JPH04221388A - Cephalosporin compound and production thereof - Google Patents

Abstract

PURPOSE:To provide the subject new antibacterial cephalosporin compounds having wide antibacterial spectra and excellent in antibacterial effects not only to Gram-positive and negative bacteria but to microorganisms belonging to Pseudomonas. CONSTITUTION:Compounds of formula I [R1 and R2 are H or amino-protecting group; R3 is -COO- or (protected)carboxyl; X is -(CH2)n - or formula II (n is 0-2; R41 is H, -CN, etc.); Y is formulae III, IV (R42 and R43 are H, acetyl, etc.; One of R44 and R45 is protectable OH and the other is H; R46 is H or protectable OH), etc.] or salts thereof, e.g. 7beta-[(Z)-2-(2-aminothiazol-4-yl)-2-(2- amino-1-ethylethoxyimino)acetamido]-3-[1-(3,4-diacetoxyphenyl) pyridinium-4- yl]thiomethyl-3-cephem-4-carboxylate trifluoroacetate. These compounds can be obtained by reacting a compound of formula V (Hal is halogen) with a compound of formula VI.

Description

Description: [0001] The present invention relates to a novel cephalosporin compound, and more particularly, to a novel cephalosporin compound, which has a broad antibacterial spectrum against Gram-positive and Gram-negative bacteria. The present invention also relates to a cephalosporin compound that is extremely effective against Pseudomonas bacteria, a pharmacologically acceptable salt thereof, a method for producing the same, and an antibacterial agent containing the compound as an active ingredient. BACKGROUND OF THE INVENTION Cephalosporin compounds are useful compounds with antibacterial activity. Conventionally, research on its synthesis has been actively conducted, and many compounds have been produced to date, some of which currently occupy a clinically important position as antibiotics with a broad antibacterial spectrum. Currently, the cephalosporin broad-spectrum antibiotics currently in clinical use are of the Pseudomonas genus (Pseudomonas spp., represented by Pseudomonas aeruginosa).
Most of them have almost no antibacterial activity against Pseudomonas), and conversely, those that have antibacterial activity against Pseudomonas bacteria are hardly effective against Gram-positive and Gram-negative bacteria. is common. For example, cephalosporin antibiotics that are classified as broad-spectrum antibiotics include ceftazidime (CAZ), cefzonam, and flomoxef, but none of these are effective against Pseudomonas spp. Although it is effective against bacteria, its antibacterial activity against other bacteria is weak. [0003]Therefore, there has been a desire to develop a cephalosporin-based broad-spectrum antibacterial substance that has antibacterial activity against gram-positive and -negative bacteria as well as bacteria of the genus Pseudomonas. [Means for Solving the Problems] The present inventors have conducted extensive research to achieve the above problems, and have found that the following general formula (
I) [Formula, R1 and R2 are each a hydrogen atom or an amino group protecting group, R3 is a carboxyl group which may be protected by -COO- or a carboxyl group protecting group, and X is [ represents [Chemical formula 20], and Y represents [Chemical formula 21], where n is an integer of 0 to 2, R41 is a hydrogen atom, -COO-, a carboxyl group optionally substituted with an ester residue, - CONH2 or -CN,
R42 and R43 represent a hydrogen atom, an acetyl group, or a hydroxyl group-protecting group, R44 and R45 represent a hydroxyl group, one of which may be protected, and the other represents a hydrogen atom, and R46 represents a hydrogen atom or a protected group. a hydroxyl group that may be protected, and R47 represents a hydroxyl group that may be protected) and pharmacologically acceptable salts thereof have a broad antibacterial spectrum,
In particular, it was discovered that the present invention has remarkable antibacterial activity against Pseudomonas bacteria, especially Pseudomonas aeruginosa, and also against Gram-positive and -negative bacteria, leading to the completion of the present invention. . Therefore, the object of the present invention is to develop a cephalosporin that has a broad antibacterial spectrum, has remarkable antibacterial activity against Pseudomonas genus, and also has remarkable antibacterial activity against Gram-positive and -negative bacteria. The object of the present invention is to provide compound (I) or a pharmacologically acceptable salt thereof. Another object of the present invention is to provide a method for producing the cephalosporin compound (I) or a pharmacologically acceptable salt thereof. Furthermore, another object of the present invention is to provide an antibacterial agent containing the cephalosporin compound (I) or a pharmacologically acceptable salt thereof as an active ingredient. [0006] In the compound (I) of the present invention, the protecting group for the amino group for groups R1 and R2 includes, for example, phthaloyl, formyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl. , t-
Butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, diphenylmethyloxycarbonyl, methoxymethyloxycarbonyl, trityl,
Examples include trimethylsilyl. 0007
] The cephalosporin compound (I) of the present invention has the following formula (
In I'), optical activity is shown for the configuration of the carbon atom or atomic group marked with *. [Formula 22] As its optically active form, there are an optically active form having an S configuration and an optically active form having an R configuration, and both of these optically active forms and their racemic forms are included in the present invention. . Since the antibacterial activity of the optically active substance having the S configuration is about one tube higher than that of the racemic substance, the optically active substance having the S configuration is more preferable. Furthermore, there are syn and anti forms, which are geometric isomers derived from the oximino group at the 7-position side chain, and although the present application includes both forms, the syn form is preferred from the standpoint of antibacterial activity. Cephalosporin compound (I) contains pyridinium ions in the molecule, so the CO in the molecule
It is electrically neutralized by the O- group. The cephalosporin compound (I) may form a pharmacologically acceptable salt. For example, the pyridinium ion present in the molecule is neutralized with an anion outside the molecule to form a salt. Examples of such anions include formate, acetate, trifluoroacetate, oxalate,
fumarate ion, maleate ion, citrate ion,
Examples include tartrate ion, methanesulfonate ion, benzenesulfonate ion, toluenesulfonate ion, chloride ion, bromine ion, sulfate ion, nitrate ion, phosphate ion, and the like. The cephalosporin compound (I) may also form an acid addition salt at its amino group. The acid for forming such an acid addition salt is not particularly limited as long as it can form a salt with the amino group moiety and is pharmaceutically acceptable. Such acids include hydrochloric acid, sulfuric acid, phosphoric acid,
Examples include mineral acids such as nitric acid, and organic acids such as oxalic acid, fumaric acid, maleic acid, citric acid, tartaric acid, methanesulfonic acid, and toluenesulfonic acid. Furthermore, the cephalosporin compound (I) of the present invention may form a salt at its carboxyl group. Examples of such salts include alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, calcium salts, etc.), and organic bases (eg, pyridine salts, etc.). The cephalosporin compound (I) of the present invention and its pharmacologically acceptable salts are produced, for example, by any of Method A, Method B, or Method C shown below. In the chemical formula shown below, for compounds in which a pyridinium ion is present in the molecule, there is an intramolecular COO- group or an extramolecular cation as described above that electrically neutralizes the compound. Method A: A compound represented by general formula (II) and a compound represented by general formula (III) are reacted according to the following reaction formula. embedded image (wherein, Hal represents a halogen atom, R1, R2, R
3. X and Y have the meanings described above) When carrying out the above reaction, in advance,
It is preferable to protect 2, R3, X, Y, etc. as appropriate. As the amino protecting group for R1 and R2, those mentioned above are used. Further, R3 represents a carboxyl group which may be protected by -COO- or a carboxyl group-protecting group, and specifically represents a COO- group, a carboxyl group, or a carboxyl group protected by a protecting group. As this protecting group, those used for the purpose of β-lactam and peptide synthesis are conveniently adopted, and specifically, t-butyl, t-amyl, benzyl, p-nitrobenzyl, p-methoxy Benzyl, benzhydryl, phenyl, p-nitrophenyl, methoxymethyl, ethoxymethyl, benzyloxymethyl, acetoxymethyl, methylthiomethyl, trityl, 2,2,2-trichloroethyl, trimethylsilyl, dimethylsilyl, diphenylmethoxybenzenesulfonylmethyl, dimethyl Examples include aminoethyl. Starting material (II) Hal in method A
represents a halogen atom, particularly preferably a chlorine atom, a bromine atom or an iodine atom. Starting material (II
) When Hal is a chlorine atom or a bromine atom, in the reaction between this compound and other starting materials, it is preferable to add an alkali metal iodide such as sodium iodide, potassium iodide, etc. to accelerate the reaction. . The reaction is carried out in a solvent, and the reaction solvent is an aprotic solvent such as N,N-dimethylformamide (D
MF), dimethyl sulfoxide (DMSO), hexamethyl phosphate triamide (HMPA), acetonitrile, dimethoxyethane, and the like. Further, the reaction temperature is usually preferably about 0°C to room temperature. The reaction time is TL
The reaction may be completed after confirming the progress of the reaction using an appropriate confirmation means such as C. Usually, the reaction time is about 1 hour to 24 hours. Moreover, as for the amount usually used, the compound of formula (III) may be added in an amount of about 1 to 20 moles, and the alkali metal iodide may be added in an amount of about 1 to 3 moles, per 1 mole of the compound of formula (II). In the compound (I) of the present invention thus obtained, when R1, R2, R3, R41 to R47 are protected or protected, they are subjected to a protecting group removal reaction, if necessary. Methods for removing the protective group include decomposition with an acid (for example, when the protective group is a formyl group, benzhydryl group, t-butoxycarbonyl group, etc., hydrochloric acid, trifluoroacetic acid, etc.) depending on the type of the protective group. decomposition with acids), decomposition with bases (for example, if the protecting group is dichloroacetyl group or trifluoroacetyl group,
decomposed with bases such as sodium hydroxide or sodium bicarbonate), decomposed with phenols (e.g., when the protecting group is
- Methoxybenzyl group, benzhydryl group, etc. are decomposed with phenol, etc.), hydrazine decomposition (for example, when the protecting group is phthaloyl group, etc.,
(decomposed with hydrazine, etc.), catalytic reduction (for example, when the protecting group is a benzyl group, benzyloxycarbonyl group, etc., it is reductively decomposed with palladium-carbon, etc.). Conventional methods used in peptide synthesis can be appropriately selected. In method A, the compound of formula (II) used as a starting material is produced according to the reference examples in this application or JP-A-56-131590. Moreover, the compound of formula (III) which is the other starting material is
It can be manufactured according to No. 28185 or the manufacturing example of the present application. Among these, the following two compounds (VIII) and (IX) produced in the production examples of the present application are novel products and are highly useful intermediates. [Formula 24] (wherein R41 and Y have the above meanings) [Formula 25] [wherein Y' is [Formula 26] (wherein R44, R45, R46, R47 have the above meanings) )] Among these, the compound of formula (VIII) may be produced according to the following reaction formula. [Chemical formula 27] (In the formula, R48 represents a carboxyl group substituted with an ester residue or -CN, and Y has the same meaning as above) That is, represented by formula (X) and formula (XI) Both compounds were subjected to aldol-type condensation to form a double bond, and then, after introducing a protecting group if necessary, the reaction product was treated with Lawson's reagent [2,4-bis(4-methoxyphenyl)-1]. ,3-dithia-2,4-diphosphetane-
[2,4-disulfide], diphosphorus pentasulfide, etc. can be used to convert the ketone group into a thioketone group. In this reaction, the group R41 in compound (VIII) is a hydrogen atom, a carboxyl group,
If a compound of -CONH2 or -CN is desired, known methods for decarboxylation, hydrolysis, aminolysis, dehydration, etc., or a combination thereof may be carried out during or after the above reaction. Further, compounds in which R41 is a hydrogen atom (V
As another method to obtain III), according to the following reaction formula,
After the compound represented by formula (XII) and the compound represented by formula (XIII) are reacted to form a compound represented by formula (XIV), deHCNization is performed by a known method, and the same as above. A method of converting a ketone group into a thioketone group can be mentioned. [Image Omitted] (In the formula, Hal and Y have the above-mentioned meanings.) On the other hand, compound (IX) can be obtained by halogenating or aminating the compound represented by formula (XV) according to the following reaction formula, and then It is produced by 4-pyridonylation or 4-thiopyridonylation by a known method, and if necessary, further converting the ketone group into a thioketone group using diphosphorus pentasulfide, Lawesson's reagent, or the like. Compound (XV) (wherein Y' has the meaning described above)
JP-A-2-42086, JP-A-1-305081
Issue or Journal of Antibiotics
It can be prepared by deacetylation if necessary according to LIII (2) p. 189 (1990),
Further, 4-pyridonylation or 4-thiopyridonylation can be carried out, for example, by the method described in JP-A-62-492. Method B: According to the following reaction formula, a 7-aminocephalosporanic acid compound represented by the general formula (V) is converted into an acyl compound with a carboxylic acid compound represented by the general formula (IV) or a reactive derivative thereof. become embedded image (In the formula, R1, R2, R3, X and Y have the same meanings as above) The acylation reaction in method B is usually This is carried out by reacting with 1 to 3 moles of carboxylic acid compound (IV) or its reactive derivative at the carboxyl group. Regarding this reaction, examples of the salt of the 7-aminocephalosporanic acid compound (V) include hydrochloride, toluenesulfonate, and the like. Examples of the reactive derivatives of carboxylic acid compound (IV) include acid halides, acid anhydrides, active amides, and active esters. Preferred examples of acid halides include acid chlorides and acid bromides; examples of acid anhydrides include mixed acid anhydrides with acetic acid, pivalic acid, isovaleric acid, trichloroacetic acid, etc.; Examples include activated amides with pyrazole, imidazole, dimethylpyrazole, benzotriazole, etc. Examples of active esters include p-nitrophenyl ester, 2,
Examples include active esters with 4-dinitrophenyl ester, trichlorophenyl ester, 1-hydroxy-1H-2-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, and the like. In addition, in this reaction, when carboxylic acid compound (IV) is used in the form of a free acid, it is preferable to carry out the reaction in the presence of a condensing agent, and examples of the condensing agent include, for example, N, N'-
Dicyclohexylcarbodiimide, 1-ethyl-3-(
3'-dimethylaminopropyl)carbodiimide, N-
Carbodiimide compounds such as cyclohexyl-N'-morpholinoethylcarbodiimide and N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide; amide compounds such as N-methylformamide and N,N-dimethylformamide; and thionyl chloride and phosphorus oxychloride. , a reagent produced by reaction with a halide such as phosgene (so-called Vilsmeier reagent), and the like. The acylation reaction using an acid halide or acid anhydride among the reactive derivatives in this reaction is generally carried out in the presence of an acid condensing agent. Examples of the acid condensing agent include triethylamine, tributylamine, ethyldiisopropylamine, N,N-dimethylaniline, N-
Organic bases such as methylmorpholine and pyridine, alkali metal salts such as sodium, potassium or calcium hydroxides, carbonates, bicarbonates, alkaline earth metal salts, etc. are used. This acylation reaction is usually carried out in a solvent that does not adversely affect the reaction, and examples of this 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
The reaction is carried out at a temperature of .degree. C. to 40.degree. C. and is completed in about 30 minutes to 10 hours. In the compound thus obtained, when R1 and/or R2 are protecting groups, or when R3 is a protecting group protected with a carboxyl group-protecting group, the compound may be subjected to a protecting group removal reaction as necessary. . The protecting group may be removed in the same manner as Method A. 0019
Compound (IV), which is a starting material, can be added to a compound represented by general formula (XVI) according to one of the following formulas.
II) by reacting the hydroxylamine represented by
Or a compound represented by general formula (XVII) and general formula (
It can be produced by reacting the compound represented by XVIII) and optionally removing R5 (provided that R5 is a protecting group). (In the formula, R5 represents a hydrogen atom or a protective group, R6 represents a group that can be substituted by a nucleophilic reagent such as halogen, tosyloxy, mesyloxy, etc., and R1 and R2 have the meanings described above) Protecting group R5 In addition to the same protecting groups as R3 described above, ester residues such as methyl and ethyl are exemplified. The reaction between compound (XVI) and hydroxylamine compound (VII) is usually carried out using N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dioxane, tetrahydrofuran, alcohol, or other additives that do not adversely affect the reaction. It is carried out in a solvent such as a solvent or a mixture thereof with water. The time required for the reaction is usually 30 minutes to 10-odd hours. Although the reaction temperature is not particularly limited, it is usually carried out between room temperature and 60°C.
Compound (IV) having no protecting group can be obtained by removing the protecting group from the compound thus obtained, if necessary, by a method similar to that described above. Additionally, this reaction generally proceeds more quickly when a free carboxylic acid is used. The reaction between compound (XVII) and compound (XVIII) is carried out in the presence of a base such as sodium hydride, potassium tert-butoxide, potassium carbonate, or sodium carbonate, and an organic solvent such as N,N-dimethylformamide,
It is carried out in N,N-dimethylacetamide, dimethylsulfoxide, dioxane, tetrahydrofuran or other solvents that do not adversely affect the reaction. The time required for the reaction is usually 30 minutes to 10-odd hours. Although the reaction temperature is not particularly limited, it is usually carried out between room temperature and 60°C. Method C: A carboxylic acid compound represented by the general formula (VI) or a reactive derivative thereof is reacted with a hydroxylamine compound represented by the following formula (VII) according to the following reaction formula, It is produced by removing the amino group or the protecting group of R3 and/or the ester residue of R41 present in the compound produced by these reactions, if necessary. embedded image Carboxylic acid compound (VI) in method C (wherein R1, R2, R3, X and Y have the same meanings as above)
The reaction between the compound (XVI) and the hydroxylamine compound (VII) can be carried out in the same manner as the reaction between the compound (XVI) and the hydroxylamine compound (VII). The starting material in method C is the compound (
VI) can be prepared by a known method, ie, by acylating 7-aminocephalosporanic acid compound (V) with compound (XVI). The compound represented by the general formula (VII) can be prepared by a known method (for example, JP-A-55-14
No. 9289), it can be produced by reacting N-hydroxyphthalimide and a corresponding active halide in the presence of a base, followed by decomposition of hydrazine. Compound (VII) can also be synthesized (6
82, 1976), a compound represented by formula (XIX) is reacted with N-hydroxyphthalimide in the presence of triphenylphosphine and diethyl azodicarboxylate to obtain a compound represented by formula (XX), It can also be obtained by decomposing it with hydrazine. This compound (wherein R2 has the same meaning as above)
The step of reacting XX) is carried out by reacting 1 mole of compound (XIX) with triphenylphosphine and 1 to 2 moles of diethyl azodicarboxylate. This reaction is usually carried out in an inert solvent such as dioxane, tetrahydrofuran, acetonitrile, methylene chloride, benzene, or ether, preferably under non-aqueous conditions. Although the reaction temperature is not particularly limited, it is usually carried out at 0 to 30°C, and the reaction is completed in about 1 to 10 hours. Compound (XX) thus obtained can be subjected to hydrazine decomposition by a conventional method to obtain the target compound (VII). The cephalosporin compound (I) of the present invention produced by the method described above can be converted into a pharmacologically acceptable salt thereof by a method known per se. The cephalosporin compound (I) or its pharmacologically acceptable salt obtained by a known method is isolated 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 and Haas) or Diaion HP-20 (manufactured by Mitsubishi Kasei) and eluted with a water-containing organic solvent. Furthermore, if necessary, chromatography using Sephadex LM-20, G-10 (manufactured by Pharmacia), etc. is also effective. As mentioned above, the cephalosporin compound (I) of the present invention and its pharmacologically acceptable salts have excellent antibacterial activity, but when used as a medicine,
A therapeutically effective amount of the compound and, optionally, a pharmacologically acceptable excipient or excipient (e.g., diluent,
Additives such as fillers, emulsifiers, lubricants, fragrances or coloring agents) are mixed with suitable dosage forms (for example, oral preparations such as tablets, sugar coatings, capsules, injections, suppositories, external preparations, etc.). It is administered as a parenteral formulation. The dosage of the cephalosporin compound (I) of the present invention or a pharmacologically acceptable salt thereof varies depending on symptoms, body weight, age, administration method, etc., but is generally 50 mg to 10 g per day for adults. Preferably, 200 mg to 5 g is administered once a day or in divided doses. The cephalosporin compound (I) of the present invention or a pharmacologically acceptable salt thereof may be used in combination with other antibacterial active substances, such as antibacterial agents (penicillins, aminoglucosides, cephalosporins, etc.) or bacteria. Medications for treating systemic symptoms caused by infection (antipyretics, analgesics, anti-inflammatory drugs, etc.) may be used in combination. Next, the results of testing the antibacterial activity of the compound (I) of the present invention will be shown. (antibacterial effect)
The minimum inhibitory concentration (MIC) of the compounds according to the invention was determined and the results are shown in Table 1. As a control, ceftazidime (C
AZ) and the compound 7-[2-(2-aminothiazol-4-yl) of Example 19 of JP-A-64-56682.
-2-(2-amino-1-ethylethoxyimino)acetamide]-cephalosporanic acid (syn isomer) (comparative example) was used. The amount of inoculated bacteria is 106 cfu/ml.
And so. (Results) [Table 1] [Effect of the invention] The cephalosporin compound according to the present invention (
I) or a pharmacologically acceptable salt thereof has significant antibacterial activity against Gram-positive and Gram-negative bacteria;
It exhibits remarkable antibacterial activity against Pseudomonas aeruginosa, for which known cephalosporin compounds do not exhibit antibacterial activity, and is also a valuable antibacterial agent against common Gram-positive and Gram-negative bacteria. Also, cephalosporin compound (I) 250
mg/kg was administered intraperitoneally to 5 rats, but no deaths were observed, indicating low toxicity and favorable pharmacokinetics.
The cephalosporin compound (I) of the present invention or a pharmacologically acceptable addition salt thereof can be used alone or as a pharmaceutical composition as a therapeutic agent for infectious diseases. [Example] Next, the present invention will be explained in more detail by referring to Reference Examples and Examples, but the present invention is not limited thereto. Reference Example 1 (a) 2-(2-tritylaminothiazol-4-yl)-2-(2-t-butyloxycarbonylamino-1
-Synthesis of hydrazine salt (syn isomer) of ethylethoxyimino)acetic acid: 2-(2-tritylaminothiazole-
Sodium salt of 4-yl)glyoxylic acid 230.0
L(+ ) tartrate
174.2 g was added and stirred at room temperature (25°C) for 0.5 hour. Tetrahydrofuran was distilled off under reduced pressure, extracted twice with 1.5 liters of ethyl acetate and then 0.5 liters, and the organic layer was washed with 1.0 liters of saturated brine and dried over anhydrous sodium sulfate. After filtering the sodium sulfate, wash with 0.2 l of ethyl acetate, add ethyl acetate to the filtrate,
The total volume was 5 liters. Add hydrazine hydrate to this 2
2.4 ml was added and left standing at 5°C for 15 hours. The precipitated crystals were collected by filtration, washed with ethyl acetate, and dried under reduced pressure to obtain 224 g of the title compound. (b) Synthesis of dicyclohexylamine salt (syn isomer) of 2-(2-tritylaminothiazol-4-yl)-2-(2-t-butyloxycarbonylamino-1-ethylethoxyimino)acetic acid :2-(2-tritylaminothiazol-4-yl)-2-(2-t-
Suspend 220 g of hydrazine salt (syn isomer) of butyloxycarbonylamino-1-ethylethoxyimino)acetic acid in 1.2 liters of ethyl acetate, and suspend 1.2 liters of 10% citric acid aqueous solution.
．． 0l, 5% saline 1.0l, then saturated saline 1
．． It was washed sequentially with 0 liters. The organic layer was dried over anhydrous sodium sulfate, and after filtering off the sodium sulfate, 0.0% ethyl acetate was added.
The filtrate was washed with 1 liter of water, and the filtrate was concentrated to about 0.8 liter under reduced pressure. Add 64.1ml of dicyclohexylamine to this.
was added thereto, and crystallization was allowed to stand for 2 hours under ice cooling (5°C). The precipitated crystals were filtered, washed with 0.2 liters of ethyl acetate, and then dried under reduced pressure to obtain 258 g of the title compound. 1H-NMR (δppm, CDCl3): 1.41 (
9H, s) 2.94 (2H, m) 3.2-3.5
(2H, m) 4.23 (1H, m) 6.55 (1H
, s) 7.2-7.4 (15H, m) MS (FAB
) 601 (MH+)0029](C)7β-[
(Z)-2-(2-tritylaminothiazol-4yl)-2-(2-t-butyloxycarbonylamino-1
-ethylethoxyimino)acetamide]-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester synthesis: 2-(2-tritylaminothiazol-4-yl)-2-(2-t- Dicyclohexylamine salt of butyloxycarbonylamino-1-ethylethoxyimino)acetic acid 22.5 g (25.9 mmo)
l) and ACLE. Add 10.93 g (25.9 mmol) of HCl salt (manufactured by Otsuka Chemical) to methylene chloride.
It was suspended in 200 ml and cooled to -10°C. 6.28 ml (77.6 mmol) of pyridine was added, and 4.83 ml (51.8 mmol) of phosphorus oxychloride was added dropwise at the same temperature over 10 minutes, followed by further stirring for 10 minutes. 1.5 liters of ethyl acetate was added, and the mixture was washed successively with a 10% aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution, and then a saturated saline solution (each 150 ml twice), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and a mixture of ethyl acetate and benzene (1:1) was added.
After dissolving in 0ml, silica gel column chromatography (
Manufactured by Merck & Co., Ltd. Art. 7734, 100 g, purified with ethyl acetate:benzene = 1:3), concentrated the target fraction, poured into a mixture of n-hexane-isopropyl ether (2:1), and obtained the title compound (light brown powder). 19.28g was obtained. 1H-NMR (δppm, DMSO-d6): 0.6~
1.2 (3H, m), 1.35 (9H, s), 1.2~
1.8 (2H, m), 2.9-3.4 (2H, m), 3
．． 60 (2H, m), 3.70 (3H, s), 3.8~
4.1 (1H, m), 4.49 (2H, s), 5.0~
5.3 (3H, m), 5.77 (1H, dd, J=5H
z, 8Hz), 6.4-6.7 (1H, br), 6.6
2 (1H, s), 6.7-7.5 (19H, m), 8.
75 (1H, bs), 9.37 (1H, d, J=8Hz
) MASS (FAB) 953,952 (MH+) Reference Example 2 (a) Synthesis of 1-[3,4-di(t-butyloxycarbonyloxy)phenyl]-4-pyridone: 1-(3
, 4-dihydroxyphenyl)-4-hydroxypyridinium bromide (1.42 g (5.0 mmol)) in a dioxane-water mixed solvent (dioxane:water = 4:1) 25
ml, 1N sodium hydroxide aqueous solution 10ml
l, di-t-butyl dicarbonate 2.18g (1
0.0 mmol) and stirred at room temperature for 18 hours. Add 50 ml of chloroform to the reaction solution, and add 50 ml of saturated saline.
Washed with 0ml. The organic layer was
an) After passing through 1PS filter paper, it was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Merck,
Art. 9385, 25g) and chloroform-methanol solvent (chloroform:methanol = 20:1).
1.42 g (70.4%) of the title compound was obtained as the eluate. 1H-NMR (δppm, CDCl3):
1.57 (18H, s), 6.48 (2H, d, J=7
．． 9Hz), 7.22 (1H, dd, J=8.9Hz
, 2.6Hz), 7.33 (1H, d, J=2.6Hz
), 7.42 (1H, d, J = 8.9Hz), 7.54
(2H, d, J=7.9Hz) MASS (FAB) 4
04(MH+) (b) 1-[3,4-di(
t-butyloxycarbonyloxy)phenyl]-4-
Synthesis of thiopyridone: 1-[3,4-di(t-butyloxycarbonyloxy)phenyl]-4-pyridone 435.5 mg (1.
1 mmol) was dissolved in 5 ml of dimethoxyethane, and 1.2 ml of pyridine was added. Add Lawson's reagent 2 to this
43 mg (0.6 mmol) was added and stirred for 1 hour. The reaction solution was concentrated under reduced pressure and subjected to silica gel column chromatography (Merck & Co., Art. 9385, 10 g).
and eluted with chloroform. After concentration under reduced pressure, a mixed solvent of ether-hexane (ether:hexane=1) was added to the residue.
:1) was added, and the precipitate precipitated was collected by filtration. A small amount of ether-hexane mixed solvent (ether:hexane=1:1
) to give 253.5 mg (54.9%) of the title compound.
get. 1H-NMR (δppm, CDCl3): 1.57 (
18H, s), 7.25 (1H, dd, J=8.9Hz
, 2.6Hz), 7.34 (2H, d, J=7.9Hz
), 7.37 (1H, d, J=2.6Hz), 7.44
(1H, d, J=8.9Hz), 7.50 (2H, d,
J=7.9Hz) MASS (FAB) 420 (MH
+) Reference Example 3 (a) Synthesis of 1-[3,4-di(t-butyloxycarbonyloxy)phenethyl]-4-pyridone: 1-(
3,4-dihydroxyphenethyl)-4-hydroxypyridinium bromide 862.7 mg (2.76 mm
ol) in a dioxane-water mixed solvent (dioxane:water=
2:1) Dissolved in 9 ml, 4 ml of 1N aqueous sodium hydroxide solution, di-t-butyl dicarbonate 2.4
4 g (11.2 mmol) was added and stirred at room temperature for 2 hours. To complete the reaction, 2 ml of 1N aqueous sodium hydroxide solution, di-t-butyl dicarbonate
2.44 g (11.2 mmol) was further added and stirred at room temperature for 2 hours. Add 50 ml of chloroform to the reaction solution, 50 ml of 50% saturated saline, and 50 ml of saturated saline.
Washed twice with l. Whatman 1P organic layer
After passing through S filter paper, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Merck, Art.
9385, 10 g) and eluted with chloroform-methanol (chloroform:methanol=15:1). After concentration under reduced pressure, ether was added to the residue, and the precipitate precipitated was collected by filtration to obtain 727.1 mg (61.0%) of the title compound. 1H-NMR (δppm, CDCl3): 1.54 (
9H, s), 1.55 (9H, s), 3.02 (2H,
t, J=7.0Hz), 3.96 (2H, t, J=7.
0Hz), 6.32 (2H, d, J=7.3Hz), 6
．． 88 (1H, dd, J=8.3Hz, 2.0Hz),
7.03 (1H, d, J = 2.0Hz), 7.12 (
2H, d, J=7.3Hz), 7.19 (1H, d,
J=8.3Hz) MASS (FAB) 432 (MH
+) (b) Synthesis of 1-[3,4-di(t-butyloxycarbonyloxy)phenethyl]-4-thiopyridone: 1-[3,4-di(t-butyloxycarbonyloxy)phenethyl ]-4-pyridone 647.3 mg (1
．． Dissolve 5 mmol) in 7 ml of dimethoxyethane,
1.8 ml of pyridine was added. 64.5 mg (0.9 mmol) of Lawson's reagent 3 was added to this, and the mixture was refluxed for 1 hour. The reaction solution was concentrated under reduced pressure and subjected to silica gel column chromatography (manufactured by Merck & Co., Art. 9385, 10 g) to obtain 620 m of the title compound as a chloroform eluate.
g (92.3%) was obtained. 1H-NMR (δppm, CDCl3): 1.55 (
18H, s), 3.05 (2H, t, J=7.0Hz)
, 4.04 (2H, t, J=7.0Hz), 6.87
(1H, dd, J=8.3Hz, 2.0Hz), 6.9
4 (2H, d, J = 7.3Hz), 7.05 (1H, d
, J=2.0Hz), 7.19 (1H, d, J=8.3
Hz), 7.39 (2H, d, J = 7.3Hz) MAS
S (FAB) 448 (MH+) 0034 Production
Example 1 (a) Synthesis of 2-chloromethyl-4,5-di(p-methoxybenzyloxy)pyridine: 2-chloromethyl-4,5-di(p-methoxybenzyloxy)pyridine prepared by the method described in JP-A-2-42086.
Hydroxymethyl-4,5-di(p-methoxybenzyloxy)pyridine 943 mg (2.5 mmol) was dissolved in benzene 15 ml, and triethylamine 2.07
ml (14.9 mmol) was added, and after cooling to 0° C., 903 μl (12.4 mmol) of thionyl chloride was added dropwise. The mixture was stirred at 0° C. for 45 minutes and then at room temperature for 1 hour. Next, the pH was adjusted to 4 with 7% aqueous ammonia, extracted with chloroform, washed with saturated saline, filtered through Whatman 1PS filter paper, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (manufactured by Merck & Co., Art. 9385).
, 43 g) to obtain 436 mg (44%) of the title compound as a methylene chloride eluate. 1H-NMR (δppm, CDCl3): 3.80 (
3H, s), 3.82 (3H, s), 4.56 (2H,
s), 5.09 (2H, s), 5.13 (2H, s
), 6.87 (2H, d, J=8.6Hz), 6.9
2 (2H, d, J = 8.6Hz), 7.04 (1H, s
), 7.31 (2H, d, J=8.6Hz), 7.36
(2H, d, J=8.6Hz), 8.10 (1H, s)
MASS (FAB) 400, 402 (MH+) (b) Synthesis of 2-(4-pyridon-1-yl)methyl-4,5-di(p-methoxybenzyloxy)pyridine: 4-hydroxypyridine 48 mg (0.5 mmol)
was suspended in 2 ml of tetrahydrofuran, and potassium
56 mg (0.5 mmol) of t-butoxide was added and stirred at room temperature for 18 hours. To this, 2-chloromethyl-
4,5-di(p-methoxybenzyloxy)pyridine
200 mg (0.5 mmol) was added and heated under reflux for 3 hours. Water was added to the reaction solution, extracted with chloroform, washed with saturated saline, filtered with Whatman 1PS filter paper,
The solvent was distilled off. The residue was subjected to silica gel column chromatography (manufactured by Merck & Co., Art. 9385, 10 g), and a chloroform-methanol mixture (chloroform:
The title compound was obtained as an eluate with methanol = 50:1).
107 mg (46%) was obtained. 1H-NMR (δppm, CDCl3): 3.81 (
3H, s), 3.83 (3H, s), 4.85 (2H,
s), 5.09 (2H, s), 5.11 (2H, s),
6.38 (2H, d, J = 7.6Hz), 6.57 (1
H, s), 6.88 (2H, d, J=8.6Hz), 6
．． 90 (2H, d, J=8.6Hz), 7.24-7.
34 (6H, m), 8.11 (1H, s) MASS (FAB) 459 (MH+) 0036]
(C) 2-(4-thiopyridon-1-yl)methyl-4
,5-di(p-methoxybenzyloxy)pyridine: 2-[4-pyridon-1-yl]methyl-4,5-di(
p-methoxybenzyloxy)pyridine 102mg (
0.22 mmol) was dissolved in 2 ml of pyridine and heated to 0°C.
