JP2525170B2 - Method for producing 2-oxaisocephem derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing a 2-oxaisosephem derivative. More specifically, the present invention relates to a method for producing a 2-oxaisocephem derivative useful as a synthetic intermediate for producing a 2-oxaisocephem antibacterial agent.

<Disclosure of the Invention> The 2-oxaisocephem antibacterial agent has a strong antibacterial action, and for example, compounds described in JP-A-57-192387 and the like are known. Examples of the azetidinone derivative that is a synthetic intermediate of the 2-oxaisocephem skeleton, which is the basic skeleton of the 2-oxaisocephem antibacterial agent, include, for example, JP-A-51-41385 and Can. J. Chem. 56 pp1335. (19
87) and the like are known, but the present invention is useful as a synthetic intermediate in the production of a 2-oxaisocephem antibacterial agent using an azetidinone derivative which is a novel compound not described in the literature. The present invention provides a novel method for producing a 2-oxaisocephem derivative.

That is, the method for producing a 2-oxaisocephem derivative of the present invention has the general formula [Wherein R ¹ is a halogen atom, a lower alkanesulfonyloxy group or a lower alkyl group optionally substituted with a halogen atom, an arylsulfonyloxy group optionally substituted with a halogen atom or a nitro group, and X ¹ is a halogen Atom, R ⁴ is an esterified carboxy group, R ³
Is an azido group, a phthalimido group or a group: —NH—R ⁵ (wherein, R ⁵ represents an amino protecting group)], and an azetidinone derivative represented by the general formula HS-R ⁶ (4) (wherein R ⁶ represents an unsaturated heterocyclic group having 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom and a sulfur atom, and the heterocyclic group is a lower alkyl group, a lower alkenyl group, a lower alkoxycarbonyl group, Carboxy group,
A phenyl lower alkoxycarbonyl lower alkyl group having 1 to 3 phenyl groups, a carboxy lower alkyl group,
From the group consisting of hydroxy lower alkyl group, hydroxyl group, oxo group, amino group, carbamoyl group, cyano group, lower alkyl-substituted amino lower alkyl group, piperidinyl lower alkyl group, pyrrolidinyl lower alkyl group, carbamoyl lower alkyl group and cyano lower alkyl group. It may have 1 to 3 selected substituents or a 4-lower alkyl-1-piperazinyl lower alkyl group. ) The thiol compound represented by (In the formula, R ³ , R ⁴ and R ⁶ are the same as the above.) A 2-oxaisocephem derivative represented by the following formula is obtained.

In addition, another manufacturing method of the present invention is a general formula (In the formula, R ¹ , R ³ , R ⁴ and X ¹ are the same as the above.) The basic compound is reacted with the azetidinone derivative represented by the general formula (In the formula, R ³ , R ⁴ and X ¹ are the same as the above.) The step of obtaining the compound represented by the formula (3) and the compound represented by the general formula HS- R ⁶ (4) (In the formula, R ⁶ is the same as above.) The thiol compound represented by the formula is reacted in the presence of a basic compound to give a compound represented by the general formula: (In the formula, R ³ , R ⁴ and R ⁶ are the same as the above.), And a step of obtaining a 2-oxaisocephem derivative represented by the following formula.

The compound represented by the general formula (1-b) has the general formula (In the formula, R ¹ , R ³ and R ⁴ are the same as the above, and X ² is a halogen atom.) The compound represented by the formula can be obtained by heat treatment in the presence of an acidic compound.

In the compound represented by the general formula (1-b), the group: Is widely known to replace keto-enol tautomerism, and is represented by the following formula, for example.

In the present specification, such keto-enol tautomerism is represented by the general formula (1-b) for convenience.

In the production method of the present invention, the azetidinone derivative represented by the general formula (1-b) can be used as a starting material to convert the 2-oxaisocephem skeleton represented by the general formula (5) in good yield by a simple method. Further, the 2-oxaisocephem skeleton thus obtained is to be modified at the 7-position and / or the 3-position as appropriate, which can lead to a useful 2-oxaisocephem antibacterial agent.

More specifically, each group shown in each of the above general formulas is as follows.

Examples of the halogen atom include chlorine, bromine, iodine and fluorine.

As the lower alkanesulfonyloxy group which may be substituted with a halogen atom, methanesulfonyloxy,
Ethanesulfonyloxy, propanesulfonyloxy,
Trifluoromethanesulfonyloxy etc. are mentioned.

Examples of the arylsulfonyloxy group which may be substituted with a lower alkyl group, a halogen atom or a nitro group include benzenesulfonyloxy, toluenesulfonyloxy, p-chlorobenzenesulfonyloxy and p-nitrobenzenesulfonyloxy. As the ester residue in the esterified carboxy group,
Ordinary ester residues such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and other alkyl groups having 1 to 6 carbon atoms; benzyl, benzhydryl, α-phenethyl, β-
Phenethyl, α, β-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, etc. (mono or di) phenyl lower alkyl groups having 1 to 6 carbon atoms in the alkyl moiety Can be illustrated.

The phenyl moiety in the (mono or di) phenyl lower alkyl group of the ester residue is, as a substituent,
For example, a halogen atom such as a chlorine atom, a bromine atom, a fluorine atom and an iodine atom; a lower alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl; It may have a lower alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy, pentyloxy, hexyloxy; and a nitro group.

