KR810001262B1 - Process for preparing beta-lactam containing compounds - Google Patents

Abstract

Title compds. (I; X = S, SO or SO2; R = C1-20 organic group; A = H or ester) useful as bactericidal and β-lactamase inhibitory activity, were manufd. by reaction of II and III. Thus, soln. of benzyl clavulanate and methylene chloride was mixed with boron trifluoride etherate and benzyl mercapthane and washed with bicarbonate of soda to give 3-(2-thiobenzyl-ethylidene)-7-oxo-4-oxa-1-azabicyclo[3,2,0 heptane-2-benzyl carboxylate.

Description

Method for preparing β-lactam containing compound

Novel β-lactam-containing compounds of the present invention, methods for their preparation, and pharmaceutical compositions containing them.

Clavulanic acid and their salts and esters of the following formula (I) are known.

It has been found by the present invention that such compounds can be converted to thioethers which have a certain antibacterial activity and properties that inhibit β-lactamase.

The present invention provides a compound of formula (II) or salts or esters thereof.

In the above formula, X is S, SO or SO ₂ , R is an organic group up to C ₂₀ , A is a group such that CO ₂ A can represent a carboxylic acid group.

R should be inert and not cause rapid degradation of the compound of formula II.

Suitable organic groups R included in the compound of formula (II) include halogen and / or OR ¹ , O.COR ¹ , CO.R ¹ , CO ₂ R ¹ , NHR ₁ , NR ¹ R ² , NH. A hydrocarbon group and an unsubstituted hydrocarbon group substituted by a CO.R ¹ , NR ² COR ¹ , NHCO ₂ R ¹ , NR ² CO ₂ R ¹ group, wherein R ¹ is a hydrogen atom or a hydrocarbon group up to C ₈ , R ² is an alkyl group of C ₁ -C ₃ .

Suitable hydrocarbon groups include alkyl groups, especially alkyl groups up to C ₆ .

Particularly suitable sub-groups of compounds of formula II are groups in which R is CH ₂ R ³ or a group in which R ⁴ , OR ⁴ or NR ⁴ R ⁵ ; Wherein R ³ is a hydrogen atom, an alkyl group up to C ₅ , or a phenyl group or naphthal group optionally substituted by halogen, hydroxyl, imino; R ⁴ is an alkyl or acyl group up to C ₃ ; R ⁵ is a hydrogen atom or an alkyl group up to C ₄ .

A more suitable subgroup of compounds of formula II is R is CR⁶R⁷R⁸It is a group; Where R⁶And R⁷Are each C₃An alkali group up to, halogen, or of the formula R⁹, OR⁹Popularity (where R⁹C₃Phenyl group optionally substituted with an alkyl group); R₈Silver hydrogen atom, C₃An alkali group up to, halogen, or of the formula R¹⁰, OR¹⁰Popularity (where R¹⁰Silver c₃Phenyl group optionally substituted with an alkyl group).

Another suitable subgroup of compounds of formula II is a group wherein R is R ¹¹ , wherein R ¹¹ is an optionally substituted 5- or 6-membered heteroaromatic group. Suitable R ¹¹ groups include triazoles, tetraazoles, thienyl, thiazoles, taadiazoles, titriazoles, oxazoles, isoxazolyl, oxadiazoles, pyridyls, pyridazinyls, pyrimidinyls and optionally substituted Similar groups are included. Suitable substituents for these groups include alkyl groups up to C ₃ , but less preferred include those alkyl groups substituted by groups such as CONH ₂ or CO ₂ H.

Suitable R groups thereof include those known as suitable groups for inclusion in the 3-position of 3-thiomethyl cephalosporins.

Another suitable subgroup of compounds of formula II is a phenyl group in which R is optionally substituted by an OR ¹ , O.COR ¹ , COR ¹ , CO ₂ R ¹ group as described above, or by chlorine, bromine, fluorine or the like. to be.

As one of the particularly suitable compounds of formula (II), there are the compounds of formula (III) and their pharmaceutically acceptable salts.

R ¹² is a phenyl group optionally substituted by fluorine, chlorine, bromine or OR ¹³ , O.CO.R ¹³ , COR ¹³ , CO ₂ R ¹³ , wherein R ¹³ is a hydrocarbon group up to C ₈ .

Other particularly suitable compounds of formula (II) include sulfoxides and sulfones that are compatible with the cellides of formula (III).

Another particularly suitable compound of formula (II) is the compound of formula (IV) and their pharmaceutically acceptable salts.

Wherein R ¹⁴ is a 5-membered heterocyclic group optionally substituted by an alkyl group up to C ₃ .

As the R ¹⁴ group, a group containing 3 or 4 heteroatoms containing at least two nitrogen atoms is suitable.

Particularly suitable R ¹⁴ groups include groups such as the following structural formulas (a) and (b).

Wherein X ¹ -Y ¹ is an SN (CH ₃ ), ON (CH ₃ ), NN (CH ₃ ), N-CH ₂ , O-CH ₂ or S-CH ₂ group.

Another particularly suitable class of compounds of formula (II) are the compounds of formula (V) and their pharmaceutically acceptable salts.

In the above formula, R ¹⁵ is a divalent hydrocarbon group of C ₁ -C ₄ , R ¹⁶ is a hydrogen atom or a hydrocarbon group of C ₁ -C ₈ .

Suitable R ¹⁵ groups include C ₁ -C ₄ alkylene groups, or C ₁ or C ₂ alkyl groups substituted by phenyl groups.

Suitable R ¹⁶ groups include hydrogen atoms and C ₁ -C ₄ alkylene groups, or C ₁ or C ₂ alkylene groups substituted by phenyl groups.

Other particularly suitable compounds of formula (II) include sulfoxides and sulfones corresponding to the sulfides of formula (V).

From the foregoing, as the R group, methyl, ethyl, n-propyl, n-butyl, 2-methoxyethyl, 2-benzyloxymethyl, 2-ethoxyethyl, 3-methoxypropyl, benzyl, P-chlorobenzyl It is understood that groups such as, P-methoxybenzyl, m-methoxybenzyl, P-methylbenzyl, phenyl, 4-fluorophenyl, 2-phenylethyl and the like are suitable.

A or a corresponding group in the compound of formula (II) and the compounds described thereafter include hydrogen and salt ions such as lithium, sodium, potassium, calcium, magnesium, ammonium and alkylamines, dialkylamines, trialkylamines, p Amine salts such as lollidine and the like.

Group A is most suitably a pharmaceutically acceptable alkali metal or alkaline earth metal ion.

The lithium salt of the compound of the present invention is very advantageous because of its easy separation and good shelf life.

The sodium and potassium salts (particularly sodium salts) of the compounds of the invention are advantageous because the pharmaceutically acceptable capacities of sodium and potassium ions are apparent.

It is preferable that the salt of this invention is crystalline. Furthermore, since they are used as a medicament or as an intermediate in the manufacture of a medicament, high purity is preferable.

Suitable esters of the compounds of formula (II) and the compounds of the following formulas are those of formula (VI) and (iii).

Wherein X and R are as defined in formula (II); A ¹ is an alkali group of C ₁ -C ₈ optionally substituted by halogen or a group of formula OA ⁴ , OCOA ⁴ , SA ⁴ , SO ₂ A ⁴ , wherein A ⁴ is a hydrocarbon group up to C ₆ ; A ² is a hydrogen atom, an alkyl group up to C ₄ or a phenyl group optionally substituted with halogen or A ⁵ , OA ⁵ , wherein A ⁵ is an alkyl group up to C ₆ ; A ³ is a phenyl group optionally substituted with halogen, A ⁵ , OA ⁵ , where A ⁵ is an alkyl group.

Benzyl and P-methoxybenzyl esters of the compounds of formula II are particularly useful hydrolyzable esters.

The invention also provides a pharmaceutical composition consisting of the compound of the invention and a pharmaceutically acceptable carrier.

Compositions of the present invention include formulations of suitable formulations for oral, topical or parenteral use, which can be used to treat infections of mammals, including humans.

Suitable formulations of the compositions of the invention include tablets, capsules, krills, syrups, suspensions, solutions, reforming powders and sterile formulations suitable for injection or infusion. Such compositions may contain conventional pharmaceutically acceptable materials such as diluents, binders, colorants, flavors, preservatives, disintegrants and the like according to conventional pharmaceutical methods well known in the art of antibiotic preparation.

Compositions for injection or injection of salts of the compounds of formula II are particularly suitable since the compounds of formula II show high tissue levels after injection or infusion. Therefore, one preferred main composition of the present invention consists of salts of the compounds of formula (II) which are sterile.

A unit dosage composition composed of the compound of formula II or a salt or ester thereof suitable for oral administration is a more preferred composition of the present invention.

When the composition for the compound of the present invention contains a buffer or enteric skin and does not come into contact with the highly acidic gastric juice of the compound of the present invention for a long time, oral use of the compound of formula (II) and their salts and esters The effectiveness of the composition may be enhanced. Such buffered or enteric coating compositions can be prepared according to conventional pharmaceutical methods.

-에스테르류와 같은 그의 앞단계 약물들도 포함된다.The compound of formula (II) or a salt or ester thereof may be present in the composition as a single therapeutic agent or in combination with other therapeutic agents such as penicillin or cephalosporin. Penicillins or cephalosporins contained in such synergists are suitable not only for being known to have high sensitivity to β-lactamase but also to have some intrinsic resistance to β-lactamase. Thus, β-lactam antibiotics suitable for inclusion in the compositions of the present invention include benzylphenicillin, phenoxymethylphenicillin, carbenicillin, methicillin, propicillin, ampicillin, amoxicillin, ticarcillin, cyclacillin, cephaolidine, Cephalotin, cefazoline, cephalexin, cephacithin, cephacetyl, cephamandol, cephapyrin, cepradine, cephalolycin and other well-known penicillins and cephalosporins, and thus hetacillin, Metaampicillin, benzylphenicillin, ampicillin, amoxicillin, acetoxymethyl, pivaloyloxymethyl, or phthalidyl esters of cephalosglycine, or carbenicillin, phenyl, tolyl, or indanyl

-Also include earlier stage drugs such as esters.

If penicillin or cephalosporin present in the composition is not suitable for oral administration, the composition will naturally be applied parenterally.

When the compound of the present invention is present in the pharmaceutical composition together with penicillin or cephalosporin, the ratio of the compound of formula (II) or a salt or ester thereof to penicillin or cephalosporin is, for example, 1:10 to 3: 1. It is extensive and useful in the ratio of 1: 5 to 2: 1 such as 1: 1 to 1: 3.

The total amount of antimicrobial present in a unit dose is usually 50-1500 mg, usually about 100-1000 mg.

The composition of the present invention is mainly used for the treatment of human respiratory, urinary and soft tissue infections.

The composition of the present invention can also be used for the treatment of infection in livestock, such as, for example, bovine breast cancer.

Compositions of the present invention can be administered up to 50-3000 mg per day for therapeutic purposes, but usually 100-1000 mg. However, higher doses may be used, depending on clinical practice, for the treatment of severe systemic infections, and particularly for the treatment of incompatible bacterial infections.

The doses of penicillin or cephalosporin in the synergist of the present invention are conventional conventional doses as monotherapy for the treatment of infection.

The composition of the present invention comprises 150-1000 mg of amoxicillin, ampicillin or a preceding drug (such as their salts, hydrates, or esters that can be hydrolyzed in vivo) and 50-500 mg of the compound of formula (II) or Particularly suitable are those containing salts or hydrolysable esters in vivo, and those containing 200-500 mg of the former and 50-250 mg of the latter.

Amoxicillin trihydrate and alkali metal salts of amoxicillin are particularly suitable in the compositions of the present invention.

The present invention also provides the preparation of a compound of formula (II), which comprises reacting an ester of clavulanic acid with a compound of formula (VII), followed by any one or more of the following processes (a)-(c). Provide a way.

(a) The resulting ester is deesterified to form a free acid or salt of acid within the range of formula (II).

(b) Re-esterification of the resulting free acid or salt of acid yields another ester within the range of formula (II).

(c) Oxide is oxidized to sulfoxide or sulfone.

H-S-R (Ⅷ)

Wherein R is as defined in formula (II).

Esters within the range of formula (II) wherein X is S can be prepared by reacting thiols of formula (VII) with the corresponding esters of compounds of formula (I) in the presence of an acid catalyst.

If the R group contains reactors such as amino or carboxylates, these reactors may be protected by conventional methods prior to the operation of the process and then regenerated.

Suitable catalysts are Lewis acid catalysts equivalent to such as boron trifluoride or boron trifluoride ether compounds [eg, BF ₃ .O (C ₂ H ₅ ) ₂ ].

The reaction is usually carried out in a solvent which is inert under anhydrous and non-hydroxyl reaction conditions such as chloroform, dichloromethane, tetrahydrofuran, dioxane and the like.

Half is best suited to be carried out at low or not high temperatures, for example up to -80 ° C + 30 ° C, preferably at a low temperature from -50 ° C to 0 ° C.

