JPH0560838B2 - - Google Patents

Description

[Detailed description of the invention]

[Object of the invention] The present invention provides novel 3-
(quinuclidinio)methyl-3-cephem derivatives. Conventionally, many compounds having a substituted thiadiazolyl acetamide group or a substituted thiazolyl acetamide group at the 7-position of the cefem skeleton are known. For example, JP-A-55-11600, JP-A-55-105689,
JP-A-57-24389, JP-A-57-81493, JP-A-Sho
No. 58-41887, JP-A-58-59992, JP-A-59-
No. 219292, JP-A-51-149296, JP-A-52-
No. 102293, JP-A-52-116492, JP-A-52-
No. 125190, Japanese Patent Application Publication No. 154786, Japanese Patent Application Publication No. 1987-
Examples include compounds described in publications such as No. 192394. However, no compound having a (4-carbamoyl-1-quinuclidinio)methyl group at the 3-position of its cefem skeleton is known. The present inventors have discovered that a compound having the above-mentioned group at the 3-position has excellent antibacterial activity. The compound of the present invention is a novel synthetic intermediate thereof. Therefore, an object of the present invention is to provide a novel compound useful as an intermediate for antibacterial agents and a method for producing the same. [Structure of the invention] The present invention is based on the general formula [In the formula, n represents 0 or 1, R ₁ and R ₂
are both hydrogen atoms, R ₁ is a monovalent protecting group for an amino group, R ₂ is a hydrogen atom, or R ₁ and R ₂ are a divalent protecting group for an amino group, X is an anion, and R ₃
3-(quinuclidinio)methyl-3-cephem derivative represented by: when is ^-COO- , m is 0; when _R3 is _-COOR4 ( _R4 is a carboxyl group protecting group), m is 1] and its salt. As the monovalent protecting group for the amino group of R ₁ in the compound of the above general formula (), there are commonly used ones, such as formyl, acetyl, chloroacetyl, dichloroacetyl, propionyl, phenylacetyl, 2-thienylacetyl. , 2-furylacetyl, phenoxyacetyl, and other substituted or unsubstituted lower alkanoyl groups; benzyloxycarbonyl, t-butoxycarbonyl, p-nitrobenzyloxycarbonyl, and other substituted or unsubstituted lower alkoxycarbonyl groups; trityl , p
Examples include substituted lower alkyl groups such as -methoxybenzyl and diphenylmethyl; substituted silyl groups such as trimethylsilyl and t-butyldimethylsilyl. In addition, examples of the divalent protecting group for the amino group formed by R ₁ and R ₂ include benzylidene, salicylidene, 3,5-di(t-butyl)-4-hydroxybenzylidene, 3,5-di(t-butyl) ) Substituted or unsubstituted benzylidene groups such as benzylidene. As the protecting group for the carboxyl group of R ₄ , commonly used ones are used, such as methyl, ethyl, propyl, t-butyl, 2,2,2-trichloroethyl, valeryloxymethyl, pivaloyloxymethyl, p- Substituted or unsubstituted lower alkyl groups such as nitrobenzyl, p-methoxybenzyl and diphenylmethyl; substituted silyl groups such as trimethylsilyl and t-butyldimethylsilyl; and the like. Examples of the anion of X include halogen ions such as chlorine ion, bromide ion, and iodo ion; and inorganic acid ions such as sulfate ion and nitrate ion. Salts of the compound of general formula () include hydrochloride,
hydrobromide, hydroiodide, sulfate, carbonate,
Inorganic acid salts such as bicarbonate; organic carboxylate salts such as acetate, maleate, lactate, tartrate, trifluoroacetate; organic salts such as methanesulfonate, benzesulfonate, toluenesulfonate Sulfonate; Examples include amino acid salts such as aspartate and glutamate. The compound of the present invention can be produced by the method shown below. general formula [In the formula, n, R ₁ , R ₂ are the same as defined above, R ₅
is a hydrogen atom or a protecting group for a carboxyl group, and Y is a halogen atom or a lower alkanoyloxy group. The compound represented by formula () or a salt thereof is reacted, and if necessary, the protecting group is removed and/or the sulfoxide is reduced to obtain the compound represented by the general formula () or a salt thereof. The above reaction when Y in the general formula () is a halogen atom is carried out at a reaction temperature of -10°C to 50°C in an inert solvent such as acetone, tetrahydrofuran, N,N-dimethylformamide, methylene chloride, chloroform, or acetonitrile. can be done. In addition, the above reaction when Y in the general formula () is a lower alkanoyloxy group can be performed using, for example, chloroform, methylene chloride, tetrahydrofuran,
The reaction can be carried out in an inert solvent such as N,N-dimethylformamide, dioxane or acetone in the presence of iodotrimethylsilane at a reaction temperature of -20°C to 60°C. The protective group can be removed by conventional methods such as hydrolysis, reduction, or enzymatic hydrolysis depending on the type of protective group used. In addition, reduction of sulfoxide can be done by reacting phosphorus trichloride, etc.