The amino protecting group has, for example, 1 to 3 phenyl groups such as benzyl, α-phenethyl, β-phenethyl, 3-phenylpropyl, benzhydryl and trityl,
And phenyl having 1 to 6 carbon atoms in the alkyl part (lower)
Alkyl group; lower alkanoyl group having 1 to 6 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, hexanoyl; monochloroacetyl, monofluoroacetyl, monobromoacetyl, monoiodoacetyl, dichloroacetyl, trichloroacetyl. , Tribromoacetyl, 3-chloropropionyl, 2,3-dichloropropionyl, 3,3,3-trichloropropionyl, 4-chlorobutyryl, 5-chloropentanoyl, 6-chlorohexanoyl, 3-fluoropropionyl, 4-fluoro Lower alkanoyl group having 2 to 6 carbon atoms, such as butyryl, substituted with 1 to 3 halogen atoms; 1-phenylethoxycarbonyl, 2-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl,
4-phenylbutoxycarbonyl, 5-phenylpentyloxycarbonyl, 6-phenylhexyloxycarbonyl, and other phenyl (lower) alkoxycarbonyl groups having 1 to 6 carbon atoms in the alkoxy moiety; methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxy. Carbon number of the alkoxy moiety such as carbonyl, butoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl is 1 to
A lower alkoxycarbonyl group of 6; phenylacetyl,
3-phenylpropionyl, 4-phenylbutyryl, 5
-Phenylpentanoyl, 6-phenylhexanoyl,
On phenyl ring such as 3-phenyl-2-methylpropionyl, 4-nitrophenylacetyl, 4-methylphenylacetyl, 4-chlorophenylacetyl, 3-nitroacetyl, 3,4-dimethylphenylacetyl, 2-methylphenylacetyl Examples of the substituent include a phenyl (lower) alkanoyl group which may have 1 to 3 substituents selected from the group consisting of nitro, lower alkyl groups and halogen atoms.

The azetidinone derivative (1-b) can be produced by various methods, for example, it can be obtained by the method shown in the following reaction formula-1.

[In the formula, R ¹ , R ³ , R ⁴ , X ¹ and X ² are the same as defined above. In the above reaction scheme, the reaction (a) for producing the compound of the general formula (1-a) from the compound of the general formula (2) is performed by reacting the compound of the general formula (2) in the presence or absence of a solvent. , A halogenating agent is reacted. Examples of the halogenating agent used include halogen such as chlorine, bromine and iodine, N-chlorosuccinimide, N-iodosuccinimide, N-halogenated succinimide such as N-bromosuccinimide, sulfuryl chloride and sulfuryl halide such as sulfuryl bromide, Pyridine, hydrobromide perbromide, pyridine hydrochloride, pyridine hydrohalide perhalide such as perchloride, hypochlorous acid, t-butyl hypochloride, chloramine B, chloramine T and the like. As the solvent used, methylene chloride, 1,2-dichloroethane,
Halogenated hydrocarbons such as chloroform, ethers such as tetrahydrofuran, dioxane and diethyl ether, alcohols such as methanol, ethanol and propanol, aprotic polar solvents such as dimethylformamide and dimethylsulfoxide, acetonitrile and the like, and mixtures thereof. Solvents may be mentioned. The reaction is preferably carried out in the presence of a basic compound, and examples of the basic compound include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like.

The use ratio of the halogenating agent to the compound of the general formula (2) is at least an equimolar amount, preferably 1 to 2 times the molar amount. The ratio of the basic compound to the halogenating agent used is at least an equimolar amount, preferably 1 to
It is preferable to use a 3-fold molar amount. The reaction is usually 0 to 50 ℃,
It is preferably carried out at room temperature and is generally completed in about 30 minutes to 10 hours.

The reaction (b) for producing the compound of the general formula (1-b) from the compound of the general formula (2) includes heating the halogenating agent to the compound of the general formula (2) in the presence or absence of a solvent. It is carried out by reacting under the conditions. Examples of the halogenating agent and solvent used in this reaction include the halogenating agent and solvent exemplified in the reaction step (a). Further, this reaction is preferably carried out in the presence of a basic compound, and as the basic compound, the basic compound mentioned in the reaction step (a) can be used. The reaction is usually carried out at 50 to 100 ° C, preferably 60 to 80 ° C, and is generally completed in about 1 to 10 hours.

The reaction (c) for producing the compound of general formula (1-b) from the compound of general formula (1-a) is carried out by heating the compound of general formula (1-a) in the presence of an acidic compound. Done. Examples of the acidic compound used in this reaction include hydrohalic acids such as hydrochloric acid, hydrobromic acid and hydroiodic acid, mineral acids such as sulfuric acid and phosphoric acid, p-toluenesulfonic acid, benzenesulfonic acid, and the like. An organic acid such as trifluoroacetic acid can be exemplified. When a hydrohalic acid is used, it is preferable to use a hydrohalic acid composed of the same halogen as X ² of the compound of formula (1-a). The reaction is preferably carried out in the presence of a solvent, and as the solvent, the solvent mentioned in the reaction step (a) can be used. In the reaction, if necessary, a basic compound may be added to the reaction system. Examples of the basic compound include sodium carbonate, potassium carbonate, sodium hydrogencarbonate, an inorganic base such as potassium hydrogencarbonate, pyridine, Examples include organic bases such as triethylamine and N-methylmorpholine. The ratio of the acidic compound used to the compound of the general formula (1-a) is at least an equimolar amount, preferably 1
Approximately 2 times the molar amount is used. The reaction is usually 50-100
C., preferably 60 to 80.degree. C., and is generally completed in about 30 minutes to 6 hours.

The compound of the general formula (1-b) obtained in the above Reaction scheme-1 can be easily converted into 2- by the process shown in the following Reaction scheme-2.
It can lead to oxa-isocephem derivatives.

(In the formula, R ¹ , R ³ , R ⁴ , R ⁶ and X ¹ are the same as above.) Reaction (a) for producing a compound of the general formula (3) from a compound of the general formula (1-b) Is carried out by reacting the compound of general formula (1-b) with a basic compound in the presence or absence of a solvent. Examples of the solvent used in this reaction include aromatic hydrocarbons such as benzene and toluene, ethers such as ethyl ether and tetrahydrofuran, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane, and methanol and ethanol. Alcohols, acetone, ketones such as methyl ethyl ketone, dimethylformamide, dimethylsulfoxide,
Aprotic polar solvents such as hexamethylphosphoric triamide, acetonitrile and the like can be mentioned. As the basic compound used, sodium hydroxide, an alkali metal hydroxide such as potassium hydroxide, sodium carbonate, potassium carbonate, an inorganic base such as an alkali metal carbonate or hydrogen carbonate such as sodium hydrogen carbonate, Triethylamine, pyridine, N, N-dimethylaniline, 1,5-diazabicyclo [4.3.0] nonene-5 (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4] .0] Organic bases such as undecene-7 (DBU) are preferred, with organic bases being preferred. The basic compound is used in an amount of at least an equimolar amount, usually a slight excess amount, with respect to the compound represented by the general formula (1-b). The reaction is carried out at 0 to 100 ° C, preferably about 20 to 80 ° C, and is completed in 1 to 20 hours, preferably 1 to 10 hours.

The reaction (b) for producing the 2-oxaisosephem derivative of the general formula (5) from the compound of the general formula (3) is carried out in a suitable inert solvent with the compound of the general formula (3) and the general formula (4). It is carried out by reacting a thiol compound in the presence of a basic compound. Examples of the basic compound used in the above reaction include organic basic compounds such as tertiary amines such as triethylamine and pyridine, and inorganic basic compounds such as sodium carbonate and potassium carbonate. As the inert solvent, any solvent can be used as long as it does not adversely affect this reaction, for example, diethyl ether, tetrahydrofuran, ethers such as dioxane,
Halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene and xylene, amines such as pyridine, piperidine and triethylamine, and aliphatic hydrocarbons such as hexane and heptane. , Methanol, ethanol,
Examples thereof include alcohols such as propanol, aprotic polar solvents such as dimethylformamide (DMF), hexamethylphosphoric triamide (HMPA) and dimethylsulfoxide (DMSO), carbon disulfide and the like.

The ratio of the compound of the general formula (4) to the compound of the general formula (3) is at least equimolar amount, preferably 1 to 2
The molar ratio is preferably double, and the ratio of the basic compound to the compound of the general formula (4) is at least equimolar, preferably equimolar to 2-fold molar. The reaction temperature is -10 ° C to 100 ° C, preferably 0 to 50 ° C, and is generally completed in about 30 minutes to 10 hours.

The reaction (c) for producing the 2-oxaisosephem derivative of the general formula (5) from the compound of the general formula (1-b) is carried out by reacting the compound of the general formula (1-b) with the general formula (1-b) in a suitable inert solvent. It is carried out by reacting the thiol compound represented by (4) in the presence of a basic compound. Examples of the inert solvent, the basic compound and the thiol compound (4) used in this reaction include those exemplified in the above reaction steps (a) and (b). Further, a basic compound and a thiol compound (4) for the compound of the general formula (1-b)
Regarding the usage ratio of the above, the description of the reaction steps (a) and (b) can be referred to. The reaction is usually 0 ° C to 100 ° C,
It is preferably carried out at room temperature to 80 ° C. and is generally completed in about 30 minutes to 10 hours.

{R ³ , R ⁴ and R ⁶ are the same as above, R ⁷ is a group: [Wherein R ⁸ is a hydrogen atom, an amino group, a lower alkanoylamino group, a halogen-substituted lower alkanoylamino group, a phenyl lower alkylamino group having 1 to 3 phenyl groups, a phenyl lower alkoxycarbonylamino group or a lower alkoxycarbonylamino group] Group; R ⁹ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group,
Cycloalkyl group, a tetrahydropyranyl group or a group: -A-R ¹⁰ (wherein, A represents a lower alkylene group, R ¹⁰ is a cyano group, a carboxy group, a lower alkoxycarbonyl group, a halogen-substituted lower alkyl group, a lower alkylthio group, Thiazolyl group,
Imidazolyl group, cycloalkyl group, phenyl group, tetrahydrofuranyl group, oxazolyl group, 4-lower alkyl-2,3-dioxo-1-piperazinylcarbonyl group,
A pyrazolyl group which may have a trityl group or a pyridyl group which may have a lower alkyl group)]. } The reaction (d) for producing the compound of the general formula (6) from the compound of the general formula (5) is a reduction reaction of the compound of the general formula (5) depending on the kind of R ³ which is the substituent, It is carried out by subjecting it to a hydrolysis reaction or a hydrazine decomposition reaction.

In the above reaction step, when the group R ³ is an azido group,
The compound of general formula (6) can be obtained by reacting the compound of general formula (5) with a reducing agent in the absence of solvent or in the presence of a suitable inert solvent to obtain the amine compound of general formula (6).

As the solvent used in this reaction, for example,
Halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran and dioxane;
Examples include amines such as triethylamine and pyridine.

Examples of the reducing agent include hydrogen sulfide. When hydrogen sulfide or the like is used, amines such as triethylamine and pyridine may be added.

The reducing agent may be used in an equimolar to 100-fold molar amount, preferably 3 to 50-fold molar amount relative to the compound of the general formula (5), and the reaction is usually -30 ° C to 50 ° C, preferably It is carried out at -10 ℃ to 10 ℃ and finishes in about 30 minutes to 10 hours.

When the group R ³ is a group: —NH—R ⁵ (wherein R ⁵ is the same as above), the compound of the general formula (5) is protected with an amino group of R ^{5 in} a solvent-free or inert solvent. The amine compound of the general formula (6) is obtained by subjecting it to a radical elimination reaction. The reaction is carried out by a method of reacting the compound of general formula (5) with an acidic compound or a basic compound, the size of the compound of general formula (5) subjected to a catalytic reduction reaction, and the like.

Examples of the inert solvent used in the above reaction include:
Halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethyl ether,
Diethyl ether, tetrahydrofuran, dioxane,
Ethers such as anisole, nitro compounds such as nitromethane and nitrobenzene, alcohols such as methanol and ethanol, acetic acid esters such as ethyl acetate and methyl acetate, aliphatic hydrocarbons such as hexane, heptane and octane, benzene and toluene, Aromatic hydrocarbons such as xylene, amines such as pyridine and piperidine, dimethylformamide (DMF), hexamethylphosphoric triamide (HMP
A), an aprotic polar solvent such as dimethylsulfoxide (DMSO), carbon disulfide, water, or a mixed solvent of water and the above organic solvent can be exemplified.

Examples of the acidic compound used include anhydrous aluminum chloride, stannic chloride, titanium tetrachloride, boron trichloride, boron trifluoride-ethyl ether complex, Lewis acids such as zinc chloride, inorganic acids such as hydrochloric acid, nitric acid and sulfuric acid. , Trichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, acetic acid and other organic acids,
Acids such as acid type ion exchange resins can be mentioned, and basic compounds include trialkylamines such as triethylamine and tributylamine, pyridine, picoline, DBU, DB.
Organic bases such as N and DABCO, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc. Examples thereof include inorganic bases and the like.

When the above reaction is carried out by the catalytic reduction method, examples of the catalytic reduction catalyst used include platinum catalysts (for example,
Platinum oxide, platinum black, platinum wire, platinum plate, sponge-like platinum,
Colloidal platinum etc.), Palladium catalyst (eg palladium black, palladium chloride, palladium oxide, palladium-carbon, palladium-barium sulfate, palladium-barium carbonate, sponge palladium etc.), nickel catalyst (eg reduced nickel, nickel oxide) , Raney nickel, etc.), a cobalt catalyst (eg, reduced cobalt, Raney cobalt, etc.), an iron catalyst (eg, reduced iron, Raney iron, etc.), a copper catalyst (eg, reduced copper, Raney copper, etc.), and the like.

When an acidic compound or a basic compound is used in the above reaction, the ratio of the acidic compound or the basic compound to the compound of the general formula (5) is 1 to 100 times the molar amount, preferably 1 to 20 times. It is preferable to use a molar amount. Also,
The reaction is carried out under temperature conditions of -20 ° C to 80 ° C, preferably -10 ° C to 50 ° C, for 30 minutes to 48 hours, preferably 1 to 24 hours.
It will finish in about time.

When the catalytic reduction method is applied, the general formula (5)
The ratio of the catalytic reduction catalyst to the compound of
It is preferable that the molar amount is double, preferably 0.1 to 1 times. The reaction is carried out under the temperature condition of 0 to 200 ° C., preferably 0 to 100 ° C., and is completed in about 30 minutes to 48 hours, preferably about 30 minutes to 6 hours.

When the group R ³ is a phthalimido group, the amine compound of the general formula (6) is obtained by subjecting the compound of the general formula (5) to a hydrazine decomposition reaction in which the compound of the general formula (5) is reacted with hydrazine or a hydrazine derivative in a solvent-free or inert solvent. can get.

As the inert solvent used in this reaction, for example,
Examples thereof include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc., metal rule, and alcohol flow rates such as ethanol. Examples of the hydrazine derivative include lower alkyl-substituted hydrazines such as methylhydrazine and ethylhydrazine, and aryl-substituted hydrazines such as phenylhydrazine.

The ratio of hydrazine or hydrazine derivative to the compound of the general formula (5) is at least an equimolar amount, preferably 1 to 2 times, and the reaction is usually 0 to
The reaction is carried out at 100 ° C, preferably 0 to 80 ° C, and the reaction is completed in about 1 to 40 hours.

The reaction (e) for producing the compound of the general formula (8) from the compound of the general formula (6) includes the amine compound of the general formula (6),
It can be produced by reacting the carboxylic acid compound of the general formula (7) or a compound in which its carboxy group is activated in a usual amide bond forming reaction.

As the amide bond formation reaction, any of the known conditions for the amide bond formation reaction can be applied, and examples thereof include the following methods.

a) Method using a condensing agent: a method of reacting a carboxylic acid compound (7) and an amine compound (6) in the presence of a condensing agent; b) a mixed acid anhydride method: a carboxylic acid compound (7) and an alkylhalocarboxylic acid. A method of reacting an acid to form a mixed acid anhydride, and reacting this with an amine compound (6); c) Active esterification method: p-carboxylic acid compound (7)
A method of reacting an amine compound (6) with an active ester such as nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester; d) dehydration of carboxylic acid compound (7) such as acetic anhydride A carboxylic acid anhydride with an agent and reacting it with an amine compound (6); e) a method of reacting a lower alcohol ester of a carboxylic acid compound (7) with an amine compound (6) under high temperature and high pressure; f ) The carboxylic acid compound (7) is used as an acid halide, that is, a carboxylic acid halide, and the amine compound (6)
Can be exemplified.

Next, an example of the amide bond forming reaction will be described more specifically.

The compound of the general formula (8) is obtained by reacting the amine compound of the general formula (6) with the carboxylic acid compound of the general formula (7) in the presence of a condensing agent, in the absence of a solvent or in the presence of an inert solvent. To be

Examples of the condensing agent used in the reaction include thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, such as (chloromethylene) dimethylammonium chloride synthesized by the reaction of dimethylformamide with thionyl chloride, phosphorus oxychloride, phosgene and the like. Billsmeier (Vl
ismeier) reagent, dicyclohexylcarbodiimide (DC
Examples of the condensing agent include C) and 2,2'-pyridinyl disulfide-triphenylphosphine.

As the solvent, any solvent can be used as long as it does not adversely affect this reaction, for example, diethyl ether, tetrahydrofuran, ethers such as dioxane,
Halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene and xylene, amines such as pyridine, piperidine and triethylamine, and aliphatic hydrocarbons such as hexane and heptane. , Methanol, ethanol,
Examples thereof include alcohols such as propanol, aprotic polar solvents such as dimethylformamide (DMF), hexamethylphosphoric triamide (HMPA) and dimethylsulfoxide (DMSO), carbon disulfide and the like.

The above reaction is more preferably performed in the presence of a basic compound. Examples of the basic compound include trialkylamines such as triethylamine and tributylamine, organic bases such as pyridine, picoline, DBU, DBN and DABCO, alkali metal hydroxides such as monotrimethylsilylacetamide, sodium hydroxide and potassium hydroxide. Substances, alkali metal carbonates such as sodium carbonate and potassium carbonate,
Examples thereof include inorganic bases such as alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate.

Further, in the above reaction, the use ratio of the carboxylic acid compound of the general formula (7) to the amine compound of the general formula (6) is 1 to 10 times the molar amount, preferably 1 to 3 times the molar amount. . The basic compound may be used in an equimolar to 40-fold molar amount, preferably 5 to 20-fold molar amount with respect to the amine compound of the general formula (6).

The above reaction is carried out at -20 ° C to 100 ° C, preferably -20 ° C to 5 ° C.
30 minutes to 24 hours under a temperature condition of 0 ° C., preferably 30 minutes to 10 hours
It is done in about an hour.

The compound of the general formula (8) obtained above is further subjected to hydrolysis reaction or catalytic reduction reaction using an acidic compound or a basic compound to deesterify the esterified carboxy group of R ⁴ , In the compound of the general formula (8), the 4-position of the 2-oxaisocephem ring can be introduced into a compound having a carboxy group. Further, in the case where the 2-position of the thiazolyl group of R ⁷ is a protected amino group, a compound having the 2-position of the thiazolyl group as an amino group can be introduced by subjecting the amino-protecting group to elimination reaction. The above hydrolysis reaction, catalytic reduction reaction and deprotection group reaction can be carried out in substantially the same manner as in the step (d) of the reaction formula-3, and the reaction conditions, reaction reagents and the like are referred to the description of the reaction step. can do.

The compound of the general formula (8) thus obtained, the deester compound at the 4-position thereof and the compound from which the amino-protecting group has been removed have an excellent antibacterial action. Below, an example of the antibacterial action is shown.

[Antibacterial Test] Test Method The minimum inhibitory concentration (MIC) was determined by the agar dilution plate method in order to investigate the antibacterial activity against various bacteria for the following test compounds.

[See CHEMOTHERAPY, 22, 1126 ~ 1128 (1974)] Various bacteria are 1 x 10 ⁶ bacteria count / ml (OD600mμ, 0.07 ~
0.16).

 The test results are shown in the table below.

Test compound 7β- [2- (2-aminothiazol-4-yl)-
2-Cyanomethoxyiminoacetamide] -3-[(1,
3,4-Thiadiazol-2-yl) thiomethyl] -Δ ³ −
O-2-Isosephem-4-carboxylic acid trifluoroacetate (syn isomer) test results <Example> Hereinafter, the present invention will be described in detail based on Reference Examples and Examples.

Reference Example 1 benzyl 2- (2'-S-mesyloxymethyl-
After 2.00 g of 3'-S-phthalimido-4'-oxo) azetidinyl-3-oxobutyrate was dissolved in 20 ml of dioxane, 1.00 g of sodium hydrogen carbonate was added. 0.3 ml of bromine was added to the above mixture, and the mixture was stirred at room temperature for 1 hour. After diluting with 20 ml of ethyl acetate, washing with water (4 times with 20 ml), the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to give benzyl 2- (2'-S-mesyloxymethyl-3'-).
S-phthalimido-4'-oxo) azetidinyl-2-
2.44 g of bromo-3-oxobutyrate was obtained as a yellow amorphous substance.

NMR (CDCl ₃ ) δ: 2.42 (1.8H, s), 2.54 (1.2H, s), 2,86 (1.2H, s), 2.
87 (1.8H, s), 4.46 ~ 4.95 (3H, m), 5.30 (1.2H, s),
5.34 (0.8H, s), 5.51 (0.4H, d, J = 5Hz), 5.56 (0.6H, s)
d, J = 5 Hz), 7.38 (5H), 7.84 (4H, m) Reference Example 2 Benzyl 2- (2'-S-mesyloxymethyl-
20.0 g of 3'-S-phthalimido-4'-oxo) azetidinyl-3-oxobutyrate was dissolved in 200 ml of dioxane, 3.6 g of sodium hydrogen carbonate was added, and the mixture was stirred at 60 ° C. 2.2 ml of bromine was added to this solution, and the mixture was stirred at the same temperature for 2.5 hours. After cooling, dilute with 200 ml of ethyl acetate and wash with water (200
(ml × 3 times), the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to give benzyl 2- (2′-S-mesyloxymethyl-3′-S-phthalimido-4′-oxo). 23.11 g of azetidinyl-3-oxo-4-bromobutyrate were obtained as a yellow amorphous substance.

NMR (CDCl ₃ ) δ: 2.85 (3H, s), 4.12 and 4.52 (2H, q, J = 8Hz), 4.65
~ 4.70 (3H, m), 5.29 and 5.39 (2H, q, J = 14Hz), 5.
55 (1H, d, J = 6.7Hz), 7.41 (5H, brs), 7.85 (4H,
m), 12.2 (1H, brs) Reference Example 3 Benzyl 2- (2'-S-mesyloxymethyl-
After dissolving 0.58 g of 3'-S-phthalimido-4'-oxo) azetidinyl-2-bromo-3-oxobutyrate in 10 ml of dioxane, 100 mg of sodium hydrogencarbonate was added to obtain 60%.
Heat to ° C. To this solution, add hydrobromic acid in acetic acid (30
%) 0.26 ml was added and stirred for 1.5 hours. The mixture was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off to give benzyl 2- (2'-S-mesyloxymethyl-3'-S-phthalimido-4'-oxo) azetidinyl-. 0.4 g of 3-oxo-4-bromobutyrate was obtained.

Example 1 Benzyl 2- (2'-S-mesyloxymethyl-
After dissolving 23.11 g of 3'-S-phthalimido-4'-oxo) azetidinyl-3-oxo-4-bromobutyrate in 200 ml of dimethylformamide, 5.4 ml of toluethylamine was added and the mixture was stirred at room temperature for 30 minutes. 200 ml of ethyl acetate and 200 ml of water
After diluting with, the organic layer is separated, and the aqueous layer is extracted with 50 ml of ethyl acetate. Wash the combined organic layers with water (200 ml x
(3 times), dried over anhydrous magnesium sulfate, decolorized with activated carbon, and then distilled off the solvent to crystallize and wash with ethyl acetate to give benzyl 7β-phthalimido-3.
- white crystals 11.6g of bromomethyl -Δ ³ -O-2- Isosefemu-4-carboxylate.

Further, the mother liquor was concentrated and treated by silica gel column chromatography, and then crystallized to obtain 1.2 g of benzyl 7β-phthalimido-3-bromomethyl-Δ ³ -O-2-isocephem-4-carboxylate.

NMR (CDCl ₃ ) δ: 3.91 to 4.00 (1H, m), 4.37 to 4.55 (2H, m), 4.42 and
4.64 (2H, q, J = 44Hz), 5.30 and 5.34 (2H, q, J = 6.5H
z), 5.89 (1H, d, J = 5.4Hz), 7.29 to 7.54 (5H, m), 7.
84 (4H, m) mp: 173~174 ℃ ( brown foam decomposition) Mass ^{spectrometry: M + = 498, M -} = 496 optical rotation: [α] _D ²⁰ = -40.675 ° (chloroform, C = 1.008) Elemental analysis H% C% N% Calculated 3.45 55.55 5.63 Found 3.38 55.29 5.25 Benzyl 7β-phthalimido-3-obtained above
To a mixture of 1 g of bromomethyl-Δ ³ -O-2-isocephem-4-carboxylate, 240 mg of 4-mercaptopyridine and 10 ml of methylene chloride was added triethylamine.
0.3 ml was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with water (200 ml x 20 times) and then dried over anhydrous magnesium sulfate,
The solvent is distilled off. The residue was purified by silica gel column chromatography and crystallized from ethyl alcohol to obtain 0.83 g of benzyl 7β-phthalimido-3- (4-pyridylthiomethyl) -Δ ³ -O-2-isocephem-4-carboxylate.

NMR (CDCl ₃ ) δ: 3.86-3.95 (1H, m), 4.19 and 4.44 (2H, q, J = 4.9H
z), 4.34 to 4.51 (2H, m), 5.29 and 5.31 (2H, q, J =
5.4Hz), 5.87 (1H, d, J = 5.2Hz), 7.19 (2H, dd, J = 1.4)
Hz, 4.8Hz), 7.30 ~ 7.52 (5H, m), 7.83 (4H, m), 8.36
(2H, dd, J = 1.4Hz, 4.8Hz) mp: 119-120 ℃ Mass spectrometry: M = 527 Optical rotation: [α] _D ²⁰ = -92.157 ° (chloroform, C = 1.020) Elemental analysis H% C% Calculated N% 4.01 63.75 7.97 Found 4.01 63.91 7.83 Example 2 benzyl 2- (2'-S-mesyloxymethyl-)
1.71 g of 3'-S-phthalimido-4'-oxo) azetidinyl-3-oxo-4-bromobutyrate are dissolved in 20 ml of dimethylformamide. Separately, a solution of 4-mercaptopyridine (0.32 g) and triethylamine (0.4 ml) in dimethylformamide (5 ml) was added to the above mixture, and the mixture was added at room temperature to 1.5
After stirring for an hour, 0.4 ml of triethylamine is added and the mixture is stirred for 30 minutes. The reaction solution is poured into 20 ml of ethyl acetate and 20 ml of water, and the organic layer is separated. The aqueous layer is further extracted with 10 ml of ethyl acetate. The organic layers are combined and washed with water (200 ml x 3 times). After drying over anhydrous magnesium sulfate, decolorizing with activated carbon, distilling off the solvent and crystallization from ethanol, benzyl 7
β-phthalimido-3- (4-pyridylthiomethyl)-
Δ ³ -O-2-Isosephem-4-carbochelate 0.84g
I got The mother liquor was concentrated, treated with silica gel column chromatography, and crystallized from ethyl alcohol to obtain 0.15 g of secondary crystals.

mp119-120 ° C Example 3 Benzyl 2- (2'-S-mesyloxymethyl-
50 g of 3'-S-phthalimido-4'-oxo) azetidinyl-3-oxobutyrate are dissolved in 500 ml of dioxane, 9 g of sodium hydrogencarbonate is added and the mixture is heated to 60 ° C. Add 5.5 ml of bromine at the same temperature and stir for 2.5 hours. After diluting with 500 ml of ethyl acetate, washing with water (500 ml x 3 times) and drying with 10 g of anhydrous magnesium sulfate, the solvent was distilled off, and benzyl 2- (2'-S-mesyloxymethyl-3'-
S-phthalimido-4'-oxo) azetidinyl-3-
62.14 g of oxo-4-bromobutyrate was obtained as an oil.

The benzyl 2- (2'-S-mesyloxymethyl-3'-S-phthalimido-4'-oxo) azetidinyl-3-oxo-4-bromobutyrate obtained is dissolved in 400 ml of dimethylformamide. Separately, 10.81 g of 4-mercaptopyridine was adjusted to 13.6 ml of triethylamine and 100 ml of a dimethylformamide solution, and the mixture was added to the above solution and stirred at room temperature for 1.5 hours, and 13.6 ml of triethylamine was further added and stirred for 30 minutes. Ethyl acetate (400ml x 1 time, 100ml x
(2 times), the organic layers are combined, washed with water and brine (300 ml), dried over anhydrous magnesium sulfate (10 g), decolorized with activated carbon (2.5 g), evaporated to remove ethanol ( Crystallization from 500 ml) yielded 25.05 g of benzyl 7β-phthalimido-3- (4-pyridylthiomethyl) -Δ ³ -O-2-isocephem-4-carboxylate. After the mother liquor was further concentrated, it was treated with silica gel column chromatography, and ethanol (300m
Crystallization from l) gave 9.97 g of secondary crystals.

mp: 119-120 ° C. Reference Example 4 Benzyl 7β-azido-3-chloroform-Δ ³ −
4.5 g of O-2-isocephem-4-carboxylate is dissolved in 100 ml of methylene chloride, to which 1.35 g of 1,3,4-thiadiazole-2-thiol and 1.6 ml of triethylamine are added, and the mixture is stirred at room temperature for 1 hour and a half. The reaction solution is washed with a 5% aqueous sodium hydrogen carbonate solution and then twice with water. Further, the solvent is removed under reduced pressure to obtain a reddish brown oily substance. This was purified by silica gel column chromatography (eluent; ethyl acetate: hexane = 1: 1), and benzyl 7β-azido-3-[(1,3,4-thiadiazol-2-yl) thiomethyl] -Δ ³ −. 3.02 g of O-2-isocephem-4-carboxylate is obtained as a light brown powder.

[Α] _D ²⁰ = −147.68 ° (C = 1, chloroform) NMR (CDCl ₃ ) δ: 3.53 to 4.08 (2H, m), 4.40 (1H, d, J = 14Hz), 4.55
(1H, dd, J = 11Hz, 3Hz), 4.77 (1H, d, J = 14Hz), 5.17
(1H, d, J = 5Hz), 5.24 (2H, s), 6.88 ~ 7.53 (5H,
m), 8.92 (1H, s) Reference Example 5 a) Benzyl 7β-azido-3-[(1,3,4-thiadiazol-2-yl) thiomethyl] -Δ ³ -O-2-
Hydrogen sulfide gas was introduced into a mixed solution of 0.8 g of isocephem-4-carboxylate, 0.34 ml of triethylamine and 10 ml of methylene chloride under ice cooling. After 1 hour, the disappearance of the raw material spots was confirmed by thin layer chromatography, and the reaction solution was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine in this order,
Dry over anhydrous magnesium sulfate. The solvent is concentrated and the residue is dissolved in 100 ml methylene chloride. 2- (2-Tritylaminothiazol-4-yl) -2-cyanomethoxyiminoacetic acid (syn isomer) (1.04 g) was added and the mixture was stirred under ice-cooling, and then dicyclohexylcarbodiimide (DCC) (0.46 g) was added and the mixture was reacted overnight. . The precipitate is filtered off, and the filtrate is washed with water, diluted hydrochloric acid, aqueous sodium hydrogen carbonate solution and saturated brine in this order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent: chloroform), and benzyl 7β-
[2- (2-tritylaminothiazol-4-yl)-
2-Cyanomethoxyiminoacetamide] -3-[(1,
3,4-Thiadiazol-2-yl) thiomethyl] -Δ ³ −
0.85 g of 2-isocephem-4-carboxylate (syn isomer) is obtained.

b) To a mixture of 0.40 g of the trityl compound obtained above and 0.4 ml of anisole, 5 ml of trifluoroacetic acid is added under ice cooling and the reaction is carried out for 10 minutes. Then, when diethyl ether is added, crystals are precipitated, which are collected by filtration, washed with diethyl ether and dried under reduced pressure to give 7β- [2- (2-aminothiazol-4-yl) -2-cyanomethoxyiminoacetamide. ] -3 - [(1,3,4-thiadiazol-2-yl) thiomethyl] - [delta ³ -2 Isosefemu 4-carboxylic acid trifluoroacetate (syn isomer) is obtained 0.2 g.

Light yellow powder mp: Color change from 113 ° C. [α] _D ²² = + 111 ° (C = 1, methanol) NMR (DMSO-d6) δ: 3.57 to 4.20 (2H, m), 4.32 to 4.84 (1H, m), 4.56 (2
H, s), 5.05 (2H, s), 5.75 (1H, dd), 6.95 (1H, s),
9.44 (1H, d), 9.56 (1H, s)

Claims (3)

(57) [Claims] 1. A general formula [Wherein R ¹ is a halogen atom, a lower alkanesulfonyloxy group or a lower alkyl group optionally substituted with a halogen atom, an arylsulfonyloxy group optionally substituted with a halogen atom or a nitro group, and X ¹ is a halogen Atom, R ⁴ is an esterified carboxy group, R ³
Is an azido group, a phthalimido group or a group: —NH—R ⁵ (wherein, R ⁵ represents an amino protecting group)], and an azetidinone derivative represented by the general formula HS-R ⁶ (4) (wherein R ⁶ represents an unsaturated heterocyclic group having 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom and a sulfur atom, and the heterocyclic group is a lower alkyl group, a lower alkenyl group, a lower alkoxycarbonyl group, Carboxy group,
A phenyl lower alkoxycarbonyl lower alkyl group having 1 to 3 phenyl groups, a carboxy lower alkyl group,
From the group consisting of hydroxy lower alkyl group, hydroxyl group, oxo group, amino group, carbamoyl group, cyano group, lower alkyl-substituted amino lower alkyl group, piperidinyl lower alkyl group, pyrrolidinyl lower alkyl group, carbamoyl lower alkyl group and cyano lower alkyl group. It may have 1 to 3 selected substituents or a 4-lower alkyl-1-piperazinyl lower alkyl group. ) The thiol compound represented by (In formula, R < ³ >, R < ⁴ > and R < ⁶ > are the same as the above.) The 2-oxaisocephem derivative represented by these is obtained, The manufacturing method of the 2-oxaisocephem derivative characterized by the above-mentioned. 2. General formula [Wherein R ¹ is a halogen atom, a lower alkanesulfonyloxy group or a lower alkyl group optionally substituted with a halogen atom, an arylsulfonyloxy group optionally substituted with a halogen atom or a nitro group, and X ¹ is a halogen Atom, R ⁴ is an esterified carboxy group, R ³
Is an azido group, a phthalimido group or a group: —NH—R ⁵ (wherein R ⁵ represents an amino-protecting group)] and a basic compound is reacted to give a compound of the general formula (In the formula, R ³ , R ⁴ and X ¹ are the same as the above.) The step of obtaining the compound represented by the formula (3) and the compound represented by the general formula HS- R ⁶ (4) (In the formula, R ⁶ represents an unsaturated heterocyclic group having 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom and a sulfur atom, and the heterocyclic group is a lower alkyl group, Lower alkenyl group, lower alkoxycarbonyl group, carboxy group,
A phenyl lower alkoxycarbonyl lower alkyl group having 1 to 3 phenyl groups, a carboxy lower alkyl group,
From the group consisting of hydroxy lower alkyl group, hydroxyl group, oxo group, amino group, carbamoyl group, cyano group, lower alkyl-substituted amino lower alkyl group, piperidinyl lower alkyl group, pyrrolidinyl lower alkyl group, carbamoyl lower alkyl group and cyano lower alkyl group. It may have 1 to 3 selected substituents or a 4-lower alkyl-1-piperazinyl lower alkyl group. ) The thiol compound represented by (In the formula, R ³ , R ⁴ and R ⁶ are the same as the above.) The method for producing a 2-oxaisocephem derivative, characterized in that . 3. The azetidinone derivative represented by the general formula (1-b) has a general formula: (Wherein R ¹ , R ³ and R ⁴ are the same as above, and X ² is a halogen atom.) A compound obtained by heat treatment in the presence of an acidic compound. Item 2 or Item 2
-A method for producing an oxaisocephem derivative.