Esters in the range of formula (II) wherein X is SO or SO ₂ can be prepared by mild oxidation of the corresponding compound where X is S.

This oxidation reaction can be carried out at room temperature or at a low temperature, such as -20 ° to + 20 ° C, with -12 ° to + 5 ° C such as about 0 ° C being more suitable.

Oxidation is best performed when organic peroxyacids are used as oxidant. Suitable acids include m-chloroperbenzoic acid and reagents equivalent thereto. The use of 1 equivalent of oxidant gives a compound of formula (II) wherein X is SO, and the use of 2 equivalents of oxidant gives a compound of formula (II) wherein X is SO ₂ .

The oxidation reaction is usually carried out in an inert solvent such as methylene chloride.

Acids and salts within the range of formula (II) include hydrolyzable esters, such as benzyl and methoxybenzyl esters, within the range of formula (II), such as 10 on carbon with a weight ratio of about 1: 3 to thioether. It can be prepared by hydrogenation using low pressure hydrogen or medium in the presence of a transition metal catalyst such as% palladium, but this method is rather difficult. Suitable solvents at this time include tetrahydrofuran and ethanol. If a base is included, the first prepared acid is converted to a salt and isolated.

Salts in the range of formula (II) wherein X is S are prepared by very weakly basic hydrolysis of esters in the range of formula (II) (e.g., by slowly adding base to a solution maintained at pH 7-9). can do. Suitable bases include lithium hydroxide, sodium hydroxide and their chemical equivalents.

Suitable esters for hydrolysis include methyl, methoxymethyl and benzyl esters, of which methoxymethyl esters are preferred.

Acids within the scope of formula (II) can be prepared by carefully acidifying the corresponding salts, such as for example sodium salts.

Salts within the scope of formula II can also be prepared by salt exchange according to conventional methods. That is, for example, a lithium salt is dissolved in water, and the solution is dissolved in about 10 times the excess of sodium type ion exchange resin (e.g., Amberlite 120; sodium salt of sulfonated polystyrene divinylbenzene copolymer) until the elution is completed. Pass through the phase. The resulting sodium salt can be obtained by freeze drying or the like. Similarly, sodium salt can also be converted into lithium salt or potassium salt.

Hereinafter, the present invention will be described in more detail with reference to Examples.

Example 1

3- (2-thiobenzylethylidene) -7-oxo-4-oxa-1-azabicyclo [3,2,0] heptane-2-carboxylic acid benzyl

Clavulanate benzyl (500 mg) was dissolved in methylene chloride (50 ml) and cooled to -30 ° C. Boron trifluoride etherate (7 drops) was added at -30 ° C, and a solution of benzyl mercaptan (220 mg) dissolved in methylene chloride (5 ml) was added dropwise at -30 ° C. The solution was stirred for 1½ hours to bring the temperature of the solution from -30 ° C to 0 ° C, washed with 3% sodium bicarbonate solution (3 x 25 ml), and the extract was dried over MgSO ₄ . The solvent was evaporated and chromatographed to give the title compound (150 mg: 25%) as colorless oil.

Infrared spectrum (IR) (CHCI ₃ ): 1800,1745,1690 cm ^-1 .

Nuclear magnetic resonance (nmr) (CDCI ₃ ): 3.00 (1H, d, J = 17 Hz, 6β-CH); 3.52 (1H, doublet of doublets, J = 17 Hz, J ¹ = 2.5 Hz, 6a-CH); 3.20 (2H, doublet, J = 8 Hz, CH ₂ SB ₂ ); 3.77 (2H, S, SCH ₂ Ph); 4.77 (1H, t, J = 8 Hz, = CH-CH ₂ ); 5.18 (1H, brs, 3-CH); 5.30 (2H, S, CO ₂ CH ₂ Ph); 5.72 (1H, doublet, J = 2.5 Hz, 6-CH); 7.40 and 7.50 (10H, two singlets, SCH ₂ Ph and CO ₂ CH ₂ Ph).

Molecular Weight (Mass Spectrometer) 395.

β-lactamase inhibition I ₅₀ (μg / ml)

Escherichia coli 0.3

Klebsiella aerogenes E70 0.2

Staphylococus aureus, Russell <0.07

Psudomonas aeruginosa A 1.8

Pseudomonas dalgleish 0.76

Citrobacter mantio 24

Example 2

3- (2-benzylsulfinylethylidene) -7-oxo-4-oxa-1-azabicyclo [3,2,0] heptane-2-carboxylic acid benzyl

3- (2-benzylthioethylidene) -7-oxo-4-oxa-1-azabicyclo [3,2,0] heptane-2-carboxylic acid benzyl (39.5 mg) in methylene chloride (5 ml) It was dissolved in and treated with m-chloroperbenzoic acid (19 mg) at 0 ° C. The solution was stirred at 0 ° C. for 1/2 hour and washed with 3% bicarbonate solution (3 × 5 ml). The solvent was evaporated and the gums were chromatographed to give the title compound (30 mg; 73%) as a mixture of P and S sulfoxide.

Ir (CHCI ₃ ): 1800,1750,1700 cm ⁻¹ .

R 및 S설폭사이드); 4.86(1H,br.t,J=8Hz,=CH-CH₂-);5.26(1H,br.S,3-OH); 5.33(2H,S,CO₂CH₂Ph); 5.83(1H,d,J=2.5Hz,5-CH); 7.48δ(10H,S,CO₂CH₂Ph 및

)Nmr (CDCI ₃ ): 3.10 (1H, doublet, J = 17 Hz, 6β-CH); 3.50 (2H, broad doublet, J = 8 Hz, = CH-CH _2- ); 3.62 (1H, doublet of doublets, J = 17 Hz, J ¹ = 2.5 Hz, 6a-CH); 3.87 and 3.97 (2H, two singlet,

R and S sulfoxide); 4.86 (1H, br.t, J = 8 Hz, = CH-CH _2- ); 5.26 (1H, br.S, 3-OH); 5.33 (2H, S, CO ₂ CH ₂ Ph); 5.83 (1H, doublet, J = 2.5 Hz, 5-CH); 7.48δ (10H, S, CO ₂ CH ₂ Ph and

)

= +7.2°(C=0.94; MeOH).

= + 7.2 ° (C = 0.94; MeOH).

In vitro antibacterial activity (㎍ / MI)

Staphylococcus aureus Oxford 62

Staphylococcus aureus Russell 62

β-lactamase inhibition I ₅₀ (μg / ml)

Example 3

3- [2- (1-methyl-1,2,3,4-tetrazol-5-yl) thioethylidene] -7-oxo-4-oxa-1-azabicyclo [3,2,0 ] Heptane-2-carboxylic acid methyl

(5 drops) of acid fluoride etherate at -20 ° C is added to methyl clavulanate (213 mg) in dichloromethane (10 ml), followed by 1-methyl-1,2,3,4-tetrazol-5-thiol ( 120 mg) was added. The reaction mixture was stirred for 2 hours, at which time the temperature was slowly brought to -10 ° C. The solution was washed with aqueous sodium bicarbonate solution (3%, 3 x 10 ml). The organic phase is dried and the solvent is evaporated off. Crude material was chromatographed to give the title compound (about 40% yield).

Ir (CHCI ₃ ): 1800,1750,1690 cm ^-1 .

Nmr (CDCI ₃ ): 3.04 (1H, doublet, J = 17 Hz, 6β-CH); 3.50 (1H, doublet of doublets, J = 17 Hz, J ¹ = 2.5 Hz, 6a-CH); 3.73 (3H, S, CO ₂ CH ₃ ); 3.88 (3H, S, N-CH ₃ ); 3.97 (2H, doublet, J = 8 Hz, = CH-CH ₂ ); 4.92 (1H, multiplet, = CH-CH ₂ ); 5.00 (1H, br.S, 3-CH) 5.72δ (1H, d, J = 2.5 Hz, 5-CH).

=+13°(C=1.34, MeOH).

= + 13 ° (C = 1.34, MeOH).

Β-lactamase inhibition I ₅₀ value (μg / ml) for the title compound is approximately as follows.

Example 4

3- (2-thiobenzylethylidene) -7-oxo-4-oxa-1-azabicyclo [3,2,0] heptane-2-carboxylic acid methyl

Methyl clavulanate (1 g) was dissolved in anhydrous methylene chloride (50 ml) and cooled to -30 ° C. Boron trifluoride etherate (15 drops) was added followed by benzyl mercaptan (620 ml) in methylene chloride (10 ml). The mixture was heated for 2 hours to bring the temperature from -30 ° C to -10 ° C, washed with 3% sodium bicarbonate solution (3x50ml), dried over magnesium sulfate, and the solvent was evaporated to give a yellow oil. Chromatography gave the title compound (219 mg; 20%) in light yellow oil.

Ir (CHCI ₃ ): 1800,1750,1690 cm ^-1 .

Nmr (CDCI ₃ ): 2.93 (1H, d, J = 17 Hz, 6β-CH); 3.15 (2H, doublet, J = 8 Hz, = CH-CH ₂ ); 3.45 (1H, doublet of doublets, J = 17 Hz, J ¹ = 2.5 Hz, 6a-CH); 3.67 (2H, S, SCH ₂ Ph); 3.74 (3H, S, CO ₂ CH ₃ ); 4.67 (1H, broad doublet, J = 8 Hz, = CH-CH ₂ ); 5.05 (1H, br. S, 3-CH); 5.67 (1H, doublet, J = 2.5 Hz, 5-CH); 7.29δ (5H, S, SCH ₂ Ph).

=+26°(C=1.69, MeOH).

= + 26 ° (C = 1.69, MeOH).

Β-lactamase inhibition I ₅₀ value (μg / ml) for the title compound is approximately as follows.

Example 5

3- (2-benzylsulfinylethylidene) -7-oxo-4-oxa-1-azabicyclo [3,2,0] heptan-2-carboxylic acid methyl and 3- (2-benzylsulfonyl Ethylidene) -7-oxo-4-oxa-1-azabicyclo [3,2,0] heptane-2-carboxylic acid methyl

3- (2-thiobenzylethylidene) -7-oxo-4-oxa-1-azabicyclo [3,2,0] heptane-2-carboxylic acid methyl (95 mg) was dissolved in anhydrous methylene dichloride (5 ml ) And then reacted with m-chloro perbenzoic acid (78 mg) at 0 ° C. The solution was stirred at 0 ° C. for 30 minutes and then washed with 3% sodium bicarbonate solution (3 × 5 ml). The organic phase was dried over magnesium sulfate, the solvent was evaporated, and then chromatographed to give 3- (2-benzylsulfonylethylidene) -7-oxo-4-oxa-1-azabicycle, the first elution product as a colorless oil. [3,2,0] heptane-2-carboxylic acid methyl (b) (28 mg; 27%) was obtained.

Ir (CHCI ₃ ): 1805,1755,1695 bm ⁻¹ .

Nmr (CDCI ₃ ): 3.02 (1H, doublet, J = 17 Hz, 6β-CH); 3.50 (1H, doublet of doublets, J = 17 Hz, J ¹ = 2.5 Hz, 6a-CH); 3.65 (2H, doublet, J = 8 Hz, = CH-CH ₂ ); 3.75 (3H, S, CO ₂ CH ₃ ); 4.13 (2H, S, CH ₂ Ph); 4.74 (1H, broad doublet, J = Hz, = CH-CH ₂ ); 5.14 (1H, broad S, 3-CH); 5.75 (1H, doublet, J = 2.5 Hz, 5-CH); 7.37 δ (5H, S, CH ₂ Ph).

=+8.2°(C=1.15, MeOH).

= + 8.2 ° (C = 1.15, MeOH).

Β-lactamase inhibition I ₅₀ value (μg / ml) for product (b) is approximately as follows.

The secondary product (a) eluted from the column was collected as colorless oil.

Ir (CHCI ₃ ): 1800,1755,1690 cm ^-1 .

Nmr (CDCI ₃ ): 3.00 (1H, doublet, J = 17 Hz, 6β-CH); 3.41 (2H, doublet, J = 8 Hz, = CH-CH ₂ ); 3.49 (1H, doublet of doublets, J = 17 Hz, J '= 2.5 Hz, 6a-CH); 3.75 (3H, S, CO ₂ CH ₃ ); 3.90 (2H, S, CH, Ph); 4.78 (1H, broad doublet, J = 8 Hz, = CH-CH ₂ ); 5.18 (1H, br. S, 3-CH); 5.73 (1H, doublet, J = 2.5 Hz, 5-CH); 7.32δ (5H, S, CH ₂ Ph).

=0°(C=0.78; MeOH).

= 0 ° (C = 0.78; MeOH).

Β-lactamase inhibition I ₅₀ value (μg / ml) for product (a) is approximately as follows.

