JPH0414117B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to a novel cephalosporin compound having high antibacterial activity that inhibits the growth of a wide range of pathogenic microorganisms, and a method for producing the same. [Prior Art] Conventionally, a large number of cephalosporin antibiotics have been obtained. The antibacterial activity of these cephalosporin antibiotics is largely influenced by the type of substituent at the 3-position in addition to the acyl group at the 7-position of the cephalosporin nucleus. Many cephem antibiotics are known that have a pyridinium group or a substituted pyridinium group at the 3-position, but there are also two-ring fused rings with a pyridine ring as the basic core, such as furopyridinium and thienopyridinium (Japanese Patent Application Laid-Open No. 1989-1999-1).
57390), substituted quinolinium, and isoquinolinium (Japanese Unexamined Patent Publication No. 58-6988), substituted products at the 3-position of the cefem nucleus have been actively synthesized and studied in recent years. [Object of the Invention] The present invention has been made based on various studies on 7-acyl cephalosporin compounds in which dihydrobicyclopyridine, which is a reduced form of bicyclopyridine, is substituted at the 3-position of the cefem nucleus. It has been discovered that a novel 7-acylcephalosporin compound having a specific dihydrocyclopyridine represented by the formula (A has the meaning given below) has excellent antibacterial activity. It is an object of the present invention to provide acceptable salts and methods for their production. [Structure of the invention] The present invention is based on the general formula [In the formula, R is a hydrogen atom, a lower alkyl group, or (n is 0 to 3, R ¹ and R ² are hydrogen atoms or lower alkyl groups, R ³ is -COOH or ), A represents a substituent represented by O, S, SO,
SO ₂ , N-alkyl, N-allyl or N ⁺ R ⁴ R ⁵
represents a group (R ⁴ and R ⁵ are the same or different alkyl groups or allyl groups). ] A cephalosporin compound and a pharmacologically acceptable salt thereof having the formula (In the formula, A has the same meaning as above) [In the formula, R ⁶ is a hydrogen atom or an amino group protecting group,
R ⁷ is a hydrogen atom, a lower alkyl group, or {n, R ¹ , R ² have the same meanings as above, R ⁸ is -
COOR ¹⁰ units or 2-(2-aminothiazol-4-yl) having (R ¹⁰ is a carboxyl group-protecting group, R ¹¹ is an amino group-protecting group)
A method for producing a cephalosporin compound of formula () and a pharmacologically acceptable salt thereof by reacting 2-syn-substituted oxyiminoacetic acid or a reactive derivative thereof at the carboxyl group, and removing a protecting group if necessary. and expression [In the formula, R ⁷ ′ is a hydrogen atom, a lower alkyl group, or {R ¹ , R ² , n have the same meanings as above, R ⁸ ' is -
COOR ¹⁰ ′ group or (R ¹⁰ ′ is a hydrogen atom or a protecting group for a carboxyl group,
R ¹¹ ′ represents a hydrogen atom or a protecting group for an amino group},
R ⁹ represents a substitutable residue of a nucleophilic reagent. This is a method for producing a cephalosporin compound of the formula () and a pharmacologically acceptable salt thereof, in which a compound having the formula (A has the same meaning as defined above) is reacted and, if necessary, a protecting group is removed. The pharmacologically acceptable salts represented by the general formula () of the present invention include pharmaceutically acceptable salts, particularly conventional non-toxic salts, such as salts with inorganic bases, e.g. Alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts,
Salts with organic bases, such as triethylamine salts,
Examples include organic amine salts such as pyridine salts, ethanolamine salts, triethanolamine salts, and dicyclohexylamine salts, and basic amino acid salts such as lysine and arginine. Specific examples of the R substituent in the formula include lower alkyl groups such as methyl, ethyl, and propyl, carboxymethyl, 2-carboxyethyl, 2-carboxypropyl, 1-methyl-2-carboxyethyl,
A group 2- such as 1-methyl-1-carboxyethyl
Amino-2-carboxyethyl, 3-amino-3
-carboxypropyl, 1-methyl-2-amino-2-carboxyethyl, and the like. The compound of the formula is a syn isomer, and when an asymmetric carbon is present in the 7-position side chain, D-form and L-form can exist, and the present invention includes both of them and DL-form. Specific examples of the compounds of the present invention include, but are not limited to, the compounds shown below. Syn-7-[2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide]-3-
(1,3-dihydrofuro[3,4b]pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn-7-[2-(2-aminothiazole-4-
yl)-2-carboxymethoxyiminoacetamide]-3-(1,3-dihydrofuro[3,4b]
pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn-7-[2-(2-aminothiazole-4-
yl)-2-(1-methyl-1-carboxy)ethoxyiminoacetamide]-3-(1,3-dihydrofuro[3,4b]pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn- 7-[2-(2-aminothiazole-4-
yl)-2-ethoxyiminoacetamide]-3-
(1,3-dihydrofuro[3,4b]pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn-7-[2-(2-aminothiazole-4-
yl)-2-(2D-2-amino-2-carboxy)
Ethoxyiminoacetamide]-3-(1,3-dihydrofuro[3,4b]pyridinium-4-yl)
Methyl-3-cephem-4-carboxylate syn-7-[2-(2-aminothiazole-4-
yl)-2-(3DL-3-amino-3-carboxy)propyloxyiminoacetamide]-3-
(1,3-dihydrofuro[3,4b]pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn-7-[2-(2-aminothiazole-4-
yl)-2-(2DL-2-amino-2-carboxy-1-methyl)ethoxyiminoacetamide]-
3-(1,3-dihydrofuro[3,4b]pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn-7-[2-(2-aminothiazole-4-
yl)-2-(1-methyl-2-carboxy)ethoxyiminoacetamide]-3-(1,3-dihydrofuro[3,4b]pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn- 7-[2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide]-3-
(2-methyl-1,3-dihydropyrrolo[3,4
-b]Pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn-7-[2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide]-3-
(2,2-dimethyl-1,3-dihydropyrrolo[3,4-b]pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn-7-[2-(2-aminothiazole-4 −
yl)-2-(2D-2-amino-2-carboxy)
Ethoxyiminoacetamide]-3-(2-methyl-1,3-dihydropyrrolo[3,4-b]pyridinium-4-yl)methyl-3-cephem-4-
Carboxylate syn-7-[2-(2-aminothiazole-4-
yl)-2-(2D-2-amino-2-carboxy)
Ethoxyiminoacetamide]-3-(2,2-dimethyl-1,3-dihydropyrrolo[3,4-b]
pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn-7-[2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide]-3-
(2-allyl-1,3-dihydropyrrolo[3,4
-b]Pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn-7-[2-(2-aminothiazole-4-
yl)-2-(1-methyl-1-carboxy)ethoxyiminoacetamide]-3-(2,2-dimethyl-1,3-dihydropyrrolo[3,4-b]pyridinium-4-yl)methyl-3 -Cefm-4
-carboxylate syn-7-[2-(2-aminothiazole-4-
yl)-2-(1-methyl-1-carboxy)ethoxyiminoacetamide]-3-(2-methyl-
1,3-dihydropyrrolo[3,4-b]pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn-7-[2-(2-aminothiazole-4-