After cooling to 74mg (0.33mmol
) was added, and the mixture was heated and stirred at 80°C. After 30 minutes, the solvent was distilled off, a small amount of water was added, the pH was adjusted to 7.5 with saturated sodium bicarbonate solution, the mixture was extracted with chloroform, and washed with saturated brine. After passing this through Whatman 1PS filter paper, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (manufactured by Merck & Co., Art. 9385, 4 g) to obtain chloroform-methanol (chloroform:methanol = 100:
58 mg (55%) of the title compound as the eluate of 1)
I got it. 1H-NMR (δppm, CDCl3): 3.81 (
3H, s), 3.84 (3H, s), 4.91 (2H,
s), 5.11 (4H, s), 6.64 (1H, s),
6.89 (2H, d, J = 8.6Hz), 6.92 (2
H, d, J = 8.6Hz), 7.13 (2H, d, J =
7.1Hz), 7.27 (2H, d, J=8.6Hz)
,7.32(2H,d,J=8.6Hz),7.42(
2H, d, J = 7.1Hz), 8.11 (1H, s) M
Made of ASS (FAB) 475 (MH+) 0037
Example 2 (a) 1-ethoxycarbonylmethyl-4
-Synthesis of pyridone: 4-hydroxypyridine 2.74g (28.8mmo
1) was suspended in 32 ml of tetrahydrofuran, and 3.26 g (29.0 mmol) of potassium t-butoxide was added.
) and stirred at room temperature for 18 hours. 2.26 ml (20.4 mmol) of ethyl bromoacetate was added, and the mixture was stirred at the same temperature for 6 hours. The reaction solution was poured into a 10% aqueous citric acid solution and extracted 20 times with chloroform. The organic layer was passed through Whatman 1PS filter paper, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (manufactured by Merck & Co., Art. 9385, 100 g),
2.34 g of the title compound as eluate with chloroform-methanol (chloroform:methanol = 15:1)
(63.3% from ethyl bromoacetate). (b) Synthesis of 3,4-di(methoxymethyloxy)benzaldehyde: 1.38 g of 3,4-dihydroxybenzaldehyde (
Dissolve 10.0 mmol) in 30 ml of tetrahydrofuran to create a mineral oil dispersion of 60% sodium hydride 840
mg (21 mmol) was added. 1.9 ml (25.0 mmol) of chloromethyl methyl ether was added at 0°C, and the mixture was gradually warmed and stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and 50 ml of chloroform was added to the residue. After washing twice with 50 ml of saturated brine, the organic layer was passed through Whatman 1PS filter paper and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (manufactured by Merck & Co., Art. 9385, 100 g) and eluted with a chloroform-hexane mixture (chloroform:hexane = 3:1) to obtain 1.18 g (52.2%) of the title compound.
I got it. (c) Synthesis of ethyl 3',4'-dimethoxymethyloxy-2-(4-pyridon-1-yl)cinnamate: 1-ethoxycarbonylmethyl-4-pyridone 543
．． 6 mg (3.0 mmol) and 678.9 mg (3.4-di(methoxymethyloxy)benzaldehyde).
Dissolve 0 mmol) in 9 ml of dry benzene and add 5 to 1
Stir at 0°C. Sodium 69mg (3.0mm
A solution prepared by dissolving ol) in 1.8 ml of ethanol was added dropwise, and the mixture was stirred at the same temperature for 10 minutes and then further stirred at room temperature for 2 hours. Pour the reaction solution into 40 ml of chloroform and
After adjusting the pH to 7.0 with % citric acid aqueous solution, the layers were separated, and the organic layer was washed twice with 40 ml of saturated saline, and then washed with Whatman 1
After passing through PS filter paper, it was concentrated under reduced pressure. The residue was purified by column chromatography (elution solvent: chloroform → chloroform:methanol = 10:1) using 10 g of silica gel (manufactured by Merck & Co., Art. 9385), and the desired fractions were collected to obtain the title compound 442.8.
mg (37.9%). 1H-NMR (δppm, CDCl3): 1.34 (
3H, t, J=7Hz), 3.45 (3H, s), 3.
50 (3H, s), 4.34 (2H, q, J=7Hz)
, 5.10 (2H, s), 5.26 (2H, s), 6.
47 (2H, d, J = 8Hz), 6.85 (1H, dd
, J=2Hz, 9Hz) 6.96 (1H, d, J=2H
z), 7.14 (1H, d, J = 9Hz), 7.17 (
2H, d, J = 8Hz), 7.75 (1H, s) MAS
S(FAB) 390(MH+) (d) p-methoxybenzyl 3',4
'-dimethoxymethyloxy-2-(4-pyridone-1
Synthesis of ethyl 3',4'-dimethoxymethyloxy-2-(
4-pyridon-1-yl) cinnamate 134.0m
g was dissolved in 1.3 ml of a tetrahydrofuran-water mixed solvent (tetrahydrofuran:water = 9:1), 16.2 mg (10.39 mmol) of lithium hydroxide monohydrate was added, and the mixture was stirred at 45°C for 4 hours. The reaction solution was concentrated under reduced pressure, and 1.3 mL of N,N-dimethylformamide was added to the resulting residue.
ml was added. 140 μl (1.05 mmol) of p-methoxybenzyl chloride was added dropwise to the reaction solution, and the mixture was stirred at room temperature overnight. Pour the reaction solution into 40 ml of chloroform and add 40 ml of saturated aqueous sodium hydrogen carbonate solution.
ml and twice with 40 ml of saturated saline. The organic layer was passed through Whatman 1PS filter paper, and then concentrated under reduced pressure. The residue was treated with silica gel (manufactured by Merck & Co., Art. 93).
85) Column chromatography using 10g (elution solvent chloroform → chloroform: methanol =
The desired fractions were collected to obtain 132.0 mg (78.3%) of the title compound. 1H-NMR (δppm, CDCl3): 3.43 (
3H, s), 3.49 (3H, s), 3.82 (3H,
s), 5.09 (2H, s), 5.24 (2H, s),
5.25 (2H, s), 6.45 (2H, d, J=7H
z), 6.83 (1H, dd, J=2Hz, 9Hz),
6.91 (2H, d, J=9Hz), 6.94 (1H,
d, J=2Hz), 7.12 (1H, d, J=9Hz)
, 7.15 (2H, d, J = 7Hz), 7.32 (2H
, d, J=9Hz), 7.73 (1H, s) MASS(
FAB) 482 (MH+) 0041] (e) p
-Methoxybenzyl 3',4'-dimethoxymethyloxy-2-(4-thiopyridon-1-yl)cinnamate synthesis: p-methoxybenzyl 3',4'-dimethoxymethyloxy-2-(4-pyridone-1 −il)
Dissolve 119.2 mg (0.25 mmol) of cinnamate in 1.2 ml of dimethoxyethane, and dissolve 0.2 mg (0.25 mmol) of cinnamate in 1.2 ml of dimethoxyethane.
3ml was added. Lawson's reagent 60.1 mg (0.1
5 mmol) was added thereto, and the mixture was refluxed for 1 hour. The reaction solution was concentrated under reduced pressure and silica gel (manufactured by Merck & Co., Art. 938
5) Purification was performed by column chromatography (chloroform) using 10 g, and the desired fractions were collected to obtain 120.3 mg (96.7%) of the title compound. 1H-N
MR (δppm, CDCl3): 3.46 (3H, s
), 3.49 (3H, s), 3.82 (3H, s),
5.12 (2H, s), 5.24 (2H, s), 5.2
5 (2H, s), 6.81 (1H, dd, J=2Hz,
9Hz), 6.91 (2H, d, J=9Hz), 6.9
3 (1H, d, J = 2Hz), 6.97 (2H, d, J
=7Hz), 7.13 (1H, d, J = 9Hz), 7.
32 (2H, d, J=9Hz), 7.47 (2H, d,
J = 7Hz), 7.76 (1H, s) MASS (FAB
) 498(MH+) [0042] Production Example 3 (a) Synthesis of 1-diphenylmethyloxy-5-(p-methoxybenzyloxy)-2-(N-phthalimidyl)methyl-4-pyridone: Journal of Antibiotics XLKI
1-diphenylmethyloxy-2-hydroxymethyl-5-(p-methoxybenzyloxy), prepared by the method described in II(2) 189 p. 8 (1990).
-4-pyridone 1.47g (3.2mmol) in THF
Dissolve in 25 ml and add 500 mg of phthalimide (3.4 m
mol) and triphenylphosphine 2.55 g (9.
7 mmol) was added thereto, and 1.53 ml (9.7 mmol) of diethyl azodicarboxylate was added dropwise under ice-cooling, followed by stirring at room temperature for 1 hour. THF was distilled off, and the residue was subjected to silica gel column chromatography (Merck & Co., Art. 7734,
90g) to obtain 1.85g (97.4%) of the title compound as a chloroform-methanol (chloroform:methanol=100:1) eluate. 1H-NMR (δppm, CDCl3): 3.80 (3
H, s), 4.62 (2H, s), 4.63 (2H, s
), 6.00 (1H, s), 6.24 (1H, s), 6
．． 64 (1H, s), 6.85 (2H, d, J = 8.6
Hz), 7.16 (2H, d, J=8.6Hz), 7.
