3.98 (m, 2H), 4.68 (s, 1H), 4.8-5.13 (m, 1H), 5.86 (AB quartet, 2H).

b. Sodium 1,1-dioxopenicillanoyloxymethyl adipate (Yield 79%) - 1 H-NMR (D 2 O) ppm (delta): 1.46 (s, 3H), 1.63 (s, 3H), 1.44 -1.8 (m, 4H), 2.1-2.6 (m, 4H), 3.1-3.96 (m, 2H),

II

19 81 353 4.56-4.76 (HOD peak, covering C-3H), 5.0-5.16 (m, 1H), 5.92 (AB quartet, 2H).

c. Sodium 1,1-dioxopenicillanoyloxymethyl dimethyl malonate 5 (Yield 94.5%) (recrystallization from ethyl acetate / hexane gives needle-like crystals) - 1 H-NMR (D 2 O) ppm (delta): 1.33 (s, 6H) , 1.44 (s, 3H), 1.58 (s, 3H), 3.16-3.9 (m, 2H), 4.65 (s, 1H), 4.93-5.1 (m , 1H), 5.93 (AB quartet, 2H); infrared spectrum (nujol), 1780 cm-1.

10 d. Sodium 1,1-dioxopenicillanoyloxymethylmalonate (Yield 88%) - 1 H-NMR (D 2 O) ppm (delta): 1.45 (s, 3H), 1.6 (s, 3H), 3.2-3, 93 (m, 2H), 4.66 (s, 1H), 4.96-5.13 (m, 1H), 5.88 (AB quartet, 2H). It was noted that the CH2-Malo-15 naphtha hydrogen atoms exchanged with D2O.

e. Sodium 1,1-dioxopenicillanoyloxymethyl sebacate (Yield 80%) - 1 H-NMR (D 2 O) ppm (delta): 1.2-1.7 (m, 18H), 2.15 (t, 1H), 2.45 (t, 2H), 3.45 (d, 1H), 3.65-3.75 (dd, 1H), 4.75 (s, 1H), 5.15-5.25 (m , 1H), 5.8-6.0 (dd, 2H), infrared spectrum (KBr) cm-1: 1570, 1770, 1800.

f. The remaining benzyl esters mentioned in Example 3 are hydrogenated and converted to the corresponding sodium salt using the above method. The corresponding potassium salt is obtained using potassium 2-ethylhexanoate in the above method.

Example 4A (final product)

Crystalline 1,1-dioxopenicillanoyloxymethyl adipic acid hydrate To 400 ml of acetone are added 48.5 g (0.19 mol) of sodium 1,1-dioxopenicillanate, 48.0 g (0.17 mol) of benzyl chloromethyl adipate and 19, 3 g (0.06 mol) of tetrabutylammonium bromide. The mixture is heated to reflux under nitrogen overnight, filtered, washed with gun-35 ton and the filtrate evaporated to dryness. The residue is dissolved in 20 8 1 3 5 3 500 ml of ethyl acetate, washed alternately with brine and water, in 250 ml portions, again with brine and dried (MgSO 4). Evaporation of the solvent in vacuo gives 89.6 g of a pale yellow oil.

The oil is dissolved in 250 ml of ethyl acetate, 20.0 g of 10% Pd / C are added and the mixture is hydrogenated at a pressure of 3.52 kg / cm2 for one hour. After the addition of 15 g of fresh catalyst, the hydrogenation is continued for 2.5 hours. The catalyst is removed by filtration, the filter cake is washed with 10 acetone (1500 ml) and the combined filtrate and washings are evaporated to dryness in vacuo to give a viscous oil, the oil is dissolved in 150 ml of acetone and water is slowly added to initiate crystallization. the female volume is 800 ml. After stirring for 30 minutes, the crystalline product is collected by filtration, washed with water and air-dried to give 58.2 g of the title carboxylic acid. Recrystallization from ethyl acetate gives a crystalline monohydrate, m.p. 100-102 ° C.

