JPS63122690A - 2beta-n-substituted tetrazolethiomethylpenicillin derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [n is 0, 1 or 2; R is phenyl substituted by halogen or alkoxy, (CH2)m-OR2 (m is integer of 1-6; R2 is protecting group commonly used in penicillin derivative); R1 is R2] and salt thereof. EXAMPLE:2beta-(1-p-Chlorophenyl-5-tetrazolylthio)methyl-2alpha-methylp enam-3alpha-carbo xylic acid p-nitrobenzyl ester. USE:A beta-lactamase inhibitor capable of improving an antimicrobial activity of beta-lactam based antibiotic in use together with said antibiotic. PREPARATION:A penicillin derivative expressed by formula II (X is Cl or Br; R<1> is penicillincarboxyl-protecting group) is reacted with a mercaptotetrazole derivative to provide a compound expressed by formula IV, which is oxidized with an oxidant such as peracetic acid, etc., to afford a dioxide expressed by formula V via a sulfoxide intermediate, followed by deesterification.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The penicillin derivatives and pharmaceutically acceptable salts thereof of the present invention are both new compounds, and they have β-lactamase inhibitory activity. It is useful as a drug.

BACKGROUND OF THE INVENTION BACKGROUND OF THE INVENTION Among commercially available antibiotics, β-lactam antibiotics having a β-lactum ring, namely penicillins and cephalosporins, are the most well-known and frequently used. These β-
Although lactam antibiotics are widely used as useful chemotherapeutic agents, they are not sufficiently effective against certain microorganisms due to their resistance. The resistance of certain microorganisms to β-lactam antibiotics is usually due to the β-lactamase produced by the microorganism,
That is, it uses an enzyme that cleaves the β-lactam ring of a β-lactam antibiotic to produce a product that does not have antibacterial activity. Therefore, in order for the β-lactam antibiotics to exhibit sufficient efficacy, it is necessary to eliminate or minimize the action of β-lactamase. This β
- Eliminating or inhibiting the action of lactamases is achieved by β-lactamase inhibitors, and such β-lactamase inhibitors can be used together with β-lactam antibiotics to enhance the antibacterial activity of the antibiotics. can be raised.

Solution: As a result of synthesizing and researching various compounds, the present inventors found that a penicillin derivative represented by the following general formula (I) and a pharmaceutically acceptable salt thereof has an excellent inhibitory effect on β-lactamase. This discovery led to the completion of the present invention.

The present invention relates to a novel penicillin derivative represented by the following general formula (I) and a pharmaceutically acceptable salt thereof.

[where n is 0.1 or 2, R is a phenyl group substituted with at least one of a halogen atom and an alkoxy group,
-(CH2)m OR2 or -(CH2)m-COO
Indicates R3. m is an integer of 1 to 6, and RISR2 and R3 are the same or different and represent a hydrogen atom or a protective group commonly used in penicillin derivatives. ] A penicillin derivative and a pharmaceutically acceptable salt thereof.

In the formula, substituents for the substituted phenyl group represented by R include halogen atoms such as fluorine, chlorine, bromine, and iodine, and linear or branched groups such as methoxy, ethoxy, propoxy, 1so-propoxy, butoxy, and tert-butoxy. Examples include alkoxy groups having 1 to 6 carbon atoms. Furthermore, examples of the protecting groups represented by R1, R2, and R3 include esters or ethers protected by well-known penicillin carboxyl group protecting groups, and esters or ethers that are hydrolyzed in vivo. Examples of secondary esters or ethers and protective groups for forming the esters or ethers include those described in JP-A-49-81380.
Publications and H-E-Fist Flying Cephalosporins
and Penicillins, Chemistry and Biology (published by Academic Press, 1972), which are commonly used as β-lactam antibiotics. Typical specific examples include substituted or unsubstituted alkyl groups such as methyl, ethyl, propyl, butyl, tert-butyl, hexyl, trichloroethyl; substituted or unsubstituted alkyl groups such as benzyl, substituted benzyl, diphenylmethyl, p-nitrobenzyl, etc. Unsubstituted aralkyl group; Acyloxy such as acetoxymethyl, acetoxyethyl, propionyloxyethyl, pivaloyloxymethyl, pivaloyloxyprobyl, benzoyloxymethyl, benzoyloxyethyl, benzylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, etc. Alkyl group; alkoxyalkyl group such as methoxymethyl, ethoxymethyl, benzyloxymethyl; lactone and substituted or unsubstituted phenyl group such as 3-phthalidyl group, 4-crotonolactonyl group, γ-butyrolactone-4-yl group: Others (2-oxo-1,3-dioxoten-4-yl)methyl group, (5-methyl-2-oxo-1,3-dioxoten-4-yl)methyl group, (5-phenyl-2
-oxo-1,3-dioxoten-4-yl)methyl group, tetrahydropyranyl group, dimethylaminoethyl group,
Examples include dimethylchlorosilyl group, trichlorosilyl group, alkylsilyl groups such as trimethylsilyl and tert-butyldimethylsilyl, and acetal type protecting groups such as methoxy and ethoxy.

Examples of the salts of the compound of the present invention represented by the general formula (I) include alkali metal salts such as sodium, potassium, and lithium, alkaline earth metal salts such as calcium and magnesium, cyclohexylamine, trimethylamine, jetanolamine, etc. organic amine salt, arginine,
Examples include basic amino acid salts such as lysine, ammonium salts, and the like.

Examples of antibiotics whose antibacterial activity is increased when used in combination with the compound of the present invention include common penicillins such as ampicillin,
amoxicillin, hetacillin, cyclacillin, mecillinam, carbenicillin, sulpenicillin, ticarcillin,
Salts such as piperagiline, ampicillin, methicillin, mezlocillin, etc.; esters such as bacampicillin, calindacillin, talampicillin, carbenicillin, bibmecillinum; and cephalosporins such as cephaloridine, cephalothin, cephapirin, cefacedryl, cefazolin, cephalexin, cefrazine, cefoxime. , cefamandole, cefoxime, cefoxime, cefmetazole, cephalothin, cefoferazone,
Examples include β-lactam antibiotics that exhibit antibacterial activity against various Durum-positive and Durum-negative bacteria, such as cephalexin, cephalexin, cefmetuxime, latamoxef, cefaclor, cefuroxazine, cefatridine, cefadroxil, cephaloglycin, and salts thereof. The compounding ratio of the compound of the present invention and the β-lactam antibiotic used in combination with the compound is usually 1:about 0.1 to 1 by weight.
0, preferably 1: about 0.2 to 5.

The penicillin derivative (I) of the present invention can be produced according to various methods shown in the following reaction scheme.

2 (In each of the above formulas, X represents a chlorine atom or a bromine atom, and R is the same as above. Also, R1 represents a penicillin carboxyl protecting group.) A penicillin carboxyl protecting group represented by R1 in the above As for this, it may be a commonly known one, specifically,
For example, the above-mentioned Japanese Patent Application Laid-Open No. 49-81380 and Etch.
Any of those described in Cephalosporins and Penicillins, Chemistry and Biology, edited by E. Frein (published by Academic Press, 1972) can be used.

Preferred R groups include, for example, substituted or unsubstituted alkyl groups such as methyl, ethyl, propyl, butyl, tert-butyl, and trichloroethyl; substituted or unsubstituted aralkyl groups such as benzyl, diphenylmethyl, and p-nitrobenzyl; acetoxymethyl; , acetoxyethyl, propionyloxyethyl, pivaloyloxymethyl, pivaloyloxyprobyl, benzoyloxymethyl, benzoyloxyethyl, benzylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, and other acyloxyalkyl groups; methoxymethyl, ethoxy Alkoxyalkyl groups such as methyl and benzyloxymethyl; other examples include tetrahydropyranyl, dimethylaminoethyl, dimethylchlorosilyl, and trichlorosilyl groups.

Each step in the above reaction scheme is carried out in more detail as follows.

Step A〉 A penicillin derivative represented by the general formula (n) and the general formula (
ffi) with a mercaptotetrazole derivative or its salt, the compound of the general formula (I-
A compound represented by c) is obtained.

In this reaction, a known penicillin derivative represented by the general formula (n) (see JP-A-58-4788) is used in an appropriate solvent in an amount of about 1 to 10 times the molar equivalent per mole of the derivative, preferably about This reaction is carried out by reacting 1 to 5 times the molar equivalent of the mercaptotetrazole derivative (II[) or a salt thereof in the presence or absence of a base. The salt of compound <m> refers to an alkali metal salt such as potassium or sodium. Examples of the base include inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, and potassium carbonate, and organic amines such as pyridine, triethylamine, and diisopropylethylamine.

There are no particular restrictions on the solvent as long as it does not affect the reaction; for example, various organic solvents such as dimethylformamide, acetone, tetrahydrofuran, dioxane, methanol, and ethanol may be used singly or in combination of two or more. A mixed solvent of a secondary organic solvent and water can be used.

This reaction usually proceeds under temperature conditions of 0°C to 60°C.

After completion of the reaction, the target product may be subjected to subsequent reactions without being isolated, or may be isolated and purified according to various commonly known methods.

Step B> The compound represented by the general formula (I-c) obtained in the above step A is oxidized to form the compound represented by the general formula (I-b) via the sulfoxide represented by the general formula (I-b) as an intermediate.
The dioxide represented by I-a) is obtained. The above oxidation reaction is carried out using conventional oxidizing agents such as permanganic acid, periodic acid, peracetic acid, trifluoroperacetic acid, perbenzoic acid, m-chloroperbenzoic acid, hydrogen peroxide, and the like. Although such oxidizing agents may be used in large excess, it is usually preferable to use the general formula (
It is preferable to use the compound in an equimolar amount to about 4 times the molar amount of the compound I-c). At this time, by appropriately selecting the reaction conditions, the oxidizing agent, and the number of moles used, the intermediate, general formula (I
-b) can be obtained.

Moreover, the reaction is generally carried out in a suitable solvent.

As a solvent, chloroform, pyridine, tetrahydrofuran, dioxane, acetone, methylene chloride,
Any substance that does not affect this reaction, such as carbon tetrachloride, acetic acid, formic acid, dimethylformamide, and water, can be used. Although the reaction temperature is not particularly limited, it is usually carried out at room temperature or under cooling.

General formula (I-c) obtained by the above steps A and B
, (I-b) to (I-a) are each compound represented by
Depending on the type of penicillin carboxyl protecting group represented by R1, the object of the present invention, that is, the general formula (
Although it may be an in vivo hydrolyzed ester of the penicillin derivative represented by I), it is more preferably followed by a deesterification reaction as shown in step C,
The compound is converted into a dioxide derivative represented by the general formula (I') of the present invention, and then, if necessary, converted into a pharmaceutically acceptable salt or an ester hydrolyzed in vivo according to a conventional method. Moreover, the above general formulas (I-a), (I-b) to (I-c
) can also be directly subjected to a transesterification reaction according to a conventional method to form an ester or a pharmaceutically acceptable salt that is hydrolyzed in vivo.

Step C> The compound represented by the general formula (I-a) is isolated from the reaction system of the B step, or is subjected to a deesterification reaction without being isolated, to obtain a penicillin derivative represented by the general formula (I'). get.

As a method for deesterification, all the usual elimination methods such as reduction and hydrolysis that lead a carboxyl protecting group to a carboxyl group can be applied. In particular, the penicillin carboxyl protecting group represented by R1 is trichloroethyl, benzyl, p
-nitrobenzyl, diphenylmethyl, etc., the method by reduction, and when the protecting group is 4-methoxybenzyl, tert-butyl, trityl, diphenylmethyl, methoxymethyl, tetrahydropyranyl, etc. Acid methods are in each case advantageously employed.

Typical examples of reduction methods include a method using a metal such as zinc or zinc amalgam, and/or a chromium salt such as chromium chloride or chromium acetate, and an acid such as formic acid or acetic acid, or a method using catalytic reduction. can give. In the case of the above catalytic reduction, examples of the catalyst include platinum, platinum oxide, palladium, palladium oxide, palladium barium sulfate, palladium calcium carbonate, palladium carbon, nickel oxide, Raney nickel and the like. The solvent is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, esters such as ethyl acetate, fatty acids such as acetic acid, and these organic solvents and water A mixed solvent with can be suitably used.

In addition, the acids used in the acid method include formic acid,
Lower fatty acids such as acetic acid, trihaloacetic acids such as trichloroacetic acid and trifluoroacetic acid, hydrohalic acids such as hydrochloric acid and hydrofluoric acid, organic sulfonic acids such as p-)-luenesulfonic acid and trifluoromethanesulfonic acid, or these Examples include mixtures of the following. The above reaction using an acid does not require any other solvent when using a liquid acid, but it can also be carried out using a solvent that does not adversely affect the reaction, such as dimethylformamide, dichloromethane, chloroform, tetrahydrofuran, acetone, etc. It is possible.

The free acid form of the general formula (I') of the present invention thus obtained
Penicillin derivatives represented by can be converted into pharmaceutically acceptable salts and esters according to salt formation and/or esterification reactions commonly used in the art.

In addition, when the ester residue is, for example, 3-phthalidyl, 4-talotonolactonyl, γ-butyrolactone-4-yl group, etc., the penicillin derivative represented by the general formula - It can be esterified with a halide such as halogenated crotonolactone and 4-halogenated γ-butyrolactone. Here, chlorine, bromine and iodine are used as the halogen in the above-mentioned halide. The reaction is carried out by dissolving the salt of the penicillin derivative represented by the general formula (I') in a suitable polar organic solvent such as N,N-dimethylformamide, and adding about an equimolar amount of the halide. be exposed. The reaction temperature is usually 0 to 100°C, preferably about 15 to 35°C.
It is better to Salts of penicillin derivatives used in this esterification reaction include alkali metal salts such as sodium and potassium salts, and tertiary amine salts such as triethylamine, ethyldiisopropylamine, N-ethylpiperidine%NlN-dimethylaniline, and N-methylmorpholine. can be exemplified. After the reaction is completed, the target product can be easily isolated by a conventionally known method.

The target compound obtained in each of the above steps, the penicillin derivative of the present invention, and its pharmaceutically acceptable salts and esters are separated and collected according to a conventional method after the completion of the reaction in each step, and if necessary, a recrystallization method, It can be purified by thin layer chromatography, column chromatography, etc.

Example Next, examples will be shown to explain the present invention more specifically.

Example 1 2β-(1-p-chlorophenyl-5-tetrazolylthio)methyl-2α-methylpenam-3α-carvone Mp
-Production of nitrobenzyl ester 2β-chloromethyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 3.70 g, 1-
p-chlorophenyl-5-mercaptotetrazole2.
12g, 840mg of sodium bicarbonate and 75g of acetone
After stirring at room temperature for 24 hours in a 25-liter atmosphere of water and water, acetone was distilled off under reduced pressure and extracted with 50 mQ of ethyl acetate. The ethyl acetate extract was somewhat concentrated under reduced pressure to precipitate crystals 3.
．． 26g was taken out. Yield 60%.

Melting point 168-169°C0 Infrared absorption spectrum (KBr) νmax (cl') = 1778.1785° Nuclear magnetic resonance spectrum (CDCi23) δ (ppm) = 1, 53 (3H, s), 3, 19.3. 60 (each IH, ABX), 3, 91
．． 4.08 (each IH, AB), 4.86 (IH, s
), 5, 30 (2H,s), 5, 30-5. 39 (IH, m), 7, 56
(4H,s), 7, 60 (2H,d), 8, 26 (2H,d).

Example 2 Preparation of 2β-(1-p-methoxyphenyl-5-tetrazolylthio)methyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 2β-chloromethyl-2α-methylpenam-3α-carboxylic acid p-nitro Benzyl ester 3.70g, 5-
Mercapto-1-p-methoxyphenyltetrazole 2
．． 08g, sodium bicarbonate 840mg acetone 7
After stirring for 18 hours at room temperature in 5 rll12 and 25 m12 of water, acetone was distilled off under reduced pressure and 50 ffli of ethyl acetate was added.
Extracted with 2. The ethyl acetate extract was concentrated under reduced pressure, and the resulting residue was subjected to column chromatography to obtain an oily substance 1.
52g was obtained.

Yield 28%.

Nuclear magnetic resonance spectrum (CDCQ3) δ (ppm) - 1.53 (3H, s), 3. 19. 5. 59 (each IH, ABX), 3.
89 (3H,s), 3, 89.4. 05 (each IH, AB), 4.85
(IH, s), 5.30 (2H, s), 5.30-5.36 (IH, m), 7.07 (2H, d), 7.45 (2H, d), 7.58 ( 2H,d), 8.26 (2H,d).

Example 3 Preparation of 2α-methyl-2β-(1-(2'-tetrahydropyranoxyethyl)-5-tetrazolylthio)methylpenam-3α-carboxylic acid p-nitrobenzyl ester 2β-chloromethyl-2α-methylpenam- 3α-carboxylic acid p-nitrobenzyl ester 3.70 g, 5-
2.30 g of mercapto-1-(2'-tetrahydropyranoxy)ethyltetrazole and 840 mg of sodium bicarbonate were dissolved in 75 g of acetone and 25 g of water at room temperature.
After stirring for 4 hours, acetone was distilled off under reduced pressure and the mixture was extracted with 50 mg of methylene chloride. The methylene chloride extract was concentrated under reduced pressure, and the resulting residue was subjected to column chromatography to obtain 1.15 g of an oil. Yield 2o96° Infrared absorption spectrum (CHC123) νmax (cm −' ) −1785,1760
0 nuclear magnetic resonance spectrum (CDCQ3) δ(pprA) - 1, 55 (3H, s), 1, 26-1.80 (6H, m), 3.05-4.
55 (IIH, m), 4.83 (LH, s), 5, 30 (2H, s), 5, 30-5. 37 (IH, m), 7, 59
(2H, d), 8.26 (2H, d).

Example 4 2β-(1-diphenylmethoxycarbonylmethyl-5
-tetrazolylthio)methyl-2α-methylpenam-3
Preparation of α-carboxylic acid p-nitrobenzyl ester 2β-chloromethyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 7.42 g, 5-
3.20 g of mercaptotetrazole-1-acetic acid and 4.0 g of potassium hydrogen carbonate were added to 54 mQ of acetone and 18 m of water.
After stirring at room temperature for 15 hours in No. 1, acetone was distilled off under reduced pressure and the mixture was extracted with 200 mg of ethyl acetate. The ethyl acetate extract was concentrated under reduced pressure, and the resulting residue was diluted with methylene chloride.
Dissolved in 1G. 2. diphenyldiazomethane under water cooling.
After adding 83 g of the mixture and stirring at room temperature for 1 hour, methylene chloride was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 1.85 g of an oily substance.

Yield 14%.

Nuclear magnetic resonance spectrum (CDCQ3) δ (ppm) - 1,47 (3H, s), 3, 13.3.57 (each IH, ABX), 3, 78
．． 3.90 (each IH, AB), 4.77 (IH,
s), 5.17 (2H, s), 5, 27 (2H, s), 5, 27-5. 35 (IH, m), 6, 94
(IH, s), 7-31 (IOH, s), 7, 55 (2H, d), 8, 25 (2H, d).

Example 5 2β(1-p-chlorophenyl-5-tetrazolylthio)methyl-2α-methylpenam-3α-carboxylic acid p
-Production of nitrobenzyl ester 1゜1-dioxide 2β-(1-p-chlorophenyl-5-tetrazolylthio)methyl-2α-methylpenam-3α-carboxylic acid
1.51 g of p-nitrobenzyl ester was dissolved in 281 g of glacial acetic acid.
The mixture was dissolved in Tl12 and 5 ml of water, and 520 mg of potassium permanganate was gradually added while stirring under water cooling, followed by stirring at the same temperature for 1.5 hours and at room temperature for 2.5 hours. Then, 30% hydrogen peroxide solution was added until the color of the reaction solution disappeared, and then the precipitate was dissipated.

Recrystallization was performed from a methanol-water mixture to obtain 0.58 g of crystals. Yield 36%.

Melting point: 146-147°C.

Infrared absorption spectrum (KBr) νmax (am-1) -1818,1800,1
752° Nuclear Magnetic Resonance Spectrum (CDC93) δ (ppm) - 1, 53 (3H, s), 3, 51-3. 56 (2H, m), 4,
08.4. 37 (each IH, AB), 4, 62-4
．． 67 (IH, m), 4, 77 (IH,
s), 5, 38 (2H, s), 7, 55 (4H, s), 7, 73 (2H, d), 8, 30 (2H, d).

Example 6 Preparation of 2β-(1-p-methoxyphenyl-5-tetrazolylthio)methyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 1,1-dioxide 2β-(1-p-methoxyphenyl-5 -Tetrazolylthio)methyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester (1.50 g) was added to 28 g of glacial acetic acid.
The mixture was dissolved in 5 liters of water, and 520 mg of potassium permanganate was gradually added while stirring under ice cooling, and the mixture was stirred at the same temperature for 2.5 hours and at room temperature for 2.0 hours. Then, 30% hydrogen peroxide solution was added until the color of the reaction solution disappeared, and then the precipitate was dissipated.

Recrystallization was performed from a methanol-water mixture to obtain 1.23 g of crystals. Yield 77%.

Melting point: 142-144°C.

Infrared absorption spectrum (KBr)! / (cm-') -1798,1750°ax Nuclear magnetic resonance spectrum (CDCI;!3) δ (ppm
) - 1, 53 (3H, s), 3.51 to 3.55 (2H, m), 3, 89 (3H, s), 4.05, 4.36 (, each IH, AB), 4. 62~
4.69 (LH, m), 4.77 (IH, s), 5, 37 (2H, s), 7, 05 (2H, d), 7, 45 (2H, d), 7, 73 (2H , d) , 8, 30 (2H, d).

Example 7 2α-methyl-2β-+1-(2′-tetrahydropyranoxyethyl)-5-tetrazolylthio)methylpenam-3α-carboxylic acid p-nitrobenzyl ester 1,
Preparation of 1-dioxide 2α-Methyl-2β-[1-(2′-tetrahydropyranoxy)ethyl-5-tetrazolylthiocomethylpenam-3α-carboxylic acid p-nitrobenzyl ester 1
．． 15 g was dissolved in 30 mQ of acetone and 30 mQ of water, and 370 mg of glacial acetic acid was added. Then, 810 mg of potassium permanganate was gradually added to the mixture under water cooling and stirring, and the mixture was heated at the same temperature for 4 hours.
Stirred at room temperature for 1 hour. Next, the precipitated manganese dioxide was filtered, and the manganese liquor was extracted with methylene chloride for 30 minutes. The methylene chloride extract was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 720 mg of an oily substance.
I got it. Yield 6026° Nuclear magnetic resonance spectrum (CDC93) δ (ppm) = 1.47 (3H, s), 1.26-1.80 (6H, m), 3,4C)-3. 60 (2H, m), 3.72-4
．． 69 (IOH, m), 4.74 (IH, s), 5, 36 (2H, s), 7.71 (2H, d), 8, 27 (2H, d).

Example 8 Preparation of 2β-[1-(2′-hydroxyethyl)-5-tetrazolylthiocomethyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 1,1-dioxide 2α-methyl-2β- [1-(2'-tetrahydropyranoxy)ethyl-5-tetrazolylthiocomethylpenam-3α-carboxylic acid p-nitrobenzyl ester 1
, 720 g of 1-dioxide and p-toluenesulfonic acid 1
229 g of the hydrate were stirred in 15 ml of methanol and 5 ml of methylene chloride at room temperature for 6 hours. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel chromatography to obtain 291 mg of an oil. Yield 47%.

Nuclear magnetic resonance spectrum (at CDC!3) δ (ppm)
- 1,44 (3H, s), 2.38 (IH, t, D20 disappearance), 3.52-3.
56 (2H, m), 4.09-4.18 (4H, m), 4.36-4.45 (2H, m), 4.61-4.68 (IH, m), 4, 87 ( IH, s), 5.32 (2H, s), 7, 67 (2H, d), 8, 28 (2H, d).

Example 9 2β-(diphenylmethoxycarbonylmethyl-5-tetrazolylthio)methyl-2α-methylpenam-3α-
Preparation of carboxylic acid p-nitrobenzyl ester 1.1-dioxide 2β-(diphenylmethoxycarbonylmethyl-5-tetrazolylthio)methyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 1.85 g was mixed with 18 precepts of glacial acetic acid. The solution was dissolved in water, and 530 mg of potassium permanganate was gradually added thereto while stirring while cooling with water.

After stirring at the same temperature for 2.5 hours and then at room temperature for 2 hours,
0% hydrogen peroxide solution was added until the color of the reaction solution disappeared. Next, ethyl acetate 30rrI! The mixture was extracted with Q and ethyl acetate was distilled off under reduced pressure.

The obtained residue was subjected to column chromatography to obtain 740 mg of an oily substance. Yield 38%.

Infrared absorption spectrum (CHC('3) L/ (cm-') = 1818.1762°aX Nuclear magnetic resonance spectrum (CDCG!3) δ (ppm)
- 1,41 (3H, s), 3.50-3.54 (2H, m), 3, 93.4. 17 (each IH, AB), 4.56~
4.66 (IH, m), 4.67 (IH, s), 5.18 (2H, s), 5.31 (2H, s), 6.94 (LH, s), 7.32 (IOH ,s), 7.64 (2H,d), 8.26 (2H,d).

Example 10 2β-(1-p-talolophenyl/l/-5-tetrazolylthio)methyl-2α-methylpenam-3α-carboxylic acid 1. Preparation of 1-dioxide sodium salt 2β-(1-T)-chlorophenyl-5 -tetrazolylthio)methyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 1°1 dioxide 289
mg of 5% palladium on carbon in the presence of 42 mg of sodium bicarbonate in 20 mQ of ethyl acetate and 20 mQ of water.
Hydrogenation was carried out at room temperature under low pressure using a . After no hydrogen absorption was observed, the reaction solution was filtered, and the dispersed aqueous layer was subjected to column chromatography using MCI gel (CHP-20P manufactured by Mitsubishi Chemical Corporation), and the eluate was freeze-dried to give a slightly yellow color. 183 mg of powder was obtained. Yield 78%.

Melting point: 172-173°C (decomposed).

Infrared absorption spectrum (KBr) νtthax (am −' ) = 1790.16
20° nuclear magnetic resonance spectrum (D20) δ (ppm) = 1.55 (3H, s), 3, 37.3.65 (each IH, ABX), 4.07,
4.20 (each IH, AB), 4.44 (IH, s)
, 4.97-5.02 (IH, m), 7,66 (4H, s).

Example 11 Preparation of 2β-(1-p-methoxyphenyl-5-tetrazolylthio)methyl-2α-methylpenam-3α-carboxylic acid 1,1-dioxide sodium salt 2β-(1-p-methoxyphenyl-5-tetrazolylthio) ) Methyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 1°1 dioxide 287
mg of 5% palladium on carbon in the presence of 42 mg of sodium bicarbonate in 30 mQ of ethyl acetate and 30 mQ of water.
Hydrogenation was carried out at room temperature under low pressure using a . After no hydrogen absorption was observed, the reaction solution was filtered, and the separated aqueous layer was subjected to column chromatography using MCI gel (Mitsubishi Kasei fAcHP-20P), and the eluate was freeze-dried to give a slightly yellow color. 214 mg of powder was obtained. Yield 92%.

Melting point: 165-167°C (decomposed).

Infrared absorption spectrum (KBr) νff1ax (cm-') = 1802.1638° Nuclear magnetic resonance spectrum (D20) δ (ppm) = 1, 54 (3H, s), 3.36.3.65 (each IH, ABX), 3, 93
(3H, s), 4.04.4.16 (each IH, AB), 4.44 (I
H,s),

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, n is 0, 1 or 2, R is a phenyl group substituted with at least one of a halogen atom and an alkoxy group,
-(CH_2)m-OR_2 or -(CH_2)m-C
Indicates OOR_3. m is an integer from 1 to 6, R_1, R_
2. R_3 is the same or different and represents a hydrogen atom or a protecting group commonly used in penicillin derivatives. ] A penicillin derivative and a pharmaceutically acceptable salt thereof.