36-7.44 (10H, m), 7.75-7.80 (
2H, m), 7.85-7.89 (2H, m) MASS
(FAB)573(MH+) 0043 (b) 2-Aminomethyl-1-diphenylmethyloxy-5-(p-methoxybenzyloxy)
Synthesis of -4-pyridone: 1-diphenylmethyloxy-5-(p-methoxybenzyloxy)-2-(N-phthalimidyl)methyl-4
- Dissolve 228 mg (0.4 mmol) of pyridone in 4 ml of methylene chloride, and dissolve 30 ml (0.4 mmol) of hydrazine monohydrate in 4 ml of methylene chloride.
．． After stirring at room temperature for 2 days, the precipitate was filtered off, washed with methylene chloride, and the filtrate was concentrated under reduced pressure. 190 mg of the obtained residue was subjected to silica gel column chromatography (manufactured by Merck & Co., Art. 9385, 6 g) to obtain 121 mg of the title compound as a chloroform-methanol (chloroform:methanol = 10:1) eluate.
(68.7%) was obtained. 1H-NMR (δppm, CDCl3): 3.56 (2
H, s), 3.79 (3H, s), 4.73 (2H, s
), 6.00 (1H, s), 6.29 (1H, s), 6
．． 71 (1H, s), 6.85 (2H, d, J = 8.6
Hz), 7.20 (2H, d, J=8.6Hz), 7.
25-7.28 (4H, m), 7.38-7.40 (6
H, m) MASS (FAB) 443 (MH+) (c) 1-diphenylmethyloxy-5
-Synthesis of (p-methoxybenzyloxy)-2-(4-thiopyridon-1-yl)methyl-4-pyridone: 2-
Aminomethyl-1-diphenylmethyloxy-5-(p
-methoxybenzyloxy)-4-pyridone 108mg
(0.24 mmol) was dissolved in 2 ml of ethanol, and 27 mg (0.24 mmol) of pyran-4-thione prepared by the method described in JP-A-62-492 was added.
Stir at 80°C for 2.5 hours. Ethanol was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (manufactured by Merck & Co., Art. 9385, 5 g), and chloroform-methanol (chloroform: methanol = 20:
1) As the eluate, 108 mg (82.5%) of the title compound
) was obtained. 1H-NMR (δppm, CDCl3): 3.78 (3
H, s), 4.51 (2H, s), 4.77 (2H, s
), 5.83 (1H, s), 6.05 (1H, s), 6
．． 71 (2H, d, J = 7.3Hz), 6.85 (2H
, d, J=8.6Hz), 6.92 (1H, s), 7.
16-7.22 (4H, m), 7.29 (2H, d, J
= 8.6Hz), 7.30 (2H, d, J = 7.3Hz
)7.40~7.47 (6H, m) MASS (FAB)
537(MH+) Production Example 4 Ethyl 3',4'-di(methoxymethyloxy)-
Synthesis of 2-(4-thiopyridon-1-yl)cinnamate: Ethyl 3',4'-dimethoxymethyloxy-2
-(4-pyridon-1-yl)cinnamate 442.8
mg (1.14 mmol) in dimethoxyethane 4.5 m
1.1 ml of pyridine was added. 273.3 mg (0.38 mmol) of Lawson's reagent was added to this, and the mixture was refluxed for 1 hour. The reaction solution was concentrated under reduced pressure and subjected to silica gel column chromatography (manufactured by Merck & Co., Art. 93).
1H-NMR (δppm, CDCl3): 1.35 (3
H, t, J=7.2Hz), 3.47 (3H, s), 3
．． 50 (3H, s) 4.34 (2H, q, J = 7.2H
z), 5.10 (2H, s), 5.26 (2H, s),
6.84 (1H, dd, J=8.6Hz, 2.0Hz)
, 6.95 (1H, d, J = 2.0Hz), 6.79 (
2H, d, J = 7.1Hz), 7.15 (1H, d, J
= 8.6Hz), 7.49 (2H, d, J = 7.1Hz
), 7.78 (1H, s) MASS (FAB) 40
6(MH+) Example 1 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-amino-1-ethylethoxyimino)
acetamido]-3-[1-(3,4-diacetoxyphenyl)pyridinium-4-yl]thiomethyl-3-
Synthesis of cephem-4-carboxylate trifluoroacetate: 7β-[(Z)-2-(2-
tritylaminothiazol-4-yl)-2-(2-t
-butyloxycarbonylamino-1-ethylethoxyimino)acetamide]-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 951.7 mg (1.0 mmol) and N,N-dimethylformamide 9. 5 ml of the solution, 300 mg (2.0 mmol) of sodium iodide was added thereto, and the mixture was stirred at 5 to 10°C for 20 minutes under an argon stream. Japanese Patent Publication No. 2-281
303.4 mg of 1-(3,4-diacetoxyphenyl)-4-thiopyridone prepared according to Example 1 of No. 85
(1.0 mmol) was added and stirred at the same temperature for 2 hours. After pouring the reaction solution into 150 ml of water and filtering the precipitate,
Washed with water. The precipitate was dissolved in chloroform, anhydrous magnesium sulfate was added, and after stirring at room temperature for 30 minutes, the magnesium sulfate was removed by filtration. The filtrate was concentrated under reduced pressure to give 7β-[(
Z)-2-(2-aminothiazol-4-yl)-2-
(2-amino-1-ethylethoxyimino)acetamide]-3-[1-(3,4-diacetoxyphenyl)pyridinium-4-yl]thiomethyl-3-cephem-
1.26 g of a protected form of 4-carboxylate iodide was obtained. 1.12 g (0.8 mmol) of the obtained protector was dissolved in 3.36 ml of anisole, and while stirring at 0 to 5°C, 5.6 ml of trifluoroacetic acid was added dropwise over 15 minutes, followed by stirring at the same temperature for 2 hours. . Add 150 ml of diethyl ether to the reaction solution and stir at the same temperature for 30 minutes. The precipitate precipitated was filtered and washed with diethyl ether to obtain 788 mg (0.8 mmol, yield) of the title compound.
93.6%). 1H-NMR (δppm, DMSO-d6): 1.03
(3H, t, J=7Hz), 1.65-1.90 (2H
, m), 2.48 (3H, s), 2.49 (3H, s)
, 3.15-3.30 (2H, m), 4.25-4.4
0 (1H, m), 4.61 (2H, s), 5.38 (1
H, d, J = 5Hz), 6.02 (1H, dd, J = 5
Hz, 8Hz), 6.97 (1H, s), 7.80 (1
H, d, J = 9Hz), 7.94 (1H, dd, J = 3
Hz, 9Hz), 8.05 (1H, d, J=3Hz),
8.29 (2H, d, J = 7Hz), 9.17 (2H,
d, J=7Hz), 9.51 (1H, d, J=8Hz)
MASS (FAB) 756 (MH+) 0047]
Example 2 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-amino-1-ethylethoxyimino)
acetamido]-3-[1-(3,4-dihydroxyphenyl)pyridinium-4-yl]thiomethyl-3-
Synthesis of cephem-4-carboxylate/acetate: 7β
-[(Z)-2-(2-tritylaminothiazole-4
-yl)-2-(2-t-butyloxycarbonylamino-1-ethylethoxyimino)acetamide]-3-
Chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 380.6 mg (0.4 mmo
1) was dissolved in 4 ml of N,N-dimethylformamide, and 120 mg (0.8 mmol) of sodium iodide was added. The mixture was stirred at 5 to 10°C for 20 minutes under an argon stream. 1-[3,4-di(t-
Add 167.8 mg (0.4 mmol) of butyloxycarbonyloxy)phenyl]-4-thiopyridone,
The mixture was stirred at the same temperature for 2 hours. The reaction solution was poured into 50 ml of water, and the precipitate precipitated was filtered, washed with water, and dried under reduced pressure to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-amino -1-ethylethoxyimino)
acetamido]-3-[1-(3,4-dihydroxyphenyl)pyridinium-4-yl]thiomethyl-3-
Protected form of cephem-4-carboxylate/iodide 5
10 mg was obtained. 200 mg (0.1
Dissolve 4 mmol) in 600 μl of anisole and
While stirring at 5° C., 1 ml of trifluoroacetic acid was added dropwise over 15 minutes, and the mixture was stirred at the same temperature for 2.5 hours. Add 12 ml of diethyl ether to the reaction solution and stir at the same temperature for 30 ml.
Stir for a minute. The deposited precipitate was filtered and washed with diethyl ether to obtain crude 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-amino-1-ethylethoxyimino)acetamide]- 3-[1-(3,4
-dihydroxyphenyl)pyridinium-4-yl]
Thiomethyl-3-cephem-4-carboxylate trifluoroacetate was obtained. This compound obtained is mixed with water.