Analysis for C15H2109NS «H2O:

Calculated: C 44.00, H 5.66, N 3.42 Found: C 43.93, H 5.65, N 3.42

Crystallinity was verified by X-ray crystallography.

25 Example 5 (end product)

Sodium 1,1-dioxopenicillanoyloxymethyl trans-1,4-cyclohexanedicarboxylate A. Benzyl chloromethyl trans-1,4-cyclohexane dicarboxylate To a mixture of 2.06 g (0.036 moles) of sodium bicarbonate, 5.46 g ( 0.018 mol) of potassium benzyl trans-1,4-cyclohexanedicarboxylate, 50 ml of water and 500 ml of chloroform, 6.17 g (0.018 mol) of tetrabutylammonium hydrogen sulphate are added and the mixture is stirred at room temperature overnight. The layers are separated. The water

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2i 81353 ros is extracted twice with chloroform and the combined chloroform layers are dried and evaporated to dryness. The resulting tetrabutylammonium salt is dissolved in methylene chloride (20 ml) and the solution is added dropwise to 20 ml of bromo-5 chloromethane at 0 ° C. The resulting mixture is stirred at ambient temperature for 70 hours, the solvent is evaporated off and ethyl acetate is added to the residue. The precipitated tetrabutylammonium bromide is removed by filtration, the filtrate is dried (Na 2 SO 4) and evaporated to dryness in vacuo to give 5 g (91%) of crude product. Purification by chromatography on silica gel, eluting with ethyl ether / hexane (1: 3), gave 1.9 g (35%) of the desired product as an oil.

1 H-NMR (CDCl 3) ppm (delta): 1.0-2.4 (m, 10H), 5.1 (s, 2H), δ 5.7 (s, 2H), 7.3 (s, 5H ).

B. Benzyl 1,1-dioxopenicillanoyloxymethyl trans-1,4-cyclohexanedicarboxylate A solution of 4.2 g (13.5 moles) of benzyl chloromethyl trans-1,4-cyclohexanedicarboxylate, 3.63 g (14 , 2 mmol) of sodium 1,1-dioxopenicillanate, 1.45 g (4.5 mmol), and 100 ml of acetone, are heated at reflux overnight. The acetone is evaporated off, ethyl acetate (100 ml) is added and the solution is washed with water (3 times), brine and dried over anhydrous sodium sulfate. The solvent is removed by evaporation to dryness in vacuo to give the crude product which is purified by column chromatography on silica gel eluting with ethyl acetate / hexane (1: 1) to give 5.3 g (78 (78%) of purified product as an oil which is used as follows: stage.

1 H-NMR (CDCl 3) ppm (delta): 1.3-1.65 (m, 6H), 1.65-2.6 (m, 10H), 3.4 (d, 2H), 4.4 ( s, 1H), 4.55 (t, 1H), 5.1 (s, 2H), 5.8 (q, 2H), 7.3 (s, 5H); infrared spectrum (CHCl 3) cm -1: 1730, 1760, 1810.

35 C. To a solution of 2.5 g (4.9 mmol) of the benzyl ester obtained in 22 B 353 above in 50 ml of ethyl acetate under a nitrogen atmosphere is added 1.5 g of 10% Pd / C catalyst. The resulting mixture is hydrogenated at 1-2 atmospheric pressure for about 20 minutes. The catalyst is removed by filtration and 0.82 g (4.9 mmol) of sodium 2-ethylhexanoate are added to the filtrate. After stirring for 30 minutes at room temperature, the mixture is concentrated to one third of its volume and three volumes of ethyl ether are added. The precipitated title compound was filtered off, washed with ether and dried under nitrogen to give 1.7 g (79% yield) of product.

* NMR (D 2 O) ppm (delta: 1.3-2.4 (m, 16H), 3.4-3.6 (m, 2H), 4.6 (s, 1H), 4.9-5, O (m, 1H), 5.7 (q, 2H) Infrared spectrum (KBr) cm-1: 1565, 1760, 1810, 1780.

Example 6 (final product)

Crystalline 1,1-dioxopenicillanoyloxymethyl-trans-1,4-cyclohexanecarboxylic acid

To a solution of 6.07 g (12 mmol) of benzyl 20,1-dioxopenicillanoyloxymethyl trans-1,4-cyclohexanedicarboxylate in 100 ml of ethyl acetate under nitrogen is added 3.2 g of 10% Pd / C- catalyst. The mixture is hydrogenated for 45 minutes with shaking at 50 psi (3.52 kg / cm2). The mixture is filtered, the filtrate is concentrated in vacuo to give a residual oil which crystallizes on standing. The product is recrystallized from ethyl acetate / hexane under a nitrogen atmosphere to give 2.35 g of crystalline product which appears to contain some oil. This is dissolved in ethyl acetate (100 ml) and an equivalent amount of sodium 2-ethylhexanoate is added. The precipitated sodium salt is stirred for 45 minutes, concentrated to one third of its volume and ethyl ether is added to complete the precipitation. The sodium salt is collected by filtration, washed with ether and dried under nitrogen. sodium

II

23 81 353 Rium salt is dissolved in water (50 ml), acidified with hydrochloric acid and the mixture is extracted with ethyl acetate. The extracts are dried (Na 2 SO 4), the solvent is evaporated off in vacuo, the residue is crystallized from ethyl acetate / hexane and dried under nitrogen to give 1.85 g (37%) of product, m.p. 118.5-119 ° C, which is found to be crystalline by X-ray diffraction.

1 H-NMR (CDCl 3) ppm (delta): 1.4 (s, 3H), 1.4-1.55 (m, 4H), 1.6 (s, 3H), 2.05-2.15 (m, 4H), 2.25-2.45 (m, 2H), 3.4-3.6 (m, 2H), 4.4 (s, 1H), 4.6-4.65 ( m, 1H), 5.7-5.95 (dd, 2H).

Infrared spectrum (KBr) cm-1: 1700, 1760, 1780, 1800. Example 7 (final product) 1,1-Dioxopenicillanoyloxymethyl terephthalate and its sodium salt 15 A. Benzyl chloromethyl terephthalate

To a solution of 18.53 g (0.062 mol) of potassium benzyl terephthalate in 300 ml of water are added 600 ml of chloroform, 10.38 g (0.121 mol) of sodium hydrogen carbonate and 20.95 g (0.062 mol) of tetrabutylammonium hydrogen sulfate. . The resulting mixture is stirred at room temperature for three hours, the organic layer is separated and the aqueous phase is extracted twice with chloroform. The organic layers are combined, dried (Na 2 SO 4) and the solvent evaporated to give the tetrabutylammonium salt of benzyl terephthalate. This is dissolved in 25 ml of methylene chloride and the solution is added dropwise to 100 ml of bromochloromethane at 0 ° C. The resulting mixture is allowed to warm to room temperature, stirred overnight and the product is isolated and purified by the procedure described in Example 5, Part A, for 30 minutes to give the title diester as crystals, m.p. 64-66 ° C.

1 H-NMR (CDCl 3) ppm (delta): 5.3 (s, 2H), 5.9 (s, 2H), 7.3 (s, 5H), 8.1 (s, 4H)

Infrared Spectrum (KBr) cm-1: 1720 and 1735.

35 B. Benzyl 1,1-dioxopenicillanoyloxymethyl 24 81 353 liter terephthalate

A solution of 6.34 g (0.021 mol) of benzyl chloromethyl terephthalate, 5.58 g (0.022 mol) of sodium 1,1-dioxopenicillanate, 2.24 g (0.0069 mol) of 5 tetrabutylammonium bromide and 200 ml of acetone , stirred at reflux under a nitrogen atmosphere for 18 hours. The acetone is then evaporated off, the residue is dissolved in ethyl acetate, washed three times with water and dried (Na2SO4). Evaporation of the solvent gives 11 g of crude product 10, which is purified by passing through a 20 x 2 cm silica gel column eluting with 1: 1 ethyl acetate / hexane. Evaporation of the product fractions to dryness gave 10 g (96%) of the desired benzyl ester as an oil.

1 H-NMR (CDCl 3) ppm (delta): 1.4 (s, 3H), 1.5 (s, 3H), 3.4 (d, 2H), 4.4 (s, 1H), 4, Δ (t, 1H), 5.4 (s, 2H), 6.1 (q, 2H), 7.4 (s, 5H), 8.1 (s, 4H). Infrared spectrum (CHCl 3) cm -1: 1725, 1745, 1780, 1810.

C. A solution of 9 g of the benzyl ester obtained in Part B in 50 ml of ethyl acetate is deaerated and replaced with a nitrogen atmosphere. To this is added 2.5 g of 10% palladium-on-carbon catalyst and the mixture is hydrated at 3 atmospheres for 20 minutes. The mixture is filtered through a filter aid, which is washed with ethyl acetate. 2.98 g of sodium 2-ethylhexanoate are added to the filtrate and washings, and the resulting mixture is stirred for 30 minutes. To the resulting thick mixture are added another 50 ml of ethyl acetate and 50 ml of ethyl ether, and this mixture is filtered, washing with ethyl ether. After drying overnight, 5.8 g (75%) of crystalline sodium salt are obtained. D. To a solution of one gram of the above sodium salt in 50 ml of water is added 5 ml of 1-norm. hydrochloric acid and the resulting mixture is extracted with 75 ml of ethyl acetate. The ethyl acetate mixture is concentrated in vacuo to a slurry and just enough ethyl acetate is added to dissolve the precipitate. This solution is stirred with the slow addition of hexane at room temperature to the cloud point. This mixture is then heated in a water bath to form a solution, and a few drops of hexane are added, the mixture is cooled to room temperature and placed in a refrigerator. The formed crystals are collected by filtration and dried under nitrogen to give 900 mg (95%) of the title acid, m.p. 167-169 ° C (dec.).

1 H-NMR (DMSO) ppm (delta): 1.4 (s, 3H), 1.5 (s, 3H), 3.4 (d, 2H), 4.6 (s, 1H), 5.1 -5.3 (m, 2H), 6.1 (q, 2H), 8.1 (s, 4H). Infrared Spectrum (KBr) cm-1: 1700, 1750, 1780, 1810.

Example 8 (final product)

Sodium 1,1-dioxopenicillanoyloxymethyl iso-phthalate A. Benzyl chloromethyl isophthalate 17.0 g (0.058 mol) of potassium benzyl isophthalate are converted into 45 ml of water and 500 ml of chloroform by the method of Example 7, Part A to give the tetrabutylammonium salt and its reacted with excess bromochloromethane. The crude product obtained, 15 g, is dissolved in ethyl acetate, this is added to 45 g of silica gel, the mixture is slurried and the solvent is evaporated off. The silica gel residue was applied dry to an 8-inch silica gel column and eluted with ethyl ether / hexane 1: 3.

Evaporation of the solvent from the product-containing fractions gives the desired diester as an oil.

1 H-NMR (CDCl 3) ppm (delta): 5.3 (s, 2H), 5.9 (s, 2H), 7.3 (s, 5H), 8.0-8.3 (m, 3H) . 8.55 (t, 1H).

B. Benzyl 1,1-dioxopenicillanoyloxymethyl isophthalate A mixture of 12.22 g (0.04 moles) of benzyl chloromethyl isophthalate, 10.75 g (0.042 moles) of sodium 1,1-dioxopenicillanate, 4, 31 g (0.0134 mol) of tetrabutylammonium bromide and 400 ml of acetone are heated at reflux for 30 hours. The acetone was evaporated off and replaced with ethyl acetate. The solution was washed with water (3x), brine (1x) and dried (Na 2 SO 4). Evaporation of the solvent and chromatography of the residue on silica gel, eluting with ethyl ether / hexane (65:35), gives the product in 41% yield as an oil which crystallizes on standing.

1 H-NMR (CDCl 3) ppm (delta): 1.3 (s, 3H), 1.5 (s, 3H), 3.4 d, 2H), 4.5 (s, 1H), 4.6 ( t, 1H), 5.3 (s, 2H), 6.0 (q, 2H), 7.4 (s, 5H), 7.5-7.7 (m, 1H), 8.1-8 .4 (m, 2H), 8.7-8.8 (m, 1H).

Infrared Spectrum (KBr) cm-1: 1720, 1750, 1805.

10 C. A mixture of 8.14 g (0.016 moles) in Part B.

the resulting benzyl ester, 2.5 g of 10% Pd / C catalyst and 50 ml of ethyl acetate are hydrogenated by the method of Example 7, Part C. The mixture is filtered to remove the catalyst and 2.70 g (0.016 mol) of sodium 2-ethyl-15-hexanoate are added. After stirring for 20 minutes, the thick slurry is concentrated to one third of its volume and ethyl ether is added to complete the precipitation. The formed crystals are collected by filtration and dried under nitrogen to give 6.33 g (90%) of the title sodium salt.

1 H-NMR (DMSO) ppm (delta): 1.3 (s, 3H), 5.0-5.2 (m, 1H), 6.05 (q, 2H), 7.45 (t, 1H) , 7.8-8.3 (m, 2 H), 8.5 (bs, 1H). Infrared spectrum (KBr) cm-1: 1575, 1620, 1740, 1810. Example 9 (intermediate) Benzyl chloromethyl sebacate

To a mixture of 48.67 g (0.155 mol) of monobenzyl sebacate, 26.04 g (0.310 mol) of sodium hydrogen carbonate, 200 ml of water and 52.55 g (0.155 mol) of tetrabutylammonium hydrogen sulphate are added 100 ml of chloroform. After shaking, the organic layer is separated, the aqueous phase is extracted again with chloroform and the combined chloroform layers are dried (Na 2 SO 4). Evaporation of the solvent gives a residue which is dissolved in 50 ml of bromochloromethane and stirred overnight at room temperature. The mixture is evaporated to dryness in vacuo and the residue is stirred

II

27 81 353 with ethyl acetate, filtered and the filtrate is evaporated to dryness in vacuo. The residual crude product is purified by column chromatography on silica gel to give 2 g of purified monoester as an oil.

1 H-NMR (CDCl 3) ppm (delta): 1.1-1.9 (m, 12H), 2.2-2.5 (m, 4H), 5.0 (s, 2H), 5.6 (s, 2H), 7.3 (s, 5H).

Example 10 (intermediate)

Chloromethyl 1,1-dioxopenicillanoyloxymethyl glutarate A solution of 3.9 g (0.0084 mol) of benzyl 1,1-dioxopenicillanoyloxymethyl glutarate in 50 ml of tetrahydrofuran (THF) was hydrogenated using 3.0 g of 10% palladium on carbon. At 50 psi (3.52 kg / cm2) hydrogen pressure in a Paar hydrogenator. The catalyst was removed by filtration and the filter cake was washed with THF and the filtrates were concentrated in vacuo to 3.5 grams of a viscous oil. The oil was dissolved in 25 ml of chloroform, 10 ml of water was poured on the surface, the mixture was stirred, and the pH was adjusted to 8.0 by adding 40% tetrabu-20-ammonium hydroxide. The chloroform layer was separated and the aqueous layer was extracted with chloroform (2 x 30 mL). The combined chloroform layers were dried (Na 2 SO 4) and evaporated to dryness in vacuo to give 5.8 g of an oil which was dissolved in 35 ml of iodochloromethane and stirred for 25 hours. Concentration in vacuo and chromatography on silica gel (ethyl acetate / hexane) gave 0.20 g (6%) of the title compound.

1 H-NMR (CDCl 3) ppm (delta): 1.44 (s, 3H), 1.63 (s, 3H), 1.82-2.2 (m, 2H), 2.26-2.7 ( m, 4H), 3.48 (d, 2H), 4.43 (s, 1H), 4.63 (t, 1H), 5.72 (s, 2H), 5.83 (AB quartet, 2H).