This can be done by conventional methods. Examples of the halogen atom of Y in the compound of general formula () include a chlorine atom, a bromine atom, and an iodine atom. Examples of the lower alkanoyloxy group of Y include acetyloxy and propionyloxy. As the protecting group for the carboxyl group of R ₃ , the above-mentioned
Examples include the groups mentioned in the explanation of R ₄ . Moreover, as the group of the compound of general formula () and general formula (), any group can be used as long as it does not interfere with the above reaction. For example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; ammonium salts; hydrochlorides, sulfates, carbonates, bicarbonates, hydrobromides, hydrogen iodide Inorganic acid salts such as acid salts; acetate;
Organic carboxylates such as maleate, lactate, tartrate, trifluoroacetate; organic sulfonates such as methanesulfonate, benzenesulfonate, toluenesulfonate; trimethylamine salt, triethylamine salt, pyridine salt , procaine salt, picoline salt, dicyclohexylamine salt,
N,N'-dibenzylethylenediamine salt, N-
Amine salts such as methylglucamine salt, diethanolamine salt, triethanolamine salt, tris(hydroxymethylamino)methane salt; Among salts such as amino acid salts such as arginine salt, aspartate, lysine salt, glutamate, serine salt, etc. It can be selected as appropriate. Using the compound of the present invention as a synthetic intermediate, Part 7
Various groups, such as 2-
(5-amino-1,2,4-thiadiazole)-
By introducing a (Z)-2-methoxyiminoacetyl group or the like, a compound having excellent antibacterial activity can be obtained. EXAMPLES Next, the present invention will be explained in more detail with reference to Examples. Example 1 7β-formamide-3-(4-carbamoyl-1
-quinuclidinio)methyl-3-cephem-4-
carboxylate 7β-formamide-3-acetoxymethyl-
1.2 g of 3-cephem-4-carboxylic acid was suspended in 12 ml of methylene chloride, 815 µ of N-methyl-N-(trimethylsilyl)trifluoroacetamide was added, and the mixture was stirred for 30 minutes. After cooling on ice, 1.25 ml of iodotrimethylsilane was added, and after stirring for 5 minutes, the mixture was returned to room temperature and further stirred for 15 minutes. The solvent was distilled off under reduced pressure, the residue was dissolved in 12 ml of acetonitrile, and 616 mg of 4-carbamoylquinuclidine was added under ice cooling, followed by stirring for 1 hour. 3 ml of methanol and 300 ml of diethyl ether were added to the reaction solution, and the resulting precipitate was collected. This precipitate was purified by silica gel column chromatography [developing solvent: acetone-water (7:1) and (5:1)] to obtain 140 mg of the target product. Example 2 7β-tritylamino-3-(4-carbamoyl-
1-quinuclidinio)methyl-3-cephem-4
-carboxylate Dissolve 2.4 g of 7β-tritylamino-3-acetoxymethyl-3-cephem-4-carboxylic acid in 24 ml of methylene chloride, and add 960 μ of N-methyl-N-(trimethylsilyl) trifluoroacetamide.
was added and stirred for 30 minutes. After cooling on ice, 720μ of iodotrimethylsilane was added, and after stirring for 5 minutes, the mixture was returned to room temperature and further stirred for 15 minutes. The solvent was removed under reduced pressure. The residue was dissolved in 24 ml of acetonitrile, and 756 mg of 4-carbamoylquinuclidine was added under ice cooling, followed by stirring for 1 hour. 3.2ml of methanol to the reaction solution,
Then, 240 ml of diethyl ether was added and the resulting precipitate was collected. This precipitate was purified by silica gel column chromatography [developing solvent: acetone-water (7:1), (5:1) and (3:1)] to obtain 207 mg of the target product. Example 3 7β-(2-thienylacetamido)-3-(4-carbamoyl-1-quinuclidinio)methyl-3-
Cefem-4-carboxylate 7β-(2-Thienylacetamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid
6.0 g was suspended in 60 ml of methylene chloride, 3.08 ml of N-methyl-N-(trimethylsilyl)trifluoroacetamide was added, and the mixture was stirred for 30 minutes. After cooling on ice,
After adding 4.73 ml of iodotrimethylsilane and stirring for 5 minutes, the mixture was further stirred at room temperature for 15 minutes. The solvent was concentrated under reduced pressure, and the residue was dissolved in 60 ml of acetonitrile.
After cooling on ice, 2.3 g of 4-carbamoylquinuclidine was added and stirred for 1 hour. 6 ml of methanol was added to the reaction solution, and then 600 ml of diethyl ether was added dropwise.
After stirring for 1 hour, the resulting precipitate was collected and purified by silica gel column chromatography [developing solvent: acetone-water (7:1) and (5:1)] to obtain 700 mg of the desired product. Example 4 7β-amino-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate hydrochloride 130 mg of the compound obtained in Example 1 was suspended in 5 ml of methanol, 0.52 ml of concentrated hydrochloric acid was added at room temperature, and the mixture was stirred for 4 hours. The reaction solution was concentrated under reduced pressure and crystallized from diethyl ether-methanol to obtain 115 mg of the desired product. Example 5 7β-amino-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate hydrochloride 100 mg of the compound obtained in Example 2 was added to 50% formic acid 5
ml and stirred at room temperature for 3 hours and 30 minutes. 20 ml of water was added to this to remove insoluble matter, and the liquid was concentrated under reduced pressure. The residue was dissolved in 1 ml of 1N hydrochloric acid, and 5 ml of isopropanol and 10 ml of diethyl ether were added thereto. The precipitated crystals were collected, washed with n-hexane, and dried to obtain 45 mg of the desired product. Example 6 7β-amino-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate hydrochloride 600 mg of the compound obtained in Example 3 was suspended in 30 ml of methylene chloride, and 1.24 mg of N,N-dimethylaniline was suspended in 30 ml of methylene chloride.
ml and add 465μ of chlorotrimethylsilane;
The mixture was stirred at 30°C for 3 hours. Next, after cooling the reaction solution to -25°C, 1.27 g of phosphorus pentachloride was added and stirred for 1 hour. To this was added a cold solution of 1.3 ml of 1,3-butanediol in 25 ml of methylene chloride, and the mixture was stirred at the same temperature for 10 minutes. The reaction solution was heated to 0° C. and stirred for an additional 40 minutes, and the resulting precipitate was collected. Add this to methanol 7
After removing the insoluble materials, 20 ml of methylene chloride and 20 ml of diethyl ether were added to the solution to collect the precipitated crystals to obtain 30 mg of the desired product. Example 7 t-Butyl 7β-amino-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate 1-oxide bromide Dissolve 600 mg of t-butyl 7β-amino-3-bromomethyl-3-cephem-4-carboxylate 1-oxide hydrobromide in 6 ml of N,N-dimethylformamide, add 456 mg of 4-carbamoylquinuclidine, In an argon gas stream,
Stirred at room temperature for 14 hours. Add 120 ml of diethyl ether to the reaction solution, collect the resulting precipitate, and add it to n
-Washing with hexane gave 580 mg of the desired product. Example 8 t-Butyl 7β-amino-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate bromide hydrochloride 570 mg of the compound obtained in Example 7 was dissolved in 10 ml of N,N-dimethylformamide, 500 µ of phosphorus trichloride was added at -25°C, and the mixture was stirred for 30 minutes. 50 ml of diethyl ether was added to the reaction solution, and the liberated oil was separated, washed with 10 ml of diethyl ether, and then dried under reduced pressure to obtain 164 mg of the desired product. Example 9 7β-amino-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate 1.5 ml of formic acid and 0.15 ml of concentrated hydrochloric acid were added to 150 mg of the compound obtained in Example 8 under ice cooling, stirred for 4 hours, and then concentrated under reduced pressure. The residue was dissolved in 5 ml of ice water and neutralized with sodium bicarbonate. This was purified by reverse phase silica gel column chromatography (developing solvent: water) to obtain 60 mg of the target product. Example 10 p-methoxybenzyl 7β-phenylacetamide-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate iodide p-Methoxybenzyl 7β-phenylacetamido-3-chloromethyl-3-cephem-4-
Suspend 980 mg of carboxylate in 20 ml of acetone,
362 mg of sodium iodide was added and stirred at room temperature for 1 hour. To this was added 313 mg of 4-carbamoylquinuclidine under ice cooling, and the mixture was stirred for 2 hours. The reaction solution was filtered, and 70 ml of diethyl ether was added to the solution. The precipitated crystals were collected to obtain 500 mg of the target product. Example 11 p-methoxybenzyl 7β-formamide-3
-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate iodide p-methoxybenzyl 7β-formamide-
To 465 ml of a solution of 9.3 g of 3-iodomethyl-3-cephem-4-carboxylate in ethyl acetate was added 176 ml of a solution of 2.94 g of 4-carbamoylquinuclidine in methanol-ethyl acetate (1:4 V/V) under ice-cooling and stirring. It dripped over time. After stirring for 30 minutes, the resulting precipitate was collected and washed with ethyl acetate and then diisopropyl ether to obtain 12.0 g of the desired product. Example 12 7β-formamide-3-(4-carbamoyl-1
-quinuclidinio)methyl-3-cephem-4-
carboxylate 11.8 g of the compound obtained in Example 11 was dissolved in 50 ml of ice-cooled formic acid, and then stirred at room temperature for 10 hours. The reaction solution was filtered, and the solution was dropped into 100 ml of acetone. Furthermore, 200 ml of diisopropyl ether was added dropwise to the same solution, and the resulting precipitate was collected and washed with acetone. The precipitate was dissolved in 30 ml of dimethylformamide, and the solution was dropped into 150 ml of acetone. The resulting precipitate was collected, washed with acetone and diisopropyl ether, and dried under reduced pressure to obtain 6.66 g of the desired product. Example 13 p-methoxybenzyl 7β-benzylideneamino-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate iodide 5.5 g of p-methoxybenzyl 7β-benzylideneamino-3-iodomethyl-3-cephem-4-carboxylate was dissolved in 330 ml of ethyl acetate. Add 4-carbamoylquinuclidine to this solution.
1.39g methanol-ethyl acetate (17ml, 68ml)
The solution was added dropwise over 35 minutes under ice cooling. After stirring for 10 minutes, the resulting crystals were collected and washed with ethyl acetate.
After drying, 5.67 g of the target product was obtained. Example 14 7β-amino-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate hydrochloride p-Methoxybenzyl 7β-benzylideneamino-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate After dissolving 500 mg of iodide in 1 ml of formic acid, add 0.2 ml of concentrated hydrochloric acid and stir at room temperature for 16 hours. Stirred. 20 ml of acetone was added to the reaction solution, and the precipitated crystals were collected. After washing this with acetone and drying it, the target material is
Obtained 330 mg. Example 15 7β-phenylacetamido-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate p-Methoxybenzyl 7β-phenylacetamide-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate 13.46 g of iodide was ice-cooled and 67 ml of formic acid was added.
The mixture was stirred at room temperature for 23 hours and then at 30°C for 1 hour. The reaction solution was dropped into 2.5 liters of acetone. 500 ml of ethyl ether was added dropwise to this, and the resulting precipitate was collected. This was washed with acetone and diethyl ether and air-dried to obtain 6.09 g of the desired product. Example 16 7β-amino-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate hydrochloride 7β-phenylacetamide-3-(4-carbamoyl-1-quinuclidinio)-3-cephem-
1 g of 4-carboxylate was suspended in 19 ml of water, and the pH of the solution was adjusted to 8.0 with an aqueous dipotassium phosphate solution to prepare a substrate solution. Carrier Fixed Penicillin G Amidase [Product name, Penicillin G Amidase derived from Escherichia coli (Carrier: Polyacrylamide)
Boehringer Mannheim Yamanouchi Co., Ltd.〕1g
After adding water to swell it, the substrate solution was added. The mixture was stirred for 1 hour while maintaining the reaction temperature at 28° C. and the pH of the solution at 8.0 (adjusted with an aqueous dipotassium phosphate solution). After filtering, the solution was made acidic with 1N hydrochloric acid, and then concentrated under reduced pressure. The residue was purified by column chromatography using Sepabeads SP207 (trade name, styrene-divinylbenzene copolymer adsorbent, manufactured by Mitsubishi Kasei Corporation) (developing solvent: water, 30% methanol) to obtain 405 mg of the target product. .

【table】

〔Effect of the invention〕

Next, an experimental example related to the production of an antibacterial agent using the compound of the present invention as an intermediate and its antibacterial activity will be shown. Experimental example 1 7β[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamide]-3-(4-carbamoyl-1-quinuclidinio)methyl-3 -Cefem-4-carboxylate 2-(5-amino-1,2,4-thiadiazole)-(Z)-2-methoxyiminoacetic acid 46 mg, 1-
Hydroxy-1H-benzotriazole hydrate 35
mg, N,N'-dicyclohexylcarbodiimide
A mixture of 52 mg and 1 ml of N,N-dimethylformamide was stirred at room temperature for 3 hours, filtered, and the liquid was cooled to 0°C. This solution was mixed with 7β-
Added to an ice-cold solution of 100 mg of amino-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylic acid hydrochloride, 2 ml of N,N-dimethylformamide and 72μ of N,N-dimethylaniline. After stirring at room temperature for 14 hours, the reaction solution was filtered and added dropwise to 100 ml of ethyl ether with stirring. The deposited precipitate was collected and washed with ethyl ether. 10 ml of water was added to remove insoluble matter, and the liquid was purified by reverse phase silica gel column chromatography to obtain 3 mg of the desired product. Infrared absorption spectrum (cm ^-1 , Nujiol):
1775 NMR spectrum (δ, D ₂ O): 2.30 (6H, m), 3.1-4.0 (m), 4.16 (3H, s),
5.43 (1H, d, J = 6 Hz), 5.97 (1H, d, J = 6
Hz) Antibacterial activity [MIC (μg/ml)]: Staphylococcus aureus 209-P
3.13 Staphylococcus aureus E31106 ^*
25 Escherichia coli NIHJ 0.1 Pseudomonas aeruginosa EP−01
0.4 Serratia marsetuscens ES−75
0.2 Pseudomonas maltophilia E04004
3.13 Citrobacter freundei EC−34 ^*
0.1 *β-lactamase producing bacteria.

Claims (1)

[Claims] 1. General formula [In the formula, n represents 0 or 1, R ₁ and R ₂
are both hydrogen atoms, R ₁ is a monovalent protecting group for an amino group, R ₂ is a hydrogen atom, or R ₁ and R ₂ are a divalent protecting group for an amino group, X is an anion, and R ₃
3-(quinuclidinio)methyl-3-cephem derivative represented by: when is ^-COO- , m is 0; when _R3 is _-COOR4 ( _R4 is a carboxyl group protecting group), m is 1] and its salt. 2 7β-amino-3-(4-carbamoyl-1-
The compound according to claim 1, which is quinuclidinio)methyl-3-cephem-4-carboxylate hydrochloride. 3 7β-amino-3-(4-carbamoyl-1-
The compound according to claim 1, which is quinuclidinio)methyl-3-cephem-4-carboxylate. 4 General formula [In the formula, n represents 0 or 1, R ₁ and R ₂
are both hydrogen atoms, R ₁ is a monovalent protecting group for an amino group, R ₂ is a hydrogen atom, or R ₁ and R ₂ are a divalent protecting group for an amino group, and R ₅ is a hydrogen atom or a carboxyl group. represents a protecting group, and Y represents a halogen atom or a lower alkanoyloxy group] or a salt thereof represented by the formula A general formula characterized by reacting a compound represented by or a salt thereof, and optionally removing a protecting group and/or reducing a sulfoxide. [In the formula, R ₁ , R ₂ and n are the same as defined above,
_{A compound} ^represented _{by _} How to make that salt.