The solution was dissolved in 20 ml and subjected to column chromatography using Diaion HP-20, eluted with 8% acetonitrile-hydrochloric acid solution (pH 0.7), and the desired fractions were collected. After concentration under reduced pressure, lyophilization yielded the title compound 84
．． 2 mg was obtained. 1H-NMR (δppm, DMSO-d6): 0.96
(3H, t, J=7Hz), 1.65-1.90 (2H
, m), 4.35-4.45 (1H, m), 4.54 (
2H, s), 5.31 (1H, d, J=5Hz), 5.
95 (1H, dd, J = 5Hz, 8Hz), 7.04 (
1H, s), 7.06 (1H, d, J=9Hz), 7.
14 (1H, dd, J = 3Hz, 9Hz), 7.27 (
1H, d, J = 3Hz), 8.17 (2H, d, J = 7
Hz), 8.98 (2H, d, J=7Hz), 9.73
(1H, d, J=8Hz) MASS (FAB) 67
2(MH+) Example 3 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-amino-1-ethylethoxyimino)
acetamido]-3-[1-(3,4-dihydroxyphenethyl)pyridinium-4-yl]thiomethyl-3
Synthesis of -cephem-4-carboxylate trifluoroacetate: 7β-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-(2-t-butyloxycarbonylamino-1- ethyl ethoxyimino)acetamide]-
3-chloromethyl-3-cephem-4-carboxylic acid p
-methoxybenzyl ester 951.6 mg (1.0 m
mol) in 9.5 ml of N,N-dimethylformamide, and dissolved 300 mg of sodium iodide (2.0 mmol) in 9.5 ml of N,N-dimethylformamide.
1) was added thereto, and the mixture was stirred at 5 to 10°C for 20 minutes under an argon stream. Add 447.6 mg (1.0 mmol) of 1-[3,4-di(t-butyloxycarbonyloxy)phenethyl]-4-thiopyridone prepared in Reference Example 3,
The mixture was stirred at the same temperature for 2 hours. The reaction solution was poured into 120 ml of water, and the precipitate precipitated was filtered and washed with water. The precipitate was dried under reduced pressure to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-amino-1-ethylethoxyimino)acetamide]-3-[1-(3 , 4-dihydroxyphenethyl)pyridinium-4-yl]thiomethyl-3-cephem-4-carboxylate/iodide (1.35 g) was obtained. Obtained protector 200
Dissolve mg (0.13 mmol) in 600 μl of anisole and add 1 ml of trifluoroacetic acid while stirring at 0 to 5°C.
ml was added dropwise over 15 minutes and stirred at the same temperature for 2.5 hours. 15 ml of diethyl ether was added to the reaction solution, and the mixture was stirred at the same temperature for 30 minutes. The precipitate precipitated was filtered and washed with diethyl ether to obtain 115 mg of the title compound.
(0.12 mmol, yield 86.3%)
Ta. 1H-NMR (δppm, DMSO-d6): 0.97 (3H, t, J = 7Hz), 1.65-1.8
5 (2H, m), 3.10 (2H, t, J=6Hz),
4.25-4.35 (1H, m), 4.45 (2H
, s) 4.69 (2H, t, J=6Hz), 5
．． 31 (1H, d, J=5Hz), 5.97
(1H, dd, J=5Hz, 8Hz), 6.48 (1H
, dd, J=3Hz, 9Hz), 6.67(1H, d,
J=3Hz), 6.72 (1H, d, J=9Hz)
6.92 (1H, s), 8.04 (2H, d, J=
7Hz), 8.73 (2H, d, J=7Hz), 9.4
5 (1H, d, J=8Hz) MASS (FAB) 7
00(MH+) Example 4 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-amino-1-ethylethoxyimino)
acetamido]-3-[1-(5-hydroxy-4-pyridon-2-ylmethyl)pyridinium-4-yl]
Synthesis of thiomethyl-3-cephem-4-carboxylate trifluoroacetate: (a) 7β-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-(2-t-butyl oxycarbonylamino-1-ethylethoxyimino)acetamide]-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 106 mg (0
．． 11 mmol) was dissolved in 500 μl of N,N-dimethylformamide, cooled to 10°C under an argon stream, added with 34 mg (0.22 mmol) of sodium iodide, and stirred at 0 to 10°C for 20 minutes, followed by production. A solution of 53 mg (0.11 mmol) of 2-(4-thiopyridon-1-yl)methyl-4,5-di(p-methoxybenzyloxy)pyridine prepared according to Example 1 in 500 μl of N,N-dimethylformamide was added dropwise. . After further stirring for 2 hours at 0 to 10°C, the reaction solution was poured into 8 ml of water, stirred for 3 minutes, and the precipitate was collected by filtration. This was washed with water, and the obtained solid was dissolved in methylene chloride.
After washing with 2 ml of % saline solution and 2 ml of saturated saline solution, and drying over anhydrous sodium sulfate, the solvent was distilled off to give 7β-[(Z)-2-(2-aminothiazole-4-
yl)-2-(2-amino-1-ethylethoxyimino)acetamide]-3-[1-(5-hydroxy-4-
pyridon-2-yl)methylpyridinium-4-yl]thiomethyl-3-cephem-4-carboxylate.
156 mg of protected iodide was obtained. Obtained protector 1
56 mg was dissolved in 450 μl of anisole, and 750 μl of trifluoroacetic acid was added dropwise in an ice bath under an argon stream. After stirring this at 0 to 10°C for 2.5 hours,
0 ml of ether was added, and the mixture was further stirred at 0 to 10°C for 50 minutes. The precipitate was collected by filtration, washed with 50 ml of ether, and dried to obtain 97 mg of the title compound. 1H-NMR (δppm, DMSO-d6): 0.98
(3H, t, J=7.3Hz), 1.65-1.83
(2H, m), 4.23-4.32 (1H, m),
4.47 (2H, s), 5.32 (1H, d, J=5
．． 3Hz), 5.69 (2H, s), 5.98 (1H
, dd, J=8.2Hz, 5.3Hz), 6.92(1
H, s), 7.01 (1H, s), 7.95 (1H, s
)8.09(2H,d,J=6.3Hz),8.87(
2H, d, J = 6.3Hz), 9.46 (1H, d,
J=8.2Hz) MASS (FAB) 687 (MH
+) Example 5 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-amino-1-ethylethoxyimino)
Acetamide]-3-[1-[1-carboxy-2-(
Synthesis of 7β-[(Z
)-2-(2-tritylaminothiazol-4-yl)
-2-(2-t-butyloxycarbonylamino-1-
ethyl ethoxyimino)acetamide]-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 194.2 mg (0.2 mmol) in N
, N-dimethylformamide (1.5 ml), 60 mg (0.4 mmol) of sodium iodide was added thereto, and the mixture was stirred at 5 to 10° C. for 20 minutes under an argon stream. p-methoxybenzyl 3',4' prepared according to Production Example 2
-dimethoxymethyloxy-2-(4-thiopyridone-
1-yl) cinnamate 101.6 mg (0.2 mm
A solution of ol) dissolved in 0.5 ml of N,N-dimethylformamide was added, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was poured into 25 ml of water, and the precipitate precipitated was filtered and washed with water. Dry under reduced pressure to obtain 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-amino-1-ethylethoxyimino)acetamide]-3-[1-[1
-carboxy-2-(3,4-dihydroxyphenyl)
]vinylpyridinium-4-yl]thiomethyl-3-
Protected form of cephem-4-carboxylate/iodide 2
78.1 mg was obtained. Obtained protection body 154m
Dissolve g (0.1 mmol) in 462 μl of anisole and add 770 μl of trifluoroacetic acid while stirring at 0 to 5°C.
μl was added dropwise over 15 minutes. After stirring at the same temperature for 2.5 hours, 21 ml of diethyl ether was added, and the mixture was stirred at the same temperature for 30 minutes. The deposited precipitate was filtered and washed with diethyl ether to obtain 99.6 mg of the title compound. 1H-NMR (δppm, DMSO-d6): 0.98
(3H, t, J=7Hz), 1.65-1.85 (2H
, m), 4.25-4.35 (1H, m), 4.56 (
2H, s), 5.34 (1H, d, J=5Hz), 6.
01 (1H, dd, J = 5Hz, 8Hz), 6.30 (
1H, s), 6.70 (1H, d, J=9Hz), 6.