Example 11 (intermediate)

Iodomethyl 1,1-dioxopenicillanoyloxymethyl dimethyl malonate A. Chloromethyl 1,1-dioxopenicillanoyloxime 35-dimethyl malonate 28 81 353

To a solution of 10 g (0.025 moles) of sodium 1,1-dioxopenicillanoyloxymethyl dimethyl malonate in 25 ml of water was added 150 ml of chloroform followed by 8.5 g (0.025 moles) of tetrabutylammonium sulfate.

The pH of the aqueous layer was adjusted to 7.5 with stirring by the addition of sodium hydrogen carbonate. The chloroform layer was separated and the aqueous phase was extracted with chloroform (1 x 100 mL). The combined chloroform layers were dried (N 22 SO 4) and evaporated to dryness in vacuo to give 19.5 g of a viscous oil which still contained chloroform, the oil was dissolved in 95 ml of chloroiodomethane and stirred overnight.

Concentration in vacuo and chromatography on 300 g of silica gel, eluting with ethyl acetate / hexane 1: 1 (v / v) gave 7.4 g (70%) of the chloromethyl ester as an oil.

1 H-NMR (CDCl 3) ppm (delta): 1.43 (s, 3H), 1.5 (s, 6H), 1.6 (s, 3H), 3.45 (d, 2H), 4.38 (s, 1H), 4.6 (t, 1H), 5.68 (s, 2H), 5.8 (AB quartet, .2H).

B. To a solution of 7.4 g (0.0156 moles) of chloro-rimethyl 1,1-dioxopenicillanoyloxymethyl dimethyl malonate in 50 mL of acetone was added 11.75 g (0.078 moles) of sodium iodide and the solution was stirred for 20 minutes. hours. Concentration in vacuo gave an oily solid which was partitioned between 50 mL of water and 100 mL of ethyl acetate. The aqueous layer was separated and the organic layer was washed with water (50 mL), brine (50 mL), dried (Na 2 SO 4) and evaporated in vacuo to a yellow oil. Chromatography on 150 g of silica gel eluting with ethyl acetate / hexane 1: 1 (v / v) gave 8.3 g (100%) of iodomethyl ester as a clear viscous oil.

1 H-NMR (CDCl 3) ppm (delta): 1.48 (s, 3H), 1.52 (s, 6H), 1.65 (s, 3H), 3.46 (d, 2H), 4.45 (s, 1H), 4.65 (t, 1H), 5.83 (AB quartet, 2H), 5.93 (s, 2H). Infrared spectrum (35-only) cm-1: 1810-1735.

Il 29 81 353 C. By repeating the above procedures, but starting from one of the other remaining sodium or potassium salts obtained in Example 4, the following c ° 2ch2x ° y / -, v. CH- ^ _ \ -N-k

xC02CH20 -C

o 10 wherein A is as defined in Example 4 and X is Cl or J.

Example 12 (final product) A. 1,1-Dioxopenicillanoyloxymethylglutaric acid

Benzyl 1,1-dioxopenicillanoyloxymethyl glutarate is hydrogenolyzed by the method of Example 4A. After evaporation of the ethyl acetate from the filtrate, the residual oil is dissolved in isopropanol, the mixture is stirred at 22 ° C for 60 minutes and kept at 50 ° C overnight. The solid formed is dissolved in isopropanol, filtered and washed with cold isopropanol and hexane. The crystals of 1,1-dioxopenicillanoyloxymethylglutaric acid formed are dried in vacuo at room temperature to give a product yield of 63%, m.p. 76-78 ° C.

B. 1,1-Dioxopenicillanoyloxymethyl-dimethylmalonic acid

A solution of 10 g of sodium 1,1-dioxopenicillin-30-yloxymethyldimethylmalonate in 100 ml of ethyl acetate is treated with hydrochloric acid (23 ml of 1N in 50 ml of water). The mixture is stirred, then allowed to stand. The organic layer is separated, dried, the solvent is evaporated off under vacuum and the residue is chromatographed on 400 g of silica gel, eluting with a 1: 1 mixture of ethyl acetate and acetone. The product fractions are combined and the solvent is evaporated off. The viscous oil formed is dissolved in ethyl ether, filtered to remove insoluble matter and the filtrate is evaporated to dryness to give an oil which crystallizes on scraping to give 7.2 g of white crystals, m.p. 121-123 ° C.

Analysis for C14H1909NS:

Calculated: C 44.56, H 5.07, N 3.71 10 Found: C 44.13, H 5.19, N 3.65

Preparation A

Dibenzyldimethylmalonate To 75 ml of water containing 4.0 g of sodium hydroxide at 0 ° C is added 17.0 g (0.05 mol) of tetrabutylammonium hydrogen sulphate, the mixture is stirred for 15 minutes, allowed to warm and 100 ml of chloroform are added. is 14.2 g (0.05 mol) of dibenzyl malonate and 6.6 ml (0.10 mol) of methyl iodide. The mixture (initial pH> 12) is stirred for 30 minutes, after which time the pH of the mixture is about 8. Stirring is continued for ten minutes, the organic phase is separated. To the organic layer are added another 4.0 gram portion of sodium hydroxide, 17.0 g of tetrabutylammonium hydrogen sulfate in 75 ml of water and 6.6 g of methyl iodide. The resulting mixture was stirred at room temperature for 30 minutes, the chloroform layer was separated, dried (Na 2 SO 4) and concentrated in vacuo. The residual oil obtained is triturated with 500 ml of ethyl ether, the solid formed is filtered off, washed well with ether and the filtrate and washings are evaporated to dryness to give 15.0 g (96%) of product, which is identified by 1 H-NMR spectrum.

Preparation B

Bentsyylidimetyylimalonaatti half-ester

A solution of 3.12 g (48 mmol) of 85% potassium hydroxide in 75 ml of benzyl alcohol is added.

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3i 81353 to 15.0 grams of dibenzyldimethylmalonate in 75 ml of benzyl alcohol. The resulting solution is stirred for 60 hours, 1.5 liters of ethyl ether are added and the resulting mixture is extracted twice with 100 ml portions of water. The combined aqueous layers are washed with 100 ml of ether. To the aqueous layer is added 100 ml of ethyl ether and the mixture is acidified to pH 2.5 with 6N hydrochloric acid. The ether layer is separated and the aqueous phase is extracted again with ether. The ether extracts are dried (Na 2 SO 4) and the solvent evaporated to give the product as a colorless oil, 8.6 g (81%). Rf 0.1 TLC, 2: 1 hexane / ethyl acetate). The structure is confirmed by 1 H-NMR.

Preparation C

Chloromethyl penicillanate 1,1-dioxide A mixture of 4.66 g of penicillanic acid 1,1-dioxide, 50 ml of dichloromethane and 35 ml of water was treated with such a sufficient amount of tetrabutylammonium hydroxide (40% aqueous solution) that the pH was 6.0. The dichloromethane layer was separated and the aqueous phase was extracted with fresh dichloromethane (2 x 50 mL). The organic layers were combined, dried over sodium sulfate and concentrated to give 10.1 g of the tetrabutylammonium salt of penicillanic acid 1,1-dioxide.

The above tetrabutylammonium penicillanate 25-1,1-dioxide was added to 50 ml of chloroiodomethane, and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo to half its volume and chromatographed on 200 grams of silica gel using ethyl acetate / hexane-30 as eluent and every 30 seconds taken from 12 ml of Jake. Fractions 41-73 were combined and evaporated to dryness to give 3.2 g of the title compound.

The NMR spectrum (CDCl 3) showed absorptions at 1.5 (s, 3H), 1.66 (s, 3H), 3.42 (d, 2H), 4.38 (s, 1H), 35 (t, 1H ) and 5.7 (dd, 2H) ppm.

32 81 353

Preparation D

Jodimetyylipenisillanaatti-1,1-dioxide

To a solution of 7.9 g of chloromethylpenicillanate-1,1-dioxide in 100 ml of dry acetone under a nitrogen-5 atmosphere was added 21.0 g of sodium iodide, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue was dissolved in 150 mL of ethyl acetate and 150 mL of water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed with water (1 x 500 mL) and brine (1 x 50 mL) and dried over sodium sulfate. Removal of the solvent gave 10.5 g of the title product, m.p. 100-102 ° C.

The NMR spectrum (CDCl 3) showed absorbances at 1.55 (s, 3H), 1.68 (s, 3H), 3.5 (d, 2H), 4.4 (S, 1H), 4, 65 (t, 1H), and 6.0 (dd, 2H) ppm.

Preparation E

Benzyl chloromethyl adipate To 350 ml of bromochloromethane cooled to 0 ° C is added 67 g (0.14 mol) of the tetrabutylammonium salt of the benzyl adipate half-ester and the mixture is stirred overnight at 0 ° C and then allowed to warm to room temperature. Excess bromochloromethane is evaporated off in vacuo, 400 ml of ethyl ether are added to the residue and the mixture is stirred to form tetrabutylammonium bromide crystals. The crystals are removed by filtration, washed with ether, stirred with ethyl acetate (300 ml) for 1 hour and filtered again and washed with ethyl acetate. The combined filtrates are evaporated to dryness in vacuo, the residue is purified by chromatography on silica gel (1 kg), eluting with hexane / ethyl acetate 2: 1 to give 19.1 g (48%) of the title compound.

1 H-NMR (CDCl 3) ppm (delta): 1.58-1.9 (m, 4H), 2.2-2.62 δ (m, 4H), 5.13 (s, 2H), 5.68 (s, 2H), 7.38 (s, 5H).

li 33 81 353

Other benzyl chloromethyl esters of the formula below are prepared in the same manner: C6H5CH2OC-A-COCH2Cl wherein formula A is as defined in the examples.

Claims (5)

34 81 353 A process for the preparation of penicillanic acid poly-1,1-dioxide derivatives of the formula (I) having beta-lactamase inhibitory activity and their pharmaceutically acceptable cationic and acid addition salts HV / CH3 30 "- fSY ^" 33 - N - O coch2oc = o '\ A 1. / HOC = O where A is (C1-C4) alkylene, - (CH3) 2C-, (C3-C7) cycloalkylene or phenylene; 20 (a) compounds of the formulas „0 0 H xch9oc = o γ — r sYch. \ 25. CH3 Da A - N-% / C00M / R10C = 0 30 or (b) compounds of the formulas: 11 35 81 353 o O n r H .S. -CH, MOC = 0 i — f ^ h3 \ 5 -NA v "cooch2x / R1oc = o 10 wherein R1 is benzyl and A is as defined above; M is a carboxylate salt-forming cation, preferably sodium, potassium or tetrabutylammonium and X is a leaving group, is reacted in the presence of a polar organic solvent 0- At 80 ° C, preferably 25-50 ° C, and the benzyl group is removed. Process according to Claim 1, characterized in that A is (C 1 -C 6) alkylene, 20 - (CH 3) 2 C-, phenylene or 1,4-cyclohexylene. A compound useful as an intermediate in the preparation of compounds of formula (I), characterized in that it has the formula <D 0 H CH 25 h4_X 3 Γ ™ 3 -N-V 'cooch2oc = o \ A, / R 10 C = O wherein A is (C 1 -C 12) alkylene, - (CH 3) 2 C-, (C 3 -C 7) cycloalkylene-35 or phenylene; and R1 is benzyl. 36 81 353 Compound according to Claim 3, characterized in that it has the formula 0. V CH3 h— Λ- N -U 0 ^ ooch9oc = o \ A -I / R10C = 0 wherein A and R1 have the same meaning as in claim 3. A compound according to claim 4, characterized in that A is -C (CH 3) 2 -, - (CH 2) 3 -, - (CH 2) 4 -, - (CH 2) 8 -, phenylene or trans-1. , 4-cyclohexylene. Il 37 81353