Example 6

3- (2-thiobenzylethylidene) -7-oxo-4-oxa-1-azabicyclo [3,2,0] heptane-2-carboxylic acid sodium

Hydrolysis of 3- (2-thiobenzylethylidene) -7-oxo-4-oxa-1-azabicyclo [3,2,0] heptane-2-carboxylic acid methyl (95.7 mg) was complete. Hydrolyzed with 1N NaOH at pH9.5 (pH). Chromatography (n-butanol / ethanol / H ₂ O, 4/1/1) and trituration with ether afforded an amorphous solid sodium salt (32 mg; 31%).

Ir (kBr): 1785,1685 cm ^-1 .

Nmr (D ₂ O): 3.05 (1H, doublet, J = 17 Hz, 6β-CH); 3.15 (1H, doublet, J = 8 Hz, = CH-CH ₂ ); 3.60 (1H, doublet of doublets, J = 17 Hz, J '= 2.5 Hz, 6a-CH); 3.80 (2H, S, CH ₂ Ph); 4.78 (CH-CH ₂ positive field partially blurred by D ₂ O peak); 4.93 (1H, br. S, 3-CH); 5.70 (1H, doublet, J = 2.5 Hz, 5-CH); 7.38δ (5H, S, CH ₂ Ph).

=+19.8°(C=0.47; MeOH).

= + 19.8 ° (C = 0.47; MeOH).

Β-lactamase inhibition I ₅₀ value (μg / ml) for the title compound is approximately as follows.

Example 7

3- (2-thiophenylethylidene) -7-oxo-4-oxa-1-azabicyclo [3,2,0] heptane-2-carboxylic acid methyl

Methyl clavulanate (1 g) was dissolved in anhydrous methylene dichloride (50 ml) and then cooled to -30 ° C. Boron trifluoride etherate (15 drops; 0.18 ml) was added at −30 ° C., followed by addition of a solution of thiophenol (500 mg) in methylene dichloride (10 ml). The mixture was stirred for 2 hours to bring the temperature from -30 ° C to -10 ° C and washed with 3% sodium bicarbonate solution (3x50 ml). The organic phase was dried over magnesium sulfate and the solvent was evaporated to give an oil which was chromatographed to give the title compound as a colorless oil (298 mg; 20%).

Ir (CHCI ₃ ): 1800,1755,1695 cm ⁻¹ .

Nmr (CDCI ₃ ): 2.76 (1H, J = 17 Hz, 6β-CH); 3.38 (1H, doublet of doublets, J = 17 Hz, J '= 2.5 Hz, 6a-CH);

3.56 (2H, doublet, J = 8 Hz, = CH-CH ₂ ); 3.64 (3H, S, CO ₂ CH ₃ ); 4.70 (1H, broad doublet, J = 8 Hz, = CH-CH ₂ ); 4.97 (1H, br. S, 3-CH); 5.60 (1H, doublet, J 2.5 Hz, 5-CH); 7.32δ (5H, br.S, SPh).

=+2°(C=1.16; MeOH).

= + 2 ° (C = 1.16; MeOH).

Β-lactamase inhibition I ₅₀ value (μg / ml) for the title compound is approximately as follows.

Example 8

3- (2-thio-5-methoxythiadiazolylethylidene) -7-oxo-4-oxa-1-azabicyclo [3,2,0] heptan-2-carboxylic acid benzyl

Clavulanic acid benzyl (2.89 g) was dissolved in anhydrous methylene dichloride (100 ml) and treated with boron trifluoride etherate (50 drops; 0.6 ml) at -30 ° C. A solution in which 5-methoxythiadiazolyl-2-thiol (1.48 g) was dissolved in methylene dichloride (10 ml) was added dropwise at -30 占 폚 for 30 minutes. The reaction solution was stirred for 2 hours to bring the temperature from -30 ° C to -10 ° C, and then operated as in the above-described example. The colorless oily title product (625 mg; 15%) was collected.

Ir (CHCI ₃ ): 1800,1750,1695 cm ⁻¹ .

Nmr (CDCI ₃ ): 2.92 (1H, doublet, J = 17 Hz, 6β-CH); 3.40 (1H, doublet of doublets, J = 17 Hz, J '= 2.5 Hz, 6a-CH); 3.76 (2H, doublet, J = 8 Hz, = CH-CH ₂ ); 4.03 (3H, S, OCH ₃ ); 5.02 (2H, br. S, = CH-CH ₂ and 3-CH); 5.17 (2H, S, CO ₂ CH ₂ Ph); 5.69 (1H, doublet, J = 2.5 Hz, 5-CH); 7.35δ (5H, S, CO ₂ CH ₂ Ph).

=+5°(C=0.92; MeOH).

= + 5 ° (C = 0.92; MeOH).

Example 9

3- [2-thio (ethoxycarbonylmethyl) ethylidene] -7-oxo-4-oxa-1-azabicyclo [3,2,0] heptan-2-carboxylic acid methyl

The title compound was prepared from methyl clavulanate in a similar manner as in Example 7, except that the same amount of 1-mercaptoacetate acetate was used instead of thiophenol.

Example 10

3- (2-thio (ethoxycarbonylmethyl) ethylidene] -7-oxo-4-oxa-1-azabicyclo [3,2,0] heptane-2-carboxylic acid sodium

The title compound was prepared by hydrolyzing the corresponding methyl ester with 1 N NaOH at pH 9-9.5 (pH constant) until the equivalent base was consumed. Chromatography and trituration with ether yielded sodium in amorphous solid form.

Example 11

3- (2-thioethyl) ethylidene-7-oxo-4-oxa-1-azabicyclo [3,2,0] heptan-2-carboxylic acid benzyl

Clavulanic acid benzyl (3.18 g) was dissolved in methylene chloride (100 ml) and cooled to -30 ° C. A solution of ethyl mercaptan (1.0 ml) in methylene chloride (5 ml) was added followed by boron trifluoride etherate (20 drops). The solution was stirred for 2.5 hours to bring the temperature from -20 [deg.] C. to -10 [deg.] C., washed with dilute sodium bicarbonate solution (3 times) and then the extract was dried over MgSO ₄ . The solvent was evaporated and chromatographed to yield the title compound (804 mg) as a colorless oil.

Ir (CHCI ₃ ): 1800,1750,1695 cm ⁻¹ .

Nmr (CDCI ₃ ): 1.22 (3H, t, J = 6 Hz, -CH ₂ -CH ₃ ); 2.40 (2H, q, J = 6 Hz, -CH ₂ -CH ₃ ); 2.95 (1H, doublet, J = 17 Hz, 6β-CH); 3.42 (1H, doublet, J = 17 Hz, J '= 2.5 Hz, 6a-CH); 3.17 (2H, doublet, J = 8 Hz, CH ₂ SC ₂ H ₅ ); 4.60 (1H, t, J = 8 Hz, = CH-CH _2- ); 5.00 (1H, br. S, 3-CH); 5.18 (2H, S, CO ₂ CH ₂ Ph); 5.73 (1H, doublet, J = 2.5 Hz, 5-CH); 7.36 (5H, S, CO ₂ CH ₂ Ph).

=+13.1°(C=0.88; MeOH).

= + 13.1 ° (C = 0.88; MeOH).

Molecular weight (mass spectrometer) C ₁₇ H ₁₉ NO ₄ S; 333.103710 (observed), 333.103469 (theoretical).

Example 12

3- (2-ethylsulfinylethylidene) -7-oxo-4-oxa-1-azabicyclo [3,2,0] heptan-2-carboxylic acid benzyl

3- (2-ethylthioethylidene) -7-oxo-4-oxa-1-azabicyclo [3,2,0] heptane-2-carboxylic acid benzyl (704 mg) was added to methylene chloride (40 ml). It was dissolved and then treated with m-chloroperbenzoic acid (370 mg). The solution was stirred at 0 ° C. for 1.0 hour and washed with dilute bicarbonate solution (twice). The extract was dried over MgSO ₄ and evaporated. Chromatography on silica gel yielded the title product as a mixture of R and S sulfoxide (295 mg).

Ir (CHCI ₃ ): 1805,1750,1695 cm ⁻¹ .

-CH);3.34(2H,d,J=7Hz,

); 4.53(1H,t,J=7Hz,=CH-CH₂); 5.03(3H,br.S,3-CH 및 CO₂CH₂Ph); 5.72(1H,d,J= 2.5Hz,5-CH); 7.30(5H,S,CO₂CH₂Ph).Nmr (CDCI ₃ ): 1.18 (3H, t, J = 6 Hz, -CH ₂ -CH ₃ ); 2.46 (2H, q, J = 6 Hz, -CH ₂ -CH ₃ ); 2.90 (1H, doublet, J = 17 Hz, 6β-CH); 3.40 (1H, d, J '= 2.5 Hz, 6

-CH); 3.34 (2H, d, J = 7 Hz,

); 4.53 (1H, t, J = 7 Hz, = CH-CH ₂ ); 5.03 (3H, br. S, 3-CH and CO ₂ CH ₂ Ph); 5.72 (1H, doublet, J = 2.5 Hz, 5-CH); 7.30 (5H, S, CO ₂ CH ₂ Ph).

Molecular Weight (Mass Spectrometer) 349.

Example 13

3- [2- (β-hydroxyethyl) -thioethylidene] -7-oxo-4-oxa-1-azabicyclo [3,2,0] heptan-2-carboxylic acid allyl

Clavulanic acid allyl (500 mg) was dissolved in methylene chloride (20 ml) and treated with 2-mercapto ethanol (0.25 ml) and boron trifluoride diethyl etherate (25 drops). The solution was stirred for 1.5 hours to bring the temperature from -20 ° C to -10 ° C, the reaction solution was quenched with dilute sodium hydroxide solution, the organic extract was washed with water and dried over MgSO ₄ . The solvent was evaporated and column chromatographed to isolate the title compound (22 mg) as colorless oil.

Ir (CHCI ₃ ): 3450-3550, 1805, 1750, 1695 cm ⁻¹ .

N. mr. (CDCI ₃ ): 2.62 (2H, t, J = 6 Hz, S-CH ₂ -CH ₂ ); 3.00 (1H, doublet, J = 17 Hz, 6β-CH); 3.17 (2H, doublet, J = 8 Hz, = CH-CH ₂ S); 3.44 (1H, doublet of doublets, J = 17 Hz, J '= 2.5 Hz, 6a-CH); 3.64 (2H, t, J = 6 Hz, CH ₂ -CH ₂ OH); 4.62 (2H, doublet, J = 6 Hz, CO ₂ CH ₂ ); 4.68 (1H, t, J = 8 Hz, = CH-CH ₂ S); 5.02 (1H, br. S, 3-CH); 5.30 (2H, m, = CH ₂ ); 5.63 (1H, doublet, J = 2.5 Hz, 5-CH); 5.7-6.1 (1H, m, CH ₂ -CH = CH ₂ ).

Example 14

3- [2- (β-ethoxycarbonyl) methylthio] ethylidene-7-oxo-4-oxa-1-azabicyclo [3,2,0] heptan-2-carboxylic acid benzyl

Clavulanic acid benzyl (1.9 g) and 2-mercaptoacetic acid ethyl (1.5 g) were dissolved in methylene chloride and stirred at -20 ° C. Boron trifluoride diethyl etherate (0.2 ml) was added, the solution was stirred for 2.0 hours to bring the temperature from -20 ° C to -10 ° C, and the reaction solution was quenched with 3% sodium bicarbonate solution. The organic extract was cooled with bicarbonate and sodium chloride solution and then dried over MgSO ₄ . Chromatography (eluent; ethyl acetate / cyclohexane) on silica gel isolated the product as a colorless oil (95 mg).

Ir (CHCI ₃ ): 1800, 1735, 1750, 1695 cm ⁻¹ .

Nmr (CDCI ₃ ): 1.28 (3H, t, J = 7 Hz, CH ₂ CH ₃ ); 3.12 (2H, S, SCH ₂ CO ₂ Et); 3.10 (1H, doublet, J = 17 Hz, 6β-CH); 3.36 (2H, doublet, J = 8 Hz, = CH-CH ₂ ); 3.55 (1H, doublet, J = 17 Hz, J '= 2.5 Hz, 6a-CH); 4.23 (2H, q, J = 7 Hz, CH ₂ CH ₃ ); 4.83 (1H, t, J = 8 Hz, CH-CH ₂ ); 5.18 (1H, S, 3-CH); 5.28 (2H, S, CO ₂ CH ₂ Ph); 5.76 (1H, doublet, J = 2 Hz, 5-CH); 7.42 (5H, S, CO ₂ CH ₂ Ph).

Example 15

3- (2-thioethyl) ethylidene-7-oxo-4-oxa-1-azabicyclo [3,2,0] heptan-2-carboxylic acid methoxymethyl

Clavulanate methoxymethyl (1.0 g) was dissolved in methylene chloride (25 ml) and cooled to -30 deg. Ethyl mercaptan (0.5 ml) was added followed by boron trifluoride etherate (0.2 ml). The solution was stirred for 2.0 hours to bring the temperature from -20 ° C to -10 ° C, washed with dilute sodium bicarbonate solution (twice) and brine (twice), and then the extract was dried over MgSO ₄ . The solvent was evaporated and chromatographed to give the title compound (101 mg) as colorless oil.

Nmr (CDCI ₃ ): 1.37 (3H, t, J = 7 Hz, S-CH ₂ -CH ₃ ); 2.60 (2H, q, J = 7 Hz, S-CH ₂ -CH ₃ ); 3.13 (1H, doublet, J = 17 Hz, 6β-CH); 3.41 (2H, doublet, J = 8 Hz, = CH-CH ₂ S); 3.65 (1H, doublet of doublets, J = 17 Hz, J '= 2.5 Hz, 6 _a -CH); 3.64 (3H, S, -OCH ₃ ); 4.94 (1H, t, J = 8 Hz, = CH-CH ₂ ); 5.27 (1H, broad S, 3-CH); 5.85 (1H, doublet, J = 2.5 Hz, 5-CH); 5.48 (2H, q, J = 4 Hz, CO ₂ CH ₂ OCH ₃ ).

(Crabulanate methoxymethyl can be prepared by reacting clavulanate sodium with chloromethyl methyl ether in dimethylformamide.)

Example 16

3- (2-thioethyl) ethylidene-7-oxo-4-oxa-1-azabicyclo [3,2,0] heptane-2-carboxylic acid methyl

Methyl clavulanate (3.0 g) was dissolved in methylene chloride, ethyl mercaptan (0.9 ml) was added followed by boron trifluoride etherate (1.0 ml). The solution was stirred at room temperature for 3.0 hours and quenched with sodium bicarbonate solution, and then the organic layer was washed with brine. The solvent was evaporated and chromatographed to give much oily title compound (78 mg).

υmax (CHCI ₃ ): 1800,1750, 1690 cm ^-1 .

Nmr (CDCI ₃ ): 1.27 (3H, t, J = 7 Hz, S-CH ₂ -CH ₃ ); 2.74 (2H, q, J-7 Hz, S-CH ₂ -CH ₃ ); 3.07 (1H, doublet, J = 17 Hz, 6β-CH); 3.30 (2H, doublet, J = 7 Hz, = CH-CH ₂ ); 3.70 (1H, doublet of doublets, J = 17 Hz, J '= 2.5 Hz, 6a-CH); 3.86 (3H, S, -CO ₂ CH ₃ ); 4.84 (1H, t, J = 7 Hz, = CH-CH ₂ ); 5.17 (1H, S, 3-CH); 5.77 (1H, d, J = 2.5 Hz, 5-CH).

Example 17

3- (2-thioethyl) ethylidene-7-oxo-4-oxa-1-azabicyclo [3,2,0] heptane-2-carboxylic acid sodium

Methyl ester (70 mg) was dissolved in tetrahydrofuran (10 ml) and water (30 ml). The thioether was hydrolyzed using 1 N NaOH at a constant pH (9.0) to give a good sodium salt (50 mg).

υmax (KBr): 1785, 1690, 1600 cm ^-1 .

Nmr (D ₂ O): 1.05 (3H, t, J = 7 Hz, SCH ₂ -CH ₃ ); 2.37 (2H, q, J = 7 Hz, SCH ₂ CH ₃ ); 2.90 (1H, doublet, J = 17 Hz, 6β-CH); 3.14 (2H, doublet, J = 7 Hz, = CH-CH ₂ ); 3.40 (1H, doublet of doublets, J = 17 Hz, J '= 2.5 Hz, 6a-CH); 4.65 (1H, t, J = 7 Hz, = CH-CH ₂ ); 4.79 (1H, S, 3-CH); 5.58 (1H, doublet, J = 2.5 Hz, 5-CH).

Example 18

3- (2-thioethyl) ethylidene-7-oxo-4-oxa-1-azabicyclo [3,2,0] heptan-2-carboxylic acid anthrylmethyl

After clavulanate anthrylmethyl (1.3 g) was dissolved in methylene chloride, the solution was treated with ethyl mercaptan (0.2 ml) and boron trifluoride etherate (20 drops) at -70 ° C. The reaction mixture was stirred to bring the temperature to -30 ° C, and then quenched with sodium bicarbonate solution. The organic extract was washed with brine (twice) and then dried over MgSO ₄ . Chromatography isolated the yellow oily product (207 mg).

υmax (CHCI ₃ ): 1800,1750, 1695 cm ^-1 .

Nmr (CDCI ₃ ): 1.13 (3H, t, J = 7 Hz, S-CH ₂ CH ₃ ); 2.28 (2H, q, J-7 Hz, S-CH ₂ -CH ₃ ); 2.95 (1H, doublet, J = 17 Hz, 6β-CH); 3.10 (2H, doublet, J = 7 Hz, = CH-CH ₂ ); 3.40 (1H, doublet of doublets, J = 17 Hz, J '= 2.5 Hz, 6a-CH); 4.54 (1H, t, J = 7 Hz, = CH-CH ₂ ); 5.05 (1H, S, 3-CH); 5.55 (1H, doublet, J = 2.5 Hz, 5-CH); 6.16 (2H, S, -CO ₂ CH ₂ ); 7.2-8.5 (9H, m, aryl).

The starting material of the previous embodiment may be prepared by the following method. That is, sodium clavulanate (0.5 g) and 9-chloromethylanthracene (1.0 g) were stirred overnight at room temperature in dimethylformamide. After evaporating the solvent, the residue was dissolved in ethyl acetate and water. The organic layer was washed with brine, dried over MgSO ₄ and evaporated. Chromatography was used to isolate the product as a yellow crystalline solid (0.5 g). Melting point 120 ℃

ma : 1800,1740, 1698cm^-1.

ma: 1800,1740, 1698 cm ^-1 .

Nmr (CDCI ₃ ): 1.36 (1H, br.S, -OH); 2.90 (1H, doublet, J = 17 Hz, 6β-CH); 3.35 (1H, doublet of doublets, J = 17 Hz, J '= 2.5 Hz, 6a-CH); 3.98 (2H, doublet, J = 7 Hz, = CH-CH ₂ ); 4.62 (1H, t, J = Hz, = CH-CH ₂ ); 4.80 (1H, S, 3-CH); 5.52 (1H, doublet, J = 2.5 Hz, 5-CH); 6.14 (2H, S, -CO ₂ CH ₂ ); 7.16-8.42 (9H, m, aryl).

Example 19

3- (2-thioethyl) ethylidene-7-oxo-4-oxa-1-azabicyclo [3,2,0] heptan-2-carboxylic acid methoxymethyl

Clavulanate methoxymethyl (2.3 g) was dissolved in methylene chloride (50 ml). The solution was stirred and then cooled to -30 ° C, and boron trifluoride etherate (0.5 ml) was added. While maintaining the temperature from -20 ° C to -10 ° C, methyl mercaptanol was slowly poured into the solution for 1.0 hour. The solution was stirred for 0.5 h at -10 ° C. Nitrogen gas was then poured into the solution, and the reaction solution was quenched with 3% sodium bicarbonate solution. The organic extract was washed with bicarbonate, brine (twice) and then dried over sodium sulfate. The solution was filtered and evaporated. Column chromatography on silica gel [eluent; Ethyl acetate / petroleum (60-80)] to give the title compound (185 mg) as a clear oil.

υmax (CHCI ₃ ): 1795-1810, 1755, 1695 cm ^-1 .

-CH); 3.45(3H,S,-OCH₃); 4.77(1H,t,J=7Hz,CH=CH₂); 5.10(1H,br.S,3-CH); 5.32(2H, m,CO₂CH₂); 5.72(1H,d,J= 2.5Hz,5-CH).Nmr (CDCI ₃ ): 1.96 (3H, S, S-CH ₃ ); 2.98 (1H, doublet, J = 17 Hz, 6β-CH); 3.17 (2H, doublet, J = 7 Hz, = CH-CH ₂ S); 3.50 (1H, dd, J = 17 Hz, J '= 2.5 Hz, 6

-CH); 3.45 (3H, S, -OCH ₃ ); 4.77 (1H, t, J = 7 Hz, CH = CH ₂ ); 5.10 (1H, br. S, 3-CH); 5.32 (2H, m, CO ₂ CH ₂ ); 5.72 (1H, doublet, J = 2.5 Hz, 5-CH).

Example 20

3- (2-thioethyl) ethylidene-7-oxo-4-oxa-1-azabicyclo [3,2,0] heptane-2-carboxylic acid lithium

Methoxymethyl ester (130 mg) was dissolved in tetrahydrofuran (10 ml) and water (40 ml) and the solution was hydrolyzed with 1 N lithium hydroxide for 30 minutes at constant pH (pH = 9). The solution was evaporated under reduced pressure to a volume of 5 ml and the residue was completely softened with acetone (15 ml). The white solid product produced was filtered and washed with ether to give the title compound (98 mg).

υmax (KBr): 1760, 1690, 1610 cm ^-1 .

-CH); 4.61(1H,t,J=7Hz,=CH-CH₂); 4.77(1H,S,3-CH); 5.61(1H,d,J= 2.5Hz,5-CH).Nmr (D ₂ O): 1.87 (3H, S, S-CH ₃ ); 2.86 (1H, doublet, J = 17 Hz, 6β-CH); 3.03 (2H, doublet, J = 7 Hz, = CH-CH ₂ ); 3.38 (1H, dd, J = 17Hz, J '= 2.5Hz, 6

-CH); 4.61 (1H, t, J = 7 Hz, = CH-CH ₂ ); 4.77 (1H, S, 3-CH); 5.61 (1H, doublet, J = 2.5 Hz, 5-CH).

Example 21

3- (2-thioethyl) ethylidene-7-oxo-4-oxa-1-azabicyclo [3,2,0] heptane-2-carboxylic acid lithium

Methoxymethyl ester (70 mg) was dissolved in tetrahydrofuran (10 ml) and water (30 ml), and the solution was hydrolyzed with 1 N lithium hydroxide for 35 minutes at constant pH (pH 9). The solution was evaporated under reduced pressure and the residue was completely softened with acetone (20 ml). The solid product was filtered and washed with ether (2 × 10 ml) to give the title compound (30 mg).

υmax (KBr): 1760, 1690, 1610 cm ^-1 .

Nmr (D ₂ O): 1.20 (3H, t, J = 7 Hz, SCH ₂ -CH ₃ ); 2.50 (2H, g, J = 7 Hz, SCH ₂ CH ₃ ); 3.05 (1 H,

-CH); 4.68(1H,t,J=7Hz,=CH-CH₂); 4.92(1H,S,3-CH); 5.70(1H,d,J= 2.5Hz,5-CH).d, J = 17 Hz, 6β-CH); 3.27 (2H, doublet, J = 7 Hz, = CH-CH ₂ ); 3.55 (1H, dd, J = 17 Hz, J '= 2.5 Hz, 6

-CH); 4.68 (1H, t, J = 7 Hz, = CH-CH ₂ ); 4.92 (1H, S, 3-CH); 5.70 (1H, doublet, J = 2.5 Hz, 5-CH).

Example 22

3- (2-methylsulfinyl) ethylidene-7-oxo-4-oxa-1-azabicyclo [3,2,0] heptane-2-carboxylic acid lithium

Thioether (60 mg) was dissolved in distilled water (10 ml) and treated with m-chloro and benzoic acid (44 mg). The mixture was stirred at ice temperature for 3 hours. m-chlorobenzoic acid was filtered off. The solution was evaporated under reduced pressure and the residue was triturated with acetone (10 ml). The white solid product was collected and washed with anhydrous ether to give the title compound (28 mg).

υmax (KBr): 1785, 1690, 1620 (wide) cm ^-1 .

Example 23

3- (2-ethylsulfinylethylidene) -7-oxo-4-oxa-1-azabicyclo [3,2,0] heptane-2-carboxylic acid lithium

Thioether (25 mg) was dissolved in distilled water (4 ml) and treated with m-chloroperbenzoic acid (20 mg). The mixture was stirred at ice temperature for 4 hours. m-chlorobenzoic acid was filtered off. The solution was lyophilized to give sulfoxide side salt (20 mg) as a white solid.

υmax (KBr): 1780, 1685, 1630 (wide) cm ^-1 .

Example 24

A. 3- (2-thiobenzylethylidene) -7-oxo-4-oxa-1-azabicyclo [3,2,0] heptane-2-carboxylic acid sodium (50 mg) in sterile physiological saline (10 ml) to obtain a solution suitable for injection.

B. 3- (2-thioethylethylidene) -7-oxo-4-oxa-1-azabicyclo [3,2,0] heptane-2-carboxylic acid sodium (50 mg) in sterile physiological saline (10 ml) and mixed with an aqueous solution for injection (5 ml) of amoxicillin sodium (250 mg) to obtain a solution suitable for immediate injection.

Claims (1)

A process for preparing the compound of formula (II) and salts thereof, characterized by reacting a derivative of clavulanic acid of formula (I) with a compound of formula (IV) or oxidizing the resulting compound.

Wherein X is S, SO, or SO ₂ , R is an organic group having up to 20 carbon atoms, and A is hydrogen or an ester residue.