85 (1H, d, J=9Hz), 6.92 (1H, s)
8.00 (1H, s), 8.28 (2H, d, J=7H
z), 8.96 (2H, d, J = 7Hz), 9.47 (
1H, d, J=8Hz) MASS (FAB) 742
(MH+) Example 6 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-amino-1-ethylethoxyimino)
acetamido]-3-[1-[1-ethoxycarbonyl-2-(3,4-dihydroxyphenyl)]vinylpyridinium-4-yl]thiomethyl-3-cephem-4
-Synthesis of carboxylate trifluoroacetate: 7-
β-[(Z)-2-(2-tritylaminothiazole-
4-yl)-2-(2-t-butyloxycarbonylamino-1-ethylethoxyimino)acetamide]-3
-Chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester 662 mg (0.7 mmol)
was dissolved in 7 ml of N,N-dimethylformamide, 209 mg (1.4 mmol) of sodium iodide was added, and A
The mixture was stirred for 20 minutes at 0-10° C. under a stream of r air. ethyl
3',4'-di(methoxymethyloxy)-2-(4
-thiopyridon-1-yl) cinnamate 284 mg (
0.7 mmol) of N,N-dimethylformamide solution (1 ml) was added thereto, and the mixture was stirred at the same temperature for 2 hours. Add 3 parts of the reaction solution to water.
Pour into 0ml, filter the precipitate, wash with water,
-[(Z)-2-(2-aminothiazol-4-yl)
-2-(2-amino-1-ethylethoxyimino)acetamide]-3-[1-[1-ethoxycarbonyl-2
852.6 mg of a protected form of -(3,4-dihydroxyphenyl)]vinylpyridinium-4-yl]thiomethyl-3-cephem-4-carboxylate iodide was obtained. Dissolve 200 mg of the obtained protector in 0.6 ml of anisole, and while stirring at 0 to 5°C, add 1 ml of trifluoroacetic acid.
1 was added dropwise, and the mixture was stirred at the same temperature for 2.5 hours. The reaction solution was poured into 20 ml of diethyl ether, and the precipitate was filtered and washed with diethyl ether to give 140 ml of the title compound.
I got g. 1H-NMR (δppm, DMSO-d6): 0.98
(3H, t, J=7.3Hz), 1.36 (3H, t,
J=6.9Hz), 1.65-1.83 (2H, m),
3.10-3.20 (2H, m,), 3.67 (1H,
d, J = 17.9Hz), 3.93 (1H, d, J = 1
7.9Hz), 4.25-4.35 (1H, m), 4.
37 (2H, q, J = 7.2Hz), 4.57 (2H,
s), 5.34 (1H, d, J=5.3Hz), 6.0
0 (1H, dd, J=8.2Hz, 5.3Hz), 6.
30 (1H, s), 6.72 (1H, d, J = 8.6H
z) 6.87 (1H, d, J=8.6Hz), 6.9
3 (1H, s), 7.43 (1H, brs), 8.05
(1H, s), 8.31 (2H, d, J=6.9Hz)
, 8.97 (2H, d, J = 6.9Hz), 9.47 (
1H, d, J=8.6Hz) MASS (FAB) 77
2(MH+) Example 7 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-(2-amino-1-ethylethoxyimino)
Acetamide]-3-[1-(1,5-dihydroxy-
4-pyridon-2-yl)methylpyridinium-4-
Synthesis of 7-β-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-(2-t- Butyloxycarbonylamino-1-ethylethoxyimino)acetamide]
-3-chloromethyl-3-cephem-4-carboxylic acid p
-methoxybenzyl ester 192 mg (0.2 mmo
l) in 1 ml of N,N-dimethylformamide,
Add 60 mg (0.4 mmol) of sodium iodide,
Stirred for 20 minutes at 0-10°C under argon stream. 1-diphenylmethyloxy-5-(p-methoxybenzyloxy)-2-(4-thiopyridon-1-yl)methyl-4-pyridone 108 mg (0.2 mmol) of N,N
-1 ml of dimethylformamide solution was added dropwise, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was poured into 8 ml of water, and the precipitate precipitated was filtered, washed with water, and dissolved in methylene chloride. 1
After washing with 2 ml of 0% brine and 2 ml of saturated brine, and drying over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure to give 7β-[(Z)-2-(2-aminothiazole-4
-yl)-2-(2-amino-1-ethylethoxyimino)acetamide]-3-[1-(1,5-dihydroxy-4-pyridon-2-yl)methylpyridinium-
252 mg of protected form of iodide of 4-yl]thiomethyl-3-cephem-4-carboxylate was obtained. 240 mg of the obtained protected body was dissolved in 720 ml of anisole, and while stirring at 0-10°C, 1.2 g of trifluoroacetic acid was added.
ml was added dropwise, and the mixture was stirred at the same temperature for 2.5 hours. 30 ml of diethyl ether was added to the reaction solution, and the mixture was stirred at the same temperature for 30 minutes. The deposited precipitate was filtered and washed with diethyl ether to obtain 145 mg of the title compound. 1H-NMR (δppm, DMSO-d6): 0.97
(3H, t, J=7.3Hz), 1.62~1.82(
2H, m), 3.08-3.22 (2H, m), 3.6
0 (1H, d, J = 18.1Hz), 3.87 (1H,
d, J=18.1Hz), 4.23-4.33 (1H,
m), 4.46 (2H, brs), 5.31 (1H, d
, J=5.0Hz), 5.74 (2H, brs), 5.
97 (1H, dd, J=8.2Hz, 5.0Hz), 6
．． 92 (1H, s), 7.29 (1H, s), 7.91
(1H, s), 8.04 (2H, d, J=6.3Hz)
, 8.92 (2H, d, J = 6.3Hz), 9.45 (
1H, d, J = 8.2Hz) MASS (FAB) 7
03 (MH+) or more [Chemical formula 22]

Claims (1)

[Scope of Claims] [Claim 1] The following general formula (I) [Formula 1] (wherein, R1 and R2 each represent a hydrogen atom or an amino group protecting group, and R3 represents -COO- or a carboxyl group) A carboxyl group that may be protected by a protecting group, X represents [Formula 2] and Y represents [Formula 3]. However, n is an integer of 0 to 2, R41 is a hydrogen atom, -COO- , represents a carboxyl group optionally substituted with an ester residue, -CONH2 or -CN,
R42 and R43 represent a hydrogen atom, an acetyl group, or a protecting group for a hydroxyl group, R44 and R45 represent a hydroxyl group, one of which may be protected, and the other represents a hydrogen atom, and R46 represents a hydrogen atom or a protective group. a hydroxyl group which may be protected, and R47 represents a hydroxyl group which may be protected) or a pharmacologically acceptable salt thereof. [Claim 2] In general formula (I), -X-Y is [
The cephalosporin compound or a pharmacologically acceptable salt thereof according to claim 1, which is any substituent selected from the group consisting of: Claim 3: (A) The following general formula (II) [Formula 5] (wherein, R1 and R2 each represent a hydrogen atom or an amino group protecting group, and R3 represents -COO- or a carboxyl group protecting group) A compound represented by the following general formula (III) [Formula 6] (wherein, X represents [Chemical 7] and Y represents embedded image where n is an integer of 0 to 2, R41 is a hydrogen atom, -COO-, a carboxyl group optionally substituted with an ester residue, -CONH2 or -CN,
R42 and R43 represent a hydrogen atom, an acetyl group, or a hydroxyl group-protecting group, R44 and R45 represent a hydroxyl group, one of which may be protected, and the other represents a hydrogen atom, and R46 represents a hydrogen atom or a protected group. R47 represents a hydroxyl group which may be protected, and R47 represents a hydroxyl group which may be protected; R2 has the same meaning as above) or a reactive derivative thereof, and a carboxylic acid compound represented by the following formula (V) [Formula 10] (wherein R3, X and Y have the same meaning as above)
or (C) the following general formula (VI) [Formula 1
1] (wherein R1, R3, X and Y have the same meanings as above) or a reactive derivative thereof, and the following formula (VII) has the same meaning as above), and if necessary, remove the amino group or the protecting group of R3 and/or the ester residue of R41 present in the compound produced by these reactions. A cephalosporin compound represented by the general formula (I) [Chemical formula 13] (wherein R1, R2, R3, X and Y have the same meanings as above) or its pharmacologically Acceptable salt manufacturing methods. 4. In general formula (I), -X-Y is [Formula 1
4. The method for producing a cephalosporin compound or a pharmacologically acceptable salt thereof according to claim 3, wherein the substituent is any one of the substituents selected from the group consisting of: Claim 5: The following general formula (I): (wherein, R1 and R2 are each protected by a hydrogen atom or an amino group-protecting group, and R3 is protected by -COO- or a carboxyl group-protecting group) X represents [Chemical 16] and Y represents [Chemical 17]. However, n is an integer of 0 to 2, and R41 is a hydrogen atom, -COO-, or an ester residue. Indicates an optionally substituted carboxyl group, -CONH2 or -CN
However, R42 and R43 represent a hydrogen atom, an acetyl group, or a protecting group for a hydroxyl group, R44 and R45 represent a hydroxyl group that may be protected, and the other represents a hydrogen atom, and R46 represents a hydrogen atom or a protected group. An antibacterial agent containing a cephalosporin compound or a pharmacologically acceptable salt thereof as an active ingredient. [Claim 6] In general formula (I), -X-Y is [
The antibacterial agent according to claim 5, which is any substituent selected from the group consisting of: