JP2599595B2 - 2β-substituted methylpenicillanic acid derivatives, salts and esters thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION INDUSTRIAL APPLICATION The 2β-substituted methylpenicillanic acid derivatives, salts and esters thereof of the present invention are all novel compounds, which have β-lactamase inhibitory activity, -Useful as 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 the action of β-lactamase or to minimize the action. 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 inhibitory effect of the compound is insufficient, and therefore, there is a need for the development of a compound having more excellent β-lactamase inhibitory activity.

The present inventors have conducted intensive studies in view of the above-mentioned problems of the prior art, and as a result, the 2β-substituted methylpenicillanic acid derivative represented by the following general formula (I), its salt and ester are superior to β-lactamase. They have found that they have an inhibitory effect, and have completed the present invention.

DISCLOSURE OF THE INVENTION The present invention relates to novel 2β-substituted methylpenicillanic acid derivatives, salts and esters thereof.

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

(In the formula, n represents 0, 1 or 2.

May have a substituent selected from an alkyl group, an alkoxycarbonyl group, a halogen atom and a nitro group,
A monocyclic or bicyclic heterocyclic group having 2 to 4 nitrogen atoms as a hetero atom is shown. However, a 1,2,3-triazolyl group is excluded. In the present specification, Examples of the nitrogen-containing heterocyclic group represented by, pyrrolyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, benzotriazolyl, benzimidazolyl, tetrazolyl and the like are exemplified.These nitrogen-containing heterocyclic groups are methyl, A linear or branched alkyl group having 1 to 6 carbon atoms such as ethyl or a methoxycarbonyl group or an ethoxycarbonyl group having 2 carbon atoms;
To 7 alkoxycarbonyl groups, furthermore, fluorine, chlorine,
It may have a substituent such as a halogen atom such as bromine or iodine or a nitro group.

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 vivo. Such esters and protecting groups forming the esters are described in, for example, JP-A-49-81.
No. 380 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. Representative examples thereof include, for example, a substituted or unsubstituted alkyl group such as a methyl, ethyl, propyl, butyl, tert-butyl, trichloroethyl group;
Benzyl, diphenylmethyl, p-nitrobenzyl, p
A substituted or unsubstituted aralkyl group such as -methoxybenzyl;
Acyloxyalkyl groups such as acetoxymethyl, acetoxyethyl, propionyloxyethyl, pivaloyloxymethyl, pivaloyloxypropyl, benzoyloxymethyl, benzoyloxyethyl, benzylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl and the like; methoxymethyl, ethoxymethyl An alkoxyalkyl group such as benzyloxymethyl; a 3-phthalidyl group,
4-crotonolactonyl group, γ-butyrolactone-4-
A lactone such as an yl group and a substituted or unsubstituted phenyl group; other (2-oxo-1,3-dioxoden-4-yl) methyl groups, (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. it can.

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 having an increased antibacterial activity in combination with the compound of the present invention include common penicillins such as ampicillin, amoxicillin, hetacillin, cyclacillin, mesilinam, carbenillin, sulbenicillin, ticarcillin, piperacillin, aparcillin, methicillin, mezlocillin, and the like. Salts and bacampicillin, calandacillin, tarampicillin, calampicillin, esters such as pibumecilinam and cephalosporins, such as cephaloridin, cephalotin, cephapirin, cefacetryl, cefazolin, cephalexin, cefradine, cefotiam, cephamandol, cefuroxime,
Antibacterial activity against various gram-positive bacteria and gram-negative bacteria such as cefoxime, cefmetazole, cefthrosin, cefoperazone, cefotaxime, ceftizoxime, cefmenoxime, ratamoxef, cefaclor, cefloxazine, cefatrizine, cefadroxil, cephalogiricin, and salts thereof. 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 schemes.

(In each of the above formulas, X represents a chlorine atom or a bromine atom, R represents a pinicillin carboxyl protecting group, Is the same as above. The penicillin carboxyl-protecting group represented by R in the above may be a commonly known one, and specifically,
For example, any of those described in JP-A-49-81380 and cephalosporins and penicillins, chemistry and biology (edited by Academic Press in 1972), edited by H, E and Fline can be used. Preferred R 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 penum derivative represented by the general formula (II) and the general formula Is reacted with a heterocyclic compound represented by the formula (I) in the presence or absence of a base to obtain a compound represented by the formula (Ia). In this reaction, a known penum derivative represented by the general formula (II) (see JP-A-58-4788) is used in an appropriate solvent in an amount of about 1 to 50 molar equivalents, preferably about 1 molar equivalent, per 1 mol of the derivative. Reacting with 10 to 30 molar equivalents of the heterocyclic compound represented by the general formula (III),
The reaction is carried out by reacting the compound of the general formula (III) in the presence of a base or a metal salt in an amount of about 0.5 to 2 molar equivalents per mol. Examples of the base or metal salt include alkali metal carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate, and cesium carbonate; alkaline earth metal carbonates such as barium carbonate and calcium carbonate; and copper group metal carbonates such as silver carbonate and copper carbonate. Oxidizes salts, copper group metal oxides such as copper oxide and silver oxide, alkaline earth metal oxides such as magnesium oxide, calcium oxide and barium oxide, and zinc group metal oxides such as zinc oxide and mercury oxide. Aluminum and metal oxides such as aluminum and thallium oxide, carbon group metal oxides such as tin oxide and lead oxide, iron group metal oxides such as iron oxide, cobalt oxide and nickel oxide, copper hydroxide and hydroxide Examples thereof include copper group metal hydroxides such as silver, organic amines such as pyridine, triethylamine and diisopropylethylamine, and anion exchange resins.

The solvent is not particularly limited as long as it does not affect the reaction, for example, acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, nitromethane, tetrahydrofuran, dioxane, methanol,
Various organic solvents such as ethanol and methoxyethanol
A single solvent, a mixture of two or more thereof, or a mixed solvent of an organic solvent and water 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. Such an oxidizing agent may be used in a large excess, but is 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, by appropriately selecting the reaction conditions, the oxidizing agent and the number of moles to be used, the intermediate sulfoxide represented by the general formula (Ib) can be obtained. 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.

The general formula (I-
Each compound represented by a), (Ib) or (Ic) is an object of the present invention, that is, a compound represented by the general formula (I), depending on the type of the pinicillin carboxy protecting group represented by R ¹ of the compound. May be an ester which is hydrolyzed in vivo of the penicillanic acid derivative represented by the formula (I). More preferably, the esterification reaction is usually followed by a de-esterification reaction as shown in step C to give a compound represented by the general formula (I ') of the present invention. Then, if necessary, it is converted into a pharmaceutically acceptable salt or an ester which is hydrolyzed in vivo according to a conventional method.

<Step C> The compound represented by the general formula (Ic) is subjected to a deesterification reaction, with or without isolation by the reaction system of the step B, to obtain a penicillanic acid represented by the general formula (I '). Obtain the derivative.

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, when the pinicillin carboxyl protecting group represented by R 'is trichloroethyl, benzyl, diphenylmethyl, p-nitrobenzyl, or the like, a reduction method 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 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. As
In the case of the above-described catalytic reduction, for example, as a catalyst, white bacteria, white oxidized bacteria, palladium, palladium oxide, palladium barium sulfate, palladium calcium carbonate, palladium carbon,
Nickel oxide, Raney nickel and the like are exemplified. The solvent is not particularly limited as long as it does not affect the reaction.Examples include alcohols such as methanol and 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 acid method 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-toluenesulfone. Examples thereof include organic sulfonic acids such as acids, and mixtures thereof. The above reaction using an acid does not require any other solvent when using a liquid acid.However, a solvent such as dimethylformamide, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, and acetone that does not adversely affect the reaction is used. It is also possible to implement using.

The thus obtained free 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.

When the ester residue is, for example, a 3-phthalidyl group, a 4-crotonolactonyl group or a γ-butyrolactone-4-yl group, the pinicillin derivative represented by the general formula (I ′) is converted to a 3-halogenated phthalide. , 4-halogenated crotonolactone group, 4-halogenated γ-butyrolactone and the like. Here, chlorine, bromine and iodine are used as the halogen in the halide. The reaction is carried out by dissolving a salt of a penicillin derivative represented by the general formula (I ') in a suitable polar solvent such as N, N-dimethylformamide, and adding about an equimolar amount of a halide. . The reaction temperature is usually 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.

After completion of the reaction in each step, the target compound obtained in each of the above steps, and the penicillin derivative of the present invention, a pharmaceutically acceptable salt and ester thereof, are separated and collected according to a conventional method. It can be purified by layer chromatography, column chromatography and the like.

 Next, the present invention will be described more specifically with reference to examples.

EXAMPLES Example 1 2α-Methyl-2β- (tetrazol-1-yl) methylpenam-3α-carboxylic acid p-nitrobenzyl ester and 2α-methyl-2β- (tetrazol-2-yl) methylpenam-3α-carboxylic acid Preparation of p-nitrobenzyl ester 2β-chloromethyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 185 mg, potassium hydrogencarbonate 50 mg and tetrazole 105 mg in acetone 3.75 m
l and 1.25 ml of water were stirred at 30 ° C for 12 hours. The reaction solution was evaporated under reduced pressure, and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and 2α-methyl-2β- (tetrazol-2-yl) methylpenam-3α-carboxylic acid p was used as the first eluate.
-71 mg of nitrobenzyl ester were obtained.

Infrared absorption spectrum (CHCl ₃ ) ν _{C = 0} = 1780 cm ⁻¹ , 1750 cm ⁻¹ Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm) = 1.29 (s, 3H) 3.15 (dd, 1 H, J = 2, 16 Hz) ) 3.67 (dd, 1H, J = 4, 16 Hz) 4.87 (s, 2H), 5.23 (s, 2H) 5.36 (s, 1H) 5.30-5.45 (m, 1H) 7.46 (d, 2H), 8.16 (d , 2H) 8.53 (s, 1H) Next, 66 mg of 2α-methyl-2β- (tetrazol-1-yl) methylpenam-3α-carboxylic acid p-nitrobenzyl ester was obtained as a second eluate.

Infrared absorption spectrum (CHCl ₃ ) ν _{C = 0} = 1770 cm ⁻¹ , 1745 cm ⁻¹ Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm) = 1.41 (s, 3H) 3.17 (dd, 1 H, J = 2, 16 Hz) ) 3.69 (dd, 1H, J = 4, 16 Hz) 4.67 (s, 2H), 4.84 (s, 1H) 5.24 (s, 2H) 5.38 (dd, 1H, J = 2, 4 Hz) 7.43 (d, 2H) , 8.13 (d, 2H) 8.82 (s, 1H) Example 2 Preparation of 2β- (imidazol-1-yl) methyl 2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 2β-chloromethyl-2α-methylpenam- 3α-carboxylic acid p-nitrobenzyl ester 185 mg, silver carbonate 1
38 mg and 68 mg of imidazole were stirred in 1.5 ml of acetonitrile and 0.5 ml of water at 30 ° C. for 5 hours. The reaction solution was passed through celite while washing with ethyl acetate, and the solution was washed with water and brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to give 2β- (imidazol-1-yl) methyl 2α
68 mg of -methylpenam-3α-carboxylic acid p-nitrobenzyl ester were obtained.

Infrared absorption spectrum (CHCl ₃ ) ν _{C = 0} = 1773 cm ⁻¹ , 1750 cm ⁻¹ Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm) = 1.37 (s, 3H) 3.13 (dd, 1 H, J = 2, 16 Hz) 3.69 (dd, 1H, J = 4, 16Hz) 4.16 (s, 2H), 4.69 (s, 1H) 5.22 (s, 2H) 5.36 (dd, 1H, J = 2, 4Hz) 7.01 (d, 2H) 7.45 (d, 2H) 7.51 (s, 1H), 8.16 (d, 2H) Example 3 2α-Methyl-2β- (1,2,4-triazol-1-yl) methylpenam-3α-carboxylic acid 9- Production of nitrobenzyl ester As in Example 2, 185 mg of 2β-chloromethyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester was reacted with 1,2,4-triazole to give 2α.
-Methyl-2β- (1,2,4-triazol-1-yl)
60 mg of methylpenam-3α-carboxylic acid p-nitrobenzyl ester were obtained.

Infrared absorption spectrum (CHCl ₃ ) ν _{C = 0} = 1770 cm ⁻¹ , 1745 cm ⁻¹ Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm) = 1.39 (s, 3H) 3.15 (dd, 1 H, J = 2, 16 Hz) 3.70 (dd, 1H, J = 4, 16 Hz) 4.39 (s, 2H), 5.14 (s, 1H) 5.26 (s, 2H) 5.43 (dd, 1H, J = 2, 4 Hz) 7.49 (d, 2H) , 7.96 (S, 1H) 8.17 (s, 1H), 8.20 (d, 2H) Example 4 As in Example 2, 2β-chloromethyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 185 mg and benzoyl Reaction with 119 mg of triazole,
2β- (benzotriazol-1-yl) methyl-2α
77 mg of -methylpenam-3α-carboxylic acid p-nitrobenzyl ester were obtained.

Infrared absorption spectrum (CHCl ₃ ) ν _{C = 0} = 1775 cm ⁻¹ , 1750 cm ⁻¹ Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm) = 1.43 (s, 3H) 3.14 (dd, 1H, J = 2, 16 Hz) 3.68 (dd, 1H, J = 4, 16 Hz) 4.86 (s, 2H), 5.20 (s, 3H) 5.37 (dd, 1H, J = 2, 4 Hz) 7.30-8.30 (m, 8H) Example 52α Preparation of -methyl-2β- (1,2,4-triazol-1-yl) methylpenam-3α-carboxylic acid p-nitrobenzyl ester 2β-chloromethyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 370 mg And 1,2,4-
1.38 g of triazole was dissolved in 3 ml of acetonitrile and 1 ml of water.
The mixture was stirred at 0 ° C for 5 hours. The reaction solution was diluted with ethyl acetate, and the solution was washed with aqueous sodium hydrogen carbonate and brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to give 2α-methyl-2β
-(1,2,4-triazol-1-yl) methylpenam-
3α-carboxylic acid p-nitrobenzyl ester 166 mg
I got

The infrared absorption spectrum and nuclear magnetic resonance spectrum of this compound were consistent with those obtained in Example 3.

Example 6 Preparation of 2α-methyl-2β- (pyrazol-1-yl) methylpenam-3α-carboxylic acid p-nitrobenzyl ester 2β-chloromethyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester 1.111 g, 3.06 g of pyrazole, anion exchange resin (Diaion WA30,
833mg in acetonitrile 9ml and water 3ml 4
Stirred at 0 ° C. for 1 hour. Have an anion exchange resin,
The liquid was separated between methylene chloride and water. The separated methylene chloride layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to give 2α-methyl-2β- (pyrazol-1-yl).
405 mg of methyl penam-3α-carboxylic acid p-nitrobenzyl ester were obtained.

Infrared absorption spectrum (KBr) ν _{C = 0} = 1780 cm ⁻¹ , 1742 cm ⁻¹ Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm) = 1.35 (s, 3H) 3.17 (dd, 1H, J = 2, 16 Hz) 3.64 (dd, 1H, J = 4, 16 Hz) 4.35 (s, 2H), 5.26 (s, 2H) 5.29 (s, 1H) 5.35-5.41 (m, 1H) 6.26-6.30 (m, 1H) 7.46-7.56 (M, 4H) 8.21 (d, 2H) Example 7 Preparation of 2α-methyl-2β- (pyrazol-1-yl) methylpenam-3α-carboxylic acid p-nitrobenzyl ester-1-oxide 2α-methyl-2β- 22 mg of (pyrazol-1-yl) methylpenam-3α-carboxylic acid p-nitrobenzyl ester, 13 mg of 30% aqueous hydrogen peroxide and 10 mg of formic acid were stirred at room temperature for 4 hours in 0.3 ml of methylene chloride. After washing with water, the extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to give 2α-methyl-
2β- (pyrazol-1-yl) methylpenam-3α-
20 mg of carboxylic acid p-nitrobenzyl ester-1-oxide were obtained.

Infrared absorption spectrum (CHCl ₃ ) ν _{C = 0} = 1802 cm ⁻¹ , 1748 cm ⁻¹ Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm) = 1.00 (s, 3H) 3.39-3.40 (m, 2H) 4.52-5.06 (M, 4H) 5.36 (s, 2H) 6.28-6.33 (m, 1H) 7.52-7.65 (m, 4H) 8.27 (d, 2H) Example 8 2α-methyl-2β- (pyrazol-1-yl) methylpenam Preparation of -3α-carboxylic acid p-nitrobenzyl ester-1,1-dioxide 2α-methyl-2β- (pyrazol-1-yl) methylpenam-3α-carboxylic acid p-nitrobenzyl ester 300 mg, 70% m-chloroperoxide Benzoic acid (552 mg) was stirred in methylene chloride (3 ml) at 40 ° C. for 4 hours. The extract was washed with aqueous sodium hydrogen carbonate, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
The residue was subjected to silica gel column chromatography,
276 mg of α-methyl-2β- (pyrazol-1-yl) methylpenam-3α-carboxylic acid p-nitrobenzyl ester-1,1-dioxide were obtained.

Infrared absorption spectrum (CHCl ₃ ) v _{C = 0} = 1802 cm ^-1 , 1760 cm ^-1 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm) = 1.31 (s, 3H) 3.50-3.53 (m, 2H) 4.55-4.96 (M, 4H) 5.31 (s, 2H) 6.27-6.32 (m, 1H) 7.35-7.62 (m, 4H) 8.24 (d, 2H) Example 9 2β- (imidazol-1-yl) methyl-2α-methylpenam Preparation of -3α-carboxylic acid p-nitrobenzyl ester-1,1-dioxide 2β- (imidazol-1-yl) methyl-2α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester (1.04 g) in acetone (28 ml) and water (5.7) Dissolve in ml and add acetic acid
5.7 ml was added. Next, 830 mg of potassium permanganate was gradually added under ice-cooling and stirring, followed by stirring at room temperature for 3 hours. Then, 30% aqueous hydrogen peroxide was added until the color of the reaction solution disappeared, and the mixture was extracted with methylene chloride. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography to give 2β- (imidazol-1-yl) methyl-2
640 mg of α-methylpenam-3α-carboxylic acid p-nitrobenzyl ester-1,1-dioxide were obtained.

Infrared absorption spectrum (KBr) ν _{C = 0} = 1808 cm ⁻¹ , 1770 cm ⁻¹ Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm) = 1.29 (s, 3H) 3.54-3.58 (m, 2H) 4.38, 4.76 ( 1H AB, J = 15Hz) 4.52 (s, 1H) 4.58−4.74 (m, 1H) 6.98 (s, 1H) 7.08 (s, 1H) 7.47 (s, 1H) 7.55,8.27 (each d 2H) Implementation Example 10 Preparation of 2β- (imidazol-1-yl) methyl-2α-methylpenam-3α-carboxylic acid 1,1-dioxide sodium salt 2β- (imidazol-1-yl) methyl-2α-methylpenam-3α-carboxylic acid p -Nitrobenzyl ester 1,1-dioxide (640 mg) in ethyl acetate (50 ml) and water (50)
Hydrogenation was carried out at room temperature under low pressure using 320 mg of 10% palladium carbon in the presence of 123 mg of sodium hydrogen carbonate in ml. Two hours later, the palladium carbon was separated, and the aqueous layer was separated from the liquid. The aqueous layer was lyophilized and then purified by MCI gel column chromatography. The eluate was freeze-dried to obtain 580 mg of the above-mentioned target substance as white powder.

Infrared absorption spectrum (KBr) ν _{C = 0} = 1785 cm ⁻¹ , 1638 cm ⁻¹ Nuclear magnetic resonance spectrum (D ₂ O) δ (ppm) = 1.47 (s, 3H) 3.47 (dd, 1H, J = 1.3, 16.7) Hz) 3.70 (dd, 1H, J = 4, 16.7 Hz) 4.39 (s, 1H) 4.75, 4.95 (1H AB, J = 17 Hz each) 4.89-5.06 (m, 1H) 6.80-7.40 (2H, broad) 7.60 -8.00 (1H, broad) Example 11 Preparation of 2α-methyl-2β- (1,2,4-triazol-1-yl) methylpenam-3α-carboxylic acid p-nitrobenzyl ester-1,1-dioxide 2α -Methyl-2β- (1,2,4-triazole-1-
Il) Methylpenam-3α-carboxylic acid p-nitrobenzyl ester 820 mg was dissolved in acetone 22 ml and water 4.5 ml, and acetic acid 4.5 ml was added. Next, 645 mg of potassium permanganate was added under ice-cooling and stirring, followed by stirring at room temperature for 3 hours. Then, 30% aqueous hydrogen peroxide was added until the color of the reaction solution disappeared,
Extracted with methylene chloride. After drying over sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography to obtain 520 mg of 2α-methyl-2β- (1,2,4-triazol-1-yl) methylpenam-3α-carboxylic acid p-nitrobenzyl ester-1,1-dioxide.

Infrared absorption spectrum (KBr) ν _{C = 0} = 1800 cm ⁻¹ , 1720 cm ⁻¹ Nuclear magnetic resonance spectrum (CDCl ₃ ) δ (ppm) = 1.37 (s, 3H) 3.54-3.58 (m, 2H) 4.61-4.68 ( m, 1H) 4.72, 4.85 (AB-q, 2H, J = 12Hz) 4.77 (s, 1H) 7.57 (d, 2H) 7.96 (s, 1H) 8.28 (d, 2H) 8.30 (s, 1H) 12 Production of 2α-methyl-2β- (1,2,4-triazol-1-yl) methylpenam-3α-carboxylic acid 1,1-dioxide sodium salt 2α-methyl-2β- (1,2,4-triazole -1-
Il) Methylpenam-3α-carboxylic acid p-nitrobenzyl ester-1,1-dioxide (274 mg) in ethyl acetate (40)
Hydrogenation was performed at room temperature under low pressure using 140 mg of 10% palladium on carbon in the presence of 53 mg of sodium hydrogen carbonate in 40 ml of water and 40 ml of water. Two hours later, the palladium carbon was separated, and the aqueous layer was separated from the liquid. The aqueous layer was lyophilized and then purified by MCI gel column chromatography. The eluate was lyophilized to a white powder 140mg is the desired product Infrared absorption spectrum _{(KBr) ν C = 0 =} 1785cm -1, 1630cm -1 NMR spectrum _{(CDCl 3) δ (ppm)} = 1.47 (s, 3H) 3.51 (dd, 1H, J = 1.8 Hz, J = 16.7 Hz) 3.70 (dd, 1H, J = 4.2 Hz, J = 16.7 Hz) 4.50 (s, 1H) 5.00, 5.17 (AB- q, 2H, J = 15.4Hz) 4.98-5.16 (m, 1H) 8.14 (s, 1H) 8.65 (s, 1H)

 ──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Tomoyasu Ohno 4-7-20 Higashidai, Honjo City, Saitama Prefecture (56) References JP-A-63-112588 (JP, A) JP-A-61-1226087 (JP, A) JP-A-64-66189 (JP, A) JP-A-60-215688 (JP, A) JP-A-58-225091 (JP, U) JP-A-1-224377 (JP, U)

Claims (1)

(57) [Claims] (1) General formula (In the formula, n represents 0, 1 or 2. May have a substituent selected from an alkyl group, an alkoxycarbonyl group, a halogen atom and a nitro group,
A monocyclic or bicyclic heterocyclic group having 2 to 4 nitrogen atoms as a hetero atom is shown. However, a 1,2,3-triazolyl group is excluded. 2) -substituted penicillanic acid derivatives represented by the following formulas: