JP2645833B2 - 2β-triazolylpenicilanic acid derivatives, salts and esters thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION INDUSTRIAL APPLICABILITY The 2β-triazolylpenicillanic acid derivatives, salts and esters thereof of the present invention are all novel compounds, which have β-lactamase inhibitory activity, Useful as β-lactamase inhibitors.

2. Description of the Related Art Among the commercially available antibiotics, β-lactam antibiotics having a β-lactam ring such as penicillins and cephalosporins are best known and widely 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. Resistance of these certain microorganisms to β-lactam antibiotics is usually due to β-lactamases produced by the microorganism,
That is, it is due to an enzyme which cleaves the β-lactam ring of the β-lactam antibiotic to produce a product having no antibacterial activity. Therefore, in order for the β-lactam antibiotic to exhibit sufficient efficacy, it is necessary to eliminate or minimize the action of β-lactamase. The elimination or suppression of the action of β-lactamase is achieved by a β-lactamase inhibitor, and such β-lactamase inhibitor can be used together with a β-lactam antibiotic to increase the antibacterial activity of the antibiotic. Can be raised.

As a conventional β-lactamase inhibitor, for example, YTR830 having the following structure (JP-A-59-148788) is known.

However, the β-lactamase activity of the compound is insufficient, and there is a need for the development of a compound having even better β-lactamase activity.

Means for Solving the Problems The present inventors have made intensive studies in view of the above-mentioned problems of the prior art, and as a result, have obtained a 2β-triazolylpenicilanic acid derivative represented by the following general formula (I), a salt thereof and Ester is β
-It was found to have an excellent inhibitory effect on lactamase, and the present invention was completed.

The present invention relates to novel 2β-triazolylpenicillanic acid derivatives, salts and esters thereof.

The 2β-triazolylpenicillanic acid derivative of the present invention is represented by the following general formula (I).

(In the formula, n represents 0, 1, or 2. R represents R ¹ and R ² are the same or different, a hydrogen atom, a lower alkyl group, a phenyl group, a lower alkoxycarbonyl group, a formyl group, a benzyloxycarbonyl group or a halogen atom, a lower alkyl group or a nitro group as a substituent. A benzyloxycarbonyl group. However, R ¹ and R ² are not hydrogen atoms at the same time, and when n is 2, R is As the lower alkyl group defined by R ¹ and R ² in the general formula (I), an alkyl group having 1 to 6 carbon atoms, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl group, etc. As the lower alkoxy of the lower alkoxycarbonyl group, an alkoxy group having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy,
Isopropoxy, butoxy, isobutoxy, pentoxy, hexyloxy and the like; and substituents of the substituted benzyloxycarbonyl group include a halogen atom such as a chlorine atom and a bromine atom, a lower alkyl group (as defined above), and a nitro group. Can be mentioned.

Examples of the ester of the penicillanic acid derivative (I) of the present invention include an ester protected by a well-known penicillin carboxyl protecting group and an ester hydrolyzed in a living body. Such esters and protecting groups for forming the esters are described in, for example,
81380 and etch. E. Fline cephalosporins and penicillins, chemistry and
Any of those commonly used for ordinary β-lactam antibiotics described in Biology (issued by Academic Press, 1972) may be used. Typical examples thereof include substituted or unsubstituted alkyl groups such as methyl, ethyl, propyl, butyl, tert-butyl, and trichloroethyl; substituted or unsubstituted alkyl groups such as benzyl, diphenylmethyl, p-nitrobenzyl, and p-methoxybenzyl. Substituted aralkyl groups; acyloxyalkyl groups such as acetoxymethyl, acetoxyethyl, propionyloxyethyl, pivaloyloxymethyl, pivaloyloxypropyl, benzoyloxymethyl, benzoyloxyethyl, benzylcarbonyloxymethyl and cyclohexylcarbonyloxymethyl;
Alkoxyalkyl groups such as methoxymethyl, ethoxymethyl and benzyloxymethyl; lactones such as 3-phthalidyl group, 4-crotonolactonyl group, γ-butyrolactone-4-yl group and substituted or unsubstituted phenyl groups; -Oxo-1,3-dioxoden-4-yl) methyl group, (5-methyl-2-oxo-1,3-dioxoden-
4-yl) methyl group, (5-phenyl-2-oxo-1,
3-dioxoden-4-yl) methyl group, tetrahydropyranyl group, dimethylaminoethyl group, dimethylchlorosilyl group, trichlorosilyl group and the like.

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

Antibiotics which can be used in combination with the compound of the present invention to increase the antibacterial activity include ordinary penicillins such as ampicillin, amoxicillin, hetacillin, cyclacillin, mesilinam, carbenicillin, sulbenicillin, ticarcillin, piperacillin, aparcillin, methicillin, mezlocillin and the like. Salts and bacampicillin, calandacillin, tarampicillin, calampicillin, esters such as pibumecilinum and cephalosporins such as cephaloridin, cephalotin, cephapirin, cefacetryl, cefazolin, cephalexin, cefradine, cefotiam, cephamandol, cefuroxime,
Antibacterial activity against various gram-positive and gram-negative bacteria such as cefoxime, cefmetazole, cefthrosin, cefoperazone, cefotaxime, ceftizoxime, cefmenoxime, latamoxef, cefaclor, cefloxazine, cefatrizine, cefadroxil, cephaloglysin, and salts thereof. The following β-lactam antibiotics can be exemplified. The compound of the present invention and β- used in combination therewith
The compounding ratio of lactam antibiotics is usually about 1: 0 by weight.
It is good to be 1-10, preferably 1: about 0.2-5.

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

(In the above formulas, X represents a chlorine atom or a bromine atom.
R, R ¹ , R ² and n are the same as above, and R ³ represents a penicillin carboxyl protecting group. The penicillin carboxyl protecting group represented by R ³ in the above may be a commonly known penicillin carboxyl protecting group, and specifically,
For example, JP-A-49-81380 and Etch. E. Any of those described in Sephalosporin and Penicillins, Chemistry and Biology (published by Academic Press in 1972), edited by Fline, can be used. Preferred R ³ groups include, for example, methyl, ethyl, propyl,
Substituted or unsubstituted alkyl groups such as butyl, tert-butyl and trichloroethyl; benzyl, diphenylmethyl, p-
Substituted or unsubstituted aralkyl groups such as nitrobenzyl and p-methoxybenzyl; acetoxymethyl, acetoxyethyl, propionyloxyethyl, pivaloyloxymethyl, pivaloyloxypropyl, benzoyloxymethyl, benzoyloxyethyl, benzylcarbonyloxymethyl And acyloxyalkyl groups such as cyclohexylcarbonyloxymethyl; alkoxyalkyl groups such as methoxymethyl, ethoxymethyl and benzyloxymethyl; and other examples include a tetrahydropyranyl group, a dimethylaminoethyl group, a dimethylchlorosilyl group and a trichlorosilyl group. You.

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

<Step A> The compound represented by the general formula (Ia) is obtained by reacting a penum derivative represented by the general formula (II) with a 1,2,3-triazole derivative in the presence or absence of a base. Get. This reaction is performed with respect to 1 mole of a known penum derivative represented by the general formula (II) (see JP-A-58-4788).
The 1,3-triazole derivative is reacted with about 1 to 50 times molar equivalent, preferably about 1 to 30 times molar equivalent, or these are reacted with about 0.5 to 2 times molar equivalent of base or metal relative to 1 mol of the penam derivative. The reaction is carried out in the presence of a salt. As a base or a metal salt, sodium hydrogen carbonate,
Alkali metal carbonates such as potassium hydrogen carbonate and cesium carbonate, alkaline earth metal carbonates such as barium carbonate and calcium carbonate, copper group metal carbonates such as silver carbonate and copper carbonate, and copper such as copper oxide and silver oxide Group metal oxides, alkaline earth metal oxides such as magnesium oxide, calcium oxide and barium oxide; zinc group metal oxides such as zinc oxide and mercury oxide; aluminum group metal oxides such as aluminum oxide and thallium oxide A carbon group metal oxide such as tin oxide and lead oxide; an iron group metal oxide such as iron oxide, cobalt oxide and nickel oxide; a copper group metal hydroxide such as copper hydroxide and silver hydroxide; Organic amines such as pyridine, triethylamine, diisopropylethylamine and the like, and anion exchange resins can also be mentioned.