yl)-2-(1-methyl-1-carboxy)ethoxyiminoacetamide]-3-(2-ethyl-2
-Methyl-1,3-dihydropyrrolo[3,4-
b] Pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn-7-[2-(2-aminothiazole-4-
yl)-2-(3DL-3-amino-3-carboxy)propyloxyiminoacetamide]-3-
(2,2-dimethyl-1,3-dihydropyrrolo[3,4-b]pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn-7-[2-(2-aminothiazole-4 −
yl)-2-carboxymethoxyiminoacetamide]-3-(2,2-dimethyl-1,3-dihydropyrrolo[3,4-b]pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn -7-[2-(2-aminothiazole-4-
yl)-2-ethoxyiminoacetamide]-3-
(2,2-dimethyl-1,3-dihydropyrrolo[3,4-b]pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn-7-[2-(2-aminothiazole-4 −
yl)-2-propyloxyiminoacetamide]
-3-(2,2-dimethyl-1,3-dihydropyrrolo[3,4-b]pyridinium-4-yl)methyl-3-cephem-4-carboxylate Syn-7-[2-(2-amino Thiazole-4-
yl)-2-methoxyiminoacetamide]-3-
(2-oxo-1,3-dihydrothieno[3,4
-b]Pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn-7-[2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide]-3-
(1,3-dihydrothieno[3,4-b]pyridinium-4-yl)methyl-3-cephem-4-
Carboxylate syn-7-[2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide]-3-
(2,2-dioxo-1,3-dihydrothieno[3,4-b]pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn-7-[2-(2-aminothiazole-4-
yl)-2-(2D-2-amino-2-carboxy)
Ethoxyiminoacetamide]-3-(2-oxo-1,3-dihydrothieno[3,4-b]pyridinium-4-yl)methyl-3-cephem-4-
Carboxylate syn-7-[2-(2-aminothiazole-4-
yl)-2-(2D-2-amino-2-carboxy)
Ethoxyiminoacetamide]-3-(2,2-dioxo-1,3-dihydrothieno[3,4-b]
pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn-7-[2-(2-aminothiazole-4-
yl)-2-(1-methyl-1-carboxy)ethoxyiminoacetamide]-3-(2-oxo-
1,3-dihydrothieno[3,4-b]pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn-7-[2-(2-aminothiazole-4-
yl)-2-(1-methyl-1-carboxy)ethoxyiminoacetamide]-3-(2,2-dioxo-1,3-dihydrothieno[3,4-b]pyridinium-4-yl]methyl-3- Cefm-4
-carboxylate syn-7-[2-(2-aminothiazole-4-
yl)-2-carboxymethoxyiminoacetamide]-3-(2-oxo-1,3-dihydrothieno[3,4-b]pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn-7- [2-(2-aminothiazole-4-
yl)-2-propyloxyiminoacetamide]
-3-(2,2-dioxo-1,3-dihydrothieno[3,4-b]pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn-7-[2-(2-aminothiazole) -4-
yl)-2-ethoxyiminoacetamide]-3-
(2-oxo-1,3-dihydrothieno[3,4
-b]Pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn-7-[2-(2-aminothiazole-4-
yl)-2-(2D-2-amino-2-carboxy)
ethoxyacetamide]-3-(1,3-dihydrothieno[3,4-b]pyridinium-4-yl)
Methyl-3-cephem-4-carboxylate syn-7-[2-(2-aminothiazole-4-
yl)-2-(1-methyl-1-carboxy)ethoxyiminoacetamide]-3-(1,3-dihydrothieno[3,4-b]pyridinium-4-yl)methyl-3-cephem-4-carboxylate The compound represented by the general formula [] is as follows:
(a) and (b) are manufactured by two methods. That is, (a) General formula [] (wherein A has the same meaning as above), a salt thereof, or a protected form of carboxyl group, the general formula [] (wherein R ⁶ and R ⁷ have the same meanings as above) or an active derivative of carboxylic acid is reacted with the compound, and then the protecting group for the amino group and carboxyl group is removed, or ( b) General formula [] (In the formula, R ⁶ and R ⁷ ' have the same meanings as above. ^{R 9}
represents a substitutable residue of a nucleophilic reagent, for example, an acetoxy group, a halogen such as chlorine, bromine, or iodine), or a compound represented by the general formula [] (wherein A has the same meaning as above) is reacted, and then, if necessary, the protecting group is removed to form the general formula []
The compound is obtained. As the protecting groups for the amino group and carboxyl group in the above general formula, those used for this purpose in the field of β-lactam and peptide synthesis are conveniently employed. Examples of protecting groups for amino groups include phthaloyl, formyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, Examples include diphenylmethyloxycarbonyl, methoxymethyloxycarbonyl, trityl, trimethylsilyl, etc., while protecting groups for carboxyl groups include, for example, t-phthyl, t-amyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, Benzhydryl, phenyl, p-
Nitrophenyl, methoxymethyl, ethoxymethyl, benzyloxymethyl, acetoxymethyl,
Examples include methylthiomethyl, trityl, trichloroethyl, trimethylsilyl, dimethylsilyl, dimethylaminoethyl and the like. The acylation reaction in production method (a) is carried out by reacting 1 to 3 moles of a carboxylic acid-reactive derivative of the compound [] to 1 mole []. Examples of the reactive derivative include acid halides, acid anhydrides, active amides, and active esters. Preferred examples include acid chlorides, acid bromides, mixed anhydrides of acetic acid, piparic acid, isovaleric acid, trichloroacetic acid, etc., activated amides with pyrazole, imidazole, dimethylpyrazole, benzotriazole, etc., and p-nitrophenyl. ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, 1-hydroxy-1H-
2-pyridone, N-hydroxysuccinimide, N
Active esters with -hydroxyphthalimide and the like can be mentioned. In this reaction, when the compound [] is used in the form of a free acid, it is preferable to carry out the reaction in the presence of a condensing agent, such as N,N-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'-
Carbodiimide compounds such as (4-diethylaminocyclohexyl)carbodiimide, amide compounds such as N-methylformamide, N,N-dimethylformamide, thionyl chloride, phosphorus oxychloride,
This can be carried out in the presence of a reagent (so-called Vilsmeier reagent) produced by reaction with a halide such as phosgene. Among the reactive derivatives in this reaction, the reaction with acid halides and acid anhydrides requires the presence of an acid condensing agent. Examples of acid binding agents include triethylamine, trimethylamine, ethyldiisopropylamine, N,N- Dimethylamine, N-
Organic bases such as methylmorpholine and pyridine, hydroxides of sodium, potassium, or calcium;
Examples include alkali metals such as carbonates and bicarbonates, and oxiranes such as ethylene oxide and propylene oxide. This reaction is usually carried out in a solvent that does not adversely affect the reaction, and examples of the solvent include water, acetone, acetonitrile, dioxane, tetrahydrofuran, methylene chloride, chloroform, dichloroethane, N,N-dimethylformamide, or a mixed solvent thereof. is used. The reaction temperature is not particularly limited, but is usually -30 to 40
The reaction time is 30 minutes to 10 hours to complete the reaction. If the acylated product thus obtained has a protecting group, removal of the protecting group will be necessary. Methods for removing protecting groups include methods using acids, bases, and hydrazine, depending on the type of the protecting group. It can be selected and carried out as appropriate. A compound in which R ⁹ of general formula [] in manufacturing method (b) is an acetoxy group and general formula [] (wherein A has the same meaning as above) is usually carried out using water, phosphate buffer, acetone, acetonitrile, N,N-dimethylformamide, N,
It is preferable to conduct the reaction in a polar solvent such as N-dimethylacetamide, tetrahydrofuran, dimethyl sulfoxide, methanol, or ethanol, or a mixed solvent with water. The reaction is preferably carried out near neutrality. Although the reaction temperature is not particularly limited, it is usually preferable to carry out the reaction at a temperature ranging from room temperature to around 70°C. The time required for this reaction varies depending on the reaction conditions, but is usually 1 to 10 hours. Further, this reaction is preferably carried out in the presence of an alkali metal halide such as sodium iodide or potassium iodide. Further, the desired compound [] can be produced from a compound in which R ⁹ of the general formula [] has a halogen. Examples of halogen include chlorine, bromine, and iodine, but iodine is generally preferred due to its reactivity. Compounds having iodine at R ⁹ in the general formula [] can be prepared from protected forms of amino groups and carboxyl groups of compounds where R ⁹ has an acetoxy group according to known methods (for example, JP-A-56-131590). Easily adjusted. This reaction is usually preferably carried out under nonaqueous conditions in a solvent such as acetone, dioxane, tetrahydrofuran, ethyl acetate, acetonitrile, dimethylformamide, or dimethylacetamide. The reaction is usually at 0℃
-50℃ Preferably carried out at 10℃-30℃, 1-5
Finish in time. The protecting group can be removed from the reaction product thus obtained by a conventional method to obtain a compound of the general formula []. The compound represented by the general formula [] can be prepared according to a known method (for example, JP-A-55-149289), that is, the compound represented by the general formula [] (In the formula, R ⁶ has the same meaning as above. R ¹⁰ represents a carboxyl group protecting group.) In the presence of a base such as potassium carbonate or sodium hydroxide, the compound represented by , N,N-dimethylformamide, tetrahydrofuran, dioxane) with the general formula [] R ⁷ X [] (wherein R ⁷ has the same meaning as above. X is chlorine,
It is produced by reacting a compound represented by (representing a halogen such as bromine or iodine). Furthermore, the compound represented by the general formula [] is the compound represented by the general formula [] (In the formula, R ⁶ has the same meaning as above) is reacted with a compound represented by the general formula [ ] H ₂ NOR ⁷ [ ] (In the formula, R ⁷ has the same meaning as above). Even if it is distorted, it can still be generated. This reaction is usually carried out in a solvent such as dimethylformamide, dimethylacetamide, acetonitrile, dioxane, tetrahydrofuran, alcohol, or another solvent that does not affect the reaction, or a mixture thereof with water. The time required for the reaction is usually 30 minutes to 10-odd hours. The reaction temperature is not particularly limited, but is usually carried out between room temperature and 60°C. Compounds of general formula [] can be prepared by known methods (for example,
According to JP-A-57-131758 and JP-A-55-149289), it can be produced by decomposing hydrazine in the presence of a base by reacting N-hydroxyphthalimide with a corresponding active halide. Also, among the compounds represented by the general formula [], the general formula [] having an amino group and a carboxyl group (In the formula, R ¹ , R ² , n have the same meanings as above. ^{R 10}
The compound represented by R 11 represents a carboxyl-protecting group and R ¹¹ represents an amino-protecting group can be produced using triphenylphosphine and diethyl azodicarboxylate under mild conditions. In other words, general formula [] (wherein R ¹ , R ² , R ¹⁰ , R ¹¹ and n have the same meanings as above) was reacted with N-hydroxyphthalimide in the presence of triphenylphosphine and diethyl azodicarboxylate. , general formula [] A compound represented by (wherein R ¹ , R ² , R ¹⁰ , R ¹¹ and n have the same meanings as above) is obtained, and this is subjected to hydrazine decomposition to obtain the compound [ ]. The reaction that produces the general formula [] is []
This is carried out by reacting 1 to 2 moles of triphenylphosphine and diethyl azodicarboxylate per mole. This reaction usually involves dioxane,
The reaction is carried out in an inert solvent such as tetrahydrofuran, acetonitrile, methylene chloride, benzene, ether, etc., preferably under non-aqueous conditions. Although the reaction temperature is not particularly limited, it is usually carried out at 0°C to 30°C, and the reaction time is 1 to 10 hours to complete the reaction. The compound [ ] thus obtained can be decomposed with hydrazine by a conventional method to obtain the desired compound [ ]. In addition, is the method of CHStammer et al. (JOC, vol. 27, 2957
It can be easily obtained by subjecting cycloserine to a hydrolysis reaction and then protecting the carboxyl group according to the method described in J. P., 1962). General formula []
Dihydrocyclopyridine represented by is synthesized by the following method. 1,3-dihydrothieno[3,4-b]pyridine and 2-oxide, 2,2-dioxide were prepared by the method of LHKlemm et al. (J. Het Chem, 843~
848, 1972), and 2-alkyl (or allyl)-1,3-dihydropyrrolo[3,4-b]
Pyridine and 2,2-dialkyl (or allyl) 1,3-dihydropyrrolo[3,4-b]pyridine were prepared by the method of WLFArmarego et al. (JCS
PerkinI 2485-2490, 1972), respectively.
Synthesized from 2,3-bis(chloromethyl)pyridine. On the other hand, dihydrofuropyridines are generally synthesized by reduction of the corresponding furopyridine compound. For example, 2,3-dihydrofuro[2,3-
b] Pyridine is synthesized by catalytic reduction of furo[2,3-b]pyridine (JWMcFarland et al. J.Het.
Chem, 8 735-738 (1971)). Similarly 2,3-
Dihydrofuro[3,2-b]pyridine is derived from furo[3,2-b]pyridine (S. Gronowitz et al. Acta.
Chemica Scandinavica B 29 233〜238
(1975)), 2,3-dihydrofuro[3,2-c]
Pyridine is furo[3,2-c]pyridine (F.
Eloy et al. J. Het.
It is partially described in Publication No. 57-192394. 1,3-dihydrofuro[3,4-b] of the present invention
Pyridine (5,7-dihydrofuro[3,4-b]pyridine in Chemical abstracts) may be obtained by partial reduction of the corresponding furo[3,4-b]pyridine as described above, but a simpler method It was synthesized using the following route. The direct starting material, 2,3-bishydroxymethylpyridine, was prepared by WLFArmarego et al. (J. Chem.
It was prepared by reduction of quinolinic acid diester according to the method of Soc 2485-2490, 1972), but no physical properties were described. Quinolinic acid diester was reduced with LiALH ₄ in ethyl ether or diethyl ether-tetrahydrofuran mixture to obtain this intermediate with a melting point of 76.5 to 77.0.
It was isolated pure as needle-like crystals at °C. This 2,3-bishydroxymethylpyridine is then treated with methanesulfonyl chloride, toluenesulfonyl chloride, etc., or 1,3- Dihydrofuro[3,4-b]pyridine was obtained as a pure oil and served as the 3-position substituent in the cefem derivatives of the present invention. The compound of the general formula [] obtained as described above is collected from the reaction mixture by a conventional method. For example, it can be purified by being adsorbed onto an adsorbent resin such as Amberlite XAD-2 (manufactured by Rohm & Hass) or Diaion HP-20 (manufactured by Mitsubishi Kasei Corporation) and eluted with a water-containing organic solvent. [Effects of the Invention] The object compound of the present invention () or its salts is a new compound and exhibits high antibacterial activity that inhibits the growth of a wide range of pathogenic microorganisms including Gram-positive and Gram-negative bacteria. In order to demonstrate the usefulness of the target compound (), the antibacterial activity measured for representative compounds () of the present invention is shown below.

【table】

〔Example〕

Reference Example 1 1,3-dihydrofuro[3,4-b]pyridine (a) 3.9 g of lithium aluminum hydride is suspended in 350 ml of anhydrous ethyl ether, 10 g of quinolinic acid diethyl ester is added under cooling, and the suspension is heated to reflux. After 1 hour, 400 ml of tetrahydrofuran was added, followed by refluxing for 4 hours. After cooling the reaction solution,
Add 60 ml of saturated sodium sulfate water, stir for 2 hours, and then filter. The filtration was concentrated under reduced pressure, applied to a silica gel column (500 ml), eluted with chloroform-methanol (10:1), and concentrated under reduced pressure.
Needle-shaped crystals of 3-bishydroxymethylpyridine
2.6g was obtained. This was recrystallized from isopropyl alcohol to obtain colorless plate crystals. Melting point 76.5-77.0℃ NMR (δ value from TMS in _d6 -DMSO) 4.63 (t, 4H), 5.04 (t, 1H), 5.23 (t,
1H), 7.31 (q, 1H), 7.84 (d, 1H), 8.40 (d,
1H) (b) 2,3-bishydroxymethylpyridine 2.8
Dissolve g in 40 ml of N,N-dimethylformamide, add 2.08 g of sodium hydride, and dissolve at room temperature.
Stir for 30 minutes. Next, 4.6 g of P-toluenesulfonyl chloride was added to this while cooling.
Subsequently, the reaction was continued for 4 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 80 ml of saturated saline.
Extract three times with 100 ml of ethyl acetate. The extract was washed with water, concentrated under reduced pressure, applied to a silica gel column (100 ml), eluted with chloroform-ethyl acetate (2:3), and dried under reduced pressure to obtain an oil of 1,3-dihydrofuro[3,4-b]pyridine. 920
I got mg. NMR (δ value from TMS in CDCl ₃ ) 5.10 (s, 2H), 5.18 (s, 2H), 7.17 (dd,
1H), 7.57 (d, 1H), 8.49 (d, 1H) (c) 1.1 g of 2,3-dihydroxymethylpyridine
2 g of diethyl azodicarboxylate was added to 30 ml of a dichloromethane solution containing 2 g of triphenylphosphine and stirred at room temperature for 1.5 hours. The reaction solution was concentrated and dissolved in 100ml of ethyl acetate.
Extract with 50ml of 1N hydrochloric acid. The aqueous layer is neutralized with sodium hydrogen carbonate and extracted twice with 50 ml of ethyl acetate. After washing the extract with water, it was concentrated to dryness.
The obtained oily substance was applied to a column of silica gel (50 ml), and chloroform-acetone (1:1) was added.
The residue was eluted and dried under reduced pressure to obtain 350 mg of an oily substance of 1,3-dihydrofuro[3,4-b]pyridine.
The spectral data of this compound matched that obtained by method (b). Reference example 2 2-methyl-1,3-dihydropyrrolo[3,4
-b] Pyridine 1.2 g of 2,3-bishydroxypyridine is dissolved in 8 ml of thionyl chloride and heated under reflux for 40 minutes. The reaction solution was concentrated to dryness under reduced pressure to crystallize 2,3-bischloromethylpyridine hydrochloride. Add this to 50 ml of dichloromethane and 5 ml of methanol.
ml, add 10 ml of 30% methylamine ethanol solution while cooling at -20°C, and react at 0°C for 2 hours and then at room temperature overnight. The reaction solution is concentrated under reduced pressure, and the residue is dissolved in 60 ml of dichloromethane. This is washed with 30 ml of 1N saturated brine solution and 20 ml of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent chloroform-
Purified with methanol 15:1) to obtain the title target 620
NMR to obtain mg (δ value from TMS in CDCl ₃ ) 2.65 (s, 3H), 4.01 (s, 4H), 7.10 (q, 1H), 7.50 (d, 1H), 8.40 (d, 1H) Reference Example 3 2,2-dimethyl-1,3-dihydropyrrolo[3,4-b]pyridinium iodide 2-methyl-1,3-dihydropyrrolo[3,4
-b] Dissolve 540 mg of pyridine in 40 ml of benzene,
Add 0.24 ml of methyl iodide to this and react overnight at room temperature. The precipitate formed is collected by filtration, washed with benzene and dried. This was crystallized from methanol-ether to obtain 770 mg of the desired product. NMR (δ value from _d4 -MeOH, TMS) 3.48 (s, 6H), 4.98 (s, 2H), 5.08 (s, 2H), 7.48 (q, 1H), 7.96 (d, 1H), 8.61 ( d, 1H) Example 1 Syn-7-[2-(2-aminothiazole-4-
yl)-2-(3DL-3-amino-3-carboxy)propyloxyiminoacetamide]-3
-(1,3-dihydrofuro[3,4b]pyridinium-4-yl)methyl-3-cephem-4-
Dissolve 11.9 g of carboxylate (a) DL-homoserine in 200 ml of water,
Add 10 g of Na ₂ CO ₃ and 150 ml of sioxane.
Add to this 27.5g of di-t-butyl digarbonate.
50 ml of a dioxane solution are added dropwise over the course of 1 hour while cooling. Further, the reaction is allowed to proceed at room temperature for 2 hours. After the reaction, dioxane is removed under reduced pressure, washed with ethyl acetate, adjusted to pH 2 with 5N hydrochloric acid under cooling, and extracted twice with 400 ml of ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, and concentrated to dryness.
-Butoxycarbonyl DL-homoserine 18.5g
get. The obtained N-t-butoxycarbonyl DL-
Dissolve 6g of homoserine in 100ml of methylene chloride,
50 ml of a methylene chloride solution containing 6 g of diphenyldiazomethane is added dropwise to this over the course of 1 hour. After the reaction is completed, the reaction solution is concentrated to a small volume and petroleum ether is added. Collect the crystals that form, and
8.6 g of -t-butoxycarbonyl DL-homoserine benzhydryl ester is obtained. (b) Dissolve 6.75 g of N-t-butoxycarbonyl DL-homoserine benzhydryl ester in 150 ml of dry tetrahydrofuran, add 2.85 g of N-hydroxyphthalimide and 4.6 g of triphenylphosphine, and to this add 2.75 g of diethyl azodicarboxylate. ml and reacted for 3 hours at room temperature under an argon atmosphere. After the reaction is completed, the reaction solution is concentrated under reduced pressure and dissolved in 30 ml of ether. The precipitated crystals were collected by filtration to obtain 7 g of Nt-butoxycarbonyl-O-phthalimide-DL-homoserine benzhydryl ester. NMR (δ value from TMS in CDCl ₃ ) 1.44 (s, 9H), 2.33 (m, 2H), 4.27 (t,
2H), 4.68 (m, 1H), 5.79 (d, 1H), 6.93 (s,
1H), 7.34 (m, 10H), 7.81 (m, 4H) (c) Dissolve 5.52 g of N-t-butoxycarbonyl-O-phthalimide-DL-homoserine-benzhydryl ester in 100 ml of dry methylene chloride; Add 0.51 ml of hydrazine hydrate to the solution and react for 1 hour under ice cooling. Furthermore, hydrazine 0.12
ml and react at the same temperature for 1 hour. After the reaction is completed, the insoluble portion is filtered off, and the filtrate is washed successively with H ₂ O dilute NH ₄ OH water, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was dissolved in 700 ml of ether, the precipitated crystals were removed by filtration, the filtrate was concentrated, the precipitated crystals were further filtered off, the filtrate was concentrated to dryness, and the target product Nt-
3.88 g of butoxycarbonyl-O-amino DL-homoserine benzhydryl ester are obtained. NMR (δ value from TMS in CDCl ₃ ) 1.43 (s, 9H), 2.08 (m, 2H), 3.68 (t,
2H), 4.53 (m, 1H), 5.27 (m, 2H), 6.93 (s,
1H), 7.35 (m, 10H) (d) (2-chloroacetylamino-thiazole-
1.71 g of 4-yl)glyoxylic acid was dissolved in 30 ml of a 1:2 mixture of tetrahydrofuran water, and Nt-butoxycarbonyl-O-amino-
DL-homoserine benzhydryl ester 2.88
Add 30 ml of tetrahydrofuran solution containing g
Adjust the pH to 5.1 with 1N-NaOH and react at room temperature for 6 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 6.5, concentrated under reduced pressure, tetrahydrofuran was removed, 100 ml of water was added, and the pH of the solution was adjusted to 8.
After washing with 100ml of ether, pH was adjusted with 2NHCl under ice cooling.
2 and extracted with 250 ml of ethyl acetate.
The ethyl acetate layer is washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. 100ml of ether from the residue
The insoluble portion was removed by filtration, and the syn-2-(2-
Chloracetylamino-thiazol-4-yl)-2-(3DL-3-t-butoxycarbonylamino-3-diphenylmethoxycarbonyl)
3.15 g of propyloxyiminoacetic acid are obtained. NMR (δ value from acetone d ₆ , TMS) 1.48 (s, 9H), 2.28 (m, 2H), 4.30 (t,
2H), 4.57 (m, 1H), 4.50 (s, 2H), 6.88 (s,
1H), 7.36 (m, 10H), 7.56 (s, 1H) (e) Syn-2-(2-chloroacetylamino-thiazol-4-yl)-2-(3DL-3-t-butoxycarbonylamino- 3-diphenylmethoxycarbonyl)propyloxyiminoacetic acid
Dissolve 1.4 g in 15 ml of N,N-dimethylformamide, add 300 ml of N-hydroxybenz-triazole and 465 mg of N,N-dicyclohexylcarbodiimide, and react at room temperature for 1 hour. To this was added 985 mg of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid benzhydryl ester under ice cooling, and the mixture was allowed to react at the same temperature for 5 hours. After the reaction is complete, the insoluble portion is filtered off, and methylene chloride is added.
Add 150 ml of the solution, wash sequentially with diluted hydrochloric acid and water, dry over magnesium sulfate, and concentrate to dryness under reduced pressure. This was purified by silica gel column chromatography (developing solvent benzene-ethyl acetate 5:2), and syn-7-[2-(2-chloroacetylaminothiazol-4-yl)-2-(3DL-3
-t-butoxycarbonylamino-3-diphenylmethoxycarbonyl)propyloxyiminoacetamide-3-acetoxymethyl-3-
1.35 g of cefem-4-carboxylic acid benzhydryl ester is obtained. (f) Dissolve this in 12 ml of anisole, add 12 ml of trifluoroacetic acid under ice cooling, and react at the same temperature for 1.5 hours. After the reaction was completed, trifluoroacetic acid was removed under reduced pressure, and the residue was poured into 150 ml of hexane cooled to -20°C to -30°C, and 70 ml of ether was added thereto.
Remove supernatant. The residue was washed with ether, and the precipitate was collected by filtration to give syn-7-[2-(2-chloroacetylamino-thiazol-4-yl)-2
750 mg of -(3DL-3-amino-3-carboxy)propyloxyiminoacetamide]-3-acetoxymethyl-3-cephem-4-carboxylic acid trifluoroacetate is obtained. After suspending this in 75 ml of water and adjusting the pH to 6.5 with a saturated aqueous sodium bicarbonate solution, 200 mg of sodium N-methyl-dithiocarbamate was added and reacted at room temperature for 3 hours. After the reaction was completed, the product was washed with ethyl acetate, purified using HP-20 column chromatography, and the fraction containing the target product was concentrated and lyophilized to obtain Syn-7-[2
-(2-aminothiazol-4-yl)-2-
490 mg of (3DL-3-amino-3-carboxy)propyloxyiminoacetamide 1-3-acetoxymethyl-3-cephem-4-carboxylate are obtained. NMR: (δ value from external standard TMS in D ₂ O) 2.06 (s, 3H), 2.09 (m, 2H), 3.51 (ABq,
2H), 4.09 (m, 1H), 4.58 (m, 2H), 4.77 (ABq,
2H), 5.20 (d, 1H), 5.79 (d, 1H), 7.06 (s,
1H) (g) Dissolve 270 mg of the compound (f) in 1 ml of water, and add
Add 750 mg of sodium iodide, 150 mg of 1,3-dihydrofuro[3,4-b]pyridine, and 1 ml of acetonitrile, and react at 60-65°C for 3 hours. After the reaction is complete, add 20 ml of acetone, collect the resulting precipitate by filtration, wash thoroughly with acetone, dissolve it in 2 ml of water, purify with HP-20 column chromatography, and concentrate the fraction containing the target product. and freeze-drying to obtain 75 mg of the title compound. NMR: (δ value from external standard TMS in D ₂ O) 2.36 (m, 2H), 3.34 (ABq, 2H), 3.90 (q,
1H), 4.46 (m, 2H), 5.18 (d, 1H), 5.22 (ABq,
2H), 5.30 (s, 2H), 5.34 (ABq, 2H), 5.76 (d,
1H), 6.92 (s, 1H), 7.85 (dd, 1H), 8.30 (d,
11H), 8.65 (d, 1H) Example 2 Syn-7-[2-(2-aminothiazole-4-
yl)-2-(2D-2-amino-2-carboxy)ethoxyiminoacetamide]-3-[1,
3-dihydrofuro[3,4-b]pyridinium-4-yl)methyl-3-cephem-4-carboxylate (a) Dissolve 2 g of D-cycloserine in 11 ml of 50% concentrated hydrochloric acid and acidify at 60°C for 3 hours. Hydrolyze. After the reaction is completed, the mixture is concentrated under reduced pressure, subjected to azeotropic distillation several times with ethanol, and then dried under reduced pressure overnight to obtain β-aminoxy-D-alanine dihydrochloride. Dissolve this in 100 ml of ethanol, and at 5-10℃, add 80 ml of ethanol solution containing 9.5 g of diphenyldiazomethane.
ml dropwise over 2.5 hours. After the reaction is completed, the reaction solution is concentrated to a small volume, and 60 ml of ether and 80 ml of hexane are added thereto. Remove supernatant. The residue was crystallized from ethanol-ether to obtain 5.5 g of β-aminoxy-D-alanine benzhydryl ester dihydrochloride. (b) (2-chloroacetylaminothiazole-4
-yl) glyoxylic acid was dissolved in 75 ml of a 2:1 mixture of tetrahydrofuran and water, and under ice cooling, 2.96 g of β-aminoxy D-alanine benzhydryl ester dihydrochloride (obtained in (a)) was added. The pH of the reaction solution was adjusted to 5 with a saturated aqueous sodium bicarbonate solution, and the reaction was allowed to proceed at room temperature for 3 hours.Then, the pH of the reaction solution was adjusted to 8.5, the crystals formed were dissolved, and di-t-butyl was added to the solution. - Add 20 ml of a tetrahydrofuran solution containing 2.15 g of dicarbonate and react at room temperature for 4.5 hours. After the reaction is complete, remove tetrahydrofuran under reduced pressure, adjust the pH to 2 with 5N hydrochloric acid under cooling, and extract twice with 200 ml of ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure.
-chloroacetylaminothiazol-4-yl)-2-(2D-2-t-butoxycarbonylamino-2-diphenylmethoxycarbonyl)
3.6 g of ethoxyiminoacetic acid are obtained. (c) 2.5 g of syn-2-(2-chloroacetylaminothiazol-4-yl)-2-(2D-2-t-butoxycarbonylamino-2-diphenylmethoxycarbonyl)ethoxyiminoacetic acid and 7-amino- 3-acetoxymethyl-3-cephem-4-carboxylic acid benzhydryl ester
1.75g was treated in the same manner as in Example 1-(e) and (f),
Syn-7-[2-(2-aminothiazole-4-
970 mg of yl)-2-(2D-2-amino-2-carboxy)ethoxyiminoacetamide]-3-acetoxymethyl-3-cephem-4-carboxylate are obtained. NMR (δ value from external standard TMS in D ₂ O) 2.06 (s, 3H), 3.51 (ABq, 2H), 4.12 (dd,
1H), 4.60 (m, 2H), 4.77 (ABq, 2H), 5.19 (d,
1H), 5.79 (d, 1H), 7.05 (s, 1H) (d) Of these, 530 mg was used and treated in the same manner as in Example 1-(g) to obtain 180 mg of the title target compound. NMR (δ value from external standard TMS in D ₂ O) 3.32 (ABq, 2H), 4.03 (m, 1H), 4.51 (m,
2H), 5.16 (d, 1H), 5.23 (ABq, 2H), 5.26 (s,
2H), 5.34 (ABq, 2H), 5.78 (d, 1H), 6.98 (s,
1H), 7.87 (dd, 1H), 8.33 (d, 1H), 8.65 (d,
1H) Example 3 Syn-7-[2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide]-3
-(1,3-dihydrofuro[3,4-b]pyridinium-4-yl)methyl-3-cephem-
4-carboxylate syn-2-(2-aminothiazol-4-yl)
400 mg of -2-methoxyiminoacetic acid was dissolved in 5 ml of N,N-dimethylformamide, and 270 mg of N-hydroxybenztriazole and N,
Add 415 mg of N'-dicyclohexylcarbodiimide and react at room temperature for 1 hour. 7-amino-3-(1,3-dihydrofuro[3,
4-b]pyridinium-4-yl)methyl-3-
Cefem-4-carboxylate 670mg N,N
- Suspended in 5 ml of dimethylformamide and cooled on ice,
Add 0.45ml of triethylamine to this, then
Add the above reaction solution and allow to react at 5°C overnight. After the reaction is complete, the insoluble portion is filtered off, and ether is added thereto. The supernatant was removed, and the resulting precipitate was thoroughly washed with ether, then dichloromethane, and ethyl acetate.
After drying, the product was purified by HP-20 column chromatography to obtain 430 mg of the title compound. NMR (δ value from external standard TMS in D ₂ O) 3.37 (ABq, 2H), 3.84 (s, 3H), 5.12 (d,
1H), 5.21 (ABq, 2H), 5.23 (s, 2H), 5.31 (ABq,
2H), 5.72 (d, 1H), 6.86 (s, 1H), 7.84 (dd,
1H), 8.29 (d, 1H), 8.61 (d, 1H) Example 4 Syn-7-[2-(2-aminothiazole-4-
yl)-2-carboxymethoxyiminoacetamide]-3-(1,3-dihydrofuro[3,4
-b]pyridinium-4-yl)methyl-3-
Cefem-4-carboxylate Syn-7-[2-(2-aminothiazole-4-
yl)-2-carboxymethoxyiminoacetamide]-3-acetoxymethyl-3-cephem-
520 mg of 4-carboxylic acid monosodium salt (syn-
Same as Example 1 from (2-chloroacetylaminothiazol-4-yl)-2-t-butoxycarbonylmethoxyiminoacetic acid and 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid benzhydryl ester. (adjust with water)
To this, 1.5 g of sodium iodide and 300 mg of 1,3-dihydrofuro[3,4-b]pyridine were added.
Incubate for 2.5 hours at °C. After the reaction is completed, 50 ml of acetone is added to the reaction solution, and the resulting precipitate is thoroughly washed with acetone, dried, and purified by HP-20 column chromatography to obtain 185 mg of the title compound. NMR (δ value from external standard TMS in D ₂ O) 3.40 (ABq, 2H), 4.60 (s, 2H), 5.15 (d,
1H), 5.23 (ABq, 2H), 5.26 (s, 2H), 5.33 (ABq,
2H), 5.74 (d, 1H), 6.91 (s, 1H), 7.84 (dd,
1H), 8.30 (d, 1H), 8.66 (d, 1H) Example 5 Syn-7-[2-(2-aminothiazole-4-
yl)-2-ethoxyiminoacetamide]-3
-(1,3-dihydrofuro[3,4-b]pyridinium-4-yl)methyl-3-cephem-
4-carboxylate syn-2-(2-aminothiazol-4-yl)
-2-ethoxyiminoacetic acid 220 mg and 7-amino-3-(1,3-dihydrofuro[3,4-b]pyridinium-4-yl)methyl-3-cephem-
215 mg of the title compound is obtained by treating in the same manner as in Example 3 using 330 mg of 4-carboxylate. NMR (δ value from external standard TMS in D ₂ O) 1.30 (t, 3H), 3.40 (ABq, 2H), 4.40 (q,
2H), 5.14 (d, 1H), 5.22 (ABq, 2H,), 5.24 (s,
2H), 5.31 (ABq, 2H), 5.74 (d, 1H), 6.90 (s,
1H), 7.84 (dd, 1H), 8.30 (d, 1H), 8,63 (d,
1H) Example 6 Syn-7-[2-(2-aminothiazole-4-
yl)-2-(2D-2-amino-2-carboxy)ethoxyiminoacetamide]-3-(1,
3-dihydrofuro[3,4-b]pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn-7-[2-(2-aminothiazole-4-
yl)-2-(2D-2-amino-2-carboxy)
Ethoxyiminoacetamide]-3-acetoxymethyl-3-cephem-4-carboxylate
Suspend 620 mg in 7 ml of cyclomethane, and add
Add 2 ml of N-methyl-N-trimethylsilyl trifluoroacetamide and heat at 35°C under argon atmosphere.
Stir for 2 hours. Add 0.21 ml of trimethylsilyl iodide to this and react for 20 minutes. This was concentrated under reduced pressure, the residue was dissolved in 5 ml of acetonitrile, and 0.1 ml of tetrahydrofuran was added thereto.
After a few minutes, 140 mg of 1,3-dihydrofuro[3,4-b]pyridine was added and the mixture was allowed to react at room temperature for 2 hours. A small amount of water is added to this, and the resulting precipitate is collected by filtration and purified by HP-20 column chromatography to obtain 230 mg of the title compound. The spectral data of this compound match that obtained by the method of Example 2. Example 7 Syn-7-[2-(2-aminothiazole-4-
yl)-2-(1-methyl-1-carboxy)ethoxyiminoacetamide]-3-(1,3-dihydrofuro[3,4-b]pyridinium-4-
yl) Methyl-3-cephem-4-carboxylate Syn-2-(2-chloroacetylaminothiazol-4-yl)-2-(1-methyl-1-t-butoxycarbonyl)ethoxyiminoacetic acid and 7-
Amino-3-(1,3-dihydrofuro[3,4-
b] Pyridinium-4-yl)methyl-3-cephem-4-carboxylate is treated in the same manner as in Example 3 and Example 1-(f)) to obtain the title compound. NMR (δ value from external standard TMS in D ₂ O) 1.44 (s, 6H), 3.37 (ABq, 2H), 5.20 (d,
1H), 5.26 (ABq, 2H), 5.28 (s, 2H), 5.36 (ABq,
2H), 5.78 (d, 1H), 6.89 (s, 1H), 7.85 (dd,
1H), 8.30 (d, 1H), 8.62 (d, 1H) Example 8 Syn-7-[2-(2-aminothiazole-4-
yl)-2-(2D-2-amino-2-carboxy)ethoxyiminoacetamide]-3-(2-
Methyl-1,3-dihydropyrrolo[3,4-
b] Pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn-7-[2-(2-aminothiazole-4-
yl)-2-(2D-2-amino-2-carboxy)
Ethoxyiminoacetamide]-3-acetoxymethyl-3-cephem-4-carboxylate
260 mg was dissolved in a mixture of 1 ml of water and 1 ml of acetonetrile, and 750 mg of sodium iodide and 2-
Methyl-1,3-dihydropyrrolo[3,4-b]
Add 170 mg of pyridine, adjust the pH of the reaction solution to 7.0 with 50% phosphoric acid aqueous solution, and react at 65°C for 3 hours.
After the reaction is complete, 10 ml of acetone is added to the reaction solution, and the resulting precipitate is collected by filtration, thoroughly washed with acetone, and dried. This was dissolved in 1 ml of water, purified by HP-20 column chromatography, and the fraction containing the target product was concentrated and freeze-dried. This was further purified using Sephadex LH-20 column chromatography (developing solvent: 50% methanol water),
20 mg of the title compound is obtained. NMR (δ value from external standard TMS in D ₂ O) 2.48 (s, 3H), 3.26 (ABq, 2H), 4.00 (m,
1H), 4.09 (s, 2H), 4.25 (s, 2H), 4.50 (m, 2H), 5.13 (d, 1H), 5.26 (ABq, 2H), 5.75 (d,
1H), 6.97 (s, 1H), 7.78 (dd, 1H), 8.24 (d,
1H), 8.56 (d, 1H) Example 9 Syn-7-[2-(2-aminothiazole-4-
yl)-2-(2D-2-amino-2-carboxy)ethoxyiminoacetamide]-3-(2,
2-dimethyl-1,3-dihydropyrrolo[3,
4-b]pyridinium-4-yl)methyl-3
-Cefem-4-carboxylate By the same method as in Example 8, instead of 2-methyl-1,3-dihydropyrrolo[3,4-b]pyridine iodide, 2,2-dimethyl-1,3- The title compound is obtained using dihydropyrrolo[3,4-b]pyridinium. Example 10 Syn-7-[2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide]-3
-(2,2-dimethyl-1,3-dihydropyrrolo[3,4-b]pyridinium-4-yl)methyl-3-cephem-4-carboxylate
Formate Syn-7-[2-(2-aminothiazole-4-
230 mg of 2-methoxyiminoacetamide]-cephalosporanic acid is suspended in 2.5 ml of dichloromethane, 0.27 ml of N,O-bis-trimethylsilyltrifluoroacetamide is added thereto, and the mixture is reacted for 45 minutes at room temperature under an argon atmosphere. Add 0.2 ml of methylsilyl iodide to this and allow to react for an additional 20 minutes. This was concentrated under reduced pressure, and the residue was dissolved in acetonitrile.
Dissolve in 1.5ml and add 0.1ml of tetrahydrofuran to this.
Add. After 10 minutes, 4 ml of an acetonitrile solution containing 140 mg of 1,3-dimethylpyrrolo[3,4-b]pyridinium iodide is added, and the mixture is allowed to react at room temperature for 2 hours. After the reaction is complete, concentrate the reaction solution to half the volume under reduced pressure.
Add 0.1ml of water. The precipitate formed is filtered and dried. Dissolve this in a small amount of formic acid, add acetone, and collect the resulting precipitate by filtration, wash thoroughly with acetone, and dry to obtain 135 mg of the title compound. NMR (δ value from external standard TMS in _d6 -DMSO- _D2O ) 3.37 (ABq, 2H), 3.44 (s, 3H), 3.48 (s,
3H), 3.86 (s, 3H), 5.05-5.30 (m, 4H), 5.23 (d, 1H), 5.50 (ABq, 2H), 5.88 (d,
1H), 6.76 (s, 1H), 8.27 (q, 1H), 8.70 (d, 1H), 8.92 (d, 1H) Example 11 Syn-7-[2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide]-3
-(2-methyl-1,3-dihydropyrrolo[3,
4-b]pyridinium-4-yl)methyl-3
-Cefem-4-carboxylate Syn-7-[2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide]-3-
240 mg of acetoxymethyl-3-cephem-4-carboxylic acid sodium salt was dissolved in 1 ml of water and 1 ml of acetonitrile, and 750 mg of potassium iodide and 2-methyl-1,3-dihydropyrrolo[3,4
-b] Add 170 mg of pyridine, adjust the pH to 6.9 with 50% phosphoric acid aqueous solution, and react at 65°C for 3.5 hours. After the reaction is completed, the reaction solution is concentrated to a small volume, 10 ml of acetone is added thereto, and the resulting precipitate is collected by filtration, thoroughly washed with acetone, and then dried. This was subjected to HP-20 column chromatography and then sepadex.
Purification by LH-20 (50% methanol water) chromatography yields 28 mg of the title compound. NMR (δ value from external standard TMS in D ₂ O) 2.49 (s, 3H), 3.26 (ABq, 2H), 3.84 (s,
3H), 4.09 (s, 2H), 4.25 (s, 2H), 5.12 (d, 1H), 5.26 (ABq, 2H), 5.72 (d, 1H), 6.86 (s,
1H), 7.78 (dd, 1H), 8.25 (d, 1H), 8.55 (d, 1H) Example 12 Syn-7-[2-(2-aminothiazole-4-
yl)-2-(1-methyl-1carboxy)ethoxyiminoacetamide]-3-(2,2-dimethyl-1,3-dihydropyrrolo[3,4-b]
pyridinium-4-yl)methyl-3-cephem-4-carboxylate syn-7-[2-(2-aminothiazole-4-
yl)-2-(1-methyl-1carboxy)ethoxyiminoacetamide]-cephalosporanic acid (syn-2-(2-chloroacetylaminothiazol-4-yl)-2-(1-methyl-1-t-butoxy) carbonyl)ethoxyiminoacetic acid and 7-amino-3-acetoxy-3-cephem-4-carboxylic acid benzhydryl ester), treated in the same manner as in Example 10, and further HP- Purify by 20 column chromatography to obtain the title compound. NMR (δ value from _d6 -DMSO- _D2O , TMS) 1.45 (s, 6H), 3.35 (ABq, 2H), 3.45 (s,
3H), 3.50 (s, 3H), 5.05-5.30 (m, 4H), 5.25 (d, 1H), 5.46 (ABq, 2H), 5.87 (d,
1H), 6.80 (s, 1H), 8.22 (q, 1H), 8.68 (d, 1H) 8.90 (d, 1H) Example 13 Syn-7-[2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide]-3
-(2-methyl-1,3-dihydropyrrolo[3,
4-b]pyridinium-4-yl)methyl-3
-Cefem-4-carboxylate Syn-7-[2-(2-aminothiazole-4-
450 mg of 2-methoxyiminoacetamide]-cephalosporanic acid was suspended in 5 ml of dichloromethane, 0.8 ml of N-methyl-N-trimethylsilyl trifluoroacetamide was added, and the
Allow time to react. Next, 0.3 ml of trimethylsilyl iodide is added and reacted for 20 minutes at room temperature. This was concentrated under reduced pressure, and the residue was dissolved in 3 ml of anhydrous acetonitrile.
dissolve in Add this to 0.2% of anhydrous tetrahydrofuran.
ml, and after 5 minutes, 160 mg of 2-methyl-1,3-dihydropyrrolo[3,4-b]pyridine was added.
Incubate for 1.5 hours at room temperature. After the reaction was completed, a small amount of water was added, the resulting precipitate was collected by filtration, and purified by HP-20 chromatography and Sephadex LH-20 column chromatography (developing solvent 50% - methanol) to obtain the title compound. Get 95mg. The spectral data of this compound matched that of the compound obtained in Example 11. Example 14 Syn-7-[2-(2-aminothiazole-4-
yl)-2-methoxyiminoacetamide]-3
-(2,2-dioxo-1,3-dihydrothieno[3,4-b]pyridinium-4-yl)methyl-3-cephem-4-carboxylate 2,2-dioxo-1,3-dihydrothieno[3,4 -b] Using pyridine, the following Example 13
The title compound is obtained by treating in the same manner as above. NMR (δ value from external standard TMS in D ₂ O) 3.35 (ABq, 2H), 3.87 (s, 3H), 4.52 (s,
2H), 4.60 (s, 2H), 5.17 (d, 1H), 5.30 (ABq,
2H), 5.80 (d, 1H), 6.86 (s, 1H), 7.65 (q, 1H), 8.10 (d, 1H), 8.74 (d, 1H).

Claims (1)

[Claims] 1. General formula [In the formula, R is a hydrogen atom, a lower alkyl group, or a formula (n is 0 to 3, R ¹ and R ² are hydrogen atoms or lower alkyl groups, R ³ is -COOH or ), A represents a substituent represented by O, S, SO,
SO ₂ , N-alkyl, N-allyl or N ⁺ R ⁴ R ⁵
represents a group (R ⁴ and R ⁵ are the same or different alkyl groups or allyl groups). A cephalosporin compound and a pharmacologically acceptable salt thereof. 2 formulas [In the formula, A is O, S, SO, SO ₂ , N-alkyl group,
N-allyl group or N ⁺ R ⁴ R ⁵ group (R ⁴ and R ⁵ represent the same or different alkyl group or allyl group)] or a salt thereof or a protected form of carboxyl group, the formula [In the formula, R ⁶ is a hydrogen atom or a protecting group for an amino group, R ⁷
is a hydrogen atom, a lower alkyl group, or {n is 0 to 3, R ¹ and R ² are hydrogen atoms or lower alkyl groups, R ⁸ is -COOR ¹⁰ group or 2-(2-aminothiazol-4-yl) having (R ¹⁰ is a carboxyl group-protecting group, R ¹¹ is an amino group-protecting group)
A formula characterized in that 2-syn-substituted oximinoacetic acid or a reactive derivative thereof at the carboxyl group is reacted and, if necessary, protective groups are removed. [In the formula, R is a hydrogen atom, a lower alkyl group, or (n is 0 to 3, R ¹ and R ² are hydrogen atoms or lower alkyl groups, R ³ is -COOH or ), A represents a substituent represented by O, S,
SO, SO ₂ , N-alkyl, N-allyl or
N ⁺ R ⁴ R ⁵ (R ⁴ and R ⁵ represent the same or different alkyl group or allyl group)] and a method for producing a cephalosporin compound and a pharmacologically acceptable salt thereof. 3 formulas [In the formula, R ⁶ is a hydrogen atom or a protecting group for an amino group,
R ⁷ ′ is a hydrogen atom, a lower alkyl group, or {n is 0 to 3, R ¹ and R ² are hydrogen atoms or lower alkyl groups, R ⁸ ′ is -COOR ¹⁰ ′ group or (R ¹⁰ ′ is a hydrogen atom or a protecting group for a carboxyl group,
R ¹¹ 'represents a hydrogen atom or a protecting group for an amino group)}, R ⁹ represents a substitutable residue of a nucleophilic reagent] or a salt thereof or a protected form of a carboxyl group. [In the formula, A is O, S, SO, SO ₂ , N-alkyl,
A formula characterized by reacting a compound having N-allyl or N ⁺ R ⁴ R ⁵ (R ⁴ and R ⁵ represent the same or different alkyl group or allyl group) and removing a protecting group if necessary. [In the formula, R is a hydrogen atom, a lower alkyl group, or (n is 0 to 3, R ¹ and R ² are hydrogen atoms or lower alkyl groups, R ³ is -COOH or ), A represents the same group as above.] A method for producing a cephalosporin compound and a pharmacologically acceptable salt thereof.