JPS6029717B2 - Novel penicillanic acid 1,1-dioxide ester, its production method and its use as a β-lactamase inhibitor - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new ester of benicillanic acid 1,1-dioxide, a process for its preparation and its use as an 8-lactamase inhibitor.

Although 8-lactam antibiotics are the most commonly used antibiotics, the problem of resistant bacteria has recently come into focus.

The resistance of pathogenic bacteria to B-lactam antibiotics is primarily based on the inactivation of B-lactam antibiotics by 3-lactamases produced by pathogenic bacteria. Therefore, when using 8-lactam antibiotics in combination with an 8-lactamase inhibitor that inactivates 3-lactamase, the inactivation of 8-lactam antibiotics is prevented, and 3-lactam antibiotics alone are less effective. The desired effect is also expected in some cases. From this point of view, benicillanic acid 1,1-dioxide (0) and its prodrug, the following formula (0'):
[wherein R is 3-phthalidyl, 4-crotonolactonyl, y-butyrolactone-4-yl, and (wherein, R,
, R2 is a hydrogen atom or an alkyl group having 1 to 2 carbon atoms, and R3 is an alkyl group having 1 to 6 carbon atoms.

] and its use as a 3-lactamase inhibitor [JP-A-54-309]
Publication No. 4, Hata timjcrobiaI Agents
andChemo ratio erapy14 414-419
(1978) and Cmr61t Chemothe
rape and InfectiousDise
ase,Proceeding of the lit
h ICC and1 rule h ICAAC, Publicis
hed by The American Society
yforMicrobiology, (1980) p.
353] The object of the present invention is to prepare novel pannicillanic acid 1,1-
The purpose is to provide esters of dioxide.

Another object of the present invention is to provide a novel ester of benicillanic acid 1,1-dioxide that exhibits excellent bioabsorption or bioavailability when administered orally.

Still another object of the present invention is to provide a novel ester of benicillanic acid 1,1-dioxide that can be administered in vivo, and which exhibits substantially no or no toxicity in vivo. It's in the country.

Yet another object of the present invention is to provide novel esters of benicillanic acid 1,1-dioxide as 8-lactamase inhibitors.

Yet another object of the present invention is to provide 3-lactam antibiotics and 3-lactam antibiotics.
Another object of the present invention is to provide a pharmaceutical composition containing the novel benicillanic acid 1,1-dioxide ester of the present invention as a lactamase inhibitor.

Still another object of the present invention is to prepare the novel benicillanic acid 1,1-dioxide ester of the present invention.
The object of the present invention is to provide a method for producing the ester from -dioxide and a novel compound that gives an ester residue to the ester. Further objects and advantages of the invention will become apparent from the description below.

According to one aspect of the present invention, these objects and advantages of the present invention provide an ester of benicillanic acid 1,1-dioxide represented by the following formula (1) (wherein R represents a methyl group or a phenyl group). This is achieved by

The ester of benicillanic acid 1,1-dioxide represented by the above formula (1) is benicillanic acid 1,1-dioxide (
5-methyl-2-oxo-1,3-dioxolene-4-
yl) methyl ester group [a compound in which R in the above formula (1) is a methyl group] and benicillanic acid 1,1-dioxide (5-phenyl-2-oxo-1,3-dioxolene-
4-yl) methyl ester [a compound in which R in the above formula (1) is a phenyl group].

According to another aspect of the present invention, the ester of benicillanic acid 1,1-dioxide represented by the above formula (1) of the present invention comprises benicillanic acid 1,1-dioxide represented by the formula: or a salt thereof and the formula: (In the formula, R represents a methyl group or a phenyl group, and X represents a halogen atom.

) is produced by reacting with the compound shown in

Benicillanic acid 1,1-dioxide (0) was developed in 1972.
It is a known compound described in Japanese Patent No. 3094, and is produced by oxidizing benicilanic acid using, for example, potassium permanganate or organic peroxycarboxylic acid.

On the other hand, the compound of the above formula (m), that is, 4-halogenomethyl-5-methyl (or 5-phenyl>-1,3-dioxolen-2-one) is a new compound, and is a 5-methyl ( or 5-phenyl)-4-methyl-
It is produced by halogenating 1,3-dioxolene-2-one (W).

[In the formula, R represents the same group as above]

Compound (W) is a known compound, and is described in Tetrahedron Letters, pp. 1701-1704 (1972 King) and Liebitz Annalen Delchemy, vol. 764, 11.
6-124 (King, 1972).

In order to produce the halogenated compound (m) from the above compound (N), the compound (W) is reacted with a halogenating agent.

Examples of the halogenating agent in this case include N-bromo (or N-chloro)succinimide, N-bromo (or N-chloro)phthalimide, bromine, and chlorine. In order to suitably carry out the above halogenation reaction, an equimolar amount to a slight excess of the halogenating agent is used with respect to the compound (W),
These are inert solvents such as methylene chloride, carbon tetrachloride,
The reaction is carried out in benzene or the like at room temperature to the boiling point temperature of the solvent.

In this case, it is preferable to use a radical inducer such as Q'-azobisisobutynitrile or to generate radicals by irradiating ultraviolet rays. The compound in which X is an iodine atom in formula (m) is produced by a known halogen substitution reaction, such as by reacting sodium iodide with a compound in formula (m) in which X is a bromine atom. Benicillanic acid 1,1-dioxide or its salt of the above formula (b) and 4-halogenomethyl-5-methyl (or 5-phenyl-1,3-dioxolene-2-
The reaction with 1 is preferably carried out using an equimolar to slightly excess amount of compound (m) relative to compound (0), preferably in an inert organic solvent.

Moreover, this reaction is preferably carried out in the presence of a base. As the inert organic solvent, aprotic inert organic solvents such as dimethylformamide, dimethyl sulfoxide, ethyl acetate, and acetone are preferably used.

As the base, preferably, for example, sodium hydrogen carbonate,
Alkali hydrogen carbonates such as potassium hydrogen carbonate, alkali carbonates such as sodium carbonate and potassium carbonate, tertiary amines such as triethylamine, and the like are used.

The reaction is usually -4000 to 8000, preferably -100
0 to room temperature.

The reaction time is about 1 to 1 morning, and is usually completed in about 2 to 5 hours. In the above method of the present invention, as the compound of the above formula (m), a compound in which x in the above formula (m) is a chlorine atom or a bromine atom is preferably used.

The novel ester (1) of the present invention is an excellent prodrug of benicillanic acid 1,1-dioxide (b) and is useful as an 8-lactamase inhibitor.

First of all, benicillanic acid 1,1-dioxide (5-
Methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester (hereinafter referred to as compound A) and benicillanic acid 1,1-dioxide (5-phenyl-2-oxo-1,3-dioxolen-4-yl) methyl ester (
When the dynamics of compound B (hereinafter referred to as compound B) in mouse blood was investigated, it was found that all of them readily produce benicillanic acid 1,1-dioxide (b).

That is, after incubating Compound A or Compound B in 40% mouse blood at 370°C for 10 minutes, bioautogram analysis revealed that both were completely converted to benicillanic acid 1,1-dioxide (D). Ta.

Second, it was confirmed that when Compound A and Compound B were orally administered, they were easily absorbed into the body and exhibited a strong 8-lactamase inhibitory effect in a dish. That is, after Compound A or Compound B was orally administered to mice, blood was collected over time, and the 8-lactamase inhibitory effect was examined using the blood as a sample. The experimental method and results are as follows. [1] Test compound, compound A...benicillanic acid 1
, 1-dioxide (5-methyl-2-oxo 1,3-
Dioxolen-4-yl) methyl ester, Compound B... Benicillanic acid 1,1-dioxide (5-phenyl-2-oxo-1,3-dioxolen-4-yl) methyl ester, Compound C... Benicillanic acid 1,1-dioxide. Na
Salt (control compound) '2- Experimental animals: ddY male mice (6 weeks old, weight 25-30 minutes) were fasted for 1 hour before administration of the test compound.

{3} Administration: Compound A and Compound B were suspended in 0.5% CMC solution, and Compound C was dissolved to prepare 12 test solutions each with a concentration of 9/I, and each was immediately administered to a group of 5 mice. Administered orally. For compound A, the dose was 9/148
kg, 9/k9 of 175 for compound B, 1 for compound C
9/k9 of 09, both of which are benicillanic acid 1,1
- Corresponds to 100 females/kg in terms of dioxide. '4}
At 30 minutes, 6 minutes, 90 minutes, and 120 minutes after administration of the assay serum test compound, blood was collected individually from five mice in each group, and each of these blood was immediately centrifuged (3 minutes).
, 00pm x 18h) of each serum obtained.
2M was combined to make 1M, which was used as serum for testing each compound.

[51 8-Lactamase inhibition assay, approx. 4800
0.1' of penicillin G potassium aqueous solution (3.12 × 1 μU/) and the test bacterium Staphylococ Usame low 2
Add 0.2 of the bacterial solution from group 0 (lm671) and further
To this, 2.00 x 1 μU/' of benicillinase (a type of 8-lactamase, manufactured by Tokyo Kasei Co., Ltd.) was added at 0.1', and an agar plate was immediately prepared. Next, apply the assay serum prepared in step ① above to a paper disc (manufactured by Toyo Roshi Co., Ltd.,
Thick-type skin (diameter: 8) was infiltrated and placed on the above agar plate (n=4).

After keeping at 37q0 for 18 hours, the diameter of the inhibition circle was measured for each assay serum. [6' Experimental results: The bacterial growth inhibition circle diameter (average of n=4) for each test compound measured for each assay serum was as shown in Table 1.

Based on the experimental results shown in Table 1, the blood concentration of benicillanic acid 1,1-dioxide at the time of administration of each test compound was determined.

To determine this, first, a calibration curve regarding the correlation between the concentration of benicillanic acid 1,1-dioxide and the diameter of the circle of inhibition of bacterial growth was created using Compound C according to the experimental method described in {5-- above.

Next, using this calibration curve, the experimental results shown in Table 1 were expressed as blood concentrations of benicillanic acid 1,1-dioxide. The results are shown in Table 2. Table 2 As shown above, Compound A and Compound B are easily absorbed into the body by oral administration, exhibiting high blood concentrations, and have extremely strong 8-
It was revealed that it exerts a lactamase inhibitory effect over a long period of time.

Note that Compound A and Compound B of the present invention are stable in artificial gastric fluid and artificial intestinal fluid, as shown by the following experimental results.

[Stability in artificial gastric juice (Test 1)]'1) Test compound Compound A, Compound B'2} Preparation of test solution 4. To 87' was added 0.125 I of a dimethyl sulfoxide solution (2/9') of the test compound.

This solution was maintained at 37°C, and the following bioautography was performed on the solution after 2 minutes, 40 minutes, and 6 minutes. {3'/ゞIoautograph - (i) Each of the above test solutions was transferred to a thin layer chromatography plate manufactured by Merck (silica gel, 6 eaves, 2 mice, No.
．． 5715) and developed with a chloroform and methanol moat solution (1 pair IV/V).

'ii} A bioautography assay plate (agar plate) was prepared in the same manner as in the case of measuring the 8-lactamase inhibitory effect.

'iii) The thin layer chromatography plate obtained in 'i' was brought into close contact with the above assay medium for 3 minutes, and then the medium from which the plate was removed was kept at 4°C for 6 minutes.

Next, this was exposed to mouse serum overnight and cultured at 37°C overnight. S on the medium cultured as above is phylac
Location of the arresting circle for cape occ aureus (Rf
value) was confirmed.

According to the results of preliminary experiments conducted under the conditions {i), {ii), and (iii}, compound A, compound B, and benicillanic acid 1,1-dioxide (control compound, compound C
) are 0.67, 0.83 and 0.67, respectively.
It was 04.

'4} As a result of the above bioautography, for compound A, the bacterial growth inhibition circle was Rfo. 67 (compound A), and Rfo. It was not observed in 04 (compound C).

In addition, for all test solutions of compound B, the bacterial growth inhibition circle was Rfo. 83 (compound B), Rfo
．． It was not observed in 04 (compound C).

[Stability in artificial intestinal fluid (Test 2)] {1} Test compounds Compound A, Compound B A test solution was prepared in the same manner as in [2] of Test 1 using 6.8).

[3’ Bioautography It was conducted in the same manner as Test 1.

'4} Regarding Compound A, the same results as Test 1 were obtained.

Regarding compound B, Rfo. A growth inhibition circle was observed only in 83 (compound B), and Rfo. It was not observed in 04 (compound C).

However, in the test sample 6 days later, Rfo. 83 (compound B) as well as Rfo. Growth inhibition circles were also observed in 04 (compound C), and the diameters of the circles were approximately the same. As described above, both of the novel benicillanic acid 1,1-dioxide esters of the present invention, that is, compound A and compound B, are excellent prodrugs of benicillanic acid 1,1-dioxide.

Furthermore, according to the research of the present inventor, both compounds A and B of the present invention have an LD5o of 1000 when administered orally to mice.
9/k9 or higher, indicating low toxicity. In addition, for example, it has been revealed that the ester residue (-CH2) of Compound A is converted to diacetyl, a food additive, in vivo, and for this reason, Compound A has very high stability upon long-term administration. Therefore, the present invention further provides an 8-lactamase inhibitor containing the novel benicillanic acid 1,1-dioxide ester of the present invention represented by the above formula (1) as an active ingredient. be done.

According to the present invention, the present invention also provides for infectious diseases containing at least one ester of the novel benicillanic acid 1,1-dioxide of the present invention represented by the above formula (1) and at least one 8-lactam antibiotic. A therapeutic composition is provided.

The novel benicillanic acid 1,1-dioxide ester of the present invention exhibits excellent 3-lactamase inhibitory activity, coexists with 8-lactam antibiotics in vivo, enhances the antibacterial activity of 8-lactam antibiotics, and also increases resistance to 8-lactam antibiotics. It also shows good antibacterial activity against bacteria.

According to the present invention, therefore, the novel benicillanic acid 1,1-dioxide esters of the present invention can be administered as a composition for treating the above-mentioned infections, but can also be administered separately from the 8-lactam antibiotic. can.

Examples of the above 8-lactam antibiotics include ampicillin, amoxicillin, cyclacillin, urampicillin,
Penicillin antibiotics suitable for oral administration, such as varampicillin, pivmecillinum, calfecillin, and calindacillin; cephaloglycine, cephalexin,
Cephalosporin antibiotics suitable for oral administration, such as cephadroxil, cefrazine, and cefatridine; penicillin antibiotics suitable for injection, such as pencilpenicillin, carbenicillin, ticarcillin, piperacillin, a/glucillin, and sulbenicillin; cephalothin, Cephalosporin antibiotics that are preferably used as injections, such as cefazoline, cefoxitin, cefamandole, and cefavirin, are used.

The ratio of the ester of the present invention to these 8-lactam antibiotics is usually 1:0.1 to 3, preferably 1:0.
．． Although it is in the range of 2 to 1 (W/W), it is not limited to this range. In the present invention, the ester of benicillanic acid 1,1-dioxide of the present invention is preferably used by oral administration.

Therefore, the ester of benicillanic acid 1,1-dioxide of the present invention is preferably administered orally as a composition with an 8-lactam antibiotic suitable for oral administration as described above, or a 3-lactam antibiotic. Administered orally separately from antibiotics.

Furthermore, the ester of benicillanic acid 1,1-dioxide of the present invention is suitable for use as an injection as described above.
– Administered separately from lactam antibiotics. In this case, it is preferable to administer the compound of the present invention orally and the 8-lactam antibiotic by injection. When the benicillanic acid 1,1-dioxide ester and 8-lactam antibiotics of the present invention are administered orally, either separately or together, each at a dosage of about 10 to about 200 9/k9 body weight per day. can be administered.

Furthermore, when the ester of benicillanic acid 1,1-dioxide of the present invention is administered orally and the P-lactam antibiotic is administered as an injection, the administration time is about 10 to about 400 per day, respectively.
It can be administered at a dosage of 1 k9 body weight per day. As mentioned above, the following are preferred modes of administration of the ester and 8-lactam antibiotic of the present invention.

First, both are administered orally, and in this case they are preferably administered as the above-mentioned compositions.

The dosage form for oral administration is not particularly limited, but both may be used together or separately with pharmaceutically acceptable carriers such as starch, lactose, excipients such as crystalline cellulose, other disintegrants, binders, preservatives, It is administered as a powder, granule, tablet, capsule, etc. together with a coating agent, diluent, lubricant, etc. The appropriate dosage is appropriately used within the above dosage range. In another embodiment, the ester of the present invention is orally administered and the 8-lactam antibiotic is parenterally administered.

That is, by orally administering the ester of the present invention 10 to 30 minutes before or simultaneously with the intravenous or intramuscular administration of the 8-lactam antibiotic, both of the above-mentioned effects exhibit the same effects as oral administration. Examples will be described below.

[Example 1] Production of benicillanic acid 1,1-dioxide (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester; '1' 4-bromomethyl-5-methyl-1
, 3-Dioxolen-2-one: 4,5-dimethyl-1,3-dioxolene-2-one (synthesized according to Tetrahedron Letters, 1972, pp. 1701-1704) by adding 3.42 hours to 150 carbon tetrachloride. 5.34 days of N-promosuccinimide and a catalytic amount of Q,Q-azobisisobutyronitrile were added to the solution.
The mixture was heated under reflux for 15 minutes.

After the reaction solution was ice-cooled to room temperature or below, unmelted materials were removed from the oven, and the oven solution was concentrated under reduced pressure to obtain a syrup-like residue. This was subjected to vacuum distillation, and a fraction with a boiling point of 115 to 120 oo/5 Yanagi Hiyo was collected to obtain the title compound 4.29 (yield 73%). Properties: Colorless liquid Elemental analysis: C5 expansion By03 Calculated value (%): C, 31.12; Day, 2.61; By,
41.40. Experimental value (%): C, 31.30; day, 2.
49; By'41.31. IR (neat) (skin-1)
: 1829 close (carbonyl), NMR (CC14) 6
(ppm): 210(,-CH3,s), 4.10(
, -CbBy,s) ■ Production of benicillanic acid 1,1-dioxide (5-methyl-2-oxo-1,3-dioxolene-4-yl) methyl ester; Benicillanic acid 1,1
- Dimethylformamide 2' p is dimethylformamide 2'
9,4-bromomethyl-5-methyl-1,3-dioxolene-2-one (170 parts) was added thereto under ice-cooling, and the mixture was allowed to stand for 5 hours under ice-cooling.

After adding 15 parts of ethyl acetate and 8 parts of water to the reaction solution and washing well, the ethyl acetate layer was separated and washed successively with water and saturated brine. Next, the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting syrup was treated with a mixture of ethyl acetate and ether to form a solid, and the title compound 140 (yield: 47%) was obtained. Obtained as a colorless solid. Melting point: 122-12y0 (decomposition) Elemental analysis: C, 3 days, 5C8NS Calculated value (%): C, 45.22: days, 4.38; N, 4
．． 06. Experimental value (%): C, 45.28; Day, 4.65
;N, 3.78. IR(KBy)Re(inhibition-1);183
5,1815,1795,1765(carbonyl)NM
R(CDC13)6(ppm): 1-40, 1-62(
Mother's day, 2nd methyl group, s), 222 (milk day,, s), 3
．． 50 (2nd, 6th proton, d, J = 4th generation), 4.4
3 (IH, proton at 3rd position, s), 4.62 (IH, proton at 5th position, t, J=4Hz), 4.97 (but, S). The above solid [melting point: 122-1290 (decomposed)] was recrystallized from ethyl acetate to obtain the title compound as crystals.

Melting point: 140-1420 1R and NMR spectra are as above.

[Example 2] Production of benicillanic acid 1,1-dioxide (5-phenyl-2-oxo-1,3-dioxolen-4-yl) methyl ester;'1} Production of 4-bromomethyl-5-phenyl-1,3-dioxolen-2-one ; 5-phenyl-4-methyl-1,3-dioxolen-2-one (Liepitz His Annalen der Hekoichi, Vol. 764,
pp. 116-124, 1972 Synthesized according to King) 24
Dissolve 100% of carbon tetrachloride in 100% of carbon tetrachloride, add 29% of N-bromosuccinimide and a catalytic amount of Q,Q'-Azobisimo, and remove in a foggy furnace. was concentrated under reduced pressure to obtain a solid.

This was recrystallized from a mixture of benzene and cyclohexane to obtain the title compound 2.3 (yield: 66%) as colorless needle crystals. Melting point: 90.5-91.5pm, Elemental analysis: C, Rainbow 7By03, Calculated value (%): C, 47.09; Day, 2.77; By,
31.3 Experimental value (%): C, 47, 22; Day, 2.6
4: By, 31.29IR (KBy) (cm-1):
182 stitches (carbonyl), NMR (CC14) 6 (
ppm): 4.35 (2 days, 1 CH2By, s), 7.
40 (spot, benzene ring, s),'2}benicillanic acid 1,
1-dioxide (5-phenyl-2-oxo-1,3-
Preparation of dioxolene-4-yl) methyl ester: Dissolve 150 parts of benicillanic acid 1,1-dioxide in 2 parts of dimethylformamide, and add 7 parts of potassium bicarbonate under ice cooling.
9,4-bromomethyl-5-phenyl-1,3-dioxolen-2-one (170 parts) was added to the mixture, and the mixture was poured into a barrel under ice cooling for 5 hours.

The reaction mixture was poured into ice water, and the precipitated solid material was collected in an oven. After thoroughly washing this solid with water, ethyl acetate (2
The ethyl acetate layer was washed with brine.
The ethyl acetate layer was then dried over anhydrous magnesium sulfate,
Concentration was carried out under reduced pressure, and the resulting syrup was crystallized from ether to obtain the title compound 125-9 (yield 48%) as colorless crystals. Melting point: 100-103 pm○, Elemental analysis: C, 3 days, 708 NS, Calculated value (%): C, 53.07: days, 4.21: N, 3
．． 44, Experimental value (%): C, 52.86: Day, 4.12
;N, 3, 36, IR (KBy) (C's -1): 18
45,1830,1795,1760 (force carbonyl),
NMR (CDCl3)6 (ppm): 1.44, 1.6
4 (group, methyl group at 2nd position, s), 3.50 (proton at 6th position, d, J=4Hz), 4.48 (IH, proton at 3rd position, s), 4.68 (IH, 5th proton, t, J=4
ship), 5, 18, 5, 34 (2 days, d, J bag m = 14
position), around 7.5 (spot, benzene ring, m), [Example
3] Tablet consisting of benicillanic acid 1,1-dioxide (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester (compound A of the present invention) and ampicillin:
Ampicillin 9 days 20 25
0 Pond Compound A 125m
9 Hydroxypropyl cellulose 10/9 Corn starch 7
5/9 Magnesium Stearate 5/9 Total 465/9 Ampicillin/$
L○, Compound A, and cornstarch were mixed, and this mixture was further kneaded with an aqueous solution of hydroxypropyl cellulose to produce jaw granules for tabletting according to a conventional method.

Next, tablets were manufactured using magnesium stearate using the obtained jaw grains according to a conventional method. [Example 4] Benicillanic acid 1,1-dioxide (5-phenyl-2-
Amoxicillin 25
Ota Compound B 125
9 hydroxypropyl cellulose 20 9 crystalline cellulose 50 female lactose
400/9 Cornstarch 155/9 Total 1000 o Amoxicillin, compound B, crystalline cellulose, lactose, and cornstarch are mixed, this mixture is kneaded with an aqueous solution of hydroxypropyl cellulose, and the jaw granules are made using an extrusion granulator. Manufactured.

[Example 5] Tablets of benicillanic acid 1,1-dioxide (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester (compound A) Compound A
125 female hydroxypropyl cellulose
4 of 9 cornstarch
25-9 Magnesium Stearate
2/9 total 156 blocks Tablets were manufactured in the same manner as in Example 3 using the above material.

Claims (1)

[Claims] 1. An ester of penicillanic acid 1,1-dioxide represented by the formula ▲ Numerical formula, chemical formula, table, etc.▼ (wherein R represents a methyl group or a phenyl group). 2. The compound according to claim 1, wherein R in formula (I) is a methyl group. 3 Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Penicillanic acid 1,1-dioxide or its salt shown by represents,X
represents a halogen atom. ): ▲There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R represents a methyl group or a phenyl group) Penicillanic acid 1,1-dioxide A method for producing esters. 4. The production method according to claim 3, wherein in the compound of formula (III), X is a chlorine atom or a bromine atom. 5 Penicillanic acid 1,1-dioxide of formula (II) and formula (
5. The method according to claim 3 or 4, wherein the compound III) is reacted in an inert organic solvent in the presence of a base. 6 A β-lactamase inhibitor whose active ingredient is a compound represented by the formula ▲Mathematical formula, chemical formula, table, etc.▼ (In the formula, R represents a methyl group or a phenyl group).