The solvent is not particularly limited as long as it does not affect the reaction, for example, acetonitrile, acetone,
Various organic solvents such as methyl ethyl ketone, dimethylformamide, nitromethane, tetrahydrofuran, dioxane, methanol, ethanol, methoxyethanol, etc. may be used alone or in combination of two or more, or a mixed solvent of such an organic solvent and water. Either can be used. This reaction is usually performed at about 0 to 80 ° C, preferably 20 to 50 ° C. After completion of the reaction, the target compound may be subjected to a subsequent reaction without isolation, and may be isolated and purified according to various known methods.

<Step B> The compound represented by the general formula (Ia) obtained in the above step A is oxidized to convert the compound represented by the general formula (Ia) via the sulfoxide represented by the general formula (Ib) as an intermediate.
To give the dioxide of formula (c). The oxidation reaction is carried out using a usual oxidizing agent, for example, permanganic acid, periodic acid, peracetic acid, trifluoroperacetic acid, perbenzoic acid, hydrogen peroxide and the like. These oxidizing agents may be used in a large excess, but are usually preferably used in an amount of about 1 to 5 molar equivalents relative to the compound of the general formula (Ia). At this time, a sulfoxide represented by the general formula (Ib), which is an intermediate, can be obtained by appropriately selecting the reaction conditions, the kind of the oxidizing agent to be used, and the proportion used. For example, by using a reaction at 0 ° C. to room temperature, or using periodic acid, peracetic acid, hydrogen peroxide or the like as an oxidizing agent, the usage ratio is adjusted to (I
The compound of (Ib) is easily obtained by using about 1 to 1.5 molar equivalents to the compound of -a). The reaction is generally performed in a suitable solvent.

As the solvent, any solvent that does not affect the reaction, such as dichloromethane, chloroform, carbon tetrachloride, pyridine, tetrahydrofuran, dioxane, acetone, formic acid, acetic acid, dimethylformamide, and water can be used. The reaction temperature is not particularly limited, but is usually about 0 to 60 ° C.
It is done in.

Depending on the kind of the penicillin carboxy protecting group represented by each compound represented by the general formula (Ia), (Ib) or (Ic) obtained by the steps A and B, and R ³ possessed by the compounds, In some cases, the target compound of the present invention, that is, an ester of the penum derivative represented by the general formula (I), which is hydrolyzed in vivo, is more preferably usually subjected to a deesterification reaction as shown in Step C, The compound is converted into a penicillanic acid derivative, and then converted into a pharmaceutically acceptable salt or an ester that is hydrolyzed in a living body, if necessary, according to a conventional method.

<Step C> The compounds represented by the general formulas (Ib) and (Ic) are isolated from the reaction system of the step B or not, and the compound of the general formula (Ia) is isolated. It is subjected to a deesterification reaction to obtain a penicillanic acid derivative represented by the general formula (I).

As the method of deesterification, all elimination methods such as ordinary reduction and hydrolysis for introducing a carboxyl protecting group into a carboxyl group can be applied. In particular, penicillin carboxyl protecting group represented by R ¹ is trichloroethyl, benzyl,
When it is diphenylmethyl, p-nitrobenzyl or the like, a method by reduction is used, and the protecting group is p-methoxybenzyl, tert-butyl, trityl, diphenylmethyl,
In the case of methoxymethyl, tetrahydropyranyl or the like, the method using an acid is respectively advantageously employed. Typical examples of the reduction method include a method using a metal such as zinc and zinc amalgam and / or a chromium salt such as chromium chloride and chromium acetate and an acid such as formic acid and acetic acid, or a method using catalytic reduction. can give. In the case of the above-mentioned catalytic reduction, examples of the catalyst include platinum, platinum oxide, palladium, palladium oxide, barium palladium sulfate, calcium palladium carbonate, palladium carbon, nickel oxide, Raney nickel and the like. The solvent is not particularly limited as long as it does not affect the reaction, for example, ethanol, alcohols such as ethanol, ethers such as tetrahydrofuran and dioxane, esters such as ethyl acetate, fatty acids such as acetic acid and the like. A mixed solvent of these organic solvents and water can be suitably used.

Examples of the acid used in the method using an acid include lower fatty acids such as formic acid and acetic acid, trihaloacetic acids such as trichloroacetic acid and trifluoroacetic acid, hydrohalic acids such as hydrochloric acid and hydrofluoric acid, and p-toluene. Examples thereof include organic sulfonic acids such as sulfonic acids, and mixtures thereof. The above reaction using an acid does not require any other solvent when using a liquid acid, but does not adversely affect this reaction such as dimethylformamide, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, and acetone. It is also possible to carry out using a solvent.

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

Further, when the ester residue is, for example, a 3-phthalidyl group,
In the case of a crotonolactonyl group, a γ-butyrolactone-4-yl group or the like, a penicillin derivative represented by the general formula (I) is converted to a 3-halogenated phthalide, a 4-halogenated crotonolactone group, or a 4-halogenated γ. Esterification with a halide such as butyrolactone; Here, chlorine, bromine and iodine are used as the halogen in the halide. The reaction is carried out by dissolving a salt of the penicillin derivative represented by the general formula (I) in a suitable polar solvent such as N, N-dimethylformamide, and adding about equimolar amount of a halide. The reaction temperature is generally about 0-80 ° C, preferably 15-35 ° C. Salts of penicillin derivatives used in the present esterification reaction include alkali metal salts such as sodium and potassium and triethylamine, ethyldiisopropylamine,
N-ethylpiperidine, N, N-dimethylaniline, N-
Tertiary amine salts such as methylmorpholine can be exemplified. After completion of the reaction, the target substance can be easily isolated by a conventionally known method.

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

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

Example 1 2β- (4-methoxycarbonyl-5-methyl-1,2,3
-Triazol-2-yl) methyl-2α-methylpenam-3αcarboxylic acid p-nitrobenzyl ester, 2
β- (5-methoxycarbonyl-4-methyl-1,2,3-
Triazol-1-yl) methyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester and 2β- (4-methoxycarbonyl-5-methyl-1,2,
Preparation of 3-triazol-1-yl) methyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 2β-chloromethyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 185 mg, 4-methoxycarbonyl- 5-methyl-1,2,3-triazole 2
13 mg and 50 mg of potassium hydrogen carbonate were added to 2 ml of acetonitrile-water (3: 1), and the mixture was stirred at 40 ° C. for 3 hours. The reaction mixture was diluted by adding 15 ml of ethyl acetate, washed twice with an aqueous sodium hydrogen carbonate solution and saturated saline, and dried over anhydrous magnesium sulfate. The eluate was concentrated under reduced pressure, and the obtained residue was eluted by silica gel column chromatography (benzene: ethyl acetate).
β- (4-methoxycarbonyl-5-methyl-1,2,3-
Triazol-2-yl) methyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 79 mg
I got

Infrared absorption spectrum (CHCl ₃ ) ν _{C = 0} (cm ⁻¹ ) = 1773, 1740, 1720 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm) = 1.27 (s, 3H), 2.46 (s, 3H) 3.08 (Dd, 1H, J = 2,16Hz) 3.61 (dd, 1H, J = 4,16Hz) 3.89 (s, 3H), 4.60 (s, 2H) 5.20 (s, 2H) 5.29 (dd, 1H, J = 2,4 Hz) 5.46 (s, 1H), 7.41 (d, 2H, aromatic) 8.13 (d, 2H, aromatic) Next, 2β- (5-methoxycarbonyl-4-methyl) was used as the second eluate. -1,2,3-triazol-1-yl)
Methyl-2α-methylpenam-3α-carboxylic acid p-
81 mg of the nitrobenzyl ester were obtained.

Infrared absorption spectrum (CHCl ₃ ) ν _{C = 0} (cm ⁻¹ ) = 1775, 1742, 1723 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm) = 1.32 (s, 3H), 2.51 (s, 3H) 3.08 (Dd, 1H, J = 2,16Hz) 3.56 (dd, 1H, J = 4,16Hz) 3.91 (s, 3H) 4.99,5.09 (AB-q, 2H, J = 14Hz) 5.23 (s, 2H), 5.15-5.35 (m, 2H) 7.48 (d, 2H, aromatic) 8.16 (d, 2H, aromatic) Next, 2β- (4-methoxycarbonyl-5-methyl-1, 2,3-triazol-1-yl)
Methyl-2α-methylpenam-3α-carboxylic acid p-
41 mg of nitrobenzyl ester were obtained.

Infrared absorption spectrum (CHCl ₃ ) ν _{C = 0} (cm ⁻¹ ) = 1775, 1750, 1720 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm) = 1.40 (s, 3H), 2.60 (s, 3H) 3.08 (Dd, 1H, J = 2,16Hz) 3.67 (dd, 1H, J = 4,16Hz) 3.93 (s, 3H) 4.49,4.57 (AB-q, 2H, J = 14Hz) 5.25 (s, 2H), 5.20-5.45 (m, 2H) 7.48 (d, 2H, aromatic) 8.18 (d, 2H, aromatic) Example 2 2β- (4-methoxycarbonyl-1,2,3-triazol-2-yl ) Methyl-2α-methylpenam-3αcarboxylic acid p-nitrobenzyl ester, 2β- (5-methoxycarbonyl-1,2,3-triazol-1-yl)
Methyl-2α-methylpenam-3α-carboxylic acid p-
Nitrobenzyl ester and 2β- (4-methoxycarbonyl-1,2,3-triazol-1-yl) methyl-
Preparation of 2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 2β-chloromethyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 185 mg, 4-methoxycarbonyl-1,2,3-triazole 190 mg and carbonic acid Add 50 mg of potassium hydrogen to 5 ml of acetone-water (3: 1), and add
Stirred at C for 3 hours. The reaction mixture was diluted by adding 15 ml of ethyl acetate, washed twice with an aqueous sodium hydrogen carbonate solution and saturated saline, and dried over anhydrous magnesium sulfate. The eluate was concentrated under reduced pressure, and the obtained residue was eluted by silica gel column chromatography (benzene: ethyl acetate). As a first eluate, 2β- (4-methoxycarbonyl-1,2,3-triazole-2) was used. 81 mg of -yl) methyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester were obtained.

Infrared absorption spectrum (CHCl ₃ ) ν _{C = 0} (cm ⁻¹ ) = 1780, 1740 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm) = 1.28 (s, 3H) 3.11 (dd, 1H, J = 2, 16Hz) 3.46 (dd, 1H, J = 4, 16Hz) 3.93 (s, 3H), 4.73 (s, 2H) 5.24 (s, 2H) 5.36 (dd, 1H, J = 2, 4Hz) 5.47 (s, 1H) 7.49 (d, 2H, aromatic) 8.09 (s, 1H, aromatic) 8.20 (d, 2H, aromatic) Next, 2β- (5-methoxycarbonyl-1,2 , 3-Triazol-1-yl) methyl-2α
44 mg of -methylpenam-3α-carboxylic acid p-nitrobenzyl ester were obtained.

Infrared absorption spectrum (CHCl ₃ ) ν _{C = 0} (cm ⁻¹ ) = 1780, 1740 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm) = 1.33 (s, 3H) 3.11 (dd, 1H, J = 2, 16Hz) 3.60 (dd, 1H, J = 4, 16Hz) 3.91 (s, 3H) 4.98, 5.20 (AB-q, 2H, J = 14Hz) 5.25 (s, 2H), 5.20-5.40 (m, 2H) 7.49 (D, 2H, aromatic) 8.09 (s, 1H, aromatic) 8.19 (d, 2H, aromatic) Next, 2β- (4-methoxycarbonyl-1,2,3 -Triazol-1-yl) methyl-2α
63 mg of -methylpenam-3α-carboxylic acid p-nitrobenzyl ester were obtained.

Infrared absorption spectrum (CHCl ₃ ) ν _{C = 0} (cm ⁻¹ ) = 1780, 1740 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm) = 1.40 (s, 3H) 3.17 (dd, 1H, J = 2, 16Hz) 3.70 (dd, 1H, J = 4, 16Hz) 3.93 (s, 3H), 4.66 (s, 2H) 4.91 (s, 1H) 5.25 (s, 2H), 5.40 (dd, 1H, J = 2, 4 Hz) 7.49 (d, 2H, aromatic) 8.19 (d, 2H, aromatic) 8.30 (s, 1H, aromatic) Example 3 2β- (4,5-dimethoxycarbonyl-1,2,3) -Triazol-2-yl) methyl-2α-methylpenam-3α-
Carboxylic acid p-nitropentyl ester and 2β-
(4,5-dimethoxycarbonyl-1,2,3-triazole-
Preparation of 1-yl) methyl-2α-methylpenam-3α-carboxylic acid p-nitropentyl ester 2β-chloromethyl-2α-methylpenam-3αcarboxylic acid p-nitropentyl ester 185 mg and 4,5-dimethoxycarbonyl-1,2 278 mg of 1,3-triazole and 50 mg of potassium hydrogen carbonate were added to 5 ml of acetone-water (3: 1), and 30
Stirred at C for 16 hours.

The reaction mixture was diluted by adding 15 ml of ethyl acetate, washed twice with an aqueous sodium hydrogen carbonate solution and saturated saline, and dried over anhydrous magnesium sulfate. The eluate was concentrated under reduced pressure, and the obtained residue was eluted by silica gel column chromatography (benzene: ethyl acetate), and 2β- (4,5-methoxycarbonyl-1,2,3-triazole was used as the first eluate. -2-yl) methyl-2α-methylpenam-
99 mg of 3α-carboxylic acid p-nitrobenzyl ester were obtained.

Infrared absorption spectrum (CHCl ₃ ) ν _{C = 0} (cm ⁻¹ ) = 1780, 1747 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm) = 1.33 (s, 3H) 3.12 (dd, 1H, J = 2, 16 Hz) 3.68 (dd, 1H, J = 4, 16 Hz) 3.93 (s, 6H), 4.74 (s, 2H) 5.22 (s, 2H), 5.15-5.40 (m, 1H) 5.37 (s, 1H) 7.46 ( d, 2H, aromatic) 8.14 (d, 2H, aromatic) Next, 2β- (4,5-dimethoxycarbonyl-1,2,3-triazol-1-yl) methyl-
90 mg of 2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester was obtained.

Infrared absorption spectrum (CHCl ₃ ) ν _{C = 0} (cm ⁻¹ ) = 1780, 1750 (sh) 1735 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm) 1.34 (s, 3H) 3.09 (dd, 1H, J = 2,16Hz) 3.57 (dd, 1H, J = 4,16Hz) 3.90 (s, 6H), 4.88 (s, 2H) 5.11 (s, 1H) 5.20 (s, 2H), 5.15-5.35 (m, 1H) 7.43 (d, 2H, aromatic) 8.10 (d, 2H, aromatic) Example 4 2β- (4-p-nitrobenzyloxycarbonyl-1,
2,3-Triazol-2-yl) methyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester, 2β- (5-p-nitrobenzyloxycarbonyl-1,2,3-triazol-1-yl) Methyl 2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester and 2β- (4-p-nitrobenzyloxycarbonyl-1,2,3-triazol-1-yl) methyl-2
Production of α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester The reaction was carried out in the same manner as in Example 2, and 2β
-(4-p-nitrobenzyloxycarbonyl-1,2,3
-Triazol-2-yl) methyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 13
0 mg was obtained.

Infrared absorption spectrum (CHCl ₃ ) ν _{C = 0} (cm ⁻¹ ) = 1780, 1740 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm) = 1.32 (s, 3H) 3.12 (dd, 1H, J = 2, 16Hz) 3.66 (dd, 1H, J = 4, 16Hz) 4.65 (s, 2H) 5.22 (s, 2H), 5.15-5.50 (m, 2H) 5.45 (s, 2H) 7.30-8.30 (m, 9H, aromatic Next, 2β- (5-p-nitrobenzyloxycarbonyl-1,2,3-triazol-1-yl) methyl-2α-methylpenam-3α-carboxylic acid was used as the second eluate.
50 mg of p-nitrobenzyl ester were obtained.

Infrared absorption spectrum (CHCl ₃ ) ν _{C = 0} (cm ⁻¹ ) = 1780, 1740 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm) = 1.36 (s, 3H) 3.03 (dd, 1H, J = 2, 16Hz) 3.55 (dd, 1H, J = 4,16Hz) 5.00,5.10 (AB-q, 2H, J = 14Hz) 5.21 (s, 2H), 5.15-5.45 (m, 2H) 5.39 (s, 2H) 7.30 −8.30 (m, 9H, aromatic) Further, as a third eluate, 2β- (4-p-nitrobenzyloxycarbonyl-1,2,3-triazol-1-yl) methyl-2α-methylpenam-3α-carboxyl acid
75 mg of p-nitrobenzyl ester were obtained.

Infrared absorption spectrum (CHCl ₃ ) ν _{C = 0} (cm ⁻¹ ) = 1780, 1750 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm) = 1.40 (s, 3H) 3.11 (dd, 1H, J = 2, 163) 3.63 (dd, 1H, J = 4,16Hz) 4.63 (s, 2H), 4.84 (s, 1H) 5.10 (m, 2H) 5.40 (s, 2H) 7.20-8.35 (m, 9H, aromatic Example 5 The following compounds were synthesized in the same manner as in Example 2.

1) 2β- (4-p-methylbenzyloxycarbonyl-1,2,3-triazol-2-yl) methyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester, 2β- (5-p-methyl Benzyloxycarbonyl-1,
2,3-triazol-1-yl) methyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester, 2β- (4-p-methylbenzyloxycarbonyl-1,
2,3-triazol-1-yl) methyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 2) 2β- (4-p-chlorobenzyloxycarbonyl-1,2,3-triazol-2-yl ) Methyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester, 2β- (5-p-chlorobenzyloxycarbonyl-1,
2,3-triazol-1-yl) methyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester, 2β- (4-p-chlorobenzyloxycarbonyl-1,
2,3-triazol-1-yl) methyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 3) 2β- (4-benzyloxycarbonyl-1,2,3-
Triazol-2-yl) methyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester, 2β- (5-benzyloxycarbonyl-1,2,3-triazol-1-yl) methyl-2α-methylpenam-3
α-carboxylic acid p-nitrobenzyl ester, 2β- (4-benzyloxycarbonyl-1,2,3-triazol-1-yl) methyl-2α-methylpenam-3
Example 6 Preparation of 2β- (4-phenyl-1,2,3-triazol-2-yl) methyl-2α-6 methylpenam-3α-carboxylic acid p-nitrobenzyl ester Example 6 The reaction was carried out in the same manner as in Example 1 to give 2β- (4-phenyl-
75 mg of 1,2,3-triazol-2-yl) methyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester were obtained.

Infrared absorption spectrum (CHCl ₃ ) ν _{C = 0} (cm ⁻¹ ) = 1780, 1750 (sh) Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm) = 1.30 (s, 3H) 3.14 (dd, 1H, J) = 2,16Hz) 3.65 (dd, 1H, J = 4,16Hz) 4.65 (s, 2H), 5.15 (s, 2H) 5.34 (dd, 1H, J = 2,4Hz) 5.65 (s, 1H) 7.15− 7.90 (m, 7H, aromatic) 7.91 (s, 1H, aromatic) 8.13 (d, 2H, aromatic) Example 7 2β- (4-formyl-1,2,3-triazole-2- Yl) methyl-2α-methylpenam-3α-carboxylic acid
Production of p-nitrobenzyl ester The reaction was carried out in the same manner as in Example 1 to give 2β- (4-formyl-
76 mg of 1,2,3-triazol-2-yl) methyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester were obtained.

Infrared absorption spectrum (CHCl ₃ ) ν _{C = 0} (cm ⁻¹ ) = 1780, 1750, 1700 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm) = 1.30 (s, 3H) 3.12 (dd, 1H, J = 2,16 Hz) 3.76 (dd, 1H, J = 4, 16 Hz) 4.72 (s, 2H), 5.22 (s, 2H) 5.33 (dd, 1H, J = 2, 4 Hz) 5.45 (s, 1H) 7.43 (d , 2H, aromatic) 8.03 (s, 1H, aromatic) 8.15 (d, 2H, aromatic) 10.00 (s, 1H) Example 8 2β- (4,5-dimethoxycarbonyl-1,2, 3-triazol-2-yl) methyl-2α-methylpenam-3α-
Preparation of carboxylic acid 1,1-dioxide p-nitrobenzyl ester 2β- (4,5-dimethoxycarbonyl-1,2,3-triazol-2-yl) methyl-2α-methylpenam-3α
-167 mg of p-nitrobenzyl carboxylate was dissolved in 3 ml of acetic acid, 1 ml of water was added, and 136 mg of potassium permanganate was added little by little under ice-cooling and stirring. The mixture was returned to room temperature and stirred for 4 hours. Next, 30% aqueous hydrogen peroxide was added under ice-cooling and stirring until the color of the reaction solution became colorless. Dichloromethane and water were added for extraction, and the dichloromethane layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and 2β- (4,5-dimethoxycarbonyl-1,2
168 mg of 2,3-triazol-2-yl) methyl-2α-methylpenam-3α-carboxylic acid 1,1-dioxide p-nitrobenzyl ester were obtained.

Infrared absorption spectrum (Neat) ν _{C = 0} (cm ⁻¹ ) = 1800, 1760, 1740 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm) = 1.40 (s, 3H) 3.57 (d, 2H, J = 3 Hz) ) 3.98 (s, 6H) 4.67 (t, 1H, J = 3 Hz) 5.05 (s, 3H), 5.22 (s, 2H) 7.48 (d, 2H, aromatic) 8.21 (d, 2H, aromatic) Example 9 2β- (4-p-nitrobenzyloxycarbonyl-1,
Preparation of 2,3-triazol-2-yl) methyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 1-oxide 2β- (4-p-nitrobenzyloxycarbonyl-)
1,2,3-Triazol-2-yl) methyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 41 mg, 30% aqueous hydrogen peroxide 16 μ, formic acid 10 mg in methylene chloride 0.4 ml at room temperature for 2.5 hours Stirred. After washing with water and drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to give 2β- (4-
p-nitrobenzyloxycarbonyl-1,2,3-triazol-2-yl) methyl-2α-methylpenam-3α
-Carboxylic acid p-nitrobenzyl ester 1-oxide 40 mg was obtained.

Infrared absorption spectrum (CHCl ₃ ) ν _{C = 0} (cm ^-1 ) = 1782, 1740 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm) = 0.86 (s, 3H) 3.42-3.46 (m, 2H) 4.67 ( (s, 1H), 4.82-44.97 (m, 1H) 5.12, 5.32 (AB-q, 2H, J = 14.7Hz) 5.37 (d, 2H, J = 2.6Hz) 5.50 (s, 2H) 7.63 (d, 4H) , J = 9 Hz) 8.16 (s, 1H) 8.26 (d, 2H, J = 9 Hz) 8.28 (d, 2H, J = 9 Hz)

 ────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Naoshi Obayashi 3334-4 Asahimachi, Honjo City, Saitama Prefecture (56) References JP-A-61-226087 (JP, A) JP-A-60-214792 (JP, A) JP-A-60-84291 (JP, A) JP-A-59-118790 (JP, A) JP-A-59-148788 (JP, A)

Claims (1)

(57) [Claims] (1) General formula (In the formula, n represents 0, 1, or 2. R represents R ¹ and R ² are the same or different, a hydrogen atom, a lower alkyl group, a phenyl group, a lower alkoxycarbonyl group, a formyl group, a benzyloxycarbonyl group or a halogen atom, a lower alkyl group or a nitro group as a substituent. A benzyloxycarbonyl group. However, R ¹ and R ² are not hydrogen atoms at the same time, and when n is 2, R is A 2β-triazolylpenicilanic acid derivative represented by
Its salts and esters.